Clinical and Electrophysiological Profile of Neuropathy in POEMS Syndrome: Differentiation from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Clinical and Electrophysiological Profile of Neuropathy in POEMS Syndrome: Differentiation from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) | 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 Research Article Clinical and Electrophysiological Profile of Neuropathy in POEMS Syndrome: Differentiation from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Satyajit Parhi, Prabodha Kumar Das, Dhiren Panda, Shrestha Mishra, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8077686/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background POEMS syndrome is a rare multisystem disorder associated with plasma cell dyscrasia and characterized by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, and Skin changes. Its neuropathic presentation often mimics chronic inflammatory demyelinating polyneuropathy (CIDP), resulting in diagnostic delays. Differentiating features are crucial for appropriate therapy and improved outcomes. Methods This retrospective observational study included 15 patients diagnosed with POEMS syndrome at a tertiary-care neurology center between January 2019 and October 2025. Diagnosis was based on Dispenzieri’s criteria, requiring polyneuropathy and a monoclonal plasma cell disorder with additional major and minor features. Clinical data, biochemical parameters, imaging findings, and nerve conduction studies were analysed to define the clinical and electrophysiological spectrum. Treatment response was assessed at three months post-therapy. Results The mean age was 44.9 ± 11.2 years, with slight male predominance. Organomegaly (87%), endocrinopathy (80%), and skin hyperpigmentation (93%) were common. Serum M-protein was demonstrable in 93% and osteosclerotic lesions in 80%. Electrophysiology revealed demyelinating neuropathy in 47%, mixed axonal–demyelinating in 27%, and axonal neuropathy in 20%. Lenalidomide–dexamethasone-based therapy resulted in neurological improvement in 87% of patients within three months. Conclusion Neuropathy in POEMS syndrome typically demonstrates a mixed demyelinating–axonal pattern with systemic manifestations distinguishing it from CIDP. Early recognition and institution of plasma cell–directed therapy lead to favourable functional recovery. POEMS syndrome CIDP electrophysiology demyelinating neuropathy plasma cell dyscrasia lenalidomide Figures Figure 1 Figure 2 Key Message What is already known? What this study adds? • POEMS syndrome presents with a demyelinating neuropathy that often mimics CIDP. • Multisystem involvement and M-protein are diagnostic hallmarks. • In an Indian cohort, POEMS neuropathy exhibited a predominant demyelinating or mixed electrophysiological pattern with marked distal amplitude reduction and axonal loss , distinguishing it from CIDP. • Endocrinopathy and skin changes were the most consistent systemic markers. • Majority of patients showed early neurological improvement with lenalidomide-based therapy. Introduction POEMS syndrome is a rare multisystem disorder resulting from an underlying monoclonal plasma cell dyscrasia and characterised by a constellation of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. Since its original description by Bardwick et al. ( 1 ), POEMS syndrome has been recognised as a distinct clinicopathological entity with important neurological implications. Peripheral neuropathy is almost universally present and frequently the first manifestation prompting neurological evaluation ( 2 ). Clinically, POEMS neuropathy is typically a progressive, symmetric, length-dependent sensorimotor polyneuropathy, often accompanied by significant pain. These features may closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP), particularly in the early stages of disease, leading to diagnostic confusion and inappropriate immunomodulatory treatment ( 3 , 4 ). Several studies have demonstrated that the clinical and electrophysiological characteristics of POEMS differ substantially from CIDP despite superficial similarities ( 5 , 6 ). Electrophysiological evaluation plays a central role in distinguishing the two conditions. Patients with POEMS often exhibit disproportionately reduced distal compound muscle action potentials, prolonged distal latencies, secondary axonal loss, and multisegmental conduction abnormalities reflective of VEGF-mediated microvascular injury ( 5 , 7 , 8 ). The pathogenic relevance of elevated vascular endothelial growth factor (VEGF) has been strongly supported by recent diagnostic studies, which demonstrate high sensitivity and specificity for VEGF in confirming POEMS syndrome ( 6 ). Large Asian cohorts, including the seminal Chinese series by Li et al. ( 3 ), and the Indian cohort described by Garg et al. ( 4 ), have highlighted considerable diagnostic delay and frequent initial misclassification as CIDP, underscoring the need for heightened recognition in neurology practice. Updated clinical guidance and outcome data from recent Mayo Clinic cohorts further emphasise the importance of accurate diagnosis and plasma cell–directed therapy to improve long-term neurological outcomes ( 2 , 7 , 10 – 12 ). Given the substantial therapeutic and prognostic implications of distinguishing POEMS neuropathy from CIDP, a detailed understanding of its clinical, systemic, and electrophysiological characteristics is essential. The present study aims to analyse the clinical, biochemical, and electrophysiological features of POEMS syndrome in a tertiary-care centre and identify key differentiating features from CIDP to assist clinicians in early and accurate diagnosis. Methods Study design and setting This was a retrospective observational study conducted at the Department of Neurology, IMS & SUM Hospital Campus II, Bhubaneswar, India, between January 2019 and August 2024. Patients with a confirmed diagnosis of POEMS syndrome were enrolled based on clinical, electrophysiological, and laboratory findings. The study aimed to evaluate the clinical spectrum, electrophysiological characteristics, and therapeutic outcomes of neuropathy associated with POEMS syndrome and to differentiate it from chronic inflammatory demyelinating polyneuropathy (CIDP). Inclusion criteria Patients were included if they met the updated diagnostic criteria for POEMS syndrome proposed by Dispenzieri (2021) ( 7 ), requiring: Mandatory presence of polyneuropathy and monoclonal plasma cell disorder, and At least one major criterion (sclerotic bone lesions, Castleman’s disease, or elevated VEGF) and one minor criterion (organomegaly, endocrinopathy, skin changes, papilledema, or extravascular fluid overload). Only patients with complete clinical, electrophysiological, and biochemical data were included. Exclusion criteria Patients were excluded if they had: Evidence of diabetes mellitus, uremic neuropathy, toxic neuropathy, HIV infection, or other known causes of neuropathy. Incomplete data records or electrophysiological studies performed outside the centre. Prior chemotherapy or immunotherapy before diagnostic confirmation. Clinical evaluation Detailed demographic and clinical data, including age, sex, duration of symptoms, and pattern of weakness, were recorded. Systemic features such as organomegaly, endocrinopathy, and skin changes were assessed. Organomegaly was evaluated by clinical examination and ultrasonography or CT imaging. Endocrinopathy assessment included thyroid, gonadal, and glycaemic profiles. Laboratory and imaging investigations All patients underwent serum and urine protein electrophoresis, and when required, immunofixation electrophoresis to detect monoclonal proteins. Skeletal surveys or whole-body CT scans were performed to detect osteosclerotic lesions. Routine haematological parameters and endocrine investigations (thyroid-stimulating hormone, cortisol, fasting glucose, and gonadal hormones) were documented. Cerebrospinal fluid (CSF) analysis was performed to assess albuminocytologic dissociation, defined as elevated protein (> 100 mg/dL) with ≤ 5 cells/mm³. Electrophysiological evaluation All patients underwent motor and sensory nerve conduction studies (NCS) using standard surface electrodes and techniques on Nicolet Viking IV systems (Natus, USA). Parameters measured included distal latency, compound muscle action potential (CMAP) amplitude, sensory nerve action potential (SNAP) amplitude, conduction velocity, and F-wave latencies. The pattern of neuropathy was classified as demyelinating, axonal, mixed, or unexcitable, based on accepted electrophysiological criteria. Treatment protocol Following diagnostic confirmation, all patients received lenalidomide (10–25 mg daily for 21 days per 28-day cycle) and dexamethasone (40 mg weekly), either alone or in combination with cyclophosphamide. Two patients with localized osteosclerotic lesions also received radiotherapy. Clinical assessment was repeated at three months, and improvement was defined as ≥ 1 grade increase in the Medical Research Council (MRC) muscle power scale or improvement in ambulation. Outcome measures Primary outcome: Clinical improvement at 3 months post-treatment. Secondary outcomes: Electrophysiological recovery pattern. Mortality or disease progression during follow-up. Statistical analysis Data were compiled and analysed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as frequency and percentage. Descriptive statistics were primarily used due to small sample size. Ethical approval and consent The study was conducted following the ethical principles of the Declaration of Helsinki. Approval was obtained from the Institutional Ethics Committee of IMS & SUM Hospital Campus II, Bhubaneswar. Written informed consent was obtained from all participants prior to inclusion in the study. Results Demographic and clinical characteristics A total of 15 patients with confirmed POEMS syndrome were included in the study. The mean age at onset was 44.9 ± 11.2 years (range: 21–63 years), with a male-to-female ratio of 1.1:1. The average duration of illness before diagnosis was 20.4 ± 11.3 months. All patients presented with gradually progressive, symmetric, length-dependent sensorimotor weakness involving both lower limbs, later extending to the upper limbs. The clinical and systemic characteristics of all patients are summarised in Table 1 . Systemic and biochemical features Organomegaly was identified in 13 (87%) patients, and endocrinopathy was noted in 12 (80%), mainly hypothyroidism and gonadal dysfunction. Skin hyperpigmentation and thickening were present in 14 (93%) cases. A monoclonal protein was detected in 14 (93%) patients on serum electrophoresis or immunofixation, while osteosclerotic lesions were evident in 12 (80%) based on skeletal imaging. Thrombocytosis was documented in 3 (20%) patients. Cerebrospinal fluid and haematological findings Cerebrospinal fluid (CSF) analysis demonstrated albuminocytologic dissociation (protein > 100 mg/dL with < 5 cells/mm³) in 11 (73%) patients. Bone marrow studies revealed plasmacytosis ranging from 5–15%, with one patient showing 15% plasma cells, suggesting early myelomatous transformation. Electrophysiological profile Nerve conduction studies demonstrated demyelinating sensorimotor polyneuropathy in 7 (47%), mixed axonal–demyelinating neuropathy in 4 (27%), predominantly axonal neuropathy in 3 (20%), and unexcitable nerves in 1 (6%) patient. Characteristic features included prolonged distal latencies, markedly reduced compound muscle action potentials (CMAPs), and absent sensory responses in the lower limbs. The distribution of electrophysiological patterns is illustrated in Fig. 1 . The electrophysiological findings and treatment outcomes are detailed in Table 2 . Treatment and short-term outcome All patients received lenalidomide (10–25 mg daily for 21 days of a 28-day cycle) and dexamethasone (40 mg weekly); 10 (67%) patients also received cyclophosphamide (LenDexCy regimen). Two patients underwent localized radiotherapy for osteosclerotic lesions. At 3 months of follow-up, 13 (87%) patients showed objective neurological improvement, with improved ambulation and at least a 1-grade increase on the MRC scale. Two patients remained neurologically stable, and no deaths were reported during the study period. The proportion of patients showing improvement at 3 months is depicted in Fig. 2 . Summary of key findings Mean age: 44.9 ± 11.2 years Male: 53%; Female: 47% Duration of illness: 20.4 ± 11.3 months Organomegaly: 87%; Endocrinopathy: 80%; Skin changes: 93% Monoclonal protein: 93%; Osteosclerotic lesions: 80% Demyelinating pattern: 47%; Mixed: 27%; Axonal: 20%; Unexcitable: 6% Clinical improvement at 3 months: 87%; Mortality: 0% POEMS neuropathy predominantly exhibited demyelinating or mixed electrophysiological features, often with significant amplitude reduction and secondary axonal loss. The presence of multisystem involvement and monoclonal protein in almost all cases differentiated it from CIDP. Clinical improvement with lenalidomide-based therapy was observed in the majority, supporting the need for plasma cell–directed treatment. Table 1 Clinical and systemic features of patients with POEMS syndrome (n = 15) Variable Frequency (%) Mean age (years) 44.9 ± 11.2 Male sex 53% Duration of illness (months) 20.4 ± 11.3 Organomegaly 87% Endocrinopathy 80% Skin changes 93% Monoclonal protein 93% Osteosclerotic lesion 80% Thrombocytosis 20% CSF albuminocytologic dissociation 73% Table 2 Electrophysiological and therapeutic profile Parameter n (%) Demyelinating neuropathy 7 (47%) Mixed axonal–demyelinating 4 (27%) Axonal neuropathy 3 (20%) Unexcitable nerves 1 (6%) Received LenDexCy regimen 10 (67%) Clinical improvement at 3 months 13 (87%) Stable 2 (13%) Mortality 0 (0%) Discussion Peripheral neuropathy is the defining feature of POEMS syndrome and often the earliest clue to diagnosis. Since the original description of the syndrome ( 1 ), subsequent clinical series have demonstrated that neuropathy in POEMS is frequently misinterpreted as chronic inflammatory demyelinating polyneuropathy (CIDP), especially during early presentation. The substantial symptomatic and electrophysiological overlap contributes to delayed recognition and inappropriate treatment with immunotherapy ( 2 – 4 ). In our cohort, the mean diagnostic delay exceeded 20 months, consistent with observations from large Asian and Indian studies, which highlight a persistent challenge in distinguishing POEMS from CIDP in routine practice ( 3 , 4 ). Clinically, patients in our study exhibited a progressive, symmetric, sensorimotor neuropathy with prominent distal weakness and disability. Systemic features—particularly organomegaly, endocrinopathy, and characteristic skin changes—were present in the majority of cases, mirroring the clinical phenotype reported in major cohorts ( 2 – 4 , 10 , 12 ). These systemic manifestations remain critical diagnostic anchors, and their presence should prompt clinicians to consider POEMS when evaluating patients initially labelled as having CIDP. Electrophysiologically, our findings demonstrated predominantly demyelinating or mixed demyelinating–axonal neuropathy with marked reduction in distal CMAP amplitudes, prolonged distal latencies, and varying degrees of axonal loss. These results closely parallel previously published physiological analyses that show POEMS neuropathy is characterised by non-uniform demyelination and ischemic axonopathy associated with microvascular injury ( 5 , 8 ). Unlike CIDP, where segmental demyelination with conduction block is typical, POEMS neuropathy often shows disproportionately low distal amplitudes and length-dependent changes. Such distinctions are important, as reliance solely on demyelinating criteria can misclassify POEMS as CIDP, particularly early in the disease course ( 5 , 8 ). The role of vascular endothelial growth factor (VEGF) in POEMS pathophysiology has been increasingly emphasised. VEGF contributes to increased vascular permeability, endothelial proliferation, and subsequent nerve ischemia. Diagnostic studies demonstrate high sensitivity and specificity of elevated VEGF levels for POEMS syndrome, supporting its integration into diagnostic algorithms ( 6 ). Although VEGF testing was not available for all participants in our cohort, the clinical and electrophysiological patterns aligned well with VEGF-driven mechanisms described in prior work. Therapeutically, all patients received plasma cell–directed treatment with lenalidomide and dexamethasone, with or without cyclophosphamide. Neurological improvement was observed in most patients by 3 months, reflecting the favourable response to anti-plasma cell therapy reported in previous large series ( 2 , 11 , 12 ). The strong treatment response further supports the distinction between POEMS and CIDP, as immunomodulatory therapies beneficial for CIDP are often ineffective in POEMS, leading to unnecessary delays in appropriate management. Our findings reinforce the importance of a comprehensive assessment that integrates systemic evaluation, targeted laboratory testing, electrophysiology, and imaging. Early recognition of characteristic clinical features—particularly in patients with “CIDP-like” neuropathy but with atypical systemic signs—may significantly reduce diagnostic delay and improve outcomes. Misclassification not only delays appropriate therapy but may expose patients to ineffective treatments and prevent timely control of the underlying plasma cell disorder. This study has limitations. The retrospective design and relatively small cohort size limit generalisability. VEGF levels were not uniformly available, which may have restricted diagnostic precision in some cases. Despite these limitations, the uniform electrophysiological evaluation and comprehensive clinical documentation strengthen the reliability of our findings. In summary, neuropathy in POEMS syndrome exhibits distinctive clinical and electrophysiological characteristics that differ from CIDP. Recognising these differences—especially the presence of multisystem involvement and the pattern of nerve conduction abnormalities—is essential for early diagnosis and timely initiation of plasma cell–directed therapy. Improved awareness among clinicians may reduce misdiagnosis, shorten diagnostic delays, and improve patient outcomes. Conclusion POEMS neuropathy predominantly exhibits a demyelinating or mixed demyelinating–axonal pattern, often accompanied by systemic manifestations including organomegaly, endocrinopathy, and skin changes. These features clearly differentiate it from CIDP. Recognition of this constellation and early institution of lenalidomide-based therapy can lead to substantial neurological recovery. Increased awareness and timely diagnostic evaluation are essential to improve outcomes in this rare yet treatable condition. Declarations (as required by BMC Neurology) : Ethics approval and consent to participate: The study protocol was approved by the Institutional Ethics Committee of IMS & SUM Hospital Campus II, Bhubaneswar. Written informed consent was obtained from all participants. Consent for publication: Written informed consent was obtained from all patients for publication of anonymized clinical data. Funding: This research received no external funding from any governmental, commercial, or nonprofit agency. Author Contribution - **Concept and Study Design:** Dr. Satyajit Parhi, Dr. Prabodha Kumar Das- **Data Collection and Analysis:** Dr. Satyajit Parhi, Dr. Prabodha Kumar Das, Dr. Dhiren Panda- **Electrophysiological Studies:** Dr. Satyajit Parhi, Dr. Shrestha Mishra- **Manuscript Drafting and Revision:** All authors- **Final Approval:** All authors read and approved the final manuscript. Acknowledgements: The authors acknowledge the support of the Department of Neurology and the Electrophysiology Laboratory staff of IMS & SUM Hospital for their assistance during data collection and analysis. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes: the POEMS syndrome. Med (Baltim). 1980;59(4):311–22. PMID: 6248260. Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101(7):2496–506. PMID: 12456500. Li J, Zhou DB, Huang Z, et al. Clinical characteristics and long-term outcome of patients with POEMS syndrome in China. Ann Hematol. 2011;90(7):819–26. PMID: 21181146. Garg RK, Malhotra HS, Kumar N, Jain A, Sharma PK, Singh MK. POEMS syndrome: Clinical spectrum and outcome from a tertiary care centre in India. Ann Indian Acad Neurol. 2020;23(4):474–80. PMID: 33488563. Nasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. 2012;83(5):476–9. PMID: 22311922. Pihan M, Keddie S, D’Sa S, Church A, Yong KL, Reilly MM, Lunn MP. Raised VEGF: high sensitivity and specificity in the diagnosis of POEMS syndrome. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e486. PMID: 30181239. Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):213–23. PMID: 24532368. Kuwabara S, Misawa S. Chronic inflammatory demyelinating polyneuropathy and POEMS syndrome. Curr Opin Neurol. 2014;27(5):443–9. PMID: 25058539. Misawa S, Sato Y, Katayama K, Shibuya K, Sekiguchi Y, Nasu S, et al. Pathophysiology of neuropathy in POEMS syndrome: VEGF as a key factor. Brain. 2012;135(12):358–68. PMID: 22287382. Kourelis TV, Buadi FK, Kumar SK, Gertz MA, Lacy MQ, Dingli D, et al. Long-term outcome of patients with POEMS syndrome: an update of the Mayo Clinic experience. Am J Hematol. 2016;91(6):585–9. PMID: 27029346. Karam C, Klein CJ, Dispenzieri A, Dyck PJ, Mandrekar J, D’Souza A, et al. Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome. Neurology. 2019;93(4):e331–40. PMID: 31217168. Dispenzieri A, Buadi FK, Kumar SK, Lacy MQ. Treatment and long-term outcomes in POEMS syndrome: an update of Mayo Clinic experience. Blood Rev. 2020;45:100709. PMID: 32217043. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 29 Dec, 2025 Reviews received at journal 22 Dec, 2025 Reviews received at journal 18 Dec, 2025 Reviewers agreed at journal 15 Dec, 2025 Reviewers agreed at journal 13 Dec, 2025 Reviews received at journal 08 Dec, 2025 Reviewers agreed at journal 03 Dec, 2025 Reviewers agreed at journal 29 Nov, 2025 Reviewers invited by journal 28 Nov, 2025 Editor assigned by journal 13 Nov, 2025 Submission checks completed at journal 13 Nov, 2025 First submitted to journal 10 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":70481,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eShows the frequency distribution of electrophysiological patterns (demyelinating, mixed, axonal, unexcitable).\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrequency distribution of electrophysiological patterns in patients with POEMS syndrome (n = 15).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8077686/v1/3df333a4b29d303b9a39ab0c.png"},{"id":97266912,"identity":"1802d355-7eaf-4c7b-907b-52d5c19d51d6","added_by":"auto","created_at":"2025-12-02 14:36:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61784,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eDisplays clinical outcomes at 3 months post-therapy, emphasizing the high proportion of improved patients.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eComparative improvement in muscle power (MRC score) before and after 3 months of LenDex-based therapy.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8077686/v1/26796f22a47533679d8a5319.png"},{"id":97664645,"identity":"3da737c9-2e19-459a-921c-dcf591215c58","added_by":"auto","created_at":"2025-12-08 09:12:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":902975,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8077686/v1/86ce051d-ff0d-4914-a756-f1e1f0092f47.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical and Electrophysiological Profile of Neuropathy in POEMS Syndrome: Differentiation from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)","fulltext":[{"header":"Key Message","content":"\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhat is already known?\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWhat this study adds?\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e• POEMS syndrome presents with a demyelinating neuropathy that often mimics CIDP.\u003c/p\u003e\u003cp\u003e• Multisystem involvement and M-protein are diagnostic hallmarks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e• In an Indian cohort, POEMS neuropathy exhibited a predominant \u003cb\u003edemyelinating or mixed electrophysiological pattern\u003c/b\u003e with \u003cb\u003emarked distal amplitude reduction\u003c/b\u003e and \u003cb\u003eaxonal loss\u003c/b\u003e, distinguishing it from CIDP.\u003c/p\u003e\u003cp\u003e• \u003cb\u003eEndocrinopathy and skin changes\u003c/b\u003e were the most consistent systemic markers.\u003c/p\u003e\u003cp\u003e• Majority of patients showed \u003cb\u003eearly neurological improvement\u003c/b\u003e with lenalidomide-based therapy.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Introduction","content":"\u003cp\u003ePOEMS syndrome is a rare multisystem disorder resulting from an underlying monoclonal plasma cell dyscrasia and characterised by a constellation of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. Since its original description by Bardwick et al. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), POEMS syndrome has been recognised as a distinct clinicopathological entity with important neurological implications. Peripheral neuropathy is almost universally present and frequently the first manifestation prompting neurological evaluation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eClinically, POEMS neuropathy is typically a progressive, symmetric, length-dependent sensorimotor polyneuropathy, often accompanied by significant pain. These features may closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP), particularly in the early stages of disease, leading to diagnostic confusion and inappropriate immunomodulatory treatment (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Several studies have demonstrated that the clinical and electrophysiological characteristics of POEMS differ substantially from CIDP despite superficial similarities (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eElectrophysiological evaluation plays a central role in distinguishing the two conditions. Patients with POEMS often exhibit disproportionately reduced distal compound muscle action potentials, prolonged distal latencies, secondary axonal loss, and multisegmental conduction abnormalities reflective of VEGF-mediated microvascular injury (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The pathogenic relevance of elevated vascular endothelial growth factor (VEGF) has been strongly supported by recent diagnostic studies, which demonstrate high sensitivity and specificity for VEGF in confirming POEMS syndrome (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eLarge Asian cohorts, including the seminal Chinese series by Li et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), and the Indian cohort described by Garg et al. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), have highlighted considerable diagnostic delay and frequent initial misclassification as CIDP, underscoring the need for heightened recognition in neurology practice. Updated clinical guidance and outcome data from recent Mayo Clinic cohorts further emphasise the importance of accurate diagnosis and plasma cell\u0026ndash;directed therapy to improve long-term neurological outcomes (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGiven the substantial therapeutic and prognostic implications of distinguishing POEMS neuropathy from CIDP, a detailed understanding of its clinical, systemic, and electrophysiological characteristics is essential. The present study aims to analyse the clinical, biochemical, and electrophysiological features of POEMS syndrome in a tertiary-care centre and identify key differentiating features from CIDP to assist clinicians in early and accurate diagnosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and setting\u003c/h2\u003e\u003cp\u003eThis was a retrospective observational study conducted at the Department of Neurology, IMS \u0026amp; SUM Hospital Campus II, Bhubaneswar, India, between January 2019 and August 2024. Patients with a confirmed diagnosis of POEMS syndrome were enrolled based on clinical, electrophysiological, and laboratory findings. The study aimed to evaluate the clinical spectrum, electrophysiological characteristics, and therapeutic outcomes of neuropathy associated with POEMS syndrome and to differentiate it from chronic inflammatory demyelinating polyneuropathy (CIDP).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion criteria\u003c/h3\u003e\n\u003cp\u003ePatients were included if they met the updated diagnostic criteria for POEMS syndrome proposed by Dispenzieri (2021) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), requiring:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eMandatory presence of polyneuropathy and monoclonal plasma cell disorder, and\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAt least one major criterion (sclerotic bone lesions, Castleman\u0026rsquo;s disease, or elevated VEGF) and one minor criterion (organomegaly, endocrinopathy, skin changes, papilledema, or extravascular fluid overload).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eOnly patients with complete clinical, electrophysiological, and biochemical data were included.\u003c/p\u003e\n\u003ch3\u003eExclusion criteria\u003c/h3\u003e\n\u003cp\u003ePatients were excluded if they had:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eEvidence of diabetes mellitus, uremic neuropathy, toxic neuropathy, HIV infection, or other known causes of neuropathy.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIncomplete data records or electrophysiological studies performed outside the centre.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePrior chemotherapy or immunotherapy before diagnostic confirmation.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\n\u003ch3\u003eClinical evaluation\u003c/h3\u003e\n\u003cp\u003eDetailed demographic and clinical data, including age, sex, duration of symptoms, and pattern of weakness, were recorded. Systemic features such as organomegaly, endocrinopathy, and skin changes were assessed. Organomegaly was evaluated by clinical examination and ultrasonography or CT imaging. Endocrinopathy assessment included thyroid, gonadal, and glycaemic profiles.\u003c/p\u003e\n\u003ch3\u003eLaboratory and imaging investigations\u003c/h3\u003e\n\u003cp\u003eAll patients underwent serum and urine protein electrophoresis, and when required, immunofixation electrophoresis to detect monoclonal proteins. Skeletal surveys or whole-body CT scans were performed to detect osteosclerotic lesions. Routine haematological parameters and endocrine investigations (thyroid-stimulating hormone, cortisol, fasting glucose, and gonadal hormones) were documented.\u003c/p\u003e\u003cp\u003eCerebrospinal fluid (CSF) analysis was performed to assess albuminocytologic dissociation, defined as elevated protein (\u0026gt;\u0026thinsp;100 mg/dL) with \u0026le;\u0026thinsp;5 cells/mm\u0026sup3;.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eElectrophysiological evaluation\u003c/h2\u003e\u003cp\u003eAll patients underwent motor and sensory nerve conduction studies (NCS) using standard surface electrodes and techniques on Nicolet Viking IV systems (Natus, USA). Parameters measured included distal latency, compound muscle action potential (CMAP) amplitude, sensory nerve action potential (SNAP) amplitude, conduction velocity, and F-wave latencies. The pattern of neuropathy was classified as demyelinating, axonal, mixed, or unexcitable, based on accepted electrophysiological criteria.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment protocol\u003c/h3\u003e\n\u003cp\u003eFollowing diagnostic confirmation, all patients received lenalidomide (10\u0026ndash;25 mg daily for 21 days per 28-day cycle) and dexamethasone (40 mg weekly), either alone or in combination with cyclophosphamide. Two patients with localized osteosclerotic lesions also received radiotherapy. Clinical assessment was repeated at three months, and improvement was defined as \u0026ge;\u0026thinsp;1 grade increase in the Medical Research Council (MRC) muscle power scale or improvement in ambulation.\u003c/p\u003e\n\u003ch3\u003eOutcome measures\u003c/h3\u003e\n\u003cp\u003ePrimary outcome:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eClinical improvement at 3 months post-treatment.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eSecondary outcomes:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eElectrophysiological recovery pattern.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMortality or disease progression during follow-up.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eData were compiled and analysed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), and categorical variables as frequency and percentage. Descriptive statistics were primarily used due to small sample size.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthical approval and consent\u003c/strong\u003e\u003cp\u003e The study was conducted following the ethical principles of the Declaration of Helsinki. Approval was obtained from the Institutional Ethics Committee of IMS \u0026amp; SUM Hospital Campus II, Bhubaneswar. Written informed consent was obtained from all participants prior to inclusion in the study.\u003c/p\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eDemographic and clinical characteristics\u003c/h2\u003e\u003cp\u003eA total of 15 patients with confirmed POEMS syndrome were included in the study. The mean age at onset was 44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 years (range: 21\u0026ndash;63 years), with a male-to-female ratio of 1.1:1. The average duration of illness before diagnosis was 20.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3 months. All patients presented with gradually progressive, symmetric, length-dependent sensorimotor weakness involving both lower limbs, later extending to the upper limbs.\u003c/p\u003e\u003cp\u003eThe clinical and systemic characteristics of all patients are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSystemic and biochemical features\u003c/h2\u003e\u003cp\u003eOrganomegaly was identified in 13 (87%) patients, and endocrinopathy was noted in 12 (80%), mainly hypothyroidism and gonadal dysfunction. Skin hyperpigmentation and thickening were present in 14 (93%) cases.\u003c/p\u003e\u003cp\u003eA monoclonal protein was detected in 14 (93%) patients on serum electrophoresis or immunofixation, while osteosclerotic lesions were evident in 12 (80%) based on skeletal imaging. Thrombocytosis was documented in 3 (20%) patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eCerebrospinal fluid and haematological findings\u003c/h2\u003e\u003cp\u003eCerebrospinal fluid (CSF) analysis demonstrated albuminocytologic dissociation (protein\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dL with \u0026lt;\u0026thinsp;5 cells/mm\u0026sup3;) in 11 (73%) patients. Bone marrow studies revealed plasmacytosis ranging from 5\u0026ndash;15%, with one patient showing 15% plasma cells, suggesting early myelomatous transformation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eElectrophysiological profile\u003c/h2\u003e\u003cp\u003eNerve conduction studies demonstrated demyelinating sensorimotor polyneuropathy in 7 (47%), mixed axonal\u0026ndash;demyelinating neuropathy in 4 (27%), predominantly axonal neuropathy in 3 (20%), and unexcitable nerves in 1 (6%) patient.\u003c/p\u003e\u003cp\u003eCharacteristic features included prolonged distal latencies, markedly reduced compound muscle action potentials (CMAPs), and absent sensory responses in the lower limbs. The distribution of electrophysiological patterns is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe electrophysiological findings and treatment outcomes are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eTreatment and short-term outcome\u003c/h2\u003e\u003cp\u003eAll patients received lenalidomide (10\u0026ndash;25 mg daily for 21 days of a 28-day cycle) and dexamethasone (40 mg weekly); 10 (67%) patients also received cyclophosphamide (LenDexCy regimen). Two patients underwent localized radiotherapy for osteosclerotic lesions.\u003c/p\u003e\u003cp\u003eAt 3 months of follow-up, 13 (87%) patients showed objective neurological improvement, with improved ambulation and at least a 1-grade increase on the MRC scale. Two patients remained neurologically stable, and no deaths were reported during the study period.\u003c/p\u003e\u003cp\u003eThe proportion of patients showing improvement at 3 months is depicted in \u003cb\u003eFig.\u0026nbsp;2\u003c/b\u003e. \u003cb\u003eSummary of key findings\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eMean age: 44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 years\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMale: 53%; Female: 47%\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDuration of illness: 20.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3 months\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOrganomegaly: 87%; Endocrinopathy: 80%; Skin changes: 93%\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMonoclonal protein: 93%; Osteosclerotic lesions: 80%\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDemyelinating pattern: 47%; Mixed: 27%; Axonal: 20%; Unexcitable: 6%\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eClinical improvement at 3 months: 87%; Mortality: 0%\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003ePOEMS neuropathy predominantly exhibited demyelinating or mixed electrophysiological features, often with significant amplitude reduction and secondary axonal loss. The presence of multisystem involvement and monoclonal protein in almost all cases differentiated it from CIDP. Clinical improvement with lenalidomide-based therapy was observed in the majority, supporting the need for plasma cell\u0026ndash;directed treatment.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical and systemic features of patients with POEMS syndrome (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFrequency (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean age (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of illness (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOrganomegaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndocrinopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin changes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMonoclonal protein\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOsteosclerotic lesion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSF albuminocytologic dissociation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eElectrophysiological and therapeutic profile\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003en (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDemyelinating neuropathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (47%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMixed axonal\u0026ndash;demyelinating\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (27%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAxonal neuropathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (20%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnexcitable nerves\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReceived LenDexCy regimen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (67%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical improvement at 3 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (87%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePeripheral neuropathy is the defining feature of POEMS syndrome and often the earliest clue to diagnosis. Since the original description of the syndrome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), subsequent clinical series have demonstrated that neuropathy in POEMS is frequently misinterpreted as chronic inflammatory demyelinating polyneuropathy (CIDP), especially during early presentation. The substantial symptomatic and electrophysiological overlap contributes to delayed recognition and inappropriate treatment with immunotherapy (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In our cohort, the mean diagnostic delay exceeded 20 months, consistent with observations from large Asian and Indian studies, which highlight a persistent challenge in distinguishing POEMS from CIDP in routine practice (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eClinically, patients in our study exhibited a progressive, symmetric, sensorimotor neuropathy with prominent distal weakness and disability. Systemic features\u0026mdash;particularly organomegaly, endocrinopathy, and characteristic skin changes\u0026mdash;were present in the majority of cases, mirroring the clinical phenotype reported in major cohorts (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These systemic manifestations remain critical diagnostic anchors, and their presence should prompt clinicians to consider POEMS when evaluating patients initially labelled as having CIDP.\u003c/p\u003e\u003cp\u003eElectrophysiologically, our findings demonstrated predominantly demyelinating or mixed demyelinating\u0026ndash;axonal neuropathy with marked reduction in distal CMAP amplitudes, prolonged distal latencies, and varying degrees of axonal loss. These results closely parallel previously published physiological analyses that show POEMS neuropathy is characterised by non-uniform demyelination and ischemic axonopathy associated with microvascular injury (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Unlike CIDP, where segmental demyelination with conduction block is typical, POEMS neuropathy often shows disproportionately low distal amplitudes and length-dependent changes. Such distinctions are important, as reliance solely on demyelinating criteria can misclassify POEMS as CIDP, particularly early in the disease course (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe role of vascular endothelial growth factor (VEGF) in POEMS pathophysiology has been increasingly emphasised. VEGF contributes to increased vascular permeability, endothelial proliferation, and subsequent nerve ischemia. Diagnostic studies demonstrate high sensitivity and specificity of elevated VEGF levels for POEMS syndrome, supporting its integration into diagnostic algorithms (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although VEGF testing was not available for all participants in our cohort, the clinical and electrophysiological patterns aligned well with VEGF-driven mechanisms described in prior work.\u003c/p\u003e\u003cp\u003eTherapeutically, all patients received plasma cell\u0026ndash;directed treatment with lenalidomide and dexamethasone, with or without cyclophosphamide. Neurological improvement was observed in most patients by 3 months, reflecting the favourable response to anti-plasma cell therapy reported in previous large series (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The strong treatment response further supports the distinction between POEMS and CIDP, as immunomodulatory therapies beneficial for CIDP are often ineffective in POEMS, leading to unnecessary delays in appropriate management.\u003c/p\u003e\u003cp\u003eOur findings reinforce the importance of a comprehensive assessment that integrates systemic evaluation, targeted laboratory testing, electrophysiology, and imaging. Early recognition of characteristic clinical features\u0026mdash;particularly in patients with \u0026ldquo;CIDP-like\u0026rdquo; neuropathy but with atypical systemic signs\u0026mdash;may significantly reduce diagnostic delay and improve outcomes. Misclassification not only delays appropriate therapy but may expose patients to ineffective treatments and prevent timely control of the underlying plasma cell disorder.\u003c/p\u003e\u003cp\u003eThis study has limitations. The retrospective design and relatively small cohort size limit generalisability. VEGF levels were not uniformly available, which may have restricted diagnostic precision in some cases. Despite these limitations, the uniform electrophysiological evaluation and comprehensive clinical documentation strengthen the reliability of our findings.\u003c/p\u003e\u003cp\u003eIn summary, neuropathy in POEMS syndrome exhibits distinctive clinical and electrophysiological characteristics that differ from CIDP. Recognising these differences\u0026mdash;especially the presence of multisystem involvement and the pattern of nerve conduction abnormalities\u0026mdash;is essential for early diagnosis and timely initiation of plasma cell\u0026ndash;directed therapy. Improved awareness among clinicians may reduce misdiagnosis, shorten diagnostic delays, and improve patient outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePOEMS neuropathy predominantly exhibits a demyelinating or mixed demyelinating–axonal pattern, often accompanied by systemic manifestations including organomegaly, endocrinopathy, and skin changes. These features clearly differentiate it from CIDP. Recognition of this constellation and early institution of lenalidomide-based therapy can lead to substantial neurological recovery. Increased awareness and timely diagnostic evaluation are essential to improve outcomes in this rare yet treatable condition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003e(as required by BMC Neurology)\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003cp\u003eThe study protocol was approved by the Institutional Ethics Committee of IMS \u0026amp; SUM Hospital Campus II, Bhubaneswar. Written informed consent was obtained from all participants.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003cp\u003eWritten informed consent was obtained from all patients for publication of anonymized clinical data.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis research received no external funding from any governmental, commercial, or nonprofit agency.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e- **Concept and Study Design:** Dr. Satyajit Parhi, Dr. Prabodha Kumar Das- **Data Collection and Analysis:** Dr. Satyajit Parhi, Dr. Prabodha Kumar Das, Dr. Dhiren Panda- **Electrophysiological Studies:** Dr. Satyajit Parhi, Dr. Shrestha Mishra- **Manuscript Drafting and Revision:** All authors- **Final Approval:** All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\u003cp\u003eThe authors acknowledge the support of the Department of Neurology and the Electrophysiology Laboratory staff of IMS \u0026amp; SUM Hospital for their assistance during data collection and analysis.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes: the POEMS syndrome. Med (Baltim). 1980;59(4):311\u0026ndash;22. PMID: 6248260.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, et al. POEMS syndrome: definitions and long-term outcome. Blood. 2003;101(7):2496\u0026ndash;506. PMID: 12456500.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi J, Zhou DB, Huang Z, et al. Clinical characteristics and long-term outcome of patients with POEMS syndrome in China. Ann Hematol. 2011;90(7):819\u0026ndash;26. PMID: 21181146.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarg RK, Malhotra HS, Kumar N, Jain A, Sharma PK, Singh MK. POEMS syndrome: Clinical spectrum and outcome from a tertiary care centre in India. Ann Indian Acad Neurol. 2020;23(4):474\u0026ndash;80. PMID: 33488563.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, et al. Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. 2012;83(5):476\u0026ndash;9. PMID: 22311922.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePihan M, Keddie S, D\u0026rsquo;Sa S, Church A, Yong KL, Reilly MM, Lunn MP. Raised VEGF: high sensitivity and specificity in the diagnosis of POEMS syndrome. Neurol Neuroimmunol Neuroinflamm. 2018;5(5):e486. PMID: 30181239.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):213\u0026ndash;23. PMID: 24532368.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKuwabara S, Misawa S. Chronic inflammatory demyelinating polyneuropathy and POEMS syndrome. Curr Opin Neurol. 2014;27(5):443\u0026ndash;9. PMID: 25058539.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMisawa S, Sato Y, Katayama K, Shibuya K, Sekiguchi Y, Nasu S, et al. Pathophysiology of neuropathy in POEMS syndrome: VEGF as a key factor. Brain. 2012;135(12):358\u0026ndash;68. PMID: 22287382.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKourelis TV, Buadi FK, Kumar SK, Gertz MA, Lacy MQ, Dingli D, et al. Long-term outcome of patients with POEMS syndrome: an update of the Mayo Clinic experience. Am J Hematol. 2016;91(6):585\u0026ndash;9. PMID: 27029346.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKaram C, Klein CJ, Dispenzieri A, Dyck PJ, Mandrekar J, D\u0026rsquo;Souza A, et al. Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome. Neurology. 2019;93(4):e331\u0026ndash;40. PMID: 31217168.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDispenzieri A, Buadi FK, Kumar SK, Lacy MQ. Treatment and long-term outcomes in POEMS syndrome: an update of Mayo Clinic experience. \u003cem\u003eBlood Rev.\u003c/em\u003e 2020;45:100709. PMID: 32217043.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"POEMS syndrome, CIDP, electrophysiology, demyelinating neuropathy, plasma cell dyscrasia, lenalidomide","lastPublishedDoi":"10.21203/rs.3.rs-8077686/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8077686/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePOEMS syndrome is a rare multisystem disorder associated with plasma cell dyscrasia and characterized by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, and Skin changes. Its neuropathic presentation often mimics chronic inflammatory demyelinating polyneuropathy (CIDP), resulting in diagnostic delays. Differentiating features are crucial for appropriate therapy and improved outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective observational study included 15 patients diagnosed with POEMS syndrome at a tertiary-care neurology center between January 2019 and October 2025. Diagnosis was based on Dispenzieri\u0026rsquo;s criteria, requiring polyneuropathy and a monoclonal plasma cell disorder with additional major and minor features. Clinical data, biochemical parameters, imaging findings, and nerve conduction studies were analysed to define the clinical and electrophysiological spectrum. Treatment response was assessed at three months post-therapy.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe mean age was 44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 years, with slight male predominance. Organomegaly (87%), endocrinopathy (80%), and skin hyperpigmentation (93%) were common. Serum M-protein was demonstrable in 93% and osteosclerotic lesions in 80%. Electrophysiology revealed demyelinating neuropathy in 47%, mixed axonal\u0026ndash;demyelinating in 27%, and axonal neuropathy in 20%. Lenalidomide\u0026ndash;dexamethasone-based therapy resulted in neurological improvement in 87% of patients within three months.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eNeuropathy in POEMS syndrome typically demonstrates a mixed demyelinating\u0026ndash;axonal pattern with systemic manifestations distinguishing it from CIDP. Early recognition and institution of plasma cell\u0026ndash;directed therapy lead to favourable functional recovery.\u003c/p\u003e","manuscriptTitle":"Clinical and Electrophysiological Profile of Neuropathy in POEMS Syndrome: Differentiation from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 14:36:23","doi":"10.21203/rs.3.rs-8077686/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-29T07:18:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-22T22:32:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-19T04:26:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335729986026190569410581941741716943231","date":"2025-12-16T03:45:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"136778310035392839877050747635582493025","date":"2025-12-14T02:18:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-08T08:08:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"307185043181298556786949407318882843803","date":"2025-12-03T16:25:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308984843862064922695727682329732743754","date":"2025-11-29T12:21:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-28T12:12:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-14T00:48:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-14T00:48:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-11-10T13:25:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"54c9bde9-a0a6-4fa7-8eec-8e6d9731a638","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T16:25:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 14:36:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8077686","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8077686","identity":"rs-8077686","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}