This article will attempt to outline processes that clinicians can use to diagnose CN when it is in its early stage and future consideration for diagnoses targets.

Charcot neuropathic osteoarthropathy can be missed by 95 % of providers prior to foot specialist referral [4]. Because Endocrinology uniquely situates the physician with many patient encounters involving patients with diabetes mellitus, it is critical for the specialty to be well aware of the signs and symptoms of Stage 0 CN. Stage 0 CN, a prodromal state of the disease, occurs when a foot demonstrates changes including redness, swelling, warmth, and pain, signs typically representing inflammation, in the neuropathic patient. These signs and symptoms are antecedent to foot architecture breakdown, seen in the later stages of CN. One of the most widely used CN classification system was proposed by Eichenholtz [5]. Stage 1 represents development, characterized by osseous debris, fragmentation, disruption, and dislocation seen of involved joints. In Stage 2, also known as the stage of coalescence, sclerosis, absorption of fine debris, and fusion of most large osseous fragments is seen. Lastly, in stage 3, the reconstruction and reconstitution stage, sclerosis becomes less, the major fragments are rounded and there is attempt at reformation of joint architecture [5]. Unfortunately, this classification system did not attempt to describe the prodromal phase and misses the earliest inflammatory phase.

Conducting a search in PubMed/NCBI, Google Scholar, and Cochrane Databases for Stage 0 CN symptoms reveals a paucity of published studies on the specific subject. Shibata [6], and later Sella [7], were the first to describe changes associated with Stage 0 CN in leprotic and diabetic patients, respectively. As far as we are aware, no paper describes the methodology to accurately diagnose Stage 0 CN patients and refer to a foot specialist. This lack of discussion about Stage 0 CN gives reason to present up to date information about CN to those most likely to encounter the Stage 0 CN patient. We also stress that CN needs to be included in the differential diagnosis for neuropathic patients that present with newly onset red, hot, swollen foot because if it not, it often goes misdiagnosed [8–11]. In this review article, we will further define stage 0 and give the practicing endocrinologist pragmatic tools to appropriately identify CN and refer to a foot specialist for further management.

Charcot neuropathic osteoarthropathy increases the affected patient’s risk of foot ulcer by more than 30-fold, with 63 % of persons with Charcot foot eventually developing foot ulcer [2]. Using Medicare data Wrobel and Mayfield demonstrated that diabetes increases the risk of major amputation by 10-fold [22]. According to Sohn et al. 2010, the risk of amputation in those patients with Charcot foot is 6.6 % in the community, and more than double in VA patients at 14.7 %. However, when Charcot Foot occurs with foot ulcer, the patient is at a 12-fold higher risk of amputation than patients with Charcot alone [23]. Charcot Foot has also been described to be an independent risk factor for mortality after controlling for foot ulcer and other comorbid conditions [2].

Rogers and Bevilacqua describe an amputation classification risk scheme illustrating how as Charcot deformity, ulceration and osteomyelitis approach the proximal foot and ankle, amputation risk increases [24] (Table 4).

A combined anatomic and complexity classification of Charcot neuroarthropathy

Adapted from Rogers and Belivqua [60]. Using both an anatomic model combined with level of complexity, it is clearly demonstrated that as one progresses both proximal (to the right on the graph) in anatomic location and/or toward osseous involvement (down on the graph), the risk of major amputation increases

Frequent misdiagnosis has been reported with conditions such as cellulitis, gout, deep-vein thrombosis (DVT), osteomyelitis [9], or even osteoarthritis [8]. Clinicians must have a high index of suspension for neuropathic patients presenting with Charcot stage 0. The addition of Charcot foot to their list of differential diagnosis for patients with the classic red, hot, swollen foot may help decrease the number of missed cases. It is important to note that patients frequently present with varying degrees of swelling, warmth and redness. Minor trauma should not be dismissed. Charcot Foot may also be preceded by events of foot surgery in 22 % of cases [10] and injuries such as ankle sprains [11].

Charcot neuropathic osteoarthropathy typically affects the midfoot. Several authors have described the anatomic location is associated with CN. One of the most recognized classification is the Sanders classification which it clearly highlights the midfoot as the most targeted area for Charcot development [25–27] (Fig. 2). It has been hypothesized that limited ankle joint range of motion coupled with neuropathy and obesity may predispose the mid-foot for breakdown.

1. C.

   Temperature Gradient and Other Clinical Signs

    

It is also important to remember that in circumstances where a biopsy can be performed that may be beneficial to differentiate between other disease processes such as osteomyelitis. In patients with a normal joint, the articular cartilage is smooth, chondrocytes line up in regular rolls and subchondral cancellous bone is intact. In joints affected by CN there are degenerating fibrillary remains of cartilage, absence of cartilage, and fibro osseous tissue [36]. La Fontaine et al. characterized the CN bone further [37]. These authors illustrate that CN bone histology has characteristics of reactive bone with presence of woven bone that was immature and structurally disorganized. Further the bone marrow spaces were infiltrated with hypervascular, myxoid tissue with spindle fibroblasts with an increase in the number of Howship’s lacunae and a decreased number of osteocytes. This was less than that observed in both the normal and DM groups of the study [37] (Fig. 3).

1. F.

   Imaging Modalities used to diagnose Charcot

    

Utilization of radiographs alone to determine the onset of Charcot foot is not advised. We suggest that clinicians utilize clinical judgment and consider other modalities in addition to radiographs to diagnose CN in its earliest stage. Radiographs should be performed to scrutinize later stages of CN where fragmentation, fracturing, dislocations and effusions of joints exist. A MRI is superior to a radiograph to diagnose CN Stage 0. We recognize that there are instances where clinical judgment supersedes the need for a MRI. There are also circumstances where MRI may not be the most cost-effective or patient friendly based on other disease states such as a diminished kidney function. However, MRI can detect bone marrow edema and is therefore far more sensitive and specific then a radiograph in the detection of Charcot earliest stage.

Bone scanning can be a useful tool in differentiation of Charcot neuropathic osteoarthropathy with and without osteomyelitis. It however must be used with caution because leukocyte labeled scintigraphy does not always demonstrate changes where bony turnover is occurring. Poor sensitivity is often attributable to chronicity of infection, while poor specificity is attributable to nonspecific inflammatory changes [39]. It must be stated that in the earliest stages of Charcot, many polymorphonuclear cells (PMNs) are present with acute inflammation [40]. The scans are therefore useful early to the astute physician and can demonstrate changes in tissue activity in a day as compared to 10–14 days with standard radiographs. With the development and addition of several tags to the leukocyte and regardless of the exact understanding of the mechanism why labeled leukocytes accumulate in the uninfected Charcot neuropathic joint [41, 42] bone scanning can continue to be a useful non-invasive imaging modality to differentiate between the diagnosis of Charcot neuropathic osteoarthropathy and osteomyelitis.

Historically, ⁹⁹technetium-MDP, gallium-67 citrate, and indium-111 played a role in the differentiation between soft tissue infection and osseous infection [43]. Gallium was used because it has high affinity toward inflammatory processes but lacked affinity for osteoblastic activity. Indium had a longer half-life than gallium and had greater specificity for infection because it depended on leukocyte chemotaxis. However, these early scintigraphy agents were not without fault because they had low specificity and were effectively useless to differentiate certain conditions [44]. Hexamethylptopyleneamine oxime (HMPAO or Ceretec) is commonly used today to differentiate osteomyelitis from Charcot joint. Traditionally, the HMPAO labeled leukocytes are injected into the subject and a three phase bone scan is performed at intervals as described as blood flow, blood pool, and bony turnover stages as discussed by Thakur et al [45]. Once the scan has been completed, the images are inspected at each stage for activity in the affected area. If there is positive activity at each stage, then the cellular activity is consistent with osteomyelitis. In 2001, Boc et al. demonstrated that while HMPAO was the most reliable non-invasive imaging study that could be done for differentiating osteomyelitis from Charcot foot changes, it was second to bone biopsy because false positives do occur [46]. More recently, Morbach et al. demonstrated MRI rather than plantar bone scintigraphy was superior for detection of chronic osteomyelitis with sensitivity of MRI at 100 % and for bone scintigraphy at 78.4 % [47].

The basis for the addition of sulfur colloid to a technetium bone scan lies in that both sulfur colloid and leukocytes have an affinity toward cellular activity in the bone marrow. Accordingly, this should be done in concert with another labeled leukocyte scan, but it is described as being done one hour after completion of the three phase bone scan [44]. Leukocytes are attracted to areas of infection and sulfur colloid is not [48]. More important is that similar patterns are demonstrated on image comparison between healthy individuals and those with abnormalities when using the sulfur colloid scan. When a patient has osteomyelitis, there is a localized increase in leukocyte uptake observed along with suppression of sulfur colloid [49]. By utilizing this inherent advantage, when there is an edematous foot with a question of infection or a Charcot event, the addition of sulfur colloid to a technetium bone scan can aide in the differentiation.

The ADA consensus report performed by Rogers and associates [3] illustrate an algorithm for diagnosis of CN. Their algorithm clearly outlines the clinician starting with a clinical suspicion of CN and navigating through x-rays, MRI or other nuclear imaging based on the patient’s clinical findings, diagnostic results followed by the response to treatment.

The pathogenesis of Charcot neuropathic osteoarthropathy (CN) is multifactorial and not entirely determined. Neuropathy, inflammation, obesity, and hyperglycemia all play major roles in CN development and progression. Peripheral neuropathy includes sensory, motor, autonomic, and neurogenic peptide dysregulation [51]. As a result, the patient does not necessarily perceive traumatic events that could lead to areas of increase pressure and potential sites of breakdown [52, 53]. This perpetuates the inflammatory cycle, leading to a vicious cycle that intimately affects bony turnover [54].

The bony turnover is also regulated by hyperglycemia which is shown to increase advanced glycation end products (AGEs). AGEs lead to an increase in receptor for AGEs (RAGE). The increase in RAGE leads to an increase in RANK-L which promotes osteoclastogenesis [15]. Finally, newer evidence demonstrates the CN joint itself is lacking sympathetic control and may allow for increase perfusion to the area [18]. This may also disturb the bony turnover ratio leading to weakened demineralized bone (Fig. 4).