Curr Diab Rep (2014) 14:561 DOI 10.1007/s11892-014-0561-6
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
The Charcot Foot as a Complication of Diabetic Neuropathy Janice V. Mascarenhas & Edward B. Jude
# Springer Science+Business Media New York 2014
Abstract Diabetes mellitus is a leading global metabolic disorder accompanied by the overwhelming burden of its associated complications. Hyperglycaemia-induced endothelial damage or endothelial dysfunction serves as the primary instigator for the development of microvascular disease. Diabetic neuropathy represents the majority of microvascular sequelae and is the renowned perpetrator of a variety of foot complications, namely the Charcot foot (CF). CF is a debilitating medical emergency which is often mismanaged either due to a delayed diagnosis or lack of clinical expertise in the management of CF. Often, misdiagnosis during the acute stages of CF leads to irreversible and persistent joint destruction which may be refractory to medical or surgical treatment. Timely intervention with offloading measures is crucial during acute CF in ceasing active bone resorption. Current antiresorptive agents may be considered as adjunctive therapy in combination with offloading. Novel agents are underway that will enable bone formation and suppress bone resorption.
Keywords Charcot neuroarthropathy . Diabetic peripheral neuropathy
This article is part of the Topical Collection on Microvascular Complications—Neuropathy J. V. Mascarenhas : E. B. Jude (*) Diabetes and Endocrinology, Tameside Hospital NHS Foundation Trust, Fountain Street, Ashton-Under-Lyne, Lancashire OL6 9RW, UK e-mail: [email protected] J. V. Mascarenhas e-mail: [email protected] J. V. Mascarenhas : E. B. Jude University of Manchester, Oxford Road, Manchester M13 9PL, UK
Introduction The incidence and prevalence of diabetic complications has escalated in the recent years owing to increased availability of various treatment options that prolong the life expectancy of affected individuals. The economic and health burden inflicted by diabetes mellitus (DM) is attributed mainly to its associated microvascular complications which include the well-known constituents of the diabetic triopathy (diabetic nephropathy, retinopathy and neuropathy). Diabetic neuropathy or diabetic peripheral neuropathy is said to affect approximately 25 to 35 % of patients with diabetes with an annual incidence of about 2 % [1, 2]. In fact, it is the prime perpetrator of diabetic foot complications (ulcers, foot deformities). Among the foot complications, the Charcot foot (CF) is the most challenging debilitating consequence of diabetic neuropathy. The Charcot foot is also observed in several other neurological diseases (tabes dorsalis, leprosy, syringomyelia, multiple sclerosis, myelomeningocele, spinal cord compression); however, diabetic neuropathy accounts for majority of the cases affecting 0.2 % of the diabetic population. Involvement of the contralateral foot occurs in 5.9 to 39.3 % of heterogenous cases [3, 4]. This review article is intended to provide the treating clinician with an insight into the evolution of CF and enable them to choose the appropriate therapeutic interventions aimed at aversion of irreversible skeletal attrition.
Pathogenesis: the Evolution of the Charcot Foot The development of CF has always been a subject of endless exploration, its multifactorial origin being the common ground of recent investigation for therapeutic advancement (see Fig. 1). In the past, two theories [5–7] have been postulated that summarise the events in the discussion below:
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Fig. 1 Pathogenesis of the Charcot foot
Neurotraumatic This theory states that the CF develops as a theory consequence of repeated trauma to an insensitive foot that is subjected to abnormal plantar pressures. Unrestricted bone distress results in microfractures with joint and ligament instability that moulds the unstable foot. Neurovascular According to this theory, the CF occurs as a theory consequence to localised bone resorption and osteopenia due to increased blood flow from underlying diabetic autonomic neuropathy. An insight into the origins of these pathogenic factors is primarily required to understand the pathogenesis of the CF.
The Unfavourable Metabolic Milieu in Diabetes Hyperglycaemia is a well-established pathological offender that acts as the fundamental basis for the manifestation of various diabetic complications. These diabetic sequelae are a reflection of the metabolic insult inflicted on the vascular integrity of both the microvasculature and macrovasculature. The endothelium, which constitutes the barrier that regulates vascular stability, plays a significant role in maintaining a balance between vasoconstriction and vasodilatation. In
diabetes, the role of the endothelium is irreversibly compromised by the negative impact of hyperglycaemia resulting in endothelial dysfunction which heralds the development of vascular complications (namely microvascular disease). Hyperglycaemia is the main metabolic perpetrator of endothelial dysfunction that is commonly involved in the intricate activation of inflammatory pathways which favour the onset of both microvascular and macrovascular disease. Furthermore, several other influential risk factors in DM predispose to the evolution of CF. AGE/RAGE Pathway Hyperglycaemia (acute and longstanding in nature) generates advanced glycation end products (AGEs) which occur from non-enzymatic reactions between glucose and glycating compounds with proteins. AGEs promote irreversible posttranslational modification of both intracellular and extracellular proteins causing these proteins to lose their functionality and become defective. Binding of AGE to its receptor (RAGE) expressed over macrophages accelerates reactive oxygen species (ROS) production which activates nuclear factor-κB (NF-κB). Increased NF-κB activity induces pathologic gene expression leading to generation of pro-inflammatory cytokines interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and macrophagecolony stimulating factor (M-CSF). RAGE expression on
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endothelial cells increases their adhesiveness to circulating leucocytes further accentuating microvascular disease [8, 9].
Diabetic Sensorimotor Neuropathy or Distal Symmetrical Polyneuropathy (DSPN)
Protein Kinase C (PKC) Pathway
DSPN affects approximately 30 % of patients with DM and has a predilection for long nerve fibres, i.e. length-dependent distribution. A similar pattern of involvement is seen with vascular calcification of the peripheral vasculature [15]. Sensory neuropathy commonly involves degeneration of unmyelinated C and Aδ fibres (pain-sensitive fibres). Aδ fibres mediate sharp pain (1st pain) which activates the spinal withdrawal reflexes while C fibres account for the dull pain (2nd pain). The nerve endings of both C and Aδ fibres are enriched with calcitonin gene-regulated peptide (CGRP), a local osteogenic mediator (discussed further below). The loss of protective sensation (LOPS) from degeneration of Aδ fibres results in an insensate foot that is exposed to unrecognised and recurrent microtrauma eventually leading to fractures, ulceration and foot deformities.
Activation of PKC, a pro-inflammatory pathway, occurs from accumulation of diacyl glycerol (DAG), a glucose intermediate derived from hyperglycaemia. The pathologic sequelae that follow PKC activation include decreased nitric oxide (NO) bioavailability through suppression of endothelial NO synthase (eNOS), amplified NF-κB expression, increased endothelin-1 (vasoconstrictor), enhanced plasminogen activator inhibitor-1 (PAI-1) activity and ROS production [10]. Phosphatidylinositol 3 Kinase (PI3 Kinase) Activity PI3 kinase normally impedes inflammation through enhanced NO production and restrained expression of adhesion molecules. This defensive pathway is compromised in DM enabling progression of endothelial dysfunction [2]. The Pro-inflammatory State
Motor Neuropathy Distal muscle weakness or wasting of pedal musculature can translate into clawing of the toes with hyperflexion of distal phalangeal joints and hyperextension of the metatarsal phalangeal joints and exaggeration of the plantar arch. This unfavourable alignment of the foot disproportionately subjects the metatarsal heads to pressure and weight bearing over a restricted plantar surface area thereby predisposing the foot to shear stress and deformity [12].
The hypercoagulable and inflammatory state in DM is an illustration of the profound effects of glucotoxicity and lipotoxicity. The pro-inflammatory state in diabetes is attributed to elevated concentrations of pro-inflammatory cytokines which are derived from increased PKC activity and AGE/ RAGE interactions accompanied by suppressed PI3 kinase activity. TNF-α and IL-1β (interleukin-1β), the main proinflammatory cytokines that predominate the metabolic milieu in DM, play a pivotal role in the inception of CF via amplified receptor activator for nuclear factor NF-κB ligand (RANKL) expression. They cause localised osteolysis that jeopardises bone integrity making the high-risk diabetic foot vulnerable to ulceration, deformity and fractures [11].
Autonomic nerve dysfunction particularly of the lower limb vasculature contributes to increased bone resorption from increased local blood flow and arteriovenous shunting. Furthermore, sudomotor dysfunction (component of autonomic neuropathy) increases the likelihood of ulceration from dry skin and fissures [12].
Diabetic Neuropathy
Diabetic Osteopathy
As cited earlier, diabetic neuropathy is a known instigator of CF which is also implicated in the pathological triad of diabetic foot ulcers (trauma, inflammation and diabetic neuropathy) [12]. This pathological sequel stems from microvascular disease or endothelial dysfunction of the vasa nervorum (blood vessels supplying the nerves). The resultant endoneural ischemia compromises neural growth and repair consequent to depletion of neurotropic growth factors (nerve growth factor [NGF], insulin growth factor-1 [IGF-1] and neurotrophin-3) [12]. The detrimental role of glucotoxicity is evident by the accumulation of AGEs within peripheral nerves as demonstrated by skin autofluorescence [13, 14].
Catabolic bone metabolism was customarily thought to affect patients with type 1 DM alone owing to loss of trophic effects of amylin and insulin. Interestingly, the paradoxical behaviour of bone activity has been elucidated in recent research. Patients with type 2 DM are predisposed to an increased fracture risk by 1.7-fold despite a high bone mineral density which is typically observed in this group [16•].
Autonomic Neuropathy
Effect of Hyperglycaemia on Bone Nitric oxide (NO) derived from bone eNOS has a boneprotective effect. Physiologically, NO induces osteoblastic
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activity demonstrated by osteoblast proliferation, osteocalcin synthesis and in vitro formation of a mineralized matrix [17]. NO suppresses osteoclastic bone resorption through retraction of pseudopodia and modification of cathepsin K (a highly expressed protease within osteoclasts that degrades bone collagen). Predictably hyperglycaemic mediated endothelial dysfunction culminates into diminished eNOS activity with reduced bioavailable NO and subsequent osteopenia. Additionally, AGEs facilitate deterioration of bone matrix by introducing cross-links into the lattice network of collagen thereby rendering collagen defective [18]. AGEs also induce apoptosis of mesenchymal stem cells and osteoblasts. AGE/ RAGE interaction is known to enhance inflammatory-induced osteolysis by elaborating the production of pro-inflammatory cytokines. The Pro-inflammatory State: the Role of the RANKL/RANK/OPG Axis The critical role of RANKL/RANK/OPG pathway in diabetic osteopathy has gained interest in recent years due to demonstration of its substantial existence in human studies. RANKL belongs to the TNF family and is predominantly expressed on osteoblasts and T cells. Interaction of RANKL with RANK (receptor for RANKL located on premature osteoclasts) activates NF-κB. NF-κB translocates to the nucleus and then initiates osteoclastogenesis [19]. However, another osteoblastic protein osteoprotegerin (OPG) competes with RANK as a decoy receptor for RANKL and hinders osteoclastogenesis. Adequate levels of OPG are required to accommodate RANKL and disrupt the RANKL/RANK interface that mediates osteoclastic resorption. However, in DM, the predominant pro-inflammatory state enables an augmented expression of RANKL. Role of Diabetic Neuropathy Diabetic neuropathy is associated with exhaustion of CGRP stores from C and Aδ nerve fibres. The anti-resorptive nature of CGRP is characterised by a) its ability to suppress RANKLinduced osteoclastogenesis (via anti-inflammatory cytokine IL-10) and b) downregulate transcription of osteoclastic genes like tartrate-resistant acid phosphatase (TRAP) and cathepsin K. CGRP also mitigates endothelial dysfunction through its vasodilatory effects and by suppression of vascular smooth muscle cell hypertrophy. Consequently, CGRP deficiency in diabetic neuropathy would accelerate the underlying osteopenia due to unrestricted RANKL activity [20].
Curr Diab Rep (2014) 14:561
high-risk insensate foot vulnerable to trauma. Repetitive or unrecognised trauma (unfavourable weight bearing, foot ulcers, infection and surgery) can trigger a cascade of inflammatory events and may lead to irreversible destruction of bone microarchitecture and ligament instability. Similar consequences are known to occur in patients with recent foot surgery (amputation), commonly ascribed to post-surgical edema or acquired foot deformities [21].
Management of Charcot Foot The Charcot foot is a challenging diabetic foot complication that mandates prompt diagnosis and early institution of therapy. Staging of the various phases of CF progression enables the treating clinician to select appropriate therapeutic measures pertinent to these phases. The Eichenholtz staging of CF provides an insight into the pathological transition through the various phases of CF that is aimed to assist in applying the appropriate therapeutic interventions [22, 23]. The prodromal period (stage 0) is depicted by the appearance of superficial signs of inflammation triggered by a traumatic event (fracture or sprain) [24]. The affected foot appears hot, red and swollen. Despite early manifestation of these inflammatory signs, X-ray findings are not evident. However, MRI sufficiently demonstrates trivial signs of the Charcot process like bone marrow edema, subchondral cysts or microtrabecular fractures [25]. If unrecognised trauma continues without any timely intervention, the CF experiences an exacerbation of the on-going inflammatory insult (stage 1 acute or developmental phase). Inflammatory-induced osteolysis can further augment the friability of the already compromised bone making it vulnerable to trivial trauma. This is evident on X-ray by the presence of joint effusion, joint subluxation and bone fragmentation. Once the inflammatory response gradually resolves, sclerotic activity around the affected joint ensues which is accompanied by resorption of bone debris and fusion of larger bone fragments (stage 2, sub-acute or coalescent phase). As the inflammatory insult settles down, the affected joint undergoes skeletal reorganisation with reformation of the joint architecture (stage 3, reconstructive phase).
Diagnosis of Charcot Foot History
Role of Trauma Interplay of the abovementioned risk factors (diabetic neuropathy, defective bone metabolism, bony deformity) makes the
Patients who present with CF usually give a history of trauma (fracture, sprain or recent surgery) that precipitated the event. A history of trauma is reported in almost 25–50 % of cases
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with acute CF [26]. Patients with diabetic neuropathy may not report any precipitating trauma but local findings such as infection or ulcers may provide an indication of the inciting factor. Examination findings that may raise suspicion of CF include the following:
MRI (Magnetic Resonance Imaging) MRI is the next radiological tool that is considered applicable if initial X-rays are inconclusive. MRI reveals early findings of dynamic bone activity in acute Charcot as mentioned earlier. Therefore, early recognition of acute CF by MRI enables the treating clinician to provide timely intervention [25].
Local examination findings usually reveal superficial signs of inflammation [11]. Superficial signs of inflammation, “The red, hot, swollen foot”—the affected foot appears edematous with surrounding erythema. A temperature difference of more than 2 °C, when compared with the contralateral foot, should suggest the possibility of CF. The clinician should be wary at this stage (stage 0) since these signs are pronounced in other foot diseases which have to be differentiated before proceeding to management. The foot conditions to be considered as a differential diagnosis include osteomyelitis, deep vein thrombosis, cellulitis and gout. Appropriate investigations relevant to these conditions need to be performed to confirm the diagnosis. Loss of protective sensation (LOPS), “The insensitive foot”—LOPS can be elicited through five simple tests. Abnormalities detected during one or more of the following tests may indicate LOPS.
Nuclear Imaging Nuclear imaging employs radioisotopic tracers to diagnose active metabolic disease. However, some modalities (three-phase bone scan) are highly sensitive for active bone pathology (100 %) whereas others (leucocytelabelled bone scans) are highly specific (69–80 %) for distinguishing between infection from CF [27].
1. Pressure perception with the 10-g Semmes Weinstein monofilament 2. Vibratory perception with 128-Hz tuning fork 3. Pin-prick sensation 4. Ankle reflexes 5. Vibration perception threshold (VPT) with a handheld biothesiometer. A VPT >25 V is considered abnormal Musculoskeletal assessment—high-risk foot deformities that predispose to CF include claw toes and hammer toe (forefoot deformities). These deformities are frequently seen in association with the classical CF deformity, the “Rocker-bottom foot” (mid-foot deformity).
Imaging Modalities X-ray X-ray is an inexpensive and convenient radiological tool used in the primary diagnosis of CF. Noteworthy findings suggestive of CF include fractures, dislocations, joint subluxation, osteolysis and osteopenia [27]. However, early radiological signs of acute CF as described above may not be apparent on X-ray initially despite a clinical suspicion of CF. In such indeterminate cases, a repeat X-ray after 2 weeks may disclose classical skeletal findings of CF [28•]. In addition X-ray facilitates characterisation of the anatomic involvement of the CF (Table 1).
Conservative Management Offloading and Immobilisation The Charcot foot is a medical emergency that tends to be progressive leading to irreversible skeletal destruction and permanent deformities if not intervened promptly. Offloading and abstinence from physical activity (immobilisation) continue to be the ultimate norm in the management of acute Charcot as emphasised by former studies. According to a recent ADA consensus [31••], immobilisation in a nonremovable total contact cast (TCC) is the idealistic approach towards the primary management of early CF. Furthermore, Kimmerle and Chantelau clearly demonstrated that early immobilisation with TCC facilitates better clinical outcomes (without deformities) [32]. By stabilising the affected foot, it affords the additional benefit of simultaneous immobilisation and thereby prevents further aggravation of the initial inflammatory insult. Retardation of pathological bone resorption also diminishes bone deterioration and pain. TCCs have been devised with an intention to redistribute weight bearing pressures over a uniform plantar surface area. The CF is immobilised in a custom-moulded cast which is initially applied for 3 days and replaced weekly in order to accommodate limb volume changes and thereafter every 2 to 4 weeks. The active Charcot foot should be immobilised in a TCC until it is rendered inactive. The duration of TCC application is governed by alleviation of superficial inflammatory signs which include reduction of surrounding oedema and a decline in skin temperature difference of less than 2 °C between both feet [33]. The average duration for TCC application can last between 6 and 12 months before considering transition to customised foot wear. Offloading—Long-Term Management Once the CF has entered the quiescent stage, which is achieved by immobilisation, then transition to appropriate prefabricated footwear may be considered. The selection of
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Table 1 Anatomic distribution of Charcot foot [29, 30] I (forefoot)
IV
Interphalangeal joints, phalanges, metatarsophalangeal joints or distal metatarsal bones Tarsometatarsal (TMT) joints Naviculocuneiform, talonavicular and calcaneocuboid joints Ankle ± subtalar joints
V
Calcaneus
II (Lisfranc joint) (most common) III (Chopart line)
footwear depends on the severity of CF and location of the foot deformity (if any) and should cater to the principal measures of accommodation and offloading. Removable cast walkers (RCWs) are associated with poor healing rates even though they afford immediate offloading. They are usually instituted during stage 2 of CF as the inflammation has resolved [33]. Extra-depth shoes are designed to accommodate mainly mid-foot deformities aimed at preventing ulceration [34]. Ankle-foot orthosis (AFO) and Charcot restart orthotic walker (CROW) are reserved for hind foot deformities [35]. In 2000, Armstrong et al. compared the effectiveness of three different offloading modalities (TCC versus RCW versus half-shoe (HS)) in the treatment of diabetic, neuropathic foot ulcers. By 12 weeks, patients immobilised with TCC achieved significantly higher healing rates when compared with the other two offloading measures (89.5, 65.0 and 58.3 %, respectively; 89.5 versus 61.4 %, P=0.026, odds ratio 5.4, 95 % CI 1.1– 26.1). A possible explanation may be due to increased physical restriction provided by TCC (600.1±320.0 daily steps) versus HS (1461.8±1452.3 daily steps, P=0.04). However, this finding was not significant when compared with RCW (767.6± 563.3 daily steps, P=0.67) [36]. Medical Management Anti-resorptive Agents Anti-resorptive agents have been implemented in several inflammatory and rheumatoid conditions typified by excessive bone turnover. As the CF is an inflammatory, destructive state, it would be ideal to employ the benefits of anti-resorptive agents to counteract bone resorption. Bisphosphonates (BPPs) BPPs are synthetic analogues of the naturally occurring inorganic pyrophosphate. The enhanced anti-resorptive capacity of BPP is explained by the presence of two phosphonate groups which facilitate binding to bone mineral (hydroxyapatite crystals). In addition, structural modifications to the original chemical configuration further enhance the potency of BPP. These agents tend to concentrate at sites of active bone remodelling (like trabeculae), beneath the osteoclasts in an acidic environment [37].
• Hourglass appearance of the phalangeal diaphysis • “Sucked candy stick” appearance attributed to the resorption of the distal metatarsal bones and phalanges Collapse of the mid-foot Collapse of the mid-foot • Medial or lateral malleolar fractures • Joint collapse • Extra-articular avulsion fracture of the posterior tubercle of the calcaneus
The first-generations BPPs [38] are minimally modified basic analogues which are non-nitrogenous in nature and are among the least potent of all BPP. They include medronate, clodronate, etidronate and tiludronate. They inhibit osteoclastic bone resorption through production of cytotoxic analogues of ATP which induces irreversible apoptosis of osteoclasts. The second-generation BPPs are 10 to 100 times more potent than their predecessors owing to the addition of amino groups. They include alendronate, ibandronate and pamidronate They mediate their activity through inhibition of farnesyl pyrophosphate synthase which is an essential enzyme of cholesterol synthesis required for the survival of osteoclasts. Farnesyl pyrophosphate and geranyl pyrophosphate are metabolic intermediates of the mevalonate pathway (cholesterol synthesis) which are necessary for activation of small GTPases. Small GTPases enable structural conformation of osteoclasts promoting their survival [39]. The third-generation BPPs (risedronate and zoledronate) are 10,000 times more potent than the above agents. The 10,000-fold increased potency of this sub-class is attributed to the presence of a nitrogenous heterocyclic ring. BPPs are available for both oral and intravenous administration. However, IV administration has a superior bioavailability (50 % compared to 5–10 % per orally). Caution should be exercised especially in patients with renal insufficiency (contraindicated if eGFR
MICROVASCULAR COMPLICATIONS—NEUROPATHY (D ZIEGLER, SECTION EDITOR)
The Charcot Foot as a Complication of Diabetic Neuropathy Janice V. Mascarenhas & Edward B. Jude
# Springer Science+Business Media New York 2014
Abstract Diabetes mellitus is a leading global metabolic disorder accompanied by the overwhelming burden of its associated complications. Hyperglycaemia-induced endothelial damage or endothelial dysfunction serves as the primary instigator for the development of microvascular disease. Diabetic neuropathy represents the majority of microvascular sequelae and is the renowned perpetrator of a variety of foot complications, namely the Charcot foot (CF). CF is a debilitating medical emergency which is often mismanaged either due to a delayed diagnosis or lack of clinical expertise in the management of CF. Often, misdiagnosis during the acute stages of CF leads to irreversible and persistent joint destruction which may be refractory to medical or surgical treatment. Timely intervention with offloading measures is crucial during acute CF in ceasing active bone resorption. Current antiresorptive agents may be considered as adjunctive therapy in combination with offloading. Novel agents are underway that will enable bone formation and suppress bone resorption.
Keywords Charcot neuroarthropathy . Diabetic peripheral neuropathy
This article is part of the Topical Collection on Microvascular Complications—Neuropathy J. V. Mascarenhas : E. B. Jude (*) Diabetes and Endocrinology, Tameside Hospital NHS Foundation Trust, Fountain Street, Ashton-Under-Lyne, Lancashire OL6 9RW, UK e-mail: [email protected] J. V. Mascarenhas e-mail: [email protected] J. V. Mascarenhas : E. B. Jude University of Manchester, Oxford Road, Manchester M13 9PL, UK
Introduction The incidence and prevalence of diabetic complications has escalated in the recent years owing to increased availability of various treatment options that prolong the life expectancy of affected individuals. The economic and health burden inflicted by diabetes mellitus (DM) is attributed mainly to its associated microvascular complications which include the well-known constituents of the diabetic triopathy (diabetic nephropathy, retinopathy and neuropathy). Diabetic neuropathy or diabetic peripheral neuropathy is said to affect approximately 25 to 35 % of patients with diabetes with an annual incidence of about 2 % [1, 2]. In fact, it is the prime perpetrator of diabetic foot complications (ulcers, foot deformities). Among the foot complications, the Charcot foot (CF) is the most challenging debilitating consequence of diabetic neuropathy. The Charcot foot is also observed in several other neurological diseases (tabes dorsalis, leprosy, syringomyelia, multiple sclerosis, myelomeningocele, spinal cord compression); however, diabetic neuropathy accounts for majority of the cases affecting 0.2 % of the diabetic population. Involvement of the contralateral foot occurs in 5.9 to 39.3 % of heterogenous cases [3, 4]. This review article is intended to provide the treating clinician with an insight into the evolution of CF and enable them to choose the appropriate therapeutic interventions aimed at aversion of irreversible skeletal attrition.
Pathogenesis: the Evolution of the Charcot Foot The development of CF has always been a subject of endless exploration, its multifactorial origin being the common ground of recent investigation for therapeutic advancement (see Fig. 1). In the past, two theories [5–7] have been postulated that summarise the events in the discussion below:
561, Page 2 of 9
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Fig. 1 Pathogenesis of the Charcot foot
Neurotraumatic This theory states that the CF develops as a theory consequence of repeated trauma to an insensitive foot that is subjected to abnormal plantar pressures. Unrestricted bone distress results in microfractures with joint and ligament instability that moulds the unstable foot. Neurovascular According to this theory, the CF occurs as a theory consequence to localised bone resorption and osteopenia due to increased blood flow from underlying diabetic autonomic neuropathy. An insight into the origins of these pathogenic factors is primarily required to understand the pathogenesis of the CF.
The Unfavourable Metabolic Milieu in Diabetes Hyperglycaemia is a well-established pathological offender that acts as the fundamental basis for the manifestation of various diabetic complications. These diabetic sequelae are a reflection of the metabolic insult inflicted on the vascular integrity of both the microvasculature and macrovasculature. The endothelium, which constitutes the barrier that regulates vascular stability, plays a significant role in maintaining a balance between vasoconstriction and vasodilatation. In
diabetes, the role of the endothelium is irreversibly compromised by the negative impact of hyperglycaemia resulting in endothelial dysfunction which heralds the development of vascular complications (namely microvascular disease). Hyperglycaemia is the main metabolic perpetrator of endothelial dysfunction that is commonly involved in the intricate activation of inflammatory pathways which favour the onset of both microvascular and macrovascular disease. Furthermore, several other influential risk factors in DM predispose to the evolution of CF. AGE/RAGE Pathway Hyperglycaemia (acute and longstanding in nature) generates advanced glycation end products (AGEs) which occur from non-enzymatic reactions between glucose and glycating compounds with proteins. AGEs promote irreversible posttranslational modification of both intracellular and extracellular proteins causing these proteins to lose their functionality and become defective. Binding of AGE to its receptor (RAGE) expressed over macrophages accelerates reactive oxygen species (ROS) production which activates nuclear factor-κB (NF-κB). Increased NF-κB activity induces pathologic gene expression leading to generation of pro-inflammatory cytokines interleukin-1 (IL-1), tumour necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β) and macrophagecolony stimulating factor (M-CSF). RAGE expression on
Curr Diab Rep (2014) 14:561
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endothelial cells increases their adhesiveness to circulating leucocytes further accentuating microvascular disease [8, 9].
Diabetic Sensorimotor Neuropathy or Distal Symmetrical Polyneuropathy (DSPN)
Protein Kinase C (PKC) Pathway
DSPN affects approximately 30 % of patients with DM and has a predilection for long nerve fibres, i.e. length-dependent distribution. A similar pattern of involvement is seen with vascular calcification of the peripheral vasculature [15]. Sensory neuropathy commonly involves degeneration of unmyelinated C and Aδ fibres (pain-sensitive fibres). Aδ fibres mediate sharp pain (1st pain) which activates the spinal withdrawal reflexes while C fibres account for the dull pain (2nd pain). The nerve endings of both C and Aδ fibres are enriched with calcitonin gene-regulated peptide (CGRP), a local osteogenic mediator (discussed further below). The loss of protective sensation (LOPS) from degeneration of Aδ fibres results in an insensate foot that is exposed to unrecognised and recurrent microtrauma eventually leading to fractures, ulceration and foot deformities.
Activation of PKC, a pro-inflammatory pathway, occurs from accumulation of diacyl glycerol (DAG), a glucose intermediate derived from hyperglycaemia. The pathologic sequelae that follow PKC activation include decreased nitric oxide (NO) bioavailability through suppression of endothelial NO synthase (eNOS), amplified NF-κB expression, increased endothelin-1 (vasoconstrictor), enhanced plasminogen activator inhibitor-1 (PAI-1) activity and ROS production [10]. Phosphatidylinositol 3 Kinase (PI3 Kinase) Activity PI3 kinase normally impedes inflammation through enhanced NO production and restrained expression of adhesion molecules. This defensive pathway is compromised in DM enabling progression of endothelial dysfunction [2]. The Pro-inflammatory State
Motor Neuropathy Distal muscle weakness or wasting of pedal musculature can translate into clawing of the toes with hyperflexion of distal phalangeal joints and hyperextension of the metatarsal phalangeal joints and exaggeration of the plantar arch. This unfavourable alignment of the foot disproportionately subjects the metatarsal heads to pressure and weight bearing over a restricted plantar surface area thereby predisposing the foot to shear stress and deformity [12].
The hypercoagulable and inflammatory state in DM is an illustration of the profound effects of glucotoxicity and lipotoxicity. The pro-inflammatory state in diabetes is attributed to elevated concentrations of pro-inflammatory cytokines which are derived from increased PKC activity and AGE/ RAGE interactions accompanied by suppressed PI3 kinase activity. TNF-α and IL-1β (interleukin-1β), the main proinflammatory cytokines that predominate the metabolic milieu in DM, play a pivotal role in the inception of CF via amplified receptor activator for nuclear factor NF-κB ligand (RANKL) expression. They cause localised osteolysis that jeopardises bone integrity making the high-risk diabetic foot vulnerable to ulceration, deformity and fractures [11].
Autonomic nerve dysfunction particularly of the lower limb vasculature contributes to increased bone resorption from increased local blood flow and arteriovenous shunting. Furthermore, sudomotor dysfunction (component of autonomic neuropathy) increases the likelihood of ulceration from dry skin and fissures [12].
Diabetic Neuropathy
Diabetic Osteopathy
As cited earlier, diabetic neuropathy is a known instigator of CF which is also implicated in the pathological triad of diabetic foot ulcers (trauma, inflammation and diabetic neuropathy) [12]. This pathological sequel stems from microvascular disease or endothelial dysfunction of the vasa nervorum (blood vessels supplying the nerves). The resultant endoneural ischemia compromises neural growth and repair consequent to depletion of neurotropic growth factors (nerve growth factor [NGF], insulin growth factor-1 [IGF-1] and neurotrophin-3) [12]. The detrimental role of glucotoxicity is evident by the accumulation of AGEs within peripheral nerves as demonstrated by skin autofluorescence [13, 14].
Catabolic bone metabolism was customarily thought to affect patients with type 1 DM alone owing to loss of trophic effects of amylin and insulin. Interestingly, the paradoxical behaviour of bone activity has been elucidated in recent research. Patients with type 2 DM are predisposed to an increased fracture risk by 1.7-fold despite a high bone mineral density which is typically observed in this group [16•].
Autonomic Neuropathy
Effect of Hyperglycaemia on Bone Nitric oxide (NO) derived from bone eNOS has a boneprotective effect. Physiologically, NO induces osteoblastic
561, Page 4 of 9
activity demonstrated by osteoblast proliferation, osteocalcin synthesis and in vitro formation of a mineralized matrix [17]. NO suppresses osteoclastic bone resorption through retraction of pseudopodia and modification of cathepsin K (a highly expressed protease within osteoclasts that degrades bone collagen). Predictably hyperglycaemic mediated endothelial dysfunction culminates into diminished eNOS activity with reduced bioavailable NO and subsequent osteopenia. Additionally, AGEs facilitate deterioration of bone matrix by introducing cross-links into the lattice network of collagen thereby rendering collagen defective [18]. AGEs also induce apoptosis of mesenchymal stem cells and osteoblasts. AGE/ RAGE interaction is known to enhance inflammatory-induced osteolysis by elaborating the production of pro-inflammatory cytokines. The Pro-inflammatory State: the Role of the RANKL/RANK/OPG Axis The critical role of RANKL/RANK/OPG pathway in diabetic osteopathy has gained interest in recent years due to demonstration of its substantial existence in human studies. RANKL belongs to the TNF family and is predominantly expressed on osteoblasts and T cells. Interaction of RANKL with RANK (receptor for RANKL located on premature osteoclasts) activates NF-κB. NF-κB translocates to the nucleus and then initiates osteoclastogenesis [19]. However, another osteoblastic protein osteoprotegerin (OPG) competes with RANK as a decoy receptor for RANKL and hinders osteoclastogenesis. Adequate levels of OPG are required to accommodate RANKL and disrupt the RANKL/RANK interface that mediates osteoclastic resorption. However, in DM, the predominant pro-inflammatory state enables an augmented expression of RANKL. Role of Diabetic Neuropathy Diabetic neuropathy is associated with exhaustion of CGRP stores from C and Aδ nerve fibres. The anti-resorptive nature of CGRP is characterised by a) its ability to suppress RANKLinduced osteoclastogenesis (via anti-inflammatory cytokine IL-10) and b) downregulate transcription of osteoclastic genes like tartrate-resistant acid phosphatase (TRAP) and cathepsin K. CGRP also mitigates endothelial dysfunction through its vasodilatory effects and by suppression of vascular smooth muscle cell hypertrophy. Consequently, CGRP deficiency in diabetic neuropathy would accelerate the underlying osteopenia due to unrestricted RANKL activity [20].
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high-risk insensate foot vulnerable to trauma. Repetitive or unrecognised trauma (unfavourable weight bearing, foot ulcers, infection and surgery) can trigger a cascade of inflammatory events and may lead to irreversible destruction of bone microarchitecture and ligament instability. Similar consequences are known to occur in patients with recent foot surgery (amputation), commonly ascribed to post-surgical edema or acquired foot deformities [21].
Management of Charcot Foot The Charcot foot is a challenging diabetic foot complication that mandates prompt diagnosis and early institution of therapy. Staging of the various phases of CF progression enables the treating clinician to select appropriate therapeutic measures pertinent to these phases. The Eichenholtz staging of CF provides an insight into the pathological transition through the various phases of CF that is aimed to assist in applying the appropriate therapeutic interventions [22, 23]. The prodromal period (stage 0) is depicted by the appearance of superficial signs of inflammation triggered by a traumatic event (fracture or sprain) [24]. The affected foot appears hot, red and swollen. Despite early manifestation of these inflammatory signs, X-ray findings are not evident. However, MRI sufficiently demonstrates trivial signs of the Charcot process like bone marrow edema, subchondral cysts or microtrabecular fractures [25]. If unrecognised trauma continues without any timely intervention, the CF experiences an exacerbation of the on-going inflammatory insult (stage 1 acute or developmental phase). Inflammatory-induced osteolysis can further augment the friability of the already compromised bone making it vulnerable to trivial trauma. This is evident on X-ray by the presence of joint effusion, joint subluxation and bone fragmentation. Once the inflammatory response gradually resolves, sclerotic activity around the affected joint ensues which is accompanied by resorption of bone debris and fusion of larger bone fragments (stage 2, sub-acute or coalescent phase). As the inflammatory insult settles down, the affected joint undergoes skeletal reorganisation with reformation of the joint architecture (stage 3, reconstructive phase).
Diagnosis of Charcot Foot History
Role of Trauma Interplay of the abovementioned risk factors (diabetic neuropathy, defective bone metabolism, bony deformity) makes the
Patients who present with CF usually give a history of trauma (fracture, sprain or recent surgery) that precipitated the event. A history of trauma is reported in almost 25–50 % of cases
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with acute CF [26]. Patients with diabetic neuropathy may not report any precipitating trauma but local findings such as infection or ulcers may provide an indication of the inciting factor. Examination findings that may raise suspicion of CF include the following:
MRI (Magnetic Resonance Imaging) MRI is the next radiological tool that is considered applicable if initial X-rays are inconclusive. MRI reveals early findings of dynamic bone activity in acute Charcot as mentioned earlier. Therefore, early recognition of acute CF by MRI enables the treating clinician to provide timely intervention [25].
Local examination findings usually reveal superficial signs of inflammation [11]. Superficial signs of inflammation, “The red, hot, swollen foot”—the affected foot appears edematous with surrounding erythema. A temperature difference of more than 2 °C, when compared with the contralateral foot, should suggest the possibility of CF. The clinician should be wary at this stage (stage 0) since these signs are pronounced in other foot diseases which have to be differentiated before proceeding to management. The foot conditions to be considered as a differential diagnosis include osteomyelitis, deep vein thrombosis, cellulitis and gout. Appropriate investigations relevant to these conditions need to be performed to confirm the diagnosis. Loss of protective sensation (LOPS), “The insensitive foot”—LOPS can be elicited through five simple tests. Abnormalities detected during one or more of the following tests may indicate LOPS.
Nuclear Imaging Nuclear imaging employs radioisotopic tracers to diagnose active metabolic disease. However, some modalities (three-phase bone scan) are highly sensitive for active bone pathology (100 %) whereas others (leucocytelabelled bone scans) are highly specific (69–80 %) for distinguishing between infection from CF [27].
1. Pressure perception with the 10-g Semmes Weinstein monofilament 2. Vibratory perception with 128-Hz tuning fork 3. Pin-prick sensation 4. Ankle reflexes 5. Vibration perception threshold (VPT) with a handheld biothesiometer. A VPT >25 V is considered abnormal Musculoskeletal assessment—high-risk foot deformities that predispose to CF include claw toes and hammer toe (forefoot deformities). These deformities are frequently seen in association with the classical CF deformity, the “Rocker-bottom foot” (mid-foot deformity).
Imaging Modalities X-ray X-ray is an inexpensive and convenient radiological tool used in the primary diagnosis of CF. Noteworthy findings suggestive of CF include fractures, dislocations, joint subluxation, osteolysis and osteopenia [27]. However, early radiological signs of acute CF as described above may not be apparent on X-ray initially despite a clinical suspicion of CF. In such indeterminate cases, a repeat X-ray after 2 weeks may disclose classical skeletal findings of CF [28•]. In addition X-ray facilitates characterisation of the anatomic involvement of the CF (Table 1).
Conservative Management Offloading and Immobilisation The Charcot foot is a medical emergency that tends to be progressive leading to irreversible skeletal destruction and permanent deformities if not intervened promptly. Offloading and abstinence from physical activity (immobilisation) continue to be the ultimate norm in the management of acute Charcot as emphasised by former studies. According to a recent ADA consensus [31••], immobilisation in a nonremovable total contact cast (TCC) is the idealistic approach towards the primary management of early CF. Furthermore, Kimmerle and Chantelau clearly demonstrated that early immobilisation with TCC facilitates better clinical outcomes (without deformities) [32]. By stabilising the affected foot, it affords the additional benefit of simultaneous immobilisation and thereby prevents further aggravation of the initial inflammatory insult. Retardation of pathological bone resorption also diminishes bone deterioration and pain. TCCs have been devised with an intention to redistribute weight bearing pressures over a uniform plantar surface area. The CF is immobilised in a custom-moulded cast which is initially applied for 3 days and replaced weekly in order to accommodate limb volume changes and thereafter every 2 to 4 weeks. The active Charcot foot should be immobilised in a TCC until it is rendered inactive. The duration of TCC application is governed by alleviation of superficial inflammatory signs which include reduction of surrounding oedema and a decline in skin temperature difference of less than 2 °C between both feet [33]. The average duration for TCC application can last between 6 and 12 months before considering transition to customised foot wear. Offloading—Long-Term Management Once the CF has entered the quiescent stage, which is achieved by immobilisation, then transition to appropriate prefabricated footwear may be considered. The selection of
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Table 1 Anatomic distribution of Charcot foot [29, 30] I (forefoot)
IV
Interphalangeal joints, phalanges, metatarsophalangeal joints or distal metatarsal bones Tarsometatarsal (TMT) joints Naviculocuneiform, talonavicular and calcaneocuboid joints Ankle ± subtalar joints
V
Calcaneus
II (Lisfranc joint) (most common) III (Chopart line)
footwear depends on the severity of CF and location of the foot deformity (if any) and should cater to the principal measures of accommodation and offloading. Removable cast walkers (RCWs) are associated with poor healing rates even though they afford immediate offloading. They are usually instituted during stage 2 of CF as the inflammation has resolved [33]. Extra-depth shoes are designed to accommodate mainly mid-foot deformities aimed at preventing ulceration [34]. Ankle-foot orthosis (AFO) and Charcot restart orthotic walker (CROW) are reserved for hind foot deformities [35]. In 2000, Armstrong et al. compared the effectiveness of three different offloading modalities (TCC versus RCW versus half-shoe (HS)) in the treatment of diabetic, neuropathic foot ulcers. By 12 weeks, patients immobilised with TCC achieved significantly higher healing rates when compared with the other two offloading measures (89.5, 65.0 and 58.3 %, respectively; 89.5 versus 61.4 %, P=0.026, odds ratio 5.4, 95 % CI 1.1– 26.1). A possible explanation may be due to increased physical restriction provided by TCC (600.1±320.0 daily steps) versus HS (1461.8±1452.3 daily steps, P=0.04). However, this finding was not significant when compared with RCW (767.6± 563.3 daily steps, P=0.67) [36]. Medical Management Anti-resorptive Agents Anti-resorptive agents have been implemented in several inflammatory and rheumatoid conditions typified by excessive bone turnover. As the CF is an inflammatory, destructive state, it would be ideal to employ the benefits of anti-resorptive agents to counteract bone resorption. Bisphosphonates (BPPs) BPPs are synthetic analogues of the naturally occurring inorganic pyrophosphate. The enhanced anti-resorptive capacity of BPP is explained by the presence of two phosphonate groups which facilitate binding to bone mineral (hydroxyapatite crystals). In addition, structural modifications to the original chemical configuration further enhance the potency of BPP. These agents tend to concentrate at sites of active bone remodelling (like trabeculae), beneath the osteoclasts in an acidic environment [37].
• Hourglass appearance of the phalangeal diaphysis • “Sucked candy stick” appearance attributed to the resorption of the distal metatarsal bones and phalanges Collapse of the mid-foot Collapse of the mid-foot • Medial or lateral malleolar fractures • Joint collapse • Extra-articular avulsion fracture of the posterior tubercle of the calcaneus
The first-generations BPPs [38] are minimally modified basic analogues which are non-nitrogenous in nature and are among the least potent of all BPP. They include medronate, clodronate, etidronate and tiludronate. They inhibit osteoclastic bone resorption through production of cytotoxic analogues of ATP which induces irreversible apoptosis of osteoclasts. The second-generation BPPs are 10 to 100 times more potent than their predecessors owing to the addition of amino groups. They include alendronate, ibandronate and pamidronate They mediate their activity through inhibition of farnesyl pyrophosphate synthase which is an essential enzyme of cholesterol synthesis required for the survival of osteoclasts. Farnesyl pyrophosphate and geranyl pyrophosphate are metabolic intermediates of the mevalonate pathway (cholesterol synthesis) which are necessary for activation of small GTPases. Small GTPases enable structural conformation of osteoclasts promoting their survival [39]. The third-generation BPPs (risedronate and zoledronate) are 10,000 times more potent than the above agents. The 10,000-fold increased potency of this sub-class is attributed to the presence of a nitrogenous heterocyclic ring. BPPs are available for both oral and intravenous administration. However, IV administration has a superior bioavailability (50 % compared to 5–10 % per orally). Caution should be exercised especially in patients with renal insufficiency (contraindicated if eGFR
