Atypical Sjögren’s Syndrome Associated with Autoimmune Autonomic Neuropathy: A Presentation Resembling Hereditary Dysautonomia

Atypical Sjögren’s Syndrome Associated with Autoimmune Autonomic Neuropathy: A Presentation Resembling Hereditary Dysautonomia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Atypical Sjögren’s Syndrome Associated with Autoimmune Autonomic Neuropathy: A Presentation Resembling Hereditary Dysautonomia Sarika Mutyala, Suhas Kataveni, Apurva Patel, Chiranjeevi K, Rahul Rahangdale This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7578677/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 Introduction: Sjögren’s Syndrome (SS) is a systemic chronic autoimmune disorder of unknown etiology characterized by salivary and lacrimal glands immune-mediated damage, leading to dryness of the mouth (xerostomia) and eyes (xerophthalmia). But atypical sjogren’s syndrome refers to cases where the syndrome’s symptoms are diverse and not limited to the classic dry eyes and dry mouth or where it presents with systemic complications like neuropathies, skin rashes, vasculitis, etc. These presentations can delay diagnosis because they don’t immediately suggest the disease, requiring doctors to consider Sjogren’s in patients with symptoms like peripheral neuropathy, joint pain without arthritis, etc. Methods-Casereport: We report a 33-year-old male with lifelong symptoms of dysautonomia, including orthostatic hypotension, fatigue, heat intolerance, paroxysmal supraventricular tachycardia, and exercise intolerance since childhood. Neurological examination revealed distal sensorimotor weakness. Laboratory workup was notable for positive lupus anticoagulant and borderline elevated anticardiolipin IgM antibodies, suggesting a possible autoimmune basis for his symptoms. Lip biopsy of the patient suggested, features can be considered to be suggestive of Sjogren’s. Discussion: His orthostatic hypotension test was positive. And his Nerve biopsy showed chronic axonopathy. His initial treatment included IVIG, with modest clinical improvement. He later was started on T. Gabapentine 100 mg OD for neuropathy and Metoprolol 25 mg OD, for the management of his blood pressure. Currently, he is just continuing the therapy as planned. Conclusion: This case highlights the importance of considering atypical Sjögren’s syndrome as a differential diagnosis when autoimmune etiologies present alongside dysautonomic features. It also emphasizes the need for further research into optimal management and treatment strategies in this area. Neurology Internal Medicine Atypical Sjögren’s Syndrome Dysautonomia Orthostatic Hypotension Peripheral Neuropathy Autoimmune Disease Axonopathy Lip Biopsy IVIG Therapy Gabapentin Metoprolol Figures Figure 1 Figure 2 Introduction Sjögren's syndrome (SS) typically presents with Sicca symptoms, xerostomia, and xeropthalmia. This study highlights atypical presentations of Sjögren's syndrome, posing diagnostic and therapeutic challenges 1 . However, atypical Sjögren's syndrome refers to cases where the syndrome's symptoms are diverse and not limited to the classic dry eyes and dry mouth, or where it presents with systemic complications, such as neuropathies, skin rashes, and vasculitis 2 . Less typical symptoms may also warrant suspecting Sjögren's syndrome. Ocular, in addition to extreme dry eyes, patients may suffer from conjunctivitis, keratitis, blepharitis, ulcerations, and perforations. Tracheal dryness causes a chronic dry cough in some patients 3 . Nosebleeds, otitis, and sinusitis can be recurring problems. Severe dry mouth can cause swallowing problems, which may lead to malnutrition and excessive weight loss. Patients may also have accelerated caries, loss of dentition, and malfunctioning dentures. Skin rashes are common, and skin eruptions and purpura may occur. Raynaud's phenomenon is a typical vascular manifestation 4 . Vasculitis is always a concern in Sjögren's patients, but symptoms vary depending on the location of the inflammation in the body. Patients may suffer from esophageal dysmotility. In severe cases, they are at increased risk for pancreatitis, hepatitis, or atrophic gastritis. Anemia, blood dyscrasias, and cryoglobulinemias are rare but may occur. In addition, Sjögren's patients are at increased risk for lymphoma. Lung involvement and coronary involvement are rare but can develop due to dryness of the bronchial tubes. Other potential manifestations include bronchitis, bronchitis obliterans, organized pneumonia, and interstitial fibrosis. Neuropathies tend to be less symmetrical in Sjögren's patients, compared with other conditions. Central nervous system disorders might manifest as changes in cognitive function or as seizures. Renal involvement is rare, but when it occurs, it is usually interstitial tube involvement and is more likely to be chronic, compared with highly progressive kidney involvement associated with lupus. Fibromyalgia occurs in 20% 30% of Sjögren's patients. Sleep disorders, often due to dryness-related discomfort, are common and may contribute to fibromyalgia. Depression is a common comorbidity, as it is in patients with other autoimmune diseases 13 . We report a case of a young man with lifelong dysautonomia ultimately diagnosed with autoimmune autonomic neuropathy involving both small and large fibers. Case Presentation A 30-year-old man presented with life-long symptoms of dysautonomia. From very young age, he experienced marked exercise intolerance, breathlessness, fatigue, increased bowel and bladder movements. Throughout adolescence, he developed progressive orthostatic intolerance manifested by light-headedness and “blackouts” upon standing for more than a few minutes. He also reported chronic fatigue, heat intolerance with reduced sweating, and intermittent episodes of rapid palpitations. In his late 20s, he was diagnosed with paroxysmal supraventricular tachycardia (SVT) after several episodes of sudden racing heart rate; these were managed acutely with vagal maneuvers and did not require ablation. By his early 30s, the patient’s exercise capacity was severely limited – even daily tasks caused exhaustion – and he had frequent bouts of blurred vision, weakness in his legs on standing, and near-fainting, forcing him to sit or lie down. Family history was negative for neurological or autonomic disorders. Given the long-standing nature of his symptoms since childhood, earlier evaluations had considered a possible hereditary autonomic neuropathy, but no definitive diagnosis was reached. On examination, his vital signs supine were blood pressure 120/80 mmHg and heart rate 70/min. Upon standing, his BP dropped to 85/50 mmHg within 2 minutes accompanied by a compensatory tachycardia to 120/min and feelings of presyncope, suggestive of orthostatic hypotension. He had mild distal leg weakness (Medical Research Council grade 4/5) and decreased ankle reflexes. Sensation to vibration and proprioception was mildly reduced in the feet, while pain and temperature sensation were relatively intact. Cranial nerve examination is normal. There was dryness of skin in his feet and reduced distal sweating. He did not report any dryness of the eyes or mouth. These findings suggested combined autonomic disturbances along with peripheral neuropathy. Sympathetic skin response (SSR) was absent in the lower limbs (feet) and reduced in amplitude in the palms, reflecting impaired sudomotor sympathetic function in distal extremities. Quantitative sudomotor axon reflex testing (QSART), demonstrated low sweat output in the feet. Standard nerve conduction studies revealed a peripheral neuropathy in the lower limbs: compound muscle action potential (CMAP) amplitudes were reduced in the peroneal and tibial nerves (distal motor amplitudes ~ 20% of normal), and sensory nerve action potentials (SNAPs) were low in the sural nerve. Conduction velocities were normal or mildly slowed, and there were no conduction blocks or demyelinating features overall – consistent with a chronic axonal sensorimotor polyneuropathy, worse in the legs. Upper limb nerve conductions were within normal limits. Given the prominent neuropathy with elevated autoantibodies, autoimmune neuropathy can be considered. Motor Nerve Conduction Studies (MNC) Nerve Site Lat 1 (mS) Lat 2 (mS) Amp (mV) Dist. (mm) CV (m/s) Status Median-Lt Wrist 3.13 15.63 18.57 - - Prolonged latency Median-Lt Elbow 8.38 22.38 14.79 320 60.95 Reduced amplitude Median-Lt Axilla 11.38 23.50 12.94 170 56.67 Reduced CV Peroneal-Lt Ankle 4.50 16.13 8.20 - - Reduced amplitude Peroneal-Lt Knee 13.38 27.13 7.22 400 45.07 Severely reduced CV Peroneal-Rt Ankle 4.63 16.13 7.16 - - Reduced amplitude Peroneal-Rt Knee 13.00 26.38 6.00 400 47.76 Severely reduced CV Tibial-Lt Ankle 4.75 15.25 14.70 - - Prolonged latency Tibial-Lt Popliteal Fossa 14.25 27.50 10.82 430 45.26 Severely reduced CV Sensory Nerve Conduction Studies (SNC) Nerve Site Lat 1 (mS) Lat 2 (mS) Amp (µV) Dist. (mm) CV (m/s) Status Median Wrist-Lt Dig2 2.50 5.50 46.4 140 56.00 Reduced CV Median Wrist-Rt Dig2 2.45 5.20 32.5 140 57.14 Reduced amplitude Ulnar Wrist-Lt Dig 5 2.35 5.20 24.8 120 51.06 Severely reduced CV Ulnar Wrist-Rt Dig 5 2.40 5.15 17.1 120 50.00 Severely reduced CV & Amp Sural-Lt Mid Calf-Rt 2.80 5.20 6.3 140 50.00 Severely reduced amplitude Sural-Rt Mid Calf-Rt 2.70 7.10 5.4 140 51.85 Severely reduced amplitude Given the possibility of an unusual neuropathy, a sural nerve biopsy was performed, which was positive for chronic axonopathy. Routine bloodwork was unremarkable. An autoimmune serological panel revealed the presence of antiphospholipid antibodies: specifically, lupus anticoagulant and anticardiolipin IgM antibody was borderline elevated (just above the upper limit of normal). Antinuclear antibody (ANA), including SS-A/SS-B for Sjögren syndrome) were negative. His both CT head (Fig. 1 ) and MRI of the brain (Fig. 2 ) (with autonomic brainstem sequences) tend to be normal, making a central cause of dysautonomia unlikely. Given the recognized association of Sjögren’s syndrome with dysautonomia, a labial salivary gland biopsy was performed as part of the evaluation. Histopathology revealed chronic focal lymphocytic sialadenitis with a focus score of 2.5 (foci per 4 mm²) with features suggestive of Sjögren’s syndrome. However, the patient did not have typical symptoms of Sjogren’s syndrome and, as noted, SS-A/Ro and SS-B/La antibodies were negative. The patient was started on immunomodulatory therapy (high-dose intravenous immunoglobulin was initiated) along with midodrine and compression stockings for orthostatic hypotension. He later was started on T. Gabapentine 100 mg OD for neuropathy and Metoprolol 25 mg OD, for the management of his blood pressure. He also received counselling on maintaining hydration and salt intake. Over 6 months of follow-up, he reported modest improvements in fatigue and orthostatic tolerance, consistent with a partial treatment response, and continued therapy was planned. Discussion This case illustrates an uncommon diagnosis of autoimmune autonomic neuropathy in a patient with chronic, lifelong dysautonomia. The diagnostic challenge was considerable – his symptoms began in childhood and slowly progressed, which initially pointed toward hereditary autonomic neuropathies, yet ultimately an acquired autoimmune cause was identified. AAN/AAG is rare, with an estimated prevalence of only a few cases per million, and even more unusual in a chronic, insidious form. 1 Most reported AAG cases present acutely (within days to weeks) as a fulminant autonomic failure, often after an infection, analogous to Guillain-Barré syndrome but targeting autonomic nerves (historically termed acute pandysautonomia). 5 By contrast, our patient’s course was indolent over decades, demonstrating that AAN can also manifest as a slowly progressive disorder. Indeed, a few cases of chronic AAG have been documented – for example, Manganelli et al. reported a patient with a 16-year history of autonomic failure and high AChR antibody titer, whose evaluation confirmed both postganglionic autonomic damage and somatic nerve fiber involvement. 7 That case and ours highlight that AAN can overlap with somatic peripheral neuropathy. In fact, Manganelli’s report was the first to show clear somatic nerve involvement in AAG, via sural nerve biopsy, similar to our patient’s large-fiber neuropathy. 7 Another report by Koike et al. described a “slowly progressive autonomic neuropathy with anti-ganglionic AChR antibody,” underscoring that AAG is not exclusively acute. 8 These observations expand the spectrum of AAN: while acute/subacute AAG is more common, clinicians should recognize that a chronic presentation with mixed fiber involvement is possible. 7 The patient’s long duration of dysautonomia since childhood prompted consideration of hereditary causes. Hereditary sensory and autonomic neuropathies (HSAN) are a group of genetic disorders that can present early with autonomic dysfunction. Notably, HSAN type II (autosomal recessive) often begins in infancy/childhood with severe loss of sensation and autonomic failure. 2 Familial dysautonomia (Riley-Day syndrome, HSAN type III) is another genetic disorder causing autonomic crises from infancy. However, these conditions usually have distinguishing features (such as insensitivity to pain, developmental abnormalities, or characteristic genetic markers like the IKBKAP mutation in familial dysautonomia), and they lack the autoimmune markers seen in our patient. Our patient’s positive lupus anticoagulant and anticardiolipin antibodies steered the diagnosis away from a purely genetic neuropathy toward an immune-mediated process. Acquired causes of dysautonomia were thoroughly evaluated. Diabetic autonomic neuropathy was ruled out by normal glucose testing. Amyloid neuropathy (which can cause autonomic features) was excluded by biopsy (no amyloid on nerve biopsy) and lack of other signs (no organ involvement). Paraneoplastic autonomic neuropathy is another consideration – certain cancers (e.g. small cell lung carcinoma) can cause subacute autonomic neuropathy, sometimes with anti-neuronal antibodies (ANNA-1, etc.). Our patient’s normal imaging and bloodwork made an occult malignancy unlikely, and the chronic course was less consistent with a paraneoplastic rapid onset. Sjögren’s syndrome can cause a sensory ganglionopathy with autonomic dysfunction in some cases. 5 While our patient initially had negative SS-A/SS-B antibodies and no sicca symptoms, a labial salivary gland biopsy later demonstrated chronic sialadenitis with a focus score of 2.5. This fulfils the histopathologic criterion for Sjögren’s syndrome (focus score ≥ 1) 9 and suggests a possible seronegative Sjögren’s syndrome underlying his neuropathy. Postural orthostatic tachycardia syndrome (POTS) was an important differential for orthostatic intolerance in a young person. However, POTS is typically characterized by orthostatic tachycardia without significant hypotension, and is not associated with a peripheral neuropathy or abnormal nerve conductions. In our patient, frank orthostatic hypotension and objective neuropathic deficits were present, pointing to an underlying neuropathy rather than isolated POTS (it is worth noting that POTS and other functional autonomic disorders can sometimes be initial diagnostic considerations in young patients with dysautonomia; careful testing is needed to distinguish them from AAN). 2 Chronic fatigue syndrome and functional somatic syndromes were also considered given the history of fatigue, but the abnormal autonomic test results and biopsy proved an organic neuropathic basis for his symptoms. 2 Thus, after exclusion of many differentials, an immune-mediated autonomic neuropathy remained as the unifying diagnosis. A striking aspect of this case is the presence of lupus anticoagulant and anticardiolipin antibodies. Antiphospholipid syndrome (APS) is known mainly for causing thromboses and obstetric complications, but it has diverse neurological manifestations. Autonomic dysfunction in APS has been reported in the literature. Schofield et al. (2017) described a series of 22 patients in whom autonomic neuropathy was the initial manifestation of primary APS, preceding any thrombosis. 10 These patients had symptoms like orthostatic intolerance (sometimes meeting POTS criteria), gastrointestinal dysmotility, neurogenic bladder, and other dysautonomic features. 10 Skin biopsies showed reduced small-fiber density, confirming an autonomic small-fiber neuropathy in those APS patients. 11 Over time, 59% of patients in that series went on to develop arterial or venous thromboses (often stroke) after an average of 4.4 years. 10 This suggests that in some individuals, antiphospholipid antibody–related neuropathy can precede the classic thrombotic APS manifestations by years. 10 The pathogenesis is thought to involve either microthrombi in the vasa nervorum or direct autoimmune nerve injury. Improvement of autonomic symptoms with immunotherapies in some reports supports an immune-mediated mechanism beyond just coagulation. 11 Bilora et al. (2012) also demonstrated abnormal autonomic function testing in primary APS patients, and noted that the degree of autonomic dysfunction correlated with coagulation markers. 12 In our patient, the antiphospholipid antibody findings (positive lupus anticoagulant, borderline aCL IgM) raise the possibility that his neuropathy could be an APS-related autoimmune neuropathy. Notably, he has not (yet) had any thrombosis – fitting the pattern of “seronegative APS” (APS by labs only) presenting as neuropathy. The patient’s care includes counselling about APS and monitoring for any thrombotic events. If he were to develop definite APS (e.g. a clot), anticoagulation would be indicated in addition to immunotherapy. This connection between APS and autonomic neuropathy is an active area of research. Increased awareness of this association is important, as treating the underlying APS (with immunosuppression or plasma exchange, in addition to standard anticoagulation) can lead to neurological improvement. 10 Our case adds to the growing recognition that autoimmune autonomic neuropathy can occur in the context of antiphospholipid antibodies, even in the absence of other APS symptoms. A notable theme in this case is the overlap between features of hereditary dysautonomia and autoimmune neuropathy. The patient’s symptoms began in childhood – far earlier than the typical age of onset for autoimmune AAG (which is usually mid-adulthood, often 40s or 50s). 6 This mimicry of a genetic disorder delayed the diagnosis. It underscores that while hereditary autonomic neuropathies (like HSAN) usually present early, clinicians should not dismiss a potential autoimmune cause simply due to young age. Conversely, it is also true that some genetic neuropathies can masquerade as acquired ones. For example, certain Charcot-Marie-Tooth (CMT) variants have autonomic involvement: CMT type 2J due to MPZ gene mutations can cause autonomic symptoms like pupillary abnormalities and bladder dysfunction. 2 Similarly, transthyretin familial amyloid polyneuropathy can present with prominent autonomic failure in young adulthood. 2 In practice, thorough evaluation is required to distinguish these conditions. In our patient, the presence of immune biomarkers (lupus anticoagulant) and the biopsy evidence of an acquired axonal injury tipped the scales toward an autoimmune etiology rather than a congenital one. It is noteworthy that about 30% of AAG patients may have coexisting autoimmune diseases (like Sjögren’s syndrome or autoimmune thyroiditis), 6 and some 10–15% have an associated tumor (paraneoplastic). 6 For our patient, however, another autoimmune condition was uncovered: the labial salivary gland biopsy confirmed focal sialadenitis consistent with Sjögren’s syndrome despite negative SS-A/SS-B serologies. In other words, a seronegative Sjögren’s syndrome appears to be present in addition to the antiphospholipid antibodies. Autoimmune autonomic neuropathy is a treatable condition, especially if recognized early. Standard therapies include immunomodulation such as corticosteroids, IVIG, plasmapheresis, and immunosuppressants (e.g. mycophenolate, rituximab). 1 Many patients show at least partial improvement with immunotherapy, validating the immune basis of the disease. 4 Our patient was started on IVIG empirically, given the suspicion of AAN; alternative approaches could include high-dose corticosteroids or plasma exchange. In the context of possible APS, IVIG was a reasonable initial choice (as it can have both immunomodulatory and some anti-thrombotic effects, and case reports have noted IVIG helping APS-related neuropathy). 10 While his improvement was not dramatic, it was encouraging and immunotherapy may need to be continued long-term. Supportive measures are crucial: for example, midodrine and fludrocortisone for orthostatic hypotension, salt and fluid loading, compression garments, and symptomatic treatments for gastrointestinal or urinary dysfunction as needed. Our patient’s SVT episodes were likely exacerbated by autonomic instability (high adrenergic state on standing); treating the underlying dysautonomia should reduce their frequency. The prognosis in chronic AAN is variable – some cases plateau or partially recover, while others have residual deficits. Unlike acute AAG (which can sometimes recover spontaneously or with treatment over months), 2 chronic AAN may require ongoing therapy. Importantly, early recognition and treatment of autoimmune dysautonomia can prevent irreversible nerve damage and significantly improve quality of life. 1 Conclusion This case highlights the importance of considering atypical Sjögren’s syndrome as a differential diagnosis when autoimmune etiologies present alongside dysautonomic features. It emphasizes the need research for optimal management and treatment strategies in this area. Apart from diagnostic challenges, such cases underscore the complexity of autoimmune disorders that extend beyond classical glandular involvement and manifest with diverse neurological, cardiovascular, or systemic features. Recognizing these atypical presentations is crucial for timely diagnosis, preventing mismanagement, and guiding appropriate interventions. Declarations I confirm that written informed consent was obtained from the patient for participation and publication of this clinical case. References Lu Z, Cao X, Wang M, Peng F, Chen L, Yin Z et al (2025) A case of relapsed gAChR-positive autoimmune autonomic ganglionopathy treated by plasma exchange and mycophenolate mofetil. Front Neurol [Internet]. Jan 10 [cited 2025 Jul 17];15. Available from: https://www.frontiersin.org/articles/ 10.3389/fneur.2024.1533840/full Nakane S, Koike H, Hayashi T, Nakatsuji Y Autoimmune Autonomic Neuropathy: From Pathogenesis to Diagnosis. IJMS [Internet]. 2024 Feb 15 [cited 2025 Jul 17];25(4):2296. Available from: https://www.mdpi.com/1422-0067/25/4/2296 Vernino S Autoimmune Autonomic Disorders. Continuum [Internet]. 2020 Feb [cited 2025 Jul 17];26(1):44–57. Available from: https://continuum.aan.com/doi/ 10.1212/CON.0000000000000812 Golden EP, Vernino S Autoimmune autonomic neuropathies and ganglionopathies: epidemiology, pathophysiology, and therapeutic advances. Clin Auton Res [Internet]. 2019 Jun 1 [cited 2025 Jul 17];29(3):277–88. Available from: https://link.springer.com/ 10.1007/s10286-019-00611-1 Idiáquez Cabezas J, Riquelme Alcázar J, Calvo Bascuñán M, Casar Leturia JC (2021) Chronic autoimmune autonomic ganglionopathy. A rare case of dysautonomia. Neurología (English Edition) [Internet]. Apr [cited 2025 Jul 17]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S2173580821000353 Mohapatra P, Agarwal A, Radhakrishnan DM, Srivastava AK, Garg D Decoding Autoimmune Autonomic Disorders: A Less-Recognized Overlap. Annals of Indian Academy of Neurology [Internet]. 2024 Sep [cited 2025 Jul 17];27(5):482–92. Available from: https://journals.lww.com/ 10.4103/aian.aian_394_24 Manganelli F, Dubbioso R, Nolano M, Iodice R, Pisciotta C, Provitera V et al (2011) Autoimmune Autonomic Ganglionopathy: A Possible Postganglionic Neuropathy. Arch Neurol [Internet]. 2011 Apr 11 [cited 2025 Jul 17];68(4):504. Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/archneurol .60 Koike H, Koyano S, Morozumi S, Kawagashira Y, Iijima M, Katsuno M et al Slowly progressive autonomic neuropathy with antiganglionic acetylcholine receptor antibody. J Neurol Neurosurg Psychiatry [Internet]. 2010 May 1 [cited 2025 Jul 17];81(5):586–7. Available from: https://jnnp.bmj.com/lookup/doi/ 10.1136/jnnp.2009.181222 Shiboski CH, Shiboski SC, Seror R et al (2016) American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s Syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol [Internet]. 2017 Jan [cited 2025 Jul 17];69(1):35–45. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650478/ Schofield JR Autonomic neuropathy—in its many guises—as the initial manifestation of the antiphospholipid syndrome. Immunol Res [Internet]. 2017 Apr [cited 2025 Jul 17];65(2):532–42. Available from: http://link.springer.com/ 10.1007/s12026-016-8889-4 Fleetwood T, Cantello R, Comi C (2018) Antiphospholipid Syndrome and the Neurologist: From Pathogenesis to Therapy. Front Neurol [Internet]. Nov 26 [cited 2025 Jul 17];9. Available from: https://www.frontiersin.org/article/ 10.3389/fneur.2018.01001/full Bilora F, Biasiolo, Zancan Z, Veronese S Autonomic dysfunction and primary antiphospholipid syndrome: a frequent and frightening correlation? IJGM [Internet]. 2012 Apr [cited 2025 Jul 17];339. Available from: http://www.dovepress.com/autonomic-dysfunction-and-primary-antiphospholipid-syndrome-a-frequent-peer-reviewed-article-IJGM Faiza Naeem, Imami SK, Khan SEA, Batool S, Akmal M, Yasir Mushtaq (2024) Atypical initial presentations of Sjogren’s syndrome: a case series. J Pak Med Assoc 75(1):125–130. https://doi.org/10.47391/JPMA.11555 Additional Declarations The authors declare no competing interests. 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. 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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-7578677","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":512834969,"identity":"e6c96ebf-541a-4e12-99d6-8958ac74af35","order_by":0,"name":"Sarika Mutyala","email":"","orcid":"","institution":"Gandhi Medical College and Hospital, Secunderabad","correspondingAuthor":false,"prefix":"","firstName":"Sarika","middleName":"","lastName":"Mutyala","suffix":""},{"id":512834970,"identity":"947d4b7d-849f-4707-8023-6b0694e25113","order_by":1,"name":"Suhas Kataveni","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIiWNgGAWjYFACHiA+AGUnGPyXA9EHHhChRQKipYDZGKwlgWgtDB+YExvAevFokJ+Re/DjjzN2dfwzko89eGDAlj4/7PBDoC12croN2LUY3MhLlua5kSwhcSMt3SDBgCd34+00A6CWZGOzAzi0SOQYSAPdI8Fw5oyZRIKBRO7G2QkgLQcSt+HQIj8jx/jnjw/1EvJnzn8DajFIN5yd/gGvFoYbOWYSPDcOSxgc72EDaklIkJfOwW+LwZk3ZtY8Z45LbjzeBnLYAcMN0jkFBxIMcPtFvj3H+OaPY9X8coeZn0n++HNAXn52+uYPHyrs5HBpwWIvWKUBscrB9jaQonoUjIJRMApGAgAAXUZkUEXzyfoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0009-2693-3996","institution":"Gandhi Medical College and Hospital, Secunderabad","correspondingAuthor":true,"prefix":"","firstName":"Suhas","middleName":"","lastName":"Kataveni","suffix":""},{"id":512834971,"identity":"5e2a7cd9-7f99-4b1e-bcfa-eaac37bd1f03","order_by":2,"name":"Apurva Patel","email":"","orcid":"","institution":"Department of Medicine, B.J. Medical College, Ahmedabad, India","correspondingAuthor":false,"prefix":"","firstName":"Apurva","middleName":"","lastName":"Patel","suffix":""},{"id":512834972,"identity":"509fa4a9-627b-46e1-8461-22e82b2ab0c9","order_by":3,"name":"Chiranjeevi K","email":"","orcid":"","institution":"Consultant Neurologist, Sigma Neuro Super Specialty Hospital, Suryapet, Telangana, India","correspondingAuthor":false,"prefix":"","firstName":"Chiranjeevi","middleName":"","lastName":"K","suffix":""},{"id":512834973,"identity":"3d22f86a-7376-4dd6-9491-07745b476873","order_by":4,"name":"Rahul Rahangdale","email":"","orcid":"","institution":"Assistant Professor, University of Oklahoma, Tulsa, USA","correspondingAuthor":false,"prefix":"","firstName":"Rahul","middleName":"","lastName":"Rahangdale","suffix":""}],"badges":[],"createdAt":"2025-09-10 04:39:53","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7578677/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7578677/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91306883,"identity":"0823dcf7-8827-41c0-8887-bf390cf3f0a2","added_by":"auto","created_at":"2025-09-15 06:33:44","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49356,"visible":true,"origin":"","legend":"\u003cp\u003eCT head which is normal\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7578677/v1/1007447dc1bef3d589eaf165.jpeg"},{"id":91306886,"identity":"9dc03160-6b35-4160-8a4c-21a4e03eef18","added_by":"auto","created_at":"2025-09-15 06:33:44","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3913,"visible":true,"origin":"","legend":"\u003cp\u003eAxial FLAIR MRI of the brain demonstrating no abnormal T2 hyperintensities in the cerebral white matter or brainstem. No signal changes suggestive of demyelination or gliosis are identified.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7578677/v1/44791c19344dc497aef5cc29.jpeg"},{"id":91308177,"identity":"74730ca5-4546-424e-b157-4d5bacfd0a8f","added_by":"auto","created_at":"2025-09-15 06:49:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":634391,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7578677/v1/27fc0832-e46c-4b00-a534-b453b4374239.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eAtypical Sjögren’s Syndrome Associated with Autoimmune Autonomic Neuropathy: A Presentation Resembling Hereditary Dysautonomia\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSj\u0026ouml;gren's syndrome (SS) typically presents with Sicca symptoms, xerostomia, and xeropthalmia. This study highlights atypical presentations of Sj\u0026ouml;gren's syndrome, posing diagnostic and therapeutic challenges\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. However, atypical Sj\u0026ouml;gren's syndrome refers to cases where the syndrome's symptoms are diverse and not limited to the classic dry eyes and dry mouth, or where it presents with systemic complications, such as neuropathies, skin rashes, and vasculitis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eLess typical symptoms may also warrant suspecting Sj\u0026ouml;gren's syndrome. Ocular, in addition to extreme dry eyes, patients may suffer from conjunctivitis, keratitis, blepharitis, ulcerations, and perforations. Tracheal dryness causes a chronic dry cough in some patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Nosebleeds, otitis, and sinusitis can be recurring problems. Severe dry mouth can cause swallowing problems, which may lead to malnutrition and excessive weight loss. Patients may also have accelerated caries, loss of dentition, and malfunctioning dentures. Skin rashes are common, and skin eruptions and purpura may occur. Raynaud's phenomenon is a typical vascular manifestation\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Vasculitis is always a concern in Sj\u0026ouml;gren's patients, but symptoms vary depending on the location of the inflammation in the body. Patients may suffer from esophageal dysmotility. In severe cases, they are at increased risk for pancreatitis, hepatitis, or atrophic gastritis. Anemia, blood dyscrasias, and cryoglobulinemias are rare but may occur. In addition, Sj\u0026ouml;gren's patients are at increased risk for lymphoma. Lung involvement and coronary involvement are rare but can develop due to dryness of the bronchial tubes. Other potential manifestations include bronchitis, bronchitis obliterans, organized pneumonia, and interstitial fibrosis. Neuropathies tend to be less symmetrical in Sj\u0026ouml;gren's patients, compared with other conditions. Central nervous system disorders might manifest as changes in cognitive function or as seizures. Renal involvement is rare, but when it occurs, it is usually interstitial tube involvement and is more likely to be chronic, compared with highly progressive kidney involvement associated with lupus. Fibromyalgia occurs in 20% 30% of Sj\u0026ouml;gren's patients. Sleep disorders, often due to dryness-related discomfort, are common and may contribute to fibromyalgia. Depression is a common comorbidity, as it is in patients with other autoimmune diseases\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. We report a case of a young man with lifelong dysautonomia ultimately diagnosed with autoimmune autonomic neuropathy involving both small and large fibers.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 30-year-old man presented with life-long symptoms of dysautonomia. From very young age, he experienced marked exercise intolerance, breathlessness, fatigue, increased bowel and bladder movements. Throughout adolescence, he developed progressive orthostatic intolerance manifested by light-headedness and \u0026ldquo;blackouts\u0026rdquo; upon standing for more than a few minutes. He also reported chronic fatigue, heat intolerance with reduced sweating, and intermittent episodes of rapid palpitations. In his late 20s, he was diagnosed with paroxysmal supraventricular tachycardia (SVT) after several episodes of sudden racing heart rate; these were managed acutely with vagal maneuvers and did not require ablation. By his early 30s, the patient\u0026rsquo;s exercise capacity was severely limited \u0026ndash; even daily tasks caused exhaustion \u0026ndash; and he had frequent bouts of blurred vision, weakness in his legs on standing, and near-fainting, forcing him to sit or lie down. Family history was negative for neurological or autonomic disorders. Given the long-standing nature of his symptoms since childhood, earlier evaluations had considered a possible hereditary autonomic neuropathy, but no definitive diagnosis was reached.\u003c/p\u003e\u003cp\u003eOn examination, his vital signs supine were blood pressure 120/80 mmHg and heart rate 70/min. Upon standing, his BP dropped to 85/50 mmHg within 2 minutes accompanied by a compensatory tachycardia to 120/min and feelings of presyncope, suggestive of orthostatic hypotension. He had mild distal leg weakness (Medical Research Council grade 4/5) and decreased ankle reflexes. Sensation to vibration and proprioception was mildly reduced in the feet, while pain and temperature sensation were relatively intact. Cranial nerve examination is normal. There was dryness of skin in his feet and reduced distal sweating. He did not report any dryness of the eyes or mouth. These findings suggested combined autonomic disturbances along with peripheral neuropathy. Sympathetic skin response (SSR) was absent in the lower limbs (feet) and reduced in amplitude in the palms, reflecting impaired sudomotor sympathetic function in distal extremities. Quantitative sudomotor axon reflex testing (QSART), demonstrated low sweat output in the feet. Standard nerve conduction studies revealed a peripheral neuropathy in the lower limbs: compound muscle action potential (CMAP) amplitudes were reduced in the peroneal and tibial nerves (distal motor amplitudes\u0026thinsp;~\u0026thinsp;20% of normal), and sensory nerve action potentials (SNAPs) were low in the sural nerve. Conduction velocities were normal or mildly slowed, and there were no conduction blocks or demyelinating features overall \u0026ndash; consistent with a chronic axonal sensorimotor polyneuropathy, worse in the legs. Upper limb nerve conductions were within normal limits. Given the prominent neuropathy with elevated autoantibodies, autoimmune neuropathy can be considered.\u003c/p\u003e\u003cp\u003eMotor Nerve Conduction Studies (MNC)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNerve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSite\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLat 1 (mS)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLat 2 (mS)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAmp (mV)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDist. (mm)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCV (m/s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStatus\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWrist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e15.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e18.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" 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colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced amplitude\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeroneal-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKnee\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e13.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e400\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e47.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced CV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTibial-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnkle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e15.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProlonged latency\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTibial-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePopliteal Fossa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e27.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e10.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e430\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e45.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced CV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSensory Nerve Conduction Studies (SNC)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNerve\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSite\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLat 1 (mS)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLat 2 (mS)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAmp (\u0026micro;V)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDist. (mm)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eCV (m/s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eStatus\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian Wrist-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDig2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e46.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e56.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced CV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian Wrist-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDig2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e32.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e57.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReduced amplitude\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUlnar Wrist-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDig 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e24.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e51.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced CV\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUlnar Wrist-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDig 5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e17.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e50.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced CV \u0026amp; Amp\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSural-Lt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMid Calf-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e50.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced amplitude\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSural-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMid Calf-Rt\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e5.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e51.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSeverely reduced amplitude\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eGiven the possibility of an unusual neuropathy, a sural nerve biopsy was performed, which was positive for chronic axonopathy. Routine bloodwork was unremarkable. An autoimmune serological panel revealed the presence of antiphospholipid antibodies: specifically, lupus anticoagulant and anticardiolipin IgM antibody was borderline elevated (just above the upper limit of normal). Antinuclear antibody (ANA), including SS-A/SS-B for Sj\u0026ouml;gren syndrome) were negative. His both CT head (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and MRI of the brain (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) (with autonomic brainstem sequences) tend to be normal, making a central cause of dysautonomia unlikely.\u003c/p\u003e\u003cp\u003eGiven the recognized association of Sj\u0026ouml;gren\u0026rsquo;s syndrome with dysautonomia, a labial salivary gland biopsy was performed as part of the evaluation. Histopathology revealed chronic focal lymphocytic sialadenitis with a focus score of 2.5 (foci per 4 mm\u0026sup2;) with features suggestive of Sj\u0026ouml;gren\u0026rsquo;s syndrome. However, the patient did not have typical symptoms of Sjogren\u0026rsquo;s syndrome and, as noted, SS-A/Ro and SS-B/La antibodies were negative. The patient was started on immunomodulatory therapy (high-dose intravenous immunoglobulin was initiated) along with midodrine and compression stockings for orthostatic hypotension. He later was started on T. Gabapentine 100 mg OD for neuropathy and Metoprolol 25 mg OD, for the management of his blood pressure. He also received counselling on maintaining hydration and salt intake. Over 6 months of follow-up, he reported modest improvements in fatigue and orthostatic tolerance, consistent with a partial treatment response, and continued therapy was planned.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case illustrates an uncommon diagnosis of autoimmune autonomic neuropathy in a patient with chronic, lifelong dysautonomia. The diagnostic challenge was considerable \u0026ndash; his symptoms began in childhood and slowly progressed, which initially pointed toward hereditary autonomic neuropathies, yet ultimately an acquired autoimmune cause was identified. AAN/AAG is rare, with an estimated prevalence of only a few cases per million, and even more unusual in a chronic, insidious form.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Most reported AAG cases present acutely (within days to weeks) as a fulminant autonomic failure, often after an infection, analogous to Guillain-Barr\u0026eacute; syndrome but targeting autonomic nerves (historically termed acute pandysautonomia).\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e By contrast, our patient\u0026rsquo;s course was indolent over decades, demonstrating that AAN can also manifest as a slowly progressive disorder. Indeed, a few cases of chronic AAG have been documented \u0026ndash; for example, Manganelli \u003cem\u003eet al.\u003c/em\u003e reported a patient with a 16-year history of autonomic failure and high AChR antibody titer, whose evaluation confirmed both postganglionic autonomic damage and somatic nerve fiber involvement.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e That case and ours highlight that AAN can overlap with somatic peripheral neuropathy. In fact, Manganelli\u0026rsquo;s report was the first to show clear somatic nerve involvement in AAG, via sural nerve biopsy, similar to our patient\u0026rsquo;s large-fiber neuropathy.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Another report by Koike \u003cem\u003eet al.\u003c/em\u003e described a \u0026ldquo;slowly progressive autonomic neuropathy with anti-ganglionic AChR antibody,\u0026rdquo; underscoring that AAG is not exclusively acute.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e These observations expand the spectrum of AAN: while acute/subacute AAG is more common, clinicians should recognize that a chronic presentation with mixed fiber involvement is possible.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe patient\u0026rsquo;s long duration of dysautonomia since childhood prompted consideration of hereditary causes. \u003cb\u003eHereditary sensory and autonomic neuropathies (HSAN)\u003c/b\u003e are a group of genetic disorders that can present early with autonomic dysfunction. Notably, HSAN type II (autosomal recessive) often begins in infancy/childhood with severe loss of sensation and autonomic failure.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Familial dysautonomia (Riley-Day syndrome, HSAN type III) is another genetic disorder causing autonomic crises from infancy. However, these conditions usually have distinguishing features (such as insensitivity to pain, developmental abnormalities, or characteristic genetic markers like the \u003cem\u003eIKBKAP\u003c/em\u003e mutation in familial dysautonomia), and they lack the autoimmune markers seen in our patient. Our patient\u0026rsquo;s positive lupus anticoagulant and anticardiolipin antibodies steered the diagnosis away from a purely genetic neuropathy toward an immune-mediated process. Acquired causes of dysautonomia were thoroughly evaluated. \u003cb\u003eDiabetic autonomic neuropathy\u003c/b\u003e was ruled out by normal glucose testing. \u003cb\u003eAmyloid neuropathy\u003c/b\u003e (which can cause autonomic features) was excluded by biopsy (no amyloid on nerve biopsy) and lack of other signs (no organ involvement). \u003cb\u003eParaneoplastic autonomic neuropathy\u003c/b\u003e is another consideration \u0026ndash; certain cancers (e.g. small cell lung carcinoma) can cause subacute autonomic neuropathy, sometimes with anti-neuronal antibodies (ANNA-1, etc.). Our patient\u0026rsquo;s normal imaging and bloodwork made an occult malignancy unlikely, and the chronic course was less consistent with a paraneoplastic rapid onset. \u003cb\u003eSj\u0026ouml;gren\u0026rsquo;s syndrome\u003c/b\u003e can cause a sensory ganglionopathy with autonomic dysfunction in some cases.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e While our patient initially had negative SS-A/SS-B antibodies and no sicca symptoms, a labial salivary gland biopsy later demonstrated chronic sialadenitis with a focus score of 2.5. This fulfils the histopathologic criterion for Sj\u0026ouml;gren\u0026rsquo;s syndrome (focus score\u0026thinsp;\u0026ge;\u0026thinsp;1)\u003csup\u003e9\u003c/sup\u003e and suggests a possible seronegative Sj\u0026ouml;gren\u0026rsquo;s syndrome underlying his neuropathy. \u003cb\u003ePostural orthostatic tachycardia syndrome (POTS)\u003c/b\u003e was an important differential for orthostatic intolerance in a young person. However, POTS is typically characterized by orthostatic tachycardia without significant hypotension, and is not associated with a peripheral neuropathy or abnormal nerve conductions. In our patient, frank orthostatic hypotension and objective neuropathic deficits were present, pointing to an underlying neuropathy rather than isolated POTS (it is worth noting that POTS and other functional autonomic disorders can sometimes be initial diagnostic considerations in young patients with dysautonomia; careful testing is needed to distinguish them from AAN).\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e \u003cb\u003eChronic fatigue syndrome\u003c/b\u003e and \u003cb\u003efunctional somatic syndromes\u003c/b\u003e were also considered given the history of fatigue, but the abnormal autonomic test results and biopsy proved an organic neuropathic basis for his symptoms.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Thus, after exclusion of many differentials, an \u003cem\u003eimmune-mediated autonomic neuropathy\u003c/em\u003e remained as the unifying diagnosis.\u003c/p\u003e\u003cp\u003eA striking aspect of this case is the presence of lupus anticoagulant and anticardiolipin antibodies. Antiphospholipid syndrome (APS) is known mainly for causing thromboses and obstetric complications, but it has diverse neurological manifestations. Autonomic dysfunction in APS has been reported in the literature. Schofield \u003cem\u003eet al.\u003c/em\u003e (2017) described a series of 22 patients in whom autonomic neuropathy was the initial manifestation of primary APS, preceding any thrombosis.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e These patients had symptoms like orthostatic intolerance (sometimes meeting POTS criteria), gastrointestinal dysmotility, neurogenic bladder, and other dysautonomic features.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Skin biopsies showed reduced small-fiber density, confirming an autonomic small-fiber neuropathy in those APS patients.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Over time, 59% of patients in that series went on to develop arterial or venous thromboses (often stroke) after an average of 4.4 years.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e This suggests that in some individuals, \u003cb\u003eantiphospholipid antibody\u0026ndash;related neuropathy\u003c/b\u003e can precede the classic thrombotic APS manifestations by years.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The pathogenesis is thought to involve either microthrombi in the vasa nervorum or direct autoimmune nerve injury. Improvement of autonomic symptoms with immunotherapies in some reports supports an immune-mediated mechanism beyond just coagulation.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Bilora \u003cem\u003eet al.\u003c/em\u003e (2012) also demonstrated abnormal autonomic function testing in primary APS patients, and noted that the degree of autonomic dysfunction correlated with coagulation markers.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e In our patient, the antiphospholipid antibody findings (positive lupus anticoagulant, borderline aCL IgM) raise the possibility that his neuropathy could be an APS-related autoimmune neuropathy. Notably, he has not (yet) had any thrombosis \u0026ndash; fitting the pattern of \u0026ldquo;seronegative APS\u0026rdquo; (APS by labs only) presenting as neuropathy. The patient\u0026rsquo;s care includes counselling about APS and monitoring for any thrombotic events. If he were to develop definite APS (e.g. a clot), anticoagulation would be indicated in addition to immunotherapy. This connection between APS and autonomic neuropathy is an active area of research. Increased awareness of this association is important, as treating the underlying APS (with immunosuppression or plasma exchange, in addition to standard anticoagulation) can lead to neurological improvement.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Our case adds to the growing recognition that autoimmune autonomic neuropathy can occur in the context of antiphospholipid antibodies, even in the absence of other APS symptoms.\u003c/p\u003e\u003cp\u003eA notable theme in this case is the overlap between features of hereditary dysautonomia and autoimmune neuropathy. The patient\u0026rsquo;s symptoms began in childhood \u0026ndash; far earlier than the typical age of onset for autoimmune AAG (which is usually mid-adulthood, often 40s or 50s).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e This mimicry of a genetic disorder delayed the diagnosis. It underscores that while hereditary autonomic neuropathies (like HSAN) usually present early, clinicians should not dismiss a potential autoimmune cause simply due to young age. Conversely, it is also true that some genetic neuropathies can masquerade as acquired ones. For example, certain Charcot-Marie-Tooth (CMT) variants have autonomic involvement: CMT type 2J due to \u003cem\u003eMPZ\u003c/em\u003e gene mutations can cause autonomic symptoms like pupillary abnormalities and bladder dysfunction.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Similarly, transthyretin familial amyloid polyneuropathy can present with prominent autonomic failure in young adulthood.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e In practice, thorough evaluation is required to distinguish these conditions. In our patient, the presence of immune biomarkers (lupus anticoagulant) and the biopsy evidence of an acquired axonal injury tipped the scales toward an autoimmune etiology rather than a congenital one. It is noteworthy that about 30% of AAG patients may have coexisting autoimmune diseases (like Sj\u0026ouml;gren\u0026rsquo;s syndrome or autoimmune thyroiditis),\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and some 10\u0026ndash;15% have an associated tumor (paraneoplastic).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e For our patient, however, another autoimmune condition was uncovered: the labial salivary gland biopsy confirmed focal sialadenitis consistent with Sj\u0026ouml;gren\u0026rsquo;s syndrome despite negative SS-A/SS-B serologies. In other words, a seronegative Sj\u0026ouml;gren\u0026rsquo;s syndrome appears to be present in addition to the antiphospholipid antibodies.\u003c/p\u003e\u003cp\u003eAutoimmune autonomic neuropathy is a \u003cem\u003etreatable\u003c/em\u003e condition, especially if recognized early. Standard therapies include immunomodulation such as corticosteroids, IVIG, plasmapheresis, and immunosuppressants (e.g. mycophenolate, rituximab).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Many patients show at least partial improvement with immunotherapy, validating the immune basis of the disease.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Our patient was started on IVIG empirically, given the suspicion of AAN; alternative approaches could include high-dose corticosteroids or plasma exchange. In the context of possible APS, IVIG was a reasonable initial choice (as it can have both immunomodulatory and some anti-thrombotic effects, and case reports have noted IVIG helping APS-related neuropathy).\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e While his improvement was not dramatic, it was encouraging and immunotherapy may need to be continued long-term. Supportive measures are crucial: for example, midodrine and fludrocortisone for orthostatic hypotension, salt and fluid loading, compression garments, and symptomatic treatments for gastrointestinal or urinary dysfunction as needed. Our patient\u0026rsquo;s SVT episodes were likely exacerbated by autonomic instability (high adrenergic state on standing); treating the underlying dysautonomia should reduce their frequency. The prognosis in chronic AAN is variable \u0026ndash; some cases plateau or partially recover, while others have residual deficits. Unlike acute AAG (which can sometimes recover spontaneously or with treatment over months),\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e chronic AAN may require ongoing therapy. Importantly, \u003cem\u003eearly recognition and treatment\u003c/em\u003e of autoimmune dysautonomia can prevent irreversible nerve damage and significantly improve quality of life.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the importance of considering atypical Sj\u0026ouml;gren\u0026rsquo;s syndrome as a differential diagnosis when autoimmune etiologies present alongside dysautonomic features. It emphasizes the need research for optimal management and treatment strategies in this area. Apart from diagnostic challenges, such cases underscore the complexity of autoimmune disorders that extend beyond classical glandular involvement and manifest with diverse neurological, cardiovascular, or systemic features. Recognizing these atypical presentations is crucial for timely diagnosis, preventing mismanagement, and guiding appropriate interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eI confirm that written informed consent was obtained from the patient for participation and publication of this clinical case.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLu Z, Cao X, Wang M, Peng F, Chen L, Yin Z et al (2025) A case of relapsed gAChR-positive autoimmune autonomic ganglionopathy treated by plasma exchange and mycophenolate mofetil. Front Neurol [Internet]. Jan 10 [cited 2025 Jul 17];15. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.frontiersin.org/article/\u003c/span\u003e\u003cspan address=\"https://www.frontiersin.org/article/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2018.01001/full\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2018.01001/full\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBilora F, Biasiolo, Zancan Z, Veronese S Autonomic dysfunction and primary antiphospholipid syndrome: a frequent and frightening correlation? IJGM [Internet]. 2012 Apr [cited 2025 Jul 17];339. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.dovepress.com/autonomic-dysfunction-and-primary-antiphospholipid-syndrome-a-frequent-peer-reviewed-article-IJGM\u003c/span\u003e\u003cspan address=\"http://www.dovepress.com/autonomic-dysfunction-and-primary-antiphospholipid-syndrome-a-frequent-peer-reviewed-article-IJGM\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFaiza Naeem, Imami SK, Khan SEA, Batool S, Akmal M, Yasir Mushtaq (2024) Atypical initial presentations of Sjogren\u0026rsquo;s syndrome: a case series. J Pak Med Assoc 75(1):125\u0026ndash;130. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.47391/JPMA.11555\u003c/span\u003e\u003cspan address=\"10.47391/JPMA.11555\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","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":"Atypical Sjögren’s Syndrome, Dysautonomia, Orthostatic Hypotension, Peripheral Neuropathy, Autoimmune Disease, Axonopathy, Lip Biopsy, IVIG Therapy, Gabapentin, Metoprolol","lastPublishedDoi":"10.21203/rs.3.rs-7578677/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7578677/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Sj\u0026ouml;gren\u0026rsquo;s Syndrome (SS) is a systemic chronic autoimmune disorder of unknown etiology characterized by salivary and lacrimal glands immune-mediated damage, leading to dryness of the mouth (xerostomia) and eyes (xerophthalmia). But atypical sjogren\u0026rsquo;s syndrome refers to cases where the syndrome\u0026rsquo;s symptoms are diverse and not limited to the classic dry eyes and dry mouth or where it presents with systemic complications like neuropathies, skin rashes, vasculitis, etc. These presentations can delay diagnosis because they don\u0026rsquo;t immediately suggest the disease, requiring doctors to consider Sjogren\u0026rsquo;s in patients with symptoms like peripheral neuropathy, joint pain without arthritis, etc.\u003c/p\u003e\u003cp\u003eMethods-Casereport: We report a 33-year-old male with lifelong symptoms of dysautonomia, including orthostatic hypotension, fatigue, heat intolerance, paroxysmal supraventricular tachycardia, and exercise intolerance since childhood. Neurological examination revealed distal sensorimotor weakness. Laboratory workup was notable for positive lupus anticoagulant and borderline elevated anticardiolipin IgM antibodies, suggesting a possible autoimmune basis for his symptoms. Lip biopsy of the patient suggested, features can be considered to be suggestive of Sjogren\u0026rsquo;s.\u003c/p\u003e\u003cp\u003eDiscussion: His orthostatic hypotension test was positive. And his Nerve biopsy showed chronic axonopathy. His initial treatment included IVIG, with modest clinical improvement. He later was started on T. Gabapentine 100 mg OD for neuropathy and Metoprolol 25 mg OD, for the management of his blood pressure. Currently, he is just continuing the therapy as planned.\u003c/p\u003e\u003cp\u003eConclusion: This case highlights the importance of considering atypical Sj\u0026ouml;gren\u0026rsquo;s syndrome as a differential diagnosis when autoimmune etiologies present alongside dysautonomic features. It also emphasizes the need for further research into optimal management and treatment strategies in this area.\u003c/p\u003e","manuscriptTitle":"Atypical Sjögren’s Syndrome Associated with Autoimmune Autonomic Neuropathy: A Presentation Resembling Hereditary Dysautonomia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-15 06:33:39","doi":"10.21203/rs.3.rs-7578677/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":"057a439c-0c7a-486c-8430-8d2d321283a9","owner":[],"postedDate":"September 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54473747,"name":"Neurology"},{"id":54473748,"name":"Internal Medicine"}],"tags":[],"updatedAt":"2025-09-15T06:33:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-15 06:33:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7578677","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7578677","identity":"rs-7578677","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}