Prevalence of Diabetic Neuropathy and Foot Ulceration: Identification of Potential Risk Factors—A Population-Based Study

Introduction There is substantial evidence that diabetic neuropathy (DN) leading to foot ulceration (FU) is associated with increased morbidity and increased risk of mortality. Previous estimates of the prevalence of diabetic peripheral neuropathy vary widely due to the different diagnostic criteria employed and study populations involved.1,2 Since a definition of DN was obtained in the San Antonio Conference3 and a more clinical approach to the diagnosis was suggested later by the Neurodiab subcommittee of the European Association, there have been only a few population-based studies that have examined the prevalence of this disorder and foot ulceration.3 However, such studies are important when a large population sample size is captured and a high response rate is obtained. These types of studies can give valuable information regarding the actual prevalence of the disease in the whole community. Furthermore, the studies that have been published so far have reported different prevalence rates and also different risk factors for DN and FUs.4–10 The aim of the present study was to estimate the prevalence of diabetic chronic sensorimotor neuropathy and foot ulceration in a geographically well-defined diabetic population and to evaluate the potential risk factors. Patients and Methods Patients who had already been diagnosed with diabetes, age 18 to 70 years, were eligible for enrollment in the study. All patients were living in the same prefecture in Northern Greece. Patients with other diseases known to cause neuropathy, such as pernicious anemia, were excluded from the study. Eight-hundred and twenty-one diabetic patients (306 men, 781 type 2) were studied. They represented 80 percent of the known diabetic population in this area (as estimated in a previous study).11 Mean age was 60 years (59.5 ± 7.96) and the mean known duration of diabetes was 7.6 ± 6.9 years. All the patients were examined by a single observer. Painful symptoms of neuropathy were assessed using a modified neuropathy symptom score (NSS) based on the original system proposed by Dyck.12 More specifically, the patients were asked if they had experienced at any time the following symptoms: pins and needles, abnormal cold or hot sensations in their feet, aching pain, burning pain, and irritation in their feet and legs by the bedclothes at night (paresthesia). One point for the presence of each of these symptoms was assigned. For the first five symptoms one extra point was added if nocturnal exacerbation was present. The Neuropathy Disability Score (NDS) was used to quantify the severity of diabetic neuropathy on clinical examination. The sensations of pain, touch, cold, and vibration were tested in both legs of all patients and were scored according to the level up to which the sensation was impaired (from 1 for toe up to 5 just below the knee). The reflexes were scored in every leg as normal (0), present with reinforcement (1), and absent (2). A NDS greater than five (maximum 28) was considered abnormal.12 The VPT was measured at the great toe of the dominant side using a Bio-Thesiometer (Biomedical Instrument, Newbury, Ohio, USA). The mean value after three readings was recorded as previously described.13 Peripheral neuropathy was diagnosed when at least two of the three quantitative measurements (NSS, NDS, and VPT) were abnormal. Retinal status was assessed from a single funduscopy. Fasting plasma glucose values were obtained from the medical records. Foot pulses were recorded as either present or absent. The absence of one or more pulse, presence of claudication, and/or a history of previous revascularization was regarded as diagnostic for peripheral vascular disease (PVD). The existence of a foot ulcer or history of previous ulceration was also recorded. Statistical Analysis For the univariate analysis, the chi-square test and student t-test were used. Multivariate analysis was further used considering that the nerves are affected simultaneously by all the potential risk factors. All the significant predictors of DN and FU in univariate analysis were entered in the model (backward logistic regression analysis). Results Univariate analysis. The prevalence of neuropathy was 33.5 percent (n = 275) (95% confidence limits 30.3–36.7%). The prevalence of neuropathy did not differ significantly between men and women (35.2% vs. 32.62%, p = NS) and between current smokers and nonsmokers (31.5% vs. 35.07%, p = NS). Patients with any kind of retinopathy had a higher overall prevalence of peripheral neuropathy than patients without (60.06% vs. 29.9%, p 0.05). Two hundred and fifty-seven patients (31.3%) had NSS greater than or equal to three, the criterion to diagnose painful neuropathy. The prevalence rate of FU was 4.75 percent (95% confidence limits 3.3%–6.2%) and of PVD 12.7 percent (10.7%–14.7%, 95% CI). Patients with FU had more severe neuropathy than those without FU (NDS 11.6 ± 5.26 vs. 6.92 ± 2.83, p Multivariate analysis (Multiple logistic regression analysis). A multiple logistic regression analysis of the prevalence of peripheral neuropathy was performed using all the above significant parameters. This analysis confirmed that age, height, duration, and fasting plasma glucose were significant independent predictors of prevalence of neuropathy (p 14,15 However, a more clear picture started emerging after the San Antonio Consensus Statement was published and more standard criteria were used. Thus, Kumar, et al., in 1994, reported a higher prevalence rate (41.6%) of neuropathy in a population-based study that included diabetic patients of any age in three cities in the United Kingdom.10 However, this survey was restricted only to type 2 patients and it did not obtain a high response rate. In the Oxford community-based study, which did not include patients over 75 years, the reported prevalence rates (26%) are quite similar to the results presented in this report.16 Similar results were also reported in two other clinical studies that were not population based. The first one, by Young, et al., in 1993, included 6,487 diabetic patients attending 118 hospital diabetes clinics in the UK and reported a neuropathy prevalence rate of 28.5 percent.17 The second one was a cross-sectional, multinational, European clinic-based study that included 3,250 type 1 patients.18 The diagnosis of neuropathy was based on clinical criteria, and its prevalence was 28 percent. Finally, a population-based study in the US that employed electrophysiology in addition to the techniques that were used in this study reported higher prevalence rates in type 1 and 2 diabetic patients of approximately 50 percent.19 Regarding the risk factors, the present survey, in agreement with previous studies, did not establish different rates of DN between male and female populations.6,10 This is in contrast with a previous study that reported the male gender as a risk factor for DN.4 In addition, our findings that age and known duration of diabetes are risk factors for DN are also in accordance with those previously reported.4,10 Finally, only a few studies have reported height as a risk factor for DN.15 An explanation that has been proposed is that longer nerve fibers are more vulnerable to the toxic effect of hyperglycemia and reduced endoneurial blood flow. Fasting plasma glucose values that were obtained from the medical records in the present study remained significant risk factors for DN, even in the multivariate analysis. HbA1c was not available in some of the tested population (especially in rural population), so we have entered in the model of the multiple logistic regression analysis the mean values of FPG since their diagnosis of diabetes mellitus. This parameter has been found to correlate with HbA1c. Glycemic control is an established risk factor in the majority of the former surveys.4,18 Paradoxically, neuropathy was unrelated to HbA1c or to fasting glucose values in a previous cross-sectional study that involved newly diagnosed type 2 diabetic patients.20 Current smoking and body weight were not positively correlated with neuropathy prevalence rates in the present study. Current smoking has been recognized as a risk factor for DN in two other studies, including one that included only type 1 patients.5,18 The reasons for this discrepancy are not easily understood. Neuropathy presence was found to relate to the presence of any kind of retinopathy, although this association disappeared in multivariate analysis. One other study reported retinopathy as a significant risk factor for DN (in type 1 and type 2 patients) in their analysis.15 However, this association cannot establish a decisive role of retinopathy in the pathogenesis of neuropathy, and retinopathy is currently considered a risk marker for neuropathy, not a risk factor. The observed prevalence rate of FU (4.75%) is similar to that reported in an English community in the UK21 and in another population-based study restricted to type 2 patients.10 In addition, Borssen, et al., found that in a Swedish community, two percent of the studied population had present ulcers and ten percent had a history of ulceration.9 In the present study, we have also found that the severity of the neuropathy (as shown by the NDS and VPT values) was associated with the development of FU and that this association remained significant in the multivariate analysis. Similar results were reported by Young and Kumar.10,17 We used clinical criteria to diagnose PVD, which was mainly the existence of claudication, the absence of foot pulses, or history of revascularization. Previous studies have shown that the sensitivity of this approach is high (93%) for the diagnosis of Doppler-proven PVD.22 Our results showed that in the multivariate regression analysis, PVD remained a significant risk factor for FU. Similar associations after multiple regression analysis were reported by Walters.21 Summary In summary, the findings of the present study indicate that a large proportion of the diabetic population are neuropathic and, therefore, at risk of foot ulceration. The study also identifies the most important risk factors for DN (glucose control, age, long duration, height). Strategies to reduce the risk of neuropathy should be developed and involve all the diabetic population (in rural and urban areas). Avoiding risk factors, such as inappropriate blood glucose control, could reduce the risk of neuropathy. Also, proper foot care and education for the total population is of great importance for neuropathic patients to reduce the risk of foot ulceration and potential amputation.