Diagnostic and Therapeutic Challenges in Anti-NMDA Receptor Encephalitis Associated with an Ovarian Immature Teratoma

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Doudin, Raghad A. Lahlouh, Ola Omarya, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8590281/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 May, 2026 Read the published version in BMC Neurology → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by antibodies against the NR1 subunit of the NMDA receptor. It predominantly affects young women and is frequently associated with ovarian teratomas. Early recognition, tumor removal, and immunotherapy are critical for favorable outcomes. Case Presentation: We report a 33-year-old woman with subacute headache, low-grade fever, generalized weakness, and mood disturbances, who developed generalized tonic–clonic seizures and cognitive impairment. Brain MRI and CSF were initially normal, and EEG showed diffuse slowing without epileptiform discharges. Pelvic imaging revealed a large right ovarian mass. She was treated with corticosteroids, plasmapheresis, and ultimately rituximab, alongside right salpingo-oophorectomy. Histopathology confirmed an immature teratoma. Anti-NMDAR antibodies were later detected in CSF, confirming the diagnosis. Following tumor removal and immunotherapy, she achieved complete neurological recovery and remained seizure-free at six months. Conclusion: This case highlights the diagnostic challenges of anti-NMDAR encephalitis, particularly when MRI and CSF are normal. Early tumor detection and removal, combined with prompt escalation to second-line immunotherapy when needed, are essential for favorable outcomes. Immature ovarian teratomas, although rare, can trigger severe disease and warrant careful evaluation in adult women presenting with acute neuropsychiatric symptoms. Autoimmune encephalitis Anti-NMDA receptor encephalitis Ovarian teratoma Immature teratoma Paraneoplastic neurologic disorder Introduction Limbic encephalitis is an inflammatory disorder of the limbic system that can be either paraneoplastic, often associated with malignancies and poor prognosis, or autoimmune, mediated by antibodies such as anti–N-methyl-D-aspartate receptor (anti-NMDAR) or anti–leucine-rich glioma-inactivated 1 (anti-LGI1) ( 1 ). Unlike paraneoplastic cases, autoimmune forms are less frequently cancer-related and generally respond well to immunotherapy ( 1 ) ( 2 ) Diagnosis relies on clinical suspicion supported by neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, and detection of autoantibodies in serum or CSF ( 2 ). Autoimmune encephalitis often begins with nonspecific prodromal symptoms—including fever, malaise, and headache—followed by acute neurological manifestations such as seizures, confusion, and psychiatric disturbances. These neuropsychiatric symptoms are typically abrupt in onset and differ from primary psychiatric disorders ( 1 ), ( 3 ) Anti-NMDAR encephalitis primarily affects children and young adults, with a mean age of 21 years and a strong female predominance (female-to-male ratio 4:1). Up to 58% of affected women have an associated ovarian teratoma ( 3 ). Brain MRI is normal in approximately 30% of cases, while EEG often demonstrates nonspecific diffuse slowing. CSF findings may range from mild lymphocytic pleocytosis to normal parameters. Confirmation of diagnosis is achieved by detection of anti-NMDAR antibodies, with CSF testing being more sensitive than serum ( 3 ). Once autoimmune encephalitis is suspected, early tumor screening is crucial ( 4 ). Pelvic ultrasound, MRI, or whole-body CT can identify an ovarian teratoma, which is present in over half of adult women with anti-NMDAR encephalitis ( 2 ) We report a challenging case of anti-NMDAR encephalitis associated with an ovarian immature teratoma, highlighting the diagnostic pitfalls, therapeutic strategy, and importance of early tumor detection. Case Presentation Clinical Presentation A 33-year-old previously healthy woman with no significant medical or psychiatric history presented with a subacute onset of headache, low-grade fever, generalized weakness, and behavioral changes characterized by mood disturbances. Within days of symptom onset, she developed a generalized tonic–clonic seizure associated with frothing at the mouth. There was no history of substance use, recent infection, or prior neuropsychiatric illness. She was initially evaluated by an outside neurologist and treated with levetiracetam (1,000 mg twice daily), lamotrigine (25 mg daily), and valproate (500 mg twice daily). Despite this regimen, she continued to experience recurrent seizures and progressive cognitive decline, prompting admission to our tertiary care center for further evaluation. On admission, the patient was hemodynamically stable and afebrile. Neurological examination revealed global aphasia, marked cognitive impairment, poor eye contact, and reduced responsiveness. Cranial nerve examination was unremarkable. Motor strength was preserved, deep tendon reflexes were normal, and plantar responses were bilaterally flexor. There were no signs of meningeal irritation. Antiseizure therapy was intensified to levetiracetam (1,500 mg twice daily), lamotrigine (25 mg daily), valproate (500 mg twice daily), and lacosamide (50 mg twice daily). Investigations Brain magnetic resonance imaging (MRI) showed no focal lesions or abnormalities on T2-weighted or FLAIR sequences. Cerebrospinal fluid (CSF) analysis demonstrated normal opening pressure, normal white blood cell count, and normal protein and glucose levels. Gram stain and bacterial cultures were negative. Electroencephalography (EEG) revealed diffuse background slowing without epileptiform discharges, consistent with an encephalopathic process. Empiric antimicrobial therapy was discontinued after infectious etiologies were excluded. Given the absence of structural, metabolic, or infectious causes, autoimmune encephalitis was strongly suspected. CSF and serum samples were sent for autoimmune and paraneoplastic antibody panels, and tumor marker evaluation was initiated. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis revealed a large right ovarian mass measuring 18 × 9.4 × 17.5 cm. The lesion was septated and cystic, containing areas of fat and calcification, radiologically suggestive of an ovarian teratoma. Treatment and Hospital Course High-dose intravenous methylprednisolone (1 g daily for 5 consecutive days) was initiated on hospital day 3. Due to minimal clinical improvement, therapeutic plasmapheresis was commenced on day 10. During her hospital course, the patient developed episodes of severe agitation and autonomic instability and required short-term endotracheal intubation for airway protection. Behavioral symptoms were managed with short-term antipsychotic therapy, including haloperidol (administered for 2 days), risperidone (1 mg twice daily), quetiapine (200 mg twice daily), and clonazepam (1 mg three times daily). These agents were gradually tapered as her mental status improved. In view of the ovarian mass, the patient underwent a right salpingo-oophorectomy. Histopathological examination confirmed an immature ovarian teratoma (FIGO stage IA, grade II). Following multidisciplinary discussion, adjuvant chemotherapy with the EP regimen (etoposide and cisplatin) was initiated in accordance with oncology guidelines. After tumor resection, the patient demonstrated gradual neurological improvement, including increased alertness, reduced agitation, and partial recovery of spontaneous speech. However, a transient clinical deterioration prompted resumption of plasmapheresis and initiation of rituximab therapy (375 mg/m², administered in two doses two weeks apart). This resulted in marked and rapid improvement in cognitive function, orientation, and language abilities. Subsequently, CSF testing returned positive for anti–N-methyl-D-aspartate receptor (anti-NMDAR) antibodies, confirming the diagnosis of anti-NMDAR encephalitis. By the time of discharge, the patient was fully oriented, seizure-free, and independent in activities of daily living. At six-month follow-up, she remained neurologically stable without seizure recurrence or neuropsychiatric relapse. Discussion Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by antibodies against the NR1 subunit of the NMDA receptor, leading to a constellation of neuropsychiatric symptoms, seizures, and autonomic dysfunction ( 2 , 3 ). The disorder predominantly affects children and young adults, with a strong female predominance, and is frequently associated with ovarian teratomas ( 3 , 5 ) Our patient presented with the prototypical features of anti-NMDAR encephalitis, including acute-onset seizures, cognitive impairment, behavioral disturbances, and transient aphasia. However, diagnosis was challenging due to normal brain MRI and unremarkable cerebrospinal fluid (CSF) findings, highlighting a well-recognized limitation: imaging and routine CSF studies can be normal in a substantial proportion of cases. EEG revealed nonspecific diffuse slowing, consistent with previously reported patterns in autoimmune encephalitis( 3 ) The detection of a large right ovarian mass was crucial in establishing the paraneoplastic nature of her illness. Ovarian teratomas are identified in over half of adult women with anti-NMDAR encephalitis, most commonly as mature cystic teratomas (2( 3 ). Our case was notable for an immature ovarian teratoma, a rare entity that may harbor a higher antigenic load due to the presence of primitive neural tissue; although ovarian teratomas are well-recognized triggers of anti-NMDA receptor encephalitis, the occurrence of this syndrome in association with an immature teratoma is uncommon, with only a few cases reported in the literature( 6 ). potentially explaining the patient’s severe presentation and delayed response to first-line therapy ( 7 ) Management of anti-NMDAR encephalitis relies on a combination of tumor removal and immunotherapy. In our patient, neurological recovery improved after removing the Teratoma supporting evidence that early tumor resection in anti‑NMDA receptor encephalitis helps patients recover faster and lowers the risk of relapse( 4 ). Regarding to immunotherapy First-line therapy typically consists of corticosteroids, intravenous immunoglobulin, or plasma exchange ( 2 ),( 3 ). In patients with incomplete response, second-line therapies such as rituximab or cyclophosphamide are recommended and are associated with improved outcomes and reduced relapse risk ( 2 ),( 3 ). In our patient, escalation to rituximab as second-line therapy, following incomplete response to corticosteroids and plasmapheresis, was associated with rapid neurological recovery, consistent with multicenter data showing that rituximab effectively reduces relapse risk and prolongs time to first relapse in anti-NMDAR encephalitis( 8 ). In our patient, initial corticosteroids and plasmapheresis produced modest improvement; however, escalation to rituximab following tumor resection resulted in dramatic neurological recovery, consistent with the current literature. Prognosis is generally favorable when early tumor removal is combined with prompt immunotherapy, with approximately 80% of patients achieving substantial recovery ( 3 ),( 7 ). Delayed diagnosis or failure to identify and remove the tumor is associated with poorer outcomes, prolonged hospitalization, and increased risk of relapse, which occurs in 12–25% of cases, particularly when immunotherapy is incomplete or the tumor remains unresected ( 3 , 7 ). Our patient remained neurologically stable and seizure-free at six months follow-up, illustrating the importance of timely recognition, aggressive immunotherapy, and early tumor management. This case underscores several key clinical lessons: the need for high clinical suspicion of autoimmune encephalitis despite normal imaging and CSF; the importance of comprehensive tumor screening in adult women presenting with new-onset neuropsychiatric symptoms; and the role of second-line immunotherapy in patients with severe or refractory disease. Additionally, it highlights that immature ovarian teratomas, though uncommon, can serve as a potent antigenic source, reinforcing the necessity of individualized, multidisciplinary management strategies. Declarations Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Patient Consent Statement: Written informed consent was obtained from the patient for publication of this case report and accompanying clinical details. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request. Conflict of Interest The authors declare no conflicts of interest. Funding No external funding was received. Author Contribution M.D. conceived and designed the study, collected clinical data, drafted the initial manuscript, and revised the final version. R.A.L. (Ragad A. Lahlouh) supervised the project, contributed to the discussion and conclusions, and critically revised the manuscript for important intellectual content. S.M.D. (Sherehan M. Doudin) assisted with data collection, performed the literature review, and drafted the clinical course section. O.O. (Ola Omarya) provided histopathological analysis and contributed to interpretation of findings, and reviewed the manuscript. A.I. (Ahmed Ismael) participated in clinical management, interpretation of findings, and revised the manuscript. All authors have read and approved the final submitted version and agree to be accountable for all aspects of the work.M.D. (Mahmoud Doudein) R.A.L. (Ragad A. Lahlouh) S.M.D. (Sherehan M. Doudin)A.I. (Ahmed Ismael)O.O. (Ola Omarya) Acknowledgement The authors would like to thank the medical and nursing staff at Istishari Arab Hospital for their support in patient care. We also acknowledge the patient and her family for their cooperation and consent to share clinical information for educational purposes. No funding was received for this study. Data Availability All data generated during this case study are included in this published article. Additional clinical details are available from the corresponding author upon reasonable request. References Samanta D, Lui F. Anti-NMDAR Encephalitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2026 Jan 3]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK551672/ Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391–404. Antibody-Mediated Encephalitis. | New England Journal of Medicine [Internet]. [cited 2026 Jan 3]. Available from: https://www.nejm.org/doi/ 10.1056/NEJMra1708712 Zhang H, Xiong W, Liu X, Liu W, Zhou D, Wu X. Long-Term Prognosis of Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis Who Underwent Teratoma Removal: An Observational Study. Front Neurol. 2022;13:874867. Day GS, Laiq S, Tang-Wai DF, Munoz DG. Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol. 2014 June;71(6):717–24. Imataka G, Yoshihara S. Immature ovarian teratoma with anti-NMDA-receptor encephalitis in a 13-year-old Japanese female patient. Med J Malaysia. 2021;76(3):436–7. Khatrawi EM, Prajjwal P, Marsool MDM, Das A, Nagre A, Inban P, et al. A case report of anti-NMDA receptor encephalitis in a 23-year-old female with acute psychiatric symptoms. Clin Case Rep. 2024;12(5):e8870. Seery N, Wesselingh R, Beech P, McLaughlin L, Rushen T, Halliday AJ, et al. Rituximab Use for Relapse Prevention in Anti-NMDAR Antibody-Mediated Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200395. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 01 May, 2026 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 20 Jan, 2026 Editor assigned by journal 14 Jan, 2026 Submission checks completed at journal 14 Jan, 2026 First submitted to journal 13 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8590281","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":573813256,"identity":"ced1476b-f87f-4451-a9f4-d8c987be6335","order_by":0,"name":"Mahmoud Doudein","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYDCCAwwGICoBREh8gDKI1yI5g2Qt0jzEaOE73rzxcWGOXZ5ue4/hbds2uzx+9gbGDx9zcGuRPHOs2HjmtuRiszNnjK1z25KLJXsOMEvO3IZbi8GNHDNp3m3MidtAjNw25sQNNxLYmHnxazH/zbutHqLFsq2eKC1mQAWHIVoY2w4T1gLyC9BhxxO3ARmWPeeOJ87sOdiM1y+gEPvMu606cRuQceNHWXViP3vzwQ8f8WhBBYxsYLKBWPUg8IcUxaNgFIyCUTBSAACRsVmFevbDLQAAAABJRU5ErkJggg==","orcid":"","institution":"Istishari Arab Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mahmoud","middleName":"","lastName":"Doudein","suffix":""},{"id":573813257,"identity":"69a067b0-59f2-4e56-8adb-37bd7d9a7178","order_by":1,"name":"Sherehan M. 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Unlike paraneoplastic cases, autoimmune forms are less frequently cancer-related and generally respond well to immunotherapy (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eDiagnosis relies on clinical suspicion supported by neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, and detection of autoantibodies in serum or CSF (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Autoimmune encephalitis often begins with nonspecific prodromal symptoms\u0026mdash;including fever, malaise, and headache\u0026mdash;followed by acute neurological manifestations such as seizures, confusion, and psychiatric disturbances. These neuropsychiatric symptoms are typically abrupt in onset and differ from primary psychiatric disorders (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAnti-NMDAR encephalitis primarily affects children and young adults, with a mean age of 21 years and a strong female predominance (female-to-male ratio 4:1). Up to 58% of affected women have an associated ovarian teratoma (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Brain MRI is normal in approximately 30% of cases, while EEG often demonstrates nonspecific diffuse slowing. CSF findings may range from mild lymphocytic pleocytosis to normal parameters. Confirmation of diagnosis is achieved by detection of anti-NMDAR antibodies, with CSF testing being more sensitive than serum (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOnce autoimmune encephalitis is suspected, early tumor screening is crucial (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Pelvic ultrasound, MRI, or whole-body CT can identify an ovarian teratoma, which is present in over half of adult women with anti-NMDAR encephalitis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eWe report a challenging case of anti-NMDAR encephalitis associated with an ovarian immature teratoma, highlighting the diagnostic pitfalls, therapeutic strategy, and importance of early tumor detection.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eClinical Presentation\u003c/h2\u003e \u003cp\u003eA 33-year-old previously healthy woman with no significant medical or psychiatric history presented with a subacute onset of headache, low-grade fever, generalized weakness, and behavioral changes characterized by mood disturbances. Within days of symptom onset, she developed a generalized tonic\u0026ndash;clonic seizure associated with frothing at the mouth. There was no history of substance use, recent infection, or prior neuropsychiatric illness.\u003c/p\u003e \u003cp\u003eShe was initially evaluated by an outside neurologist and treated with levetiracetam (1,000 mg twice daily), lamotrigine (25 mg daily), and valproate (500 mg twice daily). Despite this regimen, she continued to experience recurrent seizures and progressive cognitive decline, prompting admission to our tertiary care center for further evaluation.\u003c/p\u003e \u003cp\u003eOn admission, the patient was hemodynamically stable and afebrile. Neurological examination revealed global aphasia, marked cognitive impairment, poor eye contact, and reduced responsiveness. Cranial nerve examination was unremarkable. Motor strength was preserved, deep tendon reflexes were normal, and plantar responses were bilaterally flexor. There were no signs of meningeal irritation. Antiseizure therapy was intensified to levetiracetam (1,500 mg twice daily), lamotrigine (25 mg daily), valproate (500 mg twice daily), and lacosamide (50 mg twice daily).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInvestigations\u003c/h3\u003e\n\u003cp\u003eBrain magnetic resonance imaging (MRI) showed no focal lesions or abnormalities on T2-weighted or FLAIR sequences. Cerebrospinal fluid (CSF) analysis demonstrated normal opening pressure, normal white blood cell count, and normal protein and glucose levels. Gram stain and bacterial cultures were negative. Electroencephalography (EEG) revealed diffuse background slowing without epileptiform discharges, consistent with an encephalopathic process. Empiric antimicrobial therapy was discontinued after infectious etiologies were excluded.\u003c/p\u003e \u003cp\u003eGiven the absence of structural, metabolic, or infectious causes, autoimmune encephalitis was strongly suspected. CSF and serum samples were sent for autoimmune and paraneoplastic antibody panels, and tumor marker evaluation was initiated. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis revealed a large right ovarian mass measuring 18 \u0026times; 9.4 \u0026times; 17.5 cm. The lesion was septated and cystic, containing areas of fat and calcification, radiologically suggestive of an ovarian teratoma.\u003c/p\u003e\n\u003ch3\u003eTreatment and Hospital Course\u003c/h3\u003e\n\u003cp\u003eHigh-dose intravenous methylprednisolone (1 g daily for 5 consecutive days) was initiated on hospital day 3. Due to minimal clinical improvement, therapeutic plasmapheresis was commenced on day 10. During her hospital course, the patient developed episodes of severe agitation and autonomic instability and required short-term endotracheal intubation for airway protection.\u003c/p\u003e \u003cp\u003eBehavioral symptoms were managed with short-term antipsychotic therapy, including haloperidol (administered for 2 days), risperidone (1 mg twice daily), quetiapine (200 mg twice daily), and clonazepam (1 mg three times daily). These agents were gradually tapered as her mental status improved.\u003c/p\u003e \u003cp\u003eIn view of the ovarian mass, the patient underwent a right salpingo-oophorectomy. Histopathological examination confirmed an immature ovarian teratoma (FIGO stage IA, grade II). Following multidisciplinary discussion, adjuvant chemotherapy with the EP regimen (etoposide and cisplatin) was initiated in accordance with oncology guidelines.\u003c/p\u003e \u003cp\u003eAfter tumor resection, the patient demonstrated gradual neurological improvement, including increased alertness, reduced agitation, and partial recovery of spontaneous speech. However, a transient clinical deterioration prompted resumption of plasmapheresis and initiation of rituximab therapy (375 mg/m\u0026sup2;, administered in two doses two weeks apart). This resulted in marked and rapid improvement in cognitive function, orientation, and language abilities.\u003c/p\u003e \u003cp\u003eSubsequently, CSF testing returned positive for anti\u0026ndash;N-methyl-D-aspartate receptor (anti-NMDAR) antibodies, confirming the diagnosis of anti-NMDAR encephalitis. By the time of discharge, the patient was fully oriented, seizure-free, and independent in activities of daily living. At six-month follow-up, she remained neurologically stable without seizure recurrence or neuropsychiatric relapse.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAnti\u0026ndash;N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by antibodies against the NR1 subunit of the NMDA receptor, leading to a constellation of neuropsychiatric symptoms, seizures, and autonomic dysfunction (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The disorder predominantly affects children and young adults, with a strong female predominance, and is frequently associated with ovarian teratomas (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eOur patient presented with the prototypical features of anti-NMDAR encephalitis, including acute-onset seizures, cognitive impairment, behavioral disturbances, and transient aphasia. However, diagnosis was challenging due to normal brain MRI and unremarkable cerebrospinal fluid (CSF) findings, highlighting a well-recognized limitation: imaging and routine CSF studies can be normal in a substantial proportion of cases. EEG revealed nonspecific diffuse slowing, consistent with previously reported patterns in autoimmune encephalitis(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe detection of a large right ovarian mass was crucial in establishing the paraneoplastic nature of her illness. Ovarian teratomas are identified in over half of adult women with anti-NMDAR encephalitis, most commonly as mature cystic teratomas (2(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Our case was notable for an immature ovarian teratoma, a rare entity that may harbor a higher antigenic load due to the presence of primitive neural tissue; although ovarian teratomas are well-recognized triggers of anti-NMDA receptor encephalitis, the occurrence of this syndrome in association with an immature teratoma is uncommon, with only a few cases reported in the literature(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). potentially explaining the patient\u0026rsquo;s severe presentation and delayed response to first-line therapy (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eManagement of anti-NMDAR encephalitis relies on a combination of tumor removal and immunotherapy. In our patient, neurological recovery improved after removing the Teratoma supporting evidence that early tumor resection in anti‑NMDA receptor encephalitis helps patients recover faster and lowers the risk of relapse(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Regarding to immunotherapy First-line therapy typically consists of corticosteroids, intravenous immunoglobulin, or plasma exchange (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e),(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In patients with incomplete response, second-line therapies such as rituximab or cyclophosphamide are recommended and are associated with improved outcomes and reduced relapse risk (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e),(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). In our patient, escalation to rituximab as second-line therapy, following incomplete response to corticosteroids and plasmapheresis, was associated with rapid neurological recovery, consistent with multicenter data showing that rituximab effectively reduces relapse risk and prolongs time to first relapse in anti-NMDAR encephalitis(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In our patient, initial corticosteroids and plasmapheresis produced modest improvement; however, escalation to rituximab following tumor resection resulted in dramatic neurological recovery, consistent with the current literature.\u003c/p\u003e \u003cp\u003ePrognosis is generally favorable when early tumor removal is combined with prompt immunotherapy, with approximately 80% of patients achieving substantial recovery (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e),(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Delayed diagnosis or failure to identify and remove the tumor is associated with poorer outcomes, prolonged hospitalization, and increased risk of relapse, which occurs in 12\u0026ndash;25% of cases, particularly when immunotherapy is incomplete or the tumor remains unresected (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Our patient remained neurologically stable and seizure-free at six months follow-up, illustrating the importance of timely recognition, aggressive immunotherapy, and early tumor management.\u003c/p\u003e \u003cp\u003eThis case underscores several key clinical lessons: the need for high clinical suspicion of autoimmune encephalitis despite normal imaging and CSF; the importance of comprehensive tumor screening in adult women presenting with new-onset neuropsychiatric symptoms; and the role of second-line immunotherapy in patients with severe or refractory disease. Additionally, it highlights that immature ovarian teratomas, though uncommon, can serve as a potent antigenic source, reinforcing the necessity of individualized, multidisciplinary management strategies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest Statement:\u003c/h2\u003e \u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003ePatient Consent Statement:\u003c/h2\u003e \u003cp\u003e Written informed consent was obtained from the patient for publication of this case report and accompanying clinical details. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo external funding was received.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.D. conceived and designed the study, collected clinical data, drafted the initial manuscript, and revised the final version. R.A.L. (Ragad A. Lahlouh) supervised the project, contributed to the discussion and conclusions, and critically revised the manuscript for important intellectual content. S.M.D. (Sherehan M. Doudin) assisted with data collection, performed the literature review, and drafted the clinical course section. O.O. (Ola Omarya) provided histopathological analysis and contributed to interpretation of findings, and reviewed the manuscript. A.I. (Ahmed Ismael) participated in clinical management, interpretation of findings, and revised the manuscript. All authors have read and approved the final submitted version and agree to be accountable for all aspects of the work.M.D. (Mahmoud Doudein) R.A.L. (Ragad A. Lahlouh) S.M.D. (Sherehan M. Doudin)A.I. (Ahmed Ismael)O.O. (Ola Omarya)\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the medical and nursing staff at Istishari Arab Hospital for their support in patient care. We also acknowledge the patient and her family for their cooperation and consent to share clinical information for educational purposes. No funding was received for this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated during this case study are included in this published article. Additional clinical details are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSamanta D, Lui F. Anti-NMDAR Encephalitis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [cited 2026 Jan 3]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncbi.nlm.nih.gov/books/NBK551672/\u003c/span\u003e\u003cspan address=\"http://www.ncbi.nlm.nih.gov/books/NBK551672/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391\u0026ndash;404.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAntibody-Mediated Encephalitis. | New England Journal of Medicine [Internet]. [cited 2026 Jan 3]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nejm.org/doi/\u003c/span\u003e\u003cspan address=\"https://www.nejm.org/doi/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMra1708712\u003c/span\u003e\u003cspan address=\"10.1056/NEJMra1708712\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang H, Xiong W, Liu X, Liu W, Zhou D, Wu X. Long-Term Prognosis of Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis Who Underwent Teratoma Removal: An Observational Study. Front Neurol. 2022;13:874867.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDay GS, Laiq S, Tang-Wai DF, Munoz DG. Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol. 2014 June;71(6):717\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImataka G, Yoshihara S. Immature ovarian teratoma with anti-NMDA-receptor encephalitis in a 13-year-old Japanese female patient. Med J Malaysia. 2021;76(3):436\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhatrawi EM, Prajjwal P, Marsool MDM, Das A, Nagre A, Inban P, et al. A case report of anti-NMDA receptor encephalitis in a 23-year-old female with acute psychiatric symptoms. Clin Case Rep. 2024;12(5):e8870.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeery N, Wesselingh R, Beech P, McLaughlin L, Rushen T, Halliday AJ, et al. Rituximab Use for Relapse Prevention in Anti-NMDAR Antibody-Mediated Encephalitis. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200395.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Autoimmune encephalitis, Anti-NMDA receptor encephalitis, Ovarian teratoma, Immature teratoma, Paraneoplastic neurologic disorder","lastPublishedDoi":"10.21203/rs.3.rs-8590281/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8590281/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by antibodies against the NR1 subunit of the NMDA receptor. It predominantly affects young women and is frequently associated with ovarian teratomas. Early recognition, tumor removal, and immunotherapy are critical for favorable outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation: \u003c/strong\u003eWe report a 33-year-old woman with subacute headache, low-grade fever, generalized weakness, and mood disturbances, who developed generalized tonic–clonic seizures and cognitive impairment. Brain MRI and CSF were initially normal, and EEG showed diffuse slowing without epileptiform discharges. Pelvic imaging revealed a large right ovarian mass. She was treated with corticosteroids, plasmapheresis, and ultimately rituximab, alongside right salpingo-oophorectomy. Histopathology confirmed an immature teratoma. Anti-NMDAR antibodies were later detected in CSF, confirming the diagnosis. Following tumor removal and immunotherapy, she achieved complete neurological recovery and remained seizure-free at six months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This case highlights the diagnostic challenges of anti-NMDAR encephalitis, particularly when MRI and CSF are normal. Early tumor detection and removal, combined with prompt escalation to second-line immunotherapy when needed, are essential for favorable outcomes. Immature ovarian teratomas, although rare, can trigger severe disease and warrant careful evaluation in adult women presenting with acute neuropsychiatric symptoms.\u003c/p\u003e","manuscriptTitle":"Diagnostic and Therapeutic Challenges in Anti-NMDA Receptor Encephalitis Associated with an Ovarian Immature Teratoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-14 06:39:21","doi":"10.21203/rs.3.rs-8590281/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-20T21:17:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-14T13:57:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-14T13:55:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2026-01-13T09:36:30+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":"148f8966-d966-4fb4-833e-76f38055af13","owner":[],"postedDate":"January 14th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:01:10+00:00","versionOfRecord":{"articleIdentity":"rs-8590281","link":"https://doi.org/10.1186/s12883-026-04918-1","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2026-05-01 15:58:32","publishedOnDateReadable":"May 1st, 2026"},"versionCreatedAt":"2026-01-14 06:39:21","video":"","vorDoi":"10.1186/s12883-026-04918-1","vorDoiUrl":"https://doi.org/10.1186/s12883-026-04918-1","workflowStages":[]},"version":"v1","identity":"rs-8590281","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8590281","identity":"rs-8590281","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}