Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: possible predictors of incident neuropathy?

Abstract

Objective: We sought to evaluate the prevalence of subclinical neuropathy in intensive and conventional treatment groups at completion of the Diabetes Control and Complications Trial (DCCT).

Research design and methods: We assessed neuropathy using nerve conduction results obtained at DCCT completion after stratifying the DCCT cohort to exclude subjects with progressively less severe degrees of diagnosable neuropathy. We began with those who had confirmed clinical neuropathy (the primary DCCT end point) and eventually excluded all subjects with any clinical or electrodiagnostic evidence of neuropathy.

Results: After excluding subjects with confirmed clinical neuropathy at DCCT completion, 8 of 10 nerve conduction measures (including all lower-extremity measures) were significantly improved in the intensive treatment group (O'Brien rank-sum test across all nerve conduction measures, P < 0.0001). Conduction velocity group differences were substantial, and the peroneal conduction velocity averaged 3.1 m/s faster in the intensive compared with the conventional treatment group (45.1 vs. 42.0 m/s, P < 0.0001). Numerous significant differences in median and peroneal motor conduction velocities favoring the intensive treatment group persisted, regardless of the exclusion criteria applied.

Conclusions: Intensive and conventional treatment group subjects without diagnosable neuropathy at DCCT completion had significant differences in electrophysiologic measurements favoring the intensive treatment group. Differences in subsequent incident neuropathy between the original treatment groups may reflect, in part, their levels of subclinical neuropathy at DCCT completion, rather than persistent metabolic effects.

Figures

Figure 1

Categories of distal symmetrical polyneuropathy among the entire population of DCCT subjects, including subjects with possible clinical neuropathy (one positive response among symptoms, sensory signs, or absent or hypoactive reflexes), definite clinical neuropathy (more than or equal to two positive responses among symptoms, sensory signs, or absent or hypoactive reflexes), confirmed neuropathy (definite clinical neuropathy and an abnormal nerve conduction study), and subclinical neuropathy (without definite clinical neuropathy but with an abnormal nerve conduction study). Proportions do not reflect the actual data.

Figure 2

Concept of a dichotomous (yes/no) definition of neuropathy defined using clinical or nerve electrophysiological criteria, shown in terms of any quantitative measure of neuropathy (such as number of axons or sensory response amplitude) versus time. The boundary between the shaded and unshaded area represents the detection threshold for neuropathy. The solid and dashed lines represent two patients, one of whom (dashed line) was deteriorating (in terms of developing neuropathy) more rapidly than the other (solid line). At DCCT baseline and completion, neither patient fulfilled criteria for neuropathy, yet one subject (dashed line) had a reduced margin of safety for developing neuropathy relative to the other.