Abstract
Purpose
To investigate small nerve fibre damage and inflammation at the level of the sub-basal nerve plexus (SNP) of severe obese patients and compare the results with those of healthy subjects.
Methods
This cross-sectional, observational study investigated the data of 28 patients (14 out of 28 prediabetic or diabetic) with severe obesity (Body Mass Index; BMI ≥ 40) and 20 healthy subjects. Corneal nerve fibre density (CNFD), branch density (CNBD), fibre length (CNFL), nerve fibre area (CNFA), nerve fibre width (CNFW), and nerve fractal dimension (CNFrD) and dendritic cell (DC) density were evaluated using in vivo confocal microscopy (IVCM, Heidelberg Retinal Tomograph III Rostock Cornea Module). Automatic CCMetrics software (University of Manchester, UK) was used for quantitative analysis of SNP.
Results
Mean age was 48.4±7.4 and 45.1 ± 5.8 in the control and obese group, respectively (p = 0.09). Mean BMI were 49.1 ± 7.8 vs. 23.3 ± 1.4 in obese vs. control group, respectively (p < 0.001). Mean CNFD, CNBD, CNFL, CNFA, CNFW were significantly reduced in obese group compared with those in the control group (always p < 0.05, respectively). There were no significant differences in any ACCMetrics parameters between prediabetic/diabetic and non-diabetic obese patients. Increased DC densities were detected in obese group compared with those in control group (p < 0.0001). There were significant correlations between BMI scores and SNP parameters.
Conclusion
Imaging with IVCM is a feasible, non-invasive method to detect and quantify occult corneal nerve damage and increased inflammation in patients with obesity. This study suggests that obesity may be a separate risk factor for peripheral neuropathy regardless of DM.
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Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Friedman N, Fanning L. Overweight and obesity: an overview of prevalence, clinical impact, and economic impact. Dis Manag. 2004;7:1–6. https://doi.org/10.1089/1093507042317152
Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: Prevalence and trends, 1960–1994. Int J Obes. 1998;22:39–47. https://doi.org/10.1038/sj.ijo.0800541
Patterson RE, Frank LL, Kristal AR, White E. A comprehensive examination of health conditions associated with obesity in older adults. Am J Prev Med. 2004;27:385–90. https://doi.org/10.1016/j.amepre.2004.08.001
Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13:155–65. https://doi.org/10.1385/ENDO:13:2:155
Eckel RH, Krauss RM. American Heart Association call to action: Obesity as a major risk factor for coronary heart disease. Circulation. 1998;97:2099–100. https://doi.org/10.1161/01.cir.97.21.2099
Cheung N, Wong TY. Obesity and eye diseases. Surv Ophthalmol. 2007;52:180–95. https://doi.org/10.1016/j.survophthal.2006.12.003
Himes RW, Smith CW. Tlr2 is critical for diet‐induced metabolic syndrome in a murine model. FASEB J. 2010;24:731–9. https://doi.org/10.1096/fj.09-141929
Wu H, Ghosh S, Perrard XD, Feng L, Garcia GE, Perrard JL, et al. T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation. 2007;115:1029–38. https://doi.org/10.1161/CIRCULATIONAHA.106.638379
Wu H, Gower RM, Wang H, Perrard XYD, Ma R, Bullard DC, et al. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation. 2009;119:2708–17. https://doi.org/10.1161/CIRCULATIONAHA.108.823740
Singleton J, Volckmann E, Graham T, Smith A. Neuropathy associated with nondiabetic obesity. Neurology. 2014;82:S36.006.
Ylitalo KR, Sowers MF, Heeringa S. Peripheral vascular disease and peripheral neuropathy in individuals with cardiometabolic clustering and obesity: National health and nutrition examination survey 2001-2004. Diabetes Care. 2011;34:1642–7. https://doi.org/10.2337/dc10-2150.
Lalive PH, Truffert A, Magistris MR, Landis T, Dosso A. Peripheral autoimmune neuropathy assessed using corneal in vivo confocal microscopy. Arch Neurol. 2009;66:403–5. https://doi.org/10.1001/archneurol.2008.587
Asghar O, Petropoulos IN, Alam U, Jones W, Jeziorska M, Marshall A, et al. Corneal confocal microscopy detects neuropathy in subjects with impaired glucose tolerance. Diabetes Care. 2014;37:2643–6. https://doi.org/10.2337/dc14-0279
Cruzat A, Qazi Y, Hamrah P. In vivo confocal microscopy of corneal nerves in health and disease. Ocul. Surf. 2017;15:15–47. https://doi.org/10.1016/j.jtos.2016.09.004
Tavakoli M, Quattrini C, Abbott C, Kallinikos P, Marshall A, Finnigan J, et al. Corneal confocal microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy. Diabetes Care. 2010;33:1792–7. https://doi.org/10.2337/dc10-0253
Jiang MS, Yuan Y, Gu ZX, Zhuang SL. Corneal confocal microscopy for assessment of diabetic peripheral neuropathy: A meta-analysi. Br J Ophthalmol. 2016;100:9–14. https://doi.org/10.1136/bjophthalmol-2014-306038
Petropoulos IN, Alam U, Fadavi H, Asghar O, Green P, Ponirakis G, et al. Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy. Diabetes Care. 2013;36:3646–51. https://doi.org/10.2337/dc13-0193
Coppey L, Davidson E, Shevalye H, Obrosov A, Torres M, Yorek MA. Progressive loss of corneal nerve fibers and sensitivity in rats modeling obesity and type 2 diabetes is reversible with omega-3 fatty acid intervention: Supporting cornea analyses as a marker for peripheral neuropathy and treatment. Diabetes. Metab Syndr Obes Targets Ther. 2020;13:1367–84. https://doi.org/10.2147/DMSO.S247571
Hargrave A, Courson JA, Pham V, Landry P, Magadi S, Shankar P, et al. Corneal dysfunction precedes the onset of hyperglycemia in a mouse model of diet-induced obesity. PLoS One. 2020; 15. https://doi.org/10.1371/journal.pone.0238750.
Tóth N, Silver DM, Balla S, Káplár M, Csutak A. In vivo corneal confocal microscopy and optical coherence tomography on eyes of participants with type 2 diabetes mellitus and obese participants without diabetes. Graefes Arch Clin Exp Ophthalmol. 2021;259:3339–50. https://doi.org/10.1007/s00417-021-05251-8
Azmi S, Ferdousi M, Liu Y, Adam S, Iqbal Z, Dhage S, et al. Bariatric surgery leads to an improvement in small nerve fibre damage in subjects with obesity. Int J Obes. 2021;45:631–8. https://doi.org/10.1038/s41366-020-00727-9
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62-9. https://doi.org/10.2337/dc10-S062.
Anon.Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee.; 1995.
Davidson EP, Coppey LJ, Holmes A, Yorek MA. Changes in corneal innervation and sensitivity and acetylcholine-mediated vascular relaxation of the posterior ciliary artery in a type 2 diabetic rat. Investig Ophthalmol Vis Sci. 2012;53:1182–7. https://doi.org/10.1167/iovs.11-8806
Kalteniece A, Ferdousi M, Adam S, Schofield J, Azmi S, Petropoulos I, et al. Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities. PLoS One. 2017;12:e0183040 https://doi.org/10.1371/journal.pone.0183040
Adam S, Azmi S, Ho JH, Liu Y, Ferdousi M, Siahmansur T, et al. Improvements in Diabetic Neuropathy and Nephropathy After Bariatric Surgery: a Prospective Cohort Study. Obes. Surg. 2020. https://doi.org/10.1007/s11695-020-05052-8. Available at: https://pubmed.ncbi.nlm.nih.gov/33104989/.
England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363:2151–61. https://doi.org/10.1016/S0140-6736(04)16508-2
Lubec D, Müllbacher W, Finsterer J, Mamoli B. Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J. 1999;75:723–7. https://doi.org/10.1136/pgmj
Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981;10:222–6. https://doi.org/10.1002/ana.410100304
Callaghan B, Feldman E. The metabolic syndrome and neuropathy: therapeutic challenges and opportunities. Ann Neurol. 2013;74:397–403. https://doi.org/10.1002/ana.23986
Hanewinckel R, Drenthen J, Ligthart S, Dehghan A, Franco OH, Hofman A, et al. Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study. J Neurol Neurosurg Psychiatry. 2016;87:1336–42. https://doi.org/10.1136/jnnp-2016-314171
Callaghan BC, Gao L, Li Y, Zhou X, Reynolds E, Banerjee M, et al. Diabetes and obesity are the main metabolic drivers of peripheral neuropathy. Ann Clin Transl Neurol. 2018;5:397–405. https://doi.org/10.1002/acn3.531
Callaghan BC, Xia R, Reynolds E, Banerjee M, Rothberg AE, Burant CF, et al. Association Between Metabolic Syndrome Components and Polyneuropathy in an Obese Population. JAMA Neurol. 2016;73:1468–76. https://doi.org/10.1001/jamaneurol.2016.3745
Grupcheva CN, Wong T, Riley AF. Assessing the sub-basal nerve plexus of the living healthy human cornea by in vivo confocal microscopy. In: Clinical and Experimental Ophthalmology. 30. Clin Exp Ophthalmol; 2002;187–90. https://doi.org/10.1046/j.1442-9071.2002.00507.x.
Misra SL, Patel DV, McGhee CN, Pradhan M, Kilfoyle D, Braatvedt GD, et al. Peripheral neuropathy and tear film dysfunction in type 1 diabetes mellitus. J Diabetes Res. 2014;2014:848659 https://doi.org/10.1155/2014/848659
Ferdousi M, Azmi S, Petropoulos IN, Fadavi H, Ponirakis G, Marshall A, et al. Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy. PLoS One. 2015;10:e0139394 https://doi.org/10.1371/journal.pone.0139394
Tavakoli M, Marshall A, Pitceathly R, Fadavi H, Gow D, Roberts ME, et al. Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp Neurol. 2010;223:245–50. https://doi.org/10.1016/j.expneurol.2009.08.033
Schneider C, Bucher F, Cursiefen C, Fink GR, Heindl LM, Lehmann HC. Corneal confocal microscopy detects small fiber damage in chronic inflammatory demyelinating polyneuropathy (CIDP). J Peripher Nerv Syst. 2014;19:322–7. https://doi.org/10.1111/jns.12098
Fleischer M, Lee I, Erdlenbruch F, Hinrichs L, Petropoulos IN, Malik RA, et al. Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy. J Neuroinflammation. 2021;18:89 https://doi.org/10.1186/s12974-021-02130-1
Tavakoli M, Petropoulos IN, Malik RA. Corneal confocal microscopy to assess diabetic neuropathy: an eye on the foot. J Diabetes Sci Technol. 2013;7:1179–89. https://doi.org/10.1177/193229681300700509
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care. 2008;31:464–9. https://doi.org/10.2337/dc07-1796
Lee CC, Perkins BA, Kayaniyil S, Harris SB, Retnakaran R, Gerstein HC, et al. Peripheral Neuropathy and Nerve Dysfunction in Individuals at High Risk for Type 2 Diabetes: The PROMISE Cohort. Diabetes Care. 2015;38:793–800. https://doi.org/10.2337/dc14-2585
Lu B, Hu J, Wen J, Zhang Z, Zhou L, Li Y, et al. Determination of peripheral neuropathy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes - ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SH-DREAMS). PLoS One. 2013;8:e61053 https://doi.org/10.1371/journal.pone.0061053
Buckman LB, Hasty AH, Flaherty DK, Buckman CT, Thompson MM, Matlock BK, et al. Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system. Brain Behav Immun. 2014;35:33–42. https://doi.org/10.1016/j.bbi.2013.06.007
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30. https://doi.org/10.1172/JCI19451
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808. https://doi.org/10.1172/JCI19246
Mancuso P. The role of adipokines in chronic inflammation. ImmunoTargets Ther. 2016;5:47–56. https://doi.org/10.2147/ITT.S73223
Lin L, Lee JH, Buras ED, Yu K, Wang R, Wayne Smith C, et al. Ghrelin receptor regulates adipose tissue inflammation in aging. Aging. 2016;8:178–91. https://doi.org/10.18632/aging.100888
Yorek MS, Obrosov A, Shevalye H, Holmes A, Harper MM, Kardon RH, et al. Effect of diet-induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice. J Peripher Nerv Syst. 2015;20:24–31. https://doi.org/10.1111/jns.12111
Callaghan BC, Xia R, Banerjee M, de Rekeneire N, Harris TB, Newman AB, et al. Health ABC Study. Metabolic Syndrome Components Are Associated With Symptomatic Polyneuropathy Independent of Glycemic Status. Diabetes Care. 2016;39:801–7. https://doi.org/10.2337/dc16-0081
Ho JH, Adam S, Azmi S, Ferdousi M, Liu Y, Kalteniece A, et al. Male sexual dysfunction in obesity: The role of sex hormones and small fibre neuropathy. PLoS One. 2019;14:e0221992 https://doi.org/10.1371/journal.pone.0221992
Iqbal Z, Kalteniece A, Ferdousi M, Adam S, D’Onofrio L, Ho JH, et al. Corneal keratocyte density and corneal nerves are reduced in patients with severe obesity and improve after bariatric surgery. Invest Ophthalmol Vis Sci. 2021;62:20 https://doi.org/10.1167/iovs.62.1.20
Azmi S, Ferdousi M, Liu Y, Adam S, Siahmansur T, Ponirakis G, et al. The role of abnormalities of lipoproteins and HDL functionality in small fibre dysfunction in people with severe obesity. Sci Rep. 2021;11:12573 https://doi.org/10.1038/s41598-021-90346-9
Khan A, Li Y, Ponirakis G, Akhtar N, Gad H, George P, et al. Corneal immune cells are increased in patients with multiple sclerosis. Transl Vis Sci Technol. 2021;10:19 https://doi.org/10.1167/tvst.10.4.19
Thimm A, Carpinteiro A, Oubari S, Papathanasiou M, Kessler L, Rischpler C, et al. Corneal confocal microscopy to detect early immune-mediated small nerve fibre loss in AL amyloidosis. Ann Clin Transl Neurol. 2022;9:853–63. https://doi.org/10.1002/acn3.51565
Jiao L, Zhang Y, Wang H, Fan D. Corneal confocal microscopy in the evaluation of immune-related motor neuron disease syndrome. BMC Neurol. 2022;22:138 https://doi.org/10.1186/s12883-022-02667-5
Mayer WJ, Irschick UM, Moser P, Wurm M, Huemer HP, Romani N, et al. Characterization of antigen-presenting cells in fresh and cultured human corneas using novel dendritic cell markers. Invest Ophthalmol Vis Sci. 2007;48:4459–67. https://doi.org/10.1167/iovs.06-1184
Mayer WJ, Mackert MJ, Kranebitter N, Messmer EM, Grüterich M, Kampik A, et al. Distribution of antigen presenting cells in the human cornea: correlation of in vivo confocal microscopy and immunohistochemistry in different pathologic entities. Curr Eye Res. 2012;37:1012–8. https://doi.org/10.3109/02713683.2012.696172
Leppin K, Behrendt AK, Reichard M, Stachs O, Guthoff RF, Baltrusch S, et al. Diabetes mellitus leads to accumulation of dendritic cells and nerve fiber damage of the subbasal nerve plexus in the cornea. Invest Ophthalmol Vis Sci. 2014;55:3603–15. https://doi.org/10.1167/iovs.14-14307
D’Onofrio L, Kalteniece A, Ferdousi M, Azmi S, Petropoulos IN, Ponirakis G, et al. Small Nerve Fiber Damage and Langerhans Cells in Type 1 and Type 2 Diabetes and LADA Measured by Corneal Confocal Microscopy. Invest Ophthalmol Vis Sci. 2021;62:5 https://doi.org/10.1167/iovs.62.6.5
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SG, FOA, SAT and AET conceived, designed, and conducted the study. SG and FOA recruited participants and collated data. SG and SAT conducted data analysis. SG wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript.
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Gulkas, S., Aydin, F.O., Turhan, S.A. et al. In vivo corneal confocal microscopy as a non-invasive test to assess obesity induced small fibre nerve damage and inflammation. Eye 37, 2226–2232 (2023). https://doi.org/10.1038/s41433-022-02321-x
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DOI: https://doi.org/10.1038/s41433-022-02321-x