Mortality in diabetes patients with and without diabetic foot ulcers (DFU)
Mortality in diabetes patients with and without neuropathic diabetic foot ulcers (nDFU)
Alarmingly, foot ulceration often results in lower extremity amputation, i.e., the loss of the entire foot, and such amputations account for more than half of nontraumatic major (above-the-ankle) amputations in the diabetic population. Prevention of lower extremity amputation is thus the primary goal of diabetes management. There remains the question of whether this goal can be achieved, as data that are relevant to this issue remain elusive. The number of amputations in diabetics appears unchanged during the last decade; however, the rates of amputation vary in different institutions and in different countries [3, 4]. Figure 12.3 summarizes data on the incidence of major amputations in the past and in recent years.
Amputation rates in diabetes patients in the past and in recent years
The amputation rate data might lead one to speculate that the efforts devoted to improving diabetes care have proven ineffective and, therefore, have been useless. This remains a matter of debate for two reasons. First, the average life expectancy of those with diabetes has increased by almost a decade in a single generation in many developed countries. It is well established that neuropathy and arteriopathy, which are the pathogenetic factors that contribute most to the formation of diabetic foot ulcers, become more common with increasing age. Therefore, the number of patients with diabetic foot and, consequently, the number of candidates for amputation are predicted to increase gradually over time. With this in mind, it becomes clearer that preserving the rate of amputation is itself the achievement of an important goal. Second, in order to decrease amputation rates, we need patients to have better access to highly skilled care at medical centers. According to a recent report, the rates of hospitalizations for nontraumatic lower extremity amputations in the USA declined significantly in the diabetic population between 1996 and 2008, while rates among those without diagnosed diabetes changed little  (Fig. 12.4). These findings are particularly notable considering the higher prevalence rates and greater severity of foot disease in diabetic subjects compared with the general population. Moreover, these findings completely differ from results obtained in a previous study .
Reduction in the amputation rate in diabetes patients in the past and in recent years
These data can only be explained by increased awareness of foot problems and increased availability of highly skilled foot care in centers in the USA. Questions remain about care in many other countries. Do these countries have an adequate number of skilled diabetic foot centers? Are all diabetic patients with foot ulcers referred to specialized hospitals? These questions should concern all diabetes associations as well as the national healthcare organization. Undoubtedly, in Italy the approach to amputation prevention in patients with diabetic foot, and particularly the establishment of specialized diabetic foot clinics for comprehensive multidisciplinary foot care programs, is very appreciated by many clinicians, including those who performed the US study cited above . In Italy, the rates of major amputations at multidisciplinary centers dedicated to diabetic foot care have progressively decreased from the beginning of the 1990s into the 2000s. Faglia et al. and Lombardo et al. [8, 9] note that the amputation rate in patients with diabetes in Italy decreased by more than 30 % from 2001 to 2010 as a result of a team approach and improved awareness of diabetes-associated foot problems.
How can this goal be achieved elsewhere? Amputation is the consequence of a nonhealing foot ulcer that causes severe damage to tissues and bone. Thus, the development of effective approaches to preventing and treating diabetic foot ulcers should be the primary goal. The development of standard protocols for comprehensive, multidisciplinary diagnoses and effective treatment is mandatory for improving care (Fig. 12.5). The first step in the management of diabetic foot is to understand the problems associated with diabetic foot.
A diabetic foot care flow chart
The WHO criteria define diabetic foot as “the foot of diabetic patients with ulceration, infection and/or destruction of deep tissue, associated with neurological abnormalities and various degrees of peripheral vascular disease in the lower limb.” After the establishment of this definition, the subsequent two meetings of the Interassociative Working Group of the Italian Association of Diabetologists defined diabetic foot as “the foot with anatomical and functional alterations caused by occlusive peripheral arteriopathy and/or by diabetic neuropathy” (Fig. 12.6). In terms of prevention, this definition includes patients without evident foot lesions who are nonetheless at risk of developing foot ulcers according to established and validated classifications systems.
International consensus on the diabetic foot provided by the IWGDF and the Italian version of the consensus
Diabetic foot develops from complications of diabetic neuropathy of the lower extremities or from complications of occlusive peripheral arteriopathy; in both scenarios, the complications undermine the structural integrity and/or function of the foot. These two conditions, namely, neuropathy and ischemia, differ considerably in terms of their pathophysiology, diagnosis, therapeutic approach, and prognosis. However, the coexistence of both conditions, termed neuroischemic foot, has been reported in many diabetic patients, especially in the elderly population. Infection of foot ulcerations is one of the most common and serious complications leading to amputation in patients with diabetes.
12.3 Clinical Features of Diabetic Foot
Neuropathy usually results in a insensitive deformed foot. A neuropathic foot is warm and well perfused with palpable pedal pulses; the skin is usually dyschromic. Figure 12.7 shows images of some neuropathic feet. Bilaterality of the neuropathy is a classic characteristic independent of the presence or absence of an ulcer (Fig. 12.8).
The typical appearance of neuropathic foot in patients with diabetes
Bilateral deformities and diabetic foot ulcers in patients with diabetes
In contrast to the neuropathic foot, the ischemic foot is generally a cool, sub-cyanotic foot. The subcutaneous venous network is visible through the skin and is tiny; pedal pulses are hardly palpable or absent (Fig. 12.9). Although patients with occlusive peripheral arteriopathy usually present with bilateral steno-occlusive lesions, clinical complications usually affect only one lower extremity. However, complications may also occur over time in the contralateral limb  (Fig. 12.10). Note that while clinical signs of neuropathic foot are clearly visible, the clinical signs of ischemic foot are hard to see, and instrumental examinations are required to make the diagnosis.
The typical appearance of ischemic foot in patients with diabetes
Critical right limb ischemia in a patient with diabetes and less obvious ischemic signs on the left foot
Ischemic and neuropathic ulcers differ in their clinical presentation. The etiopathogenesis of the ischemic foot ulcer is usually related to friction. Accordingly, the site of ulceration can be located anywhere on the foot (e.g., on the dorsum of the foot or on the margins of the foot) (Fig. 12.11). In contrast, the etiopathogenesis of the neuropathic foot is related to mechanical forces of gait. Because of this, neuropathic ulcers mainly occur on the plantar aspect of the foot and on areas that, due to foot distortion, are exposed to weight-bearing forces (Fig. 12.12).
The ulceration site can be located anywhere on the feet of patients with diabetes
Neuropathic ulcers in characteristic hyperpressure areas of the feet of patients with diabetes
Diabetic foot frequently presents with unusual clinical manifestations. There may be lesions in different areas of the foot according to the type of trauma; however, the signs differ between the two ulcer types (Table 12.1). The features reported here are related to noninfected ulcers, since infected ulcers, both neuropathic and ischemic, present with different clinical signs.
Characteristics of neuropathic versus ischemic foot ulcers
Regular margins, typically punched-out appearance
Often located on plantar surface of foot
Commonly located on toes, glabrous margins
Presence of calluses
Calluses absent or infrequent
Loss of sensation, reflexes, and vibration
Variable sensory findings
Increased in blood flow (atrioventricular shunting)
Decreased in blood flow
Dry, warm foot
No bony deformities
Pale and cyanotic in appearance
Red or hyperemic in appearance
In general, neuropathic foot is associated with little or no pain, while ischemic foot is always associated with rest pain (Fig. 12.13); however, rest pain may be absent in some patients with arteriopathy. Elderly diabetic patients with arteriopathy often develop neuropathy that can attenuate or cancel ischemic pain, thus preventing prompt and accurate diagnosis of arteriopathy, which has serious consequences.
Patient with rest pain because of critical limb ischemia that was treated with analgesic drugs. The medication was administered with a pump
Differential diagnosis is the first step in the management of an ulcer. Diabetes specialist Michael Edmonds notes, “An important prelude to successful treatment is the differentiation between two main syndromes: the neuropathic foot and the neuroischemic foot” . Differential diagnosis is an important prerequisite not only to prevent amputation but also to reduce mortality .
The signs of neuropathic ulcers differ in some ways from those of ischemic ulcers (Table 12.1). Most of these differences may be irrelevant, with the exception of the absence of palpable pedal pulses in elderly neuroischemic patients. There are also some differences regarding the type of ulcer that is found in neuropathic versus neuroischemic foot. Figure 12.14 shows an example of a neuropathic foot with a typical plantar lesion and an example of a critically ischemic foot with multiple typical gangrenous ulcers. Neuropathic foot presents with ulcerations that are usually located on the plantar aspect of the metatarsal heads. However, ulcerations can also occur in areas of the foot that are exposed to biomechanical stress, such as the top or dorsum of the toes (in “pied en griffe”), the midfoot (in flat feet), lateral areas of the foot, or other areas (Fig. 12.15). Ischemic foot also presents with ulcerations of areas that are subjected to pressure, which can even include the plantar aspect of the foot (Fig. 12.16).
(a) Typical neuropathic plantar ulcer under the third metatarsal head and (b) typical ischemic gangrene of the forefoot
Neuropathic ulcers can occur on areas of the foot that are exposed to biomechanical stress, such as the top (b) or dorsum or plantar (a) aspect of the toes or the plantar aspect of the foot (c)
Ischemic feet can present with ulcerations on areas of the foot that are exposed to pressure, even on the plantar aspect
Although diabetic foot ulcers can have many signs and symptoms, selecting the most appropriate diagnostic and therapeutic approaches requires accurate identification of the type of ulcer after considering the clinical findings and etiopathogenetic factors. In addition, the appropriateness of the treatment and management must be constantly assessed to ensure that the patient receives the best possible care.
12.4 Neuropathic Diabetic Foot Ulcers
Together with arteriopathy, neuropathy contributes to the etiopathogenesis of diabetic foot ulceration [13, 14]. According to the Eurodiale study, neuropathy accounts for almost half of all foot ulcers, and arteriopathy accounts for the remaining half (Table 12.2). Although the Eurodiale study may have had some bias, the findings highlight the potential role of these two pathogenetic factors in the formation of foot ulcers in diabetic patients . Further analysis of the study showed that arteriopathy and infection, rather than neuropathy per se, were associated with poor healing  (Fig. 12.17).
The incidence of neuropathy, arteriopathy, and infection in patients with diabetic foot ulcers
The risk of nonhealing of diabetic foot ulcers in the Eurodiale study population
The 1988 San Antonio Conference on Diabetic Neuropathy defined diabetic neuropathy as the presence of symptoms and/or signs of peripheral (somatic and/or autonomic) nerve dysfunction in people with diabetes mellitus that lack other causes for peripheral neuropathy. This definition is still widely accepted by the scientific and medical communities . There are many types of diabetic neuropathies that have a variety of clinical manifestations, some of which are similar to those observed in nondiabetic neuropathies . Diabetic neuropathy can be difficult to treat . Neuropathy is most commonly classified as symmetrical sensorimotor neuropathy and autonomic neuropathy, focal/multifocal varieties (e.g., cervical radiculo-plexus neuropathies, multiple mononeuropathy) . Distal symmetrical mixed sensorimotor polyneuropathy, which typically shows a “stocking distribution,” is the most common type of neuropathy that contributes to the pathogenesis of diabetic foot ulcers (Fig. 12.18).
The typical “stocking distribution” of sensorimotor changes in diabetes
Autonomic neuropathy also contributes to the pathogenesis of diabetic foot ulcers, although to a lesser extent . Figure 12.19 shows a foot with typical signs of autonomic neuropathy, namely, dehydrated skin, ungual mycosis, and swelling. This chapter does not discuss the pathogenesis of diabetic neuropathy or other diabetes-related neuropathies. The interested reader can find further details on this topic in reference Spallone and Morganti .
A neuropathic foot showing typical signs of autonomic neuropathy: dehydrated skin, ungual mycosis, and swelling
Sensorimotor diabetic neuropathy cannot be diagnosed based on a single symptom or test. Rather, the diagnosis must be based on at least two neuropathic abnormalities in signs, symptoms, nerve conduction, or quantitative sensory test results .
Diagnostic tests include:
Symptoms/signs (clinical scores in diabetic neuropathy)
Quantitative sensory testing:
Semmes-Weinstein monofilament examination
Tuning fork/biothesiometer testing
Thermal threshold testing
Instrument-based tests (cardiovascular tests and electromyography)
A neuropathy severity grading system has been reported by the American Diabetes Association .
Clinical signs of neuropathic foot usually include:
Claw/hammer toe deformity
Valgus deformity of the great toe
Pes cavus deformity
Prominent metatarsal heads
Plantar hyperkeratosis and prominent metatarsal heads are the most common signs of motor neuropathy. Venous stiffness and dry skin are typical signs of dysautonomia. Diabetic neuropathy may affect sensory nerves (sensory neuropathy), motor nerves (motor neuropathy), and the autonomic nervous system (autonomic neuropathy). Diabetic patients with neuropathic foot exhibit muscle imbalance, alterations in sensory perception, and disordered autonomic function.
12.4.1 Sensory Neuropathy
In the foot, sensory neuropathy affects both proprioceptive sensory organs and afferent sensory nerve fibers. The most serious consequence is the loss of pain sensation. In the absence of pain, external nociceptive stimuli that are the result of excessive mechanical forces (e.g., tight-fitting shoes) are ignored; therefore, patients are not alerted to address the cause of the excessive pressure. Consequently, ulcers may develop. Thus, any physical trauma as a consequence of sensory neuropathy may result in a lesion. Sensory neuropathy can be promptly diagnosed using simple, noninvasive tools. Guidelines for sensory examination that are still valid were published in the 1990s  and include the following tests:
Pain sensation (pinprick test using a sterile pin: patients may feel pain or a needle sensation) (Fig. 12.20)
The pinprick test for pain sensation
Light touch sensation (using cotton balls) (Fig. 12.21)
The sensation test using a cotton ball
Temperature sensation (using steel or tubes filled with warm or cold water)
These tests are rather subjective assessment methods. Other inexpensive, simple, and more objective methods are available. Semiquantitative sensory testing can be performed using the Semmes-Weinstein monofilament [25, 26]. In this test, patients close their eyes while a nylon monofilament is applied to specific sites on the foot; obviously, hyperkeratotic areas should be avoided. The reliability of a patient’s response should be verified with a “false touch” . The monofilament is constructed so that it buckles when a force exceeding the level indicated on the filament is applied. The absence of a “pin and needle” sensation at one or more anatomical sites on the plantar surface of the foot is a sign of impaired sensory nerve function, and the absence of sensation on 6 or more areas of the foot is a sign of sensory loss. Figure 12.22 illustrates the technique used for monofilament testing.
The technique used for monofilament testing
Figure 12.23 shows some pictures of the monofilament test being performed on a patient. For quantitative sensory testing, a tuning fork or biothesiometer that transmits vibrations with variable frequencies is applied to the malleolus and on the dorsum of the first metatarsal heads (Fig. 12.24) of the patient’s foot. Sensory loss occurs when no vibration is sensed or when only vibrations with frequencies greater than 25 V are perceived [28, 29]. Loss of the ability to sense touch and vibration is usually associated with loss of pain sensation, which puts a patient at high risk of foot ulceration. Patients that only perceive tuning fork vibrations with frequencies greater than 25 V may be at risk for foot ulcer development. A biothesiometer may also be used as a screening tool to evaluate the efficacy of a treatment.
The monofilament test as performed on a patient. Red circles indicate the different areas to which the monofilament is applied
A tuning fork and biothesiometer are applied to the malleolus of a patient for quantitative sensory testing
Since small fiber nerve function cannot be assessed with electromyography, either biopsy or thermal threshold testing may be performed [30–33]. Notably, standardized techniques for thermal threshold testing are still lacking. A cutaneous thermometer (Molliter, Civitanova Marche Italy) or more complex instruments (case IV device, Medoc, NeuroQuick) can be used [34–36] (Figs. 12.25, 12.26, and 12.27).
Thermoskin (see the text)
An infrared thermometer is applied to the skin of a patient with diabetes
Case device (see the text)
An inability to feel pain is the major cause of foot ulcers in diabetic patients. Physical trauma due to tight shoes, a hot electric blanket, walking with bare feet, or foreign bodies in the shoes or socks, for example, may be ignored due to the loss of pain sensation. Such trauma can lead to the formation of nonhealing ulcers. Figure 12.28 shows an example of a foot lesion caused by the use of an electric heating blanket.
Foot lesion caused by an electric heating blanket: the burn led to amputation of the first ray and closure by autologous skin grafting
12.4.2 Motor Neuropathy
Motor neuropathy affects the large myelin fibers that innervate the foot muscles and leads to progressive hardening of the fascial tissues and to weakening and atrophy of the lumbrical and interosseous muscles. Motor neuropathy leads to an imbalance in toe flexor/extensor muscle strength, which leads to the typical claw-toe deformity. Claw toe involves protrusion of the metatarsal heads and high plantar arches (pes cavus deformity) (Fig. 12.29). Many studies note that diabetic neuropathy is associated with muscle atrophy . In terms of the signs of diabetic neuropathy, the tendons of the dorsum of the foot become more prominent as a consequence of extensor muscle atrophy (Fig. 12.30).
(a) A foot showing a typical claw-toe deformity with dorsal hyperkeratosis (arrows) due to excessive pressure. (b) A foot with a pes cavus deformity
A claw-toe deformity with prominent tendons of the extensor muscles in a patient with motor neuropathy
The muscle imbalance resulting from motor neuropathy also leads to alterations in the distribution of the protective fatty cushions that are underneath the heads of the metatarsal bones . As a consequence of this dysmorphism, the weight-bearing area of the foot is reduced. This is a pathogenetic factor, since pressure on the weight-bearing surface increases as the surface area decreases. Time also plays an important role in the pathogenesis of the lesion . Figure 12.31 illustrates the importance of the size of the weight-bearing surface. As a result of a decreased weight-bearing surface, some areas of the foot, such as metatarsal heads, the tips of the toes, and the calcaneus, are exposed to excessive load (Fig. 12.32).
Different weight-bearing surfaces of the foot (see the text for the description)
Schematic representation of areas of the foot that can be exposed to hyperpressure
In the neuropathic foot, the pes cavus deformity results in increased weight-bearing pressure on the metatarsal heads, while the flatfoot deformity results in increased weight-bearing pressure on the midfoot (Fig. 12.33). As a protective response to the excessive mechanical forces, hyperkeratosis develops on areas of the skin that are exposed to overload (Fig. 12.34). In general, neuropathy leads to bilateral hyperkeratosis; however, the severity and progression of hyperkeratotic lesions in neuropathic feet can vary depending on the location of the lesion (Fig. 12.35). Hyperkeratosis functions as a protective response only for a limited period of time. Indeed, persistence of overload can cause a hematoma that eventually evolves into nonhealing ulcers that are at high risk of becoming infected (Fig. 12.36).
Feet showing typical cavus foot deformities (left) and flatfoot deformities (right)
(Left to right): Examples of increasingly severe hyperkeratosis in neuropathic feet
Symmetrical bilateral hyperkeratosis in neuropathic feet
Examples of neuropathic ulcers that developed in hyperpressure areas
Along with bilateral hyperkeratosis, neuropathic patients often present with bilateral plantar foot ulcers (Fig. 12.37). However, any area of the foot can be exposed to excessive weight-bearing forces, depending on the type and the extent of the foot deformity. For example, in patients with claw toes, distal phalanges or the dorsum of the toe may be exposed to overload, and the plantar aspect of the midfoot may be affected in patients with flatfoot (Fig. 12.38). In fact, toes are frequently affected by motor neuropathy, and a great variety of foot deformities can arise. Thus, foot deformity itself may be a sign of motor neuropathy (Fig. 12.39). Motor neuropathy can be diagnosed using the Achilles tendon and patellar (knee-jerk) reflex tests; however, these methods can be difficult to perform on patients with mobility problems (Fig. 12.40).
Bilateral plantar foot ulcers
Ulcer on the (a) dorsum and (b) tip of the second toe as a result of a claw-toe deformity. (c) An ulcer on the plantar surface of the midfoot as a consequence of a flatfoot deformity
Feet showing foot deformities related to motor neuropathy
The Achilles tendon reflex test
Progressive thickening of the plantar fascia and the Achilles tendon, which seems to be related to deposits of the glycosylation products of collagen fibers, leads to retraction of the plantar fascia, Achilles tendon, and several foot joints [40, 41]. Plantar fascia retraction leaves the metatarsal heads unprotected and, together with Achilles tendon retraction, can lead to foot deformity. Then, in turn, foot deformity overloads the metatarsal heads. The hardening of joint capsules contributes to the development of a “rigid foot” that poorly absorbs shear and friction forces during gait.
The use of electroneurography for assessing motor nerve conduction velocity is still a matter of debate [42, 43]. This is a useful diagnostic test for differentiating between radiculopathies and other painful neuropathies and for assessing the effectiveness of different treatment approaches. However, it does not provide useful information about the risk of developing foot ulcers and does not help diagnose sensorimotor neuropathy in patients with foot ulceration.
12.4.3 Autonomic Neuropathy
The role of diabetic autonomic neuropathy in the pathogenesis of diabetic foot appears to be less important than the role of diabetic sensorimotor neuropathy; however, very little is actually known about its role. Autonomic neuropathy occurs in 10–15 % of patients with diabetes and in 30–40 % of patients with sensory neuropathy [21, 44]. Diagnosing autonomic neuropathy can be difficult, since many time-consuming tests (at least 3 of the 5 typical cardiovascular reflex tests) and at least one electrocardiographic evaluation should be. One commercially available diagnostic tool is the Neuropad test. This test is based on a simple visual indicator that uses color changes that reflect the integrity of skin sympathetic cholinergic innervation [45–47] (Fig. 12.41).
Application of Neuropad plaster to the plantar surface of the foot of a patient with dysautonomia. The color changes reflect sweat gland function
One visible clinical sign of autonomic neuropathy is extremely dry skin on the foot due to alterations in the sudomotor fibers that innervate the sweat glands (Fig. 12.42). Sudomotor dysfunction leading to dry skin on the foot is associated with foot ulceration  because dry skin breaks easily and can easily become infected (Fig. 12.43). Since sudomotor dysfunction and pH alterations predispose diabetes patients to dermatophyte colonization and growth, autonomic neuropathy is often associated with ungual mycosis. Autonomic neuropathy may also result in alteration of microvascular regulation [21, 45–49]. Arteriovenous anastomoses of microvascular flow in the skin are associated with skin function and trophism . The arteriovenous anastomotic shunt flow is regulated by sympathetic axons that mediate vasoconstrictor tone. By reducing this tone, autonomic neuropathy impairs the neurogenic vascular response to external stimuli such as heating and strain. Figure 12.44 shows a patient with autonomic neuropathy and typical turgidity of the veins.
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