IgG4-Related Spinal Hypertrophic Pachymeningitis: A Case Report and Systematic Review of 60 Cases

IgG4-Related Spinal Hypertrophic Pachymeningitis: A Case Report and Systematic Review of 60 Cases | 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 IgG4-Related Spinal Hypertrophic Pachymeningitis: A Case Report and Systematic Review of 60 Cases Yingjing Du, Shuosi Liu, Yuqing Ge, Qundi Luo, Xuechen Lin, yuhuan Qu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6253248/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is a rare disorder characterized by localized or diffuse fibrotic thickening of the dura mater, affecting both the cranial and spinal regions. IgG4-related spinal hypertrophic pachymeningitis (IgG4-SHP) often manifests with clinical features resembling spinal cord space-occupying lesions, complicating its differential diagnosis. Consequently, establishing an accurate and efficient diagnostic approach is critical for the timely identification and management of IgG4-RHP. Case presentation: We present a patient withIgG4-SHP observed at Zhujiang Hospital of Southern Medical University. The patient's initial symptom was numbness in both lower limbs accompanied by progressive weakness(MRC 2/5 bilaterally). Given the patient's manifestations of spinal cord compression, we initially conducted surgical intervention. The patient was subsequently transferred to the Department of Rheumatology and Immunology, where treatment with steroids was initiated, and then his muscle strength in both lower limbs had improved (MRC 4/5 bilaterally). In accordance with the criteria established by the Japanese Rheumatism Society, IgG4-SHP cases were identified from PubMed, CNKI, and other databases for systematic analysis and literature review (up to November 2024). The data were then analysed via SPSS 26.0 statistical software. Conclusion: We have compiled data from 60 relevant patients for the first time through a literature review. We found that IgG4-SHP predominantly affects middle-aged and elderly patients, with thoracic epidural masses being the most frequently observed manifestation. Clinical presentations, imaging findings, and laboratory investigations often lack specificity, complicating the diagnostic process. A definitive diagnosis relies on the integration of histopathological and immunohistochemical analyses, which provide the most reliable diagnostic criteria. Initial management typically involves corticosteroid therapy. However, in patients presenting with compressive neurological symptoms or suboptimal response to corticosteroids, surgical decompression or adjunctive immunosuppressive agents may be warranted. IgG4-related diseases IgG4-related spinal hypertrophic pachymeningitis spinal cord compression immune diseases Figures Figure 1 Figure 2 Figure 3 Figure 4 Background IgG4-related disease (IgG4-RD) is a chronic immune-mediated disorder characterized by fibrosis, tissue swelling, and IgG4-rich plasma cell infiltration. First identified in 2001 in autoimmune pancreatitis [1], it was later defined as a distinct disease by Kamisawa et al. in 2003 [2]. Common affected organs include the salivary glands, pancreas, and kidneys, while central nervous system (CNS) involvement is rare. Among neurological manifestations, hypophysitis and hypertrophic pachymeningitis are the most frequently reported [3]. Spinal involvement, particularly IgG4-related hypertrophic spinal pachymeningitis (IgG4-SHP), is exceptionally rare. First described in 2009, IgG4-SHP involves fibrotic thickening of the spinal dura, often causing nerve root or spinal cord compression [4]. Its nonspecific symptoms and resemblance to spinal tumors make early diagnosis challenging. Limited awareness among clinicians further delays treatment, increasing the risk of permanent neurological damage. In this study, we present a case of IgG4-SHP diagnosed at Zhujiang Hospital of Southern Medical University. We also reviewed published cases from PubMed and other databases to better understand the disease and improve clinical recognition. Our goal is to promote early diagnosis, optimize treatment, and prevent severe outcomes like spinal cord injury or paraplegia. Case Presentation 1.1 Medical history and physical examination A 50-year-old male presented with progressive bilateral lower limb numbness and weakness over one month, accompanied by perineal paresthesia radiating to the soles. Neurological examination revealed asymmetric weakness (right > left) without systemic symptoms (MRC 2/5 bilaterally) . Symptoms progressed to ambulatory dysfunction, lumbar fatigue, and lower limb myoclonus (1-2/min), with reduced bladder/bowel frequency. Thoracic dural lesion resection was performed on March 29, 2024. 1.2 Radiological examination Spinal magnetic resonance imaging (MRI) revealed long T1 and long T2 signal shadows within the epidural spinal canal at the level of the thoracic vertebrae (2-4), which exhibited notable visibility. (Fig. 1) 1.3 Laboratory examination Laboratory investigations demonstrated elevated inflammatory markers, including erythrocyte sedimentation rate (64 mm/h; normal <15 mm/h), C-reactive protein (9.21 mg/L; normal <5 mg/L), leukocytosis (11.3 G/L; normal 3.5–9.5 G/L), thrombocytosis (407 G/L; normal 125–350 G/L), and interleukin-6 elevation (8.73 pg/mL; normal <7 pg/mL). Mild normocytic anemia (hemoglobin 116 g/L) was concurrently observed. Notably, serological evaluations excluded alternative diagnoses: serum protein electrophoresis, humoral immunity profiles (including immunoglobulins IgA/IgM), autoimmune markers (antinuclear antibody, rheumatoid factor), vasculitis panels, and syphilis serology all fell within normal ranges. The preoperative serum IgG and IgG4 levels were not measured. Postoperatively, serum IgG was 10.3 g/L (normal 7.0–16.0 g/L) and IgG4 was 0.41 g/L (normal 0.03–2.01g/L). 1.4 Operation and histopathology An ultrasonic bone knife was used to excise the thoracic 2-4 lamina. During surgery, a novel biological sleeve surrounding the dorsal aspect of the spinal cord showed significant adhesion. The biological entity was entirely removed and sent for pathological analysis. Histopathological examination revealed sheet-like fibrosis with multifocal infiltration of lymphocytes, plasma cells, and a few neutrophils. No occlusive phlebitis was observed. Immunohistochemical analysis showed IgG4+ (>10/HPF) with an IgG4/IgG ratio of approximately 44.3% (Conform to the 2019 ACR/EULAR criteria). Positive markers included CD38 (plasma cell+), CD138 (plasma cell+), IgG (+), CD34 (vascular+), Ki-67 (+, 5%), CD20 (B-cell+), CD3 (T-cell+), Kappa (+), and Lambda (+). Negative markers included PR (-), SSTR-2 (scattered +), EMA (scattered +), CK (-).(Fig2). 1.5 Postoperative treatment and follow-up Surgical pathology confirmed the diagnosis of IgG4-related hypertrophic pachymeningitis, based on the Japanese Rheumatism Society's criteria. Despite surgery, the patient's symptoms persisted, prompting further treatment with 20 mg oral methylprednisolone in the Department of Rheumatology and Immunology. After one month of outpatient treatment, there was significant improvement in lower limb muscle strength, reduced numbness, and normalization of urinary function. Methods 2.1 Literature Retrieval and Inclusion and Exclusion Criteria The literature review followed the Japanese Society of Rheumatology's criteria[5]. Search terms included: (IgG4-related hypertrophic pachymeningitis) AND (spine), (IgG4-related spinal hypertrophic pachymeningitis), and (hypertrophic pachymeningitis) AND (spine). Searches in PubMed, CNKI, and other databases identified 200 articles as of November 25, 2024. Diagnosis was based on three criteria: (1) clinical signs of edema or mass in one or more organs; (2) elevated serum IgG4 (>135 mg/dL); (3) histopathology with lymphocyte and plasma cell infiltration and fibrosis. IgG4-positive plasma cell infiltration was defined by >40% IgG4/IgG-positive cells or >10 cells per high-powered field in biopsy. Diagnosis is confirmed when any combination of criteria is met. The exclusion criteria were clear indications such as tumours, tuberculosis, infectious disease, trauma, medication, and neurological disorders resulting from spinal dural thickening. According to the established inclusion and exclusion criteria, the articles were initially screened, and only 60 patients who were diagnosed with IgG4-related spinal hypertrophic pachymeningitis, which is comparable to the present case, were ultimately included in the study. 2.2 Data Information Input The following data were extracted: publication date, patient demographics, clinical presentations, mass location, laboratory findings, MRI results, treatments, and outcomes (Table 1). 2.3 Statistical analysis The following data were analysed with SPSS 26.0: categorical data such as n (%), chi-square tests or Fisher's tests for group comparisons (for samples<40), t tests for continuous data, and significance at P < 0.05. Results 3.1 Clinical and Imaging Findings Of the 60 patients, 36 (60%) were male and 24 (40%) were female, with a mean age of 49.05 years (SD=14.29). No significant age difference was found between genders (P > 0.05) (Fig. 4A). Symptoms were primarily linked to the location of spinal cord compression. The most common symptoms were limb weakness, sensory disturbances, and low back pain, which eventually led to ambulatory difficulties and incontinence (Fig. 4B). Fourteen patients had involvement in other systems, and 7 experienced bone destruction. The median symptom duration was 2.0 months, ranging from 1 week to 48 months. Spinal cord MRI was performed on 54 patients, showing that IgG4-SHP most often affected the thoracic spine, followed by the cervical+thoracic spine, cervical spine, lumbar spine, and combinations of these regions (Fig. 4D). Tumours were mainly found in the epidural space. On T1-weighted MRI, 29 lesions had low signal intensity, and 8 had equal intensity. On T2-weighted MRI, 29 lesions were low signal, and 13 were high signal. All lesions showed enhancement. 3.2 Laboratory Examination and Pathological Immunohistochemistry In our study of 60 IgG4-SHP patients, 41.7% had elevated serum IgG4, while 30.0% had normal levels. CRP and ESR increased by 31.7% and 33.3%, respectively. These findings highlight the importance of histopathology and inflammatory markers in diagnosing and assessing disease activity. Of the 18 patients with cerebrospinal fluid identified, 14 had comprehensive testing, revealing abnormalities in most, while 4 tests were normal (Fig. 4C). 3.3 Treatment and Outcomes In this study, 58 patients had surgery, while 2 were treated with steroids and azathioprine or steroids alone. Of the 60 patients, 50 were on steroids, and 27 had surgery; 21 received immunosuppressive agents. Nine patients had recurrence and were treated with surgery or steroids. Of the 55 with symptom relief, 6 relapsed but improved with further treatment. Two were lost to follow-up, and 3 died. Immunosuppressive regimens included cyclophosphamide, azathioprine, methotrexate, and rituximab (Fig. 3E). After adjustments, 6 patients achieved remission, with no significant outcome differences (P > 0.05). Discussion 4.1 Epidemiology and clinical manifestations IgG4-RD is an autoimmune condition that has gained recognition over the past 20 years. Its diverse clinical manifestations can lead to misdiagnosis and overlooked cases. IgG4-related pachymeningitis (IgG4-RHP) was once classified as idiopathic hypertrophic pachymeningitis (IHPM), but numerous studies have confirmed that it is an IgG4-related disease [6]. IgG4-RHP makes up less than 1% of all IgG4-RD cases, but it accounts for 8% to 29% in patients with hypertrophic pachymeningitis. A Japanese study found that IgG4-RHP is more common in males, with a male-to-female ratio of 1:0.17 and an average onset age of approximately 56.7 years [7]. Additionally, a single-center prospective cohort study identified 4 cases of IgG4-RHP among 589 patients with IgG4-RD, including 2 males and 2 females [8]. IgG4-SHP shows no significant sex difference, but is primarily observed in middle-aged and elderly individuals. The study included 60 patients, comprising 36 males and 24 females, resulting in a male-to-female ratio of 1:0.67, with a mean age of 49.05 years. There was no significant age difference between males and females (P > 0.05), which is consistent with findings from Ibrahim Sbeih's literature review. IgG4-SHP is more prevalent in middle-aged and elderly patients, and sex does not appear to significantly influence its pathogenesis. IgG4-RD can manifest in one or multiple organs, with spinal cord compression due to spinal involvement being rare. In a seminal publication, Chan first described IgG4-related hypertrophic spinal pachymeningitis, characterized by diffuse dural fibrosis. This condition typically leads to nerve root and/or spinal cord compression, resulting in associated clinical symptoms [4]. In this study, patients exhibited motor and sensory disorders, limb weakness, and low back pain, which could progress to gait difficulties and incontinence. Some patients also had nonspecific systemic symptoms like weight loss, fever, shortness of breath, and fatigue. The median duration of symptoms was 2.0 months (1 week to 48 months). Fourteen patients had involvement of other systems, and 6 showed bone destruction. MIKAWA noted that the time from the onset of pain to motor paralysis ranged from 3 days to 5 years, averaging 10 months [9]. Disease progression varies significantly; without timely treatment, most patients may deteriorate, leading to irreversible damage. Therefore, establishing an effective early diagnosis system for IgG4-SHP is crucial. 4.2 Imaging findings Magnetic resonance imaging (MRI) is the primary tool for diagnosing IgG4-SHP. Studies show it typically presents as a long banded mass outside the dura mater, often affecting the thoracic and lumbar dura, with low signal on T1WI and T2WI and homogeneous enhancement on T1WI. In this study of 52 patients, MRI results confirmed previous findings, indicating that IgG4-SHP predominantly involves the thoracic spine, followed by the cervical+thoracic spine, cervical spine, and lumbar spine, with some cases showing multiregional or total spinal cord involvement.In these cases, tumors are often found in the epidural space. T1WI typically shows low or equal signal, while T2WI may show low or high signal, with all patients displaying noticeable enhancement. MRI enhancement correlates with pathological changes; pronounced enhancement indicates inflammatory cell infiltration, whereas less discernible enhancement occurs when collagen fiber proliferation is minimal [10].Numerous studies have utilized computed tomography (CT) or positron emission tomography-computed tomography (PET-CT) to assess bone involvement in patients with IgG4-SHP and to monitor active lesions in other organs. Recent research underscores the significant role of FDG PET-CT in the evaluation of IgG-related diseases, as it facilitates the identification of previously unnoticed sites of involvement and aids in the monitoring of disease activity and treatment responses [11]. In our study, six patients exhibited varying degrees of bone destruction, with two undergoing CT and two receiving PET-CT evaluations. 4.3 Laboratory examination Serum IgG4 levels are commonly used as a diagnostic marker for IgG4-SHP. However, Kosakai and Lu found that about 80% of cases had normal serum IgG4 levels [12], suggesting that these levels are not a critical diagnostic parameter. Elevated serum IgG4 may assist in diagnosis when immunohistochemical analysis is not available [10]. In our review, among 43 patients evaluated, 25 had elevated serum IgG4 levels and 18 had normal levels, indicating the limited sensitivity and specificity of serum IgG4 in diagnosing IgG4-SHP. Additionally, IgG4 levels in cerebrospinal fluid (CSF) can serve as an important diagnostic indicator and a tool for monitoring treatment efficacy. Della Torre reported that the IgG4 CSF/IgG4 serum/albumin CSF/albumin serum ratio is a reliable marker of intrathecal IgG4 synthesis, with a normal range of 0.25 to 0.91 [13]. Furthermore, an IgG4Loc > 0.47 is an effective criterion for identifying IgG4-related hypersensitivity pneumonitis (HP) and other causes of inflammatory meningitis, demonstrating 100% sensitivity and specificity. Routine biochemical and cytological examinations of CSF are crucial for detecting infections and malignant tumors. In our study, CSF was analyzed in 18 patients, of whom 14 exhibited one or more abnormalities in the tests (including CSF pressure, IgG levels, and routine biochemical, bacterial, and fungal cultures), while 4 showed normal results. Elevated inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, are not specific indicators for diagnosing IgG4-SHP, as they are frequently observed in infections and other inflammatory conditions. Our findings further emphasize that these markers lack the specificity needed for a definitive diagnosis of IgG4-SHP. 4.4 Histopathology and immunohistochemistry Due to the lack of specificity in imaging and laboratory tests for diagnosing IgG4-SHP, histopathological and immunohistochemical findings from spinal dural biopsy remain the gold standard for diagnosis. Both the 2011 Japanese Rheumatism Association IgG4-RD diagnostic criteria and the 2019 ACR/EULAR classification criteria place significant emphasis on pathological diagnosis for IgG4-RD [5,14]. The typical histopathological features of IgG4-RD include dense lymphocyte infiltration (IgG4/IgG+ cells >40% and/or IgG4+ plasma cells >10/HPF), sheet-like swirling fibrosis (collagen fibers arranged in a radial, interlaced, swirling pattern), and obliterative phlebitis [11]. In IgG4-SHP, occlusive phlebitis is rare. Additionally, tissue eosinophilia and lymphoid follicular infiltration may also be present in some cases. In this systematic review, all patients with pathological diagnoses met the Japanese Rheumatology Association IgG4-SHP criteria. 4.5 Treatment and Outcomes In IgG4-SHP, the primary treatment is steroid therapy, which has been shown to reduce inflammation, mitigate the placeholder effect, and significantly improve patient prognosis [15]. The clinical response is rapid and highly effective, particularly in the early stages of the disease, with effectiveness rates reaching 97% to 98%. For patients with recurrent or refractory IgG4-RD who do not respond to steroids or have contraindications, immunosuppressive agents like cyclophosphamide, methotrexate, and azathioprine can be more effective in reducing recurrence and improving remission rates. Rituximab (RTX), a monoclonal antibody targeting CD20, has demonstrated a lower recurrence rate compared to steroid and traditional immunosuppressive combinations [16]. In this literature review, 27 patients were treated with a combination of surgery and steroids, while 21 patients received surgery, steroids, and immunosuppressive agents. The most commonly used immunosuppressive agent was cyclophosphamide. Six patients were treated with rituximab, and all of them showed a significant clinical response. Among the cohort, three patients who were treated with steroids alone experienced disease recurrence. However, their condition improved clinically after modifying the treatment plan to include either surgery or immunosuppressive agents. This study suggests that steroid therapy alone is insufficient for certain patients, highlighting the need for additional therapeutic interventions. Additionally, surgical intervention is necessary for patients who demonstrate nerve root and/or spinal cord compression, progressive neurological decline, or severe fibrosis. Decompression of the nerve or spinal cord is essential to maintain spinal stability and obtain adequate tissue for diagnosis [17]. Early and timely surgical intervention can prevent the disease from progressing to irreversible nerve damage or even paralysis. Despite early and timely surgical treatment, some patients still experience a poor short-term prognosis. Of the 58 patients who underwent surgery, 3 who received only surgical treatment experienced disease recurrence. However, their condition improved after the addition of drug therapy. This study found no significant difference in the outcomes of the various treatment regimens (P > 0.05). The prognosis and outcome of IgG4-SHP patients are primarily monitored through the observation of clinical manifestations, imaging, and serum IgG4 levels, with improvement in these factors serving as the primary indicator of treatment efficacy. Most patients with IgG4-SHP can achieve clinical remission with the combined use of surgical, steroid, and immunosuppressant therapies. Only a few patients succumb to their underlying medical conditions, non-adherence to treatment plans, or complications from steroid side effects. Due to the lack of long-term follow-up studies, the long-term prognosis of patients with spinal IgG4-HP remains controversial. The degree of fibrosis during treatment is thought to be inversely related to the clinical response and may serve as a prognostic factor [15]. Summary This study presented a case of IgG4-SHP, which was confirmed by pathology after surgery. The patient's clinical symptoms improved following surgical intervention and steroid administration. Subsequently, we compiled the confirmed cases of IgG4-SHP from the past 20 years and conducted a statistical analysis. IgG4-SHP primarily affects middle-aged and elderly patients, with the most common presentation being a thoracic epidural mass. The clinical manifestations, imaging findings, and laboratory test results are non-specific. A combination of histopathological and immunohistochemical findings provides the most reliable basis for diagnosis. Steroid therapy remains the first-line treatment. In cases where patients present with compression symptoms or do not respond to steroid therapy, surgical intervention or the use of immunosuppressive agents may be indicated. Furthermore, long-term follow-up for IgG4-SHP patients is essential. A better understanding of the disease by healthcare providers, along with prompt diagnosis and treatment, can effectively prevent disease progression and recurrence, ultimately improving patient survival rates. Abbreviations IgG4-RHP: IgG4-related hypertrophic pachymeningitis; IgG4-SHP: IgG4-related spinal hypertrophic pachymeningitis; IgG4-RD: IgG4-related disease; MRI: Spinal magnetic resonance imaging; CRP: C-Reactive Protein; ESR: Erythrocyte Sedimentation Rate; CSF: Cerebro-Spinal Fluid; M: Male, F: Female; NR: Not Reported; Iso: Iso Intensity; Hypo: Hypo Intensity; Hyper: Hyperintensity; CTX: Cyclophosphamide; MTX: Methotrexate; AZA: Azathioprine; RTX: Rituximab. Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Zhujiang Hospital Ethics Committee (Approval No. 2025-KY-030). Written informed consent was obtained from the patient for publication of this case report and any accompanying images. All data presented in this manuscript are anonymized, and no identifying information of the patient is included. Consent for publication Written informed consent was obtained from the patients for publication of the case reports and any accompanying images. Competing interests There are no conflicts of interest among the medical staff or the authors involved in this article. Availability of data and materials The datasets generated during the current study are available from the corresponding author on reasonable request. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ contributions All the authors were involved in the treatment of the patients and collected and organised the cases reported previously. Du wrote the initial draft of the manuscript. All the authors read and approved the final manuscript. Acknowledgements Not applicable. Authors’ information Both authors are from Zhujiang Hospital, Southern Medical University, Guangzhou, China. Author details 1 The Second School of Clinical Medicine,Southern Medical University，Guangzhou, China. 2 Zhujiang Hospital, Southern Medical University, Guangzhou, China. References Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732-8. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, Egawa N, Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982-4. Baptista B, Casian A, Gunawardena H, D'Cruz D, Rice CM. Neurological Manifestations of IgG4-Related Disease. Curr Treat Options Neurol. 2017;19:14. Chan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognised form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009;33:1249-52. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21-30. Wu LN, Lu DH, Piao YS. Advances in IgG4-related hypertrophic pachymeningitis. Zhonghua Nei Ke Za Zhi. 2023;62:1139-1143. Yonekawa T, Murai H, Utsuki S, Matsushita T, Masaki K, Isobe N, Yamasaki R, Yoshida M, Kusunoki S, Sakata K, Fujii K, Kira J. A nationwide survey of hypertrophic pachymeningitis in Japan. J Neurol Neurosurg Psychiatry. 2014;85:732-9. Peng L, Zhang P, Zhang X, Li J, Zhao J, Liu J, Fei Y, Zhang W, Zhu Y, Zhao Y, Zeng X. Clinical features of immunoglobulin G4-related disease with central nervous system involvement: an analysis of 15 cases. Clin Exp Rheumatol. 2020;38:626-632. Mikawa Y, Watanabe R, Hino Y, Hirano K. Hypertrophic spinal pachymeningitis. Spine (Phila Pa 1976). 1994;19:620-5. Alrashdi MN. Immunoglobulin G4-related spinal pachymeningitis. Saudi Med J. 2020;41:652-656. Lu LX, Della-Torre E, Stone JH, Clark SW. IgG4-related hypertrophic pachymeningitis: clinical features, diagnostic criteria, and treatment. JAMA Neurol. 2014;71:785-93. Lu Z, Tongxi L, Jie L, Yujuan J, Wei J, Xia L, Yumin Z, Xin L. IgG4-related spinal pachymeningitis. Clin Rheumatol. 2016;35:1549-53. Della Torre E, Bozzolo EP, Passerini G, Doglioni C, Sabbadini MG. IgG4-related pachymeningitis: evidence of intrathecal IgG4 on cerebrospinal fluid analysis. Ann Intern Med. 2012;156:401-3. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Schleinitz N, Takahashi N, Umehara H, Zen Y, Stone JH. Members of the ACR/EULAR IgG4-RD Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79:77-87. Sbeih I, Darwazeh R, Shehadeh M, Al-Kanash R, Abu-Farsakh H, Sbeih A. Immunoglobulin G4-Related Hypertrophic Pachymeningitis of the Spine: A Case Report and Systematic Review of the Literature. World Neurosurg. 2020;143:445-453. Campochiaro C, Della-Torre E, Lanzillotta M, Bozzolo E, Baldissera E, Milani R, Arcidiacono PG, Crippa S, Falconi M, Dagna L. Long-term efficacy of maintenance therapy with Rituximab for IgG4-related disease. Eur J Intern Med. 2020;74:92-98. Kramer DE, Kerolus MG, Furlan K, Nag S, O'Toole JE. Recurrent IgG4-Related Meningeal Disease of the Cervicothoracic Spine: A Case Report and Review of the Literature. Neurol India. 2022;70:1180-1186. Chae TS, Kim DS, Kim GW, Won YH, Ko MH, Park SH, Seo JH. Immunoglobulin G4-related spinal pachymeningitis: A case report. World J Clin Cases. 2024;12:6551-6558. Parlak A, Mueller CA, Nolte KW, Schmidt TP, Bertram U, Clusmann H, Blume C. Cervical myelopathy caused by IgG4-related hypertrophic spinal pachymeningitis: Case report and a descriptive review of the literature. Brain Spine. 2024;4:103325. Chau HHT, Lo BA, Chu WP, Ho HN, Tsui WM. A case of IgG4-related disease manifesting as a spinal epidural mass. BJR Case Rep. 2024;10:uaae022. Huang Y, Liu Y. IgG4-related disease involving the cervical spinal cord. J Clin Neurosci. 2024;124:78-80. Takeuchi T, Takizawa H, Bando Y, Hosokawa A, Sumitomo H, Miyamoto N, Sakamoto S, Morishita A, Kawakita N, Toba H. Robot-assisted thoracoscopic resection of a posterior mediastinal tumor with immunoglobulin G4-related disease: a case report. J Cardiothorac Surg. 2024;19:291. Tanaviriyachai T, Chinvattanachot G, Piyapromdee U, Sirisanthiti P. IgG4-Related Spinal Hypertrophic Pachymeningitis With Neurological Deficit: A Report of 2 Cases. JBJS Case Connect. 2023;13. Rath PD, Katoch S, Agrawal AK, Chouhan S, Bajaj HN, Bisaralli R. Mass: The Conundrum in Spine. J Orthop Case Rep. 2023;13:37-40. Yu H, Lu C, Duan W, Dong Y, Wang Z, Wang X, Jian F. A selected case series of idiopathic hypertrophic pachymeningitis in a single center: Pathological characteristics and case-oriented review. J Neuroimmunol. 2023;383:578191. Gader G, Atig FB, Jemel N, Bourgou M, Slimane A, Ghedira K, Badri M, Zammel I. Epiduritis related to IgG4 disease: A very rare cause for spinal cord compression. Surg Neurol Int. 2023;14:205. Nathan, G Sudhakshina, Raiyani, Yatin V, Subramanyan, Annapurneswari, Balamurugan, Mangaleswaran. Intradural Extramedullary IgG4-related Disease of the Dorsal Spine. Journal of Spinal Surgery,2023;10:95-98. Yang F, Liu Z, Zhang Y, Li P, Zhu Y, Zhu Q, Zhang B. Case report: Clinical highlights and radiological classification of IgG4-related spinal pachymeningitis: A rare case series and updated review of the literature. Front Oncol. 2023;12:1035056. Qi Z, Liu J, Li G, Zhang Y. Immunoglobulin G4-Related Spinal Intramedullary Inflammatory Pseudotumor: A Case Report and Literature Review. Front Neurol. 2022;13:878414. Kramer DE, Kerolus MG, Furlan K, Nag S, O'Toole JE. Recurrent IgG4-Related Meningeal Disease of the Cervicothoracic Spine: A Case Report and Review of the Literature. Neurol India. 2022;70:1180-1186. Lu Z, Tongxi L, Jie L, Yujuan J, Wei J, Xia L, Yumin Z, Xin L. IgG4-related spinal pachymeningitis. Clin Rheumatol. 2016;35:1549-53. Karthigeyan M, Rajasekhar R, Salunke P, Gupta K. IgG4-related Pachymeningitis as a Cause of Spinal Epidural Compression: Can Intraoperative Frozen Sections Predict the Underlying Pathology? Neurol India. 2022;70:1223-1225. Xia C, Li P. IgG4-related hypertrophic pachymeningitis with ANCA-positivity: A case series report and literature review. Front Neurol. 2022;13:986694. Sharma R, Kaur K, Sasidharan A, Gupta R, Laythalling RK. IgG4-Related Disease in Intradural Extramedullary Location- Detailed Case Illustration and Literature Review with Special Emphasis on Role of Surgery in its Management. Neurol India. 2021;69:1176-1183. Kim DJ, Lee S, Cheong HJ, Hong S, Kim MJ, Jung SK, Park JH. Spinal Bony Involvement of IgG4-related Disease Treated by a Spondylectomy. NMC Case Rep J. 2021;8:27-31. Elmaci I, Altinoz MA, Akdemir G, Sari R, Baskan O, Ozpinar A, Hacker E, Sav A. Neurosurgical and neuro-immunological management of IgG4-related hypertrophic sclerosing pachymeningitis. A literature survey and discussion of a unique index case. Clin Neurol Neurosurg. 2021;200:106342. Woo PYM, Ng BCF, Wong JHM, Ng OKS, Chan TSK, Kwok NF, Chan KY. The protean manifestations of central nervous system IgG4-related hypertrophic pachymeningitis: a report of two cases. Chin Neurosurg J. 2021;7:13. Murugan C, Kavishwar RA, Ramachandran K, Shetty AP, B T P, Rajasekaran S. Spinal Hypertrophic Pachymeningitis Causing Thoracic Myelopathy in a Patient of Takayasu Arteritis: A Case Report. JBJS Case Connect. 2021;11. Ogaki R, Okada E, Suzuki S, Nori S, Tsuji O, Nagoshi N, Yagi M, Watanabe K, Nakamura M, Matsumoto M. Myeloperoxidase-Antineutrophil Cytoplasmic Antibody Positive Hypertrophic Spinal Pachymeningitis at the Cervicothoracic Junction: A Case Report. Spine Surg Relat Res. 2020;5:211-213. Zhang Z, Yu W, Guan W, Lin Q. IgG4-rRelated Disease-Rare Presentation With Spinal Involvement. Arthritis Rheumatol. 2020;72:1828. Park BJ, Starks R, Kirby P, Menezes AH, Dlouhy BJ. IgG4-Related Disease of the Craniovertebral Junction. World Neurosurg. 2020;134:264-271. Li HX, Zuo L, Peng XX, Zong Q, Zhang K, Liu YZ, Wang H, Han GL. Immunoglobulin G4-related hypertrophic pachymeningitis with spinal cord compression: A case report. J Neuroimmunol. 2020;347:577325. Vakrakou AG, Evangelopoulos ME, Boutzios G, Tzanetakos D, Tzartos J, Velonakis G, Toulas P, Anagnostouli M, Andreadou E, Koutsis G, Stefanis L, Fragoulis GE, Kilidireas C. Recurrent myelitis and asymptomatic hypophysitis in IgG4-related disease: case-based review. Rheumatol Int. 2020;40:337-343. Zhang R, Gao J, Zhao T, Zhang B, Wang C, Wang C, Cui L, Chen J, Fang S. A Case With IgG4-Related Spinal Pachymeningitis Causing Spinal Cord Compression. Front Neurol. 2020;11:500. van den Elshout-den Uyl D, Spoto CPE, de Boer M, Leiner T, Leavis HL, Leguit RJ. First Report of IgG4 Related Disease Primary Presenting as Vertebral Bone Marrow Lesions. Front Immunol. 2019;10:1910. Merza N, Taha A, Lung J, Benderman AW, Wright SE. IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature. Case Reports Immunol. 2019;2019:3618510. Bridges KJ, DeDeaux CH, Than KD. IgG4-related disease presenting as intradural extramedullary lesion: a case report and review of the literature. Br J Neurosurg. 2019;33:570-576. Levraut M, Cohen M, Bresch S, Giordana C, Burel-Vandenbos F, Mondot L, Sedat J, Fontaine D, Bourg V, Martis N, Lebrun-Frenay C. Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review. Neurol Neuroimmunol Neuroinflamm. 2019;6:e568. Slade SJ, Bauer EM, Stone VV, Dave AJ. Spinal IgG4-Related Hypertrophic Pachymeningitis with Spinal Cord Compression: Case Report and Literature Review. World Neurosurg. 2019;130:65-70. Winkel M, Lawton CD, Sanusi OR, Horbinski CM, Dahdaleh NS, Smith ZA. Neuro-surgical considerations for treating IgG4-related disease with rare spinal epidural compression. Surg Neurol Int. 2018;9:209. Williams MM, Mashaly H, Puduvalli VK, Jin M, Mendel E. Immunoglobulin G4-related disease mimicking an epidural spinal cord tumor: case report. J Neurosurg Spine. 2017;26:76-80. Zhao Q, Dong A, Bai Y, Wang Y, Zuo C. FDG PET/CT in Immunoglobulin G4-Related Spinal Hypertrophic Pachymeningitis. Clin Nucl Med. 2017;42:958-961. Maher M, Zanazzi G, Faust P, Nickerson K, T Wong T. IgG4-related hypertrophic pachymeningitis of the spine with MPO-ANCA seropositivity. Clin Imaging. 2017;46:108-112. Tang R, Li F, Chen Q. A case report of atypical long segmental thoracic hypertrophic pachymeningitis with ossification of ligamentum flavum and literature review. Eur Spine J. 2017;26:202-206. Rumalla K, Smith KA, Arnold PM. Immunoglobulin G4-related epidural inflammatory pseudotumor presenting with pulmonary complications and spinal cord compression: case report. J Neurosurg Spine. 2017;26:688-693. Radotra BD, Aggarwal A, Kapoor A, Singla N, Chatterjee D. An orphan disease: IgG4-related spinal pachymeningitis: report of 2 cases. J Neurosurg Spine. 2016;25:790-794. Ferreira NR, Vaz R, Carmona S, Mateus S, Pereira P, Fernandes L, Moreira H, Chorão M, Saldanha L, Carvalho A, Campos L. IgG4-related disease presenting with an epidural inflammatory pseudotumor: a case report. J Med Case Rep. 2016;10:61. Gu R, Hao PY, Liu JB, Wang ZH, Zhu QS. Cervicothoracic spinal cord compression caused by IgG4-related sclerosing pachymeningitis: a case report and literature review. Eur Spine J. 2016;25:147-51. Ezzeldin M, Shawagfeh A, Schnadig V, Smith RG, Fang X. Hypertrophic spinal pachymeningitis: idiopathic vs. IgG4-related. J Neurol Sci. 2014;347:398-400. Zwicker J, Michaud J, Torres C. IgG4-related Disease Presenting as Dural Thickening - A Rare Cause of Myelopathy. Can J Neurol Sci. 2014;41:392-6. Kim SH, Kang Y, Oh SH, Paik S, Kim JS. Paraplegia in a Patient With IgG4-Related Sclerosing Disease: A Case Report. Ann Rehabil Med. 2014;38:856-60. Choi SH, Lee SH, Khang SK, Jeon SR. IgG4-related sclerosing pachymeningitis causing spinal cord compression. Neurology. 2010;75:1388-90. Chan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009;33:1249-52. Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABLE1.docx T1.jpg T2W.jpg file.jpg 2024121812001110.00X.jpg 2024121812001140.00X.jpg CD3840.00X.jpg cd13840.00X.jpg IGG40.00X.jpg IGG440.00X01.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6253248","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":463297305,"identity":"b9da542c-fa7b-468a-9255-0a6273a79dd3","order_by":0,"name":"Yingjing Du","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yingjing","middleName":"","lastName":"Du","suffix":""},{"id":463297306,"identity":"9d727aeb-309d-49ae-a894-a61debee9750","order_by":1,"name":"Shuosi Liu","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Shuosi","middleName":"","lastName":"Liu","suffix":""},{"id":463297307,"identity":"1650b037-9257-482b-8f4f-5548db74290f","order_by":2,"name":"Yuqing Ge","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuqing","middleName":"","lastName":"Ge","suffix":""},{"id":463297308,"identity":"cc4b9325-bd18-4b4d-9381-924d46484395","order_by":3,"name":"Qundi Luo","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qundi","middleName":"","lastName":"Luo","suffix":""},{"id":463297309,"identity":"52554cc5-c25d-4bc8-858b-197f572d690a","order_by":4,"name":"Xuechen Lin","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuechen","middleName":"","lastName":"Lin","suffix":""},{"id":463297310,"identity":"a0c6ea06-5409-4f7f-9142-00ba971ce964","order_by":5,"name":"yuhuan Qu","email":"","orcid":"","institution":"Southern Medical University","correspondingAuthor":false,"prefix":"","firstName":"yuhuan","middleName":"","lastName":"Qu","suffix":""},{"id":463297311,"identity":"edde4dbb-147b-4f7f-a223-17fd1665005a","order_by":6,"name":"Jing Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYHCChAMMDDY8bOyNjQ8/kKAlTYaP53CzsQQJNh22kZNIbxPgIUatwY2Eh4cLfjHzsEk+bGOQYLCT020grCXh8Mw+Nh426cS2BwUMycZmBwhoMQNp4e3hAWlpN5BgOJC4jUgtEkCHHWyT4CFaC88PAx42CUYitdifeQC0pSGBh40nERjIBkT4RbI9J/kzz5//9vLtxx8+/FBhJ0dQCwMDTwIDYxuMY0BQOQiwA039Q5TKUTAKRsEoGKkAAE41Qu0H7+AUAAAAAElFTkSuQmCC","orcid":"","institution":"Southern Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jing","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2025-03-18 12:38:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6253248/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6253248/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83752232,"identity":"e6c53d4d-5a8e-4694-87c7-cc7b6f1f58ee","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":555093,"visible":true,"origin":"","legend":"\u003cp\u003ePlain and contrast-enhancedmagnetic resonance imaging (MRI). Thoracic spine MR image revealedan intradural extramedullary lesion along the ventral spinal canal extending from T2-T4, which appeared to be a dural tail. A| Sagittal T1-weighted MR image showing an isointensive signal lesion in the spinal cord at the T9--10 level. B| Sagittal T2-weighted MR image demonstrating a hypointense signal mass. C| Sagittal postcontrast T1-weighted MR image showing that the mass was homogeneously enhanced. D/E| Axial postcontrast T1-weighted MR image showing thatthe mass was homogeneously enhanced. The white arrow is mainly used to show the location of the lesion.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/22ef7e21b0bad978b9da85fa.png"},{"id":83752233,"identity":"cc04ecc7-8dac-4bf5-8b2d-cc50599326b5","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4079649,"visible":true,"origin":"","legend":"\u003cp\u003eA| The histology of the intradural extramedullary lesion revealedextensive lymphoplasmacytic infiltration with fibrosis, and a 100x magnification view of hematoxylin and eosin (H\u0026amp;E) staining revealedstoriform fibrosis and inflammatory cell infiltration. B| 400x magnification view showingrich lymphoplasmacytic infiltrates (plasma cells, eosinophils, macrophages, and lymphocytes) and some neutrophil infiltration. C| Immunohistochemistry of infiltrating plasma cells (CD38+). D| Immunohistochemistry of infiltrating plasma cells (CD138+). E| A 200x magnification view of the IgG immunostaining results demonstrated that most of the plasma cells werepositively stained. F| 400x magnification view of IgG4 immunostaining (from the same area shown in (E)) showingthat when the numberof IgG4-positive cells was \u0026gt;10/HPF, the ratio of IgG4 to IgG was approximately 44.3%.\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/38781e629cbc169927aa437c.jpg"},{"id":83752363,"identity":"d6047190-c05a-486b-81d6-169c289a8c82","added_by":"auto","created_at":"2025-06-02 07:21:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":187475,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart summarizing the literature.\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/9a704ef4f332ab4e505e21ea.jpg"},{"id":83752234,"identity":"b56fd23a-8375-4849-9587-945aadfcac21","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1203286,"visible":true,"origin":"","legend":"\u003cp\u003eA|Relationship between age and sexin SHP; B|Common clinical presentations; C|Results of laboratory tests, including serum IgG4, C-reactive protein (CRP), the erythrocyte sedimentation rate (ESR) and cerebrospinal fluid (CSF); D|Localisationof the spine involved in the lesion and localisationof the dura mater; E|Different treatments and outcomes.\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/e3c87e57c241b167f61617cc.jpg"},{"id":92914842,"identity":"30eaad5f-a8ec-49f8-979a-a5fc1e9fe6c9","added_by":"auto","created_at":"2025-10-07 05:02:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6541913,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/cb2dcf01-81c2-446e-a74e-5436959a2423.pdf"},{"id":83752362,"identity":"172de3dc-45cd-4c71-8af6-96d4e83904fe","added_by":"auto","created_at":"2025-06-02 07:21:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":91654,"visible":true,"origin":"","legend":"","description":"","filename":"TABLE1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/6f96e35efd846357da7d3811.docx"},{"id":83752230,"identity":"d257c0ad-57a4-41bd-90ce-1a583b2e70db","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":272337,"visible":true,"origin":"","legend":"","description":"","filename":"T1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/addcb2027ff0081cba37350b.jpg"},{"id":83752228,"identity":"e53682e4-2804-45b8-8438-09440b6d0f2e","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":128695,"visible":true,"origin":"","legend":"","description":"","filename":"T2W.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/33d8a6145764f3ca3b19cd49.jpg"},{"id":83752235,"identity":"b6938022-8f7f-43f7-a60d-9a8e3e482f37","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":65915,"visible":true,"origin":"","legend":"","description":"","filename":"file.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/cbdcf6ad2481bf63eb2ea214.jpg"},{"id":83752365,"identity":"8b708c3c-6eea-456f-a5ca-8ecc0676eb1f","added_by":"auto","created_at":"2025-06-02 07:21:01","extension":"jpg","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":1576332,"visible":true,"origin":"","legend":"","description":"","filename":"2024121812001110.00X.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/8afd643f5f7732da676ae5dc.jpg"},{"id":83752241,"identity":"4b625a7b-19c3-45a0-b392-54ab8eb43a39","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":852627,"visible":true,"origin":"","legend":"","description":"","filename":"2024121812001140.00X.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/67e5bd430ea0b7193bc2e6f3.jpg"},{"id":83752364,"identity":"9deaf8cf-8b35-4ac3-8d9d-b14c9d92c90b","added_by":"auto","created_at":"2025-06-02 07:21:01","extension":"jpg","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":660220,"visible":true,"origin":"","legend":"","description":"","filename":"CD3840.00X.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/d383ae7db562d5ee8253ce89.jpg"},{"id":83752238,"identity":"e1154df9-285c-4ae7-bd63-cd184cfc21ce","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":646245,"visible":true,"origin":"","legend":"","description":"","filename":"cd13840.00X.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/2ace2a180b1691ba522f9296.jpg"},{"id":83752236,"identity":"8b753940-84c6-4299-82eb-78989622f429","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":798835,"visible":true,"origin":"","legend":"","description":"","filename":"IGG40.00X.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/19611e9d3e289d063351030c.jpg"},{"id":83752240,"identity":"f67c1586-373f-44c0-a050-2278d6a62012","added_by":"auto","created_at":"2025-06-02 07:13:01","extension":"jpg","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":677498,"visible":true,"origin":"","legend":"","description":"","filename":"IGG440.00X01.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6253248/v1/80e0825b6b64c57e97d85a98.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"IgG4-Related Spinal Hypertrophic Pachymeningitis: A Case Report and Systematic Review of 60 Cases","fulltext":[{"header":"Background","content":"\u003cp\u003eIgG4-related disease (IgG4-RD) is a chronic immune-mediated disorder characterized by fibrosis, tissue swelling, and IgG4-rich plasma cell infiltration. First identified in 2001 in autoimmune pancreatitis [1], it was later defined as a distinct disease by Kamisawa et al. in 2003 [2]. Common affected organs include the salivary glands, pancreas, and kidneys, while central nervous system (CNS) involvement is rare. Among neurological manifestations, hypophysitis and hypertrophic pachymeningitis are the most frequently reported [3]. Spinal involvement, particularly IgG4-related hypertrophic spinal pachymeningitis (IgG4-SHP), is exceptionally rare. First described in 2009, IgG4-SHP involves fibrotic thickening of the spinal dura, often causing nerve root or spinal cord compression [4]. Its nonspecific symptoms and resemblance to spinal tumors make early diagnosis challenging. Limited awareness among clinicians further delays treatment, increasing the risk of permanent neurological damage.\u003c/p\u003e\n\u003cp\u003eIn this study, we present a case of IgG4-SHP diagnosed at Zhujiang Hospital of Southern Medical University. We also reviewed published cases from PubMed and other databases to better understand the disease and improve clinical recognition. Our goal is to promote early diagnosis, optimize treatment, and prevent severe outcomes like spinal cord injury or paraplegia.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003e1.1 Medical history and physical examination\u003c/p\u003e\n\u003cp\u003eA 50-year-old male presented with progressive bilateral lower limb numbness and weakness over one month, accompanied by perineal paresthesia radiating to the soles. Neurological examination revealed asymmetric weakness (right \u0026gt; left) without systemic symptoms (MRC 2/5 bilaterally) . Symptoms progressed to ambulatory dysfunction, lumbar fatigue, and lower limb myoclonus (1-2/min), with reduced bladder/bowel frequency. Thoracic dural lesion resection was performed on March 29, 2024.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1.2 Radiological examination\u003c/p\u003e\n\u003cp\u003eSpinal magnetic resonance imaging (MRI) revealed long T1 and long T2 signal shadows within the epidural spinal canal at the level of the thoracic vertebrae (2-4), which exhibited notable visibility. (Fig. 1)\u003c/p\u003e\n\u003cp\u003e1.3 Laboratory examination\u003c/p\u003e\n\u003cp\u003eLaboratory investigations demonstrated elevated inflammatory markers, including erythrocyte sedimentation rate (64 mm/h; normal \u0026lt;15 mm/h), C-reactive protein (9.21 mg/L; normal \u0026lt;5 mg/L), leukocytosis (11.3 G/L; normal 3.5\u0026ndash;9.5 G/L), thrombocytosis (407 G/L; normal 125\u0026ndash;350 G/L), and interleukin-6 elevation (8.73 pg/mL; normal \u0026lt;7 pg/mL). Mild normocytic anemia (hemoglobin 116 g/L) was concurrently observed. Notably, serological evaluations excluded alternative diagnoses: serum protein electrophoresis, humoral immunity profiles (including immunoglobulins IgA/IgM), autoimmune markers (antinuclear antibody, rheumatoid factor), vasculitis panels, and syphilis serology all fell within normal ranges. The preoperative serum IgG and IgG4 levels were not measured. Postoperatively, serum IgG was 10.3 g/L (normal 7.0\u0026ndash;16.0 g/L) and IgG4 was 0.41 g/L (normal 0.03\u0026ndash;2.01g/L).\u003c/p\u003e\n\u003cp\u003e1.4 Operation and histopathology\u003c/p\u003e\n\u003cp\u003eAn ultrasonic bone knife was used to excise the thoracic 2-4 lamina. During surgery, a novel biological sleeve surrounding the dorsal aspect of the spinal cord showed significant adhesion. The biological entity was entirely removed and sent for pathological analysis. Histopathological examination revealed sheet-like fibrosis with multifocal infiltration of lymphocytes, plasma cells, and a few neutrophils. No occlusive phlebitis was observed. Immunohistochemical analysis showed IgG4+ (\u0026gt;10/HPF) with an IgG4/IgG ratio of approximately 44.3% (Conform to the 2019 ACR/EULAR criteria). Positive markers included CD38 (plasma cell+), CD138 (plasma cell+), IgG (+), CD34 (vascular+), Ki-67 (+, 5%), CD20 (B-cell+), CD3 (T-cell+), Kappa (+), and Lambda (+). Negative markers included PR (-), SSTR-2 (scattered +), EMA (scattered +), CK (-).(Fig2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1.5 Postoperative treatment and follow-up\u003c/p\u003e\n\u003cp\u003eSurgical pathology confirmed the diagnosis of IgG4-related hypertrophic pachymeningitis, based on the Japanese Rheumatism Society\u0026apos;s criteria. Despite surgery, the patient\u0026apos;s symptoms persisted, prompting further treatment with 20 mg oral methylprednisolone in the Department of Rheumatology and Immunology. After one month of outpatient treatment, there was significant improvement in lower limb muscle strength, reduced numbness, and normalization of urinary function.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e2.1 Literature Retrieval and Inclusion and Exclusion Criteria\u003c/p\u003e\n\u003cp\u003eThe literature review followed the Japanese Society of Rheumatology\u0026apos;s criteria[5]. Search terms included: (IgG4-related hypertrophic pachymeningitis) AND (spine), (IgG4-related spinal hypertrophic pachymeningitis), and (hypertrophic pachymeningitis) AND (spine). Searches in PubMed, CNKI, and other databases identified 200 articles as of November 25, 2024. Diagnosis was based on three criteria: (1) clinical signs of edema or mass in one or more organs; (2) elevated serum IgG4 (\u0026gt;135 mg/dL); (3) histopathology with lymphocyte and plasma cell infiltration and fibrosis. IgG4-positive plasma cell infiltration was defined by \u0026gt;40% IgG4/IgG-positive cells or \u0026gt;10 cells per high-powered field in biopsy. Diagnosis is confirmed when any combination of criteria is met.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria were clear indications such as tumours, tuberculosis, infectious disease, trauma, medication, and neurological disorders resulting from spinal dural thickening. According to the established inclusion and exclusion criteria, the articles were initially screened, and only 60 patients who were diagnosed with IgG4-related spinal hypertrophic pachymeningitis, which is comparable to the present case, were ultimately included in the study.\u003c/p\u003e\n\u003cp\u003e2.2 Data Information Input\u003c/p\u003e\n\u003cp\u003eThe following data were extracted: publication date, patient demographics, clinical presentations, mass location, laboratory findings, MRI results, treatments, and outcomes (Table 1).\u003c/p\u003e\n\u003cp\u003e2.3 Statistical analysis\u003c/p\u003e\n\u003cp\u003eThe following data were analysed with SPSS 26.0: categorical data such as n (%), chi-square tests or Fisher\u0026apos;s tests for group comparisons (for samples\u0026lt;40), t tests for continuous data, and significance at P \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e3.1 Clinical and Imaging Findings\u003c/p\u003e\n\u003cp\u003eOf the 60 patients, 36 (60%) were male and 24 (40%) were female, with a mean age of 49.05 years (SD=14.29). No significant age difference was found between genders (P \u0026gt; 0.05) (Fig. 4A). Symptoms were primarily linked to the location of spinal cord compression. The most common symptoms were limb weakness, sensory disturbances, and low back pain, which eventually led to ambulatory difficulties and incontinence (Fig. 4B). Fourteen patients had involvement in other systems, and 7 experienced bone destruction. The median symptom duration was 2.0 months, ranging from 1 week to 48 months.\u003c/p\u003e\n\u003cp\u003eSpinal cord MRI was performed on 54 patients, showing that IgG4-SHP most often affected the thoracic spine, followed by the cervical+thoracic spine, cervical spine, lumbar spine, and combinations of these regions (Fig. 4D). Tumours were mainly found in the epidural space. On T1-weighted MRI, 29 lesions had low signal intensity, and 8 had equal intensity. On T2-weighted MRI, 29 lesions were low signal, and 13 were high signal. All lesions showed enhancement.\u003c/p\u003e\n\u003cp\u003e3.2 Laboratory Examination and Pathological Immunohistochemistry\u003c/p\u003e\n\u003cp\u003eIn our study of 60 IgG4-SHP patients, 41.7% had elevated serum IgG4, while 30.0% had normal levels. CRP and ESR increased by 31.7% and 33.3%, respectively. These findings highlight the importance of histopathology and inflammatory markers in diagnosing and assessing disease activity. Of the 18 patients with cerebrospinal fluid identified, 14 had comprehensive testing, revealing abnormalities in most, while 4 tests were normal (Fig. 4C).\u003c/p\u003e\n\u003cp\u003e3.3 Treatment and Outcomes\u003c/p\u003e\n\u003cp\u003eIn this study, 58 patients had surgery, while 2 were treated with steroids and azathioprine or steroids alone. Of the 60 patients, 50 were on steroids, and 27 had surgery; 21 received immunosuppressive agents. Nine patients had recurrence and were treated with surgery or steroids. Of the 55 with symptom relief, 6 relapsed but improved with further treatment. Two were lost to follow-up, and 3 died. Immunosuppressive regimens included cyclophosphamide, azathioprine, methotrexate, and rituximab (Fig. 3E). After adjustments, 6 patients achieved remission, with no significant outcome differences (P \u0026gt; 0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e4.1 Epidemiology and clinical manifestations\u003c/p\u003e\n\u003cp\u003eIgG4-RD is an autoimmune condition that has gained recognition over the past 20 years. Its diverse clinical manifestations can lead to misdiagnosis and overlooked cases. IgG4-related pachymeningitis (IgG4-RHP) was once classified as idiopathic hypertrophic pachymeningitis (IHPM), but numerous studies have confirmed that it is an IgG4-related disease [6]. IgG4-RHP makes up less than 1% of all IgG4-RD cases, but it accounts for 8% to 29% in patients with hypertrophic pachymeningitis. A Japanese study found that IgG4-RHP is more common in males, with a male-to-female ratio of 1:0.17 and an average onset age of approximately 56.7 years [7]. Additionally, a single-center prospective cohort study identified 4 cases of IgG4-RHP among 589 patients with IgG4-RD, including 2 males and 2 females [8]. IgG4-SHP shows no significant sex difference, but is primarily observed in middle-aged and elderly individuals. The study included 60 patients, comprising 36 males and 24 females, resulting in a male-to-female ratio of 1:0.67, with a mean age of 49.05 years. There was no significant age difference between males and females (P \u0026gt; 0.05), which is consistent with findings from Ibrahim Sbeih's literature review. IgG4-SHP is more prevalent in middle-aged and elderly patients, and sex does not appear to significantly influence its pathogenesis.\u003c/p\u003e\n\u003cp\u003eIgG4-RD can manifest in one or multiple organs, with spinal cord compression due to spinal involvement being rare. In a seminal publication, Chan first described IgG4-related hypertrophic spinal pachymeningitis, characterized by diffuse dural fibrosis. This condition typically leads to nerve root and/or spinal cord compression, resulting in associated clinical symptoms [4]. In this study, patients exhibited motor and sensory disorders, limb weakness, and low back pain, which could progress to gait difficulties and incontinence. Some patients also had nonspecific systemic symptoms like weight loss, fever, shortness of breath, and fatigue. The median duration of symptoms was 2.0 months (1 week to 48 months). Fourteen patients had involvement of other systems, and 6 showed bone destruction. MIKAWA noted that the time from the onset of pain to motor paralysis ranged from 3 days to 5 years, averaging 10 months [9]. Disease progression varies significantly; without timely treatment, most patients may deteriorate, leading to irreversible damage. Therefore, establishing an effective early diagnosis system for IgG4-SHP is crucial.\u003c/p\u003e\n\u003cp\u003e4.2 Imaging findings\u003c/p\u003e\n\u003cp\u003eMagnetic resonance imaging (MRI) is the primary tool for diagnosing IgG4-SHP. Studies show it typically presents as a long banded mass outside the dura mater, often affecting the thoracic and lumbar dura, with low signal on T1WI and T2WI and homogeneous enhancement on T1WI. In this study of 52 patients, MRI results confirmed previous findings, indicating that IgG4-SHP predominantly involves the thoracic spine, followed by the cervical+thoracic spine, cervical spine, and lumbar spine, with some cases showing multiregional or total spinal cord involvement.In these cases, tumors are often found in the epidural space. T1WI typically shows low or equal signal, while T2WI may show low or high signal, with all patients displaying noticeable enhancement. MRI enhancement correlates with pathological changes; pronounced enhancement indicates inflammatory cell infiltration, whereas less discernible enhancement occurs when collagen fiber proliferation is minimal [10].Numerous studies have utilized computed tomography (CT) or positron emission tomography-computed tomography (PET-CT) to assess bone involvement in patients with IgG4-SHP and to monitor active lesions in other organs. Recent research underscores the significant role of FDG PET-CT in the evaluation of IgG-related diseases, as it facilitates the identification of previously unnoticed sites of involvement and aids in the monitoring of disease activity and treatment responses [11]. In our study, six patients exhibited varying degrees of bone destruction, with two undergoing CT and two receiving PET-CT evaluations.\u003c/p\u003e\n\u003cp\u003e4.3 Laboratory examination\u003c/p\u003e\n\u003cp\u003eSerum IgG4 levels are commonly used as a diagnostic marker for IgG4-SHP. However, Kosakai and Lu found that about 80% of cases had normal serum IgG4 levels [12], suggesting that these levels are not a critical diagnostic parameter. Elevated serum IgG4 may assist in diagnosis when immunohistochemical analysis is not available [10]. In our review, among 43 patients evaluated, 25 had elevated serum IgG4 levels and 18 had normal levels, indicating the limited sensitivity and specificity of serum IgG4 in diagnosing IgG4-SHP. Additionally, IgG4 levels in cerebrospinal fluid (CSF) can serve as an important diagnostic indicator and a tool for monitoring treatment efficacy. Della Torre reported that the IgG4 CSF/IgG4 serum/albumin CSF/albumin serum ratio is a reliable marker of intrathecal IgG4 synthesis, with a normal range of 0.25 to 0.91 [13]. Furthermore, an IgG4Loc \u0026gt; 0.47 is an effective criterion for identifying IgG4-related hypersensitivity pneumonitis (HP) and other causes of inflammatory meningitis, demonstrating 100% sensitivity and specificity. Routine biochemical and cytological examinations of CSF are crucial for detecting infections and malignant tumors. In our study, CSF was analyzed in 18 patients, of whom 14 exhibited one or more abnormalities in the tests (including CSF pressure, IgG levels, and routine biochemical, bacterial, and fungal cultures), while 4 showed normal results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eElevated inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, are not specific indicators for diagnosing IgG4-SHP, as they are frequently observed in infections and other inflammatory conditions. Our findings further emphasize that these markers lack the specificity needed for a definitive diagnosis of IgG4-SHP.\u003c/p\u003e\n\u003cp\u003e4.4 Histopathology and immunohistochemistry\u003c/p\u003e\n\u003cp\u003eDue to the lack of specificity in imaging and laboratory tests for diagnosing IgG4-SHP, histopathological and immunohistochemical findings from spinal dural biopsy remain the gold standard for diagnosis. Both the 2011 Japanese Rheumatism Association IgG4-RD diagnostic criteria and the 2019 ACR/EULAR classification criteria place significant emphasis on pathological diagnosis for IgG4-RD [5,14]. The typical histopathological features of IgG4-RD include dense lymphocyte infiltration (IgG4/IgG+ cells \u0026gt;40% and/or IgG4+ plasma cells \u0026gt;10/HPF), sheet-like swirling fibrosis (collagen fibers arranged in a radial, interlaced, swirling pattern), and obliterative phlebitis [11]. In IgG4-SHP, occlusive phlebitis is rare. Additionally, tissue eosinophilia and lymphoid follicular infiltration may also be present in some cases. In this systematic review, all patients with pathological diagnoses met the Japanese Rheumatology Association IgG4-SHP criteria.\u003c/p\u003e\n\u003cp\u003e4.5 Treatment and Outcomes\u003c/p\u003e\n\u003cp\u003eIn IgG4-SHP, the primary treatment is steroid therapy, which has been shown to reduce inflammation, mitigate the placeholder effect, and significantly improve patient prognosis [15]. The clinical response is rapid and highly effective, particularly in the early stages of the disease, with effectiveness rates reaching 97% to 98%. For patients with recurrent or refractory IgG4-RD who do not respond to steroids or have contraindications, immunosuppressive agents like cyclophosphamide, methotrexate, and azathioprine can be more effective in reducing recurrence and improving remission rates. Rituximab (RTX), a monoclonal antibody targeting CD20, has demonstrated a lower recurrence rate compared to steroid and traditional immunosuppressive combinations [16]. In this literature review, 27 patients were treated with a combination of surgery and steroids, while 21 patients received surgery, steroids, and immunosuppressive agents. The most commonly used immunosuppressive agent was cyclophosphamide. Six patients were treated with rituximab, and all of them showed a significant clinical response. Among the cohort, three patients who were treated with steroids alone experienced disease recurrence. However, their condition improved clinically after modifying the treatment plan to include either surgery or immunosuppressive agents. This study suggests that steroid therapy alone is insufficient for certain patients, highlighting the need for additional therapeutic interventions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdditionally, surgical intervention is necessary for patients who demonstrate nerve root and/or spinal cord compression, progressive neurological decline, or severe fibrosis. Decompression of the nerve or spinal cord is essential to maintain spinal stability and obtain adequate tissue for diagnosis [17]. Early and timely surgical intervention can prevent the disease from progressing to irreversible nerve damage or even paralysis. Despite early and timely surgical treatment, some patients still experience a poor short-term prognosis. Of the 58 patients who underwent surgery, 3 who received only surgical treatment experienced disease recurrence. However, their condition improved after the addition of drug therapy. This study found no significant difference in the outcomes of the various treatment regimens (P \u0026gt; 0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prognosis and outcome of IgG4-SHP patients are primarily monitored through the observation of clinical manifestations, imaging, and serum IgG4 levels, with improvement in these factors serving as the primary indicator of treatment efficacy. Most patients with IgG4-SHP can achieve clinical remission with the combined use of surgical, steroid, and immunosuppressant therapies. Only a few patients succumb to their underlying medical conditions, non-adherence to treatment plans, or complications from steroid side effects. Due to the lack of long-term follow-up studies, the long-term prognosis of patients with spinal IgG4-HP remains controversial. The degree of fibrosis during treatment is thought to be inversely related to the clinical response and may serve as a prognostic factor [15].\u003c/p\u003e"},{"header":"Summary","content":"\u003cp\u003eThis study presented a case of IgG4-SHP, which was confirmed by pathology after surgery. The patient's clinical symptoms improved following surgical intervention and steroid administration. Subsequently, we compiled the confirmed cases of IgG4-SHP from the past 20 years and conducted a statistical analysis. IgG4-SHP primarily affects middle-aged and elderly patients, with the most common presentation being a thoracic epidural mass. The clinical manifestations, imaging findings, and laboratory test results are non-specific. A combination of histopathological and immunohistochemical findings provides the most reliable basis for diagnosis. Steroid therapy remains the first-line treatment. In cases where patients present with compression symptoms or do not respond to steroid therapy, surgical intervention or the use of immunosuppressive agents may be indicated. Furthermore, long-term follow-up for IgG4-SHP patients is essential. A better understanding of the disease by healthcare providers, along with prompt diagnosis and treatment, can effectively prevent disease progression and recurrence, ultimately improving patient survival rates.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIgG4-RHP: IgG4-related hypertrophic pachymeningitis; IgG4-SHP: IgG4-related spinal hypertrophic pachymeningitis; IgG4-RD: IgG4-related disease; MRI: Spinal magnetic resonance imaging; CRP: C-Reactive Protein; ESR: Erythrocyte Sedimentation Rate; CSF: Cerebro-Spinal Fluid; M: Male, F: Female; NR: Not Reported; Iso: Iso Intensity; Hypo: Hypo Intensity; Hyper: Hyperintensity; CTX: Cyclophosphamide; MTX: Methotrexate; AZA: Azathioprine; RTX: Rituximab.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Zhujiang Hospital Ethics Committee (Approval No. 2025-KY-030). Written informed consent was obtained from the patient for publication of this case report and any accompanying images. All data presented in this manuscript are anonymized, and no identifying information of the patient is included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients for publication of the case reports and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no conflicts of interest among the medical staff or the authors involved in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the\u003c/p\u003e\n\u003cp\u003epublic, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors were involved in the treatment of the patients and collected and organised the cases reported previously. Du wrote the initial draft of the manuscript. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth authors are from Zhujiang Hospital, Southern Medical University, Guangzhou, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eThe Second School of Clinical Medicine,Southern Medical University，Guangzhou, China. \u003csup\u003e2\u003c/sup\u003eZhujiang Hospital, Southern Medical University, Guangzhou, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732-8.\u003c/li\u003e\n\u003cli\u003eKamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, Okamoto A, Egawa N, Nakajima H. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982-4.\u003c/li\u003e\n\u003cli\u003eBaptista B, Casian A, Gunawardena H, D'Cruz D, Rice CM. Neurological Manifestations of IgG4-Related Disease. Curr Treat Options Neurol. 2017;19:14.\u003c/li\u003e\n\u003cli\u003eChan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognised form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009;33:1249-52.\u003c/li\u003e\n\u003cli\u003eUmehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21-30.\u003c/li\u003e\n\u003cli\u003eWu LN, Lu DH, Piao YS. Advances in IgG4-related hypertrophic pachymeningitis. Zhonghua Nei Ke Za Zhi. 2023;62:1139-1143.\u003c/li\u003e\n\u003cli\u003eYonekawa T, Murai H, Utsuki S, Matsushita T, Masaki K, Isobe N, Yamasaki R, Yoshida M, Kusunoki S, Sakata K, Fujii K, Kira J. A nationwide survey of hypertrophic pachymeningitis in Japan. J Neurol Neurosurg Psychiatry. 2014;85:732-9.\u003c/li\u003e\n\u003cli\u003ePeng L, Zhang P, Zhang X, Li J, Zhao J, Liu J, Fei Y, Zhang W, Zhu Y, Zhao Y, Zeng X. Clinical features of immunoglobulin G4-related disease with central nervous system involvement: an analysis of 15 cases. Clin Exp Rheumatol. 2020;38:626-632.\u003c/li\u003e\n\u003cli\u003eMikawa Y, Watanabe R, Hino Y, Hirano K. Hypertrophic spinal pachymeningitis. Spine (Phila Pa 1976). 1994;19:620-5.\u003c/li\u003e\n\u003cli\u003eAlrashdi MN. Immunoglobulin G4-related spinal pachymeningitis. Saudi Med J. 2020;41:652-656.\u003c/li\u003e\n\u003cli\u003eLu LX, Della-Torre E, Stone JH, Clark SW. IgG4-related hypertrophic pachymeningitis: clinical features, diagnostic criteria, and treatment. JAMA Neurol. 2014;71:785-93.\u003c/li\u003e\n\u003cli\u003eLu Z, Tongxi L, Jie L, Yujuan J, Wei J, Xia L, Yumin Z, Xin L. IgG4-related spinal pachymeningitis. Clin Rheumatol. 2016;35:1549-53.\u003c/li\u003e\n\u003cli\u003eDella Torre E, Bozzolo EP, Passerini G, Doglioni C, Sabbadini MG. IgG4-related pachymeningitis: evidence of intrathecal IgG4 on cerebrospinal fluid analysis. Ann Intern Med. 2012;156:401-3.\u003c/li\u003e\n\u003cli\u003eWallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Schleinitz N, Takahashi N, Umehara H, Zen Y, Stone JH. Members of the ACR/EULAR IgG4-RD Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis. 2020;79:77-87.\u003c/li\u003e\n\u003cli\u003eSbeih I, Darwazeh R, Shehadeh M, Al-Kanash R, Abu-Farsakh H, Sbeih A. Immunoglobulin G4-Related Hypertrophic Pachymeningitis of the Spine: A Case Report and Systematic Review of the Literature. World Neurosurg. 2020;143:445-453.\u003c/li\u003e\n\u003cli\u003eCampochiaro C, Della-Torre E, Lanzillotta M, Bozzolo E, Baldissera E, Milani R, Arcidiacono PG, Crippa S, Falconi M, Dagna L. Long-term efficacy of maintenance therapy with Rituximab for IgG4-related disease. Eur J Intern Med. 2020;74:92-98.\u003c/li\u003e\n\u003cli\u003eKramer DE, Kerolus MG, Furlan K, Nag S, O'Toole JE. Recurrent IgG4-Related Meningeal Disease of the Cervicothoracic Spine: A Case Report and Review of the Literature. Neurol India. 2022;70:1180-1186.\u003c/li\u003e\n\u003cli\u003eChae TS, Kim DS, Kim GW, Won YH, Ko MH, Park SH, Seo JH. Immunoglobulin G4-related spinal pachymeningitis: A case report. World J Clin Cases. 2024;12:6551-6558.\u003c/li\u003e\n\u003cli\u003eParlak A, Mueller CA, Nolte KW, Schmidt TP, Bertram U, Clusmann H, Blume C. Cervical myelopathy caused by IgG4-related hypertrophic spinal pachymeningitis: Case report and a descriptive review of the literature. Brain Spine. 2024;4:103325.\u003c/li\u003e\n\u003cli\u003eChau HHT, Lo BA, Chu WP, Ho HN, Tsui WM. A case of IgG4-related disease manifesting as a spinal epidural mass. BJR Case Rep. 2024;10:uaae022.\u003c/li\u003e\n\u003cli\u003eHuang Y, Liu Y. IgG4-related disease involving the cervical spinal cord. J Clin Neurosci. 2024;124:78-80.\u003c/li\u003e\n\u003cli\u003eTakeuchi T, Takizawa H, Bando Y, Hosokawa A, Sumitomo H, Miyamoto N, Sakamoto S, Morishita A, Kawakita N, Toba H. Robot-assisted thoracoscopic resection of a posterior mediastinal tumor with immunoglobulin G4-related disease: a case report. J Cardiothorac Surg. 2024;19:291.\u003c/li\u003e\n\u003cli\u003eTanaviriyachai T, Chinvattanachot G, Piyapromdee U, Sirisanthiti P. IgG4-Related Spinal Hypertrophic Pachymeningitis With Neurological Deficit: A Report of 2 Cases. JBJS Case Connect. 2023;13.\u003c/li\u003e\n\u003cli\u003eRath PD, Katoch S, Agrawal AK, Chouhan S, Bajaj HN, Bisaralli R. Mass: The Conundrum in Spine. J Orthop Case Rep. 2023;13:37-40.\u003c/li\u003e\n\u003cli\u003eYu H, Lu C, Duan W, Dong Y, Wang Z, Wang X, Jian F. A selected case series of idiopathic hypertrophic pachymeningitis in a single center: Pathological characteristics and case-oriented review. J Neuroimmunol. 2023;383:578191.\u003c/li\u003e\n\u003cli\u003eGader G, Atig FB, Jemel N, Bourgou M, Slimane A, Ghedira K, Badri M, Zammel I. Epiduritis related to IgG4 disease: A very rare cause for spinal cord compression. Surg Neurol Int. 2023;14:205.\u003c/li\u003e\n\u003cli\u003eNathan, G Sudhakshina, Raiyani, Yatin V, Subramanyan, Annapurneswari, Balamurugan, Mangaleswaran. Intradural Extramedullary IgG4-related Disease of the Dorsal Spine. Journal of Spinal Surgery,2023;10:95-98.\u003c/li\u003e\n\u003cli\u003eYang F, Liu Z, Zhang Y, Li P, Zhu Y, Zhu Q, Zhang B. Case report: Clinical highlights and radiological classification of IgG4-related spinal pachymeningitis: A rare case series and updated review of the literature. Front Oncol. 2023;12:1035056.\u003c/li\u003e\n\u003cli\u003eQi Z, Liu J, Li G, Zhang Y. Immunoglobulin G4-Related Spinal Intramedullary Inflammatory Pseudotumor: A Case Report and Literature Review. Front Neurol. 2022;13:878414.\u003c/li\u003e\n\u003cli\u003eKramer DE, Kerolus MG, Furlan K, Nag S, O'Toole JE. Recurrent IgG4-Related Meningeal Disease of the Cervicothoracic Spine: A Case Report and Review of the Literature. Neurol India. 2022;70:1180-1186.\u003c/li\u003e\n\u003cli\u003eLu Z, Tongxi L, Jie L, Yujuan J, Wei J, Xia L, Yumin Z, Xin L. IgG4-related spinal pachymeningitis. Clin Rheumatol. 2016;35:1549-53.\u003c/li\u003e\n\u003cli\u003eKarthigeyan M, Rajasekhar R, Salunke P, Gupta K. IgG4-related Pachymeningitis as a Cause of Spinal Epidural Compression: Can Intraoperative Frozen Sections Predict the Underlying Pathology? Neurol India. 2022;70:1223-1225.\u003c/li\u003e\n\u003cli\u003eXia C, Li P. IgG4-related hypertrophic pachymeningitis with ANCA-positivity: A case series report and literature review. Front Neurol. 2022;13:986694.\u003c/li\u003e\n\u003cli\u003eSharma R, Kaur K, Sasidharan A, Gupta R, Laythalling RK. IgG4-Related Disease in Intradural Extramedullary Location- Detailed Case Illustration and Literature Review with Special Emphasis on Role of Surgery in its Management. Neurol India. 2021;69:1176-1183.\u003c/li\u003e\n\u003cli\u003eKim DJ, Lee S, Cheong HJ, Hong S, Kim MJ, Jung SK, Park JH. Spinal Bony Involvement of IgG4-related Disease Treated by a Spondylectomy. NMC Case Rep J. 2021;8:27-31.\u003c/li\u003e\n\u003cli\u003eElmaci I, Altinoz MA, Akdemir G, Sari R, Baskan O, Ozpinar A, Hacker E, Sav A. Neurosurgical and neuro-immunological management of IgG4-related hypertrophic sclerosing pachymeningitis. A literature survey and discussion of a unique index case. Clin Neurol Neurosurg. 2021;200:106342.\u003c/li\u003e\n\u003cli\u003eWoo PYM, Ng BCF, Wong JHM, Ng OKS, Chan TSK, Kwok NF, Chan KY. The protean manifestations of central nervous system IgG4-related hypertrophic pachymeningitis: a report of two cases. Chin Neurosurg J. 2021;7:13.\u003c/li\u003e\n\u003cli\u003eMurugan C, Kavishwar RA, Ramachandran K, Shetty AP, B T P, Rajasekaran S. Spinal Hypertrophic Pachymeningitis Causing Thoracic Myelopathy in a Patient of Takayasu Arteritis: A Case Report. JBJS Case Connect. 2021;11.\u003c/li\u003e\n\u003cli\u003eOgaki R, Okada E, Suzuki S, Nori S, Tsuji O, Nagoshi N, Yagi M, Watanabe K, Nakamura M, Matsumoto M. Myeloperoxidase-Antineutrophil Cytoplasmic Antibody Positive Hypertrophic Spinal Pachymeningitis at the Cervicothoracic Junction: A Case Report. Spine Surg Relat Res. 2020;5:211-213.\u003c/li\u003e\n\u003cli\u003eZhang Z, Yu W, Guan W, Lin Q. IgG4-rRelated Disease-Rare Presentation With Spinal Involvement. Arthritis Rheumatol. 2020;72:1828.\u003c/li\u003e\n\u003cli\u003ePark BJ, Starks R, Kirby P, Menezes AH, Dlouhy BJ. IgG4-Related Disease of the Craniovertebral Junction. World Neurosurg. 2020;134:264-271.\u003c/li\u003e\n\u003cli\u003eLi HX, Zuo L, Peng XX, Zong Q, Zhang K, Liu YZ, Wang H, Han GL. Immunoglobulin G4-related hypertrophic pachymeningitis with spinal cord compression: A case report. J Neuroimmunol. 2020;347:577325.\u003c/li\u003e\n\u003cli\u003eVakrakou AG, Evangelopoulos ME, Boutzios G, Tzanetakos D, Tzartos J, Velonakis G, Toulas P, Anagnostouli M, Andreadou E, Koutsis G, Stefanis L, Fragoulis GE, Kilidireas C. Recurrent myelitis and asymptomatic hypophysitis in IgG4-related disease: case-based review. Rheumatol Int. 2020;40:337-343.\u003c/li\u003e\n\u003cli\u003eZhang R, Gao J, Zhao T, Zhang B, Wang C, Wang C, Cui L, Chen J, Fang S. A Case With IgG4-Related Spinal Pachymeningitis Causing Spinal Cord Compression. Front Neurol. 2020;11:500.\u003c/li\u003e\n\u003cli\u003evan den Elshout-den Uyl D, Spoto CPE, de Boer M, Leiner T, Leavis HL, Leguit RJ. First Report of IgG4 Related Disease Primary Presenting as Vertebral Bone Marrow Lesions. Front Immunol. 2019;10:1910.\u003c/li\u003e\n\u003cli\u003eMerza N, Taha A, Lung J, Benderman AW, Wright SE. IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature. Case Reports Immunol. 2019;2019:3618510.\u003c/li\u003e\n\u003cli\u003eBridges KJ, DeDeaux CH, Than KD. IgG4-related disease presenting as intradural extramedullary lesion: a case report and review of the literature. Br J Neurosurg. 2019;33:570-576.\u003c/li\u003e\n\u003cli\u003eLevraut M, Cohen M, Bresch S, Giordana C, Burel-Vandenbos F, Mondot L, Sedat J, Fontaine D, Bourg V, Martis N, Lebrun-Frenay C. Immunoglobulin G4-related hypertrophic pachymeningitis: A case-oriented review. Neurol Neuroimmunol Neuroinflamm. 2019;6:e568.\u003c/li\u003e\n\u003cli\u003eSlade SJ, Bauer EM, Stone VV, Dave AJ. Spinal IgG4-Related Hypertrophic Pachymeningitis with Spinal Cord Compression: Case Report and Literature Review. World Neurosurg. 2019;130:65-70.\u003c/li\u003e\n\u003cli\u003eWinkel M, Lawton CD, Sanusi OR, Horbinski CM, Dahdaleh NS, Smith ZA. Neuro-surgical considerations for treating IgG4-related disease with rare spinal epidural compression. Surg Neurol Int. 2018;9:209.\u003c/li\u003e\n\u003cli\u003eWilliams MM, Mashaly H, Puduvalli VK, Jin M, Mendel E. Immunoglobulin G4-related disease mimicking an epidural spinal cord tumor: case report. J Neurosurg Spine. 2017;26:76-80.\u003c/li\u003e\n\u003cli\u003eZhao Q, Dong A, Bai Y, Wang Y, Zuo C. FDG PET/CT in Immunoglobulin G4-Related Spinal Hypertrophic Pachymeningitis. Clin Nucl Med. 2017;42:958-961.\u003c/li\u003e\n\u003cli\u003eMaher M, Zanazzi G, Faust P, Nickerson K, T Wong T. IgG4-related hypertrophic pachymeningitis of the spine with MPO-ANCA seropositivity. Clin Imaging. 2017;46:108-112.\u003c/li\u003e\n\u003cli\u003eTang R, Li F, Chen Q. A case report of atypical long segmental thoracic hypertrophic pachymeningitis with ossification of ligamentum flavum and literature review. Eur Spine J. 2017;26:202-206.\u003c/li\u003e\n\u003cli\u003eRumalla K, Smith KA, Arnold PM. Immunoglobulin G4-related epidural inflammatory pseudotumor presenting with pulmonary complications and spinal cord compression: case report. J Neurosurg Spine. 2017;26:688-693.\u003c/li\u003e\n\u003cli\u003eRadotra BD, Aggarwal A, Kapoor A, Singla N, Chatterjee D. An orphan disease: IgG4-related spinal pachymeningitis: report of 2 cases. J Neurosurg Spine. 2016;25:790-794.\u003c/li\u003e\n\u003cli\u003eFerreira NR, Vaz R, Carmona S, Mateus S, Pereira P, Fernandes L, Moreira H, Chor\u0026atilde;o M, Saldanha L, Carvalho A, Campos L. IgG4-related disease presenting with an epidural inflammatory pseudotumor: a case report. J Med Case Rep. 2016;10:61.\u003c/li\u003e\n\u003cli\u003eGu R, Hao PY, Liu JB, Wang ZH, Zhu QS. Cervicothoracic spinal cord compression caused by IgG4-related sclerosing pachymeningitis: a case report and literature review. Eur Spine J. 2016;25:147-51.\u003c/li\u003e\n\u003cli\u003eEzzeldin M, Shawagfeh A, Schnadig V, Smith RG, Fang X. Hypertrophic spinal pachymeningitis: idiopathic vs. IgG4-related. J Neurol Sci. 2014;347:398-400.\u003c/li\u003e\n\u003cli\u003eZwicker J, Michaud J, Torres C. IgG4-related Disease Presenting as Dural Thickening - A Rare Cause of Myelopathy. Can J Neurol Sci. 2014;41:392-6.\u003c/li\u003e\n\u003cli\u003eKim SH, Kang Y, Oh SH, Paik S, Kim JS. Paraplegia in a Patient With IgG4-Related Sclerosing Disease: A Case Report. Ann Rehabil Med. 2014;38:856-60.\u003c/li\u003e\n\u003cli\u003eChoi SH, Lee SH, Khang SK, Jeon SR. IgG4-related sclerosing pachymeningitis causing spinal cord compression. Neurology. 2010;75:1388-90.\u003c/li\u003e\n\u003cli\u003eChan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009;33:1249-52.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgG4-related diseases, IgG4-related spinal hypertrophic pachymeningitis, spinal cord compression, immune diseases","lastPublishedDoi":"10.21203/rs.3.rs-6253248/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6253248/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eIgG4-related hypertrophic pachymeningitis (IgG4-RHP) is a rare disorder characterized by localized or diffuse fibrotic thickening of the dura mater, affecting both the cranial and spinal regions. IgG4-related spinal hypertrophic pachymeningitis (IgG4-SHP) often manifests with clinical features resembling spinal cord space-occupying lesions, complicating its differential diagnosis. Consequently, establishing an accurate and efficient diagnostic approach is critical for the timely identification and management of IgG4-RHP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eWe present a patient withIgG4-SHP observed at Zhujiang Hospital of Southern Medical University. The patient's initial symptom was numbness in both lower limbs accompanied by progressive weakness(MRC 2/5 bilaterally). Given the patient's manifestations of spinal cord compression, we initially conducted surgical intervention. The patient was subsequently transferred to the Department of Rheumatology and Immunology, where treatment with steroids was initiated, and then his muscle strength in both lower limbs had improved (MRC 4/5 bilaterally). In accordance with the criteria established by the Japanese Rheumatism Society, IgG4-SHP cases were identified from PubMed, CNKI, and other databases for systematic analysis and literature review (up to November 2024). The data were then analysed via SPSS 26.0 statistical software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eWe have compiled data from 60 relevant patients for the first time through a literature review. We found that IgG4-SHP predominantly affects middle-aged and elderly patients, with thoracic epidural masses being the most frequently observed manifestation. Clinical presentations, imaging findings, and laboratory investigations often lack specificity, complicating the diagnostic process. A definitive diagnosis relies on the integration of histopathological and immunohistochemical analyses, which provide the most reliable diagnostic criteria. Initial management typically involves corticosteroid therapy. However, in patients presenting with compressive neurological symptoms or suboptimal response to corticosteroids, surgical decompression or adjunctive immunosuppressive agents may be warranted.\u003c/p\u003e","manuscriptTitle":"IgG4-Related Spinal Hypertrophic Pachymeningitis: A Case Report and Systematic Review of 60 Cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-02 07:12:56","doi":"10.21203/rs.3.rs-6253248/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af761140-60ad-4385-a54d-b49ba91ea131","owner":[],"postedDate":"June 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-07T04:54:03+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-02 07:12:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6253248","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6253248","identity":"rs-6253248","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}