Beyond Classics: Area Postrema Syndrome as a Rare Presentation of Neuromyelitis Optica Spectrum Disorder

Beyond Classics: Area Postrema Syndrome as a Rare Presentation of Neuromyelitis Optica Spectrum Disorder | 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 Beyond Classics: Area Postrema Syndrome as a Rare Presentation of Neuromyelitis Optica Spectrum Disorder Himel Kumar Biswas, Rama Biswas, Shamah Marzuqah, Sheikh Nafis-Ur Rahman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7378715/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 20 You are reading this latest preprint version Abstract Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathic disease of the central nervous system. It typically involves the optic nerves, spinal cord, and brainstem, but can also manifest atypically. Area postrema syndrome (APS), a recognized core clinical manifestation of NMOSD, is characterized by intractable nausea, vomiting, or hiccups. When APS presents in isolation, diagnosis can be challenging, as symptoms are frequently attributed to gastrointestinal disorders, leading to delays in appropriate management. Recognition relies on characteristic neuroimaging findings and the detection of serum aquaporin-4 immunoglobulin G (AQP4-IgG), after the exclusion of alternative causes. Case Report: The reported case highlights area postrema syndrome as an uncommon initial presentation of neuromyelitis optica spectrum disorder in a 33-year-old female. The patient presented with intractable nausea and vomiting, which initially led to extensive investigations of gastrointestinal etiologies. The subsequent development of neurological symptoms, including nystagmus, ataxia and a characteristic lesion in the dorsal medulla on magnetic resonance imaging (MRI), ultimately led to the diagnosis of NMOSD. This case, underscores the importance of considering NMOSD in patients presenting with otherwise unexplained APS, even in the absence of typical findings such as optic neuritis or transverse myelitis. Although cerebrospinal fluid (CSF) analysis was normal and the initial CSF test for Aquaporin-4-IgG (AQP4-IgG) was negative, a subsequent blood test for the same antibody returned positive. This confirmed the diagnosis of Neuromyelitis Optica Spectrum Disorder (NMOSD). Immediate treatment with intravenous methylprednisolone led to significant clinical improvement. At the one-month follow-up, she was symptom-free and ambulating independently. Conclusion: Physicians in developing countries need to be more aware of the rare disease NMOSD. This case shows that a high level of suspicion is crucial for a quick diagnosis and to prevent treatment delays. Neuromyelitis optica Neuromyelitis optica spectrum disorders Area postrema syndrome Figures Figure 1 Figure 2 Introduction Neuromyelitis optica spectrum disorder (NMOSD) is a group of autoimmune, inflammatory disorders of the central nervous system (CNS) ( 1 – 7 ). Previously, optic nerves and the spinal cord were believed to be the primary affected sites, but in 2015 the International Panel for NMO Diagnosis (IPND) added area postrema, brainstem, diencephalic and cerebral manifestations as part of NMOSD presentation ( 2 , 7 – 9 ). Unlike multiple sclerosis, NMOSD is strongly associated with serum AQP4-IgG. ( 4 , 9 , 10 ). Aquaporin-4 is a water channel mostly abundant in the CNS, more specifically, expressed in the astrocytic processes located at the blood brain barrier (BBB) ( 11 ). The spectrum of clinical presentations makes the diagnosis of NMOSD sometimes difficult. One of its rare presentations is the area postrema syndrome. Due to the unique site of inflammation, patients present with unexplained nausea, vomiting and hiccups and subsequently may present with neurological deficits if remains untreated ( 3 ). Case Report A 33-year-old female, previously healthy, developed nausea and intractable vomiting with no apparent relationship with food. No other family member experienced similar symptoms. She has visited multiple doctors, including gastroenterologists. Her blood test reports including a complete blood count (CBC), renal function test (RFT), liver function test (LFT) and serum electrolytes were normal. Abdominal ultrasound and subsequent upper gastrointestinal (GI) endoscopy revealed no abnormalities. She was prescribed with antiemetics, antiulcer drugs and triptans. Her symptoms improved somewhat after approximately two weeks. One month later, her symptoms returned and she experienced a tingling sensation throughout her entire body. Since repeated routine laboratory tests were normal, she had MRI of brain which was normal. In the meantime, her symptoms gradually worsened and she was unable to walk steadily. She developed headache, dizziness, right ear fullness and blurred vision. A 2nd brain MRI was performed 10 days after the previous imaging, unfortunately, a small hyperintense shadow in the dorsal medulla on fluid-attenuated inversion recovery (FLAIR) ( Fig. 1 - A, B) was missed and considered normal. Five days later, she appeared in the neurology outpatient department of our hospital. On examination, her vital signs were normal. However, neurologically, she had a marked vertical and horizontal nystagmus with a fast phase on right lateral gaze, no cranial nerve abnormalities and muscle power was intact with the bilateral planter flexor. However, she exhibited slowed coordination reflexes on the right side including finger-nose test, dysdiadochokinesia and heel-shin test. She also had difficulty with tandem walking. After admission, we decided to repeat noncontrast brain MRI of Brain. This time, a lesion in dorsomedial medulla hyperintense on T2 Flair with hypointense on T1 was found. This lesion had increased in size in the last scan ( Fig. 2 - C, D) . CSF parameters were normal. The CSF was initially negative for AQP4-IgG, however, when AQP4-IgG was tested from the blood a few weeks later, it was positive. MRI spine and visual evoked potentials were normal. She was immediately given 5 doses of intravenous methylprednisolone (IVMP) as 1gm per day for 5 days. After 2 doses of IVMP, her vision improved and nystagmus reduced slightly. By the end of the IVMP doses, vertigo and tingling sensation of her limbs had significantly improved. At the one month follow up visit, her symptoms improved, and no more vertigo or vomiting occured. She can walk unaided. The timeline of patient’s clinical course and diagnostic milestones is shown in Table 1 . Table 1 Timeline of Patient's clinical course and diagnostic milestones Approximate Time (Relative to Initial Presentation) Key Symptoms Initial Investigations/ Findings Initial Diagnosis/ Management Subsequent Progress Neurological Findings Definitive Diagnosis Treatment Out come Day 0 Persistent nausea, intractable vomiting Normal CBC, RFT/ LFT electrolytes; Normal abdominal USG, upper GI endoscopy Symptomatic (anti-emetics, antiulcerants, triptans) Partial relief only for 2 weeks None reported Undetermined Symptomatic Partial relief ~ 1 month later Recurrence of nausea/ vomiting, generalized tingling sensation Repeat labs unremarkable; Brain MRI reported as normal Undetermined Gradual worsening of symptoms None reported Undetermined None reported Worsening ~ 1 month + 10 days Worsening symptoms, unsteadiness, headache, dizziness, right ear fullness, blurred vision Second brain MRI: small FLAIR hyperintensity in dorsal medulla overlooked Undetermined Symptoms continued to worsen None reported Undetermined None reported Worsening ~ 1 month + 15 days Presentation to neurology outpatient department Repeat noncontrast brain MRI: T2-FLAIR hyperintense and T1 hypointense lesion in dorsomedial medulla (increased size); CSF analysis normal; CSF AQP4-IgG negative NMOSD suspected Serum AQP4-IgG confirmed positive a few weeks later; MRI spine & VEPs unremarkable Prominent vertical/horizontal nystagmus (fast phase right lateral gaze); Impaired right-sided coordination (finger-to-nose, dysdiadochokinesia, heel-to-shin); Impaired tandem gait; Preserved cranial nerves/ motor strength/ plantar responses NMOSD with APS High-dose IVMP (5 days) Vision improved, nystagmus lessened after 2 doses; Vertigo, limb paresthesias significantly improved by end of treatment 1 month post treatment Complete resolution of vertigo and vomiting; Independent walking N/A N/A N/A N/A N/A N/A Complete resolution of symptoms, independent ambulation Discussion Historically, the term “neuromyelitis optica (NMO)”, previously known as Devic’s syndrome, was recognized as a neuroinflammatory demyelinating condition manifested as relapsing bilateral optic neuritis and transverse myelitis ( 12 ). The understanding of this condition has evolved significantly, particularly with the discovery in 2005 of specific antibodies targeting the aquaporin-4 (AQP4) water channel (AQP4-IgG) ( 9 ). This breakthrough allowed for a clear distinction between NMO and multiple sclerosis (MS), leading to the development of the 2006 Wingerchuk criteria and subsequently the more comprehensive 2015 International Panel for NMO Diagnosis (IPND) criteria (Table 1 ), which unified NMO and NMOSD under a single term ( 9 ). The pathogenesis of NMOSD involves an autoimmune response targeting aquaporin-4, the most abundant water channel protein in the central nervous system, particularly in astrocytes ( 13 ). AQP4 is highly expressed in the area postrema, which may explain the vulnerability of this region in NMOSD ( 14 ). The binding of AQP4-IgG antibodies to AQP4 leads to complement activation, astrocyte injury, and subsequent inflammation and demyelination ( 13 ). The disorder itself is rare, with a prevalence rate of 0.37-10 per thousand people worldwide ( 15 ). The disease has a female predominance in young and middle aged individuals and has a higher incidence among African and Asian individuals than in white population ( 1 , 16 ). One of the core clinical presentations of NMOSD is APS ( 8 , 9 ). Anatomically, the area postrema (AP) is located in the dorsal medulla, specifically on the floor of the fourth ventricle ( 3 , 7 , 17 ). As a circumventricular organ, the AP possesses a more permeable blood-brain barrier (BBB) than most other brain regions do, characterized by a lack of tight junctions between endothelial cells and the presence of fenestrated capillaries ( 4 , 7 , 13 ). This inherent "leakiness" of the BBB allows for direct entry of pathogenic NMO-IgGs (AQP4-IgG antibodies) into the CNS. Furthermore, the AP is highly enriched with AQP4 water channels, which are the specific targets of these autoantibodies, making it an early and frequent site of immune-mediated attack in NMOSD. Clinically, APS is characterized by unexplained attacks of intractable nausea, vomiting, or hiccups (INVH). These symptoms stem directly from the physiological role of the AP as the chemosensitive vomiting center in the brain, which is responsible for detecting toxins in the blood and initiating emetic responses. Clinical studies have reported that INVH episodes in NMOSD patients can last for an average of 20 days, with some cases extending for up to three months. Due to the unique presentation of AP, patients are frequently evaluated by gastroenterologists before finally presenting to neurologists. An international multicenter study reported that 44 out of 100 patients visited gastroenterologists and underwent extensive workups, including upper gastrointestinal endoscopy and abdominal computed tomography (CT) scan ( 5 ). The diagnostic significance of the APS is substantial. When INVH is accompanied by an MRI lesion in the dorsal medulla, it is considered highly specific for AQP4-seropositive APS ( 6 ). A notable feature of AP lesions is their pathological description as often non-destructive. This non-destructive nature allows for full remission of symptoms after the resolution of inflammation, which contrasts with the more severe, often destructive lesions seen in the spinal cord or optic nerves in patients with NMOSD ( 6 , 7 , 13 ). This suggests that prompt and effective treatment of APS can lead to rapid and complete symptomatic resolution, as observed in the presented case, thereby preventing long-term morbidity specifically associated with the AP lesion, while still emphasizing the critical nature of the acute attack. The diagnosis of NMOSD can be made on the basis of the 2015 International Consensus Diagnostic Criteria, as shown in Table 2 ( 9 ). Table-2: 2015 international consensus diagnostic criteria: If AQP4-antibody status Diagnostic Criteria If AQP4-antibodies are positive the diagnostic criteria are: 1. At least 1 core clinical characteristic 2. Positive test for AQP4-IgG using best-available detection method (cell-based assay strongly recommended) 3. Exclusion of alternative diagnoses However, if AQP4-antibodies are not determined or negative, the diagnostic criteria will be 1. At least two fundamental clinical features occurring as a result of one or more clinical attacks and fulfilling all of the following requirements: a. A minimum of 1 core clinical characteristic should be optic neuritis, acute myelitis with Longitudinally Extensive Transverse Myelitis (LETM), or area postrema syndrome b. Dissemination across space (2 or more distinct clinical characteristics) c. Meeting of additional MRI requirements that may be necessary 2. Negative test for AQP4-IgG using best-available detection method or test unavailable 3. Exclusion of alternative diagnoses Core clinical characteristics include: 1. Optic neuritis 2. Acute myelitis 3. Area postrema syndrome: Episodes of otherwise unexplained hiccups or nausea or vomiting 4. Acute brainstem syndrome 5. Acute diencephalic clinical syndrome with NMOSD characteristic of diencephalic MRI lesions or symptomatic Narcolepsy 6. Symptomatic cerebral syndrome with brain lesions characteristic of NMOSD Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status 1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, or (b) optic nerve MRI with T2-hyperintense lesion of T1-weighted gadolinium-enhancing lesion extending over > 1/2 optic nerve length or involving optic chiasm. 2. Acute myelitis: requires associated intramedullary MRI lesion extending ≥ 3 contiguous segments (LETM) or ≥ 3 contiguous segments of focal spinal cord atrophy in patients with a history compatible with acute myelitis. 3. Corresponding dorsal medulla/area postrema lesions are necessary for area postrema syndrome. 4. Acute brainstem syndrome requires peri ependymal brainstem lesions Our patient fulfilled two of the six core clinical criteria, including area postrema syndrome, and acute brainstem syndrome, with no alternative diagnosis, dissemination in space within a one-month period, unknown AQP4-IgG antibody status initially, and consistent MRI findings, as shown in Figure A,B,C and D. In individuals with a diagnosis of NMO or NMOSD, myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are detected in approximately 10% of all cases, although the result was negative in our patient. Notably, MOG-Ab positivity is considerably higher among patients who are seronegative for aquaporin-4 antibodies (AQP4-Ab), accounting for approximately 32.5% of all AQP4-Ab–negative NMO/NMOSD cases and 41.6% of AQP4-Ab–negative NMOSD cases meeting the 2015 International Consensus Diagnostic Criteria ( 9 , 18 ). The diagnosis of NMOSD can be challenging, especially when APS is the initial symptom. In our patient, the initial CSF AQP4-IgG test was negative, but subsequent testing of blood samples revealed the presence of AQP4-IgG antibodies. This highlights the importance of repeated testing and the potential for false-negative results in CSF ( 12 ). Importantlywhile AQP4-IgG is highly specific for NMOSD, a subset of patients may be seronegative, posing further diagnostic challenges ( 9 ). Prompt diagnosis and treatment are crucial for preventing irreversible neurological damage in patients with NMOSD. In our case, the patient responded well to intravenous methylprednisolone, with significant improvement in her symptoms. Immunosuppressive therapies, such as rituximab, azathioprine, and mycophenolate mofetil, are often used for long-term management to prevent relapses ( 9 ). Conclusion This case adds to the growing body of literature highlighting the importance of recognizing APS as a potential presentation of NMOSD. Clinicians should be aware of this association and consider NMOSD in the differential diagnosis of patients presenting with unexplained nausea, vomiting, or hiccups. Early diagnosis and treatment can significantly improve outcomes and prevent long-term disability. While the incidence and prevalence of NMOSD vary worldwide, heightened awareness of atypical presentations such as isolated APS is crucial for timely and accurate diagnosis. Abbreviations NMOSD- Neuromyelitis optica spectrum disorder NMO- Neuromyelitis optica AP- Area postrema APS- Area postrema syndrome AQP4- Aquaporin-4 AQP4- IgG-Aquaporin-4 immunoglobulin-G MRI- Magnetic Resonance Imaging CSF- Cerebrospinal fluid CNS- central nervous system IPND- International Panel for NMO Diagnosis BBB- Blood brain barrier CBC- Complete blood count RFT- Renal function test LFT- Liver function test GI- Gastrointestinal FLAIR- Fluid-Attenuated Inversion Recovery IVMP -Intravenous Methylprednisolone USG- Ultrasound Sonography VEP- Visual Evoked Potential MS- Multiple Sclerosis INVH- Intractable nausea, vomiting, or hiccups CT- Computed tomography LETM- Longitudinally Extensive Transverse Myelitis MOG-Ab- Myelin oligodendrocyte glycoprotein antibodies Declarations Ethics approval and consent to participate: According to ethical committee of Square Hospitals Ltd. ethical approval is not needed for case reports and case series. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the consent form is available from the corresponding author upon request. Availability of Data & Materials: All the required information is available in the manuscript itself. Competing interests : The authors declare that they have no competing interests Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contributions: HKB and SM drafted and revised the manuscript, RB was responsible for the conception, interpretation and supervision of this study. SNUR interpreted the radiological imaging. All authors read and approved the final manuscript. Acknowledgement: The authors are grateful to the patient for consenting to the publication of his case report. Authors’ Information: Himel Kumar Biswas, Clinical Staff, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected] , https://orcid.org/0000-0001-5548-6165 Rama Biswas, Consultant, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected] , https://orcid.org/0009-0003-2356-0852 Shamah Marzuqah, Specialist, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected] , https://orcid.org/0009-0005-2439-3544 Sheikh Nafis Ur Rahman, Department of Radiology and Imaging, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected] References Liu T, Li L, Guo X, Li Q, Jia D, Ma L. Clinical analysis of neuromyelitis optica spectrum disease with area postrema syndrome as the initial symptom. Eur J Med Res. 2022 Dec 29;27(1):315. Raj A, Valappil AV, Alapatt PJ, Kamar J. Area postrema syndrome: An unusual presentation of neuromyelitis optica spectrum disorder. J Neurosci Rural Pract. 2023;14(2):361–2. Poiasnyk IM, Gryb VA. CLINICAL CASE OF NEUROMYELITIS OPTICA SPECTRUM DISORDERS IN YOUNG WOMAN TREATED WITH RITUXIMAB. Wiadomosci Lek Wars Pol 1960. 2022;75(1):132–7. Majed M, Fryer JP, McKeon A, Lennon VA, Pittock SJ. Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians. Neurol Neuroimmunol Neuroinflammation. 2016 Jun;3(3):e231. Dandu V, Siddamreddy S, Meegada S, Muppidi V, Challa T. Isolated Area Postrema Syndrome Presenting as Intractable Nausea and Vomiting. Cureus. 2020 Feb 20;12(2):e7058. Lana-Peixoto MA, Talim N. Neuromyelitis Optica Spectrum Disorder and Anti-MOG Syndromes. Biomedicines. 2019 Jun 12;7(2):42. Khedr EM, Farweez HM, Abo Elfetoh N, Badawy ER, Hassanein S, Mahmoud DM, et al. Area postrema syndrome in neuromyelitis optica spectrum disorder: diagnostic challenges and descriptive patterns. Egypt J Neurol Psychiatry Neurosurg. 2021 Nov 12;57(1):155. Khan F, Sharma N, Din MU, Aziz M. A Missed Case of Area Postrema Syndrome Presenting with Neuromyelitis Optica Spectrum Disorder. Am J Case Rep. 2022 Jan 20;23:0–0. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177–89. Prabhu K, Woodman M. Area postrema syndrome: Intractable hiccups and vomiting as a result of neuromyelitis Optica Spectrum disorder. JRSM Open. 2023 Apr;14(4):20542704231159601. Mader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019 Jan 27;8(2):90. Alkabie S, Budhram A. Testing for Antibodies Against Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in the Diagnosis of Patients With Suspected Autoimmune Myelopathy. Front Neurol. 2022;13:912050. Lucchinetti CF, Guo Y, Popescu BFG, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol Zurich Switz. 2014 Jan;24(1):83–97. Shosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, et al. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018 Oct 23;91(17):e1642–51. Shrestha R, Kharel G. A case report on recurrent area postrema syndrome in AQP4-IgG-positive NMOSD. Oxf Med Case Rep. 2022 Oct;2022(10):omac109. Papp V, Magyari M, Aktas O, Berger T, Broadley SA, Cabre P, et al. Worldwide Incidence and Prevalence of Neuromyelitis Optica. Neurology. 2021 Jan 12;96(2):59–77. DE Souza TFS. A concise historical perspective of the area postrema structure and function. Arq Neuropsiquiatr. 2020 Feb;78(2):121–3. Li X, Zhang C, Jia D, Fan M, Li T, Tian DC, et al. The occurrence of myelin oligodendrocyte glycoprotein antibodies in aquaporin-4-antibody seronegative Neuromyelitis Optica Spectrum Disorder: A systematic review and meta-analysis. Mult Scler Relat Disord. 2021 Aug 1;53:103030. Additional Declarations No competing interests reported. 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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-7378715","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":501201370,"identity":"11abb606-e7ef-498c-b3e6-9d19d8e39258","order_by":0,"name":"Himel Kumar Biswas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYBACA2Yg8bBBAi4gByIOPCCkJRFJizFYSwI+LQxgLQgBCBufFnN27sQHiTss7A2OH3/AdDPHLn1+2OGHQFvs5HQbsGuxbObdbJB4RiJxw5kcA+bcbcm5G2+nGQC1JBubHcDhsMO82yQS2yQSzA7kMAC1HMjdODsBpOVA4jbcWrb/AGqxNzv//AFIS7rh7PQPhLRsYwBqYdx2IwHksAMJ8tI5BG3ZLAHyy/4bbwwOA/1iuEE6p+BAggEev5w/u/HDxx119pL96Q8f526zk5efnb75w4cKOzlcWlAAWI0BhCRCORzIN5CiehSMglEwCkYCAABAQWcQGvfX3QAAAABJRU5ErkJggg==","orcid":"","institution":"Square Hospitals","correspondingAuthor":true,"prefix":"","firstName":"Himel","middleName":"Kumar","lastName":"Biswas","suffix":""},{"id":501201372,"identity":"a913b0e8-0e95-411f-af46-5397c19afa28","order_by":1,"name":"Rama Biswas","email":"","orcid":"","institution":"Square Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Rama","middleName":"","lastName":"Biswas","suffix":""},{"id":501201374,"identity":"e0ae238b-b47d-4158-8a0b-25d2b367a611","order_by":2,"name":"Shamah Marzuqah","email":"","orcid":"","institution":"Square Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Shamah","middleName":"","lastName":"Marzuqah","suffix":""},{"id":501201377,"identity":"388ef7d6-0997-438c-925a-6cf2184904d8","order_by":3,"name":"Sheikh Nafis-Ur Rahman","email":"","orcid":"","institution":"Square Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Sheikh","middleName":"Nafis-Ur","lastName":"Rahman","suffix":""}],"badges":[],"createdAt":"2025-08-15 06:08:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7378715/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7378715/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89273978,"identity":"c68b72c5-26ab-4344-9a1a-43387e86f14b","added_by":"auto","created_at":"2025-08-18 09:12:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":459832,"visible":true,"origin":"","legend":"\u003cp\u003e(A,B) Hyperintense shadow in dorsal medulla of brainstem on FLAIR (Red Marked)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7378715/v1/71041a6e9a4a6baca91b32c9.png"},{"id":89273982,"identity":"7eb017da-b518-403d-81a1-ece76d37c1e4","added_by":"auto","created_at":"2025-08-18 09:12:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":412888,"visible":true,"origin":"","legend":"\u003cp\u003eC-Enlarged hyperintense shadow in dorsomedial medulla on T2 and D-hypointense on T1. 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Previously, optic nerves and the spinal cord were believed to be the primary affected sites, but in 2015 the International Panel for NMO Diagnosis (IPND) added area postrema, brainstem, diencephalic and cerebral manifestations as part of NMOSD presentation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Unlike multiple sclerosis, NMOSD is strongly associated with serum AQP4-IgG. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Aquaporin-4 is a water channel mostly abundant in the CNS, more specifically, expressed in the astrocytic processes located at the blood brain barrier (BBB) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The spectrum of clinical presentations makes the diagnosis of NMOSD sometimes difficult. One of its rare presentations is the area postrema syndrome. Due to the unique site of inflammation, patients present with unexplained nausea, vomiting and hiccups and subsequently may present with neurological deficits if remains untreated (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 33-year-old female, previously healthy, developed nausea and intractable vomiting with no apparent relationship with food. No other family member experienced similar symptoms. She has visited multiple doctors, including gastroenterologists. Her blood test reports including a complete blood count (CBC), renal function test (RFT), liver function test (LFT) and serum electrolytes were normal. Abdominal ultrasound and subsequent upper gastrointestinal (GI) endoscopy revealed no abnormalities. She was prescribed with antiemetics, antiulcer drugs and triptans. Her symptoms improved somewhat after approximately two weeks.\u003c/p\u003e\u003cp\u003eOne month later, her symptoms returned and she experienced a tingling sensation throughout her entire body. Since repeated routine laboratory tests were normal, she had MRI of brain which was normal. In the meantime, her symptoms gradually worsened and she was unable to walk steadily. She developed headache, dizziness, right ear fullness and blurred vision. A 2nd brain MRI was performed 10 days after the previous imaging, unfortunately, a small hyperintense shadow in the dorsal medulla on fluid-attenuated inversion recovery (FLAIR) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e- A, B)\u003c/b\u003e was missed and considered normal.\u003c/p\u003e\u003cp\u003eFive days later, she appeared in the neurology outpatient department of our hospital. On examination, her vital signs were normal. However, neurologically, she had a marked vertical and horizontal nystagmus with a fast phase on right lateral gaze, no cranial nerve abnormalities and muscle power was intact with the bilateral planter flexor. However, she exhibited slowed coordination reflexes on the right side including finger-nose test, dysdiadochokinesia and heel-shin test. She also had difficulty with tandem walking.\u003c/p\u003e\u003cp\u003eAfter admission, we decided to repeat noncontrast brain MRI of Brain. This time, a lesion in dorsomedial medulla hyperintense on T2 Flair with hypointense on T1 was found. This lesion had increased in size in the last scan \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e- C, D)\u003c/b\u003e. CSF parameters were normal. The CSF was initially negative for AQP4-IgG, however, when AQP4-IgG was tested from the blood a few weeks later, it was positive. MRI spine and visual evoked potentials were normal.\u003c/p\u003e\u003cp\u003eShe was immediately given 5 doses of intravenous methylprednisolone (IVMP) as 1gm per day for 5 days. After 2 doses of IVMP, her vision improved and nystagmus reduced slightly. By the end of the IVMP doses, vertigo and tingling sensation of her limbs had significantly improved.\u003c/p\u003e\u003cp\u003eAt the one month follow up visit, her symptoms improved, and no more vertigo or vomiting occured. She can walk unaided. The timeline of patient\u0026rsquo;s clinical course and diagnostic milestones is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTimeline of Patient's clinical course and diagnostic milestones\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" 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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApproximate Time (Relative to Initial Presentation)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKey Symptoms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eInitial Investigations/\u003c/p\u003e\u003cp\u003eFindings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInitial Diagnosis/ Management\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSubsequent Progress\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNeurological Findings\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDefinitive Diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOut\u003c/p\u003e\u003cp\u003ecome\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDay 0\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePersistent nausea, intractable vomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal CBC, RFT/ LFT electrolytes; Normal abdominal USG, upper GI endoscopy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSymptomatic (anti-emetics,\u003c/p\u003e\u003cp\u003eantiulcerants, triptans)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePartial relief only for 2 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUndetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSymptomatic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePartial relief\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e~\u0026thinsp;1 month later\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecurrence of nausea/ vomiting, generalized tingling sensation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRepeat labs unremarkable; Brain MRI reported as normal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUndetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGradual worsening of symptoms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUndetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNone reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWorsening\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e~\u0026thinsp;1 month\u0026thinsp;+\u0026thinsp;10 days\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWorsening symptoms, unsteadiness, headache, dizziness, right ear fullness, blurred vision\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSecond brain MRI: small FLAIR hyperintensity in dorsal medulla overlooked\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUndetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSymptoms continued to worsen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNone reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUndetermined\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNone reported\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eWorsening\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e~\u0026thinsp;1 month\u0026thinsp;+\u0026thinsp;15 days\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresentation to neurology outpatient department\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRepeat noncontrast brain MRI: T2-FLAIR hyperintense and T1 hypointense lesion in dorsomedial medulla (increased size); CSF analysis normal; CSF AQP4-IgG negative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNMOSD suspected\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSerum AQP4-IgG confirmed positive a few weeks later; MRI spine \u0026amp; VEPs unremarkable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eProminent vertical/horizontal nystagmus (fast phase right lateral gaze); Impaired right-sided coordination (finger-to-nose, dysdiadochokinesia, heel-to-shin); Impaired tandem gait; Preserved cranial nerves/ motor strength/ plantar responses\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNMOSD with APS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHigh-dose IVMP (5 days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eVision improved, nystagmus lessened after 2 doses; Vertigo, limb paresthesias significantly improved by end of treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003e1 month post treatment\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComplete resolution of vertigo and vomiting; Independent walking\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eComplete resolution of symptoms, independent ambulation\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\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHistorically, the term \u0026ldquo;neuromyelitis optica (NMO)\u0026rdquo;, previously known as Devic\u0026rsquo;s syndrome, was recognized as a neuroinflammatory demyelinating condition manifested as relapsing bilateral optic neuritis and transverse myelitis (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The understanding of this condition has evolved significantly, particularly with the discovery in 2005 of specific antibodies targeting the aquaporin-4 (AQP4) water channel (AQP4-IgG) (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). This breakthrough allowed for a clear distinction between NMO and multiple sclerosis (MS), leading to the development of the 2006 Wingerchuk criteria and subsequently the more comprehensive 2015 International Panel for NMO Diagnosis (IPND) criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), which unified NMO and NMOSD under a single term (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The pathogenesis of NMOSD involves an autoimmune response targeting aquaporin-4, the most abundant water channel protein in the central nervous system, particularly in astrocytes (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). AQP4 is highly expressed in the area postrema, which may explain the vulnerability of this region in NMOSD (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The binding of AQP4-IgG antibodies to AQP4 leads to complement activation, astrocyte injury, and subsequent inflammation and demyelination (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The disorder itself is rare, with a prevalence rate of 0.37-10 per thousand people worldwide (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The disease has a female predominance in young and middle aged individuals and has a higher incidence among African and Asian individuals than in white population (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOne of the core clinical presentations of NMOSD is APS (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Anatomically, the area postrema (AP) is located in the dorsal medulla, specifically on the floor of the fourth ventricle (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). As a circumventricular organ, the AP possesses a more permeable blood-brain barrier (BBB) than most other brain regions do, characterized by a lack of tight junctions between endothelial cells and the presence of fenestrated capillaries (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This inherent \"leakiness\" of the BBB allows for direct entry of pathogenic NMO-IgGs (AQP4-IgG antibodies) into the CNS. Furthermore, the AP is highly enriched with AQP4 water channels, which are the specific targets of these autoantibodies, making it an early and frequent site of immune-mediated attack in NMOSD.\u003c/p\u003e\u003cp\u003eClinically, APS is characterized by unexplained attacks of intractable nausea, vomiting, or hiccups (INVH). These symptoms stem directly from the physiological role of the AP as the chemosensitive vomiting center in the brain, which is responsible for detecting toxins in the blood and initiating emetic responses. Clinical studies have reported that INVH episodes in NMOSD patients can last for an average of 20 days, with some cases extending for up to three months. Due to the unique presentation of AP, patients are frequently evaluated by gastroenterologists before finally presenting to neurologists. An international multicenter study reported that 44 out of 100 patients visited gastroenterologists and underwent extensive workups, including upper gastrointestinal endoscopy and abdominal computed tomography (CT) scan (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe diagnostic significance of the APS is substantial. When INVH is accompanied by an MRI lesion in the dorsal medulla, it is considered highly specific for AQP4-seropositive APS (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A notable feature of AP lesions is their pathological description as often non-destructive. This non-destructive nature allows for full remission of symptoms after the resolution of inflammation, which contrasts with the more severe, often destructive lesions seen in the spinal cord or optic nerves in patients with NMOSD (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This suggests that prompt and effective treatment of APS can lead to rapid and complete symptomatic resolution, as observed in the presented case, thereby preventing long-term morbidity specifically associated with the AP lesion, while still emphasizing the critical nature of the acute attack.\u003c/p\u003e\u003cp\u003eThe diagnosis of NMOSD can be made on the basis of the 2015 International Consensus Diagnostic Criteria, as shown in Table\u0026nbsp;2 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTable-2: 2015 international consensus diagnostic criteria:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIf AQP4-antibody status\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiagnostic Criteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIf AQP4-antibodies are positive the diagnostic criteria are:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1. At least 1 core clinical characteristic\u003c/p\u003e\u003cp\u003e2. Positive test for AQP4-IgG using best-available detection method (cell-based assay strongly recommended)\u003c/p\u003e\u003cp\u003e3. Exclusion of alternative diagnoses\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHowever, if AQP4-antibodies are not determined or negative, the diagnostic criteria will be\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1. At least two fundamental clinical features occurring as a result of one or more clinical attacks and fulfilling all of the following requirements:\u003c/p\u003e\u003cp\u003ea. A minimum of 1 core clinical characteristic should be optic neuritis, acute myelitis with Longitudinally Extensive Transverse Myelitis (LETM), or area postrema syndrome\u003c/p\u003e\u003cp\u003eb. Dissemination across space (2 or more distinct clinical characteristics)\u003c/p\u003e\u003cp\u003ec. Meeting of additional MRI requirements that may be necessary\u003c/p\u003e\u003cp\u003e2. Negative test for AQP4-IgG using best-available detection method or test unavailable\u003c/p\u003e\u003cp\u003e3. Exclusion of alternative diagnoses\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCore clinical characteristics include:\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1. Optic neuritis\u003c/p\u003e\u003cp\u003e2. Acute myelitis\u003c/p\u003e\u003cp\u003e3. Area postrema syndrome: Episodes of otherwise unexplained hiccups or nausea or vomiting\u003c/p\u003e\u003cp\u003e4. Acute brainstem syndrome\u003c/p\u003e\u003cp\u003e5. Acute diencephalic clinical syndrome with NMOSD characteristic of diencephalic MRI lesions or symptomatic Narcolepsy\u003c/p\u003e\u003cp\u003e6. Symptomatic cerebral syndrome with brain lesions characteristic of NMOSD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdditional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, or (b) optic nerve MRI with T2-hyperintense lesion of T1-weighted gadolinium-enhancing lesion extending over \u0026gt;\u0026thinsp;1/2 optic nerve length or involving optic chiasm.\u003c/p\u003e\u003cp\u003e2. Acute myelitis: requires associated intramedullary MRI lesion extending\u0026thinsp;\u0026ge;\u0026thinsp;3 contiguous segments (LETM) or \u0026ge;\u0026thinsp;3 contiguous segments of focal spinal cord atrophy in patients with a history compatible with acute myelitis.\u003c/p\u003e\u003cp\u003e3. Corresponding dorsal medulla/area postrema lesions are necessary for area postrema syndrome.\u003c/p\u003e\u003cp\u003e4. Acute brainstem syndrome requires peri ependymal brainstem lesions\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\u003eOur patient fulfilled two of the six core clinical criteria, including area postrema syndrome, and acute brainstem syndrome, with no alternative diagnosis, dissemination in space within a one-month period, unknown AQP4-IgG antibody status initially, and consistent MRI findings, as shown in \u003cb\u003eFigure A,B,C and D.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn individuals with a diagnosis of NMO or NMOSD, myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) are detected in approximately 10% of all cases, although the result was negative in our patient. Notably, MOG-Ab positivity is considerably higher among patients who are seronegative for aquaporin-4 antibodies (AQP4-Ab), accounting for approximately 32.5% of all AQP4-Ab\u0026ndash;negative NMO/NMOSD cases and 41.6% of AQP4-Ab\u0026ndash;negative NMOSD cases meeting the 2015 International Consensus Diagnostic Criteria (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe diagnosis of NMOSD can be challenging, especially when APS is the initial symptom. In our patient, the initial CSF AQP4-IgG test was negative, but subsequent testing of blood samples revealed the presence of AQP4-IgG antibodies. This highlights the importance of repeated testing and the potential for false-negative results in CSF (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Importantlywhile AQP4-IgG is highly specific for NMOSD, a subset of patients may be seronegative, posing further diagnostic challenges (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePrompt diagnosis and treatment are crucial for preventing irreversible neurological damage in patients with NMOSD. In our case, the patient responded well to intravenous methylprednisolone, with significant improvement in her symptoms. Immunosuppressive therapies, such as rituximab, azathioprine, and mycophenolate mofetil, are often used for long-term management to prevent relapses (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case adds to the growing body of literature highlighting the importance of recognizing APS as a potential presentation of NMOSD. Clinicians should be aware of this association and consider NMOSD in the differential diagnosis of patients presenting with unexplained nausea, vomiting, or hiccups. Early diagnosis and treatment can significantly improve outcomes and prevent long-term disability. While the incidence and prevalence of NMOSD vary worldwide, heightened awareness of atypical presentations such as isolated APS is crucial for timely and accurate diagnosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNMOSD- Neuromyelitis optica spectrum disorder\u003c/p\u003e\n\u003cp\u003eNMO- Neuromyelitis optica\u003c/p\u003e\n\u003cp\u003eAP- Area postrema\u003c/p\u003e\n\u003cp\u003eAPS- Area postrema syndrome\u003c/p\u003e\n\u003cp\u003eAQP4- Aquaporin-4\u003c/p\u003e\n\u003cp\u003eAQP4- IgG-Aquaporin-4 immunoglobulin-G\u003c/p\u003e\n\u003cp\u003eMRI- Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003eCSF- Cerebrospinal fluid\u003c/p\u003e\n\u003cp\u003eCNS- central nervous system\u003c/p\u003e\n\u003cp\u003eIPND- International Panel for NMO Diagnosis\u003c/p\u003e\n\u003cp\u003eBBB- Blood brain barrier\u003c/p\u003e\n\u003cp\u003eCBC- Complete blood count\u003c/p\u003e\n\u003cp\u003eRFT- Renal function test\u003c/p\u003e\n\u003cp\u003eLFT- Liver function test\u003c/p\u003e\n\u003cp\u003eGI- Gastrointestinal\u003c/p\u003e\n\u003cp\u003eFLAIR- Fluid-Attenuated Inversion Recovery\u003c/p\u003e\n\u003cp\u003eIVMP -Intravenous Methylprednisolone\u003c/p\u003e\n\u003cp\u003eUSG- Ultrasound Sonography\u003c/p\u003e\n\u003cp\u003eVEP- Visual Evoked Potential\u003c/p\u003e\n\u003cp\u003eMS- Multiple Sclerosis\u003c/p\u003e\n\u003cp\u003eINVH- Intractable nausea, vomiting, or hiccups\u003c/p\u003e\n\u003cp\u003eCT- Computed tomography\u003c/p\u003e\n\u003cp\u003eLETM- Longitudinally Extensive Transverse Myelitis\u003c/p\u003e\n\u003cp\u003eMOG-Ab- Myelin oligodendrocyte glycoprotein antibodies\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eAccording to ethical committee of Square Hospitals Ltd. ethical approval is not needed for case reports and case series.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the consent form is available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data \u0026amp; Materials:\u0026nbsp;\u003c/strong\u003eAll the required information is available in the manuscript itself.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHKB and SM drafted and revised the manuscript, RB was responsible for the conception, interpretation and supervision of this study. SNUR interpreted the radiological imaging. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eThe authors are grateful to the patient for consenting to the publication of his case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Information:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eHimel Kumar Biswas, Clinical Staff, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected], https://orcid.org/0000-0001-5548-6165\u003c/li\u003e\n \u003cli\u003eRama Biswas, Consultant, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected], https://orcid.org/0009-0003-2356-0852\u003c/li\u003e\n \u003cli\u003eShamah Marzuqah, Specialist, Department of Neurology, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected], https://orcid.org/0009-0005-2439-3544\u003c/li\u003e\n \u003cli\u003eSheikh Nafis Ur Rahman, Department of Radiology and Imaging, Square Hospitals Ltd., Dhaka, Bangladesh, Email: [email protected]\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLiu T, Li L, Guo X, Li Q, Jia D, Ma L. Clinical analysis of neuromyelitis optica spectrum disease with area postrema syndrome as the initial symptom. Eur J Med Res. 2022 Dec 29;27(1):315. \u003c/li\u003e\n\u003cli\u003eRaj A, Valappil AV, Alapatt PJ, Kamar J. Area postrema syndrome: An unusual presentation of neuromyelitis optica spectrum disorder. J Neurosci Rural Pract. 2023;14(2):361\u0026ndash;2. \u003c/li\u003e\n\u003cli\u003ePoiasnyk IM, Gryb VA. CLINICAL CASE OF NEUROMYELITIS OPTICA SPECTRUM DISORDERS IN YOUNG WOMAN TREATED WITH RITUXIMAB. Wiadomosci Lek Wars Pol 1960. 2022;75(1):132\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eMajed M, Fryer JP, McKeon A, Lennon VA, Pittock SJ. Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians. Neurol Neuroimmunol Neuroinflammation. 2016 Jun;3(3):e231. \u003c/li\u003e\n\u003cli\u003eDandu V, Siddamreddy S, Meegada S, Muppidi V, Challa T. Isolated Area Postrema Syndrome Presenting as Intractable Nausea and Vomiting. Cureus. 2020 Feb 20;12(2):e7058. \u003c/li\u003e\n\u003cli\u003eLana-Peixoto MA, Talim N. Neuromyelitis Optica Spectrum Disorder and Anti-MOG Syndromes. Biomedicines. 2019 Jun 12;7(2):42. \u003c/li\u003e\n\u003cli\u003eKhedr EM, Farweez HM, Abo Elfetoh N, Badawy ER, Hassanein S, Mahmoud DM, et al. Area postrema syndrome in neuromyelitis optica spectrum disorder: diagnostic challenges and descriptive patterns. Egypt J Neurol Psychiatry Neurosurg. 2021 Nov 12;57(1):155. \u003c/li\u003e\n\u003cli\u003eKhan F, Sharma N, Din MU, Aziz M. A Missed Case of Area Postrema Syndrome Presenting with Neuromyelitis Optica Spectrum Disorder. Am J Case Rep. 2022 Jan 20;23:0\u0026ndash;0. \u003c/li\u003e\n\u003cli\u003eWingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177\u0026ndash;89. \u003c/li\u003e\n\u003cli\u003ePrabhu K, Woodman M. Area postrema syndrome: Intractable hiccups and vomiting as a result of neuromyelitis Optica Spectrum disorder. JRSM Open. 2023 Apr;14(4):20542704231159601. \u003c/li\u003e\n\u003cli\u003eMader S, Brimberg L. Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells. 2019 Jan 27;8(2):90. \u003c/li\u003e\n\u003cli\u003eAlkabie S, Budhram A. Testing for Antibodies Against Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in the Diagnosis of Patients With Suspected Autoimmune Myelopathy. Front Neurol. 2022;13:912050. \u003c/li\u003e\n\u003cli\u003eLucchinetti CF, Guo Y, Popescu BFG, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol Zurich Switz. 2014 Jan;24(1):83\u0026ndash;97. \u003c/li\u003e\n\u003cli\u003eShosha E, Dubey D, Palace J, Nakashima I, Jacob A, Fujihara K, et al. Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018 Oct 23;91(17):e1642\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eShrestha R, Kharel G. A case report on recurrent area postrema syndrome in AQP4-IgG-positive NMOSD. Oxf Med Case Rep. 2022 Oct;2022(10):omac109. \u003c/li\u003e\n\u003cli\u003ePapp V, Magyari M, Aktas O, Berger T, Broadley SA, Cabre P, et al. Worldwide Incidence and Prevalence of Neuromyelitis Optica. Neurology. 2021 Jan 12;96(2):59\u0026ndash;77. \u003c/li\u003e\n\u003cli\u003eDE Souza TFS. A concise historical perspective of the area postrema structure and function. Arq Neuropsiquiatr. 2020 Feb;78(2):121\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eLi X, Zhang C, Jia D, Fan M, Li T, Tian DC, et al. The occurrence of myelin oligodendrocyte glycoprotein antibodies in aquaporin-4-antibody seronegative Neuromyelitis Optica Spectrum Disorder: A systematic review and meta-analysis. Mult Scler Relat Disord. 2021 Aug 1;53:103030.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neuromyelitis optica, Neuromyelitis optica spectrum disorders, Area postrema syndrome","lastPublishedDoi":"10.21203/rs.3.rs-7378715/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7378715/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eNeuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathic disease of the central nervous system. It typically involves the optic nerves, spinal cord, and brainstem, but can also manifest atypically. Area postrema syndrome (APS), a recognized core clinical manifestation of NMOSD, is characterized by intractable nausea, vomiting, or hiccups. When APS presents in isolation, diagnosis can be challenging, as symptoms are frequently attributed to gastrointestinal disorders, leading to delays in appropriate management. Recognition relies on characteristic neuroimaging findings and the detection of serum aquaporin-4 immunoglobulin G (AQP4-IgG), after the exclusion of alternative causes.\u003c/p\u003e\u003ch2\u003eCase Report:\u003c/h2\u003e\u003cp\u003eThe reported case highlights area postrema syndrome as an uncommon initial presentation of neuromyelitis optica spectrum disorder in a 33-year-old female. The patient presented with intractable nausea and vomiting, which initially led to extensive investigations of gastrointestinal etiologies. The subsequent development of neurological symptoms, including nystagmus, ataxia and a characteristic lesion in the dorsal medulla on magnetic resonance imaging (MRI), ultimately led to the diagnosis of NMOSD. This case, underscores the importance of considering NMOSD in patients presenting with otherwise unexplained APS, even in the absence of typical findings such as optic neuritis or transverse myelitis. Although cerebrospinal fluid (CSF) analysis was normal and the initial CSF test for Aquaporin-4-IgG (AQP4-IgG) was negative, a subsequent blood test for the same antibody returned positive. This confirmed the diagnosis of Neuromyelitis Optica Spectrum Disorder (NMOSD). Immediate treatment with intravenous methylprednisolone led to significant clinical improvement. At the one-month follow-up, she was symptom-free and ambulating independently.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003ePhysicians in developing countries need to be more aware of the rare disease NMOSD. This case shows that a high level of suspicion is crucial for a quick diagnosis and to prevent treatment delays.\u003c/p\u003e","manuscriptTitle":"Beyond Classics: Area Postrema Syndrome as a Rare Presentation of Neuromyelitis Optica Spectrum Disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-18 09:12:06","doi":"10.21203/rs.3.rs-7378715/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-11-01T07:30:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-25T16:28:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-24T03:14:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-20T14:54:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-20T04:22:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219981631527760217065920046765387950188","date":"2025-10-19T23:15:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62795016185769167477141075382388203761","date":"2025-10-19T20:56:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-19T14:49:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-19T03:48:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80262428235160667181083139260610252553","date":"2025-10-18T15:54:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36458785580803110895151066230084401548","date":"2025-10-18T15:18:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"302616047910137819321275374727576017934","date":"2025-10-18T14:40:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259757178684181449373956612579329746318","date":"2025-10-18T12:56:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5065359710930998233136123860579456715","date":"2025-10-18T10:02:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27408154902478502986100936269859728948","date":"2025-10-18T08:25:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-18T08:20:06+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-19T12:04:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-17T23:57:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-17T23:57:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-08-15T05:55:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"15ad7a9f-b136-4a13-ba7c-a01ad0cf4d7c","owner":[],"postedDate":"August 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-10-18T08:23:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-18 09:12:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7378715","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7378715","identity":"rs-7378715","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}