Neuropathy As A Risk Factor For Diabetic Foot Ulcer

A key factor in the pathogenesis of diabetic foot complications is the loss of protective sensation because of advanced neuropathy. Two case-control studies and four prospective studies demonstrate a higher risk of foot ulcer in association with sensory lower limb neuropathy as measured with the 5.07 monofilament or the biothesiometer. The earlier of the two case-control studies addressed whether neuropathy and vasculopathy were risk factors for foot ulceration in 46 subjects with diabetes and foot ulcers and 322 control subjects in a general medicine clinic (53). Neuropathy was assessed by vibratory, monofilament, and ankle tendon reflex testing. Ankle-arm blood pressure indices and transcutaneous oxygen pressure (TcPO2) on the dorsal foot were used to assess the presence of peripheral vascular disease. In multivariable logistic regression analysis, absence of Achilles tendon reflexes (adjusted OR 6.48, 95% CI 2.37-18.06), abnormal 5.07 monofilament test (adjusted OR 18.42, 95% CI 3.83-88.47), and TcPO2 < 30 mmHg (adjusted OR 57.87, 95% CI 5.08-658.96) were significant risk factors for foot ulceration (53).

In the second case-control study, 225 age-matched subjects with diabetes were enrolled sequentially at several clinics in one large diabetes center (54). Seventy-six cases had existing foot ulceration or recently healed foot ulceration, and 149 controls without ulceration were also recruited. Neuropathy, defined as a vibration perception threshold > 25 volts measured with a biothesiometer, was the most significant risk factor for foot ulceration (OR 15.2). Other risk factors included history of amputation (OR 10); elevated plantar pressure (> 65 N per cm2, OR 5.9); > one subjective symptom of neuropathy (OR

5.1); hallux rigidus, hallus valgus, or toe deformity (OR 3.3); poor diabetes control (OR

3.2); longer duration of diabetes (OR 3), and male sex (OR 2.7). This study was thorough in its assessment of all risk factors documented in previous studies. However, the clinic-based study population was not a random sample, and it was not prospective (Table 2).

In the earliest of the four prospective studies, diabetic American Indians (n = 356) with impaired foot sensation to the 5.07 monofilament had a 9.9 fold increase in risk of incident foot ulcer over a mean of 2.7 years of follow-up (55). Higher vibration perception threshold (>25 V) as measured with a biothesiometer was associated with a nearly sevenfold increase in foot ulcer risk among 469 diabetic subjects followed for at least 3 years (56). In the third prospective study, two hundred forty-eight subjects from three large diabetic foot centers were screened for neuropathy using the Neuropathy Symptom Score, the Neuropathy Disability Score, the biothesiometer, and the 5.07 monofilament (57). Over 30 months, risk factors for foot ulcers were a Neuropathy Disability Score > 5 (RR 3.1. 95% CI1.3-7.6), a VPT > 25 V (RR 3.4, 95% CI 1.7-6.8), abnormal 5.07 monofilament test (RR 2.4, 95% CI 1.1-5.3), and a plantar foot pressure >6 kg per cm2 (RR 2.0,95% CI 1.2-3.3). Recruiting consecutive subjects was less likely to yield a healthy population. Also, it is not clear how closely subjects were followed for the development and treatment of new ulcers.

The largest of these prospective cohort studies followed 749 subjects with diabetes enrolled in a VA general medicine clinic for an average of 3.7 years (58). At baseline the subjects underwent a very thorough evaluation of multiple potential risk factors. Case ascertainment bias was minimized by regular surveillance of subjects by study personnel and as needed assessments of newly developed foot lesions by study staff. Potential bias owing to loss to follow-up was minimized, and, on completion, data was available for 77% of

Table 2

Epidemiological Studies of Neuropathy as a Risk Factor for Foot Ulceration


Type of study


Screening tool for neuropathy

Follow-up time

Risk factors

Odds ratio or relative risk ratio (95% CI)

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