Foot problems in patients with diabetes mellitus are a major public health concern in the United States. In 1990 the national Centers for Disease Control estimated there were 14 million people in the United States affected by diabetes of whom an estimated 25 percent will develop foot problems (1). Presently, foot problems account for 20 percent of the annual diabetic-related hospitalizations (2). More than 50 percent of the 120,000 non-traumatic, lower-extremity amputations each year result from complications of diabetes (3).
Neuropathy, mechanical stresses and angiopathy (ischemia) are the major causes of foot ulcers in diabetic patients; however, a number of other factors have been cited (4-8). Jauw-Tjen and Brown reported that approximately three times as many patients with diabetes are hospitalized for neuropathic injuries than ischemic (9). Since that report, the role of ischemia appears to be less critical.
This article reviews the etiology of plantar foot ulceration and highlights those risk factors amenable to intervention. The information presented is vital to clinicians who are interested in methods and appliances designed to treat and prevent diabetic foot problems.
Altered nerve metabolism resulting from chronic hyperglycemia is the likely cause of polyneuropathy in diabetes (10). The prevalence of diabetic neuropathy has been shown to be higher in diabetic patients with poorly controlled glucose (11). A distal, mixed sensory-motor-autonomic neuropathy is most common, involving both the large- and small-diameter fibers. There is a predominance of sensory over motor involvement (12). Loss of pain and temperature sensation predisposes the area of involvement to repeated injuries such as burns, abrasions or mechanical stresses. Distal motor neuropathy results in weakness of the foot's intrinsic muscles, leading to the development of claw toe and cavus foot deformities. Weakness of extrinsic peroneal nerve muscles contributes to equinovarus deformities. These deformities cause an abnormal weightbearing distribution (5).
Loss of pain sensation is widely accepted as the primary cause of ulceration of the diabetic foot (3,4,13). Brand demonstrated this important concept in the development of plantar ulceration in leprosy and diabetes patients. Boulton et al. found diabetic patients with plantar ulceration had significantly decreased vibratory sensation and increased plantar pressures compared to diabetic patients without ulceration or normal controls (4). In a recent study of the causal pathways in lower-extremity amputation of 80 diabetic patients, sensory loss was found in 82 percent of the cases while ischemia was found in only 46 percent (3).
Assessing sensory loss by various means has been well studied. Sosenko et al. compared sensory testing with pressure, vibratory and thermal measures and found pressure thresholds using nylon filaments are the most sensitive and specific. Several studies support the use of the 10-gram (Semmes-Weinstein 5.07) nylon filament as the threshold for protective sensation (14-17). Patients unable to feel a 10-gram nylon filament are considered unable to protect their feet from injury and are at risk of ulceration. Patients with loss of protective sensation should be properly fitted with footwear designed to protect the foot and reduce stresses.
The contribution of autonomic neuropathy in foot ulceration has not been well studied, but it may be a factor in both ulceration and faulty healing of such. Loss of sweat gland function may result, allowing ulcer development due to dry, cracked skin (5,13).
Sympathetic denervation results in dilation of the arteries and arterioles increasing blood flow to the foot (18-20). This condition is associated with arteriovenous shunting that rushes blood from the arterial to the venous side of circulation, thus bypassing the capillary nutrient circulation. Long-term sympathetic denervation may cause structural changes in the artery and lead to medial wall calcification. Reduced capillary flow may increase the tissues' susceptibility to injury, slow tissue healing and reduce tissue resistance to infection (21). Manley and Darby found denervated rat pads subjected to repeated stresses ulcerated at a faster rate than their nondenervated controls (22).
Autonomic neuropathy also may result in loss of the venivasomotor reflex (18, 20). This reflex controls rises in venous pressure, especially during standing, by increasing precapillary resistance to blood flow. Loss of this reflex causes increased venous pressure and pooling, which promotes tissue edema. Edema can be a complicating factor in wound healing.
The dilation and shunting of vessels increases the blood supply to the bones of the foot. Bone scan studies with radiopharmaceutical agents showed increased uptake proportional to increased blood flow and osteoblastic activity in neuropathic patients compared to nondiabetic controls (5, 23). Accelerated osteoblastic activity results in demineralization and predisposes the bones to damage (Charcot osteoarthropathy) by minor trauma. Loss of pain sensation from sensory neuropathy lets minor trauma occur.
In summary, autonomic neuropathy causes loss of sweating; rigid, dilated arteries; and arteriovenous shunting. These symptoms result in dry skin, relative distal ischemia, edema, demineralization of bone and increased blood flow to the foot while bypassing the capillary nutrient circulation. In general, the foot faces greater risk of injury and infection, and healing may be impaired.
Neuropathic ulcers are generally painless, round, surrounded by callus and located over prominent bony areas of the toes or plantar surface of the foot (24). There may be multiple lesions, but usually there is just one. The most common sites of ulceration are the first metatarsal head and the plantar aspect of the great toe (16,25). The foot is warm, dry and pink. The patient is initially unaware of the lesion and only notices it by the presence of blood or pus. Loss of sensation is an essential predisposing factor accompanied by mechanical, thermal or chemical injury (5,13,24).
Brand described three mechanisms of injury in the neuropathic foot: ischemia, direct trauma and repetitive stress (13). Ischemia occurs when blood flow to the tissues is blocked by low pressures (1 to 5 psi) over long periods of time. lschemic injury is most commonly caused by wearing tight shoes. Direct trauma results from a single high pressure greater than 1,000 psi and only occurs if a patient walks barefoot on a sharp object or a nail penetrates a shoe. The most common cause of injury is repetitive stress. Moderate pressures (about 20 psi) repeated thousands of times a day can cause ulceration. In a study on denervated footpads of rats, repetitive moderate pressure resulted in inflammation, autolysis and, finally, ulceration over a 10-day period (26). Feet are subjected to similar repetitive stresses during walking. A person with normal sensation may develop inflammation from repetitive walking stresses, but pain will cause him to remove the source of irritation, change the way he walks or stop the activity. The person with loss of protective sensation, however, continues to walk in the same manner, unaware of impending injury.
Brand suggested relatively normal pressures could cause injury to the neuropathic foot (6,13). However, several studies show plantar ulcerations occur at the sites of highest pressure, and these loads are significantly higher in ulcerated-as compared to nonulcerated-feet. Stokes et al. measured load under the feet of normal subjects and diabetic patients using a force plate (27). No differences in force due to age or sex were found within the normals. Maximal loading was increased in diabetic patients with ulcers compared to those without ulcers and normals. The position of maximal loading corresponded to the site of ulceration with greater than normal loading corresponding to callus sites. There was an association between body weight and loading. Diabetic patients with ulcer had decreased loading on the toes compared to normals.
Ctercteko et al. studied forces on the feet of diabetic patients with ulceration, those with neuropathy but no ulceration, and normal subjects while walking on a load-sensitive platform (25). Their findings supported those of Stokes et al. Toe loading was found to be decreased in diabetic patients compared to normals, and the site of maximum force was found under the site of ulceration. Ulcerated patients were also heavier than those without ulceration.
Cavanagh et al., using a pressure platform, also found the site of ulceration in diabetic patients corresponded to the location of highest pressures on the foot and confirmed the decrease of toe loading in diabetic patients (28). They concluded structural deformities resulted in areas of abnormally high pressure and recommended pressure assessment as part of routine foot screening in the early stages of the patient's disease. When deformities are found in the presence of neuropathy or peripheral vascular disease, the foot is at a high risk of ulceration. Ulcers may be prevented by orthoses and modified footwear designed to reduce foot deformity-induced areas of high pressure.
A number of factors contribute to the development of areas of high loading on the foot, including body weight, deformity and hypomobility. Gibbs and Boxer described the relationship of biomechanical deformities of feet and hyperkeratosis (29). They noted the most common biomechanical abnormalities were rearfoot varus, forefoot varus, rigid plantar flexed first ray and equinus. Rearfoot and forefoot varus were causes of hyperkeratosis along the lateral and plantar aspects of the forefoot in the foot lacking compensatory pronation. In the varus foot with compensatory pronation and normal dorsiflexion mobility of the first ray, hyperkeratosis forms on the middle three metatarsal heads. When the first ray is rigid, however, keratosis will develop over the first and fifth metatarsal heads. Hypermobility of the first ray into dorsiflexion results in abnormal pressure on the medial aspect of the great toe and a "pinch callus" develops. Equinus results in increased pressure under all metatarsal heads because tightness of the Achilles tendon forces patients to walk on the balls of their feet. In patients with diabetes mellitus and loss of protective sensation, these deformities may cause ulcers and, eventually, deep sinus tracts (see Figure 1 , Figure 2 , Figure 3a , Figure 3b , Figure 4a , and Figure 4b . Orthoses designed to balance the foot with biomechanical deformities, and thereby reduce mechanical stresses, have been recommended (30). Studies are needed to show the effectiveness of biomechanically designed orthoses in reducing pressures.
By studying the effect of barographic pressure on nondiabetic patients, Lang-Stevenson et al. found that high pressures over the area of healed ulcerations were reduced by surgical correction of deformities (31).
The most severe deformities in diabetic patients are associated with Charcot osteoarthropathies (23). As previously described, the Charcot foot results from minor trauma to the insensitive foot having demineralized bone secondary to increased blood flow or osteoporosis resulting from disuse. Initially, Charcot feet look swollen, warm and red and are easily misdiagnosed as infection. Radiological changes quickly occur with bone destruction and disruption of articular surfaces. Two well-recognized deformities develop: the "rocker bottom" associated with midtarsal bone destruction and subluxation, and a marked, pronated deformity resulting from medial displacement of the talonavicular joint or laterolantar calcaneocuboid dislocation. Both deformities predispose ulcer formation in the midfoot. The early recognition of osteoarthropathy by assessing increased foot temperature (by hand or thermometer), followed by prompt X-rays, is vital in early diagnosis and treatment. The design of custom-molded, supportive footwear with deeply molded insoles is needed to accommodate deformities after healing (32,33).
The relationship of joint limitation and plantar ulceration was established in a study by Delbridge et al. (34). Significant joint limitation at the subtalar joint was found in diabetics with a history of ulceration compared to diabetics without ulceration and normal controls. There was a significant correlation between joint mobility at the subtalar joint and mobility at the first metatarsophalangeal joint.
Additionally, Mueller et al. found significant decreases in sensation, ankle dorsiflexion and subtalar joint motion in diabetic patients with ulceration compared to normal controls (17). They demonstrated the linkage of neuropathy and joint limitation with plantar ulceration in patients with diabetes.
Birke et al. demonstrated the relationship of hallux limitus with great toe ulceration (35). They found significantly decreased great toe extension using a torque range-of-motion system in diabetic patients with a history of great toe ulcers compared to diabetic patients with a history of ulcers at other sites and normal controls.
Fernando DJS et al. studied the role of limited joint mobility (LJM) in causing abnormal foot pressures and foot ulceration. They found significantly increased foot pressures using pedobarography in diabetic patients with limited subtalar and metatarsophalangeal joints compared to diabetic patients and controls without limited mobility (36). Sixty-five percent of patients with neuropathy and limited joint mobility had a history of ulceration. There was a strong correlation between plantar pressures and joint mobility (r = -.7). As shown by these studies, sensory loss and joint hypomobility may result in increased pressure and plantar ulceration. Orthoses and footwear, designed to spread the stresses over time or reduce the function motion requirements (e.g., rocker sole) during walking time, are needed to compensate for hypomobility in the feet of patients with hypomobility (32,33,37)
There is evidence that both the function and structure of proteins in diabetics are changed as a result of hyperglycemia. Free glucose spontaneously attaches to proteins by a process called "nonenzymatic glycosylation" (38,39). Several investigations have shown that joint limitation may result from increased nonenzymatic glycosylation which leads to the molecular cross-linking of collagen protein and causes thickening and stiffness of periarticular tissues. Delbridge et al. observed similar increased nonenzymatic glycosylation of keratin protein in the statum corneum of skin in 30 diabetic patients and proposed these abnormalities may contribute to hyperkeratosis and plantar ulceration (40). Repetitive stresses of gait are the primary cause of callus formation. Mechanical injuries develop from neglected, thickened callus that increases local pressure (5,24). Patients need to be instructed in proper callus care or have a trained clinician regularly trim their calluses.
Thickness of the sole pad also may contribute to ulcer formation in diabetic patients. Gooding et al. found by sonography that thickness of the pad under the heel and first and second metatarsals was decreased in diabetics compared to controls (41). These decreases may be due to atrophy of muscle or connective tissue, or anterior migration of the metatarsal head pads associated with claw toe deformities.
Atherosclerosis is accelerated in diabetic patients compared to nondiabetics. It commonly involves the tibial and peroneal arteries but usually is not found in the foot's arteries (42,43). Atherosclerosis may result in foot ischemia characterized by intermittent claudication, pain with rest and elevation, ulceration and gangrene. Ischemic ulcers are pale, necrotic, often painful, lack callus formation and are localized to the toes, sides of the foot or heel (5). The concomitant presence of neuropathy and ischemia predisposes the foot to minor trauma, which is often the precipitating factor in ischemic lesions. Pecoraro found the sequence of minor trauma, cutaneous ulceration and woundhealing failure was the most common causal pathway to amputation in a study of 80 diabetic patients (3). Ischemia was recognized in 46 percent, neuropathy in 61 percent and infection in 59 percent of the cases. Loss of protective sensation (not defined by the authors) was found in 82 percent. The authors underscored the importance of the pathway of minor trauma, skin ulceration and faulty wound healing (72 percent). Early use of patient education and protective footwear for patients with loss of protective sensation could prevent this pathway. A risk category (see Table 1 ) has been developed for appropriate early intervention in diabetic patients (32,44).
Noninvasive measurement of systolic blood pressures using Doppler ultrasound and digital photoplethysmography has been used to predict foot ulcers' healing potential. Wagner recommended pressure relief as the basic approach for treating foot ulcers when the ischemic index (ankle systolic pressure/ arm systolic pressure) is greater than .45 (45). He reported a 90 percent healing rate for foot ulcers when this criterion was applied. Other criteria predictive of ulcer healing, using the ischemic index or systolic pressure, have been reported (46-48). Barnes et al. reported toe systolic pressure measurements to be more accurate than ankle systolic pressures in predicting wound healing in diabetic patients (47). They found 25-mm Hg toe pressure to be the lower limit for healing in the foot.
Microangiopathy has not been shown to be a cause of ulceration but may be a complicating factor. Diabetic microangiopathy is characterized by thickening of the capillary basement membrane, which may be caused by nonenzymatic glycosylation of collagen. These changes may result in transcapillary leakage of large protein molecules, such as albumin, and limited white blood cell movement. Decreased migration of lymphocytes would reduce resistance to infection (20,43). The diffusion of oxygen does not appear to be reduced by abnormalities in microcirculation, and no evidence supports the role of microangiopathy in ischemic foot lesions (20,43).
Infection is an important complicating factor in ulceration. Diabetic patients are more prone to infection, and the rate of infection parallels the level of blood glucose control. Increased incidence of infection also may be related to impairment of the cell-mediated immunity (24). Infection may progress rapidly with devastating consequences.
Brand describes infection as an additional mechanism of injury in the foot (6,13). Since they experience no pain, patients continue to walk on the infected foot, pushing the infected exudate deeper. Only rest can prevent progression of infection in the foot (49). Many patients develop abscess formation, osteomyelitis and gangrene. Sepsis can track along the planes of the plantar fascia and flexor tendon sheaths. In the infected foot, edema may be responsible for the thrombosis of digital vessels and gangrene of the toes.
Poorly trimmed or ingrown nails are sources of increased toe pressure and portals for infection. Heavy callus formation over sites of bony prominences further increases pressure and may hide ulcerations and abscesses. Dry skin is prone to cracking and requires daily moisturizing.
Poor vision and generalized joint stiffness, both common complications of diabetes, prevent patients from seeing or reaching their feet for inspection and self-care. Help from family members and routine inspection and care of feet by a clinician should be part of any diabetic program. Programs emphasizing foot care have significantly reduced the amputation rates in numerous institutions (50-53).
Many ulcerations occur at the toes due to poorly fitting footwear. Shoes lacking adequate width and height in the toe box area or made of nonstretchable materials pose the greatest danger. Patients with known risk should be fitted with protective footwear and receive regular follow-up for foot and shoe inspection and skin care (see Table 2 ) (30,32,33).
Loss of protective sensation is the primary factor in foot ulceration in diabetics. Mechanical stresses resulting from joint deformity, hypomobility and poor foot care/footwear are important in the causal pathway of both neuropathic and ischemic foot ulcers. Infection is a major factor in ulcer complications and is aggravated by repeated mechanical stresses. Autonomic neuropathy, microangiopathy and connective tissue changes in diabetes also may contribute to ulceration or faulty healing.
Many lesions in the diabetic foot are preventable or treatable with patient education, properly designed and fitted orthoses and footwear, and careful periodic monitoring. A diabetic foot program based on assessment of risk factors-especially sensory loss, deformity, joint limitation and poor circulation-provides a database for early and appropriate management of foot problems. Further research is needed to improve the effectiveness of orthotic and footwear designs in reducing mechanical stresses in the diabetic patient.
James A. Birke, MS, PT, is director of the Physical Therapy Department at Gillis W. Long Hansen's Disease Center, Carville, La. 70721.
Andrew Novick, MA, PT, is a research therapist at Gillis W. Long Hansen's Disease Center, Carville, La. 70721.
Elizabeth S. Hawkins, DPM, MPH, is a research podiatrist at Gillis W. Long Hansen's Disease Center, Carville, La. 70721.
Charles Patout Jr., MD, is director of the Rehabilitation Branch at Gillis W. Long Hansen's Disease Center, Carville, La. 70721.