two studies that have used identical methods. Nevertheless, a pattern can be discerned in these studies. The prevalence in hospital-based populations is probably around 30%, falling to about 20% when people with established diabetes are selected from a community base. Amongst the complete diabetic population, including both diagnosed and undiagnosed diabetes, the prevalence of DSP is probably less than 20%.
Prevalence in Impaired Glucose Tolerance
Although the development of diabetic polyneuropathy is typically insidious over several years, it may occasionally be the presenting feature in type 2 diabetic patients [39]. It is not known whether this “early” nerve alteration has developed during a period of unrecognized diabetes or evolves gradually during a state of impaired glucose tolerance (IGT) prior to the transition to overt diabetes. In this context, it is unclear whether there is a glycemic threshold beyond which nerve dysfunction develops. If IGT constitutes such a threshold which needs to be passed, subjects with IGT should not have a degree of neuropathy higher than that of nondiabetic subjects [40] The results of several studies comparing the prevalence of nerve dysfunction in patientswith IGT and normal glucose tolerance (NGT) are summarized in Table 3.4. The hospital-based studies could not demonstrate a difference in peripheral nerve function and structure between patients with IGT and NGT, except for an abnormal expiration/inhalation ratio, a marker of cardiovascular autonomic neuropathy (CAN), which was found to be more frequent in IGT than in NGT [40]. In one population-based study ankle reflexes were detected less frequently in patients with IGT than in those with NGT [29]. Thus, there is preliminary evidence suggesting that peripheral neuropathy may be slightly more frequent in IGT than in NGT, but further studies are needed to confirm these findings.
Incidence and Natural History
Most of the data describing the frequency of diabetic neuropathy relate to prevalence. The long-term natural history and progression of diabetic neuropathy has been difficult to study owing to the following problems: (1) various nerve fiber populations may be affected at different rates, (2) expected changes may take place over several years. (3) minor changes may not be detected due to a low reproducibility of some methods, (4) measures of nerve function such as nerve conduction velocity (NCV) may deteriorate with age in nondiabetic subjects, and (5) glycemic control or risk factor profile may change and nerve dysfunction may be reversible over time. It has been emphasized that inception cohorts followed from the diagnosis onward are needed to determine the impact of diabetic neuropathy, because prevalence rates consider only the surviving cases and therefore might underestimate the true risk of acquiring the disease [43].
A long-term clinic-based study carried out in a large group of type 1 and type 2 diabetic patients, designed to investigate the relationship between the duration and degree of hyperglycemia and the prevalence of clinically overt neuropathy from the onset of diabetes, was performed by Pirart [44] over a period of 25 years. He defined neuropathy as a loss of Achilles and/or patellar reflexes combined with a reduced vibration sensation or presence of “a more dramatic polyneuropathy or monoor multi-neuropathy.” The prevalence of neuropathy increased from about 8% among the 1900 patients evaluated at the time of diagnosis to about 50% among 100 patients reassessed after a follow-up of 25 years. The incidence of neuropathy increased from three cases per 100 unaffected patients per year to about 19 cases per 100 patients after 25 years. However, Pirart's study had several drawbacks: it was not population-based, no standardized diagnostic measures were employed, the various forms of neuropathy were not differentiated, control subjects were not assessed, and the types of diabetes were not evaluated separately.
In a study focusing on 133 Finnish patients with newly diagnosed (following clinical presentation) type 2 diabetes, the10-year incidence of DSP among those who were free of neuropathy at baseline was 17-20% depending on whether electrophysiological or clinical parameters were used [33]. This gives an annual incidence of approximately 2%. However, the development of DSP and CAN was divergent in that approximately the same proportions of patients with and without peripheral neuropathy developed CAN, either with predominant parasympathetic or sympathetic involvement or both [45]. To explain this finding different underlying mechanisms involved in the evolution of peripheral neuropathy and CAN have been suggested: while hypoinsulinemia predicted the development of DSP, it was hyperinsulinemia that predicted the development of CAN [45].
Over the first 12 years of the UK Prospective Diabetes Study (UKPDS), which similarly studied people newly presenting with type 2 diabetes, neuropathy (as judged by a VPT >25 V) developed in approximately 20% of subjects irrespective of treatment arm, giving an annual incidence of just under 2% [46]. In the American San Luis Valley study [47], DSP was determined by a combination of symptoms and clinical signs. Over nearly five years, its average annual incidence was 6.1 % (6.1 per 100 person-years). A study of US veterans reported neuropathy (monofilament insensitivity) developing in 20% of subjects over approximately 2.5 years [17]. The higher incidence in the last two studies was probably due to the fact they only included people with established diabetes, who, consequent on their longer disease duration, would have had a higher baseline risk than the subjects with newly diagnosed diabetes who were included in the other two studies.
In the Rochester Diabetic Neuropathy Study (RDNS), after two years the Neuropathy Impairment Score (NIS) was unchanged in 81%, worse in 10%, and better in 9% of the patients and the Neuropathy Symptom Score (NSS) was unchanged in 92% and worse or better in 4% of the patients, respectively. The most prominent monotone (consistent) worsening over two years was found for a composite score combining neuropathic deficits and quantitative measures of DSP (NIS[lower limbs] + 7 tests), which worsened on average by 0.34 points per year in the entire cohort and by 0.85 points per year in patients with DSP [48].
The Epidemiology of Diabetes Complications Study (EDCS) reported on a six-year follow-up of 453 type 1 diabetic patients who were free of DSP at baseline. 15% of whom developed DSP in six years, giving an incidence of 2.8 per 100 person-years and a cumulative probability of 0.29 [49], DSP was defined as the presence of two or more of the following: symptoms, sensory and/or motor signs, and/or absent (or present only with reinforcement) tendon reflexes. In the DCCT, which included groups of highly selected individuals with type 1 diabetes, polyneuropathy (abnormal history or examination, confirmed by abnormal nerve conduction or autonomic function) developed in 9.6% of those who were conventionally treated, and in 2.8% of those in the intensively treated group, over five years [2].
Comparing to the data for type 2 diabetes, it appears that the incidence of neuropathy in type 1 diabetes (using the data from the conventionally treated group - approximately 2% per year) is similar to that in newly diagnosed type 2 diabetes, but less than that in previously diagnosed type 2 diabetes. However,
