Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy

Abstract

Objective: To describe the natural history, clinical, neurophysiological, and histological features, and outcomes of diabetic patients presenting with acute painful neuropathy associated with glycemic control, also referred to as insulin neuritis.

Methods: Sixteen subjects presenting with acute painful neuropathy had neurological and retinal examinations, laboratory studies, autonomic testing, and pain assessments over 18 months. Eight subjects had skin biopsies for evaluation of intraepidermal nerve fiber density.

Results: All subjects developed severe pain within 8 weeks of intensive glucose control. There was a high prevalence of autonomic cardiovascular, gastrointestinal, genitourinary, and sudomotor symptoms in all subjects. Orthostatic hypotension and parasympathetic dysfunction were seen in 69% of subjects. Retinopathy worsened in all subjects. Reduced intraepidermal nerve fiber density (IENFD) was seen in all tested subjects. After 18 months of glycemic control, there were substantial improvements in pain, autonomic symptoms, autonomic test results, and IENFD. Greater improvements were seen after 18 months in type 1 versus type 2 diabetic subjects in autonomic symptoms (cardiovascular p < 0.01; gastrointestinal p < 0.01; genitourinary p < 0.01) and autonomic function tests (p < 0.01, sympathetic and parasympathetic function tests).

Interpretation: Treatment-induced neuropathy is characterized by acute, severe pain, peripheral nerve degeneration, and autonomic dysfunction after intensive glycemic control. The neuropathy occurred in parallel with worsening diabetic retinopathy, suggesting a common underlying pathophysiological mechanism. Clinical features and objective measures of small myelinated and unmyelinated nerve fibers can improve in these diabetic patients despite a prolonged history of poor glucose control, with greater improvement seen in patients with type 1 diabetes.

Figure 1

The upper portion of the graph reveals the glycosylated hemoglobin (A1C) scores over time and the lower portion of the graph reveals neuropathic pain scores at the same visits. Patient numbers correspond to the data shown in Supplementary Tables 1-3. Red lines represent those with type 1 diabetes, black lines represent those with type 2 diabetes. The pain relief that occurred after 1 year was not associated with any pharmaceutical intervention. All pain medications had been stable for more than 6 months at the time of pain improvement (detailed in supplementary Table 1).

Figure 2

Autonomic symptoms were rated using a modified Likert scale where 0=no symptoms, 10 = worst possible symptoms. The graph reveals the mean and standard deviations of the questionnaire scores at baseline (shown in red) and 18 months later (shown in yellow). The questionnaire was administered at the time of autonomic testing; clinically meaningful scores are > 2. Results of baseline vs. 18 months tests for type 1 diabetes (Column A) and type 2 diabetes (Column B); baseline comparisons of type1 vs. type 2 diabetes (Column C) and 18 month comparisons of type1 vs. type 2 diabetes (Column D) are shown. NS=not significant; *= p<0.005; **= p<0.001. OS = Orthostatic symptoms. All results include 9 subjects with type 1 diabetes and 7 subjects with type 2 diabetes, except erectile dysfunction which was limited to male subjects (2 individuals with type 1 diabetes and 5 with type 2).