Diabetic neuro-ischaemic foot syndrome and the key underlying interactions between chronic arterial disease and peripheral neuropathy
Main Article Content
Vlad Adrian Alexandrescu, MD, PhD
http://orcid.org/0000-0002-9181-7993
Arnaud Kerzmann, MD
http://orcid.org/0000-0002-9434-3076
Vincent Tchana-Sato, MD, PhD
http://orcid.org/0000-0001-8838-814X
http://orcid.org/0000-0002-9181-7993
Arnaud Kerzmann, MD
http://orcid.org/0000-0002-9434-3076
Vincent Tchana-Sato, MD, PhD
http://orcid.org/0000-0001-8838-814X
Abstract
Chronic limb-threatening ischaemia and diabetic peripheral neuropathy are common complications of poorly controlled hyperglycaemia. Numerous clinical evidences suggest that peripheral arterial disease and diabetic peripheral neuropathy may be interconnected pathological entities with bidirectional interactions that respond to hyperglycaemia. The deleterious effects of hyperglycaemia manifest on a systemic scale as well as at the neuro-ischaemic limb level. Persistent hyperglycaemia-related injuries are induced by either direct cellular toxicity or indirect endothelial macrocirculatory damage, leading to cellular dysfunction, increased hypoxia, chronic inflammation, and cellular loss. This paper discusses some of the interactions between chronic limb-threatening ischaemia and diabetic peripheral neuropathy that constitute a complex bidirectional interplay. The scope of this editorial was to explore in depth these possible interactions, as encountered in daily clinical practice, from subclinical to clinical morphological and pathophysiological manifestations. It is also aimed to emphasize the important role played by these two entangled entities, as intricate risk factors for tissue and limb loss, linked to the harmful effects of persistent hyperglicaemia in diabetic, neuro-ischemic limbs.
Each significant clinical interaction (or groups of reciprocal interplay) is discussed in association with practical recommendations that are developed in distinct paragraphs, for better clinical applicability.
Keywords:
chronic limb-threatening ischemia, diabetic neuropathy, wound healing, diabetic foot, chronic hyperglycaemia, peripheral angioplasty, microangiopathy, arterial calcification, inferior limb salvage
Article Details
How to Cite
ALEXANDRESCU, Vlad Adrian; KERZMANN, Arnaud; TCHANA-SATO, Vincent.
Diabetic neuro-ischaemic foot syndrome and the key underlying interactions between chronic arterial disease and peripheral neuropathy.
Medical Research Archives, [S.l.], v. 13, n. 2, mar. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6364>. Date accessed: 17 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6364.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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21. Jörneskog G. Why critical limb ischemia criteria are not applicable to diabetic foot and what the consequences are. J Scan Surg. 2012; 101(2): 114-118. doi: 10.1177/145749691210100207.
22. Csonka V, Varju C, Lendvay M. Diabetes mellitus-related musculoskeletal disorders: unveiling the cluster of diseases. Prim Care Diabetes; 2023; 17: 548-553. doi: 10.1016/j.pcd.2023.08.003.
23. Li Y, Miao Y, Feng Q, et al. Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study. Front Endocrinol. 2024; 15: 1401531. doi: 10.3389/fendo.2024.1401531. eCollection 2024.
24. Cheng Y, Chen Y, Li K, et al. How inflammation dictates diabetic peripheral neuropathy: an enlightening review. CNS Neurosci Ther. 2024;30(4): e14477. doi: 10.1111/cns.14477.
25. Fiordaliso F, Clerici G, Maggioni S, et al. Prospective study on microangiopathy in type 2 diabetic foot ulcer. Diabetologia. 2016;59(7):1542–1548. doi: 10.1007/s00125-016-3961-0.
26. Alexandrescu VA, Neville RF, Kerzmann A, et al. Applicability of intentional topographic revasculari-zation following the angiosome model in patients with chronic limb-threatening ischemia: from theory, to current clinical challenges. Clin Surg. 2024;9:3701. https://dx.doi.org/10.25107/cis-v9-id3701.
27. Arora S, Pomposelli F, LoGerfo FW, et al. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg. 2002;35(3):501–505.
doi: 10.1067/mva.2002.121126.
28. Alexandrescu VA, Brochier S, Schoenen S, et al. Grades of below-the-ankle arterial occlusive disease following the angiosome perfusion: a new morphological assessment and correlations with the in¬framalleolar GVG stratification in CLTI patients. Ann Vasc Surg. 2022.1;1-20. https://doi.org/10.1016/j.avsg.2021.09.031
29. Mönckeberg JG: Über die reine Mediaverkalkung der extremitätenarterien und ihr verhalten zur arteriosklerose. Virch Arch. 1903; 169: 141-67.
30. Lanzer P, Ferraresi R. Medial sclerosis-epidemiology and clinical significance. Dtsch Arztebl Int. 2023; 120(21): 365–372.
doi: 10.3238/arztebl.m2023.0066.
31. Ferraresi R, Ucci A, Pizzuto A, et al. A novel scoring system for small artery disease and medial arterial calcification is strongly associated with major adverse limb events in patients with chronic limb-threatening ischemia. J Endovasc Ther. 2021;28(2):194-207. doi: 10.1177/1526602820966309.
32. Liu IH, Wu B, Krepkiy V, et al. Pedal arterial calcification score is associated with hemodynamic change and major amputation after infrainguinal revascularization for chronic limb-threatening ischemia. J Vasc Surg. 2022; 76: 1688–1697.
33. Lanzer P, Hannan FM, Lanzer JD, et al. Medial arterial calcification, JACC state-of-the-art review. J Am Coll Cardiol. 2021;78(11): 1145–1165. doi: 10.1016/j.jacc.2021.06.049.
34. Edmonds ME, Morrison N, Laws JW, Watkins PJ. Medial arterial calcification and diabetic neuropathy. Br Med J. 1982;284(6320):928–930. doi:10.1136/ bmj.284.6320.928
35. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infrapoplit-eal calcification patterns in critical limb ischemia: di-agnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardio-vasc Surg (Torino). 2017;58(3):383-401. doi:10.237 36/S0021-9509.17.09878-0
2. Hingorani A, LaMuraglia GM, Henke P, et al. The management of the diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3S–21S. doi: 10.1016/j.jvs.2015.10.003.
3. Zaffar H. An introduction to Diabetic Neuropathy: A Review. World J Pharm Sciences. 2016; (Print): 2321-3310, (Online): 2321-3086. http://www.wjpsonline.org/
4. Chang MC, Yang S. Diabetic peripheral neuropathy essentials: a narrative review. Ann Paliat Med. 2023;12(2):390-398.
https://dx.doi.org/ 10.21037/apm-22-693.
5. Mallick -Searle T, Adler JA. Update on treating painful diabetic peripheral neuropathy: a review of current US guidelines with a focus on the most recently approved management options. J Pain Res. 2024; 17:1005-1028.
doi: 10.2147/JPR.S442595. eCollection 2024.
6. Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetes neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diab Care. 2010;33:2285-2293. doi: 10.2337/dc10-1303.
7. Jensen TS, Karlsson P, Gylfadottir SS, et al. Painful and non-painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain. 2021; 144; 1632-1645. doi:10.1093/brain/awab079.
8. Alexandrescu VA, Van Overmeire L, Makrygiannis G, et al. Clinical implications of diabetic peripheral neuropathy in primary infrapopliteal angioplasty approach for neuro-ischemic foot wounds. J Endovasc Ther. 2022;30(6)920-930.
doi: 10.1177/15266028221106312.
9. Conte MS, (4) Bradbury AW, Kolh P, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vasc Endovasc Surg. 2019;58(1S):S1-S109.e33.70:662.
doi: 10.1016/j.ejvs.2019.05.006.
10. Uccioli L, Meloni M, Izzo V, Giurato L, Merolla S, Gandini R. Critical limb ischemia: current challenges and futures perspectives. Vasc Health Risk Manag. 2018;14:63-74.
11. Rosenberg DC, Blechschmidt V, Timmerman H, Wolff A, Treede RD. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm. 2020; 127(4):589-624.
doi: 10.1007/s00702-020-02145-7.
12. Alexandrescu VA, Kerzmann A, Boesmans E, et al. Singularities of the pedal circulation in CLTI: time for novel merging guidelines. J Crit Limb Ischem. 2023;3: E1.
13. O'Neal LW. Surgical pathology of the foot and clinicopathologic correlations. The end-artery occlusive disease conception. In: Bowker JH, Pfeifer MA. Chapter 18, Levin and O'Neal's The Diabetic Foot. 7th Ed. Mosby Elsevier, Philadelphia. 2007:367-401.
14. Shang Y, Zilin C, Dongye Z, Shuangmei L. Different types of cell death in diabetic neuropathy: a focus on mechanisms and therapeutic strategies. Int J Mol Sci. 2024;25(15):8126.
https://doi.org/10.3390/ ijms25158126.
15. Wei J, Tian J, Tang C, et al. The influence of different types of diabetes on vascular complications. J Diabetes Res. 2022;22:2022:344818.
doi: 10.1155/2022/3448618. eCollection 2022.
16. Mauricio D, Gratacos M, Franch-Nadal J. Diabetic microvascular disease in non-classical beds: the hidden impact beyond the retina, the kidney, and the peripheral nerves. Cardiovasc Diabetol. 2023;22: 314. doi: 10.1186/s12933-023-02056-3.
17. Alexandrescu VA, Pottier M, Balthazar S, Azdad K. The foot angiosomes as integrated level of lower limb arterial perfusion: amendments for chronic limb threatening ischemia presentations. J Vasc Endovasc Ther. 2019;4(1):1-7. http://vascular-endovascular-surgery.imedpub.com/
18. Mansour A, Mousa M, Abdelmannan D, Tay G, Hassoun A, Alsafar H. Microvascular and macrovascular complications of type 2 diabetes mellitus: exome wide association analyses. Front Endocrinol. 2023; 14:1143067.
doi: 10.3389/fendo.2023.1143067.
19. Taylor GI, Gianoutsos MP, Morris SF. The neurovascular territories of the skin and muscles: anatomic study and clinical implications. Plast Reconstr Surg. 1994; 94(1): 1-36.
20. Atmaca A, Ketenci A, Sahin I, et al. Expert opinion on screening, diagnosis and management of diabetic peripheral neuropathy: a multidisciplinary approach. Front Endocrinol. 2024; 17:15:1380929 doi: 10.3389/fendo.2024.1380929. eCollection 2024.
21. Jörneskog G. Why critical limb ischemia criteria are not applicable to diabetic foot and what the consequences are. J Scan Surg. 2012; 101(2): 114-118. doi: 10.1177/145749691210100207.
22. Csonka V, Varju C, Lendvay M. Diabetes mellitus-related musculoskeletal disorders: unveiling the cluster of diseases. Prim Care Diabetes; 2023; 17: 548-553. doi: 10.1016/j.pcd.2023.08.003.
23. Li Y, Miao Y, Feng Q, et al. Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study. Front Endocrinol. 2024; 15: 1401531. doi: 10.3389/fendo.2024.1401531. eCollection 2024.
24. Cheng Y, Chen Y, Li K, et al. How inflammation dictates diabetic peripheral neuropathy: an enlightening review. CNS Neurosci Ther. 2024;30(4): e14477. doi: 10.1111/cns.14477.
25. Fiordaliso F, Clerici G, Maggioni S, et al. Prospective study on microangiopathy in type 2 diabetic foot ulcer. Diabetologia. 2016;59(7):1542–1548. doi: 10.1007/s00125-016-3961-0.
26. Alexandrescu VA, Neville RF, Kerzmann A, et al. Applicability of intentional topographic revasculari-zation following the angiosome model in patients with chronic limb-threatening ischemia: from theory, to current clinical challenges. Clin Surg. 2024;9:3701. https://dx.doi.org/10.25107/cis-v9-id3701.
27. Arora S, Pomposelli F, LoGerfo FW, et al. Cutaneous microcirculation in the neuropathic diabetic foot improves significantly but not completely after successful lower extremity revascularization. J Vasc Surg. 2002;35(3):501–505.
doi: 10.1067/mva.2002.121126.
28. Alexandrescu VA, Brochier S, Schoenen S, et al. Grades of below-the-ankle arterial occlusive disease following the angiosome perfusion: a new morphological assessment and correlations with the in¬framalleolar GVG stratification in CLTI patients. Ann Vasc Surg. 2022.1;1-20. https://doi.org/10.1016/j.avsg.2021.09.031
29. Mönckeberg JG: Über die reine Mediaverkalkung der extremitätenarterien und ihr verhalten zur arteriosklerose. Virch Arch. 1903; 169: 141-67.
30. Lanzer P, Ferraresi R. Medial sclerosis-epidemiology and clinical significance. Dtsch Arztebl Int. 2023; 120(21): 365–372.
doi: 10.3238/arztebl.m2023.0066.
31. Ferraresi R, Ucci A, Pizzuto A, et al. A novel scoring system for small artery disease and medial arterial calcification is strongly associated with major adverse limb events in patients with chronic limb-threatening ischemia. J Endovasc Ther. 2021;28(2):194-207. doi: 10.1177/1526602820966309.
32. Liu IH, Wu B, Krepkiy V, et al. Pedal arterial calcification score is associated with hemodynamic change and major amputation after infrainguinal revascularization for chronic limb-threatening ischemia. J Vasc Surg. 2022; 76: 1688–1697.
33. Lanzer P, Hannan FM, Lanzer JD, et al. Medial arterial calcification, JACC state-of-the-art review. J Am Coll Cardiol. 2021;78(11): 1145–1165. doi: 10.1016/j.jacc.2021.06.049.
34. Edmonds ME, Morrison N, Laws JW, Watkins PJ. Medial arterial calcification and diabetic neuropathy. Br Med J. 1982;284(6320):928–930. doi:10.1136/ bmj.284.6320.928
35. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infrapoplit-eal calcification patterns in critical limb ischemia: di-agnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardio-vasc Surg (Torino). 2017;58(3):383-401. doi:10.237 36/S0021-9509.17.09878-0