|Year : 2016 | Volume
| Issue : 1 | Page : 1-12
An overview of diabetic foot disease
Ismail Lawal Dahiru1, Kenneth Ezenwa Amaefule1, Innocent Onoja Okpe2, Abdulrasheed Ibrahim3, Salisu Babura Muazu2
1 Department of Trauma and Orthopaedic Surgery, Ahmadu Bello University, Zaria, Nigeria
2 Department of Medicine, Division of Endocrinology, Ahmadu Bello University, Zaria, Nigeria
3 Division of Plastic and Reconstructive Surgery, Ahmadu Bello University, Zaria, Nigeria
|Date of Web Publication||12-Feb-2016|
Ismail Lawal Dahiru
Department of Trauma and Orthopaedic Surgery, Ahmadu Bello University, Zaria
Source of Support: None, Conflict of Interest: None
The incidence of diabetes globally is reaching an epidemic proportion and with it carries the risk of complications and diabetic foot disease inclusive. The pathophysiology of diabetic foot disease is multifactorial and includes neuropathy, infection, ischaemia and abnormal foot structure and biomechanics. Early recognition of the aetiology of these lesions is important for good functional outcome. Managing the diabetic foot is a complex clinical problem requiring a multidisciplinary collaboration of health care workers to achieve limb salvage. Adequate off-loading, frequent debridement, moist wound care, treatment of infection and revascularisation of ischaemic limbs are the mainstays of treatment. Even with proper management, some of the foot ulcers do not heal and are arrested in a state of chronic inflammation. These wounds can frequently benefit from various adjuvants, such as aggressive debridement, growth factors, bioactive skin equivalents and negative pressure wound therapy. We reviewed current literature including original and review articles obtained through a search of PubMed database, Medline, Google scholar and hand searching of bibliographies of published articles using the keywords: Diabetes, diabetic foot, neuropathy, peripheral arterial disease and ulceration. The enormity of the challenges associated with the management of this important complication of diabetes, coupled with the various progresses being made in this area, and the need to streamline the principles of management, especially in our environment prompted us to review this subject matter.
Keywords: Diabetes, diabetic foot, neuropathy, peripheral arterial disease, ulceration
|How to cite this article:|
Dahiru IL, Amaefule KE, Okpe IO, Ibrahim A, Muazu SB. An overview of diabetic foot disease. Niger J Basic Clin Sci 2016;13:1-12
|How to cite this URL:|
Dahiru IL, Amaefule KE, Okpe IO, Ibrahim A, Muazu SB. An overview of diabetic foot disease. Niger J Basic Clin Sci [serial online] 2016 [cited 2019 May 23];13:1-12. Available from: http://www.njbcs.net/text.asp?2016/13/1/1/176206
| Introduction|| |
Diabetic foot disease is one of the most significant and devastating complications of diabetes. It is defined as a foot affected by ulceration that is associated with neuropathy and/or peripheral arterial disease of the lower limb in a patient with diabetes.,, The term 'diabetic foot disease' also refers to a mix of pathologies including diabetic neuropathy, peripheral vascular disease, Charcot's neuroarthropathy, foot ulceration, osteomyelitis and potentially preventable endpoint and limb amputation. Foot problems in patients with diabetes have remained a major public health issue and are the most common reason for admission of diabetic patients in a hospital., Routine ulcer care, treatment of infections, amputations and hospitalisations costs a huge sum of money and places a tremendous burden on the health care system of nations. The average cost of healing a single ulcer in USA is $8000, of an infected single ulcer is $17,000 and of a major amputation $45,000. More than 80,000 amputations are performed each year on diabetic patients in the United States.
The prevalence of diabetic foot ulceration in the diabetic population is 4–10%, with the peak prevalence being between 60 and 80 years of age.,,, It is estimated that about 5% of all patients with diabetes present with a history of foot ulceration while the lifetime risk of diabetic patients developing this complication is 15%.,,,,,
The majority of foot ulcers (60–80%) will heal while 10–15% of them will remain active and 5–24% of them will finally lead to limb amputation within a period of 6–18 months after first evaluation. Diabetes accounts for up to 80% non-traumatic amputations, with 85% of these being preceded by a foot ulcer., Amputation carries with it a significant elevated mortality at follow-up, ranging from 13 to 40% at 1 year to 39–80% at 5 years. Further, 50% of the people with amputation will develop ulcerations and infections in the contralateral foot within 18 months. An alarming 58% will have contralateral amputation 3–5 years after the first amputation.
As the majority of limb amputations in patients with diabetes are preceded by foot ulceration, it is essential that strategies are directed towards preventing this. Subjects with diabetic foot problems are also likely to harbour other associated complications of nephropathy, retinopathy, ischaemic heart disease and cerebrovascular disease. Hence, the subjects are more likely to benefit from a multidisciplinary approach with a view to addressing these challenging complications. This model involves intensive input from a multidisciplinary team, which includes a consultant orthopaedic surgeon, consultant plastic surgeon, consultant endocrinologist (diabetologist), consultant microbiologist, a senior physiotherapist, podiatrist and members of their respective teams. Regular communication among members on a daily basis facilitates rapid decision-making based on new clinical information. The network facilitates the decision making for key events which help direct treatment. Furthermore, there is evidence to suggest that the incidence of major amputation can be reduced by implementation of a multidisciplinary team approach. The aim of this review is to enhance the optimal management of diabetic foot disease and potentially reduce the incidence of infection-related morbidities, hospital length of stay and major limb amputation and mortality.
| Pathogenesis|| |
Diabetic foot ulcers result from the simultaneous action of multiple contributory factors. The major underlying causes are noted to be peripheral neuropathy and ischaemia from peripheral vascular disease.
More than 60% of diabetic foot ulcers are the result of underlying neuropathy.,, The development of neuropathy in affected patients is as a result of hyperglycaemia-induced metabolic abnormalities.,,, One of the most commonly described mechanisms of action is the polyol pathway. In the development of neuropathy, the hyperglycaemic state leads to an increase in the action of the enzymes aldose reductase and sorbitol dehydrogenase. This results in the conversion of intracellular glucose to sorbitol and fructose. The accumulation of these sugar products results in a decrease in the synthesis of nerve cell myoinositol required for normal neuron conduction. In addition, the chemical conversion of glucose results in a depletion of nicotinamide adenine dinucleotide phosphate stores which are necessary for the detoxification of reactive oxygen species (ROS) and synthesis of the vasodilator nitric oxide. There is a resultant increase oxidative stress on the nerve cell and an increase in vasoconstriction leading to ischaemia which will promote nerve cell injury and death. Hyperglycaemia and oxidative stress also contribute to the abnormal glycation of nerve cell proteins and the inappropriate activation of protein kinase C, resulting in further nerve dysfunction and ischaemia.,,,
Although diabetics are at risk for multiple types of neuropathies, distal symmetric length-dependent diabetic polyneuropathy is the most common type in 80% of cases of diabetic neuropathy. The exact pathophysiology underlying the development of diabetic neuropathy remains unknown; however, it has been shown that the metabolic abnormalities of diabetes render the peripheral nerve more susceptible to chronic compression. A possible explanation for this is the conversion of glucose to sorbitol which osmotically increases intraneural water content, creating nerve oedema. In addition, the nerve courses through fixed anatomical structures with a low threshold for any variation in the size of the nerve. Thus, swelling will put the nerve at risk for compression within its anatomical 'tunnel', causing entrapment that will lead to both distal nerve ischaemia and a decrease in axoplasmic flow. Furthermore, intraneural accumulation of advanced glycation end products created by the baseline elevation of serum glucose eventually manifests as a slowing of axoplasmic protein transport for repair and signal transduction. The combined effects of these processes, at the known anatomical compression sites, will impair the ability of the nerve to communicate with its end organ, which frequently are muscle fibres or mechanoreceptors in the skin, resulting in loss of function or sensation. This process usually occurs in a symmetrical and length-dependent manner, affecting the most distal part of the lower extremities first.
Neuropathy in diabetic patients is manifested in the motor, autonomic and sensory components of the nervous system. Damage to the innervation of the intrinsic foot muscles leads to an imbalance between flexion and extension of the affected foot. This produces anatomic foot deformities that create abnormal bony prominences and pressure points which gradually cause skin breakdown and ulceration.
Autonomic neuropathy leads to a diminution in sweat and oil gland functionality. As a result, the foot loses its natural ability to moisturise the overlying skin and becomes dry and increasingly susceptible to tears and the subsequent development of infection. The loss of sensation as a part of peripheral neuropathy exacerbates the development of ulceration. As trauma occurs at the affected site, patients are often unable to detect the insult to their lower extremities. As a result, many wounds go unnoticed and progressively worsen as the affected area is continuously subjected to repetitive pressure and shear forces from ambulation and weight bearing [Figure 1].
|Figure 1: Feet-affected neuropathy leading to ulceration and infection from inappropriate footwear|
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Peripheral arterial disease is a contributing factor to the development of foot ulcers in up to 50% of cases.,, It commonly affects the tibial and peroneal arteries of the calf. Endothelial cell dysfunction and smooth cell abnormalities develop in peripheral arteries as a consequence of the persistent hyperglycaemic state., There is a resultant decrease in endothelium-derived vasodilators leading to constriction. Further, the hyperglycaemia in diabetes is associated with an increase in thromboxane A2, a vasoconstrictor and platelet aggregation agonist, which leads to an increased risk of plasma hypercoagulability. There is also the potential for alterations in the vascular extracellular matrix leading to stenosis of the arterial lumen. Moreover, smoking, hypertension and hyperlipidaemia are other factors that are common in diabetic patients and contribute to the development of peripheral arterial disease. Cumulatively this leads to occlusive arterial disease that results in ischaemia in the lower extremity and an increased risk of ulceration in diabetic patients [Figure 2].
|Figure 2: Foot affected by peripheral arterial disease leading to ischaemia, toes gangrene, infection and ulceration|
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Assessment of the diabetic foot
Assessing the diabetic foot represents a very important element of the annual diabetic review. It is crucial to identify the foot at risk earlier, so as to target preventive and therapeutic measures at the earliest opportunity. This approach helps in reducing the significant morbidity and mortality associated with diabetic foot disease as well as having a major health care-associated economic benefit.
The presence of dry skin, tinea and onychomycosis needs to be identified and treated early. Footwear also needs to be carefully inspected to ensure proper fit. Other factors known to be associated with increased risk of foot ulceration include past history of ulceration, past history of lower extremity amputation, long duration (>10 years) of diabetes, poor glycaemic control, impaired vision and nephropathy. The diabetic foot assessment should include a thorough neuropathic, structural and vascular assessment at least on an annual basis.
A thorough history should include neuropathic symptoms such as burning, tingling, numbness and nocturnal leg pains. Examination should comprise of careful inspection for muscle wasting, foot deformities such as claw toes, loss of hair and trophic changes. Sensory assessment includes testing for pressure, vibration, joint position and pain or temperature sensation. Pressure sensation is usually assessed by using a 10 g nylon Semmes–Weinstein monofilament. It is a good objective way of assessing diabetic neuropathy. Patients with normal foot sensation usually can feel a 4.17 monofilament (equivalent to 1 g linear pressure). Patients who cannot detect a 5.07 monofilament (equivalent to 10 g of linear pressure) are considered to have lost protective sensation. The monofilament is placed at a right angle to the skin on the plantar surface with the pressure being applied until the filament buckles, indicating that a specified pressure has been applied. Inability to perceive the 10 g force applied by the monofilament is associated with clinically significant large fibre neuropathy., The monofilament test has a sensitivity test of 66–91% in identifying persons at increased risk of foot ulceration.,, Testing four plantar sites on the forefoot (great toe and the base of the first, third and fifth metatarsal) identifies 90% of patients with an insensate foot., Vibration sensation is tested using a 128Hz tuning fork applied on the bony prominence of the great toe, gradually moving upwards if there is any impairment noted. Sensitivity is around 53% and tuning fork is less predictive of foot ulceration compared to monofilament testing. A biothesiometer is used to assess vibration perception threshold. A vibration perception threshold of more than 25 V has been reported to have a sensitivity of 83%.
It is important to examine the feet for structural abnormalities such as calluses, bunions, hammer toes, claw toes and flat foot. Foot ulceration may result from excessive plantar pressures resulting from limited joint mobility, particularly at the ankle, subtalar and first metatarsophalangeal joints. Devices are used to identify high plantar pressures. These devices include specialised mats that measure barefoot plantar load distribution and transducers in a removable shoe insole that measure pressure inside footwear. It is also crucial to identify the presence of Charcot neuroarthropathy as this is likely to go unnoticed by the patient until a grossly deformed insensitive foot results, which is at an increased risk of ulceration. During the acute stage, the Charcot foot is swollen, painful and warm, with a temperature differential >2°C in comparison to the contralateral foot. Acute Charcot foot may be misdiagnosed as cellulitis, osteomyelitis, inflammatory arthropathy or deep vein thrombosis. Once the acute phase of Charcot subsides, which may take several months, the foot enters a chronic stage. The chronic Charcot foot is painless and deformed, without a temperature differential. The mid-foot is commonly involved in Charcot neuroarthropathy and can result in mid-foot collapse with a plantar bony prominence and rocker bottom foot. This is associated with a significantly increased risk of ulceration.,
Artherosclerotic vascular disease is present in most subjects with diabetes.,, It is routine to palpate pedal pulses in diabetic clinics; however, this test is subjective and can be influenced by many factors. Intermittent calf claudication is an uncommon presenting symptom in diabetes patients, as the calf muscles derive their blood supply from geniculate arteries that arise proximal to the popliteal trifurcation, a site often spared in diabetes-related peripheral vascular disease. The tibio-peroneal trunk and crural arteries are affected more commonly, and this can lead to foot claudication. The symptoms of foot claudication may however be obscured by peripheral neuropathy. As a result, the initial detection of peripheral vascular disease is often heralded by the presence of cutaneous trophic changes such as corns, calluses, ulcers or frank digital gangrene., Ankle brachial pressure index (ABPI) is an important tool in assessing perfusion to the foot. It is the ratio of systolic blood pressure at the ankle to the systolic at the brachial artery and is used to detect the presence of peripheral vascular disease. Normal ABPI values range from 1.0 to 1.3 since the pressure is higher in the ankle than in the arm. Values over 1.3 suggest non-compressible calcified vessels. An ABPI <0.9 is indicative of peripheral vascular disease and is associated with 50% or more stenosis in one or more major vessels. An ABPI of 0.4–0.9 suggests a degree of arterial obstruction associated with claudication. An ABPI <0.4 or an ankle systolic pressure <50 mmHg represents advanced ischaemia. The ABPI correlates with clinical measures of lower extremity function, such as walking distance, velocity, balance and overall physical activity. In addition, a low ABPI has been associated with a higher risk of coronary heart disease, stroke, transient ischaemic attack and progressive renal insufficiency, and all these can lead to mortality., A potential limitation of the ABPI is that calcified vessels may not compress normally, resulting in falsely elevated Doppler signals. Thus, an ABPI of over 1.3 is suggestive of calcified vessels. In such patients, an accurate pressure may be obtained by measuring the toe brachial pressure index (TBI)., TBI is increasingly used as an effective alternative screening tool in diabetics as it is less influenced by arterial calcification than ABPI. However, the influence of peripheral neuropathy on toe blood pressures remain uncertain, thus compromising the accuracy of this tool in the presence of established peripheral neuropathy., Doppler arterial waveform is another non-invasive tool used to assess the vascular status. The normal arterial waveform is pulsatile with a positive forward flow in systole, followed by a short reverse flow and further forward flow in diastole. Even in the presence of neuropathy, the successful demonstration of this triphasic waveform can effectively exclude significant arterial disease in more than 90% of limbs.
The result of foot and ulcer evaluation should aid in developing an appropriate management plan. Once an ulcer develops, it is essential to monitor its progress. Several foot ulcer classification have been proposed. These classification systems are based on a variety of physical findings. The commonly used Meggitt-Wagner classification defines wounds by the depth of ulceration and the extent of gangrene [Table 1]., The University of Texas system (UT) grades wounds by depth and then stages them by the presence or absence of infection and ischaemia [Table 2]. None of these, however, takes into account measures of neuropathy or ulcer area. The International Working Group on the Diabetic Foot (IWGDF) has proposed the Perfusion Extent Depth Infection and Sensation (PEDIS) classification which grades the ulcer on the basis of perfusion (arterial supply), extent (area), depth, infection and sensation. This classification was developed to assist in research concerning diabetic foot ulcers. It is complex and difficult to use in clinical practice. Kings College, United Kingdom, developed the Kings classification which is simple and consists of five stages [Table 3]. This system guides in therapy but is not used. Jeffcoate et al. modified an earlier scoring system for diabetic foot ulcers with a score based on assessment of size (area, depth) sepsis, arteriopathy and denervation. These five criteria are objectively graded on a scale of 0–4, and the score has been validated in a prospective single-centre cohort study. The S (AD) SAD protocol is easy to remember in clinical practice and four of its five constituent variables were independently significantly associated with wound healing in the validation study.
The PEDIS score is based on the same five variables as the S (AD) SAD score and was designed by the IWGDF for population stratification in prospective research. A recent comparison of the PEDIS, Meggitt-Wagner and UT score revealed that the strongest association with outcome was obtained with the Meggitt-Wagner system. Infection was more strongly correlated with outcome following assessment by S (AD) SAD scoring than by PEDIS scoring, as S (AD) SAD scoring distinguishes bone infection from soft-tissue infection.
Assessing foot ulcers for the presence of infection is an important issue. All open wounds are likely to get colonised with microorganisms, and it needs to be recognised that even virulent pathogens such as Staphylococcus aureus may sometimes represent colonisers. Hence, the presence of infection needs to be defined clinically in addition to a microbiological assessment. Clinically, the presence of infection is represented by purulent secretions or by presence of inflammation. Other signs suggesting infection include presence of friable tissues, undermined edges and foul odour. Systemic manifestations such as fever or leucocytosis are uncommon, but their presence may suggest a severe infection. Cultures should be sent, preferably from tissue specimens rather than wound swabs. The specimen should be subjected to gram staining and be processed for aerobic and anaerobic cultures. Other investigations include a full blood count, inflammatory markers erythrocyte sedimentation rate (ESR)/c-reactive protein and a plain radiograph. Plain radiographs can identify foreign bodies, presence of gas in tissues and bone involvement. Magnetic resonance imaging (MRI), bone scans and leucocyte scans may be indicated in certain special situations. The most important pathogens causing diabetic foot infections are the aerobic Gram-positive cocci such as S. aureus, beta-haemolytic streptococcus and coagulase negative staphylococcus. They often cause mono-microbial infection although patients with chronic ulcers or those who have recently been treated with antibiotics often tend to have polymicrobial infections with aerobic Gram-positive cocci in association with Gram-negative bacilli.,, Obligate anaerobes may also contribute to this polymicrobial mix, especially in patients with foot ischaemia.
The presence of underlying osteomyelitis is usually a diagnostic challenge. The presence of underlying osteomyelitis can be expected if bone is visible or palpable on probing. A significantly elevated ESR (>70 mm/h) is also suggestive although these findings may be less sensitive. For osteomyelitis to produce abnormalities on plain radiographs, infection should be present for at least 2 weeks. Bony abnormalities on plain radiographs could also represent non-infectious Charcot's neuroarthropathy. Further radiological investigations such as Technetium bone scans, leucocyte scans and MRI may be necessary in some patients to define underlying bony involvement. Diagnosing osteomyelitis in the presence of underlying Charcot's neuroarthropathy can however be particularly challenging, especially in the presence of overlying skin ulceration as no form of imaging can reliably exclude osteomyelitis in this setting.
Treatment of diabetic foot ulcer
The gold standard for diabetic foot ulcer treatment includes debridement of the wound, management of any infection, revascularisation procedures when indicated and off-loading of the ulcer. Other methods have also been suggested to be beneficial as add-on therapies, such as hyperbaric oxygen therapy, use of advanced wound care products and negative pressure wound therapy (NPWT)., However, data so far have not provided adequate evidence of the efficacy and cost-effectiveness of this add-on treatment method.
Debridement should be carried out in all chronic wounds to remove surface debris and necrotic tissues. It improves healing by promoting the production of granulation tissue and can be achieved surgically, enzymatically, biologically, and through autolysis [Figure 3].
Surgical debridement, also known as the 'sharp method', is performed by scalpels and is rapid and effective in removing hyperkeratosis and dead tissue. Particular care should be taken to protect healthy tissue, which has a red or deep pink (granulation tissue) appearance.,, Using a scalpel blade with the tip pointed at a 45° angle, all non-viable tissue must be removed until a healthy bleeding ulcer bed is produced with saucerisation of the wound edges. If severe ischaemia is suspected, aggressive debridement should be postponed until a vascular examination has been carried out and if necessary, a revascularisation procedure performed.
Enzymatic debridement can be achieved using a variety of enzymatic agents, including crab-derived collagenase, collagen from krill, papain and a combination of streptokinase and streptodornase and dextrans. These can remove necrotic tissue without damaging the healthy tissue. Although expensive, enzymatic debridement is indicated for ischaemic ulcers because surgical debridement is extremely painful in these cases.
Biological debridement has been applied recently using sterile maggots. Maggots have the ability to digest surface debris, bacteria and necrotic tissues only, leaving healthy tissue intact. This method is also effective in the elimination of drug-resistant pathogens, such as methicillin-resistant S. aureus, from wound surfaces.,
Autolytic debridement involves the use of dressing that creates moist wound environment so that host defence mechanisms (neutrophils, macrophages) can clear devitalised tissue using the body's enzymes. Autolysis is enhanced by the use of proper dressings, such as hydrocolloids, hydrogels and films. Autolysis is highly selective, avoiding damage to the surrounding skin.
Debridement, especially the 'sharp method', is one of the gold standards in wound healing management, significantly contributing to the healing process of the diabetic ulcer.,
Foot pressure off-loading
Off-loading of the ulcer area is extremely important for the healing of plantar ulcers. Elevated plantar pressures significantly contribute to the development of plantar ulcers in diabetic patients., In addition, any existing foot deformities may increase the possibility of ulceration, especially in the presence of diabetic peripheral neuropathy and inadequate off-loading. Furthermore, inadequate off-loading of the ulcer has been proven to be a significant reason, for the delay of ulcer healing even in an adequately perfused limb.,, The value of ulcer off-loading is increasing as the risk of recurrence of a healed foot ulcer is high if the foot is not properly off-loaded even after closure of the ulcer.,
The most effective method of off-loading, which is also considered to be the gold standard, is the non-removable total contact cast (TCC). It is made of plaster or fast-setting fibreglass cast material, has relatively low costs and permits restricted activity. Non-removable TCCs are indicated for the effective off-loading of ulcers located at the fore- or mid-foot. Severe foot ischaemia, a deep abscess, osteomyelitis and poor skin quality are absolute contraindications to the use of a non-removable TCC. Non-removable TCCs work by distributing the plantar pressures from the forefoot and mid-foot to the heel. They allow complete rest of the foot while also permitting restricted activity. Non-removable TCCs also reduce oedema, and compliance with treatment is necessarily high.,
There are a number of removable cast walkers (RCW), which usually have a lightweight, semi-rigid shell that helps support the limb while also providing full-cell protection. The sole is of a rocker type, offering off-loading of the forefoot during standing and walking. The foot base is wide and there is enough room for dressings. In some RCWs, there are additional layers of foam or other soft material, offering total contact.
A modification of RCWs is an instant TCC (ITCC), where there is a wrapping layer of cohesive tape or plaster bandage around the RCW., The aim of the ITCC is to combine the efficacy of a TCC with the easy application of an RCW.
Half shoes are another solution for patients who cannot tolerate other methods of off-loading although they provide less pressure relief than a cast boot and are difficult to walk in. Therapeutic shoes and custom insoles are alternative methods to off-load wounds located on the forefoot and can reduce pressure at the site of ulceration by 4–50%.
Ulcers heal more quickly and are often less complicated by infection when in a moist environment. The only exception is dry gangrene, where the necrotic area should be kept dry to avoid infection and conversion to wet gangrene. A wound's exudate is rich in cytokines, platelets, white blood cells, growth factors, matrix metalloproteinases (MMPs) and other enzymes. Most of these factors promote healing via fibroblast and keratinocyte proliferation and angiogenesis while others such as leucocytes and toxins produced by bacteria inhibit the healing process. Moreover, local concentrations of growth factors (platelet-derived growth factors-beta (PDGF-beta), transforming growth factor-beta) are low in patients with chronic ulcers. The ideal dressing should be free from contaminants, be able to remove excess exudates and toxic components, maintain a moist environment at the wound-dressing interface, be impermeable to microorganisms, allow gaseous exchange and finally, be easily removed and cost-effective. Various dressings are available that are intended to prevent infection and enhance wound healing.
Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee. This natural product has potent antibacterial activity and is effective in preventing and clearing diabetic wound infections. Honey has several natural substances that contribute to its antimicrobial activity including a naturally low pH, an osmotic effect and the production of hydrogen peroxide. Honey also combats antibiotic-resistant strains of bacteria and prevents bacterial growth even when wounds are heavily infected. Furthermore, because honey is a natural product, it does not induce microbial resistance even if the honey is unsuccessful in killing the microbes.
Over several years, honey from different parts of the world has been shown to be one of the highest potential natural products in which phenolics, flavonoids, ascorbic acids and some enzymes (glucose oxidase and catalase) serve as potent antioxidants. The antioxidants found in honey work on wounds through two pathways. First, the antioxidants fight against microorganisms and decrease infections at the site of the wound. Second, the antioxidants reduce ROS and inflammations caused by the wound and aid in the healing process. The combined antioxidant effects may have contributed to some successful clinical evidence from diabetic wounds showing more effective wound healing following topical honey applications.,,
PDGF-beta (becaplermin) has been developed as a topical therapy for the treatment of non-infected diabetic foot ulcers. It is applied in the form of once-daily gel along with debridement on a weekly basis. Initial studies have indicated a significant positive effect of becaplermin., On ulcer healing, however, recent studies have reported an increased incidence of cancer in patients treated with becaplermin, especially at high doses.,
Platelet-rich plasma (PRP) is an autologous product, extracted from patient's plasma, which includes a high platelet concentration in a fibrin clot that can be easily applied to the ulcer area. The fibrin clot is absorbed during wound healing within days to weeks following its application. Studies have reported a shorter closure time and higher healing percentage in patients using PRP and platelet-derived products.,
The results of the subcutaneous administration of granulocyte colony-stimulating factor in patients with infected foot ulcers vary, with some studies indicating faster resolution of the infection and faster healing , while others did not report any significant difference., Basic fibroblast growth factor is known to be beneficial in the formation of granulation tissue and normal healing. Epidermal growth factor acts on epithelial cells, fibroblast and smooth muscle cells to promote healing.
Bioengineered skin substitutes
Tissue-engineered skin substitutes are classified into allogenic cell-containing, autologous cell-containing and acellular matrices. The first two types of matrix contain living cells, such keratinocytes or fibroblast, in a matrix while acellular matrices are free of cells and act by releasing growth factors to stimulate neovascularisation and wound healing.
Evidence showed that bioengineered skin substitutes may be a promising therapeutic adjunct therapy to the standard wound care for the management of non-infected diabetic foot ulcers.,
Extracellular matrix proteins
Hyaff R is a semi-synthetic ester of hyaluronic acid which facilitates the growth and movement of fibroblast and controls hydration.
Other available products contain lyophilised collagen from various sources (bovine, porcine), alone or in combination with alginates, cellulose or antibiotics. Collagen seems to induce the production of endogenous collagen and to promote platelet adhesion and aggregation. It has been reported to be safe and effective as an adjunctive therapy in the management of foot ulceration.
Matrix metalloproteinases modulators
MMPs regulate extracellular matrix components. During normal wound healing, there is a balance between the construction and the destruction of the extracellular matrix. In chronic wounds, a high expression of MMP-2 in fibroblasts and the endothelium is detected and is believed to favour destruction. Thus, down-regulation of MMP-2 expression may enhance the healing process.
Dermax R is a dressing containing metal ions and citric acid, and its topical application is associated with a lower expression of MMP-2 by fibroblast and endothelial cells. Metal ions inhibit the production ROS by polymorphonuclear cells, and citric acid acts as a scavenger of superoxide anions.
Negative pressure wound therapy
NPWT has emerged as new treatment for diabetic foot ulcers. It involves the use of intermittent or continuous sub-atmospheric pressure through a special pump (vacuum-assisted closure) connected to resilient open-celled foam surfaced dressing covered with an adhesive drape to maintain a closed environment. The pump is connected to canister to collect wound discharge and exudates. NPWT optimises blood flow, decreases tissue oedema and removes exudates, pro-inflammatory cytokines and bacteria from the wound area. It is performed after debridement continued until the formation of healthy granulation tissue at the surface of the ulcer. NPWT is currently indicated for complex diabetic wounds. It is however contraindicated for patients with an active bleeding ulcer. Studies have provided some encouraging data concerning the possible benefit of NPWT in the healing rate and time of diabetic foot ulcers.,
There is strong evidence that fibroblast, endothelial cells and keratinocytes are replicated at higher rates in an oxygen-rich environment. Moreover, leucocytes kill bacteria more effectively when supplied with oxygen. It is also known that fibroblasts from diabetic individuals show diminished cell turnover in comparison with those from non-diabetic persons. Based on these data, administration of oxygen at high concentration might accelerate wound healing in diabetes. Treatment with hyperbaric oxygen therapy involves the intermittent administration of 100% oxygen at a pressure greater than that at sea level. It is performed in a chamber with the patient breathing 100% oxygen intermittently while the atmospheric pressure is increased to 2–3 atmospheres for a duration of 1–2 h. A full course involves 30–40 sessions. Available data suggest significant reduction of the ulcer area as well as reduction of the risk for major amputation., Hyperbaric oxygen can be applied as an adjunctive therapy for patients with severe soft-tissue foot infections and osteomyelitis who have not responded to conventional treatment.,
Prophylactic foot surgery
Reconstructive foot surgery for diabetic foot has continued to attract the interest of Surgeons in the last decade. Non-vascular foot surgery in diabetes may be classified as elective surgery (to alleviate pain), prophylactic surgery (to reduce the risk of ulceration), curative surgery (to heal an open wound) and emergency surgery (to control limb and life-threatening infection). A short Achilles tendon may be associated with an elevated foot plantar pressure and hence may benefit from Achilles tendon lengthening surgery. Tenotomy of toe extensors may reduce toe deformities, thus preventing recurrent ulcerations in this group of patients., Metatarsal osteotomy may reduce the risk of ulcer recurrence in subjects with prominent metatarsal heads. Similarly, patients with a mid-foot prominence may benefit from surgical removal of the prominence, with a view to create a more plantigrade foot. Amputation may be needed to save the rest of the patient's limb or even his life. Indications for amputation in patients with diabetic foot may include severe soft-tissue infection, peripheral arterial occlusion, extensive osteomyelitis and gangrene. The decision to amputate is usually difficult for both patient and surgeon. However, it is sometimes preferred when a patient has undergone unsuccessful treatment over a long period. Once a decision has been made to amputate, the goal should be to perform the most distal amputation that will heal satisfactorily.
Treating Charcot's neuroarthropathy
This depends on the stage during which the disease is diagnosed. During the acute phase, off-loading the affected foot by using a TCC is the most effective therapy., Use of TCC should continue until the swelling and hyperaemia have resolved. If the skin temperature is monitored, the temperature difference between the affected and non-affected foot should be <1°C before the cast can be removed. Once the cast is removed, custom-made footwear should be used. Bisphosphonates are potent inhibitors of osteoclast activation and may be used in the acute phase Charcot's neuroarthropathy., Intravenous pamidronate therapy has been shown to reduce disease activity as measured by markers of bone turnover. Patients with Charcot's neuroarthropathy remain at an increased risk of future foot problems and hence need continued follow-up.
Early detection of potential risk factors for ulceration can decrease the frequency of wound development. It is recommended that all patients with diabetes undergo foot examination at least annually to determine predisposing conditions to ulceration. Patients should be educated regarding the importance of maintaining good glycaemic control, wearing appropriate footwear, avoiding trauma and performing frequent self-examination.
| Conclusion|| |
Patients with diabetes are at an increased risk for developing foot ulcerations. The consequences of persistent and poorly controlled hyperglycaemia lead to neuropathic and vascular abnormalities that cause deformities and ulceration. The feet of diabetic patients should be examined at least annually to determine predisposing conditions to ulceration. Treatment plans should be based on examination findings and the individual risk for ulceration.
If ulcers are present, the treatment strategy should include debridement, off-loading and appropriate dressings. Further, the presence of infections should be determined by clinical findings and appropriate wound cultures and treated based on culture results. If evidence for ischaemia is present, revascularisation may be indicated to restore arterial blood flow and increase the chance for limb salvage. Adjunctive therapies are available and can also contribute to the overall healing process of the wounds in affected patients.
By carrying out periodic foot survey in diabetic patients and incorporating the appropriate basic and specialised care as warranted, the risk of ulceration and its associated morbidities can be reduced.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Alexiadou K, Doupis J. Management of diabetic foot ulcers. Diabetes Ther 2012;3:4.
Abbott CA, Carrington AL, Ashe H, Bath S, Every LC, Griffiths J, et al.
The North-West diabetes foot care study: Incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med 2002;19:377-84.
Centers for Disease Control and Prevention (CDC). Lower extremity disease among persons aged>or=40 years with and without diabetes – United States, 1999-2002. MMWR Morb Mortal Wkly Rep 2005;54:1158-60.
Khanolkar MP, Bain SC, Stephens JW. The diabetic foot. QJM 2008;101:685-95.
Kruse I, Endelman S. Evaluation and treatment of diabetic foot ulcers. Clin Diabetes 2006;24:91-3.
Lauterbach S, Kostev K, Kohlmann T. Prevalence of diabetic foot syndrome and its risk factors in the UK. J Wound Care 2010;19:333-7.
Trautner C, Haastert B, Giani G, Berger M. Incidence of lower limb amputations and diabetes. Diabetes Care 1996;19:1006-9.
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005;293:217-28.
Rathur HM, Boulton AJ. The diabetic foot. Clin Dermatol 2007;25:109-20.
Bateman AH, Bradford S, Hester TW, Kubelka I, Tremlett J, Morris V, et al.
Modern orthopedic inpatient care of the orthopedic patient with diabetic foot disease. Int J Low Extrem Wounds 2015;14:384-92.
Clayton W, Elasy TA. A review of the pathophysiology, classification, and treatment of foot ulcers in diabetic patients. Clin Diabetes 2009;27:52-8.
Bowering CK. Diabetic foot ulcers. Pathophysiology, assessment, and therapy. Can Fam Physician 2001;47:1007-16.
Dyck PJ, Davies JL, Wilson DM, Service FJ, Melton LJ 3rd
, O'Brien PC. Risk factors for severity of diabetic polyneuropathy: Intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care 1999;22:1479-86.
Feldman EL, Russell JW, Sullivan KA, Golovoy D. New insights into the pathogenesis of diabetic neuropathy. Curr Opin Neurol 1999;12:553-63.
Simmons Z, Feldman EL. Update on diabetic neuropathy. Curr Opin Neurol 2002;15:595-603.
Zochodne DW. Diabetic polyneuropathy: An update. Curr Opin Neurol 2008;21:527-33.
Said G. Diabetic neuropathy – A review. Nat Clin Pract Neurol 2007;3:331-40.
Dellon AL, Mackinnon SE, Seiler WA 4th
. Susceptibility of the diabetic nerve to chronic compression. Ann Plast Surg 1988;20:117-9.
Jakobsen J. Peripheral nerves in early experimental diabetes: Expansion of the endoneurial space as a cause of increased water content. Diabetologia 1978;14:113-9.
Aszmann OC, Dellon ES, Dellon AL. Anatomical course of the lateral femoral cutaneous nerve and its susceptibility to compression and injury. Plast Reconstr Surg 1997;100:600-4.
Ducic I, Felder JM 3rd
, Iorio ML. The role of peripheral nerve surgery in diabetic limb salvage. Plast Reconstr Surg 2011;127 Suppl 1:259S-69S.
Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des 2008;14:953-61.
Huijberts MS, Schaper NC, Schalkwijk CG. Advanced glycation end products and diabetic foot disease. Diabetes Metab Res Rev 2008;24 Suppl 1:S19-24.
Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al.
Comprehensive foot examination and risk assessment: A report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of clinical endocrinologists. Diabetes Care 2008;31:1679-85.
Paraskevas KI, Baker DM, Pompella A, Mikhailidis DP. Does diabetes mellitus play a role in restenosis and patency rates following lower extremity peripheral arterial revascularization? A critical overview. Ann Vasc Surg 2008;22:481-91.
Armstrong DG. The 10-g monofilament: The diagnostic divining rod for the diabetic foot? Diabetes Care 2000;23:887.
Boyko EJ, Ahroni JH, Stensel V, Forsberg RC, Davignon DR, Smith DG. A prospective study of risk factors for diabetic foot ulcer. The Seattle diabetic foot study. Diabetes Care 1999;22:1036-42.
Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: A prospective multicenter trial. Diabetes Care 2000;23:606-11.
Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria. Diabetes Care 1992;15:1386-9.
Smieja M, Hunt DL, Edelman D, Etchells E, Cornuz J, Simel DL. Clinical examination for the detection of protective sensation in the feet of diabetic patients. International cooperative group for clinical examination research. J Gen Intern Med 1999;14:418-24.
Boulton AJ, Cavanagh PR, Rayman G. The Foot in Diabetes. 4th
ed. Chichester: John Wiley & Sons Ltd.; 2006. p. 92-107.
Puttemans T, Nemery C. Diabetes: The use of color Doppler sonography for the assessment of vascular complications. Eur J Ultrasound 1998;7:15-22.
Williams DT, Harding KG, Price P. An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes. Diabetes Care 2005;28:2206-10.
Brooks B, Dean R, Patel S, Wu B, Molyneaux L, Yue DK. TBI or not TBI: That is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients? Diabet Med 2001;18:528-32.
Chew JT, Tan SB, Sivathasan C, Pavanni R, Tan SK. Vascular assessment in the neuropathic diabetic foot. Clin Orthop Relat Res 1995;320:95-100.
Oyibo SO, Jude EB, Tarawneh I, Nguyen HC, Harkless LB, Boulton AJ. A comparison of two diabetic foot ulcer classification systems: The Wagner and the University of Texas wound classification systems. Diabetes Care 2001;24:84-8.
Schaper NC. Diabetic foot ulcer classification system for research purposes: A progress report on criteria for including patients in research studies. Diabetes Metab Res Rev 2004;20 Suppl 1:S90-5.
Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for diabetic foot ulcers. Lancet 2005;366:1725-35.
Jeffcoate WJ, Macfarlane RM, Fletcher EM. The description and classification of diabetic foot lesions. Diabet Med 1993;10:676-9.
Treece KA, Macfarlane RM, Pound N, Game FL, Jeffcoate WJ. Validation of a system of foot ulcer classification in diabetes mellitus. Diabet Med 2004;21:987-91.
Abbas ZG, Lutale JK, Game FL, Jeffcoate WJ. Comparison of four systems of classification of diabetic foot ulcers in Tanzania. Diabet Med 2008;25:134-7.
Heggers JP. Defining infection in chronic wounds: Does it matter? J Wound Care 1998;7:389-92.
Abdulrazak A, Bitar ZI, Al-Shamali AA, Mobasher LA. Bacteriological study of diabetic foot infections. J Diabetes Complications 2005;19:138-41.
El-Tahawy AT. Bacteriology of diabetic foot. Saudi Med J 2000;21:344-7.
Goldstein EJ, Citron DM, Nesbit CA. Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases. Diabetes Care 1996;19:638-41.
Gerding DN. Foot infections in diabetic patients: The role of anaerobes. Clin Infect Dis 1995;20 Suppl 2:S283-8.
Soysal N, Ayhan M, Guney E, Akyol A. Differential diagnosis of Charcot arthropathy and osteomyelitis. Neuro Endocrinol Lett 2007;28:556-9.
Doupis J, Veves A. Classification, diagnosis, and treatment of diabetic foot ulcers. Wounds 2008;20:117-26.
Hinchliffe RJ, Valk GD, Apelqvist J, Armstrong DG, Bakker K, Game FL, et al.
Specific guidelines on wound and wound-bed management. Diabetes Metab Res Rev 2008;24 Suppl 1:S188-9.
Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Wound Repair Regen 2010;18:433-8.
Smith RG. Enzymatic debriding agents: An evaluation of the medical literature. Ostomy Wound Manage 2008;54:16-34.
Hilton JR, Williams DT, Beuker B, Miller DR, Harding KG. Wound dressings in diabetic foot disease. Clin Infect Dis 2004;39 Suppl 2:S100-3.
Game FL, Hinchliffe RJ, Apelqvist J, Armstrong DG, Bakker K, Hartemann A, et al.
A systematic review of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Diabetes Metab Res Rev 2012;28 Suppl 1:119-41.
Saap LJ, Falanga V. Debridement performance index and its correlation with complete closure of diabetic foot ulcers. Wound Repair Regen 2002;10:354-9.
Frykberg RG, Lavery LA, Pham H, Harvey C, Harkless L, Veves A. Role of neuropathy and high foot pressures in diabetic foot ulceration. Diabetes Care 1998;21:1714-9.
Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: A prospective study. Diabetologia 1992;35:660-3.
Burns J, Begg L. Optimizing the offloading properties of the total contact cast for plantar foot ulceration. Diabet Med 2011;28:179-85.
Cavanagh PR, Bus SA. Off-loading the diabetic foot for ulcer prevention and healing. J Vasc Surg 2010;52 3 Suppl: 37S-43S.
Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB. Off-loading the diabetic foot wound: A randomized clinical trial. Diabetes Care 2001;24:1019-22.
Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: A randomized controlled trial. Diabetes Care 2005;28:551-4.
Clark RA, editor. Wound repair: Overview and general considerations. In: The Molecular and Cellular Basis of Wound Repair. New York: Plenum Press; 1996. p. 3-50.
Harding KG, Jones V, Price P. Topical treatment: Which dressing to choose. Diabetes Metab Res Rev 2000;16 Suppl 1:S47-50.
Jull AB, Rodgers A, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev 2008;4:CD005083.
Bang LM, Buntting C, Molan P. The effect of dilution on the rate of hydrogen peroxide production in honey and its implications for wound healing. J Altern Complement Med 2003;9:267-73.
Molan PC. The evidence supporting the use of honey as a wound dressing. Int J Low Extrem Wounds 2006;5:40-54.
Ahmed AK, Hoekstra MJ, Hage JJ, Karim RB. Honey-medicated dressing: Transformation of an ancient remedy into modern therapy. Ann Plast Surg 2003;50:143-7.
Khalil MI, Alam N, Moniruzzaman M, Sulaiman SA, Gan SH. Phenolic acid composition and antioxidant properties of Malaysian honeys. J Food Sci 2011;76:C921-8.
Cooper RA, Molan PC, Harding KG. Antibacterial activity of honey against strains of Staphylococcus aureus
from infected wounds. J R Soc Med 1999;92:283-5.
Estevinho L, Pereira AP, Moreira L, Dias LG, Pereira E. Antioxidant and antimicrobial effects of phenolic compounds extracts of Northeast Portugal honey. Food Chem Toxicol 2008;46:3774-9.
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg 1995;21:71-8.
Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double-blind study. Diabetes Care 1998;21:822-7.
Driver VR, Hanft J, Fylling CP, Beriou JM; Autologel Diabetic Foot Ulcer Study Group. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2006;52:68-70, 72, 74.
Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2001;24:483-8.
Cruciani M, Lipsky BA, Mengoli C, de Lalla F. Are granulocyte colony-stimulating factors beneficial in treating diabetic foot infections? A meta-analysis. Diabetes Care 2005;28:454-60.
Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005;28:2155-60.
Yönem A, Cakir B, Güler S, Azal O O, Corakçi A. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Diabetes Obes Metab 2001;3:332-7.
de Lalla F, Pellizzer G, Strazzabosco M, Martini Z, Du Jardin G, Lora L, et al.
Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Antimicrob Agents Chemother 2001;45:1094-8.
Uchi H, Igarashi A, Urabe K, Koga T, Nakayama J, Kawamori R, et al.
Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 2009;19:461-8.
Tuyet HL, Nguyen Quynh TT, Vo Hoang Minh H, Thi Bich DN, Do Dinh T, Le Tan D, et al.
The efficacy and safety of epidermal growth factor in treatment of diabetic foot ulcers: The preliminary results. Int Wound J 2009;6:159-66.
Edmonds M, Bates M, Doxford M, Gough A, Foster A. New treatments in ulcer healing and wound infection. Diabetes Metab Res Rev 2000;16 Suppl 1:S51-4.
Caravaggi C, De Giglio R, Pritelli C, Sommaria M, Dalla Noce S, Faglia E, et al.
HYAFF 11-based autologous dermal and epidermal grafts in the treatment of noninfected diabetic plantar and dorsal foot ulcers: A prospective, multicenter, controlled, randomized clinical trial. Diabetes Care 2003;26:2853-9.
Xie X, McGregor M, Dendukuri N. The clinical effectiveness of negative pressure wound therapy: A systematic review. J Wound Care 2010;19:490-5.
Veves A, Sheehan P, Pham HT. A randomized, controlled trial of Promogran (a collagen/oxidized regenerated cellulose dressing) vs standard treatment in the management of diabetic foot ulcers. Arch Surg 2002;137:822-7.
Kessler L, Bilbault P, Ortéga F, Grasso C, Passemard R, Stephan D, et al.
Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: A prospective randomized study. Diabetes Care 2003;26:2378-82.
Karim RB, Brito BL, Dutrieux RP, Lassance FP, Hage JJ. MMP-2 assessment as an indicator of wound healing: A feasibility study. Adv Skin Wound Care 2006;19:324-7.
Broussard CL. Hyperbaric oxygenation and wound healing. J Vasc Nurs 2004;22:42-8.
Armstrong DG, Frykberg RG. Classifying diabetic foot surgery: Toward a rational definition. Diabet Med 2003;20:329-31.
Maluf KS, Mueller MJ, Strube MJ, Engsberg JR, Johnson JE. Tendon Achilles lengthening for the treatment of neuropathic ulcers causes a temporary reduction in forefoot pressure associated with changes in plantar flexor power rather than ankle motion during gait. J Biomech 2004;37:897-906.
Fleischli JE, Anderson RB, Davis WH. Dorsiflexion metatarsal osteotomy for treatment of recalcitrant diabetic neuropathic ulcers. Foot Ankle Int 1999;20:80-5.
Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR, et al.
Bisphosphonates in the treatment of Charcot neuroarthropathy: A double-blind randomised controlled trial. Diabetologia 2001;44:2032-7.
Calhoun JH, Overgaard KA, Stevens CM, Dowling JP, Mader JT. Diabetic foot ulcers and infections: Current concepts. Adv Skin Wound Care 2002;15:31-42.
American Diabetes Association. Consensus development conference on diabetic foot wound care: 7-8 April 1999, Boston, Massachusetts. American Diabetes Association. Diabetes Care 1999;22:1354-60.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]