Charcot Neuropathic Osteoarthropathy

Etiology

Charcot neuropathic osteoarthropathy is seen in the lower extremity and is characterized by bone and joint fragmentation of the foot and ankle in individuals with various peripheral neuropathies. Diabetes, neuropathy, trauma, and metabolic abnormalities of the bone result in an acute localized inflammatory condition. The inflammatory response can permanently disrupt the bony architecture of the foot resulting in abnormal plantar pressures that are at risk for ulceration, osteomyelitis, and amputation.[4][5][6][7]

Charcot is a debilitating condition affecting the lower extremity of patients with established peripheral neuropathy caused by many complicated etiologies; however, diabetic neuropathy has become the most common etiology.  Other etiologies include spinal cord injury, poliomyelitis, leprosy, syphilis, syringomyelia, or chronic alcoholism. 

Epidemiology

It has been reported that Charcot affects between 0.1% to 0.9% of people with diabetes. [8] [9] An estimated 63% of patients with Charcot neuropathic osteoarthropathy will develop a foot ulceration. McEwen et al. found a significant association between elevated body mass index and Charcot arthropathy.[10]

Pathophysiology

There are two commonly accepted theories used to describe the pathogenesis of Charcot: neuro-traumatic and neurovascular. The neuro-traumatic theory proposes neuropathy, and repeated micro-trauma produces joint destruction. The neurovascular theory suggests the increased peripheral blood flow results in osteolysis and demineralization.

Pathophysiologically, key inflammatory markers have been identified that contribute to the development of an acute Charcot foot. Calcitonin gene-related peptide (CGRP) acts typically at the nerve terminal to antagonist the synthesis of nuclear factor-kB ligand (RANKL), a cytokine involved in the inflammatory process. However, in the neuropathic foot, the CGRP is not functioning, and therefore RANKL is synthesized without inhibition. RANKL is a very important marker in the development of Charcot as it is responsible for the proliferation of osteoclastogenesis. The RANKL osteoclastic relationship is normally moderated by osteoprotegerin (OPG) by acting as a decoy receptor to RANKL binding. In the Charcot foot, this relationship between RANKL and OPG is disrupted. The unregulated synthesis of RANKL accounts for the excessive bony turnover and accumulation that is seen in the Charcot limb. Additionally, CGRP may have a further role in Charcot in that it is involved in upholding the integrity of the joint capsule.  Therefore, in its absence, it is presumed to lead to joint destruction and dislocation that is characteristic of the Charcot foot.

Histopathology

Histologically, specimens will appear similar to degenerative joint disease including ghost chondrocytes, subchondral cysts, sclerotic bone, fragmented and irregular cartilage thinning. [11] Histology and bone biopsies are important to differentiate acute Charcot joint versus osteomyelitis. Histologically, features of osteomyelitis include plasma cells, lymphocytes, and neutrophils with reactive new bone formation and bone necrosis. Capillary fibrosis and proliferation may also be present. [12]

History and Physical

High suspicion for Charcot needs to be present to diagnose the condition accurately. Charcot presents as an erythematous foot with edema and calor. Often, it is unilateral with a sudden onset of symptoms that may be precipitated by macro-trauma (ankle sprain) or repetitive micro-trauma (walking). Charcot may be initially misdiagnosed as a deep venous thrombosis or cellulitis. Charcot can also be confused with osteomyelitis due to the similar clinical appearance of a red, hot swollen foot with skeletal lysis on radiographs and often unilateral presentation.  Although distinct and separate processes, these entities can occur simultaneously. Additionally, there is evidence that osteomyelitis can cause Charcot. This is due to the inflammatory cascade of cytokine release osteomyelitis triggers in the body.  This risk of osteomyelitis evolving into Charcot is further escalated if surgical intervention was performed to remove the infected bone.  This is because both osteomyelitis and surgery are forms of trauma that promote an inflammatory response which triggers the opportunity for Charcot to manifest.

In addition to the trauma caused by surgery, the changes to the bony architecture of the foot post-surgery can also lead to inflammatory triggering events due to biomechanical and gait alterations in plantar pressures. For example, amputations and other surgical interventions of the foot can lead to altered pressure points for which the foot is unable to compensate. These changes in plantar pressure, even if mild, can cause microtrauma which initiates the inflammatory events that lead to an acute Charcot.[13][14][15][16]

Evaluation

Stages of Charcot

Common classifications that map the phases of Charcot include the Eichenholtz classification and the Sanders and Frykberg classification.  Eichenholtz classifications describe the three stages of disease progression based on clinical and radiographic findings. The Sanders/Frykberg classification is used to type and class the five common anatomical locations of Charcot in the foot.

Eichenholtz [17]

Stage 0 Pre-Charcot/Prodromal

• Clinically: red, hot, swollen foot. No deformity.
• Radiographically: no changes yet are seen. Normal radiograph

Stage I Development/Destruction

• Clinically: Erythema, foot edema, elevated temperature, no pain
• Radiographically: Boney debris at joints, fragmentation of subchondral bone, joint subluxation, and/or fracture-dislocation

Stage II Coalescence

• Clinically: Decreased signs of inflammation
• Radiographically: Worsening of stage 1 features.  Absorption of boney debris with new bone formation. Coalescence of large fragments with sclerosis of bone ends.  Some increased stability

Stage III Consolidation

• Clinically:  Resolution of inflammation.  Changes in overall foot architecture due to underlying final bony remodeling that can lead to new pressure points which are at risk of ulceration
• Radiographically: Remodeling of affected bones and joints

Sanders and Frykberg [18]

1. Metatarsophalangeal to interphalangeal joints: 15%
2. Tarsometatarsal joints: 40%
3. Naviculocuneiform joint, navicular-cuneiform, talonavicular and calcaneocuboid joints: 30%
4. Ankle and subtalar joints: 10%
5. Calcaneus: 5%

Treatment / Management

Treatments of Charcot aim to decrease permanent foot deformity and ultimately allow for a stable and plantigrade foot that is stable and suitable for ambulation. In the acute phase, it is imperative to immobilize the foot and restrict weight bearing to prevent permanent deformity. Non-operatively, this is achieved through off weight-bearing via total non-weight bearing or protective weight-bearing devices. Assistive devices such as crutches and wheelchairs can aid with non-weight bearing. Total contact casts (TCC) with a controlled ankle motion (CAM) walker can provide protected weight-bearing. TCC redistribute and reduce pressures on the plantar foot while allowing ambulation. The hyperemic phase of the Eichenholtz classification can last for weeks. By using these types of protective measures, the foot may heal the fractures in a stable position if the stress does not exceed the rate of healing.

Pharmacological treatments also exist to control the osteoclastic activity including bisphosphonates and calcitonin supplements.  Bisphosphonates may help the acute phase of Charcot as they inhibit osteoclastic reabsorption. Calcitonin also serves as an antiresorptive agent. Alternative agents include pamidronate or zoledronic acid which act on new hydroxyapatite crystal by blocking osteoclast precursors in the newly formed bone matrix.

Surgery is also a treatment option and it remains controversial if one should intervene in the acute or chronic Charcot phase. During the acute phase, there is a firestorm of inflammatory modulators and cytokines (tumor necrosis factor-alpha, interleukin 1, and interleukin 6) that promote edema and bone resorption/fragmentation. [19] The main rationale behind Charcot reconstruction is surgical off-loading to prevent ulceration and deformity progression. A surgeon can achieve this goal via multiple techniques including exostectomy, tenotomy, isolated, or multiple fusions with external and/or internal fixation. Due to softer bone, surgeons tend to "double-up" on hardware to create a solid "super-construct" to prevent breakdown. Minimally invasive intramedullary techniques are also used based on surgeon experience.

Medical optimization including smoking cessation, HbA1c control under 7-8%, and recognizing micro or macro-vascular disease can lessen potential complications post-operatively. [20](B2)

Differential Diagnosis

The most important differential diagnosis of Charcot is osteomyelitis as both can appear clinically and radiographically similar. Cellulitis, septic arthritis, gout, pseudogout, foot/ankle sprain or fracture, and deep vein thrombosis are also important differentials. Charcot is misdiagnosed 25% of the time which can cause a 7-month delay in the true diagnosis.[6][21]

Pertinent Studies and Ongoing Trials

Currently, there are 7 ongoing trials, including:

1. Investigating the Use of Prolia (Denosumab) in the Treatment of Acute Charcot Neuroarthropathy
2. Characterization of the Charcot Foot
3. Characterizing and Diagnosis's of the Charcot Foot (Charcot Osteoarthropathy) in Diabetic Patients
4. Efficacy of Teriparatide in Diabetic Inactive Charcot Neuroarthropathy of Foot
5. Assessment of Surgical Correction of Deformity in Diabetic Charcot Arthropathy of the Foot and Ankle
6. Zoledronic Acid or Methylprednisolone for Active Charcot's Neuroarthropathy of Foot in Patients With Diabetes Mellitus
7. Genetic Contribution to the Pathophysiology of the Charcot Foot in Qatari Patients With Diabetes

Treatment Planning

Diagnostic imaging including initial radiographs is key to making and confirming a clinically suspected Charcot foot. [22] Serial foot or ankle radiographs are then used to monitor the disease progression through the Eichenholtz stages. Surgically, a CT may be warranted to visualize the extent of the bone destruction for pre-operative planning. When trying to differentiate Charcot versus osteomyelitis, labeled white blood cell nuclear imaging has high sensitivity and specificity. [23]

Prognosis

It has been shown that the resolution time of acute Charcot to progress through all stages around 8 months. [24] [25][26]  In a study by Jansen et. al., 67% of Charcot patients developed complications such as ulcerations.  Additionally, non-adherence to the treatment was noted to significantly worsen the prognosis.

Complications

• Foot deformities such as flatfoot, rocker-bottom foot, hammertoes, ankle equinus contracture.
• Boney prominences which can lead to ulceration, infection, and in some cases loss of limb (amputation) or life.
• Recurrence of Charcot joint
• From the first diagnosis of acute Charcot, the 5-year mortality rate is 13%, which is similar to diabetics without Charcot. [24]