Diabetic Ulcer

Etiology

The Six Stages of a Diabetic Foot as described by the 7th Practical Diabetes International Foot Conference 

• Stage 1 - Normal foot with no risk factors;
• Stage 2 - High-risk foot
• Stage 3 - Ulcerated foot
• Stage 4 - Cellulitic foot
• Stage 5 - Necrotic foot
• Stage 6 - Foot that cannot be rescued

There are three types of diabetic foot ulcer described namely neuropathic, neuroischaemic, and ischaemic.[2] [3]  Sensory neuropathy leads to the majority of ulcers as a result of minor trauma which is not perceived by the patient and further goes untreated as there are no associated pain symptoms unless there is a routine evaluation to assist in identification. [4] Myocardial infarction is one of the most significant events related to peripheral arterial disease increased risk of ischemia. However, ischemia leading to diabetic ulcers adds severe morbidity and health care cost as it can be a chronic complication which is difficult to treat as there is insufficient blood supply.

Major Risk Factors [5]

• Peripheral motor neuropathy: Abnormal foot anatomy and biomechanics, with clawing of toes, high arch, and subluxed metatarsophalangeal joints, leading to excess pressure, callus formation, and ulcers
• Peripheral sensory neuropathy: Lack of protective sensation, leading to unattended minor injuries caused by excess pressure or mechanical or thermal injury
• Peripheral autonomic neuropathy: Deficient sweating leading to dry, cracking skin
• Neuro-osteoarthropathy deformities (i.e., Charcot disease) or limited joint mobility
• Abnormal anatomy and biomechanics, leading to excess pressure, especially in the midplantar area
• Vascular (arterial) insufficiency: Impaired tissue viability, wound healing, and delivery of neutrophils
• Hyperglycemia and other metabolic derangements: Impaired immunological (especially neutrophil) function and wound healing and excess collagen cross-linking 

Epidemiology

The pooled worldwide prevalence of diabetic foot ulceration was 6.3%. North America had the highest prevalence of 13%; Oceania had the lowest prevalence of 3%. The prevalence in Africa was 7.2% which was higher than Asia 5.5%. Diabetic foot ulceration was more prevalent in male patients with diabetes mellitus, 4.5%, than female patients, 3.5%. Patients with type 2 diabetes mellitus (T2DM) had a higher prevalence of ulceration at 6.4% compared to patients with type 1 diabetes mellitus (T1DM), 5.5%. [6][7]

In a systematic review and meta-analysis by Zhang et al. published in 2016, patients with diabetic foot ulceration had the following characteristics: older age (61.7 plus or minus 3.7 versus 56.1 plus or minus 3.9), longer diabetic duration (11.3 plus or minus 2.5 versus 7.4 plus or minus 2.2), lower body mass Index (BMI, 23.8 ± 1.7 versus 24.4 plus or minus 1.7), higher percentage of smokers (29.1%, 95%CI: 18.3% to 39.8% versus 17.4%, 95% CI: 12.4% to 22.4%), hypertension (63.4%, 95%CI: 49.4% to 88.3% versus 53.1%, 95%CI: 33.8% to 72.5%), and diabetic retinopathy (63.6%, 95%CI: 38.8% to 88.3%% versus 33.3%, 95%CI: 13.8% to 52.7%) than patients that did not develop diabetic foot ulceration. 

Pathophysiology

Atherosclerosis and diabetic peripheral neuropathy are the two main causes leading to a complication of diabetes such as ulcers. Atherosclerosis leads to decreased blood flow in large and medium-sized vessels secondary to thickening of capillary basement membrane, loss of elasticity, and deposition of lipids within the walls. Further arteriosclerosis leads to small vessel ischemia. Peripheral neuropathy affects the sensory, motor, and autonomic nervous system. There are multifactorial causes such as vascular disease occluding the vasa nervorum, endothelial dysfunction, chronic hyperosmolarity, and effects of increased sorbitol and fructose. 

History and Physical

The evaluation of patients presenting with diabetic ulcers can be divided into a clinical and radiologic assessment.

A clinically pertinent history of the type of diabetes, medication history, comorbidities, symptoms of peripheral neuropathy, and vascular insufficiency should be elucidated. Symptoms of neuropathy include hypoesthesia, hyperesthesia, paresthesia, dysesthesia, and radicular pain. Vascular insufficiency has varying presentations and most patients are asymptomatic. However, they can present with intermittent claudication, rest pain, and healing or non-healing ulcers.

In the examination of the legs and foot, an inspection should be performed in a well-lit room with appropriate exposure. Proper documentation using descriptions of ulcer characteristics with size, depth, appearance, and location performed. Presence of discoloration, necrosis, or areas of drainage are signs of infection, and further care is required. Other abnormalities such as nail discoloration, callus formation, and deformities should be noted. Imbalance in the innervations of the foot muscles from neuropathic damage can lead to the development of common deformities seen in affected patients. Hyperextension of the metatarsal-phalangeal joint with interphalangeal or distal phalangeal joint flexion leads to hammer toe and claw toe deformities, respectively. Charcot arthropathy is a commonly seen deformity. Assessment of footwear is important as it can be a contributing factor to the development of foot ulceration. The presence of callus or nail abnormalities should be noted. 

Examine the cardiovascular system, checking popliteal, posterior tibial, and dorsalis pedis pulse. Claudication, loss of hair, and the presence of pale, thin, shiny, or cool skin are physical findings suggestive of potential ischemia. If a vascular disease is a concern, the evaluator should measure the ankle-brachial index (ABI). ABIs can, however, be falsely elevated in patients with diabetes mellitus due to calcification of vessels. More reliable methods of assessing the potential for healing foot ulcers in patients with diabetes mellitus suspected of having peripheral ischemia involve systolic toe pressure measurements by photoplethysmography or measurement of distal transcutaneous oxygen tension. 

Evaluation

Based on wound depth and necrotic tissue, diabetic ulcers can be classified by the Wagner ulcer classification system. [8][9][10]

Wagner-Meggitt Classification of Diabetic Foot

• Grade 0 - Foot symptoms like pain, only
• Grade 1 - Superficial ulcers involving skin and subcutaneous tissue
• Grade 2 - Deep ulcers involving ligaments, muscles, tendons, etc
• Grade 3 - Ulcer with bone involvement  
• Grade 4 - Forefoot gangrene
• Grade 5 - Full-foot gangrene

CBC

Serum Inflammatory Markers

X-Ray/Ultrasound: Performed for the detection of the spread of the lesion and soft tissue involvement.

MRI: Radiologic evaluation involves plain radiographs in two-thirds of the views assessing for deformity.If there is suspicion of osteomyelitis, tendonitis, or joint inflammation MRI imaging should be performed.

Probe-to-bone Test

Monofilament Test

Bone Scan: Can identify the involvement of deep wounds.

Biopsy and Culture: Specimen of bone and other tissue involved and histopathological examination is performed with the culture. This can also guide antibiotic treatment in case of a bacterial infection.

Treatment / Management

Multimodal Diabetic Ulcer Management[11][12]

• Patient Education: Education on foot care, as well as control of blood sugar levels, should be performed early. This can also be done with the aid of diabetic educators and social workers. 
• Blood-Sugar Control: This is managed using a team approach of primary care physician, podiatry, and vascular specialist and based on the severity of the disease and the patient’s attitude toward medication, especially insulin. 
• Decreasing Pressure, preventing further or new trauma: Offloading pressure to the area can be done with crutches, wheelchairs, and casting. Ulcer healing is improved with total contact casting, irremovable cast walkers compared to removable cast walkers. [13]
• Improve Peripheral Vascular Circulation: Antiplatelet agents are the initial drug therapy; however, insufficiency requires surgical bypass. 
• Prevent or Control Infection: Systemic and source control is achieved using antibiotics and surgical debridement.  
• Topical Ulcer Care:  Principles of wound care include the use of topical agents with dressing and debridement. Shallow ulcers can be managed with occlusive and semi-occlusive dressings. A specialized dressing containing hyaluronic acid, collagen, and surgical intervention for debridement is usually required in full-thickness ulcers.

Differential Diagnosis

• Venous Ulcers: It is caused by chronic elevation of venous pressure leading to incompetent valves. Venous blood from deep veins refluxes into superficial veins causing varicose veins and lower limb edema.Leakage of plasma proteins and leukocytes causing edema and free radical damage to the tissue resulting in ulcer formation. The most common locations are the pretibial area and above the medial malleolus. Usually, a shallow ulcer with irregular borders and overlying fibrinous exudate is present.
• Diabetic Dermatopathy: These are purplish, round asymptomatic lesions that usually occur in the lower extremities but can be present anywhere on the body of diabetic patients. These lesions usually require no intervention.  
• Malignancy:- Different malignancies can present as cutaneous ulcers but systemic signs and symptoms ( fever, weight loss, malaise, etc) are also usually present. The diagnosis can be confirmed by microscopic examination of the biopsy specimen.
• Superficial Thrombophlebitis: Characterized by pain, erythema, tenderness overlying inflamed and thrombosed superficial veins.
• Leukocytoclastic Vasculitis: Inflammation of blood vessels and surrounding tissues caused by the deposition of immune complexes.
• Gouty Arthritis: Monosodium urate crystal deposits in joints can result in inflammation, usually associated with hyperuricemia.
• Infection: Primary infectious ulcer results either by direct inoculation or systemic spread. Clinical features vary with the types of infection.
• Sickle Cell Disease: Sickle cell disease can result in painful leg ulcers commonly on medial and lateral malleoli.
• Drugs:-Some drugs e.g, warfarin, heparin, hydroxyurea can result in ulcer formation.

Prognosis

The prognosis of diabetic ulcers is dependant on various factors such as strict diabetes control, patient education, a healthy lifestyle, and proper wound care. Poor blood supply, infection, prolonged duration, and recurrent ulcers are associated with poor prognosis. These prognostic indicators are utilized to take necessary interventions and precautionary measures to reduce the risk of severe complications such as osteomyelitis and amputation.[14][15]

Complications

 Diabetic ulcers can lead to many complications and are responsible for hospitalizations and functional disabilities in diabetic patients.[16]

• Cellulitis
• Gangrene
• Sepsis
• Abscess
• Ascending lymphangitis
• Osteomyelitis
• Limb ischemia
• Amputation[17][18]