Value of Repeated Measures of Nerve Conduction and Quantitative Sensory Testing in a Diabetic Neuropathy Trial

Bird SJ, Brown MJ, Spino C, Watling S, Foyt H. Muscle & Nerve. May 2006.

Diabetic distal symmetrical polyneuropathy (DPN) is by far one of the most common complications of diabetes mellitus. It is characterized as a slowly progressive disease in which ongoing changes, caused by either disease progression or therapy intervention, are difficult to detect; thus, measurements taken can be unreliable and are dependent on the capriciousness of a multitude of tests. However, it is important to understand the impact of DPN; this goal can best be achieved by detecting small changes in an individual over a long period of time. The San Antonio neuropathy consensus aimed to document the progression of DPN and its response to therapy through several electrophysiological, quantitative, sensory, and clinical tools as a means to pave the way for future studies.

In order to quantify the changes occurring in patients with DPN, a study consisting of over 1100 patients at 40 sites in the US and Canada participated. Individuals were stratified at baseline by A1C (≤ or >8%) and randomized into 1 of 3 zenarestat (a highly potent aldose reductase inhibitor) treatment groups (placebo, 600 mg/day, or 1200 mg/day). Eligible patients consisted of men or women between the ages of 18 and 70 with a confirmed presence of mild DPN and at least one abnormal measurement from a nerve conduction study (NCS) or quantitative sensory test (QST). Additionally, bilateral, recordable, and a Central Reading and Coordinationg Center (CRCC)-confirmed sural sensory responses and a left median distal motor latency of <4.6 ms were required for eligibility. NCS measurements consisting of velocity, F-wave latency, and amplitude were repeated 3 times on separate days within a 4–week period. The initial test used a 2-channel Viking Quest electromyography machine and was conducted at baseline, followed by a repeat assessment annually thereafter until 24 months. QST testing, which measures the actual sensory loss experienced by patients based on vibration detection threshold and cool thermal threshold, was also administered 3 times on separate days using the CASE IV system. NCS and QST testing were performed by trained and certified individuals; this was significant largely because reliability and reproducibility was a vital component of the study.

Due to adverse renal effects as a result of zenarestat treatment, the study was discontinued after 12 months, and development of the drug was terminated. Despite this, results were analyzed based on the 12-month study period and treatment intervention. Overall study results indicate that nerve conduction studies are an integral quantifying technique for DPN, and precision and attention to detail plays a vital role in reliable and reproducible data. NCS assessment demonstrated a significant deterioration in nerve conduction velocity in the placebo group, but patients who received zenarestat showed a statistically significant decline in disease progression or an improvement in the complication. Interestingly, QST showed a remarkable reproducibility, comparable to that of NCS, even when performed at multiple sites. Its measurement of cold thermal sensation in the placebo group demonstrated a notable decline over 12 months, and vibratory testing was imperceptive to changes during the first year. But unlike NCS, neither cool thermal or vibratory testing was able to distinguish any effect zenarestat had throughout the 12 months of treatment. The reproducibility of the triplicate measures of NCS and QST suggests that with each additional test, the variability of each measure also decreased, and also significantly decreased the number of patients needed to show a statistically significant treatment effect. F-wave measurements were also extremely reproducible, which further supports the requirement of a small sample size.

Although this study was large, expensive, and time consuming, it is important to understand and be cognizant of the variability inherent in each measurement and endpoint. The NCS and QST are critical tools in quantifying the minute changes that occur in DPN, and from a cost-effectiveness standpoint, it is also necessary to quantify the appropriate number of subjects needed for a study so that time, energy, and money are not wasted.