the main underlying cause of the charcot foot in diabetes involves neuropathy , associated with a trivial trauma in many cases ( 13 , 6 , 7 ) . the cardinal pathogenic mechanisms underlying diabetic neuropathy are chronic hyperglycemia and microvascular disease , leading to nerve injury via osmotic changes and ischemia , respectively ( 8) . foot trauma can be ascertained on detailed medical history , although many patients do not recall such injury ( 13 ) . trauma may be sustained during daily activities ( such as prolonged walking ) , and , importantly , it may also include surgery of the affected foot . in the recent audit on acute charcot foot in united kingdom and ireland ( 6 ) , 36% of patients reported some trauma , and 12% reported foot surgery during the preceding 6 months . while neuropathy is certainly the common denominator , the type of neuropathy is a matter of discussion ( 13 ) . neuropathy may affect the peripheral nervous system leading to sensory loss or the autonomic system , impairing arterial perfusion and cellular turnover of foot and ankle bones ( 13 ) . the consequences of these neuropathic changes will be discussed in the next section . traditionally , one school of thought supported the former and another supported the latter neuropathy type ( 13 , 9 , 10 ) . however , it appears more likely that both the peripheral and the autonomic nervous system may be affected ( 11 ) , although one or the other manifestation may predominate in the individual patient ( 11 , 12 ) . moreover , a specific type of neuropathy predominantly affecting cold sensation with relative sparing of other sensory modalities has been reported ( 13 ) , but this theory has not gained widespread acceptance ( 7 ) . autonomic neuropathy may result in impaired vascular reflexes with arteriovenous shunting and increased arterial perfusion ( 14 , 15 ) . this becomes clinically manifested as localized increased temperature with redness and dilated dorsal veins ( 1820 ) . increased blood flow has also been noted in the foot bones and held responsible for increased bone resorption with reduced bone mineral density and , hence , predilection for fractures ( 21 ) . more recently , increased blood flow has been shown in patients with acute charcot foot ( 22 ) . importantly , reduced bone mineral density has been confirmed in patients with charcot foot ( 2325 ) , and increased osteoclastic activity in such patients has been documented as well ( 26 ) . additionally , the literature suggests that autonomic neuropathy predisposes to charcot foot via increased blood flow and increased bone resorption ( 1 , 3 ) . it also attempts to explain why subjects with peripheral arterial disease , in whom increased blood flow is restricted by arterial lesions , are relatively protected from the development of charcot foot ( 1 , 3 ) . in contrary , the  neurotraumatic theory ( 1 , 3 , 10 , 27 ) states that peripheral neuropathy , also called distal sensorimotor polyneuropathy , is responsible for sensory loss in the feet ( 8) . consequently , the feet lose protective sensation and become vulnerable with increased risk of unrecognized trauma ( 1 , 3 , 10 ) . the latter can be a minor acute injury during normal daily activities such as walking , running or dancing , or it may be a chronic injury resulting from inappropriate footwear ( 1 , 3 , 10 ) . in both cases , continued weight - bearing due to the absence of pain may induce local aseptic inflammation and aggravate bone destruction ( 1 , 3 , 10 ) . naturally , the harmful effect of continued weight - bearing is more important in obese subjects ( 12 ) . of note , chantelau et al . ( 28 ) have used magnetic resonance imaging ( mri ) to document bone trauma in the earliest stages of charcot foot , providing further evidence on the pathophysiologic role of unperceived trauma . such unnoticed bone trauma is not uncommon in patients with polyneuropathy ( 29 ) , including the contralateral foot of charcot patients ( 30 ) , again highlighting unnoticed trauma as a dangerous triggering factor . in neuropathic patients , the intensity of weight - bearing has been correlated with development of charcot foot ( 31 ) , further strengthening the argument for the nonetheless , neuropathy in the traditional sense can not fully explain the development of charcot foot and why it is not encountered in the majority of neuropathic patients ( 1 ) . ( 22 ) have provided evidence that local hyperemia in the affected charcot foot is not accompanied by more severe neuropathic deficits in such patients . the authors suggested that increased blood flow was attributable to excess local inflammation rather than neuropathy per se 
 ( 22 ) . nowadays , a markedly excessive local inflammatory response to trauma is known to be elicited in patients with acute charcot foot ( 1 , 2 , 7 , 3234 ) . in contrast to the local inflammation , there is no systemic inflammatory response ( 35 ) . as a result of local inflammation , pro - inflammatory cytokines [ mainly tumor necrosis factor alpha ( tnf- ) and interleukin 1 beta ( il-1 ) ] are produced excessively and beyond control ( 1 , 2 , 7 , 3234 ) . the next pathophysiologic event is cytokine - driven elevation of the receptor activator of nuclear factor kappa b ligand ( rankl ) , which , in turn , enhances the synthesis of nuclear factor b ( nf-b ) . the latter promotes osteoclast maturation and osteoclastic activity , leading to osteoporosis in the affected bones ( 2 , 7 , 3234 ) . in parallel , nf-b enhances the production of osteoprotegerin from osteoblasts , in order to provide an antagonist of rankl and mitigate its effects ( 2 , 7 , 3234 ) . increased osteoclastic activity is manifested by an increase in their resorptive capacity in vitro , which is predominantly , but not exclusively , driven by rankl ( 26 ) . intriguingly , healthy neurons secrete the beneficial calcitonin gene - related peptide ( cgrp ) , which reduces the synthesis of rankl and contributes to the maintenance of joint integrity ( 2 , 7 ) . it follows that any reduction of cgrp will be detrimental , because it will , indirectly , increase the action of rankl , aggravating the disease process ( 2 , 7 ) . the role of cgrp is particularly relevant in cases of neuropathy , whereby its secretion has been documented to be reduced ( 2 , 7 ) . hence , it is now deemed most likely that neuropathy exerts a contributory role to the inflammation - induced osteolysis through reduced secretion of cgrp from affected neurons ( 2 , 7 ) . alternatively , one may argue that a specific form of neuropathy is required to induce the charcot foot , but supporting literature is still sparse . in a small series , stevens et al . ( 13 ) have reported that charcot patients exhibited a relative preservation of warm and light touch perception with complete loss of cold perception . this contrasted with patients who had recurrent neuropathic foot ulcerations , in whom there was severe perturbation of both warm and cold sensation , as well as light touch perception ( 13 ) . young et al . ( 23 ) have reported more severe neuropathy in charcot patients as compared to their neuropathic peers without charcot foot . among the former , autonomic neuropathy was significantly ( p=0.03 ) more frequent than among the latter ( 23 ) . however , the recent consensus report on charcot osteoarthropathy ( 7 ) has not provided further support to the notion that a specific type of neuropathy may be accountable . some other factors have been also implicated in the pathophysiology of the charcot foot ( 1 , 3 ) . among these , in particular , non - enzymatic collagen glycation may lead to achilles tendon shortening , which , in turn , will increase forefoot pressures , predisposing to trauma and bone destruction ( 36 ) . elevated plantar pressures have been found in patients with acute charcot foot as compared to their peers without charcot ( 37 ) . such pressure elevation would lead to forefoot strain , which , in turn , would be transmitted as increased mechanical stress in the midfoot ( primarily , the region of the lisfranc ligament ) ( 37 ) . more recently , genetic factors , notably polymorphisms of the gene encoding the beneficial glycopeptide osteoprotegerin , are beginning to be discussed as potential contributors to pathophysiology ( 38 ) . korzon - burakowska et al . ( 38 ) examined 54 patients with charcot foot , 35 patients with diabetic neuropathy but no charcot foot and 95 healthy controls ( all from poland ) . significant differences were seen in 1217c > t and 245t > g polymorphisms between charcot patients and patients with neuropathy but no charcot foot , while differences were noted in every two - group comparison ( 38 ) . these findings open new perspectives for improved understanding and further research in the field of pathophysiology , but confirmation in other populations is eagerly awaited . interestingly , there may be some differences in the pathophysiology between type 1 ( t1 dm ) and type 2 diabetes ( t2 dm ) , but little is known on the subject . ( 12 ) have found significantly ( p<0.001 ) younger age but significantly ( p<0.001 ) longer diabetes duration in charcot patients with t1 dm than in those with t2 dm . more impressively , the same group has found generalized reduction of bone mineral density in charcot patients with t1 dm but not t2 dm ( 24 ) . at the same time , charcot patients with t2 dm exhibited more severe peripheral neuropathy ( impaired temperature and vibration perception ) than their t1 dm peers ( impaired temperature perception but normal vibration sensation ) ( 24 ) . thus , it would appear that the neurotraumatic theory with severe loss of protective sensation and mechanical stress from weight - bearing in the setting of obesity might apply more to t2 dm than t1 dm ( 24 ) . conversely , the neurovascular theory with pronounced bone resorption might apply more to t1 dm than t2 dm , but clearly further information is needed in this area ( 24 ) . in the light of available knowledge , the complex pathophysiology of the charcot foot may be currently outlined as follows . autonomic neuropathy with increased blood flow and osteolysis , as well as peripheral neuropathy impairing protective sensation predispose to the charcot foot ( 1 , 7 , 11 ) . in the individual patient , the former or latter component of neuropathy may predominate ( 1 , 11 ) . the condition is triggered by a minor trauma , which initiates an inappropriately excessive local inflammatory response , culminating in bone resorption ( 1 , 2 , 7 , 10 , 11 ) . in this conundrum , neuropathy has yet another contributory role to exert via reduced secretion of cgrp from injured neurons ( 2 , 7 ) . other factors , including the emerging role of genes ( 38 ) , may be of importance ( 1 , 3 ) , while additional inquiry is welcome to ascertain the potential differences between t1 dm and t2 dm . ultimately , the cascade of all pathophysiologic changes leads to the development of the charcot foot and this point is critical for its natural history ( 1 , 3 , 7 , 39 ) . if the condition is correctly diagnosed and the patient is appropriately immobilized , the local inflammation will subside and further bony destruction including progressive loss of mineral density can be minimized or avoided ( 7 , 39 ) . in contrary , sustained mechanical stress perpetuates the disease process and may lead to ligament strain , fracture - dislocations of forefoot bones , midfoot collapse and severe foot deformity and/or joint instability ( 1 , 3 , 7 , 39 , 40 ) . charcot foot deformities may be further complicated by an ulceration that is frequently difficult to heal and frequently encountered by high recurrence rates ( 1 , 3 , 7 , 39 ) . the charcot foot can be classified in terms of clinical stage , anatomical localization , and stage of natural history . in clinical practice , the charcot foot can be classified into the acute and chronic stage ( 1 , 3 , 7 , 10 , 27 ) . in the acute ( also called active ) stage , the foot is remarkably red , warm and swollen . pain is not a prominent feature and patients may report no pain or only some discomfort , which is usually much less in comparison to patients without neuropathy and similar degree of local inflammation ( 1 , 3 , 7 ) . using a portable infrared thermometer ( 41 ) , the physician may document a 26c temperature elevation in the affected vs. the contralateral foot ( 1 , 3 , 7 , 10 ) . at this stage , there is no deformity and the plain foot radiographs are most typically normal . the importance of early diagnosis to arrest the disease progress and avoid further bony destruction can not be emphasized enough ( 1 , 3 , 7 , 10 ) . in the chronic ( also called inactive ) stage , signs of local inflammation progressively recede ( 1 , 3 , 7 , 10 ) . the associated lower - extremity redness subsides , and the difference in skin temperature between the two feet diminishes . instead , stable deformities may develop ( 1 , 3 , 7 , 10 ) including the most frequent as : a ) collapse of the plantar arch in the midfoot with rocker bottom deformity ; and b ) prominent medial aspect of the foot in the midfoot ( medial convexity ) . both of these deformities result in abnormal high - pressure areas that are particularly prone to ulceration ( 1 , 3 , 7 , 10 ) . the most frequently used anatomical classification was proposed by sanders and frykberg ( 42 ) . i ( 15% ) , the forefoot [ metatarsophalangeal ( mtp ) and interphalangeal ( ip ) joints ] is affected ; in pattern ii ( 40% ) , tarso - metatarsal ( tmt ) joints are affected ; in pattern iii ( 30% ) , the naviculocuneiform , talonavicular , and calcaneocuboid joints are involved ; in pattern iv ( 10% ) , the ankle and subtalar joints are affected ; in pattern v ( 5% ) , the calcaneum is affected ( 42 ) . these are : the forefoot type involving the ip and mtp joints , the midfoot type involving the tmt and tarsal joints , and the hindfoot variation , in which the ankle joint and calcaneum are involved ( 43 ) . , the midfoot ( tmt , naviculocuneiform , talonavicular , and calcaneocuboid joints ) is affected ( 44 ) . type iii involves the hindfoot causing severe instability and is classified into iiia ( involving the ankle joint ) , iiib ( involving the subtalar joint ) and iiic ( resorption of talus and/or calcaneus with impaired weight - bearing ) ( 44 ) . it is a radiological classification describing the natural history of the charcot foot from initiation through coalescence to consolidation and has been recently reviewed in more detail by the authors elsewhere ( 1 ) . in stage i ( development ) , there is erythema , foot edema and elevated temperature . plain foot radiographs are commonly normal , but bony debris at joints , fragmentation of subchondral bone , joint subluxation and fracture dislocation of joints may soon ensue ( 45 ) . in stage ii ( coalescence ) , signs of local inflammation gradually diminish , but radiological pathology becomes more evident . this includes absorption of debris with new bone formation , coalescence of larger fragments and sclerosis of bone ends ( 45 ) . at this stage , affected joints may become more stable ( 45 ) . in stage iii ( consolidation ) , signs of local inflammation are no longer discernible , and radiographs reveal remodelling of affected bones and joints ( 45 ) . it is during this advanced stage that severe deformities may change foot architecture , predisposing to ulceration ( 45 ) . in clinical practice , the charcot foot can be classified into the acute and chronic stage ( 1 , 3 , 7 , 10 , 27 ) . in the acute ( also called active ) stage , the foot is remarkably red , warm and swollen . pain is not a prominent feature and patients may report no pain or only some discomfort , which is usually much less in comparison to patients without neuropathy and similar degree of local inflammation ( 1 , 3 , 7 ) . using a portable infrared thermometer ( 41 ) , the physician may document a 26c temperature elevation in the affected vs. the contralateral foot ( 1 , 3 , 7 , 10 ) . at this stage , there is no deformity and the plain foot radiographs are most typically normal . the importance of early diagnosis to arrest the disease progress and avoid further bony destruction can not be emphasized enough ( 1 , 3 , 7 , 10 ) . in the chronic ( also called inactive ) stage , signs of local inflammation progressively recede ( 1 , 3 , 7 , 10 ) . the associated lower - extremity redness subsides , and the difference in skin temperature between the two feet diminishes . instead , stable deformities may develop ( 1 , 3 , 7 , 10 ) including the most frequent as : a ) collapse of the plantar arch in the midfoot with rocker bottom deformity ; and b ) prominent medial aspect of the foot in the midfoot ( medial convexity ) . both of these deformities result in abnormal high - pressure areas that are particularly prone to ulceration ( 1 , 3 , 7 , 10 ) . the most frequently used anatomical classification was proposed by sanders and frykberg ( 42 ) . i ( 15% ) , the forefoot [ metatarsophalangeal ( mtp ) and interphalangeal ( ip ) joints ] is affected ; in pattern ii ( 40% ) , tarso - metatarsal ( tmt ) joints are affected ; in pattern iii ( 30% ) , the naviculocuneiform , talonavicular , and calcaneocuboid joints are involved ; in pattern iv ( 10% ) , the ankle and subtalar joints are affected ; in pattern v ( 5% ) , the calcaneum is affected ( 42 ) . these are : the forefoot type involving the ip and mtp joints , the midfoot type involving the tmt and tarsal joints , and the hindfoot variation , in which the ankle joint and calcaneum are involved ( 43 ) . another classification in three types has been proposed by dounis ( 44 ) . in type the midfoot ( tmt , naviculocuneiform , talonavicular , and calcaneocuboid joints ) is affected ( 44 ) . type iii involves the hindfoot causing severe instability and is classified into iiia ( involving the ankle joint ) , iiib ( involving the subtalar joint ) and iiic ( resorption of talus and/or calcaneus with impaired weight - bearing ) ( 44 ) . it is a radiological classification describing the natural history of the charcot foot from initiation through coalescence to consolidation and has been recently reviewed in more detail by the authors elsewhere ( 1 ) . in stage i ( development ) , there is erythema , foot edema and elevated temperature . plain foot radiographs are commonly normal , but bony debris at joints , fragmentation of subchondral bone , joint subluxation and fracture dislocation of joints may soon ensue ( 45 ) . in stage ii ( coalescence ) , signs of local inflammation gradually diminish , but radiological pathology becomes more evident . this includes absorption of debris with new bone formation , coalescence of larger fragments and sclerosis of bone ends ( 45 ) . at this stage , affected joints may become more stable ( 45 ) . in stage iii ( consolidation ) , signs of local inflammation are no longer discernible , and radiographs reveal remodelling of affected bones and joints ( 45 ) . it is during this advanced stage that severe deformities may change foot architecture , predisposing to ulceration ( 45 ) . the charcot foot is a specific complication of diabetes mellitus ( 1 , 3 , 7 ) . its main pathophysiological mechanisms are peripheral and autonomic neuropathy , as well as excessive local inflammatory response to minor trauma ( 1 , 3 , 7 ) . clinically , it may be classified into an acute and chronic stage ( 13 ) . other classifications are based on anatomical localization and staging of natural history ( 13 ) . in clinical practice , a high level of suspicion , including urgent specialist referral when appropriate , is required for timely diagnosis and treatment ( 1 , 3 ) , as is generally true for diabetic foot pathology ( 46 ) . this increased awareness may be anticipated to help towards avoiding more severe complications and improving diabetic foot outcomes ( 4749 ) .
in people with diabetes mellitus , the charcot foot is a specific manifestation of peripheral neuropathy that may involve autonomic neuropathy with high blood flow to the foot , leading to increased bone resorption 
 . it may also involve peripheral somatic polyneuropathy with loss of protective sensation and high risk of unrecognized acute or chronic minor trauma . in both cases , there is excess local inflammatory response to foot injury , resulting in local osteoporosis . in the charcot foot , 
 the acute and chronic phases have been described . 
 the former is characterized by local erythema , edema , and marked temperature elevation , while pain is not a prominent symptom . in the latter , signs of inflammation gradually recede and deformities may develop , increasing the risk of foot ulceration . 
 the most common anatomical classification describes five patterns , according to the localization of bone and joint pathology . 
 this review article aims to provide a brief overview of the diabetic charcot foot in terms of etiology , pathophysiology , and classification .