Treating Charcot Neuro-Osteoarthropathy in the Wound Care Clinic

Charcot neuroarthropathy is a progressive, destructive disease affecting patients who live with diabetes and peripheral neuropathy. Characterized by acute fractures, dislocations, and joint destruction in the weight-bearing neuropathic foot, it often presents in the acute phase as misdiagnosed gout or infection and can rapidly lead to severe deformity, ulceration, and amputation.   

Named after and described by French neurologist Jean-Martin Charcot (commonly known as the “founder of modern neurology”) in 1868 for a condition he noted among patients being treated for tabes dorsalis, Charcot neuroarthropathy’s true prevalence is unknown due to the high incidence of mistaken or delayed diagnosis. The literature reports that diagnosis of Charcot is missed in as many as 79% of cases and an accurate diagnosis can be delayed up to 29 weeks.¹

This article will discuss causes, symptoms, appropriate diagnosis, differences between acute and chronic occurrences, and treatment modalities.

EPIDEMIOLOGY & PREVALENCE
Diabetic peripheral neuropathy is regarded as the most common cause of Charcot neuroarthropathy in the Westernized country.² There are certainly less-common causes such as leprosy, poliomyelitis, syringomyelia, alcohol abuse, traumatic injury, heavy metal poisoning, multiple sclerosis, congenital neuropathy, and rheumatoid arthritis.³

Population-based studies have reported an estimated prevalence of 0.4-13% in the diabetic population,⁴ but can be increased up to 10% when X-ray findings are used.⁵ Incident rates range from 3.0-11.7 per 1,000 patients per year. Patients who have undergone amputation of the first toe will have up to 24% increased frequency of developing Charcot.⁶ Incidence of bilateral involvement can vary from 9-75%.⁷ Diabetic Charcot almost exclusively affects the foot and ankle, but other locations can present in extremely rare cases. It commonly presents in the midfoot, but can occur in the forefoot and the hindfoot.⁸ There has not been a predilection between men and women, and the difference is negligible.  Patients affected are usually ages 50-60, and 80% have been diagnosed at least 10 years prior.⁹ Type 1 diabetes will cause Charcot foot at or after age 50 while type 2 patients can be more prone to development of Charcot at or after age 60. Moreover, longer duration of diabetes was reported among those living with type 1 as compared to type 2.¹⁰

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PREDISPOSING FACTORS & PATHOGENESIS
There are several predisposing factors, but peripheral neuropathy seems to be most prevalent. Charcot can also be seen in patients experiencing autonomic neuropathy. Most of these patients will have normal circulation. Osteopenia is likely in type 1 diabetes, but not in type 2 diabetes.¹¹ Trauma, often minor, including foot deformities, joint infections, or surgery, can also predispose one to the development of Charcot changes.¹² Also, renal impairment, with a medical history of renal transplantation, is associated with high risk¹³ while trauma has been reported in 22-53% of these cases.¹⁴ 

Peripheral sensory neuropathy is an important component for the onset of acute Charcot with no reported cases developing in its absence. The mechanism is very complicated, with angiopathy and hyperglycemia-induced metabolic changes playing the major role. Long-term hyperglycemia causes metabolic disorders that then lead to the activation of additional growth metabolism pathways, in particular activation of the polyol pathway.¹⁵ In this pathway, several changes can be seen that lead to the accumulation of sorbitol in the cells of nervous tissue. Sorbitol is then an intermediate product, a glucose-fructose conversion. This reaction is catalyzed by aldose reductase. We find glucose is then reduced to sorbitol, and then sorbitol is oxidized to fructose. In hyperglycemia, this is intensified and leads to the accumulation of sorbitol and axons, followed by cellular water influx, swelling, Schwann cell damage, and apoptosis.^16,17 Chronic hyperglycemia also leads to vascular damage. Elevated sugar levels can lead to epithelial cell dysfunction, which results in a decrease of proangiogenic signaling. This then can lead to decreased production of nitrous oxide.¹⁸ Nitrous oxide causes relaxation of vascular smooth muscle that is necessary to ameliorate vasoconstrictor properties that chronic inflammation induces. Its absence will decrease the vasodilatory capability of these arterial vessels, therefore impairing blood supply to the nerves.¹⁹ 

Certainly, there are other pathways that lead to severe vascular damage, those being advanced glycosylation end product production, oxidative stress, protein kinase C, isoglycerol pathway, and hexosamine pathway. These pathways also result in the regeneration of reactive toxic metabolites, which then lead to the activation of cell-signaling molecules such as protein kinase C, mitogen-activated protein kinases, nuclear factor kappa beta, etc. This then leads to altered gene expression of VEGF, PDGF, ET-1, TGF-beta, etc., which can lead to altered protein function such as Na+/K+-ATPase, and NADPH oxidase, etc. 

All these pathways will then lead to significant cellular dysfunction and damage that includes abnormal angiogenesis, abnormal blood flow, base-of-membrane thickening, contractility dysfunction, hyperpermeability, excessive apoptosis, increased matrix accumulation, severe inflammation, and increased leucocyte adhesion.

CLINICAL PRESENTATION &DIAGNOSIS
Charcot should always be suspected in any patient living with diabetes and peripheral neuropathy who presents with a red, hot, swollen foot. The absence of pain and the diffuse redness may help differentiate this condition from cellulitis or deep vein thrombosis (DVT).²⁰ Milne et al offer an effective evidence-based clinical pathway for acute Charcot that’s divided into four key phases: 1) assessment, 2) investigations, 3) diagnosis, and 4) management in Figure 1. Unfortunately, some areas pertaining to these phases of management are devoid of quality research. In these instances low-level evidence, such as expert opinion, has been utilized.

In the acute Charcot presentation, we see a warm, erythematous, edematous ankle that usually occurs most often through the midfoot. Pain is not typically a factor and it may be difficult for patients to recall an inciting traumatic event to cause occurrence. When pain is reported, it is usually less than what is anticipated. We will find that the skin temperature is elevated by 2-6° C compared to the contralateral foot. Hyperemia may persist for weeks or months and, in some cases, the acute phase rapidly progresses to chronic Charcot, sometimes less than six months.^21-24 Temperature will decline in chronic cases. Erythema declines as well, and permanent deformities may develop as a result of the coalescing. Arch collapse may occur, resulting in rocker bottom and medial convexity of the foot. This will lead to elevated plantar pressures and, ultimately, ulcerations that may become infected and result in osteomyelitis.²⁵ The natural course of Charcot can be, and is most often, self-limiting because Charcot practically will never reactivate, but may later affect the contralateral foot. We find the long-term survival of patients with Charcot is diminished even after successful treatment. This is attributable to chronic inflammation — the link between endothelial dysfunction and insulin resistance that is going to engender and dysregulate metabolism and eventuates in clinical vascular disease. Reduced survival is also due to morbidity associated with distal symmetrical neuropathy.^26-29 

Clinical presentations of a red, hot, swollen, painless foot in patients living with diabetic neuropathy should prompt diagnosis until proven otherwise.^30,31 Plain X-rays may initially be negative from a few days up to 3-4 weeks. The only finding in the acute Charcot may be soft tissue swelling.³²

Atrophic X-ray changes: 

• bony reabsorption
• little fragmentation

Hypertrophic X-ray changes:

• bony proliferation

• destruction of joints

• fragmentation

• new bone formation³³

• osteophytes, subchondral sclerosis, narrowing of joint spaces³⁴

Forefoot changes: 

• demineralization

• bone destruction

• periosteal reaction

• pencil-and-cup deformity at metatarsal phalangeal joint or fragmentation of metatarsal heads³⁵

Midfoot changes:

• Lisfranc fracture dislocation

• fragmentation of tarsal metatarsal joint

• collapse of longitudinal arch³⁶

Hindfoot changes:

• talocalcaneal dislocation

• talar collapse

• atypical calcaneal fractures

There is an array of findings that can be seen, but the earliest findings in Charcot joints are going to be focal demineralization followed by flattening of the metatarsal (often the first sign of Charcot changes).³⁷ Plain X-rays have very little sensitivity and specificity in fewer than 50% of cases.³⁸ CT scan has no potential role in acute Charcot because it cannot detect bone marrow edema or microfracturing.³⁹

MRI is the most sensitive modality in the detection of early Charcot arthropathy changes. Acute findings will include soft tissue edema, Lisfranc ligament disruption, joint effusions, and subchondral bone marrow edema of the involved joints.⁴⁰ When we look at the changes of bone marrow edema on MRI, we start to see low-signal intensity on the T2 series of delineations. Extensions of edema throughout the medullary bone are also present and this predominates in the subchondral region on gadolinium enhancement.⁴¹ Fractures will contribute to the signal changes as evidenced by microtrabecular fracturing and bone bruising.

CHRONIC CHARCOT & DIFFERENTIAL DIAGNOSES
A lack of warmth and redness will indicate chronic Charcot. Edema may also persist, but can be waning at this point. Skin temperatures that are < 2° C lower than in the contralateral side, are typical. MRI will reveal edema and enhancement becoming less prominent. Subchondral cysts may also appear.⁴⁴ At this point we also start to see what could be infection (eg, cellulitis, osteomyelitis), which can be ruled out when there is no presence or history of foot ulceration. The chronic stage is best characterized by the rule of the “6 D’s” as noted by Lederman et al:⁴⁵

1. joint distension

2. joint destruction

3. dislocation

4. disorganization

5. debris

6. increased bone density.

When the limb is elevated the limb, infection does not change color (always red), whereas acute Charcot will turn pale upon elevation.⁴⁶ Therefore, elevation remains a reliable test to distinguish infection from this chronic inflammation as it is the elevational pallor that we see in acute Charcot. As a rule, patients living with acute Charcot only exhibit local signs of inflammation (increased skin temperature) without systemic signs and symptoms.⁴⁷

Potential DVT, acute gout, neuropathic/traumatic fractures, sprain, and inflammatory arthritis must be ruled out. Retrospective studies that have been reported show 80% of acute Charcot cases were initially misdiagnosed as having a sprain (N=11), DVT (N=3), osteomyelitis (N=4), tumor (N=3), cellulitis (N=6), and rheumatoid arthritis (N=2).⁴⁸ Therefore, the wound care clinician must have a high clinical index of suspicion for acute Charcot in these particular instances, as the result of misdiagnosis can be quite devastating.

TREATMENT & THERAPY RECCOMENDATIONS

Offloading with TCC

Even when diagnosis is “suspected,” immediate immobilization and offloading is the wisest practice.⁴⁹ Total contact casting (TCC) is the “gold standard” to offload and immobilize. If any neuropathic joint is suspected, immediately immobilize the patient to prevent potential collapsing and fracture. TCC should be replaced in three days and checked according to the clinician’s discretion. (This author aims for at least twice per week.) The TCC should be changed frequently to avoid pistoning, as the edema will subside. Frequently, there may be a compression bandage that is placed underneath the cast to reduce local pathologic edema. It is imperative to continue casting until the edema has subsided and the temperatures are then within 2° C of the contralateral foot.

There are instances where patients may be more amenable to instant TCC, particularly in those who develop Charcot in the driving foot, in those who have significant balance issues, and in those with claustrophobic concerns. The downside of initial TCC is that patients may remove these very easily. Be sure to maintain inspection of the non-Charcot limb, as patients will be placing more pressure on that side. Assess during each clinic visit and consider a custom-molded shoe or diabetic shoe on the non-Charcot limb.

In general, Charcot causes increased risk of falling and fractures as a result of multiple comorbidities including loss of proprioception and postural hypotension. Duration and aggressiveness of offloading should be guided by clinical assessment of edema, erythema, and changes in skin temperature. Once evidence of healing on X-rays and MRI strengthens the clinical decision, transition the patient to a custom-molded shoe, ankle-foot orthosis, or CROW walker.

All patients will require long-term (perhaps lifelong) offloading due to risk of reoccurrence or occurrence on the contralateral side. Severe deformity increases plantar pressures and the risk for ulcerations. Reoccurrence of this deformity could be significant if metabolic control is lost. Assessment of patients must be diligent and often. For any clinical suspicion that arises, providers should place the patient in some type of rigid immobilization. 

Antiresorptive Therapy

Proposed because bone turnover is excessive in patients with active Charcot.⁵⁰ Currently there are conflicting reports on specific uses. Systematic reviews of clinical trials have indicated bisphosphonates are ineffective and may even be harmful to the resolution time of the acute phase of Charcot.⁵¹ In contrast, other studies at the same level of evidence have supported their use, suggesting that bisphosphonates may improve resolution time of the acute phase by reducing skin temperature and disease activity.⁵²

In acute cases, this author utilizes intranasal calcitonin, (Miacalcin nasal spray), which is synthesized in the thyroid medullary cells and mainly affects osteoclastic activity through inhibition of cytoplasm motility, secretory activity, and reduction in the number of osteoclasts.⁵³ There currently is inconclusive evidence to guide the use of this therapy, but this author utilizes the spray for its capabilities in reducing osteoplastic activation, reabsorption, and inflammation. 

Bem et al performed a randomized controlled trial with intranasal calcitonin and oral calcium versus oral calcium alone in 32 diabetic patients living with acute Charcot in 2006. Treatment with calcitonin was associated with significantly greater reduction in C-reactive protein levels during the first three months. Bone-specific alkaline phosphatase levels were significantly decreased at three months compared to the control group. Skin temperature of the foot was also reduced and the nasal spray has the significant advantage to use in patients experiencing abnormal renal functions, as this has to be monitored in those using bisphosphonates with renal impairment. Therefore, it is recommended that bisphosphonates be used at the discretion of the treating clinician for acute Charcot because the evidence is inconclusive at this time, but trials are currently underway.

Bone-Growth Simulators

There is limited evidence for usage, but conducted studies have validated utilization as an adjunct therapy. This author maintains use of stimulators both during the acute stage and at the time of surgical fusions because diabetic bone marrow is very poor to heal due to being very soft. Additionally, there is decreased mobilization of stem cells from the bone marrow due to microangiopathy, neuropathy, stem cell rare fraction, and excess fat deposition in the diabetic population.

Protective Weight-Bearing

Required after an active episode has coalesced and quieted. Utilizing some type of custom-molded shoe with rocker bottom, ankle foot orthosis, or CROW walker is recommended.

Surgical Treatment

Primarily based on expert opinion; however, those who benefit most from surgery tend to be those patients who are recalcitrant to bracing, have tried custom CROW walker or patellar tracking orthosis brace and custom-molded shoes, and who continue to see breakdown. There is low-quality evidence and certainly no randomized controlled trials have been performed to perpetrate which surgical treatment works best for each specific type of Charcot, but the time to refer to an experienced surgeon is when bracing is no longer an option or the foot/ankle becomes unstable. Remember: A vascular study should be conducted before any surgery on any patient living with diabetes is scheduled. Surgical treatment generally has been advised for resection of infected bone, removing bony prominences that could not be accommodated in orthotic shoewear, or correcting significant deformities that could not be accommodated with therapeutic footwear, custom ankle-foot orthoses, or CROW walkers.⁵⁴

Several investigators have recommended that Achilles lengthening combined with TCC decreases the deforming forces at the midfoot and decreases morbidity associated with Charcot.⁵⁵ Through ostectomy this procedure offers the potential to reduce pressures caused by bony prominences. Surgery is generally avoided during active inflammatory stages because, due to risk of infection, mechanical failure of this fixation can be very high due to the porotic nature of the bone. Due to poor bone quality, expert opinion has advised an extended period of non-weight-bearing after surgery because of poor bone healing and inherent weaknesses of these osseous structures.⁵⁶ This author advises patients to be casted after surgical correction of acute Charcot in the diabetic population twice as long as would be done in the nondiabetic population because of poor bone-healing capabilities due to reduced numbers of cytokines, chemokines, growth factors, and extracellular matrix proteins. The concept of “super construct,” in which internal fixation is utilized to extend beyond the zone of fusion, has evolved to address the issues of poor bone quality.⁵⁷ Therefore, the recommendations for surgical treatment are beneficial in Charcot cases refractory to offloading and immobilization or the case of recalcitrant ulcerations. The initial management of acute neuropathic fractures and dislocations should not differ from other fractures. Exostectomy is useful in relieving bony pressures that cannot be accommodated with orthotics or prosthetic means. Lengthening of the Achilles or gastrocnemius tendon can reduce forefoot pressure and approve alignment of the ankle, hindfoot, and forefoot, as well as reduce reoccurrence of ulceration. Arthrodesis can also be useful in patients experiencing instability, pain, or recurrent ulcerations that fail non-operative treatment, despite a high rate of incomplete bony union or pseudarthrosis. In severe ankle Charcot, surgical management could be considered primary treatment.⁵⁸

Matthew Regulski is medical director of the Wound Institute of New Jersey.

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