Charcot Neuroarthropathy of the Foot and Ankle PDF Review (2013)

The Journal of Foot & Ankle Surgery 52 (2013) 740–749 Contents lists available at ScienceDirect The Journal of Foot & Ankle Surgery...

The Journal of Foot & Ankle Surgery 52 (2013) 740–749 Contents lists available at ScienceDirect The Journal of Foot & Ankle Surgery journal homepage: www.jfas.org Review Charcot Neuroarthropathy of the Foot and Ankle: A Review Ajit Kumar Varma, MS Professor, Department of Endocrinology, Diabetic Lower Limb and Podiatric Surgery, Amrita Institute of Medical Sciences and Research Center, Ponekkara, Kerala, India a r t i c l e i n f o a b s t r a c t Level of Clinical Evidence: 3 Charcot neuroarthropathy is a limb-threatening, destructive process that occurs in patients with neuropathy associated with medical diseases such as diabetes mellitus. Clinicians’ treating diabetic patients should be Keywords: amputation vigilant in recognizing the early signs of acute Charcot neuroarthropathy, such as pain, warmth, edema, or bisphosphonate pathologic fracture in a neuropathic foot. Early detection and prompt treatment can prevent joint and bone Charcot’s foot deformity destruction, which, if untreated, can lead to morbidity and high-level amputation. A high degree of suspicion diabetic neuroarthropathy is necessary. Once the early signs have been detected, prompt immobilization and offloading are important. offloading Treatment should be determined on an individual basis, and it must be determined whether a patient can be osteomyelitis treated conservatively or will require surgical intervention when entering the chronic phase. If diagnosed early, medical and conservative measures only will be required. Surgery is indicated for patients with severe or unstable deformities that, if untreated, will result in major amputations. A team approach that includes a foot and ankle surgeon, a diabetologist, a physiotherapist, a medical social councilor, and, most importantly, the patient and immediate family members is vital for successful management of this serious condition. Ó 2013 by the American College of Foot and Ankle Surgeons. All rights reserved. Since its first description by Sir William Musgrave in 1703, the The Charcot foot is a condition affecting the bones, joints, and soft pathogenesis of Charcot neuroarthropathy (CN) has bewildered even tissues of the foot and ankle and is characterized by inflammation in the most experienced clinicians. In 1883, Jean-Martin Charcot the earliest phase. The Charcot foot has been documented to occur as described the “tabetic foot,” because tabes dorsalis was the most a consequence of various peripheral neuropathies; however, diabetic common cause of neuroarthropathy at that time (1). Diabetes mellitus neuropathy has become the most common etiology. The interaction of has long surpassed syphilis as the leading cause of CN, and the several component factors (diabetes, sensory-motor neuropathy, prevalence of diagnosed CN in patients with diabetes has been re- autonomic neuropathy, trauma, and metabolic abnormalities of the ported to be 0.08% to 7.5% (2). Armstrong and Peters (3) have reported bone) results in an acute localized inflammatory condition that can the prevalence of Charcot foot to be approximately 0.16% in the lead to varying degrees and patterns of bone destruction, subluxation, general population. Although uncommon, CN, a chronic and dislocation, and deformity (Fig. 1). The hallmark deformity associated progressive disease of the bone and joints, is 1 of the most destructive with this condition is midfoot collapse, described as a “rocker- complications of diabetes, leading to subluxation, dislocation, defor- bottom” foot, although the condition can appear in other joints and mity, and ulceration of the foot and ankle joints. with other presentations (6). The prevalence of diabetes has been rapidly increasing and is likely to reach epidemic proportions by the year 2020. More than 371 million patients have diabetes worldwide. It has been estimated that Pathophysiology India had about 31.7 million adult diabetic patients (age group 20 to 79 years) in 2000, and the number is expected to increase to 73 The exact nature of Charcot arthropathy remains unknown, but the million by 2025 (4). Thus, India, with 61.3 million diabetic patients, following were major theories regarding the pathophysiology of has the second largest number of diabetic patients in the world, after Charcot arthropathy (7). China (5). Previous Theories of the Pathophysiology of CN Financial Disclosure: None reported. Conflict of Interest: None reported. Neurotraumatic Theory Address correspondence to: Ajit Kumar Varma, MS, Department of Endocrinology, Diabetic Lower Limb and Podiatric Surgery, Amrita Institute of Medical Sciences and The nontraumatic theory stated that Charcot arthropathy is caused Research Center, Ponekkara, PO Kochi, Kerala 682041, India. by an unperceived trauma or injury to an insensate foot. The sensory E-mail address: [email protected] neuropathy renders the patient unaware of the osseous destruction 1067-2516/$ - see front matter Ó 2013 by the American College of Foot and Ankle Surgeons. All rights reserved. http://dx.doi.org/10.1053/j.jfas.2013.07.001  A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 741 Current Theory of the Pathophysiology of CN Charcot recognized the role of acute inflammation (8). It is the uncontrolled inflammation that results in the final common pathway for the decreased bone density in CN with an osteoclast and osteo- blast imbalance. Gough et al (9) proved that excessive osteoclastic activity occurs in patients with acute CN. The role of inflammation in upsetting the osteoclast–osteoblast homeostasis was investigated by Baumhauer et al (10). The investi- gators stained 20 surgical bone specimens from patients with CN using hematoxylin and eosin, interleukin (IL)-1 antibody, tumor necrosis factor-a antibody, and IL-6 antibody. These inflammatory cytokines lead to bone resorption by promoting osteoclast recruit- ment, proliferation, and differentiation. Osteoclasts demonstrated a moderate pattern of staining for tumor necrosis factor-a and IL-1 and a diffuse pattern of staining for IL-6. These results suggested that osteoclasts express inflammatory cytokines during the acute and reparative phases of CN. Hematoxylin and eosin staining also showed the presence of excessive numbers of multinucleated osteoclasts in lacunae surrounded by lamellar bone. Uccioli et al (11) further eluci- dated the role of inflammation in the Charcot process by character- Fig. 1. Digital photograph of destroyed mid and hind foot because of Charcot neuroarthropathy. izing the cytokine phenotype of monocytes in patients with acute CN. The presence of proinflammatory cytokines alone does not account for the entire influx of osteoclasts in CN. Receptor activator of that occurs with ambulation. This microtrauma leads to progressive nuclear factor-kappa B ligand (RANKL) has been studied extensively destruction and damage to the bone and joints. for its role in activating osteoclasts in diabetic CN. RANKL is an important mediator of osteoclastogenesis and is essential in osteo- Neurovascular Theory clast formation and modulation (Fig. 3). The antagonist of the RANKL The neurovascular theory suggested that the underlying condition pathway is osteoprotegerin. Jeffcoate (12) suggested that disruption of leads to the development of autonomic neuropathy, mainly sympa- the RANKL/osteoprotegerin pathway is responsible for the osteopenia thetic denervation, causing the arteriovenous shunts to open into the seen in CN. Volkmann and haversian canals (Fig. 2). This causes about 30% to 60% Mabilleau et al (13) demonstrated the role of RANKL in CN and also increased blood flow into the bone, which causes the minerals to be suggested that a RANKL-independent pathway might exist. They washed off and also stimulates the osteoclasts. These, in their turn, showed that the osteoclast precursor cells in patients with acute cause increased bone destruction, leading to osteopenia. Charcot are “primed” to become osteoclasts with aggressive behavior (13). They also showed that the increased levels of circulating proin- Combination Theory flammatory cytokines, tumor necrosis factor-a, IL-6, and IL-8 induce Charcot arthropathy most likely results from a combination of the osteoclast formation, independent of RANKL. Inflammation is the final processes described by these theories. The autonomic neuropathy common pathway in the pathogenesis of CN. Studies have evaluated leads to abnormal bone formation, and the sensory neuropathy leads the use of bisphosphonates in patients with CN. Pitocco et al (14) to an insensate joint that is susceptible to trauma. The development of performed a study of 20 patients in which the treatment group abnormal bone with no ability to protect the joint results in gradual received 70 mg of alendronate once weekly and the control group bone fracture and subluxation of the joint. received placebo. Both groups were prescribed standard offloading Increased blood glucose Lack of RAGE Increased AGEs OPG (antagonist) Increased RANKL Decreased CGRP Neuropathy Repetitive Trauma IL-6 Osteoclasts Decreased eNOS Neuropathy IL-1 TNF-Alpha BONE DESTRUCTION Fig. 3. The role of receptor activator of nuclear factor-kappa B ligand (RANKL) in bone destruction in Charcot neuroarthropathy. AGE, advanced glycation end product; CGRP, calcitonin gene-related peptide; eNOS, endothelial nitric oxide synthase; IL, interleukin; OPG, osteoprotegerin; RAGE, receptor for advanced glycation end products; TNF, tumor Fig. 2. Arteriovenious shunts. necrosis factor. 742 A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 methods. Although these investigators found significant reductions in THE CHARCOT FOOT hydroxyproline and serum C-terminal telopeptide of type 1 collagen, markers of bone turnover, they did not report differences in the Long NEUROPATHY Neuropathic resolution of the clinical symptoms (14). They did, however, demon- standing disease strate a reduction in the serum levels of insulin-like growth factor 1 diabetes (IGF-1) in the treatment group. IGF-1 causes vasodilation, adding to Injury, sprain Ligament laxity Infection the hyperemia already present with CN. This finding prompted the Surgery same group to study the relationship among IGF-1, neuropathy, Painless ambulation inflammation, and the RANKL system (15). Bisphosphonates might decrease IGF-1 and help regulate RANKL; however, their clinical efficacy remains to be proven. Joint degeneration, Subluxation Peripheral and autonomic neuropathy can minimize the release of the neuropeptide calcitonin gene-related peptide (CGRP), which Continued weight bearing antagonizes the expression of RANKL. CGRP inhibits osteoclast motility, recruitment, and differentiation (16). CGRP is produced in Ulcer, ACUTE CHARCOT the hypothalamus and found in the periosteum and bone marrow and infection FOOT plays an active role in bone remodeling (17). With a lack of CGRP, Fig. 4. Natural history of Charcot neuroarthropathy. osteoclasts are recruited by RANKL in an unchecked fashion. La Fontaine et al (18) substantiated the CGRP hypothesis in their study in 2008. They performed immunohistologic studies of bone samples Classifications from 3 groups: diabetic patients without neuropathy, diabetic patients with neuropathy, and diabetic patients with stage 2 or 3 CN. Numerous classification systems exist for the categorization of the They found that the Charcot group had the least amount of CGRP. They Charcot foot according to the severity and location and complexity of also considered the relative amounts of endothelial nitric oxide the condition. The earlier classification systems were based on the synthase, an isoenzyme that regulates nitric oxide production. Nitric radiographic findings or anatomic location (22). oxide is a free radical that suppresses osteoclasts. They found a statistically significant decrease in endothelial nitric oxide synthase Eichenholz Classification: Disease Progress in the Charcot bone compared with the other 2 groups. The Eichenholz classification describes the evolution of the Another mechanism by which RANKL, and thus osteoclast func- condition through time (23). A “stage 0” has come into use to describe tion, is increased is by the accumulation of advanced glycation end the swollen, hot, usually somewhat painful, foot in which the findings products (AGEs). The formation of AGEs is driven by hyperglycemia from plain radiographs are normal but magnetic resonance imaging and primarily affects collagen in tissues with the slowest turnover, (MRI) will show bone edema and stress fractures. such as cortical bone (19). AGEs have been found to increase RANKL activation and to induce osteoblast apoptosis (20). In patients with Stage 0: Hot foot, normal radiographic findings; MRI will show diabetes, formation of AGEs is increased but a receptor for AGEs is bone edema and stress fractures lacking. Witzke et al (19) found a significant reduction in calcaneal Stage 1: Fragmentation, bone resorption, dislocations, fractures stiffness in patients with CN. In all subjects, a positive correlation was Stage 2: Coalescence, sclerosis, fracture healing, debris resorption found between calcaneal bone stiffness and the AGE receptor Stage 3: Bone remodeling concentration, indicating that receptor for AGEs is protective against osteoclastic resorption. They also found an elevated level of osteo- calcin, a marker of bone turnover, in patients with CN. Brodsky Classification: Disease Distribution CN usually begins in the tarsometatarsal region; however, some- times, it will be seen in the midtarsal or ankle joints or as pathologic Natural History calcaneal fractures. The distribution can be expressed using the Brodsky classification (24). Most of the patients who develop CN have had a known duration of diabetes of more than 10 years. The long duration of diabetes before Type 1: Involves tarsometatarsal and naviculocuneiform joints as the initiation of the Charcot process reflects the degree of neuropathy most common locations (60% of cases); collapse leads to fixed present in these patients. The blood supply to the Charcot foot is rocker-bottom foot with valgus angulation always good. The initiating event of CN is often a seemingly trivial Type 2: Involves subtalar, talonavicular, or calcaneocuboid joints injury, or, in many cases, the patient is unable to recall a history of (10% of cases); unstable, requires long periods of immobilization injury. The patient might notice a change in the shape of the foot and (up to 2 years) might feel the bones of the feet crunching as they walk. Subsequently, Type 3A: Involves tibiotalar joint (20% of cases); late varus or valgus a rapid onset of swelling, an increase in the temperature in the foot, deformity produces ulceration and osteomyelitis of malleoli and, sometimes, pain or discomfort develops. It is these processes Type 3B: Follows fracture of calcaneal tuberosity; late deformity that, if left untreated, will lead to the characteristic patterns of results in distal foot changes or proximal migration of the deformity in the Charcot foot, including the collapse of the longitu- tuberosity dinal and transverse arches, resulting in the rocker-bottom foot seen Type 4: Involves a combination of areas in mid-foot CN or the collapsed and destroyed ankle joints seen in Type 5: Occurs solely within the forefoot hind-foot Charcot (Fig. 4). The natural history of CN passes from this acute phase of development through a stage of coalescence, in which the bone fragments are reabsorbed, the edema lessens, and the foot Sanders and Frykberg Classification heals, to the stage of consolidation, in which the final repair and Sanders and Frykberg (25) classified Charcot arthropathy remodeling of bone occurs, to leave a stable, chronic Charcot foot. The anatomically into patterns of joint involvement (Fig. 5). They divided time course of these events will vary (21). the foot and ankle into 5 patterns of destruction.  A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 743 Fig. 5. Diagram showing Sanders and Frykberg classification. Pattern I involves the forefoot joints; common radiographic Fig. 6. Graph showing Roger’s classification. changes include osteopenia, osteolysis, juxta-articular cortical bone defects, subluxation, and destruction Pattern II involves the tarsometatarsal joints, including the meta- of CN developing in the absence of neuropathy have been reported. tarsal bases, cuneiforms, and cuboid; involvement at this location Accordingly, peripheral sensory neuropathy associated with reduced can present as subluxation or fracture or dislocation and sensation of pain is the essential predisposing condition that permits frequently results in the classic rocker-bottom foot deformity the development of the arthropathy (27). A personal history con- Pattern III involves Chopart’s joint or the naviculocuneiform joints; cerning antecedent trauma is often unreliable (28). Typical clinical radiographic changes typically show osteolysis of the naviculocu- findings include a markedly swollen, warm, and often erythematous neiform joints with fragmentation and osseous debris dorsally and foot, with only mild to moderate pain (27). Acute local inflammation is plantarly often the earliest sign of underlying bone and joint injury (29). This Pattern IV involves the ankle with or without subtalar joint initial clinical picture can resemble cellulites, deep vein thrombosis, involvement; radiographs will reveal erosion of bone and cartilage, or acute gout and can be misdiagnosed. Most often, a temperature with extensive destructive of the joint, which can result in differential of several degrees is present between the 2 feet. Acute complete collapse of the joint and dislocation (typically, this Charcot activity should be diagnosed if the temperature of the pattern of involvement results in a severe unstable deformity) affected foot is 2 C or more than the contralateral unaffected foot. This Pattern V is isolated to the calcaneus and usually results from is usually measured using an infrared thermometer. Pedal pulses will avulsion of the Achilles tendon off the posterior tubercle characteristically be bounding, with a biphasic sound when examined with a hand-held Doppler probe. Patients with chronic deformities, Sanders and Frykberg (25) reported the midfoot (patterns II and III) however, can develop subsequent limb-threatening ischemia. were the most common area of involvement, and these patterns are Musculoskeletal deformity can be very slight or grossly evident, most often associated with plantar ulceration at the apex of the deformity. often owing to the chronicity of the problem and the anatomic site of involvement (30). The classic rocker-bottom foot, with or without Roger’s Classification of Charcot Foot plantar ulceration, represents a severe chronic deformity and is Rogers and Bevilacqua (26) proposed a new classification sche- typical for this condition. Radiography and other imaging modalities me, which accounts for the degree of complications in the Charcot can detect subtle changes consistent with active CN (31). joint (Fig. 6). This new system considers deformity, ulceration, and osteomyelitis and could be helpful in predicting amputation. Clinical Features Theirs is a 2-axis system (XY) and combines the features of the clinical examination, radiography, and anatomy. The X-axis marks the A high degree of suspicion is necessary. CN must be suspected in anatomic location of involvement, and the foot and ankle are divided any diabetic patient who presents with swelling, redness, and, into 3 regions: forefoot, midfoot, and rearfoot and ankle. The Y-axis sometimes, pain in the foot and ankle that is of short duration (within describes the degree of complications in the Charcot joint. A indicates 4 to 6 weeks). Usually, the patient will not report a history of any acute Charcot with no deformity; B, a Charcot foot with deformity; known trauma. The clinical picture would resemble cellulites. C, a Charcot foot with deformity and ulceration; and D includes However, systemic features of infection could be absent. The osteomyelitis. Therefore, one moves across the X-axis (anatomic peripheral pulses, the dorsalis pedis and the posterior tibial, usually involvement) and/or down the Y-axis (complicating factors) as the would be well palpable in patients with CN. The erythrocyte sedi- Charcot foot becomes “more complicated” and is accordingly at mentation rate and C-reactive protein values will be normal in the greater risk of amputation (22,26). presence of CN. The symptoms of Charcot foot can include the following: redness, Diagnosis swelling, pain or soreness, warmth within the foot, a strong pedal pulse, instability in the joints, loss of sensation in the foot, subluxation The diagnostic clinical findings include components of neurologic, (misalignment of the bones that form a joint), and foot deformity vascular, musculoskeletal, and radiographic abnormalities. No cases (which can be severe). 744 A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 Approximately 50% of patients with Charcot foot will remember early changes can resemble osteoarthritis, and the bone collapse seen a precipitating, minor traumatic event, and about 25% of patients will in the late stage can resemble osteonecrosis and post-traumatic ultimately develop similar changes in the contralateral foot. Because osteoarthritis (32). trauma is not a prerequisite for Charcot foot, a patient with diabetes MRI allows detection of subtle changes in the early stages of active and neuropathy, erythema, edema, an increased foot temperature, CN when the radiographic findings could still be normal. MRI and normal radiographic findings most likely has an acute Charcot primarily images protons in fat and water and can depict the anatomy process (25). These patients will be afebrile, have stable insulin and pathologic features in both soft tissue and bone in great detail. requirements and normal white blood cell counts, and often have no Because of its unique capability of differentiating tissues with high break in skin integrity. These are all conditions that make infection detail, MRI has a high sensitivity and specificity for osteomyelitis and unlikely. has become the test of choice for the evaluation of the complicated The existence of little or no pain can often mislead the patient and foot in diabetic patients. MRI can be very useful in making the diag- physician (26). nosis at its earliest onset before the changes become evident on plain Brodsky (24) described a test to distinguish a Charcot process from films. MRI will show involved joints that appear diffusely swollen and infection in patients with associated plantar ulcers. With the patient demonstrate a low signal intensity. The fat plane adjacent to the skin supine, the involved lower extremity is elevated for 5 to 10 minutes. If ulceration will appear hypointense. The signs on MRI consistent with the swelling and rubor dissipate, the diagnosis of a Charcot process is CN include ligamentous disruption, concomitant joint deformity, and supported. If the swelling and rubor persist, an infectious process is the center of signal enhancement within the joints and subchondral likely (24). The acute Charcot foot can mimic cellulites. It is strongly bone. MRI will also show subchondral bone marrow edema. The recommend that the diagnosis of acute Charcot foot be considered for subcutaneous soft tissues will not be much involved. MRI can also any patient with diabetes and unilateral swelling of the lower differentiate CN from transient regional osteoporosis. extremity and/or foot (30). Transient regional osteoporosis has a different anatomic location and does not cause fractures and dislocations, and patients will not Imaging of the Charcot Foot have a clinical history of pain. The signal intensities on MRI might not discriminate between an active Charcot joint and osteomyelitis. Radiographs are the primary initial imaging method for evaluation MRI had a sensitivity of 76.9% and an accuracy of 75% in previous of the foot in diabetic patients. Easily available and inexpensive, they studies (6,33). provide information on bone structure, alignment, and mineraliza- Computed tomography (CT) uses x-rays to generate an image. CT, tion. The radiographic findings can be normal or show subtle fractures although more sensitive than radiography for detecting osteomyelitis, and dislocations or later will show more overt fractures and sublux- can still fail to detect osteomyelitis in the early stage of disease. ations (Fig. 7). In later stages, the calcaneal inclination angle will be Additionally, CT might not be able to distinguish neuropathic osteo- reduced and the talo–first metatarsal angle will be broken. However, arthropathy from the sequelae of chronic infection. Contrast- the radiographic changes of CN are typically delayed and have low enhanced CT can detect soft tissue and osseous abscess formation. sensitivity. The radiologic features of CN are the same, irrespective of The discovery of an abscess can alter the clinical management, the etiology and distribution. Early stage radiographic findings will because the treatment of abscess is typically surgical debridement. CT include persistent or progressive joint effusion, narrowing of the joint lacks sensitivity for differentiating the changes associated with space, soft tissue calcification, minimal subluxation, osteopenia, and infection, edema, fibrosis, and granulation tissue. The risk of iodinated bone fragmentation. contrast in diabetic patients might not be trivial, because chronic In the late stage, radiographs will show destruction of the articular renal insufficiency is commonly a comorbidity in patients with surfaces, subchondral sclerosis, osteophytosis, intra-articular loose diabetes (34). bodies (bag of bones), subluxation, Lisfranc fracture or dislocation Nuclear medicine includes a number of examinations that use of the midtarsal bones, and rapid bone resorption demonstrating radioisotopic tracers. Three-phase bone scans, based on technetium- pencil-in-a-cup deformity. 99m, are highly sensitive for active bone pathologic features. The radiographic features found in the severe form of neuropathic However, diminished circulation can result in false-negative findings, arthropathy are pathognomonic. Fracture, subluxation, and joint and, perhaps more importantly, uptake is not specific for osteo- disorganization can be more profound in this disorder. However, the arthropathy. The role of radioisotopic studies has also been to detect osteomyelitis in a neuropathic joint. Three-phase phosphate scintig- raphy has a high sensitivity (85%) but a low specificity (55%) because of bone remodeling from other causes. Studies using uptake of the gallium-67 citrate have had a high false-positive rate. Scanning using indium-111–labeled leukocytes has had the greatest sensitivity (87%) and specificity (81%) for detecting osteomyelitis in the neuropathic foot. Labeled white blood cell scanning (using indium-111 or technetium-99m) can provide improved specificity for infection in the setting of neuropathic bone changes (6,35); however, it can be diffi- cult to differentiate soft tissue from bone. Therefore, this examination should be combined with a 3-phase bone scan or sulfur colloid marrow examination when superimposed osteomyelitis is suspected (6,36). More recently, positron emission tomography has been recognized as having the potential for the diagnosis of infection and differentiating the Charcot foot from osteomyelitis (6,37,38). However, its use remains investigational at present. The role of positron emission tomography with fluorodeoxyglucose is promising. In Fig. 7. Radiograph showing destroyed fore, mid, and hind foot in patient with Charcot diabetic patients in the setting of a concomitant foot ulcer, neuroarthropathy. fluorodeoxyglucose-positron emission tomography accurately rules  A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 745 out osteomyelitis, with 100% sensitivity and 93.8% accuracy in the including loss of proprioception and postural hypotension. Nonethe- diagnosis of Charcot foot (39). less, total immobility also has disadvantages, including a loss of The evaluation of bone mass density (BMD) can be useful in those muscle tone, a reduction in bone density, and reduced muscle tone with diabetes to assess the onset of CN, as well as the fracture risk. The and strength. BMD can be assessed using dual-energy x-ray absorptiometry or The duration of offloading should be guided by the clinical calcaneal ultrasound. The BMD has been related to the pathologic assessment of healing of CN according to the presence of edema, pattern of CN, such that joint dislocation is more prevalent in those erythema, and skin temperature changes (41,44). Evidence of healing with normal mineralization and fracture is more prevalent in those on radiographs or, if required, MRI or nuclear scans, will strengthen with a diminished BMD (6,40). the clinical decision to transition the patient to footwear. To prevent In a patient with low clinical suspicion of osteomyelitis and no sign recurrence, ulceration, or subsequent deformities after an acute or of CN on the radiographs, either a 3-phase bone scan or noncontrast active episode has resolved, the patient should be prescribed diabetic MRI can be very effective at excluding osseous disease. If the patient footwear with a custom molded Plastazote insole, or a Charcot has ulceration, with a high likelihood of deep infection, MRI is the best restraint orthotic walker. Frequent monitoring, once every 12 weeks diagnostic modality. Nonetheless, 1 test might not be adequate for or so, is required. a full evaluation. In the setting in which the MRI findings are indeterminate, a subsequent labeled white blood cell scan can provide Bisphosphonates more specificity and should be correlated with the clinical findings. The decision of nuclear imaging versus MRI has largely been Bisphosphonates have sometimes been advised owing to the high determined by personal preference, availability, and local experience. bone turnover in patients with active CN. Both oral and intravenous In general, if metal is present in the foot, nuclear medicine bisphosphonates (45) have been studied in the treatment of CN in examinations are preferred, but diffuse or regional ischemia will small, randomized, double-blind, controlled trials (14,46) or retro- mean MRI is the preferred examination (6). spective, controlled studies (47). Some patients cannot tolerate oral bisphosphonates but can benefit from intravenous therapy using Medical Management pamidronate or zoledronic acid (48). Bisphosphonates help by reducing osteoclastic resorption and increasing the osteoblastic The most important aspect in the medical treatment of CN is redeposition of bone. Intranasal calcitonin is another antiresorptive to offload the foot and prevent additional foot and ankle fractures agent that has been studied for CN. Calcitonin has a safer profile for and deformities (41). Increasing bone redeposition and reducing those with renal failure than bisphosphonate therapy (49–52). additional resorption of bone should also be considered. However, a single dose of intravenous bisphosphonate generally does not require renal adjustment. To date, no conclusive evidence is Offloading available for using bisphosphonates to treat the active Charcot foot. The effect of bisphosphonates has been reported to last for about 6 Offloading at the acute active stage of the Charcot foot is the most months after administration, with a repeat course administered if important management strategy and can arrest the progression to required. More trials are currently underway. deformity. Total offloading with graduated compression with an elastocrepe bandage should be applied for the initial 5 to 7 days, until Bone Growth Stimulation the edema, redness, and pain have subsided. Then, for hindfoot CN involving the ankle and/or the calcaneum, a nonwalking or an Limited evidence is available for the use of external bone stimu- irremovable total contact cast (TCC) should be applied. The patient lation in the treatment of CN. Ultrasonic bone stimulation was should ambulate in a “walker” if possible. If not, a wheelchair is reported for the treatment of CN of the ankle and to promote the advised. The patient and caregivers should be informed of the care of healing of fresh fractures. Direct current electrical bone growth the TCC. The patient should be examined as an outpatient every 3 to stimulators have been used specifically in patients with CN under- 4 weeks to determine the progress of the condition and search for any going arthrodesis and was clinically tested to promote healing of maceration or ulceration of the skin. Dorsoplantar, lateral, and oblique fractures in the acute phase of CN in small case series. Its use has radiographs of the foot and ankle can be taken to determine whether been supported only as adjunct therapy during the postoperative signs of progression of the condition and bony union are present. In period (51–55). the case of midfoot and/or forefoot CN, a walking fiberglass TCC In brief, offloading the foot and immobilization with a graduated should be provided (42,43). The advantage is that the patient can compression elastocrepe bandage to reduce edema should be the perform limited ambulation and the TCC can be removed at night mainstay of conservative therapy for CN. These help in bony consol- before going to bed. The foot can then be inspected for any abnor- idation and prevents additional destruction. To date, little evidence is malities, and proper foot care performed. However, good patient available to guide the use of the available pharmacologic therapies to compliance is required. The walking TCC offloads the forefoot and promote the healing of CN. After the active episode has resolved, midfoot by 80%. The pressure will be transferred to the hindfoot. ambulation should be performed with prescription footwear, espe- Hence, the walking TCC must not be used to treat hindfoot Charcot. cially a Plastazote molded custom-made insole. Lifetime surveillance Again, the patient should be examined every 4 weeks as an outpa- is advised to monitor for signs of recurrent or new CN episodes and tient, and the clinical and radiologic findings reviewed to determine other diabetic foot complications. the progression of the condition. Casting should be continued until the swelling has resolved, the temperature of the affected foot is Surgical Reconstruction within 2 C of the contralateral foot, and the radiographs show good bony reunion (44). It is important to remember that use of a TCC can Surgical treatment of Charcot arthropathy has generally been actually have unfavorable consequences on the non-Charcot limb and advised to remove infected bone (osteomyelitis), excise bony promi- induce unnatural stress patterns, causing ulcerations and even frac- nences that cannot be accommodated with therapeutic footwear or tures. Furthermore, patients with CN have an increased instability and custom orthoses, and correct deformities that cannot be successfully risk of falling and fracture as a result of multiple comorbidities, accommodated with therapeutic footwear, custom ankle-foot 746 A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 orthoses, or a Charcot restraint orthotic walker (56). Surgery has also been advised for arthrodesis of destroyed joints of the foot and ankle to provide a functional foot and ankle (57). Several investigators have suggested that Achilles tendon length- ening combined with total contact casting has the potential to decrease the deforming forces at the midfoot and decrease the morbidity associated with CN (58–63). Exostectomy offers the potential to reduce the pressure caused by bony prominences. This treatment has often been combined with accommodative bracing and appears to obtain more favorable results in patients without associated ulcers (64–66). Surgery has generally been avoided during the active inflamma- tory stage because of the perceived risk of wound infection or mechanical failure of fixation. Early correction of the deformity combined with arthrodesis can be performed in selected cases (67,68). Salvage fusion of the foot and ankle presents a unique set of problems to the surgeon. In these cases, the surgeon must frequently manage extensive scar tissue, bone and soft tissue loss, osteopenic bone, and anatomic changes that have occurred since the primary injury or surgery. Although numerous advances have occurred in Fig. 8. External fixator applied after internal fixation in reconstruction of destroyed surgical techniques during the past few years, many of the adapta- Charcot foot. tions have involved the use of internal or external fixation devices to stabilize the bony construct while awaiting consolidation (69). These with or without collapse and provides stabilization and alignment, devices can include screws, blade plates, intramedullary nails, and enhancing the possibility of a functional foot (87). external fixators (69,70). Charcot arthropathy of the ankle is particularly challenging, Most case series have focused on reconstruction of the deformity because resorption of the talar body or significant angular deformity by reduction and arthrodesis using standard methods of internal with or without instability is often present. Several small studies have fixation. However, an extended period of non-weightbearing of about recommended augmented internal fixation followed by prolonged 4 months will be required after surgery to account for the poor bone periods of immobilization and non-weightbearing for neuropathic healing and inherent weakness of the underlying osseous structures patients who sustain acute ankle fractures (88–90). In addition, (71–75). The use of internal fixation and some forms of external a prolonged period is required for complete stable fusion, which can fixation, however, might not be possible or optimal when extensive cause a loosening of fixation as the process evolves. This is especially bone loss, local metabolic dissolution, nonunion, osteopenia, and true once the patient becomes ambulatory, resulting in repeat osteoporosis are present. Studies have shown an overall 56% collapse and deformity in the long term. complication rate and 55% nonunion rate with the use of an external Alternative methods of fixation can be necessary for this group of fixator (76). The combination of poor bone quality and a weak soft patients to provide stability for a prolonged period (69,70,91–96). tissue envelope in a relatively immunocompromised population has Ring fixators can be helpful for such salvage fusions. These ring led many surgeons to use a modification of the external fixation fixators use tensioned, small-diameter wires to achieve the necessary method of Ilizarov to correct the deformity with a limited risk of stability (97). Acute ankle fractures in patients with complicated surgical-associated morbidity (77–82). diabetes have been associated with significantly greater rates of Midfoot Charcot collapse commonly occurs at the tarsometatarsal noninfectious complications and the need for surgical revision and/or midtarsal joints, creating the “rocker-bottom” deformity. compared with diabetic patients without comorbidities (98–102). Intramedullary metatarsal fixation spanning the tarsus into the talus Complications of external fixation are very common, with pin tract and/or calcaneum is 1 method for correcting these deformities (83). infections the most frequent (Fig. 8). Published studies have reported This technique of “beaming” the medial and lateral longitudinal the rate of pin tract infections to be 5% to 100%, with most studies columns has certain advantages. These include proper anatomic reporting a range of 10% to 20% (92,103,104). Most of the patients who realignment, a minimally invasive procedure, multiple joint fusions, joint fixation beyond the level of the collapsed foot bones, rigid fixation, and maintenance of the foot length (84). The goal is to create a stable, plantigrade foot that can be ambulated using prescription diabetic footwear (85). However, these surgical techniques can be quite challenging owing to the bone and tissue changes seen in dia- betic patients. Electron microscopic findings will show increased packing density of collagen fibrils, decreases in fibrillar diameter, and abnormal fibril morphology (86). “Beaming” the longitudinal columns of the foot has previously been described with the use of cannulated screws, which are inherently weaker than solid-core screws. The midfoot fusion bolt offers a technical advantage compared with other forms of fixation in these challenging cases (83). The midfoot fusion bolt is a solid, 6.5-mm, intramedullary implant that can be used to fuse the medial metatarsocuneiform, naviculo- cuneiform, and talonavicular joints. The midfoot fusion bolt can also Fig. 9. Pre- and postoperative radiograph showing polymethyl methacrylate replacement be used to fuse the lateral column, calcaneocuboid, and fourth met- of proximal phalanx of the great toe, which had been destroyed by osteomyelitis. Note the atarsocuboid joint. This can be used in patients with gross instability osteopenic nature of the bones, commonly seen in Charcot foot bones.  A.K. Varma / The Journal of Foot & Ankle Surgery 52 (2013) 740–749 747 toxic level of systemic administration. This has helped us avoid amputation and provide patients with a cosmetically acceptable and functional foot (106). Patient selection is very important before surgery. Only patients who will comply with the postoperative instructions should be given this option of prosthetic replacement. The patient must have sufficient vascularity in the lower limbs, determined by the ankle brachial index (0.9 to 1.2) and transcutaneous partial oxygen pressure (>50 mm Hg pressure), to permit adequate healing of the surgical wounds (106). In conclusion, CN is a limb-threatening destructive process that occurs in patients with sensory, motor, and autonomic neuropathy associated with medical diseases such as diabetes mellitus (3). All physicians treating diabetic patients should be vigilant in recognizing the early signs of an acute process such as unexplained pain, warmth, edema, or pathologic fracture in a neuropathic foot. Early detection and prompt treatment can prevent joint and osseous destruction, which can result in morbidity and high-level amputation (27,29). Prompt immobilization and offloading are indispensible. Patients with CN in the quiescent stage with significant deformity are at high risk of amputation and should be referred to an appropriate center for treatment. The diagnosis begins at the physician level, with monitoring of the protective sensation in diabetic patients and a strong suspicion of an acute Charcot process when the patient presents with the classic signs (30). Treatment must then be determined on an individual patient basis, in particular, whether the patient can be treated conservatively or will require surgical intervention when entering the chronic phase. A firm understanding of the etiopathogenesis, diagnostic modalities, and treatment protocols must be achieved by both the clinician and the patient to obtain success. If diagnosed early, medical and conservative measures will usually suffice in this regard. Surgery has most often been reserved for those patients with severe or unstable deformities that, if untreated, will result in major amputations, which should be prevented whenever possible (56,57). This is because, when walking, even with the best of prosthesis, the mortality at 5 years after Fig. 10. (A) Preoperative computed tomography scan and (B) postoperative radiograph of a unilateral below the knee amputation has been 50%, and the polymethyl methacrylate replacement of destroyed hind-foot bones destroyed by Charcot neuroarthropathy. mortality after above the knee amputation at 3 years has been 50% for diabetic patients using a lower limb prosthesis (107). In diabetes mellitus, the target organ involved is the blood vessels. It thus affects all organs. Once the blood supply to the foot has been compromised by peripheral obstructive vascular disease, cardiac compromise will have undergone foot and ankle reconstruction have been severely have occurred. Even with the best of prosthesis, the cardiac strain will osteopenic. In these cases, compression screws or even threaded be increased to greater than 15%, leading to cardiac failure, the reason Kirschner wires will not hold well, with the risk of repeat collapse for the high mortality rates for diabetic patients using a prosthesis very high. after major amputations. About one half of amputees will develop To overcome this complication and the problems associated with a serious lesion on the contralateral limb within 2 years (108). A team external fixation, we have developed an alternative technique of foot approach is recommended to prevent patients with these high-risk and ankle stabilization after internal fixation, termed the “Amrita foot deformities from experiencing limb loss. sling technique” (105). 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