Diabetic foot overview

# Overview
Diabetic foot ulceration is one of the well known complications of diabetes and it is associated with high rate of hospitalization based on numerous studies. The discovery of the association between diabetes, foot ulceration, and subsequent infection dates back to the 1850s. Diabetic foot is classified based on the ulcer's features in order to assist with clinical decision-making regarding the need for oral or parenteral antibiotics, outpatient management, hospitalization, and surgical intervention. There are multiple methods of classification for diabetic foot. Neuropathy, ischemia, and trauma are three main pathogenesis of diabetic foot. Neuropathy is the most common and is responsible for more than 60% of diabetic foot cases. Motor nerve involvement can lead to some mechanical changes in the foot of a diabetic patient, which causes more plantar pressure and higher risk of callus formation. Each and every factor leads to a higher rate of skin breakdown and ulceration. Some genetic associations (such as the MAPK14 gene located on chromosome 6, decreased expression of certain cytokines and growth factors, and the HSPA1B genotype) have been explained in diabetic foot development. Charcot arthropathy, some psychosocial conditions, necrotizing fasciitis (NF), vitamin D deficiency, tinea pedis, onychomycosis, and diabetic retinopathy are associated conditions in diabetic foot. Microorganisms such as staphylococcus aureus, pseudomonas aeruginosa, proteus mirabilis, escherichia coli, and bacteroides fragilis are responsible for diabetic foot ulcer infection. Diabetic foot must be differentiated from other diseases that cause foot ulceration, erythema, swelling, and skin lesions, such as skin and soft-tissue infections, gas gangrene, cellulitis, deep venous thrombosis, and inflammatory disorders. The incidence of diabetic foot ulcer is approximately 1,500 per 100,000 diabetic individuals world wide. The 5 year risk of mortality in diabetic patients with a foot ulcer is 2.5 times higher than diabetic individuals without a foot ulcer. Based on a systematic review and metanalysis done on diabetes patients, diabetic foot was more common among older patients. White people develop diabetic peripheral neuropathy (which is a serious risk factor for diabetic foot) more frequently. Male gender is more prone to diabetic foot, compared to females. There are numerous risk factors for diabetic foot development in a diabetic patient, such as poor glycaemic control, inappropriate foot care and footwear, foot deformities, history of previous foot ulcer or amputation, high body mass index, and poor socioeconomic status. For a desired diabetic foot screening, it is critical to perform a careful foot examination at least annually in diabetic patients who are over the age of 15. Nevertheless, there are some risk stratification systems that can provide a better understanding of how often foot screening should be performed based on each patient. The healing process of diabetic foot usually takes a long time (2-5 months) with proper treatment and it can become slower in patients with elevated body mass index or osteomyelitis. Diabetic foot ulcers can cause numerous complications, such as sepsis, osteomyelitis, gangrene, lower limb amputation, and death. History of previous foot ulceration and poor glycemic control are two common positive histories in many patients suffering from diabetic foot. Neuromuscular examination of patients with diabetic foot is usually normal, except in their foot. Findings such as impaired vibration and pressure perception, position sense, and abnormal thresholds for warm thermal perception favor the diagnosis of sensory neuropathy. It is critical to check the extremities for findings such as ulcers, peeling skin, dilated or varicose veins, shiny skin with reduced hair distribution, and broken nails while examining for diabetic foot. For detection of the main responsible microorganisms, biopsy or, curettage or aspiration, of a tissue sample is recommended. It is recommended to obtain a sample from discharge of the ulcer's base. Although a plain X-ray is not successful in osteomyelitis diagnosis within the first weeks of involvement, it is recommended to be performed in any diabetic foot patients with a deep or enduring ulcer. Magnetic resonance imaging (MRI) is specific for osteomyelitis diagnosis. This imaging modality has a 90% sensitivity and an 85% specificity in diagnosis of diabetic foot ulcers. Appropriate wound care is essential for the management of all diabetic foot ulcers. Uninfected diabetic ulcers do not require antibiotic therapy. On the contrary, for acutely infected wounds, empiric antibiotic therapy with coverage against Gram-positive cocci should be started right after obtaining a post-debridement specimen for aerobic and anaerobic cultures. One of the centerpieces of diabetic foot treatment is debridement of necrotic and fibrotic tissues as well as calluses. Foot ulcers can be prevented by frequent physical examinations, proper glycemic control, good foot hygiene, diabetic socks and shoes, and by avoiding injury.

# Historical Perspective
The discovery of the association between diabetes, foot ulceration, and subsequent infection dates back to the 1850s. Significant breakthroughs in the management of diabetic foot wounds include the introduction of surgical debridement in the early 1900s by Frederick Treves. He also introduced the critical role of footwear in diabetic foot ulcers. Furthermore, the discovery of penicillin in 1928 by Alexander Fleming, significantly reduced the mortality rate of diabetic foot patients and their related complications. Throughout the 20th century, advances in surgical limb revascularization and the advent of angioplasty drastically reduced the need for amputation. The latter method remained the mainstays of diabetic foot management in the 2004 and 2012 Infectious Disease Society of America guidelines.

# Classification
Diabetic foot is classified based on ulcer's features in order to assist with clinical decision-making regarding the need for oral or parenteral antibiotics, outpatient management, hospitalization, and surgical intervention. There are multiple methods of classification for diabetic foot. One of them has been published by The Infectious Disease Society of America (IDSA) in their 2004 guidelines and has been mainly focused on the extent of infection and inflammation of the ulcer. In addition, another similar classification system has been released by The International Working Group on the Diabetic Foot (IWGDF) in 2012. The aforementioned systems were externally validated in a longitudinal study to assess prognostic value, which demonstrated increased risk for amputation among patients with infections classified as severe. Another widely accepted diabetic foot ulcer classification is the Wagner ulcer classification system, which uses some ulcer's features such as depth, in addition to presence of osteomyelitis or gangrene.

# Pathophysiology
Diabetic foot is an umbrella term for foot problems in patients with diabetes mellitus. Neuropathy, ischemia, and trauma are three main pathogenesis of diabetic foot. Neuropathy is the most common and is responsible in more than 60% of diabetic foot cases. Factors such as high blood glucose, reactive oxygen species, insufficient oxygenation of the nerves, and inflammation leads to neuropathy development in diabetic patients and it gets worse with alcohol use and smoking. Neuropathy can involve motor, autonomic, or sensory nerves and is able to involve both large and small fibers. Motor nerve involvement can lead to some mechanical changes in the foot of a diabetic patient, which causes more plantar pressure and a higher risk of callus formation. Each and every factor leads to a higher rate of skin breakdown and ulceration. Autonomic neuropathy leads to anhidrosis and impaired function of oil glands, subsequent skin dryness, higher chance of skin breakdown, and ulcer formation. Diabetic patients with sensory neuropathy are more prone to ulcer formation and related complications, since they don't feel pain with ever-deepening ulcers. Ischemia is the second best known pathogenesis of diabetic foot that could occur due to a higher rate of lower limb atherosclerosis in diabetic patients, compared to the normal population. Diabetes related complications such as Micro and macrovascular complications further intensify ischemia. Ischemic changes can be discovered by an impaired ankle brachial index (ABI). Trauma to the foot usually acts as a trigger for diabetic foot. A defective hypoxic response has been explained in diabetic foot, which is related to a transcription factor named hypoxiainducible factor1 (HIF1). Lower levels of HIF1 in biopsies of diabetic foot could be related to its role in wound healing. Some genetic associations (such as MAPK14 gene located on chromosome 6, decreased expression of certain cytokines and growth factors, and the HSPA1B genotype) have been explained in diabetic foot development. Charcot arthropathy, some psychosocial conditions, necrotizing fasciitis (NF), vitamin D deficiency, tinea pedis, onychomycosis, and diabetic retinopathy are associated conditions in diabetic foot. On gross pathology, the most common site of ulceration is on the soles of the feet, under the metatarsal head with various depths and possible anatomical deformities of the foot. In microscopic evaluations of the ulcers, evidence of necrosis, hyperkeratosis, fibrosis, inflammation, cellular debris, granulation tissue, and angiogenesis have been found.

# Causes
Conditions such as peripheral neuropathy and ischemia are two common causes of diabetic foot ulcer formation. Decreased sensation due to peripheral neuropathy increase the risk of trauma which is another known cause of ulcer formation. Microorganisms such as staphylococcus aureus, pseudomonas aeruginosa, proteus mirabilis, escherichia coli, and bacteroides fragilis are responsible for diabetic foot ulcer infection.

# Differentiating Diabetes foot other Diseases
Diabetic foot must be differentiated from other diseases that cause foot ulcerations, erythema, swelling, and skin lesions, such as skin and soft-tissue infections, gas gangrene, cellulitis, deep venous thrombosis, and inflammatory disorders.

# Epidemiology and Demographics
The incidence of diabetic foot ulcers is approximately 1,500 per 100,000 diabetic individuals world wide. Just among US veterans, the incidence of active diabetic foot ulcers is approximately 500 per 100,000 individuals. On the other hand, the incidence of active diabetic foot ulcers in the United Kingdom has been estimated to be 220 per 100,000 individuals. Furthermore, its prevalence has been reported as 170 per 100,000 individuals among the United Kingdom population. The 5 year risk of mortality in diabetic patients with a foot ulcer is 2.5 times higher than diabetic individuals without a foot ulcer. Based on 2 studies with different follow up durations, the mortality rate of diabetic foot has been estimated as 10% and 24% in a 16 month and a 5 year follow up, respectively. Based on a systematic review and metanalysis done on diabetes patients, diabetic foot was more common among older patients. White people develop diabetic peripheral neuropathy (which is a serious risk factor for diabetic foot) more frequently. In 1987, Borch-Johnsen et al. described a male preponderance for the development of severe microvascular complications and diabetic foot disease is not an exception to this rule. The highest prevelance of diabetic foot has been reported in North America. In contrast, Oceania has the lowest prevelance of diabetic foot.

# Risk Factors
There are numerous risk factors for diabetic foot development in a diabetic patient, such as poor glycaemic control, inappropriate foot care and footwear, foot deformities, peripheral arterial disease, peripheral neuropathy, history of previous foot ulcer or amputation, infection, high body mass index, and poor socioeconomic status. Other comorbidities such as hypertension and dyslipidemia are also responsible as risk factors for diabetic foot ulcerations.

# Screening
The main focus of diabetic foot screening should be on peripheral neuropathy detection, since foot ulcer development is rare in the absence of neuropathy. In addition to examining the peripheral neuropathy, physicians should search for any evidence of skin integrity loss, anatomical deformities, nail changes, and distal pulses when they screen diabetic patients. It is recommended to perform a careful foot examination at least annually in diabetic patients who are over the age of 15. Nevertheless, there are some risk stratification systems that can provide a better understanding of how often foot screenings should be performed based on each patient. These systems utilize factors such as peripheral arterial disease, impaired protective sensation of foot, anatomical deformities, history of previous foot ulcer or amputation, and the presence of other concurrent disorders. One of the IWGDF guidelines on the management and prevention of diabetic foot recommended a foot screening assessment sheet for physical examination in each screening. Physicians should educate patients to perform self foot examinations more often. There are diagnostic tools in order to perform a better screening such as the Semmes-Weinstein monofilament, a tuning fork, and a biothesiometer.

# Natural History, Complications and Prognosis
Diabetic foot is a known complication of diabetes. Diabetic patients who are at risk of foot ulceration develop diabetic foot, which may get infected later. The healing process of diabetic foot usually takes a long time (2-5 months) with proper treatment. The final state of diabetic foot is a necrotic foot. The wound healing process can get prolonged in patients with elevated body mass index or osteomyelitis. Diabetic foot ulcers can cause numerous complications, such as sepsis, osteomyelitis, gangrene, lower limb amputation, and death. The chance of amputation is increased with factors such as old age, peripheral vascular disease (PAD), transcutaneous oxygen reduction, poor glycemic control, being on dialysis, and osteomyelitis. If left untreated, prognosis could be very bad and it can eventually lead to death. Male gender, old age, peripheral vascular disease, and concurrent chronic renal failure are related to a higher rate of death. The presence of a single ulcer is associated with a particularly good prognosis among patients with diabetic foot, compared to multiple ulcers. Glycemic control improvement, treatment of neuropathy, and immediate treatment of ulcers improves the prognosis.

# Diagnosis

## History and Symptoms
History of previous foot ulceration and poor glycemic control are two common positive histories in many patients suffering from diabetic foot. Other possible histories in a diabetic foot patient are nephropathy, retinopathy, neuropathy, previous amputation, trauma, and smoking. Diabetic foot patients may present to physicians with numerous symptoms. Nevertheless, the most common symptoms reported in these patients are burning, pins and needles sensation, discharge, and pain. In the late stages of ulcer infection, fever and rigor are also common.

## Physical Examination
Patients with a diabetic foot ulcer could appear ill if ulcers are severe or infected. In severe and chronic infected ulcers, patients may have fever, tachycardia, and low blood pressure. Neuromuscular examination of patients with diabetic foot is usually normal, except in their foot. Altered motor tone, reflexes, and sensation is expected in these patients. Neuropathy symptoms scores (NSS) and neuropathy disability scores (NDS) are helpful in neuropathy assessment of patients with diabetic foot. Findings such as impaired vibration and pressure perception, position sense, and abnormal thresholds for warm thermal perception favor the diagnosis of sensory neuropathy. It is critical to check the extremities for findings such as ulcers, peeling skin, dilated or varicose veins, shiny skin with reduced hair distribution, and broken nails while examining diabetic foot. Moreover, infection possibility should be evaluated. Findings such as pus, erythema, warmth, induration, and bad odor suggest the presence of infection. In some cases, unroofing a small scar demonstrates a deeper infected abscesses. In other words, evaluating an ulcer for infection must be done after debridement. Other necessary physical examinations in these patients are checking the capillary filling time, ankle brachial index, tactile and vibration sensation, and pressure perception.

## Laboratory Findings
Worsened glycemic control could be seen in the laboratory evaluation of diabetic foot patients. Even in the presence of infection, there is no guarantee that measures such as WBC, ESR, and CRP be elevated. For detection of the main responsible microorganisms, biopsy or, curettage or aspiration, of a tissue sample is recommended. It is recommended to obtain a sample from discharge of the ulcer's base. Moreover, due to the contamination of all ulcers, a culture from a non-infectious ulcer is not recommended. For confirming osteomyelitis diagnosis and for appropriate antibiotic treatment, it is critical to obtain a bone biopsy. Properly obtained specimens for a culture prior to initiating empiric therapy, provide useful information for guiding antibiotic selection, particularly in those with chronic or previously treated infections which are commonly caused by gram-negative bacilli or obligate anaerobic organisms.

## Electrocardiogram
There are no ECG findings associated with diabetic foot.

## X Ray
Although a plain X-ray is not successful in osteomyelitis diagnosis within the first weeks of involvement, it is recommended to be performed in any diabetic foot patients with a deep or enduring ulcer. X-rays of the diabetic foot can be helpful in detecting foreign bodies, gas, joint effusion, and osteolysis.

## CT
It is recommended to perform a CT scan only if an MRI is contraindicated. A CT scan is a sensitive modality for detecting abnormal bone appearance in patients with a diabetic foot ulceration. Altered appearance of bones such as bone erosions, charcot joint, reduced joint space, osteopenia, and osteophyte formation can be detected on a CT scan.

## MRI
Magnetic resonance imaging (MRI) is specific for osteomyelitis diagnosis. This imaging modality has a 90% sensitivity and an 85% specificity in the diagnosis of diabetic foot ulcers. While an MRI is very efficient in the diagnosis of diabetic foot, its usage with contrast materials such as gadolinium is not recommended in diabetic patients with evidence of renal diseases. A magnetic resonance angiography (MRA) can be helpful in the evaluation of limb perfusion. Nevertheless, it has limited spatial resolution and reports could be influenced by previous stents or implants.

## Ultrasound
Colorful doppler ultrasound has an 89% and a 68% sensitivity for the iliac artery and the popliteal artery, respectfully. Nevertheless, its sensitivity is higher for anterior and posterior tibial arteries (90%). For a complete evaluation of lower limb perfusion all of the iliac, femoral, popliteal, and tibial arteries they should be scanned by a colorful doppler ultrasound. Doppler ultrasound is not accurate when there is considerable calcification.

## Other Imaging Findings
A bone scan and a white blood cell scan are two imaging modalities that can be used to assist physicians to better diagnose diabetic foot ulcerations. Both could be used when there is a high clinical suspicion for osteomyelitis while plain X-rays are negative. A leukocyte or white blood cell scan has a higher specificity for ostemyelitis diagnosis and is accurate even in neuropathic patients, in contrast to the bone scan.

## Other Diagnostic Studies
Transcutaneous oxygen pressure (TcPO2) measurements can provide data on the perfusion of the involved limb. Although, its accuracy is not totally accepted in presence of severe ischemia and edema. Transcutaneous oxygen pressure (TcPO2) that measures less than 30 mmHg represents the necessity of a complete treatment, due to a very low chance of a spontaneous wound healing. On the other hand, measures more than 40 mmHg predict an acceptable chance of a spontaneous wound healing.

# Treatment

## Medical Therapy
Appropriate wound care is essential for the management of all diabetic foot ulcers. Uninfected diabetic ulcers do not require antibiotic therapy. On the contrary, for acutely infected wounds, empiric antibiotic therapy with coverage against Gram-positive cocci should be started right after obtaining a post-debridement specimen for aerobic and anaerobic cultures. Infections with antibiotic-resistant organisms, chronic or severe ulcers, or which have been previously treated usually require broader spectrum regimens. Treatment strategies are dependent on the ulcer's grade, presence of infection, and perfusion. For an effective treatment which lowers the chance of future diabetic foot ulcers, control of blood sugar, pressure off-loading, and treatment of other comorbidities are also critical. Aim of treatment should be focused on improving prognosis and decreasing complications such as amputation. In very severe ulcers, when the patient has history of previous MRSA infection or when there has been colonization within the past year in regions with high prevalence of MRSA infection, MRSA should also be covered by antibiotic treatments. For an ideal treatment, physicians should evaluate the severity of ulcers and possible risk factors of pseudomonas aeruginosa or extended-spectrum -lactamase (ESBL)producing organisms.

## Surgery
One of the centerpieces of diabetic foot treatment is debridement of necrotic and fibrotic tissues as well as calluses. Debridement should be done until it reaches the bleeding tissue, which is both a treatment and a diagnostic method to evaluate ulcer margin and abscess's presence.

## Primary Prevention
Foot ulcers can be prevented by frequent physical examinations, proper glycemic control, good foot hygiene, diabetic socks and shoes, and by avoiding injury. Studies recommend annual screening by the physician for every diabetic patient older than 15 years old and more frequently for patients who are at risk (such as neuropathy). A careful examination should consist of a peripheral neuropathy assessment, which should be done by checking ankle reflexes, vibration, and sensation. A study showed the importance of using a 10-g Semmes-Weinstein monofilament with a 10 fold risk elevation of foot ulcer development and a 17 fold increase in amputation rate within a 32-month follow up in patients who had abnormal 10-g Semmes-Weinstein monofilament examinations.

## Secondary Prevention
For an appropriate secondary prevention, physicians should focus on strategies such as pressure offloading, appropriate footwear (such as pressure-relieving footwear), treatment of existing infection, and debridement. Early amputation and reconstruction of the damaged vessels could also assist in faster wound healing and will prevent further destruction.