ABSTRACT

Diabetic foot ulcers (DFU) are associated with significant impairment of quality of life, increased morbidity and mortality, and are a huge drain on health care resources. In Western countries, the annual incidence of foot ulceration in the diabetic population is around 2%. DFUs develop as a consequence of a combination of factors, most commonly peripheral neuropathy (loss of the gift of pain), peripheral arterial disease (PAD), and some form of unperceived trauma. Recent studies emphasize the very high prevalence of foot ulceration in people with diabetes on dialysis as a consequence of end-stage renal disease. The mortality in this patient group is higher than for most forms of cancer. All patients with diabetes should have an annual screen to identify their foot ulcer risk status: those with any risk factors require specific foot care education as well as regular contact with a health care professional, usually a podiatrist. DFUs should heal if there is an adequate arterial inflow, infection is aggressively managed, and pressure is removed from the wound and its margins. In the management of plantar neuropathic ulcers, offloading is critical and all efforts must be made to enhance patient understanding of the need for offloading. Antibiotic usage should be guided by clinical signs of infection and microbiologic analysis of deep tissue specimens: evidence now exists to show that oral antibiotics are equally efficacious as intravenous in treating most cases of osteomyelitis in the diabetic foot. Most adjunctive therapies have little evidence to support their use although recent trials suggest efficacy for a number of topical therapies including LeucoPatch (3C patch) and sucrose octasulphate; and negative pressure wound therapy has also been shown to be helpful in certain cases. There is currently no indication for hyperbaric oxygen usage, whereas recent studies suggest that topical oxygen therapies help wound healing. Charcot neuroarthropathy (CN) should be easily preventable: most important is to treat any neuropathic patient with a warm swollen foot as having CN until proven otherwise. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

At the beginning of the 21^st Century, diabetic foot problems, although eminently preventable, represent one of the commonest causes of hospital inpatient admission in Western countries. In 2005, the International Diabetes Federation realized the global importance of diabetic foot disease and chose to focus their campaign during the whole year on raising awareness with a worldwide campaign to “put feet first” and highlight the common problem of amputation amongst diabetic patients throughout the world. To coincide with World Diabetes Day 2005 (November 14, birth date of Frederick Banting), the Lancet elected to dedicate a whole issue to diabetic foot problems (1).

In this chapter, the global term “diabetic foot” refers to the variety of pathological conditions that might affect the feet in patients with diabetes. Foot ulcers are defined as lesions involving a skin break with loss of epithelium: they can extend into the dermis and deeper layers sometimes involving bone and muscle. Amputation is defined as “the removal of a terminal, non-viable portion of the limb”. The lifetime risk of a person with diabetes developing a foot ulcer (DFU) has been estimated to be as high as 34% (2).

The suffering of affected individuals and the cost of DFUs are both equally staggering. Those individuals with DFUs usually have other complications of diabetes including nephropathy: data from the UK and the USA confirmed that the outlook for those people with foot complications who are on dialysis is very poor with a high mortality risk (1-3). Data from our group confirm that those people with diabetes who have had an amputation and who are on dialysis have a 75% two-year mortality; the majority of these were of cardiovascular etiology. Data such as these are worse than most malignant diseases, with the possible exception of lung and pancreas. There is therefore an urgent need for preventative strategies to reduce the incidence of foot complications amongst those with diabetes. With respect to costs, in 2008 Rogers et al (4) reported that in the US $18 billion was spent on the care of DFUs and US $11.7 billion on lower extremity amputations. More recently, data from the UK in 2019 suggest that a conservative estimate of the annual cost of diabetic foot problems exceeds UK £900 million which represents approximately 1% of the total budget of the National Health Service (5).

The importance of regular diabetic foot care in very high-risk patients is emphasized by an observational study from Arizona where the State decided to remove routine podiatry from high-risk patients to reduce their health budget. This led to an annual saving of US $351,000 but the cost of this action measured by increased hospitalization, length of stay, and amputations was $16.7 million (6).

This chapter will include a discussion on the epidemiology of foot problems including foot ulceration, amputations, and Charcot neuroarthropathy (CN). The etiopathogenesis will then be described and aspects of management of neuropathic, neuroischemic, and infected DFUs considered. The question of how to address primary and secondary prevention of diabetic foot problems will then be discussed followed by a section on Charcot neuroarthropathy. For more detailed discussion, the reader is referred to review articles on these topics (2,7-9).

EPIDEMIOLOGY OF THE DIABETIC FOOT

The study of the epidemiology of diabetic foot disease has been beset by numerous problems relating to both diagnostic tests used, and population selected. However, there is little doubt that foot complications are common. In the UK, the North West Diabetes Foot Care Study (a community-based study of over 15,000 people) reported that the annual incidence of foot problems amongst the population with diabetes was just under 2% (10), with similar results having been reported from the Netherlands. Similarly, when discussing amputations, the figures vary widely again due to diagnostic criteria as well as regional differences. It must be remembered that many individuals at diagnosis of type 2 diabetes have significant neuropathy: in the United Kingdom Prospective Diabetes Study, for example, 13% of patients at diagnosis had neuropathy of sufficient severity to put them at risk for foot ulceration (7).

With respect to ethnicity, studies from the UK suggest that foot ulcers and amputations appear to be less common in Asians of Indian sub-continental origin and Afro-Caribbean men. In contrast, reports from the USA suggest that amputation rates are more common amongst African-Americans with diabetes than amongst white Americans. Similarly, ulceration is much more common in Hispanic Americans and native Americans than in non-Hispanic whites (2). More recently, reviews have confirmed the importance of healthcare inequities in diabetic foot disease: race, ethnicity, socioeconomic status, and geography are powerful mediators of risk for DFU and lower-extremity amputation (2,11).

ETIOPATHOGENESIS OF DIABETIC FOOT ULCERATION

The foot does not break down spontaneously and in this section, the many warning signs that the feet are at risk of breakdown will be discussed. This was recognized by Elliott Joslin almost 90 years ago when he stated that “diabetic gangrene is not heaven-sent but is earth-borne” (12). It was previously believed that neuropathy, vascular disease, and infection were the main causes of ulceration: it is now recognized that infection occurs as a consequence of ulceration, and is not a cause thereof. There are many contributory factors to foot ulceration, the most important of which are diabetic neuropathy and peripheral arterial disease (PAD). These and other causative factors are listed in table 1.

THE PATHWAY TO FOOT ULCERATION IN DIABETES

As discussed and outlined in Figure 1, the pathway to ulceration is indeed complex and involves an interaction of numerous factors. Whereas none of the factors listed in the last section will alone result in ulceration, it is the interaction and combination of risk factors working together that leads to skin breakdown. In the prospective study of Reiber et al, 63% of all foot ulcers resulted from a combination of neuropathy, deformity, and trauma: in Western countries, the commonest cause of trauma is ill-fitting footwear (17). It must be remembered that as those with neuropathy have reduced sensory input, they will commonly be unable to feel the fit of a shoe until the pressure from the shoe is quite high. Thus, people with neuropathy frequently choose shoes that are too small. All such individuals should be advised to have their feet measured prior to the purchase of any “off the shelf” footwear.

Other simple examples of two risk factors working together in the pathway to ulceration are neuropathy and mechanical trauma (a common scenario is a neuropathic individual with a foreign body in the shoe), neuropathy and thermal trauma (holidays are particularly dangerous), and neuropathy and chemical trauma (such as inappropriate use of over-the-counter chemical corn treatments which should never be used in those with neuropathy).

In summary, whereas neuropathy was present in four out of five cases of new foot ulcers in the Reiber study (17), as noted above, the combination of neuropathy and ischemia is becoming more common in Western countries, and neuro-ischemic ulcers are the commonest type seen in 2023 in diabetic foot clinics.

FOOT ULCERATION

DFUs are common, associated with much morbidity and even mortality but should be eminently preventable. It used to be believed that diabetic foot ulcers were difficult to heal: this is not true: a foot ulcer will heal if it is permitted to do so and this requires attention to three factors-

A That there is adequate arterial inflow to the foot.

B That any infection is appropriately and aggressively managed.

C That all pressure is removed from the wound and its margins.

Figure 1.

Pathways to Diabetic Foot Ulceration.

Despite increased knowledge of the pathogenesis and treatment of diabetic foot ulcers in recent years, it is still the third point, offloading the wound, that is poorly adhered to by health care professionals. Many forget that those with a neuropathic or neuroischemic ulcer have “lost the gift of pain”. That pain is a gift which is only realized when it is lost, as first described by Dr Paul Brand when studying leprosy (28). However, before going into more detail on management, it is important to classify wounds appropriately in order to guide therapeutic management.

CLASSIFICATION OF DIABETIC FOOT WOUNDS

Accurate and concise ulcer description and classification systems are required to improve multidisciplinary collaboration and communication, as well as for aiding treatment choices. For many years, the Meggitt-Wagner grading system was regarded as the gold standard. One problem with this system is that the ischemic status of the wound is not included. Thus, a number of new classification systems for diabetic foot wounds have been proposed and validated over the last 20 years. A commonly used system in the United States is the University of Texas Wound Classification System (29). This incorporates the Meggitt-Wagner grades but also enables the practitioner to stage the wound with respect to the presence or absence of infection and/or ischemia (Figure 2). In a comparative prospective study across two Centers, one in the UK and one in the US, the University of Texas Classification System was shown to be superior to the Meggitt-Wagner system at predicting outcomes (30). However, this study also showed that the traditional Meggitt-Wagner system was itself generally accurate in predicting outcomes.

Most recently, the WIFI (Wound Ischemia, Foot Infection) classification was introduced and is the most commonly used today in the USA, particularly in vascular clinics. This was developed and validated as a method to assess three variables – the wound, level of ischemia and the presence and severity of foot infection – to predict the risk of amputation (Figure 3)

Figure 2.

The University of Texas Wound Classification System.

Figure 3.

WIFI system. Wound, Ischemia, and Foot Infection (WIfI) Classification of Limb Threating diabetic foot disease, tissue loss, ischemia, and infection frequently overlap. However, one is frequently more dominant than the other at different times in the life cycle of an acute-on-chronic event. Here, the amount of tissue loss, ischemia, and foot infection can be ordinally graded to help predict outcome and assist in communicating a plan of action. ^aA higher score on the WIfI scale is associated with lower extremity amputation and morbidity and can be used to determine the need for revascularization. WIfI scores of 1, 2, 3, and 4 were associated with 1-year amputation rates of 0%, 8%, 11%, and 38%, respectively. Figure from JAMA 2023 Jul 3;330(1):62-75 with permission.

EVALUATION OF THE DIABETIC FOOT ULCER

Clinical evaluation of the foot wound should include a detailed description of the site, size, and depth of the wound. The neuropathic and vascular status of the wound should then be assessed (for details see below). In general, neuropathic ulcers typically occur in the warm but insensate foot, often under pressure bearing areas, and are surrounded by callus. In contrast, ischemic wounds tend to occur in the cool, poorly perfused foot, and are often at lateral fifth metatarsal head regions or the medial first metatarsal head regions. In a predominantly ischemic wound, callus tissue is uncommon. In a neuroischemic wound, the morphology will depend upon the predominance of each of these two pathologies. The correct identification of the degree of ischemia is of the utmost importance when evaluating a wound. If the foot is cool with impalpable pulses, then non-invasive Doppler ultrasound studies are indicated. Conventional methods of assessing tissue perfusion in the peripheral circulation may not be entirely reliable in patients with diabetes. For example, the Ankle Brachial Pressure Index, which is routinely used to screen for PAD in individuals without diabetes, may well be falsely elevated in the those with diabetes because of medial arterial calcification. Toe pressure indices may therefore be more reliable.

Role of Plain X-Ray in Diagnosing Osteomyelitis

The plain radiograph remains the commonest first radiological investigation of an acutely presenting diabetic foot problem. Despite this, it may be dismissed because of relatively low sensitivity for acute osteomyelitis, with literature over the last 10 years concentrating on CT scanning, MR scanning, and nuclear medicine studies (particularly Gallium Citrate, labelled leucocyte scans and recently PET, PET-CT, SPECT-CT and PET-MR). These latter studies are of limited availability and are expensive, and some carry a high radiation burden. They have their own sensitivity and specificity problems and may not be available in a timely manner. The initial sensitivity of the plain radiograph for acute osteomyelitis is improved by serial studies at one to two-week intervals, during which time therapy for presumed osteomyelitis may be instigated for clinical reasons and whilst awaiting the results of further “high tech” imaging (if still required). The plain radiographic findings could then be considered of high sensitivity and specificity, but with a two-week lag, both for diagnosis and for response to treatment. Appropriate clinical information for the reporting radiologist must include that the patient is diabetic, whether the foot is neuropathic, whether an ulcer is present and if so, its precise anatomical location, and whether it probes to bone. The radiologist should be aware that most sites of acute osteomyelitis in the diabetic foot occur in the floor of an ulcer that probes to bone and that if the foot is neuropathic there may be acute fractures without a history of trauma or acute Charcot neuroarthropathy may be present.

Whilst periosteal reaction is an early feature of osteomyelitis, it is not commonly seen around the small bones of the foot, and if present, is most often seen around metatarsals, and may be due to fracture rather than osteomyelitis.

The hallmark plain radiographic feature of osteomyelitis in the diabetic foot is focal loss of bone density, almost invariably adjacent to the floor of an ulcer. Whilst sometimes described as bone destruction, it is initially bone de-mineralization that causes this appearance, which can reverse on successful treatment, with radiographic re-appearance of the apparently destroyed bone (Figure 4). Obtaining the radiographic view most likely to demonstrate the bone in the floor of an ulcer is therefore an important consideration, often overlooked now that requests are electronic and radiographic views are selected from limited drop-down menus. For example, toe-tip ulcers and ulcers on the dorsum of the inter-phalangeal joints require lateral toe views - best obtained using dental radiographs if available; the inferior surfaces of metatarsal heads are best demonstrated on sesamoid views; the heel requires both lateral and axial views. As a general rule, radiographs tangential to the bone surface at the site of suspected osteomyelitis are ideal, in addition to the standard radiographs of the region. A dedicated team of radiographers familiar with these requirements will improve the relevance and quality of the resultant radiographs.

Plain radiology remains an important investigation in the diagnosis and management of diabetic foot osteomyelitis, but it needs to be of high quality, with appropriate views, and regularly repeated to fulfil its potential.

Figure 4.

Acute presentation with an ulcer at the tip of the great toe, probing to bone. The terminal phalangeal tuft does show some irregularity (left panel). B) two weeks later there is marked bone demineralization consistent with osteomyelitis (middle panel). C) After 2 months of treatment there has been partial remineralization of the bone but with an underlying pathological fracture (right panel).

MANAGEMENT OF DIABETIC FOOT ULCERS

The principles of management of different types of foot ulcers will be discussed in brief in this section. The University of Texas Wound Classification System (Figure 2) will be used throughout.

CHARCOT NEUROARTHROPATHY (CN)

Charcot neuroarthropathy, although uncommon, is a potentially devastating late complication of diabetic neuropathy (68). Although the exact mechanisms resulting in the development of CN remain unclear, much progress has been made in our understanding of the etiopathogenesis of this disorder over the last two decades. CN occurs in a well-perfused foot with both somatic and autonomic neuropathy: the patient presenting with acute CN tends to be slightly younger than is usual for those presenting with foot ulcers. A history of trauma may be present though may be missed because of the severe sensory loss. Although, in its pathogenesis, there are many unanswered questions, improved understanding in recent years of the role of inflammatory pathways might lead to new pharmacologic approaches in the acute phase of the condition. The outcomes in terms of management of CN have been generally poor because of ignorance that leads to delayed diagnosis.

Most important in the management of this condition is recognition of the acute Charcot foot. Any patient with known neuropathy who presents with a warm, swollen foot of unknown causation should be presumed to have acute CN until proven otherwise. Contrary to earlier reports, many patients may present with painful, difficult to describe symptoms in the affected foot despite significant neuropathy.

In its early stages, all investigations may be normal, including the foot x-ray. The role of the radiologist in the diagnosis of acute and chronic CN is discussed in the next section.

Role of Radiologist in in Diagnosing CN

As with acute osteomyelitis (see above), the initial radiographs in acute CN may appear (almost) normal, though it is common for soft tissue swelling to be present and radiographically visible, usually over the dorsum of the foot. It is consequently imperative that both the clinician and the radiologist are aware of the possibility of this condition being present. The first more specific radiographic feature is bone demineralization, usually subchondral or periarticular, around the joint(s) involved by the acute CN process (in contrast to acute osteomyelitis, where it is related to the ulcer location). Focal peri-articular fractures may then develop (Figure 5). If CN is suspected, despite non-diagnostic initial radiographs, then the options are to treat as acute CN (see below) and perform serial radiographs at one-to-two-week intervals until the diagnosis is confirmed or no longer clinically suspected, or treat similarly whilst arranging urgent radiological investigation with a more sensitive test (whilst repeating the radiographs if the further tests are delayed). CT scanning may show small avulsion fractures around midfoot articulations that are invisible on plain radiographs, with minimal increase in the sensitivity and specificity over the plain radiograph, but MR scanning (to include fat suppressed sequences) is better, demonstrating soft tissue edema, bone marrow edema and/or ligamentous disruption. If the MR scan shows no marrow signal abnormality in the foot, acute CN is unlikely. Where the appearances or clinical presentation are complex, with both osteomyelitis and acute CN being suspected, Indium labelled white cell scans and PET/CT have a role, though both can be false positive for osteomyelitis in the presence of acute CN. In infection, MR may demonstrate soft tissue abscesses or sinus tracks that may extend to the (infected) bone surface.

In chronic inactive CN, plain radiographs demonstrate the features of joint distension, destruction, dislocation, disorganization, debris, increased bone density (sclerosis) and deformity. On MR scanning, marrow edema of acute CN is replaced by low signal from sclerosis of the bone. Acute osteomyelitis superimposed on chronic CN produces a mixed picture requiring careful clinical-radiological review.

Diagnosis of acute Charcot neuroarthropathy remains a synthesis of high clinical awareness, clinical findings and radiological findings. The latter should always include serial plain radiography and, where necessary, MR scans.

An overview of imaging in the Charcot foot is available online (69).

Figure 5.

Acute Charcot neuroarthropathy. There is widening of the interosseous distance between the medial cuneiform and 2^nd metatarsal (arrowheads), indicating disruption of the Lis-Franc ligament and a subtle flake fracture fragment (arrow).

PREVENTION OF FIRST AND RECURRENT ULCERS

Prevention will only be successful with the early identification of those patients who have risk factors for foot ulceration. In the 1990s, the concept of the “annual review” was developed, and all those with diabetes should, at whatever stage, be screened for evidence of complications at least annually. The principle aim of such a review is to identify those with early signs of complications and institute appropriate management to prevent progression. The “Comprehensive Diabetic Foot Examination” (CDFE), was developed by a taskforce of the American Diabetes Association (ADA) that was charged with describing what should be included in the annual review for those at risk of foot complications (16). As noted above, the most important aspect of the annual foot review is the removal of shoes and socks with very careful inspection of both feet including between toes. Many neuropathic feet can be identified by this simple clinical observation, looking for features such as small muscle wasting, clawing of the toes, prominence of the metatarsal heads, distended dorsal foot pains (a sign of sympathetic autonomic neuropathy), dry skin, and callus formation. The key components of the diabetic foot annual examination are displayed in table 2.

The ADA Taskforce recommended that for evidence of neuropathy, that the perception of pressure using the 10g monofilament should be used at four sites in each foot (16). An additional test which might include a vibrating 128 Hz tuning fork or others outlined in table 2 should also be used to confirm any abnormality.

For the vascular assessment, foot pulse palpation is most important. Again, as noted above, the ankle brachial index may be falsely elevated in many people with diabetic neuropathy and therefore listening to the Doppler signal may be more helpful as may be a more detailed non-invasive vascular assessment.

More recently, other simple devices for clinical screening have been described. The simplest of all is the “Ipswich Touch Test” developed by Rayman et al in Ipswich, UK. This test simply assesses the ability of the patient to perceive the touch of a finger on the toes (71). The Vibratip which is a battery-operated disposable vibrating stylus can also be used to assess vibration sensation (72), and this has the advantage of using a forced-choice methodology. Both of these tests have been validated in clinical studies (71, 72).

CONCLUSIONS

Although there has been much progress in our understanding of the etiopathogenesis and management of diabetic foot disorders over the last 30 years, much of what we use in clinical practice today still lacks an evidence-base. This is particularly true for example for dressings. The International Working Group on the Diabetic Foot has reported on the details required in the planning and reporting of intervention studies in the prevention and management of diabetic foot lesions (81). Details of the necessary trial design, conduct, and reporting should be taken into account when assessing published studies on interventions in the diabetic foot. Most important of all however in the management of patients with diabetic foot disorders, is to remember that the patient has frequently lost the “gift of pain” that protects most of us from developing significant foot problems but, when absent, can lead to devastating consequences.

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