Enigma of painful diabetic neuropathy: can we use the basic science, research outcomes and real-world data to help improve patient care and outcomes?

The pathogenesis of painful diabetic neuropathy (PDN) is very complex and its detailed understanding often beyond the remit of the diabetologist or the diabetes multidisciplinary team. Nonetheless it is a very common and difficult to treat complication of diabetes, with significant co-morbidity and mortality, and some basic understanding may help the health care professional with its day to day management. In this review, we discuss the basic pathological mechanisms of PDN, and its clinical manifestations, and present both scientific and real world data on its management, in an attempt to help improve patient care and outcomes.

Showing neuropathy is related to increased mortality in diabetic patients - a survival analysis using an accelerated failure time model.

Diabetic subjects still have a reduced life expectancy despite many potential advances in patient care. Furthermore, population-based studies in well-defined cohorts of patients, to investigate the reduced life expectancies, are generally lacking. Computerized baseline data on a cohort of diabetic patients first attending our clinic during 1982-1985 were used to identify risk factors for increased mortality. This was carried out using an accelerated failure time (ACF) model. Out of 794 patients entered into the model, 201 (25.3%) patients died between 1982 and 1995. Baseline microvascular diabetic complications (peripheral sensory neuropathy and nephropathy) were found to be associated with increased mortality in patients, indicating that these are important, often overlooked, markers for those at greatest risk. Patients with type I (insulin dependent) diabetes mellitus were also identified as being at greater risk.

The natural history of diabetic peripheral neuropathy determined by a 12 year prospective study using vibration perception thresholds.

The development and long term progression of diabetic peripheral neuropathy was studied using vibration perception threshold (VPT) as a validated measure. Three hundred and ninety-two patients had a normal age corrected VPT (12.1 +/- 3.7 volts) at baseline, with an age corrected logarithmic VPTscore < 12. 19.9% developed an abnormal VPT over a 12 year period, increasing from 14.2 +/- 3.7 volts (VPTscore 10.4 +/- 0.6) at baseline to 35.9 +/- 9.5 volts (VPTscore 12.6 +/- 0.45) at follow up (P = 0.0001), and from 10.1 +/- 3.7volts (VPTscore 9.4 +/- 0.8) to 14.2 +/- 4.7 (VPTscore 9.8 +/- 0.8) in the rest. Over 80% thus retained a "normal" VPT after a mean diabetes duration of 16 years despite only average glycaemic control, suggesting that non-ideal long term glycaemic control leads to neuropathy in a subset of predisposed patients. VPT was correlated in 123 diabetic patients with definitive criteria for neuropathy and a range of quantitative sensory and autonomic tests. 62/63 patients with abnormal VPT fulfilled neuropathy criteria; of patients with normal VPT who fulfilled neuropathy criteria, all had at least one abnormal thermal threshold test result. We conclude that a combination of log-transformed VPT values (VPTscore > 10.1) and thermal thresholds can identify diabetic patients at risk of developing peripheral neuropathy and select patients likely to benefit from prophylaxis in clinical trials.

Established diabetic neuropathy seems irreversible despite improvements in metabolic and vascular risk markers--a retrospective case-control study in a hospital patient cohort.

AIMS: To gain insight into the natural history of diabetic peripheral neuropathy (DPN) and its risk factors by means of sequential quantitative testing in a hospital patient cohort. METHODS: A retrospective case-control study involving 300 diabetic patients (100 subjects with neuropathy and 200 control subjects) attending Poole Hospital diabetes clinic between 1995 and 2002. All subjects had a detailed annual clinic assessment including vibration perception threshold (VPT) and physical and metabolic assessments and were categorized according to neuropathy status. Established neuropathy was defined as a VPT > 25 V. Cross-sectional data were analysed by means of a t-test and longitudinal data by means of ANOVA. RESULTS: VPTs increased over time in neuropathy patients, with no change in control patients (P < 0.001). Glycaemic control was better over that period in control patients but the rate of improvement in HbA1c over time was similar in both groups. Triglyceride and high-density lipoprotein cholesterol levels improved in both groups, with significantly greater change in the control group. CONCLUSIONS: Data on reversibility of neuropathy are scarce and our 8-year series shows a continual deterioration in VPT in patients with a threshold > 25 V despite modest improvements in glycaemic control and lipid parameters. This work also supports a vascular association with neuropathy and identifies neuropathic patients as a high-risk cardiovascular group in whom, despite little influence on neuropathy itself, the above metabolic factors should be actively addressed.

A case of hand ulceration in the diabetic foot clinic--a reminder of hand neuropathy in 'at risk' patients.

BACKGROUND: A case of hand ulceration in a diabetic patient with known lower extremity complications is presented. Although often asymptomatic, quantitative testing in patients indicates reduced hand sensation in patients with lower extremity neuropathy. Hand neuropathy may occasionally lead to anaesthetic injuries, particularly in certain 'manual' occupations, as seen in our patient. CONCLUSIONS: Education on hand care is virtually nonexistent in most clinic settings, and our case highlights the need for more awareness on this potentially troublesome complication.

The pathogenesis and management of painful diabetic neuropathy: a review.

Painful diabetic neuropathy has always been a challenging complication of diabetes mellitus. Emerging theories suggest that early dysaesthesia associated with painful neuropathy may act as a marker for the development of the 'at risk' foot, allowing preventative clinical strategies to be undertaken. The mechanisms of neuropathic pain are complex. The authors' intentions are to help members of the diabetes care team better understand and appreciate the diverse symptoms reported by patients. The various treatments available for painful neuropathy are discussed in detail. Robust comparative studies on such treatments are, however, unavailable and the authors have designed a logical approach to management based on best current evidence and their own clinical experience.

Linking a hospital diabetes database and the National Health Service Central Register: a way to establish accurate mortality and movement data.

We have established a records linkage between 'Diabeta' (the computerized clinical records system in the Diabetes Unit of St Thomas' Hospital) and the National Health Services Central Register (NHSCR) of the United Kingdom. Over 7000 diabetic patient records have been collected since 1973. Demographic data on all diabetic patients were retrieved and submitted to the NHSCR via a floppy disk. A matching system (automatic or manual) was used by the NHSCR to identify deceased patients and the most recent demographic data was provided on patients alive. This linkage resulted in an update of 91% of records in Diabeta. The findings of the update included: (1) 86% of diabetic patient's death had not been notified to the hospital and were not recorded on Diabeta. Mortality can now be assessed accurately as an outcome measure in our diabetic population. (2) Provision of the NHS number to Diabeta, as before it was not available on many patients seen in the hospital. The NHS number is a key patient identifier which can be used to exchange information within the NHS-wide network. (3) Diabetes was recorded as a cause of death in only 36% of death certificates. Analyses of death certificates alone must thus give poor information about mortality in diabetes. (4) Geographical location of patients on the database was updated, enabling tracing of patients for long-term studies and analyses of movement.

Geographic and social factors are related to increased morbidity and mortality rates in diabetic patients.

AIMS: To investigate differences in metabolic control, access to healthcare, clinical outcomes and mortality rates in people from different cultural and ethnic backgrounds living in different geographical areas within central London. METHODS: Out of a cohort of 610 patients living within the Greater London boundary and having a first visit to St Thomas' hospital in 1982-1985, 332 patients (54%) were reviewed in 1995, 186 patients (30%) died between 1982 and 1995 and 92 patients (16%) were lost to follow-up. The patients' corresponding 'electoral wards' were ascertained in relation to postcodes of residence (Mapinfo). Each electoral ward has a Jarman 'Underprivileged Area Score' (UPA) so that patients can be clustered into prosperous, intermediate or deprived areas. RESULTS: Patients living in deprived areas (n = 181) were older (61.3 years (95% confidence interval (CI) 59.5-63.1) vs. 58.6 years (95% CI 55.1-62.1), P = 0.01) and had a higher body mass index (29.2 kg/m2 (95% CI 28.4-30.0) vs. 25.7 kg/m2 (95% CI 24.1-27.2), P = 0.003) and worse glycaemic control (HbA1 (%), 10.5 (95% CI 10.1-10.9) vs. 9.1 (95% CI 8.2-10.0), P = 0.003) than patients in prosperous areas (n = 59). Patients in deprived areas were more likely to be Caucasian (P < 0.005), and were less likely to be insulin-treated (P = 0.004). Smoking was more prevalent in deprived areas (P = 0.02). The prevalence of microvascular complications was related to geographical location and the age-sex adjusted mortality rate was significantly higher in deprived than prosperous areas (2.6 vs. 1.91 per 100 person-years). CONCLUSIONS: Environmental factors affect diabetes outcomes; increased morbidity and mortality rates in diabetic patients are related to socio-economic and ethnic status.

Outcome on diabetic foot complications in relation to clinical examination and quantitative sensory testing: a case-control study.

A total of 405 diabetic patients who first attended St Thomas' Diabetes Clinic between 1982 and 1985 had a detailed standardized computerized first visit record, including a structured foot examination and toe vibration perception thresholds (VPT, Biothesiometer), were reviewed in 1995. None of the patients had a history of foot ulceration at first visit. Twenty-five patients (6.2%) developed foot ulcers (n = 11, 2.7%) or had an amputation (n = 14, 3.5%) over a mean 12-year period. Twenty of these patients were then individually matched with 3 non-ulcer patients. Statistically significant odds ratios (OR) were found for a baseline abnormal age-adjusted toe VPT (OR 4.38, CI 1.11-17.26; p = 0.01); abnormal clinical examination (at least 1 abnormality out of: ankle jerks, tuning fork or cotton wool sensation; OR 2.3, CI 1.00-5.20; p < 0.01); and HbA1 (OR 1.30, CI 1.01-1.66; P < 0.02) in patients who subsequently developed lower extremity complications. The sensitivity of VPT (70%) was better than that for clinical testing (55 %) in predicting long-term complications, although all tests showed similar specificity (70-72%). The risk of events also doubled for every 10 years of diabetes (OR 2.10, CI 1.11-4.30; p = 0.02). We conclude that age-corrected VPT measurements, which are objective and simple to perform, are better predictors of future foot complications than semi-quantitative tests in diabetes clinics. We encourage their use in the campaign to reduce the morbidity of diabetic peripheral neuropathy.