It is obvious that a significant role in the pathogenesis of the Charcot osteoarthropathy is played by OPG/RANKL (osteoprotegerin/receptor activator of nuclear factor-k ligand) signalling pathway, which is further influenced by many cytokines, such as TNF-α, IGF and TGF [7, 50]. Activation of this transcription factor increases together with other factors secretion of osteoprotegerin and receptor activator of nuclear factor (RANK) [45, 46].

These causes probably contribute to the clinical manifestation of acute CHOA through RANKL–NF-kB signalling pathway. Inadequate control of this system participating in bone formation activates bone resorption which then prevails over the new bone formation, resulting ultimately in osteoarthropathy. It has been proved that neuropathy leads to increased RANKL secretion as a result of depletion of neuropeptides known for the cytokine system antagonistic effect, including calcitonin gene-related peptides. Impairment of circulating peptides, such as leptin and amylin, may also affect the cytokine system in diabetes [45, 46, 51, 52]; endocrine causes IGF-1 disorder (insulin growth factor, known as C somatomedin, stimulating proliferation of cartilage and new bone formation) caused by insulin deficiency that may impair growth and integrity of the foot skeleton.

One of the causes of the disease may be considered also improper footwear with chronic excessive pressure at the sites of bone contact with shoes, resulting in defects of the trophic skin with sudomotor dysfunction.

Neuropathic foot causes changes in normal foot configuration, when the predominance of shortening flexors elevates the medial longitudinal arch, forming excavation or varus deformity of the foot, with hammer toes (Fig. 15.4). During gradual foot excavation, distribution of pressures is changing, with plantar pressures of the hypotrophic foot increasing typically under distal heads of metatarsals, mainly the first ray, less the fifth and the second rays. These excessive pressures of more than 65 N/1 cm² with subsequent formation of plantar callosities are a high risk factor in terms of development of skin defects and ulcerations. Armstrong [2] has proved that in patients with CHOA and neuropathic ulcerations, the incidence of excessive plantar pressures is markedly higher than in patients with neuropathy without ulcerations or ischemic disorders (Figs. 15.5 and 15.6). It is not clear why in patients with a unilateral acute CHOA there are no similar increased plantar pressures on the contralateral (intact) side [3, 11, 71, 74, 103].

Despite frequent disorders of the gait mechanism due to loss of proprioception and nociception, as well as muscle weakness, and despite limited mobility and impaired foot configuration, walking on flat, level ground is only slightly altered, while walking on uneven ground is difficult [74].

Where neuroarthropathy has developed from long-term polyneuropathic changes triggered by external injuries, capsular cheiroarthropathy and osteoclasia of bone and joint structures, the midfoot arch will be falling, with a gradual change of the foot configuration from excavation to calcaneo-planovalgus deformity.

For this reason lesions causing the most severe forms of disintegration of the foot arch, particularly of the medial arch responsible for development of the rocker bottom foot deformity, occur as a rule in the Lisfranc joint and the subtalar region [3, 5, 13, 68, 71, 74, 103].

Schon´s classification system of CHOA [104] is based on four types of deformities, with three subtypes each, divided by individual deformity patterns caused by disorders of the foot arch and osteoclasis associated with necrosis, fragmentation or loosening of soft tissue structures in individual parts of the foot:

The outcomes of treatment of the involvement of the proximal foot with a collapse of the medial or lateral longitudinal arch are considered to be the worst, regardless of whether they were treated conservatively or operatively.

Type I involvement tends to result in valgus deformity, widening of the foot with symptomatic bony prominences and skin breakdown. Medial arch collapse and development of rocker bottom foot deformity prevails in types II–IV of the Schon’s classification.

A more precise and currently the most commonly used classification is the scheme developed by Sanders and Frydberg [101] (Fig. 15.7) which differentiates between all locations of the involvement of the fore-, mid- and hindfoot.

If there develops osteoclasia, ligamentous and capsular structures become lax with the following disruption and minor or larger hematomas and hemarthrosis. Bone mass loss, bone matrix in particular, causes trabecular microfractures in the subchondral bone with osteoclast–osteoblast imbalance.

Fragmentation and avulsions can be seen mainly along the edges of articular facets. Their healing reduces elasticity and increases stiffness of the bone [67]. The initial changes in the form of fragmentation occur at the site of maximum action of static and dynamic forces, particularly on the distraction, less on the compression side, which is the first site to exhibit sclerosis of articular facets, destruction of edges, usuration, osteolysis, with formation of osteophytes and later also with fragmentation. Flattening of the arch of the neuropathic foot (pes excavatus) in the subtalar region and Chopart joint leads to posterior fragmentation of this and the talonavicular joints, resulting in a progressive collapse of the arch by subluxation of tarsus downwards. This is followed by decrease of excessive pressures of distal heads of metatarsals and toes on the planta, causing osteopenia or even osteolysis of these heads, and of the stress that was responsible for fractures of metatarsal shafts. Valgus deformity of the midfoot will increase pressure in the distal part of the first metatarsal and distal phalanx of the great toe contributing to another pattern of distribution of skin defects and ulcerations in CHOA, as compared to the neuropathic foot.

Early diagnosis is of key importance to a successful treatment. Within the current European medicine approach which puts emphasis primarily on the location of pathological processes, CHOA is considered to be merely a marginal issue of internal diabetology, neurology, orthopaedics, podiatry, rheumatology and dermatology, despite the severity of this disease and its prognosis and in spite of the fact that its treatment is not always successful and may lead to repeated amputations [62, 63, 94, 124].

Diagnosis is established on the basis of the patient´s medical history, clinical and radiographic examination and laboratory tests.

The patient’s medical history should be checked for family history of diabetes mellitus of both types and other metabolic disorders. Examination of the medical history of a diabetic patient should focus also on initial lower extremity neuropathic disorders of all types, both sensorimotor and autonomous, including sudomotor (sweating) disorders, local hyperthermia, swellings, mobility and balance problems and rapid changes in foot configuration while differentiating between static age-related deformities and CHOA. CHOA is markedly more frequent if other diabetic complications are identified, nephropathy and retinopathy in particular [24, 94].

In case of the patient’s subjective complaints, attention should be paid to proprioception and nociception disorders, taking into account that in CHOA sensitivity to heat may persist for a longer time, while sensitivity to cold disappears quite soon, as well as to all signs of muscle weakness and limited mobility. It is necessary to follow up any common injury in the region of the ankle and foot (sprain, capsular lesion with a periarticular hematoma, contusion or fracture) in order to eliminate it as a cause of CHOA onset and progression, even if the patient does not report any clinical manifestations indicating the presence of polyneuropathy.

Both clinical and radiographic findings may mimic mainly inflammatory diseases. In a diabetic patient with trophic defects and ulcerations, distinction between the two conditions is complicated particularly in case of deep infection defects and gangrenes, with a potential of development of cellulitis, abscess and continuous osteomyelitis by propagation of the infected defect. Of great help in the diagnosis may be assessment of the blood supply as an ischemic and neuroischemic foot only rarely progresses to a neuroarthropathic foot [50]. On the contrary, a relatively well preserved or even exaggerated arterial blood flow in the foot on the dorsum of the foot indicates a potential presence of CHOA and causes local hyperthermia, as compared to the contralateral foot or intact parts of the symptomatic foot, with a temperature differential of more than 2 °C [24, 66]. This temperature differential indicates a pathological activity of the process, mainly osteoclasia, and after its decline or resolution, CHOA may be reclassified into the coalescence and remodelling stage [24, 67, 100].

Clinical examination should include examination of peripheral sensomotor and autonomic neuropathy. The preserved sensitivity to touch (filaments) and heat, with a rapid loss of sensitivity to cold in the early stages, indicates a special type of sensitive neuropathy in the first stage of CHOA. In later stages, sensitivity gets impaired in general [67].

In radiographic examination, detection of initial changes is determined by the resolution capacity of plain radiographs. In addition, given the average age of patients with CHOA, the changes may be overlapped by structural changes of degenerative, osteoporotic and rheumatoid nature corresponding to the patient’s age, gender and habitus [43, 109, 111]. Computer tomography and magnetic resonance imaging have a much higher sensitivity and specificity, although they are less available. Hyperaemia may be confirmed by three-phase bone scan based on 99mTc-labelled methylene diphosphonate; however, it is impossible to clearly differentiate between osteomyelitis and increased resorption metabolic activity. Similarly, also gallium bone scan is usually positive both in case of infection and noninfected neuropathic bone lesion. The best resolution capacity is provided by the combined technetium bone scintigraphy (99mTe) with indium-labelled leucocytes [24, 34, 67, 100]. A negative scan excludes the incidence of acute CHOA in the phase of rapid bone resorption [3, 5, 6, 9, 10].

In laboratory tests, diagnosis of the chronic form of CHOA is associated mainly with markedly elevated alkaline phosphatase level – the bone metabolism marker. These tests relate particularly to calcification, although they may not always reflect synthesis of bone matrix and collagen [24]. Concentration of carboxy-terminal telopeptide of type 1 collagen (1CTP) as the marker of osteoclastic bone resorption is markedly elevated in the venous system of the dorsum of the foot affected by acute CHOA as compared to its chronic form, while there are no significant differences in concentration of carboxy-terminal propeptide of type 1 procollagen (P1CP) as the indicator of osteoblastic bone formation in both forms, which proves excessive osteoclastic activity in the acute phase without the concomitant increase of osteoblastic activity [24]. On the basis of these differences, Gough [37] has demonstrated a disorder of physiological balance between the physiological osteoclasia and osteoplasia, ensuring the skeletal integrity under normal conditions, in diabetic patients with CHOA, where excessive bone matrix resorption through increased osteoclastic activity is not accompanied by increased osteoplastic synthetic activity. If we accept the opinion of Jeffcoat [51] and Hoffbauer [45, 46] on the role of pro-inflammatory cytokines in CHOA onset and progression, laboratory tests of serum activity may be helpful in diagnosis. The diagnostic value in differentiation of inflammatory parameters, especially in case of ulcerations, has however a limited value also with regard to other diseases, particularly myoskeletal tuberculosis, that may exhibit medium- and lower-level inflammatory serum activity, or seroactivity may be absent [60].

Complete blood count and erythrocyte sedimentation rate should be part of the initial routine examination in order to eliminate inflammation. However, it has to be taken into account that deep infection and CHOA may occur simultaneously in the same patient [4, 34].

According to Eichenholtz, CHOA is clinically manifested in three basic forms:

Chronic stage may progress to the phase of healing or, more often, the pathological process after latent periods exacerbates probably due to the adverse effects of external factors [43, 44]. This is why other authors divide the CHOA course into two stages, namely, the acute and post-acute ones [3, 13].

Criteria of acute CHOA (Table 15.1) include a typical presentation of a swollen and erythematous foot with marked temperature differences (2–7 °C) between the affected and intact locations and the contralateral foot [24, 81], without general fibrillation. It is associated with laxity of capsular and ligamentous structures, bone hyperaemia and bone resorption and destruction.

Mild pain may be caused by fragmentation and incongruence of the joint, although reduction or loss of nociception keeps it below the level experienced by nondiabetic patients after an injury [81]. Within 2–3 weeks there occur fragmentations, subluxations in small joints [5, 24] with symptoms of instability and impairment of joint functions [81]. Examination of passive range of motion may reveal loss of the joint configuration and congruency. Ulcerations may develop in typical locations. The patient´s medical history often contains information about injury shortly before the onset of the disease, indicating the triggering mechanism of acute CHOA.

Swelling associated later with foot deformities, mainly progression to planovalgus deformity, with mild pain without fluctuations are the main clinical features of the acute phase of CHOA. Absence of infected defects indicates absence of inflammatory bone changes.

The patient´s medical history should be checked for family history of diabetes mellitus of both types and other metabolic disorders. Examination of the medical history of a diabetic patient should focus also on initial lower extremity neuropathic disorders of all types, both sensorimotor and autonomous, including sudomotor (sweating) disorders [120], local hyperthermia, swellings, mobility and balance problems and rapid changes in foot configuration while differentiating between static age-related deformities and CHOA [12].

Mild periarticular swellings with no obvious seroactivity are usually caused by cheiroarthropathy, resulting from type I collagen-type disorder, particularly in the insidious onset of the disease. They decrease elasticity of ligaments, causing their subsequent fragility and laxity of joint and ligamentous structures. Acute forms with marked swelling are often associated with inflammatory changes resulting from minor injuries and ligament laxity for the above-mentioned causes. They may trigger a cascade of pre-inflammatory changes through increased production of inflammatory cytokines, including TNF-α and IL-1β, leading to a marked osteoclastogenesis through increased expression of pro-inflammatory factor NF-kB. Its activation increases secretion of osteoprotegerin and receptor activator of nuclear factor (RANK [46, 51, 52]). These causes probably participate in clinical manifestation of acute CHOA through RANKL–NF-kB pathway. External factors include mainly injury, both single and repeated [12].

Criteria of chronic CHOA include the presence of characteristic radiological changes, such as bone destruction, fragmentation, osteolysis and disorganisation of bone–joint structures and hypertrophic changes in bone tissue undergoing the process of reparation, proliferation, sclerotisation and bone fusion. The clinical condition is assessed as a chronic form when radiography does not show substantial changes for more than 6 months; the foot is without swelling and local temperature differences [5, 32].

The chronic form of the diabetic CHOA foot (Fig. 15.9) develops also when the florid form progressed subclinically and gradually, being overlapped by angiopathic ischaemic or even ulcerative changes with swelling, and going almost unnoticed due to reduced nociception. CHOA diagnosis is confirmed only after obtaining radiological evidence of fragmentation and destruction, exhibiting typical osteoclastic changes with development of planovalgus or rocker bottom foot deformity [13, 16], sometimes even without clinical manifestation of acute form of CHOA, only with slowly developing features typical of stage I or II according to Eichenholtz that is in the extended Eichenholtz´s scheme classified as stage IV. It is characterised by “6 D” changes: density, destruction, debris, distension, dislocation and disorganisation.

The sign of subsidence of osteoclastic activity and progressive reparation (Eichenholtz stage III) is a complete reversal of the negative development of structural changes, rounding of the bone ends, presence of advanced reparation with sclerotic changes in sharp edges, synostoses with callus formation and fusions of residual osteoarticular structures.

Although the CHOA symptoms may be preceded by symptoms of polyneuropathy with ischemic changes, in other cases only the acute CHOA form may be the first evident clinical symptomatology. Polyneuropathy, mainly in elderly patients, may have a subclinical form, and certain evident disorders may be attributed to the general age-related habitus, primarily in patients with undiagnosed type 2 diabetes mellitus.

As the so far used Eichenholtz classification into three stages (Table 15.2) does not include the additional two possible forms of the complete range of features (clinical and radiological), the delay of identification of radiological changes caused by certain limitations of imaging by plain radiographs as compared to other substantially more sensitive imaging (CT, MRI, PET) may lead in initial acute symptomatology to a negative radiographic finding. Therefore, authors recommend addition of stage 0 defining this CHOA form. Based on our experience in long-term follow-up of patients with various forms of CHOA, we recommend to add also stage IV for insidious form of slow radiological development of typical structural changes, including the osteoarticular ones, typical of CHOA without a primary clinical manifestation of the acute form.

Radiological presentation mainly of the early acute stage is unspecified and changes according to the location of involvement.

Some authors [118] distinguish between two forms of CHOA radiological manifestation:

There is no sharp dividing line between these two forms; they may turn into each other or occur concomitantly. The underlying factor in both of them is osteoclasia with loss of bone matrix and of bone structure with residual fragments.

In 1986, Wagner described five types of bone changes in CHOA [128]:

Decrease in bone density may lead to decrease of the bone strength as structural bone density is the main factor of its strength [16, 17] and the risk rate of its fragmentation [92].

Classification of radiological changes of the skeleton of the ankle and the foot affected by CHOA into three stages [1, 14, 15, 27, 31, 43, 62] respects the original Eichenholtz´s scheme:

In terms of clinical and radiological development of the disease and its treatment, we propose a more accurate differentiation (Table 15.5).

The time interval between individual stages is variable. The process is often discontinued in the first or second stage and may continue even after several years [21] or exacerbate [43].

Radiography is the basic diagnostic method, although interpretation of radiographs may be problematic, particularly in the early stage of CHOA, as there may occur negative findings or doubts concerning differentiation between early CHOA symptoms and common age-related degenerative static changes. Atrophic and hypertrophic changes may develop simultaneously and are sometimes difficult to be differentiated from the age-related, hypoestrogenic osteoporosis, post-trauma Sudeck´s syndrome and inflammatory changes [26, 37, 61, 100, 102].

According to Armstrong [2, 3], osteoarthropathic changes occur most frequently in the region of the Lisfranc (48 %) and Chopart (34 %) joints and then in the ankle and subtalar region (13 %), in the forefoot (3 %) and in the calcaneus (2 %). Other authors [5, 6, 11, 13] report different percentage based on evaluation of their groups of patients. Philip [88] reports their incidence in midfoot in 20–50 %, at the level of Lisfranc joint in 15–45 %, Chopart joint in 30 %, in the ankle in 3–10 % and calcaneus in 1 % of cases. The most commonly used Sanders and Frykberg classification [101] into five patterns presents the following distribution of involvement:

Radiological abnormalities observed in CHOA may be divided into:

Quality images are an indispensable part of the basic examination within differential diagnosis (Figs. 15.10, 15.11 and 15.12). In the early phase of the disease, radiography may cause certain diagnostic doubts due to its limited differentiation capacity. Detection of initial changes is determined by the resolution capacity of plain radiographs. In addition, the changes may be overlapped by structural changes of degenerative, osteoporotic and rheumatoid nature corresponding to the patient´s age, gender and habitus [15, 16, 62, 86].