AChR and Titin double antibody positive myasthenia gravis with isolated medullary palsy as the first manifestation: a case report

AChR and Titin double antibody positive myasthenia gravis with isolated medullary palsy as the first manifestation: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report AChR and Titin double antibody positive myasthenia gravis with isolated medullary palsy as the first manifestation: a case report Qiuyue Wang, Yongzhong Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7331831/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 Myasthenia gravis (MG) is an autoimmune disease with acquired nerve-muscle junction transmission disorders mediated by autoantibodies.Typical manifestations of MG are weakness of the eye muscles or the whole body, with isolated medullary paralysis as the first symptom being rare (< 5%), and it is very easy to be misdiagnosed as a structural disorder of the pharynx. Positive double antibodies to acetylcholine receptor (AChR) and titin strongly suggest the presence of a thymoma and severe medullary symptoms. In this article, we report a case of double antibody-positive myasthenia gravis with this rare form of onset of disease. Isolated medullary palsy can be a rare first manifestation of AChR/Titin double antibody-positive MG, and double antibody positivity is an important marker of thymoma and critical illness. Early screening for AChR/Titin antibodies and chest imaging is needed in patients with unexplained bulbar palsy. Double antibody-positive MG requires aggressive immunotherapy, and efgartigimod combined with hormones demonstrated significant efficacy in this case. Thymectomy remains the curative treatment for combined thymoma. Myasthenia gravis medullary palsy acetylcholine receptor antibodies myosin antibodies thymoma efgartigimod Figures Figure 1 Figure 2 Figure 3 Introduction Myasthenia gravis is an autoimmune neuromuscular junction disorder that occurs as a result of the production of antibodies against acetylcholine receptors on the postsynaptic membrane[ 1 ].Approximately 1/3 of cases are over 50 years of age and these constitute late-onset myasthenia gravis.[ 2 , 3 ]. The disease presents as generalized or focal (ocular, medullary) muscle weakness with fluctuations and fatigue as characteristic features. In addition, voice changes may be the initial complaint or, in rare cases, the only major complaint, such as in patients with laryngeal myasthenia gravis [ 4 , 5 ].Titin antibodies are most commonly seen in thymoma-associated MG (TAMG, positivity rate 20%-40%), and their coexistence with AChR antibodies is associated with a significantly higher risk of thymoma (positive predictive value > 90%) and a greater likelihood of involving the medullary muscle groups [ 6 , 7 , 8 ]. Isolated medullary palsy as the only first symptom of MG has a prevalence of less than 5% [ 9 ], and is often misdiagnosed as a brainstem lesion or pharyngeal disease due to the lack of typical ocular muscle/limb weakness, and delayed treatment can lead to aspiration or myasthenia gravis [ 10 ]. This paper is the first to report a case of MG with isolated bulbar palsy onset and double antibody positivity combined with thymoma, aiming to raise awareness of this rare phenotype. A 59-year-old female complained of progressive dysarthria and dysphagia for 8 months and dyspnea for 4 days. There was a past history of suspicious mediastinal occupation and pancytopenia.Examination showed typical signs of bulbar palsy (dysarthria, inability to lift the soft palate, and loss of pharyngeal reflexes) with mild ocular muscle weakness. Neostigmine test was positive. Serology:AChR antibody > 20 nmol/L (ELISA), Titin antibody 1:1000+ (CBA). Chest CT showed anterior mediastinal occupancy (possible thymoma). Diagnosis: MG (MGFA type IVb) combined with thymoma. Due to intolerance to cholinesterase inhibitors, efgartigimod (500 mg/week× for 4 weeks) in combination with prednisone (20 mg/day) was given. 1 course of treatment resulted in significant improvement of symptoms (QMG score 7→ 1; MG-ADL score 9→ 2) and weight gain. Case report Patient, female, 59 years old. She was admitted to the Department of Neurology of our hospital on August 15, 2024 with the complaint of "progressive slurred speech, dysphagia for 8 months and dyspnea for 4 days". Eight months before admission, he had slurred speech (hoarse, low-pitched voice)without any triggers, accompanied by difficulty in chewing and swallowing, and was still able to eat solids and occasionally choked on water. Symptoms were fluctuating (mild in the morning and severe in the evening, speech was clearer when lying down). Symptoms progressively aggravated, only able to eat semi-fluid food 2 months ago, speech slurred. He was treated in an outside hospital, and his electromyography showed no abnormalities in the nerves of the upper and lower extremities. She took oral brompheniramine tablets (60 mg every 4 hours) for 2 days without any improvement in symptoms and experienced excessive sweating and abdominal pain, so she stopped taking the tablets. The symptoms worsened 4 days prior to admission to our hospital, with self-consciousness of dyspnea,which occurred mostly after eating and swallowing saliva, so she went to the emergency room of our hospital, and a CT scan of the cranial brain showed a cavernous foci on the right side of the basal ganglia region. He was admitted to our hospital on August 15, 2024 for inpatient treatment. Past history:4 years ago, there was a history of hoarseness and choking on drinking water, which lasted for about 2 months and then resolved on its own. 2018 lung CT in our hospital suggested that the left mediastinum was occupying a space, and the possibility of malignant tumors was high (due to the lack of symptoms at that time, no further diagnosis and treatment). 2020 diagnosis of "total blood count reduction", after giving symptomatic transfusion and improvement, he was given oral medication on a regular basis.After that, he regularly took oral cyclosporine (100mg in the morning and 50mg in the evening),stanozolol (2mg in the morning and 2mg in the evening), and dicyclomine (25mg three times a day).Due to worsening of dysphagia prior to the present admission, the above medications were discontinued on his own 3 days prior to the hospitalization. The rest of his personal and family medical history was unremarkable. Neurological examination at the time of admission showed that the patient was coherent with dysarthria. The upward movement of both eyes was limited, the closure of both eyelids was laborious,and the nasolabial folds became shallow bilaterally. Bilateral biting muscle, temporal muscle strength is weakened, chewing weakness, choking on drinking water, dysphagia, bilateral soft palate lifting can not, bilateral pharyngeal reflex disappeared, tongue muscle mild atrophy, the rest of the examination did not find obvious abnormalities. Score: Quantitative myasthenia gravis score (QMG): 7 points;myasthenia gravis activity of daily living score (MG-ADL): 9 points. Ancillary tests: Ice pack test (+), neostigmine test (+). LABORATORY EXAMINATIONS: Blood count: leukocytes 3.34× 10⁹/L, hemoglobin 108 g/L, platelets 107× 10⁹/L (tertiary reduction). Coagulation function, rheumatoid immunity-related antibody profile, thyroid function 5, liver and kidney function, electrolytes were basically normal. Cranial CT plain: cavernous foci in the right basal ganglia region. Chest CT:occupying lesion on the left side of the anterior mediastinum (possible thymoma)(Fig. 1 ). Diffusion-weighted imaging (DWI), upper-middle-lower abdominal + pelvic CT: no significant abnormalities. Thyroid ultrasound: bilobar thyroid nodule (cystic TI-RADS grade 2; left lobe solid with calcification TI-RADS grade 4A, remaining solid/mixed TI-RADS grade 3). Neurophysiology: transient reflex: right-sided stimulation of the left side recorded without eliciting a positive waveform, with normal latency and low amplitude of the remaining R-wave. Nerve conduction: reduced CMAP wave amplitude in the left facial nerve. Concentric needle electromyography (lingual muscle): a small number of spontaneous potentials (fibrillatory potentials/positive sharp waves) were seen. Repetitive Nerve Stimulation (LF/HF): no decrements or increases seen (RNS negative). Electron laryngoscopy: no significant abnormalities. Lumbar puncture: cerebrospinal fluid pressure 85 mmH₂O, colorless and clear. Total cell count 1 × 10⁶/L, leukocytes 1× 10⁶/L. Pan test (-). Cerebrospinal fluid protein, sugar and chloride were normal. No antacids, bacteria, fungi, cryptococcus were found in the smear. Autoantibody test (Jiangsu Precision Medical Diagnostic Laboratory): serum paraneoplastic syndrome antibody profile (CBA method): Titin antibody IgG positive (1:1000+)(Fig. 2 ). Cerebrospinal fluid antibody profile for paraneoplastic syndrome (CBA method): Titin antibody IgG positive (1:10+)(Fig. 3 ). Neuromuscular junction disease autoantibody profile (ELISA method): AChR antibody IgG > 20 nmol/L (positive), Titin antibody IgG positive (4.22). Diagnosis: MG (MGFA type IVb) combined with thymoma; chronic aplastic anemia. Reatment and regression: MG treatment: efgartigimod (500mg/week× for 4 weeks) + prednisone (20mg/day) was enabled due to brompheniramine intolerance. Hematologic management: nasal cyclosporine (100mg am + 50mg pm). Thymoma: surgery recommended, patient refused. Efficacy:after 1 course of treatment, QMG score decreased to 1, MG-ADL decreased to 2, and weight gain was 7 kg. patient was followed up by phone after 1 month, patient was discharged from the hospital with strict adherence to medication and continued improvement of symptoms (microstatus), and refused to be readmitted for follow up. DISCUSSION The core value of this case is to report an extremely rare case of MG with isolated medullary palsy as the first and main clinical manifestation, and the patient's serology showed strong positivity of double antibodies to AChR and Titin, and imaging suggested thymoma. The diagnostic and treatment process of this patient is an important revelation to improve the understanding of this type of special manifestation of MG. Association of double antibody positivity (AChR + Titin) with thymoma and disease severity: the literature reports that Titin antibodies are detected in about 20%-40% of MG patients, while the rate of Titin antibody positivity is about 20%-30% in AChR antibody-positive MG patients [ 4 , 5 , 6 ]. Double antibody positivity for AChR and Titin is strongly suggestive of a combined thymoma ( The positive predictive value is up to 90% or more) [ 6 , 7 , 11 , 12 ]. In our case, the significantly elevated titer of serum Titin antibody (1:1000+) and the chest CT clearly suggested anterior mediastinal space, which was highly consistent with the diagnosis of TAMG. Several studies have confirmed that patients with AChR + Titin double antibody-positive MG have more severe clinical manifestations, are more likely to develop systemic symptoms (especially medullary palsy), convert from oculomotor to systemic at an earlier age, have a higher incidence of myasthenia gravis, and have a higher prevalence of thymoma [ 7 , 8 , 11 , 13 ]. In our case, the first episode of myelopathy was medullary paralysis, which rapidly progressed to respiratory distress requiring hospitalization (MGFA type IVb), which is fully consistent with the severe disease of double antibody-positive MG.The pathogenic mechanism of Titin antibody has not been fully elucidated, and may be related to its ability to interfere with the function of calcium release channels in myofibers (e.g., Ryanodine receptor) and to disrupt the ability of intra-membrane myosin (Titin) to maintain the elasticity and passive tone of muscle fibers. elasticity and passive tone of muscle fibers [ 14 , 15 ], which may be one of the reasons why fatigue-prone muscles such as the medulla oblongata are more susceptible to involvement and severity of symptoms, consistent with the prominent bulbar palsy manifestation in this case. Rarity and diagnostic challenges of isolated medullary palsy as the first manifestation of MG: Although medullary symptoms are common in mid-to late-stage MG, they are extremely rare as the first, isolated, and persistent sole symptom (literature estimates < 5%) [ 9 ].Yang et al. showed that among patients with laryngeal symptom-predominant MG,only 23.3% were correctly diagnosed as having MG at the time of their first visit to the doctor, and as many as 63% of their first visit to an ENT department [ 10 ]. The difficulty of diagnosing our patient is emphasized by the fact that his initial symptoms (slurred speech and dysphagia) lasted for 8 months,during which time he had been misdiagnosed. Reasons for misdiagnosis include: lack of typical manifestations of eye muscle or limb weakness; symptoms of medullary palsy (dysarthria, dysphagia) are easily confused with brainstem stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),and even localized pharyngeal disorders; routine cranial imaging (CT/MRI) may have nonspecific findings (e.g., in this case, only lacunar infarct foci were seen); and repetitive neurostimulation (RNS)was not performed in the MG with bulbar involvement alone may have a low positivity rate (RNS was negative in this case). This case serves as a warning that MG must be included in the differential diagnosis of isolated bulbar palsy of unknown origin, even if RNS is negative or there are no significant abnormalities on cranial imaging. TREATMENT STRATEGY SELECTION AND IMPLICATION: Double antibody-positive MG usually requires a more intensive immunotherapy regimen [ 11 ]. In our case, the patient was intolerant to cholinesterase inhibitors (brompheniramine), so immunotherapy was initiated directly. We chose a regimen of efgartigimod in combination with a glucocorticoid (prednisone).Efgartigimod is a human IgG1 antibody Fc fragment that promotes IgG degradation in the lysosome by competitively binding to the neonatal Fc receptor (FcRn) and by blocking the binding of endogenous IgG, including pathogenic AChR and Titin antibodies, to the FcRn. lysosomal degradation,thereby accelerating the clearance of pathogenic antibodies [ 16 ]. egartigimod's significant efficacy and safety in AChR Ab + systemic MG, including those with ocular symptoms, has been demonstrated in the ADAPT phase 3 trial and its subgroup analysis [ 16 ]. Its use in perioperative TAMG has also shown promise [17]. In our case, after receiving 1 course (4 weeks) of efgartigimod in combination with low-dose prednisone, there was a rapid and significant improvement in both bulbar palsy symptoms (speech, swallowing) and ophthalmologic symptoms (QMG decreased from 7 to 1, and MG-ADL decreased from 9 to 2), and weight was regained, which is a satisfactory efficacy. This suggests that rapid clearance therapy (e.g., efgartigimod) against pathogenic IgG antibodies in combination with glucocorticoids may be an effective strategy for the treatment of double-antibody-positive MG,especially in combination with severe globus pallidus MG, and particularly for those who are intolerant of, or have poor results with, cholinesterase inhibitors. Of course, thymectomy remains the cornerstone of TAMG treatment and could not be performed in this case due to patient refusal. IMPLICATIONS FOR CLINICAL PRACTICE (SCREENING AND FOLLOW-UP): EARLY ANTIBODY SCREENING IS CRITICAL: Comprehensive MG-associated antibody testing, including, at a minimum, AChR antibodies, must be routinely performed in patients who start with isolated globus pallidus. Given the strong association of double antibody positivity with thymoma and severe disease,concomitant Titin antibody testing is strongly recommended, especially in elderly or severely ill patients [ 12 , 18 ]. Imaging is indispensable: All patients with newly diagnosed MG, especially those with positive AChR antibodies, positive Titin antibodies, or late-onset disease, should undergo chest CT or MRI to screen for thymoma or thymic hyperplasia [ 19 ]. In this case, previous CT had suggested mediastinal occupancy, but the lack of attention led to a delay in diagnosis. Specificity of double antibody-positive patients: Such patients need to be aware that their disease may be more severe, more rapidly progressive, and at very high risk for thymoma. Treatment may require more aggressive immunologic intervention. Long-term follow-up requires special vigilance for the development of myasthenia gravis crisis and recurrence of thymoma (even after surgery) [ 11 , 18 , 20 ]. Regular monitoring of changes in antibody titers (e.g., Titin antibodies) may be of value in assessing disease and prognosis [ 11 , 18 , 20 ]. Limitations of this study: Single-center, single-case report; extrapolation of conclusions requires caution. Patients refused to undergo thymectomy and pathologic confirmation of thymoma, and thymoma diagnosis was dependent on imaging. Failure to dynamically monitor changes in AChR and Titin antibody titers during treatment to assess their correlation with clinical symptom improvement. The patient's comorbidity with chronic aplastic anemia and its treatment (cyclosporine) may have potentially affected the immune status and course of MG, adding to the complexity of the condition. In summary, this case report emphasizes the extreme rarity of isolated medullary palsy as the first manifestation of MG and its great diagnostic challenges.Positive dual antibodies to AChR and Titin are important serologic markers of MG severity and comorbid thymoma. In patients with unexplained bulbar palsy, clinicians should be highly alert to the possibility of MG, and must perform AChR antibody and Titin antibody testing as well as chest imaging (CT/MRI) to make a definitive diagnosis and assess the risk of thymoma. Early recognition and early diagnosis are critical to avoid misdiagnosis and delayed treatment. Double antibody-positive MG often requires intensive immunotherapy.efgartigimod combined with glucocorticoids showed rapid and significant efficacy in this case,providing a new treatment option for this refractory patient. Thymectomy remains the curative treatment for patients with MG combined with thymoma. Double antibody-positive patients need to be closely followed up for a long period of time to be alert for crisis and tumor recurrence. Declarations Ethics approval and consent to participate Written informed consent was obtained from the patient for the publication of this case report series and any accompanying images. Clinical Trial Not applicable. Consent for publication Written informed consent was obtained from the patient for the publication of this case report series and any accompanying images. Availability of data and material The datasets used during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions WQY wrote the original manuscript, LYZ reviewed and edited the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330(25):1797 – 810. doi: 10.1056/NEJM199406233302507. PMID: 8190158. Alkhawajah NM, Oger J. Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing. Muscle Nerve. 2013;48(5):705 – 10. 10.1002/mus.23964 . PMID: 23893883. Aragon ès JM, Bol íbar I, Bonfill X, Bufill E, Mummany A, Alonso F, Illa I. Myasthenia gravis: a higher than expected incidence in the elderly. Neurology. 2003;60(6):1024–6. 1212/01. wnl.0000050461.05432.c5. PMID: 12654975. Mao VH, Abaza M, Spiegel JR, Mandel S, Hawkshaw M, Heuer RJ, Sataloff RT. Laryngeal myasthenia gravis: report of 40 cases. J Voice. 2001;15(1):122 – 30. doi: 10.1016/S0892-1997(01)00012-1. PMID: 12269627.5. Shakir R. Brucellosis. J Neurol Sci. 2021;420:117280. Michalska T, Rowi ńska-Marci ńska K, Strugalska H, Maniecka-Aleksandrowicz B, Emeryk-Szajewska B. Miastenia rozpoczynajaca sie od dysfon ii. Badania kliniczne i elektrofizjologiczne [Myasthenia preceded by dysphonia. Clinical and electrophysical study]. Neurol Neurochir Pol. 1996 Sep-Oct;30(5):783–96. polish. pmid: 9148175. Romi F, Skeie GO, Gilhus NE, et al. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance[J]. Arch Neurol. 2005;62(3):442–6. Gilhus NE, Skeie GO, Romi F, et al. Myasthenia gravis-autoantibody characteristics and their implications for therapy [J]. Nat reviews Neurol. 2016;12(5):259–68. Sela BA. Titin: some aspects of the largest protein in the body [J]. Harefuah. 2002;141(7):631–5. Wang JL, Chen DQ, Yang Y et al. Clinical characteristics of 166 cases of myasthenia gravis with medullary type[J]. Chin J Neurol 2007,40(6):395–8. Yang X, Niu L, Yang C, et al. Clinical features of laryngeal myasthenia gravis: a case series. Am J Otolaryngol. 2018;40:292–6. Chen Y, Tao X, Wang Y, et al. Clinical characteristics and prognosis of anti-AChR positive myasthenia gravis combined with anti-LRP4 or anti-titin antibody [J]. Front Neurol. 2022;13:873599. Skeie GO, Freiburg A, Kolmerer B, et al. Titin transcripts in thymomas[J]. J Autoimmun. 1997;10(6):551–7. Skeie GO, Aarli JA, Matre R, et al. Titin antibody positive myasthenia gravis patients have a cellular immune response against the main immunogen ic region of titin[J]. Eur J Neurol. 1997;4(2):131–7. Skeie GO. Skeletal muscle titin: physiology and pathophysiology [J]. Cell Mol Life Sci CMLS. 2000;57:1570–6. Aarli JA, Stefansson K, Marton LSG, et al. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin[J]. Clin Experimental Immunol. 1990;82(2):284–8. Howard JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalized myasthenia gravis (ADAPT): a multicentre randomized, placebo-controlled, phase 3 trial[J]. Lancet Neurol. 2021;20(7):526–36. Vijayan J, Menon D, Barnett C, et al. Clinical profile and impact of comorbidities in patients with very-late-onset myasthenia gravis[J]. Volume 64. Muscle & Nerve; 2021. pp. 462–6. 4. Buckley C, Newsom-Davis J, Willcox N, et al. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?[J]. Neurology. 2001;57(9):1579–82. Chinese Society of Immunology, Neuroimmunology Branch. Guidelines for the diagnosis and treatment of myasthenia gravis in China (2020 edition) [J]. Chin J Neuroimmunol Neurol. 2021;28(1):1–12. Uzawa A, Kanai T, Oda F, et al. Frequency and features of myasthenia gravis develo** after thymectomy [J]. Eur J Neurol. 2020;27(1):175–80. 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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-7331831","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":512034030,"identity":"0b284493-4744-4dc5-a94c-e0163d07cb35","order_by":0,"name":"Qiuyue Wang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qiuyue","middleName":"","lastName":"Wang","suffix":""},{"id":512034035,"identity":"64dec0c7-a0da-40b0-bf1d-ca7b9308329c","order_by":1,"name":"Yongzhong Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIie3PoQvCQBTH8ScHZ3m3qxuI/gsHVsF/5Q5hTTBeMCzIDGpf8X8wGm8Mls5unAg2YRax6brizma4T/594T0Az/tDAQEwtX4i7SaqknrenlACnTyzpMfRnEVlS4cEgBRsQUZRpi7RaUEcki4zBUsoCjOJtUoo8OVKthwWyHy7xyYp46Pa9yC0h11L0oyvNkSRr5vEUhDh1CFhqUBR8PtMpcQtyVkqMUohBvckswY5wiSUtsTWXzi3w7rWZkwHlbo99LzPl5vvyRv8be55nud99AIbNUkm/JZRkAAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Affiliated Hospital of Dalian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yongzhong","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-08-09 06:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7331831/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7331831/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90982979,"identity":"b1118e8f-dff9-4b32-8925-d33ea72ffa8e","added_by":"auto","created_at":"2025-09-10 09:33:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":171454,"visible":true,"origin":"","legend":"\u003cp\u003eChest CT: The mediastinal window shows a space-occupying lesion in the left anterior mediastinum。\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7331831/v1/a0e7a90e49b375187b983635.png"},{"id":90982980,"identity":"049649c2-01df-452f-b16e-2aa5366fd1a4","added_by":"auto","created_at":"2025-09-10 09:33:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":240026,"visible":true,"origin":"","legend":"\u003cp\u003eTitin receptor IgG antibodies detected in the patient's serum using an indirect immunofluorescence method.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7331831/v1/e6fc90aaaaa297d5581bad74.png"},{"id":90982981,"identity":"e148ff4b-4169-464f-bb41-986264e4d533","added_by":"auto","created_at":"2025-09-10 09:33:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":213024,"visible":true,"origin":"","legend":"\u003cp\u003eTitin receptor IgG antibodies detected in the patient's CSF using an indirect immunofluorescence method.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7331831/v1/e363d74be09edb57db05903f.png"},{"id":93927328,"identity":"805e2ec5-d97f-4ee4-bc42-fabc1ca7e2ce","added_by":"auto","created_at":"2025-10-20 10:53:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1173594,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7331831/v1/6c1f934f-90ca-4d1c-a73a-82000a5a1bb4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"AChR and Titin double antibody positive myasthenia gravis with isolated medullary palsy as the first manifestation: a case report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMyasthenia gravis is an autoimmune neuromuscular junction disorder that occurs as a result of the production of antibodies against acetylcholine receptors on the postsynaptic membrane[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].Approximately 1/3 of cases are over 50 years of age and these constitute late-onset myasthenia gravis.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The disease presents as generalized or focal (ocular, medullary) muscle weakness with fluctuations and fatigue as characteristic features. In addition, voice changes may be the initial complaint or, in rare cases, the only major complaint, such as in patients with laryngeal myasthenia gravis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e5\u003c/span\u003e].Titin antibodies are most commonly seen in thymoma-associated MG (TAMG, positivity rate 20%-40%), and their coexistence with AChR antibodies is associated with a significantly higher risk of thymoma (positive predictive value\u0026thinsp;\u0026gt;\u0026thinsp;90%) and a greater likelihood of involving the medullary muscle groups [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Isolated medullary palsy as the only first symptom of MG has a prevalence of less than 5% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and is often misdiagnosed as a brainstem lesion or pharyngeal disease due to the lack of typical ocular muscle/limb weakness, and delayed treatment can lead to aspiration or myasthenia gravis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This paper is the first to report a case of MG with isolated bulbar palsy onset and double antibody positivity combined with thymoma, aiming to raise awareness of this rare phenotype.\u003c/p\u003e\u003cp\u003eA 59-year-old female complained of progressive dysarthria and dysphagia for 8 months and dyspnea for 4 days. There was a past history of suspicious mediastinal occupation and pancytopenia.Examination showed typical signs of bulbar palsy (dysarthria, inability to lift the soft palate, and loss of pharyngeal reflexes) with mild ocular muscle weakness. Neostigmine test was positive. Serology:AChR antibody\u0026thinsp;\u0026gt;\u0026thinsp;20 nmol/L (ELISA), Titin antibody 1:1000+ (CBA). Chest CT showed anterior mediastinal occupancy (possible thymoma). Diagnosis: MG (MGFA type IVb) combined with thymoma. Due to intolerance to cholinesterase inhibitors, efgartigimod (500 mg/week\u0026times; for 4 weeks) in combination with prednisone (20 mg/day) was given. 1 course of treatment resulted in significant improvement of symptoms (QMG score 7\u0026rarr; 1; MG-ADL score 9\u0026rarr; 2) and weight gain.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003ePatient, female, 59 years old. She was admitted to the Department of Neurology of our hospital on August 15, 2024 with the complaint of \"progressive slurred speech, dysphagia for 8 months and dyspnea for 4 days\". Eight months before admission, he had slurred speech (hoarse, low-pitched voice)without any triggers, accompanied by difficulty in chewing and swallowing, and was still able to eat solids and occasionally choked on water. Symptoms were fluctuating (mild in the morning and severe in the evening, speech was clearer when lying down). Symptoms progressively aggravated, only able to eat semi-fluid food 2 months ago, speech slurred. He was treated in an outside hospital, and his electromyography showed no abnormalities in the nerves of the upper and lower extremities. She took oral brompheniramine tablets (60 mg every 4 hours) for 2 days without any improvement in symptoms and experienced excessive sweating and abdominal pain, so she stopped taking the tablets. The symptoms worsened 4 days prior to admission to our hospital, with self-consciousness of dyspnea,which occurred mostly after eating and swallowing saliva, so she went to the emergency room of our hospital, and a CT scan of the cranial brain showed a cavernous foci on the right side of the basal ganglia region. He was admitted to our hospital on August 15, 2024 for inpatient treatment. Past history:4 years ago, there was a history of hoarseness and choking on drinking water, which lasted for about 2 months and then resolved on its own. 2018 lung CT in our hospital suggested that the left mediastinum was occupying a space, and the possibility of malignant tumors was high (due to the lack of symptoms at that time, no further diagnosis and treatment). 2020 diagnosis of \"total blood count reduction\", after giving symptomatic transfusion and improvement, he was given oral medication on a regular basis.After that, he regularly took oral cyclosporine (100mg in the morning and 50mg in the evening),stanozolol (2mg in the morning and 2mg in the evening), and dicyclomine (25mg three times a day).Due to worsening of dysphagia prior to the present admission, the above medications were discontinued on his own 3 days prior to the hospitalization. The rest of his personal and family medical history was unremarkable.\u003c/p\u003e\u003cp\u003eNeurological examination at the time of admission showed that the patient was coherent with dysarthria. The upward movement of both eyes was limited, the closure of both eyelids was laborious,and the nasolabial folds became shallow bilaterally. Bilateral biting muscle, temporal muscle strength is weakened, chewing weakness, choking on drinking water, dysphagia, bilateral soft palate lifting can not, bilateral pharyngeal reflex disappeared, tongue muscle mild atrophy, the rest of the examination did not find obvious abnormalities. Score: Quantitative myasthenia gravis score (QMG): 7 points;myasthenia gravis activity of daily living score (MG-ADL): 9 points. Ancillary tests: Ice pack test (+), neostigmine test (+). LABORATORY EXAMINATIONS: Blood count: leukocytes 3.34\u0026times; 10⁹/L, hemoglobin 108 g/L, platelets 107\u0026times; 10⁹/L (tertiary reduction). Coagulation function, rheumatoid immunity-related antibody profile, thyroid function 5, liver and kidney function, electrolytes were basically normal. Cranial CT plain: cavernous foci in the right basal ganglia region. Chest CT:occupying lesion on the left side of the anterior mediastinum (possible thymoma)(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Diffusion-weighted imaging (DWI), upper-middle-lower abdominal\u0026thinsp;+\u0026thinsp;pelvic CT: no significant abnormalities. Thyroid ultrasound: bilobar thyroid nodule (cystic TI-RADS grade 2; left lobe solid with calcification TI-RADS grade 4A, remaining solid/mixed TI-RADS grade 3). Neurophysiology: transient reflex: right-sided stimulation of the left side recorded without eliciting a positive waveform, with normal latency and low amplitude of the remaining R-wave. Nerve conduction: reduced CMAP wave amplitude in the left facial nerve. Concentric needle electromyography (lingual muscle): a small number of spontaneous potentials (fibrillatory potentials/positive sharp waves) were seen. Repetitive Nerve Stimulation (LF/HF): no decrements or increases seen (RNS negative). Electron laryngoscopy: no significant abnormalities. Lumbar puncture: cerebrospinal fluid pressure 85 mmH₂O, colorless and clear. Total cell count 1 \u0026times; 10⁶/L, leukocytes 1\u0026times; 10⁶/L. Pan test (-). Cerebrospinal fluid protein, sugar and chloride were normal. No antacids, bacteria, fungi, cryptococcus were found in the smear. Autoantibody test (Jiangsu Precision Medical Diagnostic Laboratory): serum paraneoplastic syndrome antibody profile (CBA method): Titin antibody IgG positive (1:1000+)(Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Cerebrospinal fluid antibody profile for paraneoplastic syndrome (CBA method): Titin antibody IgG positive (1:10+)(Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Neuromuscular junction disease autoantibody profile (ELISA method): AChR antibody IgG\u0026thinsp;\u0026gt;\u0026thinsp;20 nmol/L (positive), Titin antibody IgG positive (4.22). Diagnosis: MG (MGFA type IVb) combined with thymoma; chronic aplastic anemia.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eReatment and regression: MG treatment: efgartigimod (500mg/week\u0026times; for 4 weeks)\u0026thinsp;+\u0026thinsp;prednisone (20mg/day) was enabled due to brompheniramine intolerance. Hematologic management: nasal cyclosporine (100mg am\u0026thinsp;+\u0026thinsp;50mg pm). Thymoma: surgery recommended, patient refused. Efficacy:after 1 course of treatment, QMG score decreased to 1, MG-ADL decreased to 2, and weight gain was 7 kg. patient was followed up by phone after 1 month, patient was discharged from the hospital with strict adherence to medication and continued improvement of symptoms (microstatus), and refused to be readmitted for follow up.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe core value of this case is to report an extremely rare case of MG with isolated medullary palsy as the first and main clinical manifestation, and the patient's serology showed strong positivity of double antibodies to AChR and Titin, and imaging suggested thymoma. The diagnostic and treatment process of this patient is an important revelation to improve the understanding of this type of special manifestation of MG.\u003c/p\u003e\u003cp\u003eAssociation of double antibody positivity (AChR\u0026thinsp;+\u0026thinsp;Titin) with thymoma and disease severity: the literature reports that Titin antibodies are detected in about 20%-40% of MG patients, while the rate of Titin antibody positivity is about 20%-30% in AChR antibody-positive MG patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Double antibody positivity for AChR and Titin is strongly suggestive of a combined thymoma ( The positive predictive value is up to 90% or more) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In our case, the significantly elevated titer of serum Titin antibody (1:1000+) and the chest CT clearly suggested anterior mediastinal space, which was highly consistent with the diagnosis of TAMG. Several studies have confirmed that patients with AChR\u0026thinsp;+\u0026thinsp;Titin double antibody-positive MG have more severe clinical manifestations, are more likely to develop systemic symptoms (especially medullary palsy), convert from oculomotor to systemic at an earlier age, have a higher incidence of myasthenia gravis, and have a higher prevalence of thymoma [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our case, the first episode of myelopathy was medullary paralysis, which rapidly progressed to respiratory distress requiring hospitalization (MGFA type IVb), which is fully consistent with the severe disease of double antibody-positive MG.The pathogenic mechanism of Titin antibody has not been fully elucidated, and may be related to its ability to interfere with the function of calcium release channels in myofibers (e.g., Ryanodine receptor) and to disrupt the ability of intra-membrane myosin (Titin) to maintain the elasticity and passive tone of muscle fibers. elasticity and passive tone of muscle fibers [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which may be one of the reasons why fatigue-prone muscles such as the medulla oblongata are more susceptible to involvement and severity of symptoms, consistent with the prominent bulbar palsy manifestation in this case. Rarity and diagnostic challenges of isolated medullary palsy as the first manifestation of MG: Although medullary symptoms are common in mid-to late-stage MG, they are extremely rare as the first, isolated, and persistent sole symptom (literature estimates\u0026thinsp;\u0026lt;\u0026thinsp;5%) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e].Yang et al. showed that among patients with laryngeal symptom-predominant MG,only 23.3% were correctly diagnosed as having MG at the time of their first visit to the doctor, and as many as 63% of their first visit to an ENT department [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The difficulty of diagnosing our patient is emphasized by the fact that his initial symptoms (slurred speech and dysphagia) lasted for 8 months,during which time he had been misdiagnosed. Reasons for misdiagnosis include: lack of typical manifestations of eye muscle or limb weakness; symptoms of medullary palsy (dysarthria, dysphagia) are easily confused with brainstem stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS),and even localized pharyngeal disorders; routine cranial imaging (CT/MRI) may have nonspecific findings (e.g., in this case, only lacunar infarct foci were seen); and repetitive neurostimulation (RNS)was not performed in the MG with bulbar involvement alone may have a low positivity rate (RNS was negative in this case). This case serves as a warning that MG must be included in the differential diagnosis of isolated bulbar palsy of unknown origin, even if RNS is negative or there are no significant abnormalities on cranial imaging.\u003c/p\u003e\u003cp\u003eTREATMENT STRATEGY SELECTION AND IMPLICATION: Double antibody-positive MG usually requires a more intensive immunotherapy regimen [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In our case, the patient was intolerant to cholinesterase inhibitors (brompheniramine), so immunotherapy was initiated directly. We chose a regimen of efgartigimod in combination with a glucocorticoid (prednisone).Efgartigimod is a human IgG1 antibody Fc fragment that promotes IgG degradation in the lysosome by competitively binding to the neonatal Fc receptor (FcRn) and by blocking the binding of endogenous IgG, including pathogenic AChR and Titin antibodies, to the FcRn. lysosomal degradation,thereby accelerating the clearance of pathogenic antibodies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. egartigimod's significant efficacy and safety in AChR Ab\u0026thinsp;+\u0026thinsp;systemic MG, including those with ocular symptoms, has been demonstrated in the ADAPT phase 3 trial and its subgroup analysis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Its use in perioperative TAMG has also shown promise [17]. In our case, after receiving 1 course (4 weeks) of efgartigimod in combination with low-dose prednisone, there was a rapid and significant improvement in both bulbar palsy symptoms (speech, swallowing) and ophthalmologic symptoms (QMG decreased from 7 to 1, and MG-ADL decreased from 9 to 2), and weight was regained, which is a satisfactory efficacy. This suggests that rapid clearance therapy (e.g., efgartigimod) against pathogenic IgG antibodies in combination with glucocorticoids may be an effective strategy for the treatment of double-antibody-positive MG,especially in combination with severe globus pallidus MG, and particularly for those who are intolerant of, or have poor results with, cholinesterase inhibitors. Of course, thymectomy remains the cornerstone of TAMG treatment and could not be performed in this case due to patient refusal. IMPLICATIONS FOR CLINICAL PRACTICE (SCREENING AND FOLLOW-UP): EARLY ANTIBODY SCREENING IS CRITICAL: Comprehensive MG-associated antibody testing, including, at a minimum, AChR antibodies, must be routinely performed in patients who start with isolated globus pallidus. Given the strong association of double antibody positivity with thymoma and severe disease,concomitant Titin antibody testing is strongly recommended, especially in elderly or severely ill patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Imaging is indispensable: All patients with newly diagnosed MG, especially those with positive AChR antibodies, positive Titin antibodies, or late-onset disease, should undergo chest CT or MRI to screen for thymoma or thymic hyperplasia [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In this case, previous CT had suggested mediastinal occupancy, but the lack of attention led to a delay in diagnosis. Specificity of double antibody-positive patients: Such patients need to be aware that their disease may be more severe, more rapidly progressive, and at very high risk for thymoma. Treatment may require more aggressive immunologic intervention. Long-term follow-up requires special vigilance for the development of myasthenia gravis crisis and recurrence of thymoma (even after surgery) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Regular monitoring of changes in antibody titers (e.g., Titin antibodies) may be of value in assessing disease and prognosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLimitations of this study:\u003c/p\u003e\u003cp\u003eSingle-center, single-case report; extrapolation of conclusions requires caution.\u003c/p\u003e\u003cp\u003ePatients refused to undergo thymectomy and pathologic confirmation of thymoma, and thymoma diagnosis was dependent on imaging.\u003c/p\u003e\u003cp\u003eFailure to dynamically monitor changes in AChR and Titin antibody titers during treatment to assess their correlation with clinical symptom improvement.\u003c/p\u003e\u003cp\u003eThe patient's comorbidity with chronic aplastic anemia and its treatment (cyclosporine) may have potentially affected the immune status and course of MG, adding to the complexity of the condition.\u003c/p\u003e\u003cp\u003eIn summary, this case report emphasizes the extreme rarity of isolated medullary palsy as the first manifestation of MG and its great diagnostic challenges.Positive dual antibodies to AChR and Titin are important serologic markers of MG severity and comorbid thymoma. In patients with unexplained bulbar palsy, clinicians should be highly alert to the possibility of MG, and must perform AChR antibody and Titin antibody testing as well as chest imaging (CT/MRI) to make a definitive diagnosis and assess the risk of thymoma. Early recognition and early diagnosis are critical to avoid misdiagnosis and delayed treatment. Double antibody-positive MG often requires intensive immunotherapy.efgartigimod combined with glucocorticoids showed rapid and significant efficacy in this case,providing a new treatment option for this refractory patient. Thymectomy remains the curative treatment for patients with MG combined with thymoma. Double antibody-positive patients need to be closely followed up for a long period of time to be alert for crisis and tumor recurrence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report series and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for the publication of this case report series and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWQY\u0026nbsp;wrote the original manuscript, LYZ reviewed and edited the manuscript.\u0026nbsp;All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDrachman DB. 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Clin Experimental Immunol. 1990;82(2):284\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoward JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalized myasthenia gravis (ADAPT): a multicentre randomized, placebo-controlled, phase 3 trial[J]. Lancet Neurol. 2021;20(7):526\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVijayan J, Menon D, Barnett C, et al. Clinical profile and impact of comorbidities in patients with very-late-onset myasthenia gravis[J]. Volume 64. Muscle \u0026amp; Nerve; 2021. pp. 462\u0026ndash;6. 4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBuckley C, Newsom-Davis J, Willcox N, et al. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?[J]. Neurology. 2001;57(9):1579\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChinese Society of Immunology, Neuroimmunology Branch. Guidelines for the diagnosis and treatment of myasthenia gravis in China (2020 edition) [J]. Chin J Neuroimmunol Neurol. 2021;28(1):1\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUzawa A, Kanai T, Oda F, et al. Frequency and features of myasthenia gravis develo** after thymectomy [J]. Eur J Neurol. 2020;27(1):175\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\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":"Myasthenia gravis, medullary palsy, acetylcholine receptor antibodies, myosin antibodies, thymoma, efgartigimod","lastPublishedDoi":"10.21203/rs.3.rs-7331831/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7331831/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMyasthenia gravis (MG) is an autoimmune disease with acquired nerve-muscle junction transmission disorders mediated by autoantibodies.Typical manifestations of MG are weakness of the eye muscles or the whole body, with isolated medullary paralysis as the first symptom being rare (\u0026lt;\u0026thinsp;5%), and it is very easy to be misdiagnosed as a structural disorder of the pharynx. Positive double antibodies to acetylcholine receptor (AChR) and titin strongly suggest the presence of a thymoma and severe medullary symptoms. In this article, we report a case of double antibody-positive myasthenia gravis with this rare form of onset of disease. Isolated medullary palsy can be a rare first manifestation of AChR/Titin double antibody-positive MG, and double antibody positivity is an important marker of thymoma and critical illness. Early screening for AChR/Titin antibodies and chest imaging is needed in patients with unexplained bulbar palsy. Double antibody-positive MG requires aggressive immunotherapy, and efgartigimod combined with hormones demonstrated significant efficacy in this case. Thymectomy remains the curative treatment for combined thymoma.\u003c/p\u003e","manuscriptTitle":"AChR and Titin double antibody positive myasthenia gravis with isolated medullary palsy as the first manifestation: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-10 09:25:35","doi":"10.21203/rs.3.rs-7331831/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":"132e54be-9f99-46d8-ad29-cdbf2515d650","owner":[],"postedDate":"September 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T10:53:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-10 09:25:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7331831","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7331831","identity":"rs-7331831","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}