Peripheral nerve damage in leprosy patients located in the Brazilian Amazon: High-Resolution sonography versus clinical evaluation

Peripheral nerve damage in leprosy patients located in the Brazilian Amazon: High-Resolution sonography versus clinical evaluation | 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 Article Peripheral nerve damage in leprosy patients located in the Brazilian Amazon: High-Resolution sonography versus clinical evaluation Brenda Ramos¹, Marília Xavier², Camilo Ramos³, Thaila Lima This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7552422/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 8 You are reading this latest preprint version Abstract Ultrasonography has increasingly been used to support the diagnosis and follow-up of peripheral neuropathy associated with leprosy. This study aims to compare and correlate clinical findings based on the Simplified Neurological Assessment, a protocol recommended by the Brazilian Ministry of Health, with ultrasonographic findings of the ulnar and median nerves in patients diagnosed with leprosy. A total of 50 patients were clinically evaluated and underwent high-resolution nerve ultrasonography. The correlation between clinical and sonographic findings was assessed using the Kappa coefficient. The most frequent ultrasound alterations included hypoechogenicity, increased cross-sectional area (CSA), and increased neural vascularity. A weak agreement (Kappa = 0.12) was found between the two assessment methods. These findings raise important questions regarding the sensitivity of clinical evaluation and the potential role of ultrasonography as a complementary and more objective diagnostic tool in the context of leprosy neuropathy. Our results highlight the relevance of incorporating ultrasonographic evaluation into leprosy care protocols to enhance early detection and improve patient outcomes. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology Leprosy Peripheral neuropathy High-resolution ultrasound Nerve thickening Neglected tropical disease Figures Figure 1 Introduction Leprosy is a chronic, primarily neural infectious disease and remains the leading cause of a treatable peripheral neuropathy worldwide.¹ Caused by Mycobacterium leprae, an obligate intracellular, acid-fast bacillus, the disease has persisted for centuries as one of the most impactful and debilitating conditions to affect humans.² Despite advancements in infectious disease control and the availability of multidrug therapy (MDT), leprosy continues to be an important public health problem, particularly in low- and middle-income countries such as Brazil, which ranks second globally in annual new case detection.³ Although curable, leprosy poses significant consequences for patients across its clinical spectrum, particularly in terms of functional impairment and reduced quality of life. The disease also impacts public health indicators such as Disability-Adjusted Life Years (DALYs), reflecting its societal burden.⁴ According to the World Health Organization (WHO), over 200,000 new cases were reported globally in 2019, with a detection rate of 25.9 per million population.⁵ In recognition of its persistent burden, leprosy is classified by WHO as a neglected tropical disease (NTD) and remains a target for global elimination under the United Nations Sustainable Development Goals (SDGs) 5 . In Brazil, recent epidemiological reports from the Ministry of Health have emphasized the urgency of strengthening national efforts to combat leprosy 3 . Government measures include increased federal funding for municipal leprosy control programs, public awareness campaigns, and training of healthcare professionals to ensure early detection, appropriate treatment, and continuous surveillance 3 . Early diagnosis is essential, as delayed recognition often leads to irreversible disabilities, stigma, and social exclusion. Clinically, leprosy presents a wide range of manifestations, influenced by the host's immune response. The Ridley-Jopling classification system describes a spectrum with two poles: tuberculoid (TT), characterized by strong cell-mediated immunity and limited disease, and lepromatous (LL), marked by poor immune response and widespread bacterial proliferation, and three intermediate borderline forms 2 . The gold standard for leprosy diagnosis remains clinical evaluation, based on the identification of cardinal signs: (1) skin lesions with sensory loss; (2) thickened peripheral nerves with associated sensory, motor, or autonomic dysfunction; and (3) detection of M. leprae via slit-skin smear or biopsy. 6 While these signs are often sufficient in typical cases, early or atypical presentations may require additional tools. High-resolution ultrasonography (HRUS) has emerged as a promising, accessible, and cost-effective method for assessing peripheral nerves. HRUS is non-invasive and radiation-free, utilizing high-frequency sound waves to generate detailed images of nerve morphology. 7 As a diagnostic aid, it offers the ability to assess long nerve segments—including those inaccessible to palpation—and provides insights into fascicular architecture, echotexture, and vascularity. 5, 7 Several studies suggest HRUS is more sensitive than clinical examination in identifying nerve thickening, asymmetry, and morphological changes, which may persist or worsen even after treatment. 7 Considering the importance of early and accurate diagnosis and the limitations of clinical assessment alone, this study aims to compare clinical findings with ultrasonographic evaluations of the ulnar and median nerves in patients with leprosy. By analyzing the concordance between these methods, we aim to contribute to the broader understanding of leprosy neuropathy and support the integration of HRUS into diagnostic protocols. Methods The project was approved by the Research Ethics Committee of the Federal University of Pará (NMT-UFPA), under registration 78084924.8.0000.5172. The researcher committed to complying with all institutional ethical guidelines and conduct standards throughout the duration of the study. Participants provided informed consent, with assurance of confidentiality before, during, and after the research, and the right to withdraw at any stage. No personally identifiable information was recorded, This was a cross-sectional observational study that was conducted at the Tropical Medicine Center (NMT/UFPA) with 50 adult leprosy patients. The study aimed to describe the ultrasonographic findings of leprosy-related neuropathy and to evaluate the concordance of these alterations with clinical findings. Clinical evaluation followed the Simplified Neurological Assessment, a clinical protocol recommended by the Brazilian Ministry of Health3, and high-resolution ultrasonography was performed by a radiologist using a Vinno 6® device. The review of medical records of leprosy patients aimed to collect clinical and epidemiological data. For analytical purposes, the Madrid and Operational classifications were grouped as follows: indeterminate (paucibacillary), tuberculoid (paucibacillary), borderline (multibacillary), and lepromatous (multibacillary). Dermato-neurological assessment and completion of the standardized SNA form were performed by the institutional physiotherapy team, and data were extracted directly from these records. The SNA variables of interest were restricted to upper limb assessment (ulnar and median nerves) and included: main complaint , palpation , muscle strength , sensory evaluation , physical disability grade (PDG) 3 . For statistical analysis, all variables were dichotomized into normal and altered . The criteria for classification were as follows: Main complaint : “normal” if no complaint was reported; “altered” if patients reported symptoms such as numbness, weakness, pain, itching, edema, nodules, or irritation; Palpation: Initially categorized as normal (N), thickened (E), painful (D), or with electric shock sensation (C), as per the SNA form. For analysis, results were grouped as “Normal” or “Altered,” with the latter including E, D, or C classifications; M uscle strength: Evaluated through abduction of the fifth finger (ulnar nerve) and abduction of the thumb (median nerve). Strength was graded from 0 to 5, as per SNA guidelines: grade 5 (normal strength), grades 2–4 (reduced strength), and grade 1 (paralysis). For analysis, “normal” was defined as grade 5 and “altered” as grades 1–4; Sensory evaluation: Performed with Semmes-Weinstein monofilaments (0.05 gf to 300 gf). Altered sensitivity was defined as thresholds >0.2 gf in the hands; ≤0.2 gf was considered normal. Sensory status was assessed bilaterally for each nerve, according to its dermatome distribution 8 ; Physical Disability Grade: Classified according to Brazilian Ministry of Health guidelines: grade 0 (no disability), grade 1 (loss of sensitivity without visible deformity), grade 2 (visible deformity or disability, such as lagophthalmos, claw hand, bone resorption, or foot drop). For analysis, grade 0 was classified as “normal” and grades 1–2 as “altered.” High-resolution ultrasound (HRUS) was used to assess peripheral nerves and collect the following outcome variables: quantitative variable: 1) absolute cross-sectional area (CSA) in mm²; and qualitative variables 2) echogenicity; 3) fascicular pattern; and 4) intraneural or perineural vascularity on color Doppler7. A nerve was considered ultrasonographically “altered” if at least one of the following was present: increased CSA and/or altered echogenicity (with or without fascicular disruption) end/or vascular changes with Doppler signal (Fig. 1). Reference values for CSA were adopted from Voltan et al. (2023)9, who established parameters in healthy Brazilian individuals. The mean ± standard deviation (SD) and median (Med) CSA values reported were: Median nerve at the carpal tunnel: 6.3 ± 1.9 mm²; Med = 6.0 mm²; Ulnar nerve at the cubital tunnel: 6.2 ± 1.6 mm²; Med = 6.1 mm²; Ulnar nerve proximal to the tunnel: 5.6 ± 1.7 mm²; Med = 5.4 mm². For classification, a nerve was considered “thickened” if the CSA exceeded the mean reference value plus two standard deviations. It is important to note that other reference values exist in the literature, such as those reported by Jain et al. (2009) 7 in a healthy Indian population. However, due to population-specific differences, this study adopted the Brazilian reference parameters from Voltan et al. (2023) 9 . Results Among the 50 patients, 62% were male and 38% female. The most affected age group was 30–60 years. According to the Madrid classification, 60% had lepromatous leprosy; the WHO classification showed 88% multibacillary cases. HRUS abnormalities included hypoechogenicity (63%), increased CSA (48%), and increased vascularity (3%). Agreement between clinical and HRUS findings was weak (Kappa=0.12). Notably, HRUS detected abnormalities in 49.1% of clinically normal nerves. These results suggest that ultrasound provides additional diagnostic value and can reveal subclinical nerve damage not detectable by palpation or symptom report. A total of 14 patients (28%) experienced reactional episodes, predominantly Type 2 reactions (71.4%). Clinical neuritis was identified in 6 of these cases, with one additional patient presenting neuritis in the absence of reaction, totaling 7 cases. All patients with reactions were multibacillary, most classified as lepromatous. The majority of the cohort (n = 36) did not present reactional episodes. Ultrasonography detected neuritis in 6 patients, while clinical evaluation identified 7 cases. Only 3 patients overlapped between both methods, with a Kappa coefficient of 0.38, indicating weak agreement. The most frequent ultrasonographic alteration was nerve echogenicity changes (63%), followed by CSA enlargement (48%) and Doppler signal (3%), the latter observed exclusively in lepromatous patients (Table 1). Lepromatous cases showed the highest frequency of alterations, followed by borderline and tuberculoid forms. Significant differences between echogenicity and CSA changes were found only in recent disease and early treatment, whereas no differences were observed in moderate/late stages or in post-MDT follow-up. Table 1 - Frequency of ultrasonographic alterations. Numbers inside the bars: total number of individuals and proportion in %. Clinical form Echogenicity altered n (%) CSA enlargement n (%) Positive Doppler n (%) Tuberculoid (6 patients; 24 nerves) 10 (41.6%) 7 (29.2%) 0 (0%) Borderline (14 patients; 56 nerves) 30 (53.6%) 22 (39.3%) 0 (0%) Lepromatous (30 patients; 120 nerves) 86 (71.7%) 67 (55.8%) 6 (5.0%) TOTAL (50 patients; 200 nerves) 126 (63%) 96 (48%) 6 (3%) Ultrasonography detected more abnormalities than clinical evaluation, identifying alterations in nearly half of clinically normal nerves and in 73% of those classified as clinically altered. Agreement between clinical palpation and CSA enlargement on ultrasound was weak (Kappa = 0.12), and overall concordance across all clinical parameters remained low, reflecting the higher sensitivity of ultrasonography compared with clinical assessment (Table 2). Table 2 - Neural thickening: clinical palpation versus ultrasonographic evaluation (CSA increase). Clinical palpation US-CSA thickened Thickened Normal Thickened Normal n % n % n % n % Right ulnar 7 14% 43 86% 28 56% 22 44% Left ulnar 13 26% 37 77% 27 54% 23 46% Right median 6 12% 44 88% 19 38% 31 62% Left median 7 14% 43 86% 22 44% 28 56% TOTAL 33 167 96 104 Discussion The sociodemographic profile of the sample—predominantly male, aged 30–60 years, multibacillary, and with a high frequency of lepromatous cases—aligns with prior reports 10,6,11 . These studies also observed a predominance of men and multibacillary forms, particularly the lepromatous type. The low representation of paucibacillary and tuberculoid patients was also consistent with previous findings and reflects the fact that our data were collected in a reference center, which may naturally concentrate more severe and multibacillary cases. Although this imbalance limits statistical comparisons, it mirrors daily clinical practice and highlights relevant differences between forms. Reactional states were observed in 14 patients (28%), with type 2 reactions predominating. Clinical neuritis was diagnosed in seven patients, while ultrasonography identified Doppler flow in six. However, correlation between Doppler positivity and clinical neuritis was weak, as three patients with positive Doppler had no clinical or reactional manifestations. This finding is consistent with prior work showing that Doppler changes can precede clinically detectable neuritis, suggesting that ultrasonography may provide early warning signs 12,13,14 . Conversely, underdiagnosis of acute neuritis in clinical practice may also explain this weak correlation, as neurological examinations are often less consistently performed than dermatological assessments 10 . Ultrasonographic abnormalities were present across all clinical forms of leprosy, reinforcing the concept that neuropathic involvement is widespread and not restricted to more severe cases. However, lepromatous patients showed the highest frequency of abnormalities, followed by borderline cases, while tuberculoid patients had the lowest frequency and no Doppler positivity. These findings replicate prior studies showing that MB, particularly lepromatous patients, are most severely affected 15 . The greater frequency of abnormalities in lepromatous patients may reflect the insidious but widespread progression of nerve infection and inflammation in this group, compounded by their propensity to develop type 2 reactions during treatment, leading to fibrosis and permanent nerve damage 9 . The pattern of ultrasonographic abnormalities differed from most published series. While many authors describe CSA enlargement as the most common alteration 6,10,16 , in this study echogenicity changes were most frequent (63%), followed by CSA increase (48%) and Doppler positivity (3%). This hierarchy is similar to Jain et al. (2009) 7 , who found echogenicity abnormalities in 50% of nerves, compared with CSA enlargement in 46%. Variability in findings may reflect methodological factors, as echogenicity is subjectively assessed and influenced by surrounding tissue, nerve depth, and disease duration 12 . It may also be affected by prior reactions and chronic inflammation. Importantly, echogenicity changes are not specific to leprosy and are observed in diabetic neuropathy, carpal tunnel syndrome, and other conditions. Nevertheless, echogenicity remains valuable for distinguishing normal from pathological nerves, and quantitative grayscale analysis has been proposed to reduce observer bias. CSA enlargement is an objective marker of neural involvement. In this study, 48% of nerves were thickened. Previous studies confirm that CSA increases over time and with advancing age, reflecting cumulative axonal damage and demyelination. Indeed, our analysis by disease duration showed that in recent cases, echogenicity changes predominated with statistical significance, whereas in late cases the frequencies of echogenicity and CSA changes converged, suggesting temporal evolution. A similar pattern was observed between patients under treatment and those in post-discharge follow-up: differences were significant during therapy but not after completion, consistent with a temporal effect. By nerve, the ulnar was most frequently affected, with greatest thickening at the pre-cubital tunnel. Mean CSA values in our series (right 15.9 ± 9.3 mm²; left 11.1 ± 8.0 mm²) were similar to those reported by Lugão et al. (2015) 10 , although Bathala et al. (2012) 13 found higher values. For the median nerve, the highest CSAs were again observed in lepromatous patients, around 12 mm², consistent with prior studies. Interestingly, two paucibacillary patients showed median nerve involvement, differing from Lugão et al. (2015) 10 , who found none; however, these patients also had ulnar involvement, reinforcing leprosy as the cause rather than carpal tunnel syndrome. Indeed, differential diagnosis with CTS requires careful attention, as leprosy typically produces proximal thickening, whereas CTS thickening is confined to the tunnel 7. The comparison between clinical and ultrasonographic findings showed consistently weak concordance. Ultrasonography detected abnormalities in nearly half of clinically normal nerves and in 73% of clinically altered nerves. Agreement between palpation and CSA enlargement was poor (Kappa 0.12), and concordance across all five clinical items of the SNA was low, with US consistently showing more abnormalities. The negative predictive value, however, was high (89%), suggesting that a negative US strongly indicates the absence of clinical thickening. The weak correlation may stem from both the greater sensitivity of US and the limitations of clinical methods. Palpation is subjective, subject to interobserver variability, and often less reliable in deep nerves such as the median. Even among trained professionals, concordance is suboptimal 17 . Moreover, neurological assessment is less frequently performed than dermatological examination in practice, leading to possible underdiagnosis of acute neuritis 10 . In contrast, US can evaluate long nerve segments, including anatomically difficult sites, and provide features beyond thickening, making it more sensitive and specific . Our findings diverge from Jain et al. (2009) 7 and Venugopal et al. (2021) 6 , who found moderate correlation between clinical thickening and CSA enlargement (Kappa 0.30 and 0.59, respectively). The consistently weak Kappa in our series raises two possibilities: that ultrasonography should be given greater diagnostic weight, or that the clinical method requires refinement and stricter standardization. A key limitation of this study was the lack of neurophysiological evaluation, which could provide complementary functional information. Prior work shows that patients may have anatomical abnormalities with preserved function or vice versa, highlighting the importance of multimodal assessment. Conclusion High-resolution ultrasonography (HRUS) proved valuable for detecting nerve changes in leprosy, even when clinical findings were absent, supporting its role as a complementary diagnostic tool. Incorporation into standard protocols could facilitate earlier diagnosis and prevention of disability. However, the cross-sectional and single-center design of this study must be considered as a limitation. Declarations AUTHOR CONTRIBUTIONS STATEMENT B.R. conceived and designed the study, recruited patients, performed ultrasonographic examinations, analyzed the data, and drafted the manuscript. M.X. contributed to patient evaluation, data collection, and critical review of the manuscript. C.R. assisted in data interpretation and manuscript preparation. All authors approved the final manuscript. COMPETING INTERESTS The authors declare no competing interests. DATA AVAILABILITY The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Goulart IMB, Bernardes Souza DO, Marques CR, Pimenta VL, Gonçalves MA, Goulart LR, et al. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol. 2008;15(1):101–5. doi: 10.1128/CVI.00372-07. PMID: 17989339. Gunatilake SB, Settinayake S. Leprosy. Pract Neurol. 2004;4(4):194–203. Ministério da Saúde do Brasil. Protocolo clínico e diretrizes terapêuticas da hanseníase. Brasília: Ministério da Saúde; 2022. Available from: https://www.gov.br/saude/pt-br/assuntos/saude-de-a-a-z/h/hanseniase/publicacoes/protocolo-clinico-e-diretrizes-terapeuticas-da-hanseniase-2022/view [Accessed 2023 Dec 15]. Ferreira AF, et al. Mortality from leprosy in high-endemicity contexts: integrated spatiotemporal analysis in Brazil. Rev Panam Salud Publica. 2019;43:1. World Health Organization. Leprosy: management of reactions and prevention of disabilities. Technical guidance. Geneva: WHO; 2020. Venugopal R, et al. Comparison of high-resolution ultrasonography with clinical examination in the assessment of peripheral nerve involvement in leprosy. Indian Dermatol J. 2021;12:536–40. Jain S, et al. High-resolution sonography: a new technique to detect nerve damage in leprosy. PLoS Negl Trop Dis. 2009;3(8):e498. doi: 10.1371/journal.pntd.0000498. Guzzo FG. Avaliação da neuropatia na hanseníase por mensuração eletrônica [master’s thesis]. Ribeirão Preto: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; 2007. Voltan G. Ultrassom point-of-care dos nervos periféricos para o diagnóstico da hanseníase e avaliação de contatos [doctoral thesis]. Ribeirão Preto: Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; 2022. Lugão HB, et al. Asymmetric nerve enlargement: a characteristic of leprosy neuropathy demonstrated by ultrasonography. PLoS Negl Trop Dis. 2015;9(12):e0004276. doi: 10.1371/journal.pntd.0004276. Gaschignard J, et al. Pauci- and multibacillary leprosy: two distinct, genetically neglected diseases. PLoS Negl Trop Dis. 2016;10(5):e0004345. doi: 10.1371/journal.pntd.0004345. Rai T, et al. High-resolution ultrasound in evaluation of peripheral neuropathy in patients of Hansen’s disease. Indian Dermatol Online J. 2024;15:213–7. Birdi TJ. Mechanisms involved in peripheral nerve damage in leprosy with special reference to insights obtained from in vitro studies and the experimental mouse model. Int J Lepr Other Mycobact Dis. 2003;71(4):345–54. Van Brakel WH, et al. Early diagnosis of neuropathy in leprosy: comparing diagnostic tests in a large prospective study. PLoS Negl Trop Dis. 2008;2(4):e212. doi: 10.1371/journal.pntd.0000212. Aggarwal N, et al. Sonographic evaluation of peripheral nerve involvement in leprosy with electrophysiologic correlation: a cross-sectional study in the sub-Himalayan region. Egypt J Radiol Nucl Med. 2024;55:97. doi: 10.1186/s43055-024-01269-0. Kumaran M, et al. Ultrasonography versus clinical examination in detecting leprosy neuropathy. Lepr Rev. 2019;90:1–8. Chen S, et al. Inter-observer reliability in assessment of sensation of skin lesion and enlargement of peripheral nerves in leprosy patients. Lepr Rev. 2006;77:371–6. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 27 Mar, 2026 Reviews received at journal 26 Mar, 2026 Reviewers agreed at journal 24 Mar, 2026 Reviewers invited by journal 23 Mar, 2026 Editor invited by journal 24 Feb, 2026 Editor assigned by journal 10 Sep, 2025 Submission checks completed at journal 09 Sep, 2025 First submitted to journal 06 Sep, 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. 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-7552422","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":611269464,"identity":"54f62137-9b17-4ad1-9f24-d2119206c4da","order_by":0,"name":"Brenda Ramos¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYBACAxiDn735AANjA5QHZ+DTItlzLIFELQY3fAyI02Iuffjhp5s7bOwlZ/B8k/i5w0aOgf3w0Q2MO+7h1GLZl2YsnXsmLbFfunebZO+ZNGMGnrS0G4xninE77AwPg3Ru2+EEyTlnt0nwth1ObJDgMbvB2JaATwvzb6AWe4MbOc8k/xKphQ1kC+OGGzls0kTZYtnDZmYN8svMnmPG1rJtacZsIL8knsGtxZyH+fHtXGCIAaPy4c23bTZy/OyHj934uAO3FjCAxgKLBIhkAxEENMC1MH8gpHAUjIJRMApGJgAA78pW3QXRulUAAAAASUVORK5CYII=","orcid":"","institution":"Federal University of Pará, Tropical Medicine Center (NMT/UFPA)","correspondingAuthor":true,"prefix":"","firstName":"Brenda","middleName":"","lastName":"Ramos¹","suffix":""},{"id":611269467,"identity":"b87d1708-08a6-43e9-8cd9-ee87c90a5712","order_by":1,"name":"Marília Xavier²","email":"","orcid":"","institution":"Federal University of Pará, Tropical Medicine Center (NMT/UFPA)","correspondingAuthor":false,"prefix":"","firstName":"Marília","middleName":"","lastName":"Xavier²","suffix":""},{"id":611269469,"identity":"26b95b92-1590-49ff-9d16-2f715a9c28da","order_by":2,"name":"Camilo Ramos³","email":"","orcid":"","institution":"Federal University of Pará, Tropical Medicine Center (NMT/UFPA)","correspondingAuthor":false,"prefix":"","firstName":"Camilo","middleName":"","lastName":"Ramos³","suffix":""},{"id":611269471,"identity":"a6fa0d04-0245-4104-a73d-713f0dcac448","order_by":3,"name":"Thaila Lima","email":"","orcid":"","institution":"Federal University of Pará, Tropical Medicine Center (NMT/UFPA)","correspondingAuthor":false,"prefix":"","firstName":"Thaila","middleName":"","lastName":"Lima","suffix":""}],"badges":[],"createdAt":"2025-09-06 17:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7552422/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7552422/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105456755,"identity":"74e8b327-43a0-4b75-8564-cc69891c67e5","added_by":"auto","created_at":"2026-03-26 09:15:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":672500,"visible":true,"origin":"","legend":"\u003cp\u003eUltrasound of the ulnar nerve: (A) normal fascicles; (B) neural thickening with increased CSA and loss of fascicular pattern; (C) normal echotexture; (D) hypoechogenicity; (E) transverse and (F) longitudinal views showing endoneural blood flow on color Doppler. Source: Author’s archive.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7552422/v1/28dea8a4c6e7d229c2dbe486.png"},{"id":105456782,"identity":"188c3ddb-2122-489f-b826-1df0d0d5f583","added_by":"auto","created_at":"2026-03-26 09:15:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1325483,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7552422/v1/be0b4581-8f47-4364-b2c9-91726318a630.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Peripheral nerve damage in leprosy patients located in the Brazilian Amazon: High-Resolution sonography versus clinical evaluation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLeprosy is a chronic, primarily neural infectious disease and remains the leading cause of a treatable peripheral neuropathy worldwide.¹ Caused by Mycobacterium leprae, an obligate intracellular, acid-fast bacillus, the disease has persisted for centuries as one of the most impactful and debilitating conditions to affect humans.² Despite advancements in infectious disease control and the availability of multidrug therapy (MDT), leprosy continues to be an important public health problem, particularly in low- and middle-income countries such as Brazil, which ranks second globally in annual new case detection.³\u003cbr\u003e\u0026nbsp;\u003cbr\u003eAlthough curable, leprosy poses significant consequences for patients across its clinical spectrum, particularly in terms of functional impairment and reduced quality of life. The disease also impacts public health indicators such as Disability-Adjusted Life Years (DALYs), reflecting its societal burden.⁴ According to the World Health Organization (WHO), over 200,000 new cases were reported globally in 2019, with a detection rate of 25.9 per million population.⁵ In recognition of its persistent burden, leprosy is classified by WHO as a neglected tropical disease (NTD) and remains a target for global elimination under the United Nations Sustainable Development Goals (SDGs)\u003csup\u003e5\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn Brazil, recent epidemiological reports from the Ministry of Health have emphasized the urgency of strengthening national efforts to combat leprosy\u003csup\u003e3\u003c/sup\u003e. Government measures include increased federal funding for municipal leprosy control programs, public awareness campaigns, and training of healthcare professionals to ensure early detection, appropriate treatment, and continuous surveillance\u003csup\u003e3\u003c/sup\u003e . Early diagnosis is essential, as delayed recognition often leads to irreversible disabilities, stigma, and social exclusion.\u003c/p\u003e\n\u003cp\u003eClinically, leprosy presents a wide range of manifestations, influenced by the host's immune response. The Ridley-Jopling classification system describes a spectrum with two poles: tuberculoid (TT), characterized by strong cell-mediated immunity and limited disease, and lepromatous (LL), marked by poor immune response and widespread bacterial proliferation, and three intermediate borderline forms \u003csup\u003e2\u0026nbsp;\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe gold standard for leprosy diagnosis remains clinical evaluation, based on the identification of cardinal signs: (1) skin lesions with sensory loss; (2) thickened peripheral nerves with associated sensory, motor, or autonomic dysfunction; and (3) detection of M. leprae via slit-skin smear or biopsy.\u003csup\u003e6\u003c/sup\u003e While these signs are often sufficient in typical cases, early or atypical presentations may require additional tools.\u003c/p\u003e\n\u003cp\u003eHigh-resolution ultrasonography (HRUS) has emerged as a promising, accessible, and cost-effective method for assessing peripheral nerves. HRUS is non-invasive and radiation-free, utilizing high-frequency sound waves to generate detailed images of nerve morphology.\u003csup\u003e7\u003c/sup\u003e As a diagnostic aid, it offers the ability to assess long nerve segments—including those inaccessible to palpation—and provides insights into fascicular architecture, echotexture, and vascularity.\u003csup\u003e5, 7\u0026nbsp;\u003c/sup\u003eSeveral studies suggest HRUS is more sensitive than clinical examination in identifying nerve thickening, asymmetry, and morphological changes, which may persist or worsen even after treatment.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eConsidering the importance of early and accurate diagnosis and the limitations of clinical assessment alone, this study aims to compare clinical findings with ultrasonographic evaluations of the ulnar and median nerves in patients with leprosy. By analyzing the concordance between these methods, we aim to contribute to the broader understanding of leprosy neuropathy and support the integration of HRUS into diagnostic protocols.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe project was approved by the Research Ethics Committee of the Federal University of Par\u0026aacute; (NMT-UFPA), under registration 78084924.8.0000.5172. The researcher committed to complying with all institutional ethical guidelines and conduct standards throughout the duration of the study. Participants provided informed consent, with assurance of confidentiality before, during, and after the research, and the right to withdraw at any stage. No personally identifiable information was recorded,\u003c/p\u003e\n\u003cp\u003eThis was a cross-sectional observational study that was conducted at the Tropical Medicine Center (NMT/UFPA) with 50 adult leprosy patients. The study aimed to describe the ultrasonographic findings of leprosy-related neuropathy and to evaluate the concordance of these alterations with clinical findings. Clinical evaluation followed the Simplified Neurological Assessment, a clinical protocol recommended by the Brazilian Ministry of Health3, and high-resolution ultrasonography was performed by a radiologist using a Vinno 6\u0026reg; device.\u003c/p\u003e\n\u003cp\u003eThe review of medical records of leprosy patients aimed to collect clinical and epidemiological data. For analytical purposes, the Madrid and Operational classifications were grouped as follows: indeterminate (paucibacillary), tuberculoid (paucibacillary), borderline (multibacillary), and lepromatous (multibacillary).\u003c/p\u003e\n\u003cp\u003eDermato-neurological assessment and completion of the standardized SNA form were performed by the institutional physiotherapy team, and data were extracted directly from these records. The SNA variables of interest were restricted to upper limb assessment (ulnar and median nerves) and included: \u003cstrong\u003emain complaint\u003c/strong\u003e, \u003cstrong\u003epalpation\u003c/strong\u003e, \u003cstrong\u003emuscle strength\u003c/strong\u003e, \u003cstrong\u003esensory evaluation\u003c/strong\u003e, \u003cstrong\u003ephysical disability grade (PDG)\u003csup\u003e3\u003c/sup\u003e\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFor statistical analysis, all variables were dichotomized into \u003cem\u003enormal\u003c/em\u003e and \u003cem\u003ealtered\u003c/em\u003e. The criteria for classification were as follows: \u003cstrong\u003eMain complaint :\u0026nbsp;\u003c/strong\u003e\u0026ldquo;normal\u0026rdquo; if no complaint was reported; \u0026ldquo;altered\u0026rdquo; if patients reported symptoms such as numbness, weakness, pain, itching, edema, nodules, or irritation; \u003cstrong\u003ePalpation:\u003c/strong\u003e Initially categorized as normal (N), thickened (E), painful (D), or with electric shock sensation (C), as per the SNA form. For analysis, results were grouped as \u0026ldquo;Normal\u0026rdquo; or \u0026ldquo;Altered,\u0026rdquo; with the latter including E, D, or C classifications; M\u003cstrong\u003euscle strength:\u003c/strong\u003e Evaluated through abduction of the fifth finger (ulnar nerve) and abduction of the thumb (median nerve). Strength was graded from 0 to 5, as per SNA guidelines: grade 5 (normal strength), grades 2\u0026ndash;4 (reduced strength), and grade 1 (paralysis). For analysis, \u0026ldquo;normal\u0026rdquo; was defined as grade 5 and \u0026ldquo;altered\u0026rdquo; as grades 1\u0026ndash;4; \u003cstrong\u003eSensory evaluation:\u003c/strong\u003e Performed with Semmes-Weinstein monofilaments (0.05 gf to 300 gf). Altered sensitivity was defined as thresholds \u0026gt;0.2 gf in the hands; \u0026le;0.2 gf was considered normal. Sensory status was assessed bilaterally for each nerve, according to its dermatome distribution\u003csup\u003e8\u003c/sup\u003e; \u003cstrong\u003ePhysical Disability Grade:\u003c/strong\u003e Classified according to Brazilian Ministry of Health guidelines: grade 0 (no disability), grade 1 (loss of sensitivity without visible deformity), grade 2 (visible deformity or disability, such as lagophthalmos, claw hand, bone resorption, or foot drop). For analysis, grade 0 was classified as \u0026ldquo;normal\u0026rdquo; and grades 1\u0026ndash;2 as \u0026ldquo;altered.\u0026rdquo;\u003c/p\u003e\n\u003cp\u003eHigh-resolution ultrasound (HRUS) was used to assess peripheral nerves and collect the following outcome variables: quantitative variable: 1) absolute cross-sectional area (CSA) in mm\u0026sup2;; and qualitative variables 2) echogenicity; 3) fascicular pattern; and 4) intraneural or perineural vascularity on color Doppler7. A nerve was considered ultrasonographically \u0026ldquo;altered\u0026rdquo; if at least one of the following was present: increased CSA and/or altered echogenicity (with or without fascicular disruption) end/or vascular changes with Doppler signal (Fig. 1).\u003c/p\u003e\n\u003cp\u003eReference values for CSA were adopted from Voltan et al. (2023)9, who established parameters in healthy Brazilian individuals. The mean \u0026plusmn; standard deviation (SD) and median (Med) CSA values reported were: Median nerve at the carpal tunnel: 6.3 \u0026plusmn; 1.9 mm\u0026sup2;; Med = 6.0 mm\u0026sup2;; Ulnar nerve at the cubital tunnel: 6.2 \u0026plusmn; 1.6 mm\u0026sup2;; Med = 6.1 mm\u0026sup2;; Ulnar nerve proximal to the tunnel: 5.6 \u0026plusmn; 1.7 mm\u0026sup2;; Med = 5.4 mm\u0026sup2;. For classification, a nerve was considered \u0026ldquo;thickened\u0026rdquo; if the CSA exceeded the mean reference value plus two standard deviations.\u003c/p\u003e\n\u003cp\u003eIt is important to note that other reference values exist in the literature, such as those reported by Jain et al. (2009)\u003csup\u003e7\u003c/sup\u003e in a healthy Indian population. However, due to population-specific differences, this study adopted the Brazilian reference parameters from Voltan et al. (2023)\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 50 patients, 62% were male and 38% female. The most affected age group was 30\u0026ndash;60 years. According to the Madrid classification, 60% had lepromatous leprosy; the WHO classification showed 88% multibacillary cases. HRUS abnormalities included hypoechogenicity (63%), increased CSA (48%), and increased vascularity (3%). Agreement between clinical and HRUS findings was weak (Kappa=0.12). Notably, HRUS detected abnormalities in 49.1% of clinically normal nerves.\u003c/p\u003e\n\u003cp\u003eThese results suggest that ultrasound provides additional diagnostic value and can reveal subclinical nerve damage not detectable by palpation or symptom report.\u003c/p\u003e\n\u003cp\u003eA total of 14 patients (28%) experienced reactional episodes, predominantly Type 2 reactions (71.4%). Clinical neuritis was identified in 6 of these cases, with one additional patient presenting neuritis in the absence of reaction, totaling 7 cases. All patients with reactions were multibacillary, most classified as lepromatous. The majority of the cohort (n = 36) did not present reactional episodes.\u003c/p\u003e\n\u003cp\u003eUltrasonography detected neuritis in 6 patients, while clinical evaluation identified 7 cases. Only 3 patients overlapped between both methods, with a Kappa coefficient of 0.38, indicating weak agreement.\u003c/p\u003e\n\u003cp\u003eThe most frequent ultrasonographic alteration was nerve echogenicity changes (63%), followed by CSA enlargement (48%) and Doppler signal (3%), the latter observed exclusively in lepromatous patients (Table 1). Lepromatous cases showed the highest frequency of alterations, followed by borderline and tuberculoid forms. Significant differences between echogenicity and CSA changes were found only in recent disease and early treatment, whereas no differences were observed in moderate/late stages or in post-MDT follow-up.\u003c/p\u003e\n\u003cp\u003eTable 1 - Frequency of ultrasonographic alterations. Numbers inside the bars: total number of individuals and proportion in %.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical form\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEchogenicity altered n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCSA enlargement n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive Doppler n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTuberculoid\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(6 patients; 24 nerves)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e10 (41.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e7 (29.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBorderline\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(14 patients; 56 nerves)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e30 (53.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e22 (39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLepromatous\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(30 patients; 120 nerves)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e86 (71.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e67 (55.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e6 (5.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(50 patients; 200 nerves)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e126 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e96 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e6 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eUltrasonography detected more abnormalities than clinical evaluation, identifying alterations in nearly half of clinically normal nerves and in 73% of those classified as clinically altered. Agreement between clinical palpation and CSA enlargement on ultrasound was weak (Kappa = 0.12), and overall concordance across all clinical parameters remained low, reflecting the higher sensitivity of ultrasonography compared with clinical assessment (Table 2).\u003c/p\u003e\n\u003cp\u003eTable 2 - Neural thickening: clinical palpation versus ultrasonographic evaluation (CSA increase).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical palpation\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUS-CSA thickened\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eThickened\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 107px;\"\u003e\n \u003cp\u003eThickened\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54px;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 48px;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 59px;\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 49px;\"\u003e\n \u003cp\u003e\u003cem\u003e%\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 58px;\"\u003e\n \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cem\u003e%\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRight ulnar\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e14%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e86%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e56%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e44%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeft ulnar\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e26%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e77%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e54%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e46%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRight median\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e12%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e88%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e38%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e62%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeft median\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e14%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e86%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e44%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e56%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 54px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e167\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 59px;\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 49px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 58px;\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe sociodemographic profile of the sample\u0026mdash;predominantly male, aged 30\u0026ndash;60 years, multibacillary, and with a high frequency of lepromatous cases\u0026mdash;aligns with prior reports \u003csup\u003e10,6,11\u003c/sup\u003e. These studies also observed a predominance of men and multibacillary forms, particularly the lepromatous type. The low representation of paucibacillary and tuberculoid patients was also consistent with previous findings and reflects the fact that our data were collected in a reference center, which may naturally concentrate more severe and multibacillary cases. Although this imbalance limits statistical comparisons, it mirrors daily clinical practice and highlights relevant differences between forms.\u003c/p\u003e\n\u003cp\u003eReactional states were observed in 14 patients (28%), with type 2 reactions predominating. Clinical neuritis was diagnosed in seven patients, while ultrasonography identified Doppler flow in six. However, correlation between Doppler positivity and clinical neuritis was weak, as three patients with positive Doppler had no clinical or reactional manifestations. This finding is consistent with prior work showing that Doppler changes can precede clinically detectable neuritis, suggesting that ultrasonography may provide early warning signs \u003csup\u003e12,13,14\u003c/sup\u003e. \u0026nbsp;Conversely, underdiagnosis of acute neuritis in clinical practice may also explain this weak correlation, as neurological examinations are often less consistently performed than dermatological assessments \u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eUltrasonographic abnormalities were present across all clinical forms of leprosy, reinforcing the concept that neuropathic involvement is widespread and not restricted to more severe cases. However, lepromatous patients showed the highest frequency of abnormalities, followed by borderline cases, while tuberculoid patients had the lowest frequency and no Doppler positivity. These findings replicate prior studies showing that MB, particularly lepromatous patients, are most severely affected\u003csup\u003e15\u003c/sup\u003e. \u0026nbsp;The greater frequency of abnormalities in lepromatous patients may reflect the insidious but widespread progression of nerve infection and inflammation in this group, compounded by their propensity to develop type 2 reactions during treatment, leading to fibrosis and permanent nerve damage \u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe pattern of ultrasonographic abnormalities differed from most published series. While many authors describe CSA enlargement as the most common alteration\u003csup\u003e6,10,16\u003c/sup\u003e, in this study echogenicity changes were most frequent (63%), followed by CSA increase (48%) and Doppler positivity (3%). This hierarchy is similar to Jain et al. (2009)\u003csup\u003e7\u003c/sup\u003e, who found echogenicity abnormalities in 50% of nerves, compared with CSA enlargement in 46%. Variability in findings may reflect methodological factors, as echogenicity is subjectively assessed and influenced by surrounding tissue, nerve depth, and disease duration\u003csup\u003e12\u003c/sup\u003e. It may also be affected by prior reactions and chronic inflammation. Importantly, echogenicity changes are not specific to leprosy and are observed in diabetic neuropathy, carpal tunnel syndrome, and other conditions. Nevertheless, echogenicity remains valuable for distinguishing normal from pathological nerves, and quantitative grayscale analysis has been proposed to reduce observer bias.\u003c/p\u003e\n\u003cp\u003eCSA enlargement is an objective marker of neural involvement. In this study, 48% of nerves were thickened. Previous studies confirm that CSA increases over time and with advancing age, reflecting cumulative axonal damage and demyelination. Indeed, our analysis by disease duration showed that in recent cases, echogenicity changes predominated with statistical significance, whereas in late cases the frequencies of echogenicity and CSA changes converged, suggesting temporal evolution. A similar pattern was observed between patients under treatment and those in post-discharge follow-up: differences were significant during therapy but not after completion, consistent with a temporal effect.\u003c/p\u003e\n\u003cp\u003eBy nerve, the ulnar was most frequently affected, with greatest thickening at the pre-cubital tunnel. Mean CSA values in our series (right 15.9 \u0026plusmn; 9.3 mm\u0026sup2;; left 11.1 \u0026plusmn; 8.0 mm\u0026sup2;) were similar to those reported by Lug\u0026atilde;o et al. (2015)\u003csup\u003e10\u003c/sup\u003e, although Bathala et al. (2012)\u003csup\u003e13\u003c/sup\u003e found higher values. For the median nerve, the highest CSAs were again observed in lepromatous patients, around 12 mm\u0026sup2;, consistent with prior studies. Interestingly, two paucibacillary patients showed median nerve involvement, differing from Lug\u0026atilde;o et al. (2015)\u003csup\u003e10\u003c/sup\u003e, who found none; however, these patients also had ulnar involvement, reinforcing leprosy as the cause rather than carpal tunnel syndrome. Indeed, differential diagnosis with CTS requires careful attention, as leprosy typically produces proximal thickening, whereas CTS thickening is confined to the tunnel \u003csup\u003e7.\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe comparison between clinical and ultrasonographic findings showed consistently weak concordance. Ultrasonography detected abnormalities in nearly half of clinically normal nerves and in 73% of clinically altered nerves. Agreement between palpation and CSA enlargement was poor (Kappa 0.12), and concordance across all five clinical items of the SNA was low, with US consistently showing more abnormalities. The negative predictive value, however, was high (89%), suggesting that a negative US strongly indicates the absence of clinical thickening.\u003c/p\u003e\n\u003cp\u003eThe weak correlation may stem from both the greater sensitivity of US and the limitations of clinical methods. Palpation is subjective, subject to interobserver variability, and often less reliable in deep nerves such as the median. Even among trained professionals, concordance is suboptimal \u003csup\u003e17\u003c/sup\u003e. Moreover, neurological assessment is less frequently performed than dermatological examination in practice, leading to possible underdiagnosis of acute neuritis \u003csup\u003e10\u003c/sup\u003e. In contrast, US can evaluate long nerve segments, including anatomically difficult sites, and provide features beyond thickening, making it more sensitive and specific .\u003c/p\u003e\n\u003cp\u003eOur findings diverge from Jain et al. (2009)\u003csup\u003e7\u003c/sup\u003e and Venugopal et al. (2021)\u003csup\u003e6\u003c/sup\u003e, who found moderate correlation between clinical thickening and CSA enlargement (Kappa 0.30 and 0.59, respectively). The consistently weak Kappa in our series raises two possibilities: that ultrasonography should be given greater diagnostic weight, or that the clinical method requires refinement and stricter standardization.\u003c/p\u003e\n\u003cp\u003eA key limitation of this study was the lack of neurophysiological evaluation, which could provide complementary functional information. Prior work shows that patients may have anatomical abnormalities with preserved function or vice versa, highlighting the importance of multimodal assessment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHigh-resolution ultrasonography (HRUS) proved valuable for detecting nerve changes in leprosy, even when clinical findings were absent, supporting its role as a complementary diagnostic tool. Incorporation into standard protocols could facilitate earlier diagnosis and prevention of disability. However, the cross-sectional and single-center design of this study must be considered as a limitation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAUTHOR CONTRIBUTIONS STATEMENT\u003c/p\u003e\n\u003cp\u003eB.R. conceived and designed the study, recruited patients, performed ultrasonographic examinations, analyzed the data, and drafted the manuscript. M.X. contributed to patient evaluation, data collection, and critical review of the manuscript. C.R. assisted in data interpretation and manuscript preparation. All authors approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eCOMPETING INTERESTS\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDATA AVAILABILITY\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGoulart IMB, Bernardes Souza DO, Marques CR, Pimenta VL, Gon\u0026ccedil;alves MA, Goulart LR, et al. Risk and protective factors for leprosy development determined by epidemiological surveillance of household contacts. Clin Vaccine Immunol. 2008;15(1):101\u0026ndash;5. doi: 10.1128/CVI.00372-07. PMID: 17989339.\u003c/li\u003e\n\u003cli\u003eGunatilake SB, Settinayake S. Leprosy. Pract Neurol. 2004;4(4):194\u0026ndash;203.\u003c/li\u003e\n\u003cli\u003eMinist\u0026eacute;rio da Sa\u0026uacute;de do Brasil. Protocolo cl\u0026iacute;nico e diretrizes terap\u0026ecirc;uticas da hansen\u0026iacute;ase. Bras\u0026iacute;lia: Minist\u0026eacute;rio da Sa\u0026uacute;de; 2022. Available from: https://www.gov.br/saude/pt-br/assuntos/saude-de-a-a-z/h/hanseniase/publicacoes/protocolo-clinico-e-diretrizes-terapeuticas-da-hanseniase-2022/view [Accessed 2023 Dec 15].\u003c/li\u003e\n\u003cli\u003eFerreira AF, et al. Mortality from leprosy in high-endemicity contexts: integrated spatiotemporal analysis in Brazil. Rev Panam Salud Publica. 2019;43:1.\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Leprosy: management of reactions and prevention of disabilities. Technical guidance. Geneva: WHO; 2020.\u003c/li\u003e\n\u003cli\u003eVenugopal R, et al. Comparison of high-resolution ultrasonography with clinical examination in the assessment of peripheral nerve involvement in leprosy. Indian Dermatol J. 2021;12:536\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eJain S, et al. High-resolution sonography: a new technique to detect nerve damage in leprosy. PLoS Negl Trop Dis. 2009;3(8):e498. doi: 10.1371/journal.pntd.0000498.\u003c/li\u003e\n\u003cli\u003eGuzzo FG. Avalia\u0026ccedil;\u0026atilde;o da neuropatia na hansen\u0026iacute;ase por mensura\u0026ccedil;\u0026atilde;o eletr\u0026ocirc;nica [master\u0026rsquo;s thesis]. Ribeir\u0026atilde;o Preto: Faculdade de Medicina de Ribeir\u0026atilde;o Preto, Universidade de S\u0026atilde;o Paulo; 2007.\u003c/li\u003e\n\u003cli\u003eVoltan G. Ultrassom point-of-care dos nervos perif\u0026eacute;ricos para o diagn\u0026oacute;stico da hansen\u0026iacute;ase e avalia\u0026ccedil;\u0026atilde;o de contatos [doctoral thesis]. Ribeir\u0026atilde;o Preto: Faculdade de Medicina de Ribeir\u0026atilde;o Preto, Universidade de S\u0026atilde;o Paulo; 2022.\u003c/li\u003e\n\u003cli\u003eLug\u0026atilde;o HB, et al. Asymmetric nerve enlargement: a characteristic of leprosy neuropathy demonstrated by ultrasonography. PLoS Negl Trop Dis. 2015;9(12):e0004276. doi: 10.1371/journal.pntd.0004276.\u003c/li\u003e\n\u003cli\u003eGaschignard J, et al. Pauci- and multibacillary leprosy: two distinct, genetically neglected diseases. PLoS Negl Trop Dis. 2016;10(5):e0004345. doi: 10.1371/journal.pntd.0004345.\u003c/li\u003e\n\u003cli\u003eRai T, et al. High-resolution ultrasound in evaluation of peripheral neuropathy in patients of Hansen\u0026rsquo;s disease. Indian Dermatol Online J. 2024;15:213\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eBirdi TJ. Mechanisms involved in peripheral nerve damage in leprosy with special reference to insights obtained from in vitro studies and the experimental mouse model. Int J Lepr Other Mycobact Dis. 2003;71(4):345\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eVan Brakel WH, et al. Early diagnosis of neuropathy in leprosy: comparing diagnostic tests in a large prospective study. PLoS Negl Trop Dis. 2008;2(4):e212. doi: 10.1371/journal.pntd.0000212.\u003c/li\u003e\n\u003cli\u003eAggarwal N, et al. Sonographic evaluation of peripheral nerve involvement in leprosy with electrophysiologic correlation: a cross-sectional study in the sub-Himalayan region. Egypt J Radiol Nucl Med. 2024;55:97. doi: 10.1186/s43055-024-01269-0.\u003c/li\u003e\n\u003cli\u003eKumaran M, et al. Ultrasonography versus clinical examination in detecting leprosy neuropathy. Lepr Rev. 2019;90:1\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eChen S, et al. Inter-observer reliability in assessment of sensation of skin lesion and enlargement of peripheral nerves in leprosy patients. Lepr Rev. 2006;77:371\u0026ndash;6.\u003c/li\u003e\n\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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Leprosy, Peripheral neuropathy, High-resolution ultrasound, Nerve thickening, Neglected tropical disease","lastPublishedDoi":"10.21203/rs.3.rs-7552422/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7552422/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Ultrasonography has increasingly been used to support the diagnosis and follow-up of peripheral neuropathy associated with leprosy. This study aims to compare and correlate clinical findings based on the Simplified Neurological Assessment, a protocol recommended by the Brazilian Ministry of Health, with ultrasonographic findings of the ulnar and median nerves in patients diagnosed with leprosy. A total of 50 patients were clinically evaluated and underwent high-resolution nerve ultrasonography. The correlation between clinical and sonographic findings was assessed using the Kappa coefficient. The most frequent ultrasound alterations included hypoechogenicity, increased cross-sectional area (CSA), and increased neural vascularity. A weak agreement (Kappa = 0.12) was found between the two assessment methods. These findings raise important questions regarding the sensitivity of clinical evaluation and the potential role of ultrasonography as a complementary and more objective diagnostic tool in the context of leprosy neuropathy. Our results highlight the relevance of incorporating ultrasonographic evaluation into leprosy care protocols to enhance early detection and improve patient outcomes.","manuscriptTitle":"Peripheral nerve damage in leprosy patients located in the Brazilian Amazon: High-Resolution sonography versus clinical evaluation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-26 09:15:32","doi":"10.21203/rs.3.rs-7552422/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-27T05:09:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-26T08:27:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333564270127718397671454941220529752069","date":"2026-03-24T09:52:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-23T14:36:50+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-25T04:47:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-10T07:29:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-09T09:20:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-06T17:28:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0b7c5bc8-4e7d-458b-bca8-fb3ce69fd70b","owner":[],"postedDate":"March 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":65036164,"name":"Health sciences/Diseases"},{"id":65036165,"name":"Health sciences/Health care"},{"id":65036166,"name":"Health sciences/Medical research"},{"id":65036167,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2026-04-24T04:39:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-26 09:15:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7552422","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7552422","identity":"rs-7552422","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}