Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes

Abstract

Treatment-induced neuropathy in diabetes (also referred to as insulin neuritis) is considered a rare iatrogenic small fibre neuropathy caused by an abrupt improvement in glycaemic control in the setting of chronic hyperglycaemia. The prevalence and risk factors of this disorder are not known. In a retrospective review of all individuals referred to a tertiary care diabetic neuropathy clinic over 5 years, we define the proportion of individuals that present with and the risk factors for development of treatment-induced neuropathy in diabetes. Nine hundred and fifty-four individuals were evaluated for a possible diabetic neuropathy. Treatment-induced neuropathy in diabetes was defined as the acute onset of neuropathic pain and/or autonomic dysfunction within 8 weeks of a large improvement in glycaemic control-specified as a decrease in glycosylated haemoglobin A1C (HbA1c) of ≥2% points over 3 months. Detailed structured neurologic examinations, glucose control logs, pain scores, autonomic symptoms and other microvascular complications were measured every 3-6 months for the duration of follow-up. Of 954 patients evaluated for diabetic neuropathy, 104/954 subjects (10.9%) met criteria for treatment-induced neuropathy in diabetes with an acute increase in neuropathic or autonomic symptoms or signs coinciding with a substantial decrease in HbA1c. Individuals with a decrease in HbA1c had a much greater risk of developing a painful or autonomic neuropathy than those individuals with no change in HbA1c (P < 0.001), but also had a higher risk of developing retinopathy (P < 0.001) and microalbuminuria (P < 0.001). There was a strong correlation between the magnitude of decrease in HbA1c, the severity of neuropathic pain (R = 0.84, P < 0.001), the degree of parasympathetic dysfunction (R = -0.52, P < 0.01) and impairment of sympathetic adrenergic function as measured by fall in blood pressure on tilt-table testing (R = -0.63, P < 0.001). With a decrease in HbA1c of 2-3% points over 3 months there was a 20% absolute risk of developing treatment-induced neuropathy in diabetes, with a decrease in HbA1c of >4% points over 3 months the absolute risk of developing treatment-induced neuropathy in diabetes exceeded 80%. Treatment-induced neuropathy of diabetes is an underestimated iatrogenic disorder associated with diffuse microvascular complications. Rapid glycaemic change in patients with uncontrolled diabetes increases the risk of this complication.

Keywords: autonomic neuropathy; diabetic neuropathy; insulin neuritis; painful neuropathy.

Figure 1

Study participants. All patients without diabetes were excluded from analysis. The remaining subjects were divided into those with large decreases in glycosylated haemoglobin over 3 months (HbA1c decrease ≥2% over 3 months) and those lesser changes to HbA1c. These groups were further subdivided into those that had an acute increase in neuropathic or autonomic symptoms, and those that did not.

Figure 2

Complications and risks associated with TIND. (A–F) The 104 individuals with TIND are grouped by change in glycosylated HbA1c scores. (A) The 27 individuals with a decrease in HbA1c of 2–3.9% are shown. (B) The 52 individuals with a decrease in HbA1c of 4–7% are shown. (C) The 25 individuals with a decrease in AbA1c of >7% are shown. (A–C) The lower portion of the graph (left y-axis) reveals the glycosylated haemoglobin (HbA1c) scores over time. The mean value is shown in red and the standard deviation in black. The upper portion of the graph (right y-axis) reveals neuropathic pain scores during the same time frame. The mean value is shown in black and the standard deviation in red. The representative distribution of neuropathic is shown in D–F, with the area in red representing pain common to all individuals, and the area in grey common to many individuals. (D) The least widespread pain distribution in the individuals with the smallest change in HbA1C (corresponding to A). (E) The pain distribution in the individuals with moderate decreases in HbA1C (B). (F) The group with the largest decrease in HbA1C (C) has widespread neuropathic pain.

Figure 3

Risk of developing TIND. (A) A survival curve plotting the total number of patients (n = 168) with a decrease in HbA1c of ≥2% over 3 months. The absolute risk of developing TIND is plotted against the change in HbA1c over a 3-month period of time. (B) Individual data lines for all 168 individuals with a change in HbA1c ≥2% over 3 months. Individuals that develop TIND are shown with red lines and those that do not develop TIND are shown with grey lines.

Figure 4

Relative risk of complications by change in HbA1c. The relative risk of developing complications (shown in black circles) with 95% confidence intervals is shown for changes in HbA1c of 2–3%, 3–4% or >4% over 3 months. The relative risk of developing each complication is reported against the rate exhibited by the 742 individuals without large glycaemic change. The dotted lines display a relative risk of 1 (i.e. the confidence intervals that cross the dotted line do not have a statistically significant increase in risk of that complication).