Download PDF
Klinische Neurophysiologie 2020; 51(02): 67-72
DOI: 10.1055/a-1134-2547
Originalia

Die Rolle der diabetischen Neuropathie bei der Genese des Charcot-Fußes

Diabetic Neuropathy and the Charcot foot
Maike F. Dohrn
1   Neurologische Klinik, Universitätsklinik der RWTH Aachen, Aachen
,
Sigurd Kessler
2   OTHOEVO, München
,
Manuel Dafotakis
1   Neurologische Klinik, Universitätsklinik der RWTH Aachen, Aachen
› Author Affiliations
› Further Information
Also available at
   Permissions and Reprints

Zusammenfassung

Die neuropathische Osteo(arthro-)pathie, auch Charcot-Fuß genannt, ist eine progressive, nicht-infektiöse Schwellung mit Überwärmung und Demineralisierung, gefolgt von Knochendestruktion und Deformierung, die in ca. 75% unilateral auftritt und in einer Defektheilung zum Stillstand kommt. Resultierende Fehlstellungen können zu neuropathischen Ulzera führen, die sich infizieren und Amputationen erforderlich machen können. Die häufigste, aber nicht einzige Ursache ist der Diabetes mellitus. Etwa 2% aller Diabetiker entwickeln einen Charcot-Fuß. Der pathophysiologische „Charcot-Prozess“ ist komplex, scheint aber untrennbar mit der vorausgehenden Neuropathie verbunden zu sein. Die C- und Aδ- Fasern sind im Rahmen der diabetischen Neuropathie früh und häufig geschädigt, was ein Ungleichgewicht an CGRP, VIP, Substanz P und weiteren Transmittern erklärt. Störungen der Knocheninnervation verschieben das Verhältnis von Knochenan- und -abbau, von OPG und RANKL zugunsten des Abbaus. Demnach stellt die Fehlregulation nozizeptiver Nervenfasern auf molekularer Ebene eine pathophysiologische Brücke zwischen Diabetes mellitus und neurogener Inflammation dar.

Abstract

The neuropathic osteo(arthro-)pathy, also called Charcot foot, constitutes a progressive, non-infectious, self-limiting, foot inflammation and demineralization followed by bone destruction and deformity, which occurs unilaterally in 75% of cases resulting in permanent defect of the foot involved. As a consequence of malposition, ulcers, potentially complicated by infections, can make amputations necessary. With about 2% of all diabetics affected, diabetes mellitus is the most frequent, but not exclusive cause of Charcot foot to date. The pathophysiological process leading to this condition is complex; it is, however, closely linked to a preceding neuropathy. The small C- und Aδ nerve fibers are particularly prone to damage in the early course of diabetic neuropathy leading to an imbalance of neurotransmitters such as CGRP, VIP, substance P, and others. Disturbances in bone innervation shift the equilibrium between bone formation and degradation represented by OPG and RANKL, respectively, in favor of demineralization. It is suspected that dysregulation of nociceptive nerve fibers builds the pathophysiological bridge between diabetes mellitus and neurogenic inflammation causing the formation of Charcot foot.

Schlüsselwörter

Charcot-Fuß - Diabetische Neuropathie - Neurogene Inflammation - Knocheninnervation - Diabetes mellitus

Key words

Charcot foot - diabetic neuropathy - neurogenic inflammation - bone innervation - diabetes mellitus


Publication History

Article published online:
28 April 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • Literatur

  • 1 Papanas N, Maltezos E. Etiology, pathophysiology and classifications of the diabetic Charcot foot. Diabetic foot & ankle. 2013 4.
    PubMedGoogle Scholar
  • 2 Trieb K. The Charcot foot: pathophysiology, diagnosis and classification. The bone & joint journal 2016; 98-b 1155-1159
    PubMedGoogle Scholar
  • 3 Nather A, Bee CS, Huak CY. et al. Epidemiology of diabetic foot problems and predictive factors for limb loss. Journal of diabetes and its complications 2008; 22: 77-82
    CrossrefPubMedGoogle Scholar
  • 4 Kaynak G, Birsel O, Guven MF. et al. An overview of the Charcot foot pathophysiology. Diabetic foot & ankle 2013; 4
    PubMedGoogle Scholar
  • 5 Kelly M. De Arthritide Symptomatica of William Musgrave (1657–1721): His Description of Neuropathic Arthritis. Bulletin of the history of medicine 1963; 37: 372-377
    PubMedGoogle Scholar
  • 6 Hartemann-Heurtier A, Van GH, Grimaldi A. The Charcot foot. Lancet (London, England) 2002; 360: 1776-1779
    CrossrefPubMedGoogle Scholar
  • 7 Obrosova IG. Update on the pathogenesis of diabetic neuropathy. Current diabetes reports 2003; 3: 439-445
    CrossrefPubMedGoogle Scholar
  • 8 Dyck PJ. Detection, characterization, and staging of polyneuropathy: assessed in diabetics. Muscle & nerve 1988; 11: 21-32
    CrossrefPubMedGoogle Scholar
  • 9 Dohrn MF, Othman A, Hirshman SK. et al. Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?. European journal of neurology 2015; 22: 806-814, e855
    CrossrefPubMedGoogle Scholar
  • 10 Sandireddy R, Yerra VG, Areti A. et al. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. International journal of endocrinology 2014; 2014: 674987
    PubMedGoogle Scholar
  • 11 Cameron NE. Role of endoplasmic reticulum stress in diabetic neuropathy. Diabetes 2013; 62: 696-697
    CrossrefPubMedGoogle Scholar
  • 12 Bertea M, Rutti MF, Othman A. et al. Deoxysphingoid bases as plasma markers in diabetes mellitus. Lipids in health and disease 2010; 9: 84
    CrossrefPubMedGoogle Scholar
  • 13 Dyck PJ, Albers JW, Andersen H. et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes/metabolism research and reviews 2011; 27: 620-628
    CrossrefPubMedGoogle Scholar
  • 14 O’Connor AB. Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. PharmacoEconomics 2009; 27: 95-112
    CrossrefPubMedGoogle Scholar
  • 15 Dyck PJ, Kratz KM, Karnes JL. et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993; 43: 817-824
    CrossrefPubMedGoogle Scholar
  • 16 Haensch CA, Luhrs A. Autonomic Disorders (Reprinted). Klinische Neurophysiologie 2018; 49: 161-164
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Barohn RJ, Sahenk Z, Warmolts JR. et al. The Bruns-Garland syndrome (diabetic amyotrophy). Revisited 100 years later. Archives of neurology 1991; 48: 1130-1135
    CrossrefPubMedGoogle Scholar
  • 18 Umapathi T, Tan WL, Loke SC. et al. Intraepidermal nerve fiber density as a marker of early diabetic neuropathy. Muscle & nerve 2007; 35: 591-598
    CrossrefPubMedGoogle Scholar
  • 19 Severinsen K, Andersen H. Evaluation of atrophy of foot muscles in diabetic neuropathy – a comparative study of nerve conduction studies and ultrasonography. Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 2007; 118: 2172-2175
    PubMedGoogle Scholar
  • 20 Ndip A, Williams A, Jude EB. et al. The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes 2011; 60: 2187-2196
    CrossrefPubMedGoogle Scholar
  • 21 Jeffcoate WJ. Charcot neuro-osteoarthropathy. Diabetes/metabolism research and reviews 2008; 24 (Suppl 1) S62-S65
    CrossrefPubMedGoogle Scholar
  • 22 Uccioli L, Sinistro A, Almerighi C. et al. Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot. Diabetes care 2010; 33: 350-355
    CrossrefPubMedGoogle Scholar
  • 23 Bruhn-Olszewska B, Korzon-Burakowska A, Wegrzyn G. et al. Prevalence of polymorphisms in OPG, RANKL and RANK as potential markers for Charcot arthropathy development. Scientific reports 2017; 7: 501
    CrossrefPubMedGoogle Scholar
  • 24 Serre CM, Farlay D, Delmas PD. et al. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone 1999; 25: 623-629
    CrossrefPubMedGoogle Scholar
  • 25 Chenu C. Role of innervation in the control of bone remodeling. Journal of musculoskeletal & neuronal interactions 2004; 4: 132-134
    PubMedGoogle Scholar
  • 26 Jones KB, Mollano AV, Morcuende JA. et al. Bone and brain: a review of neural, hormonal, and musculoskeletal connections. The Iowa orthopaedic journal 2004; 24: 123-132
    Google Scholar
  • 27 Duncan CP, Shim SS J. Edouard Samson Address: the autonomic nerve supply of bone. An experimental study of the intraosseous adrenergic nervi vasorum in the rabbit. The Journal of bone and joint surgery British volume 1977; 59: 323-330
    PubMedGoogle Scholar
  • 28 Hohmann EL, Elde RP, Rysavy JA. et al. Innervation of periosteum and bone by sympathetic vasoactive intestinal peptide-containing nerve fibers. Science (New York, NY) 1986; 232: 868-871
    CrossrefPubMedGoogle Scholar
  • 29 Lerner UH, Persson E. Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. Journal of musculoskeletal & neuronal interactions 2008; 8: 154-165
    PubMedGoogle Scholar
  • 30 Li J, Kreicbergs A, Bergstrom J. et al. Site-specific CGRP innervation coincides with bone formation during fracture healing and modeling: A study in rat angulated tibia. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 2007; 25: 1204-1212
    PubMedGoogle Scholar
  • 31 Gomes RN, Castro-Faria-Neto HC, Bozza PT. et al. Calcitonin gene-related peptide inhibits local acute inflammation and protects mice against lethal endotoxemia. Shock (Augusta, Ga) 2005; 24: 590-594
    CrossrefPubMedGoogle Scholar
  • 32 Chiu IM, Heesters BA, Ghasemlou N. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 2013; 501: 52-57
    PubMedGoogle Scholar
  • 33 Sohn SJ. Substance P upregulates osteoclastogenesis by activating nuclear factor kappa B in osteoclast precursors. Acta oto-laryngologica 2005; 125: 130-133
    CrossrefPubMedGoogle Scholar
  • 34 Lavoie B, Lian JB, Mawe GM. Regulation of Bone Metabolism by Serotonin. Advances in experimental medicine and biology 2017; 1033: 35-46
    PubMedGoogle Scholar
  • 35 Richardson JD, Vasko MR. Cellular mechanisms of neurogenic inflammation. The Journal of pharmacology and experimental therapeutics 2002; 302: 839-845
    PubMedGoogle Scholar
  • 36 Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nature neuroscience 2012; 15: 1063-1067
    CrossrefPubMedGoogle Scholar
  • 37 Sorkin LS, Eddinger KA, Woller SA. et al. Origins of antidromic activity in sensory afferent fibers and neurogenic inflammation. Seminars in immunopathology 2018; 40: 237-247
    CrossrefPubMedGoogle Scholar
  • 38 Gouin O, L'Herondelle K, Lebonvallet N. et al. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein & cell 2017; 8: 644-661
    CrossrefPubMedGoogle Scholar
  • 39 Marche P, Dubois S, Abraham P. et al. Neurovascular microcirculatory vasodilation mediated by C-fibers and Transient receptor potential vanilloid-type-1 channels (TRPV 1) is impaired in type 1 diabetes. Scientific reports 2017; 7: 44322
    CrossrefPubMedGoogle Scholar
  • 40 Benson MD. The hereditary amyloidoses. Best practice & research Clinical rheumatology 2003; 17: 909-927
    PubMedGoogle Scholar
  • 41 Feldman DS, Ruchelsman DE, Spencer DB. et al. Peripheral arthropathy in hereditary sensory and autonomic neuropathy types III and IV. Journal of pediatric orthopedics 2009; 29: 91-97
    CrossrefPubMedGoogle Scholar
  • 42 Marinus J, Moseley GL, Birklein F. et al. Clinical features and pathophysiology of complex regional pain syndrome. The Lancet Neurology 2011; 10: 637-648
    CrossrefPubMedGoogle Scholar
  • 43 Harden RN, Bruehl S, Galer BS. et al. Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive?. Pain 1999; 83: 211-219
    CrossrefPubMedGoogle Scholar
  • 44 Oaklander AL, Rissmiller JG, Gelman LB. et al. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 2006; 120: 235-243
    CrossrefPubMedGoogle Scholar
  • 45 Albrecht PJ, Hines S, Eisenberg E. et al. Pathologic alterations of cutaneous innervation and vasculature in affected limbs from patients with complex regional pain syndrome. Pain 2006; 120: 244-266
    CrossrefPubMedGoogle Scholar
  • 46 Birklein F. Complex regional pain syndrome. Journal of neurology 2005; 252: 131-138
    CrossrefPubMedGoogle Scholar
  • 47 Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology 2010; 113: 713-725
    CrossrefPubMedGoogle Scholar
  • 48 de Mos M, Laferriere A, Millecamps M. et al. Role of NFkappaB in an animal model of complex regional pain syndrome-type I (CRPS-I). The journal of pain : official journal of the American Pain Society 2009; 10: 1161-1169
    PubMedGoogle Scholar
  • 49 Kramer HH, Hofbauer LC, Szalay G. et al. Osteoprotegerin: a new biomarker for impaired bone metabolism in complex regional pain syndrome?. Pain 2014; 155: 889-895
    CrossrefPubMedGoogle Scholar