Charcot Neuroarthropathy: Pathogenesis, Diagnosis and Medical Management
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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by OAR@UM Review Article Charcot neuroarthropathy: pathogenesis, diagnosis and medical management Sandro Vella, Mario J. Cachia Abstract Introduction Charcot neuroarthropathy (CN) is a progressive degenerative First reported in 1831 by the American physician John arthropathy which rarely complicates diabetes mellitus. Most Kearsley Mitchell as secondary to tuberculosis induced commonly, though not exclusively affecting the foot, it seems to spinal damage,1 denervation-induced joint destruction was be determined by the interaction of neuropathy, osteopaenia and described by the French neurologist Jean-Martin Charcot in proinflammatory cytokines on a calcified peripheral vasculature 1868 as a complication of tertiary syphilis.2 This degenerative that maintains its ability to vasodilate despite widespread neuropathic arthropathy was first associated with diabetes in arteriosclerosis. Although often unrecalled, this arthropathy is 1936.3 Indeed, diabetes is thought to be the commonest cause probably triggered by trauma. Diagnosis is essentially clinical, of CN in the developed world,4,5 although it may also complicate given the paucity and non-specificity of radiological and other diseases associated with peripheral neuropathy such as biochemical findings at the acute stage. CN should be considered leprosy, syringomyelia, following traumatic denervation of a in the differential diagnosis of any diabetic patient presenting limb, and as a complication of alcohol abuse. With a reported with a warm swollen lower extremity. Bone turnover markers, incidence of around 0.1-0.5%,6-8 CN in diabetes almost always, magnetic resonance imaging and radioisotope scanning may be though not exclusively, involves the foot. The midfoot or ankle useful diagnostic aids. Offloading is essential and improves limb joints are the most commonly affected joints. Involvement of survival. There is considerable interest, though limited data, on the knee,9 hip,10 spine11 and wrist12 has also been reported. CN the benefits of bisphosphonates and calcitonin. The possible may develop in up to 16% of patients with diabetic neuropathy.13 roles of ultrasound and radiotherapy need to be assessed in Both type 1 (T1DM) and type 2 diabetes (T2DM) patients appear larger trials. Failure to institute corrective measures at an early to be equally at risk, although the former seem to present at stage results in a foot that is prone to deformity, ulceration, a slightly earlier age.14 There is no sex predilection. Bilateral amputation and loss of function. It is hoped that a better involvement may occur in up to 30%.4 Affected individuals understanding of the aetiopathogenesis at a cytokine level will generally present in the fourth or fifth decades of life, several allow the targeting of new effective agents. years after the onset of diabetes.6,15 CN has been associated with premature mortality.16 Pathogenesis Although the pathogenesis of acute Charcot foot remains unclear, neuropathy and inflammation are key features. A case series of 101 subjects with CN confirmed the presence of distal sensory neuropathy in all patients.6 Charcot himself proposed the so called ‘French theory’,2 wherein the joint deformity was attributed to damaged central nervous system centres Key words that control bone and joint nutrition. Volkman and Virchow Arthropathy, neuropathy, cytokines, proposed the ‘German theory,’17,18 which suggested that multiple bisphosphonates, calcitonin subclinical traumata in a denervated joint were the initial precipitating factor. It is postulated that minor trauma may trigger an inflammatory cascade through a complex pathway.19 The Sandro Vella* MD, MRCP (UK) precipitating event is unrecalled in around two thirds of affected Diabetes and Endocrine Centre, Mater Dei Hospital, Malta patients.4 CN has also been noted to follow local surgery, Email: [email protected] including revascularisation20 and orthopaedic procedures.21 Mario J. Cachia MD, FRCP (Lond) Trauma may lead to microfracture, sublaxation or dislocation. Diabetes and Endocrine Centre, Mater Dei Hospital, Malta Abnormal joint loading is potentially further exacerbated by the neuropathy, such that a partial or complete lack of pain *corresponding author Malta Medical Journal Volume 20 Issue 03 September 2008 3 Table 1: Anatomical classification Table 2: Classification of Charcot of Charcot neuroarthropathy (CN) of the foot5 neuroarthropathy (CN) of the foot42 Type of CN Joint/s involved Type of CN Joint/s involved I metatarsophalangeal, interphalangeal forefoot metatarsophalangeal, interphalangeal, II tarso-metatarsal midfoot tarso-metatarsal, tarsal III tarsal hindfoot ankle, calcaneum IV sub-talar V calcaneum TNF-α appear to be mutually enhancing, such that a vicious leads to continued weight bearing and further joint damage. cycle is established.36 Osteoprotegerin, a glycoprotein member Interestingly, both neuropathy and diabetes are associated of the tumour necrosis factor family, acts as a decoy receptor with osteopaenia, the link being stronger with T1DM.22,23 for RANKL, effectively inactivating it when production is Osteopaenia seems to carry a higher risk of microfracture excessive. It is postulated that a coordinated synthesis of compared to dislocation.24 However, there is no evidence so far RANKL and osteoprotegerin is crucial in bone remodelling, for a difference in the presentation of CN between T1DM and allowing an appropriate balance between bone formation T2DM. In a study on a small group of patients presenting with a and resorption.37 The RANKL-NF-κB pathway is implicated hot swollen foot, Rawesh et al. demonstrated that reduced bone in the aetiopathogenesis of arterial wall smooth muscle mineral density in the lower limb led to subsequent development calcification.38,39 Vascular calcification (Monckeberg’s sclerosis) of CN compared to patients with a higher bone mineral density is a prominent feature of diabetic neuropathy and Charcot foot, at baseline.25 It is generally accepted that neuropathy impairs being present in up to 90% patients with the latter pathology.6 healing after an incidental traumatic fracture. The altered It is thought that, in the absence of neuropathy, pain- integrity of ligaments, possibly compromised in the acute phase induced joint immobilisation halts the above inflammatory by motor neuropathy,26,27 may account for a predilection for the osteolytic process by reducing local blood flow.40 Baseline blood involvement of joints dependent on ligamentous mechanical flow is increased in neuropathic feet as a result of a reduced stability, such as the midtarsal joint.28 Limited mobility of the peripheral vascular resistance and sympathetic denervation, but first metatarsophalangeal joint and plantar fascia dysfunction does not increase in response to warming. Charcot feet retain has been associated with mid-foot CN,31 although it is unclear the capacity to increase vascular flow further, exacerbating the whether these features precede or follow the onset of the joint inflammatory process. damage.29 Patients with acute CN have been found to have In summary, it is possible that CN is the result of a higher plantar pressures in the metatarsophalangeal joints precipitating insult on a susceptible individual. The relative when compared to patients with distal sensorimotor neuropathy contribution of the above factors may vary between T1DM and or neuropathic ulceration.30 It is postulated that the forefoot T2DM, and from one patient to another.41 acts as a lever and causes collapse of the midfoot, which is the commonest site of involvement. Electron microscopy of Clinical presentation and diagnosis the Achilles tendon has shown an increased packing density CN of the foot may be anatomically classified into five of collagen fibrils, decreased fibrillar diameter and abnormal different types, based on the joints involved5 (Table 1). A fibril morphology.31 These changes may lead to shortening of different classification system42 (Table 2) divides CN into tendons. The abnormal collagen may predispose to CN in these forefoot, midfoot and hindfoot CN. Midfoot43 or type II CN is the patients.31,32 commonest variety. Acute CN of the ankle, hindfoot or midfoot Histological examination of surgical specimens revealed heals at a slower rate than forefoot arthropathy.44 that osteoclasts significantly outnumber osteoblasts in Charcot reactive bone. These osteoclasts showed immunoreactivity A high index of suspicion is essential, particularly in for interleukin 1, interleukin 6 and tumour necrosis factor the acute stage. The situation is further complicated by the alpha (TNF-α).33 The inflammatory cascade is thought to be absence of a clear working definition of this disease entity.45 triggered by proinflammatory cytokines, principally TNF-α and Not uncommonly, acute CN is misdiagnosed as cellulitis, interleukin 1 beta, which in turn trigger increased expression osteomyelitis or an inflammatory arthropathy.6 Deep vein of the nuclear transcription factor-kappa B (NF-κB). This thrombosis should also be considered in the differential transcription factor plays an important part in bone dissolution diagnosis. Avascular necrosis of the navicular bone is less by favouring osteoclast activation. An intermediate step in common, but may show similar features to Charcot foot.46 the activation of NF-κB may involve an increased expression The diagnosis of acute CN remains predominantly clinical. of a specific