Diabetic neuropathic arthropathy - Charcot neuropathic arthropathy (CNA): a case report
By
Sarah MacLeod, Saint James School of Medicine Anguilla Campus
Preceptor:
Daniel Ivankovich M.D., Orthopedic Surgeon
Westlake Hospital, Orthopedics
Abstract
Charcot neuropathic arthropathy (CNA) is a complication of long-standing diabetes mellitus associated with significant morbidity and mortality. It is often difficult to differentiate CNA from osteomyelitis, making it a true diagnostic challenge. Unfortunately, there are no universally agreed-upon diagnostic imaging guidelines, and traditional imaging typically used to evaluate the diabetic foot is of limited value. Because the most important prognostic factor is early and accurate diagnosis and treatment, we must explore other diagnostic imaging modalities. We presented a case of CNA complicated by osteomyelitis, in whom diagnosis and treatment was delayed, eventually requiring bilateral amputation. The case emphasizes the importance of additional imaging studies in patients with diabetes and osteomyelitis.
Key words: Charcot neuropathic arthropathy, diabetic neuropathic arthropathy, osteomyelitis, diagnosis, diagnostic imaging
Introduction
Charcot neuropathic arthropathy (CNA) was first described in 1868 by Jean-Martin Charcot in the context of tabesdorsalis. Similar findings can be seen in other neurological disorders, (syringomyelia and syphilis, for example) but the most common cause of charcot neuropathic arthropathy today is diabetes mellitus (Renner, Wirth, Osterhoff, BoniBerli, 2016). The pathogenesis of CNA is poorly understood, but there are several theories that have been proposed. These theories involve damage due to sensory loss in the joint, repetitive minor trauma to insensate joints causing fractures and joint destruction, autonomic dysfunction increasing blood supply to limbs leading to bone resorption, and the role of pro-inflammatory cytokines such as tumor necrosis factor α and interleukin-1β causing receptor activator of nuclear factor κb ligand [RANKL], causing maturation of osteoclasts and therefore osteolysis. (MadanPai, 2013).Noguerol et al (2017) concluded that the biomechanical cycle of repetitive trauma, atrophy, and poor healing result in bone fractures, soft-tissue involvement, and eventually in foot deformity, further predisposing these patients with CNA to developing foot ulcers, and a means for bacterial invasion. This provides an explanation as to why CNA and infectious processes such as osteomyelitis often co-exist together with common clinical signs and imaging findings (Noguerol et al, 2017).
The prevalence of this complication of diabetes is difficult to measure both due to a lack of population-based studies, and a lack of consensus on diagnostic criteria. Prevalence has been reported from 0.1% to 8% (MadanPai, 2013). One large study of insulin dependent diabetes mellitus patients by the European Disease Centers reported an overall prevalence of neuropathy of 28%, and a prevalence of CNA to be approximately 1% of all neuropathic patients (Kaynak et al, 2013). True incidence of CNA is difficult to accurately determine due to the fact that reported series are most often from specialty centers frequently treating more severe cases of diabetes, as well as due to the varying criteria for diagnosing CNA between series (Hordon, 2017).
The most common etiology in the development of CNA is repetitive trauma leading to capillary leakage and edema. Additional possible etiologies include osteomyelitis and local surgery of the affected foot,Kaynak et al report a retrospective study of 55 patients with acute CNA presentation, where 4% of patients had had recent surgery as the only etiological factor. The authors also note that obesity is a common predisposing factor, with 2/3 of CNA patients being obese (Kaynak et al, 2013).
CNA is frequently misdiagnosed, especially in the initial stages of the disease, because the characteristic presenting symptoms of CNA resemble other more common diabetic foot pathologies (osteomyelitis, cellulitis and other soft tissue infections). Accurate diagnosis requires high degree of clinical suspicion for CNA. There are several approaches to treatment and management of this disease, however there are no current, widely accepted evidence-based guidelines for diagnosis or treatment.
Although CNA typically does not present with ulceration, it can coexist with ulceration, and ulceration and infection can also be a result of foot deformity associated with late disease. (Hordon, 2017). Because of the clinical similarities between CNA and other disorders, such as osteomyelitis, the diagnosis is missed or delayed in up to 25% of cases (Kaynak et al, 2013). One study reported by Womack showed 19 out of 24 patients (80%) with CNA were initially misdiagnosed (Womack, 2017).
In cases of CNA complicated even by a well-managed infection, morbidity and mortality rates can exceed 35% (Womack, 2017).
Long term CNA is associated with patient reported diminished quality of life, poor mobility, increased mortality and greater treatment costs (Petrova & Edmonds, 2017). Petrova & Edmonds reviewed 15 published reports of 301 patients and found 11 reports of death in a 2.5 year follow up, 20 reports of partial or complete lower extremity amputation, and 83 reports of mobility limitations (2017). The authors also noted that treatment costs of diabetic patients with CNA to be 17.2% greater than that of diabetic patients with peripheral neuropathy alone (Petrova & Edmonds, 2017).
There are no universally agreed upon criteria for diagnosis of CNA, however one study noted by MadanPai (2013) reported that a delay in diagnosis of up to eight weeks may lead to a more rapid progression and an increased complication rate. One of the most important prognostic factors in ensuring good outcomes is early presentation and diagnosis, and rapid offloading of the foot (Hordon, 2017). Earlier detection leads to better long-term outcomes with fewer complications, and conditions that must be excluded in the differential diagnoses include cellulitis, osteomyelitis, septic arthritis, gout, osteoarthritis, and inflammatory arthritis (Hordon, 2017). One of the more devastating complications of long term CNA is amputation, and the risk of lower extremity amputation is 12x higher in patients with CNA complicated by ulceration compared with CNA without ulcerations (Petrova & Edmonds, 2017).
The case of a 60 years old African American man with bilateral Charcot neuropathic arthropathy of the foot and ankle initially managed for osteomyelitis, who presents with advanced diabetic neuropathic arthropathic disease will be discussed.
Case Presentation
A 60 years old African American male from Chicago, Illinois presents to ourorthopedic surgery clinic with complaints of bilateral foot pain. Past medical records available were limited. The patient has a past medical history of non-insulin dependent diabetes mellitus complicated by diabetic neuropathy as well as several severe foot ulcers requiring surgical debridement. His past medical history is also significant for hypertension. Surgical history includes debridement of several infected and poorly healing foot ulcers, bilaterally. Family history is non-contributory. Social history includes previous tobacco use of 1 pack per day for approximately 20 years, quit two years ago.
Prior to referral to our orthopedic surgery clinic the patient reports having bilateral foot pain and swelling for approximately four years. This was initially evaluated with laboratory investigation and plain radiographic imaging which ruled out an infectious etiology. Initial laboratory investigations at that time showed no evidence of leukocytosis and no elevation of markers of inflammation, and radiographic imaging showed only nonspecific findings of edema which was not followed up with further imaging at that time. Deep vein thrombosis was ruled out with Doppler studies reported to be within normal limits. There was no further workup at that time and the patient’s pain was managed with analgesia, however he reports that he continued to have pain and progression of foot swelling, deformity, and difficulty with ambulation. He did not seek further medical advice until he developed bilateral foot ulcerations, approximately 18 months prior to presentation to our clinic.
At that time, he presented again to his primary care provider for management of multiple, bilateral poorly healing foot ulcers, but severe foot deformity consistent with CNA was noted at that time. These deformities were not initially addressed by his primary care provider. The patient was referred to podiatry, diagnosed with and treated for osteomyelitis for twelve consecutive months, including several surgeries for debridement of multiple, bilateral foot ulcers as well as oral and parenteral antibiotic therapy and pain management with tramadol and MS Contin, the patient however reports continued severe pain. Six months into this management, he was officially diagnosed with diabetic neuropathic arthropathy (Charcot neuropathic arthropathy), placed in rigid non-weight bearing casts and referred to our orthopedic clinic for management of CNA and limb salvage.
On admission, the patient reports having bilateral foot pain and swelling for the past four years, and rates the pain today as severe, at 10/10 on a pain scale. On exam, the patient is ambulating with a wheelchair. Bilateral foot exam shows obvious, severe “rocker bottom foot” deformity. The left foot is wrapped with an ACE bandage, and on the right foot the patient has a removable rigid total contact boot cast. Bilateral feet are erythematous and swollen, capillary refill 2 seconds, dorsalispedisartery and posterior tibialisartery pulses are present bilaterally. Range of motion was not assessed at this time due to extreme pain.
Initial early imaging from several years prior to presentation was reviewed, with plain radiographic showing nonspecific findings of edema. Venous Doppler study reports were within normal limits. No further imaging modality was utilized at that time. More recent imaging (from within the last 18 months) was also reviewed, with results suggesting bilateral deformities typical of CNA, as well as ulceration of the skin and adjacent bone changes suggestive of concomitant osteomyelitis. Current MRI imaging suggests further progression of osteomyelitis and CNA, with joint effusion and evidence of cellulitis.
We concluded that the original etiology four years ago was in fact CNA, which was eventually complicated by foot ulcers, cellulitis and osteomyelitis, as a result of the CNA deformities and peripheral diabetic neuropathy. We suspect that the progression of CNA and complications of this disease process may have been prevented by early and accurate diagnosis. Unfortunately, due to the extent of the CNA-related joint deformity at the time of presentation to the orthopedic surgery clinic as well as the complications of poorly healing ulcers, osteomyelitis and cellulitis, this patient has been scheduled for bilateral amputation.
Discussion
Our patient presented to the orthopedic surgery clinic with extensive, bilateral foot pain, swelling and deformity consistent with CNA, complicated by multiple non-healing foot ulcers and osteomyelitis. Differentiating CNA from osteomyelitis in the foot of a diabetic patient can be a diagnostic challenge, but this case was especially complicated due to late and atypical presentation.Based on the history provided by the patient, this case involved bilateral lower extremities, and seemed to have an insidious onset, and was severely painful. This is inconsistent with the typical presentation of CNA, which is usually a sudden onset and painless arthropathy. However, there are cases reported that presented with progressive swelling and, in one series, pain was reported in 76% of cases (Hordon, 2017).
CNA may present as an acute or chronic condition, with peripheral neuropathy as a prerequisite. Typical presentation includes erythema, calor, swelling, and pain over the joint, with intact skin findings. CNA can affect any weight bearing joint, although it most commonly affects the foot and ankle, with the mid-foot being the most frequently affected part of the joint. Vascular supply is typically preserved and the patient may present with bounding peripheral pulses (MadenPai, 2013). In addition to history, physical examination, and laboratory findings, early diagnosis is usually based on the characteristic symptomsof CNA (erythema, redness, swelling) and radiographic imaging findings that rule out other possible diagnoses (fracture, osteomyelitis). As several diseases (including cellulitis, osteomyelitis, septic arthritis, gout, osteomyelitis, and inflammatory arthritis) have similar findings, a high level of clinical suspicion of a CNA is important for diagnosis. CNA may be misdiagnosed as infectious processes, as in this case.
In contrast to CNA, osteomyelitis in diabetic patients typically presents with a gradual onset of symptoms including pain at the affected area, tenderness, warmth, erythema and swelling, as well as systemic symptoms such as fever or rigors. On exam there is often an infected pedal ulcer that can be probed to bone. Laboratory investigation in osteomyelitis may demonstrate leukocytosis, and potentially elevated levels of inflammatory markers (erythrocyte sedimentation rate and/or C-reactive protein). Blood cultures may also be positive. (Lalani, 2018) Plain radiographic imaging will show findings typical of osteomyelitis, for example, periosteal reaction or elevation and loss of cortex with bony erosion; however, plain radiography itself only has 50% to 60% accuracy in differentiating osteomyelitis from CNA, and findings may not be present until several weeks after onset of clinical symptoms (Womack, 2017).
The diagnostic imaging modalities that have been historically used to evaluate the diabetic foot (plain radiography, ultrasonography, and computed tomography) are no longer considered most useful. Studies have shown limited sensitivity dueto their suboptimal assessment of soft-tissue and bone edema patterns. (Noguerol et al, 2017). While bone marrow edema is a common, nonspecific finding of both disease processes, combining the clinical correlation with the specific patterns of bone marrow edema may yield a more accurate diagnosis.
Because of its high contrast resolution, magnetic resonance (MRI) imaging has been shown to be useful to evaluate patterns of involvement and characteristics of bone and soft tissue.MRI may be a better modality for differentiating between neuropathic arthropathy and osteomyelitis, especially early in the disease process (Noguerol et al, 2017).MRI imaging has a high sensitivity and specificity (90% and 79%, respectively) for diagnosing osteomyelitis. (Noguerol et al, 2017). In CNA, bone marrow edema is found in periarticular areas of the midfoot (tarsometatarsal or metatarsophalangeal joints), and is often associated with subchondral cysts and intra-articular bodies, often referred to the “ghost sign”, are not found in osteomyelitis. Soft tissue(synovial diverticulae or adventitial bursae)involvement in CNA can be difficult to distinguish from abscess. In contrast, osteomyelitis is near the skin surface, and the bone marrow edema pattern of this disease is more evident in weight-bearing areas (tarsometatarsal joints, toes and calcaneous), and soft tissue involvement in osteomyelitis is more severe and includes skin ulcers, sinus tracts and abscesses.
Diabetic foot evaluation with MRI has typically been based on morphologic sequence protocols, however utilization of newer MRI technology such as the Chemical Shift and Dixon imaging, diffusion-weighted imaging (DWI) and dynamic contrast material-enhanced (DCE) have shown promising utility in the evaluation of the diabetic foot, specifically with regards to differentiation between CNA and osteomyelitis (Noguerol et al, 2017).
Chemical Shift and Dixon imaging are fat-suppression sequences that differentiate water signals from fat signals located in the same area to accurately differentiate bone marrow edema or hematopoietic marrow from lesions replacing bone marrow such as tumor or infection, and early data supports the use of these modalities for improved detection of osteomyelitis of the foot (Noguerol et al, 2017). Diffusion weighted imaging (DWI) evaluates free water movement in tissues at a microscopic level, estimating cell membrane integrity. It is useful in the diabetic foot for more detailed evaluation of the patterns of soft tissue and bone edema (Nogueorl et al, 2017). Finally, DCE MRI uses high resolution 3D images obtained at 3-5 second intervals (versus 12-20 seconds in conventional MRI) to evaluate tissue perfusion and microvasculature and has been shown useful to differentiate between necrosis and viable tissue in the setting of the diabetic foot (Noguerol et al, 2017).
MRI imaging, specifically the newer techniques and protocols certainly appears to have future potential in improving outcomes in diagnosis of the diabetic foot, with an overall sensitivity and specificity of 76% and 75% respectively. However, Womack reports results of a recent meta-analysis sensitivity and specificity of 90% and 79%, respectively, and suggests that MRI imaging may not be superior to nuclear imaging scans (Womack, 2017). Nuclear imaging used for diagnosing bone infections may be useful for diagnosing osteomyelitis may be used to differentiate from CNA and include 3-phase bone scintigraphy which have a sensitivity of 80-100%, but poor specificity, for identifying bone infections, and labelled leukocyte scans, which are similarly sensitive, but more specific. Three-phase bone scintigraphy is not reliable to differentiate between CNA and osteomyelitis because of high bone remodelling in both disease processes. Of the labelled leukocyte scans, Technetium MDP scans label hydroxyapatite and may not be useful to differentiate infectious processes from traumatic processes (such as CNA) due to the high bone turnover. Indium scans localize inflammatory processes mediated by neutrophils, does not accumulate in areas of high bone turnover (such as in a fracture or CNA) and will be positive in osteomyelitis while negative in uncomplicated CNA (Womack, 2017). The recommendation for differentiating between both disease processes using nuclear imaging is PET & SPECT which showed a sensitivity and specificity of 100% and 93% (Womack, 2017).
Conclusions and recommendations
Early diagnosis and treatment with weight offloading is the key to reducing complications, morbidity and mortality of CNA. It is important that primary care physicians continue to perform regular foot exams on diabetic patients to evaluate for peripheral neuropathy, and to continue to educate their diabetic patients on the importance of regular foot care. We emphasize the importance of recognizing the limitations of plain radiography in evaluating a diabetic foot, specifically the difficulty with differentiating osteomyelitis from CNA, and the need for early utilization of more advanced imaging modalities to obtain an early and accurate diagnosis. Moving forward, it is important for us to develop standard diagnostic imaging guidelines for evaluation of the diabetic foot. An area of future research that would be most useful is population studies to evaluate the potential impact of early utilization of MRI imaging, including the newer techniques and protocols, as well as studies to evaluatethe use of nuclear imaging, and analysis comparing the two.
Conflict of Interest
The authors describe no conflict of interest arising out of the publication of this manuscript.
Consent
The patient has given his consent for this report to be published.