IntroductionA reliable and valid clinical tool to capture symptoms and signs of diabetic sensorimotor polyneuropathy (DSP) for use in clinical research trials is urgently needed. The validated Toronto Clinical Neuropathy Score (TCNS) was modified to improve sensitivity to early DSP changes. We aimed to assess the reproducibility of this modified tool, the mTCNS and to determine its validity relative to the precursor TCNS.MethodsSixty-five patients (six Type 1, 59 Type 2 diabetes) with diabetes duration 13 ± 8 years were accrued from four study sites and examined on 2 days for internal consistency and inter- and intra-rater reliability of the mTCNS. In the absence of a single quantitative gold-standard measure for DSP, results of the mTCNS were compared with the precursor TCNS for the purpose of estimating validity.ResultsInternal consistency of the two domains within the mTCNS was good (Cronbach's alpha 0.78). Very good inter-rater reliability for the mTCNS was demonstrated by an intra-class correlation coefficient for the mTCNS of 0.87 (95% confidence interval, 0.79–0.91), which was similar in magnitude to that of the TCNS (0.83; 95% confidence interval, 0.75–0.89). Intra-rater reliability testing of the mTCNS showed moderate to good correlation for individual symptoms and sensory tests (Cohen's kappa values of 0.54–0.73). The mTCNS shared moderate correlation with the precursor TCNS (Pearson correlation coefficient, 0.58).DiscussionThe mTCNS, a clinical score with higher face validity for tracking mild to moderate DSP, has sufficient reliability and validity relative to its precursor TCNS for use in clinical research.

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OBJECTIVEAldose reductase inhibitors (ARIs) are potential disease modifiers for diabetes complications. We aimed to determine whether ranirestat, an ARI, could slow or reverse the course of diabetic sensorimotor polyneuropathy (DSP).RESEARCH DESIGN AND METHODSA total of 549 patients with DSP were randomly assigned to treatment with placebo or 10, 20, or 40 mg/day ranirestat for 52 weeks in this multicenter, double-blind study. Efficacy was evaluated by nerve conduction studies, the modified Toronto Clinical Neuropathy Score (mTCNS), and quantitative sensory tests (QSTs).RESULTSAt week 52, the summed sensory (bilateral sural plus proximal median sensory) nerve conduction velocity (NCV) did not show significant changes from baseline (2.0 m/s for placebo compared with 3.2–3.8 m/s for ranirestat). Significant improvement in the summed motor (peroneal, tibial, and median) NCV was observed with 20 and 40 mg/day ranirestat treatment at week 12 (P ≤ 0.05) and at weeks 24 and 36 and in peroneal motor NCV at weeks 36 and 52 (P ≤ 0.05) for the 20 mg/day ranirestat group. The mTCNS and QST results did not differ among the groups during the study. Ranirestat was well tolerated with no pertinent differences in drug-related adverse events or in effects on clinical laboratory parameters, vital signs, or electrocardiograms among the four groups.CONCLUSIONSTreatment with ranirestat appears to have an effect on motor nerve function in mild to moderate DSP, but the results of this study failed to show a statistically significant difference in sensory nerve function relative to placebo.

OBJECTIVE -The primary purpose of this investigation was to determine whether AS-3201, a new aldose reductase inhibitor, penetrates the sural nerve and inhibits sorbitol and fructose accumulation in patients with diabetic sensorimotor polyneuropathy (DSP). An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy.RESEARCH DESIGN AND METHODS -Patients with mild to moderate DSP based on nerve conduction studies were randomized into one of three treatment groups in a doubleblind fashion: placebo or AS-3201 at 5 or 20 mg/day. After 12 weeks of administration, the sural nerve was biopsied for measurement of sorbitol, fructose, and AS-3201.RESULTS -At baseline, no important clinical, electrophysiological, or laboratory differences were found between the three groups. The nerve sorbitol concentration of 3.14 ϫ 10 Ϫ2 nmol/mg wet nerve in patients in the placebo group was inhibited by 65 and 84% in patients on AS-3201 at 5 and 20 mg/day, respectively (P Ͻ 0.001). Fructose levels were similarly inhibited. Sensory nerve conduction velocities improved by Ն1 m/s (P Ͻ 0.05).CONCLUSIONS -AS-3201 penetrates the sural nerve and inhibits sorbitol accumulation in patients with DSP. Additional studies are needed to confirm the electrophysiological suggestion that AS-3201 delays progression or leads to regression of DSP. Diabetes Care 27:2369 -2375, 2004D espite advances in the management of diabetes, diabetic sensorimotor polyneuropathy (DSP) continues to be a frequent and potentially serious complication leading to foot ulceration and amputation (1). A fundamental pathophysiologic mechanism in DSP is aberrant activity of the polyol pathway in which hyperglycemia increases aldose reductase enzyme activity (2). This activation in turn results in an increased conversion of glucose to sorbitol, leading to an accumulation of sorbitol and fructose in several organ systems, including erythrocytes, retina, kidneys, and various nerves. Laboratory studies in animals with diabetes have shown that increased nerve sorbitol is associated with nerve damage with decreased conduction velocity as a result of osmotic changes and oxidative stress (3). If the aldose reductase enzyme system could be pharmacologically inhibited with a decrease in nerve sorbitol and fructose levels, then nerve damage could be prevented or even possibly reversed.A number of aldose reductase inhibitors (ARIs) have been developed, but none have achieved clinical success for diverse reasons (4,5). The study failures have provided information on the natural progression of DSP and have led to suggested criteria for clinical development of ARIs (5). In a recent trial, inhibition of nerve sorbitol levels was associated with improved motor nerve conduction velocity (NCV) and an increase in the density of small-diameter sural nerve myelinated fibers (6). These encouraging results support the role of the polyol pathway in the pathogenesis of DSP. Experience has shown that inhibition of human nerve sorbitol levels must be demonstrat...