Autonomic Nerve Testing Predicts the Development of Complications

Abstract

OBJECTIVE -Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical autonomic nerve test abnormalities has not been systematically studied in adolescents. We aimed to reassess an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests. -From 1990-From to 1993, adolescents with type 1 diabetes (n ϭ 335) were assessed for autonomic neuropathy (median age 14.7 years [interquartile range 13.0 -16.8], duration of diabetes 6.3 years [4.0 -9.6], and A1C 8.3% [7.5-9.4]). Between 2003 and 2005, contact was made with 59% of the original group. Individual assessment 12 years later included completion of a validated hypoglycemia unawareness questionnaire (n ϭ 123) and urinary albumin-to-creatinine ratio (n ϭ 99) and retinal (n ϭ 102) screening, as well as analysis of reports from external doctors (n ϭ 35). RESEARCH DESIGN AND METHODSRESULTS -At baseline, there was no difference in age, duration of diabetes, or complications between those who participated in the follow-up phase (n ϭ 137) and those who did not participate (n ϭ 196). However, baseline A1C was lower in the follow-up participants (8.2 vs. 8.5% for participants vs. nonparticipants, respectively, P ϭ 0.031). At 12 years of follow-up, 93% were aware and 7% were unaware that they had hypoglycemia; 32 (31%) had no retinopathy, but 10% required laser therapy, and 80 (81%) had no microalbuminuria. Small pupil size at baseline was independently associated with the development of microalbuminuria (odds ratio 4.36 [95% CI 1.32-14.42], P ϭ 0.016) and retinopathy (4.83 [1.3-17.98], P ϭ 0.019) but not with the development of hypoglycemia unawareness. There was no association with baseline cardiovascular tests and the development of complications 12 years later.CONCLUSIONS -In this study, we found an association between baseline pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This suggests that pupillometry abnormalities may be early indicators of patients who are at high risk of future microvascular disease. (1) presented a landmark study that reported a predictive relationship between symptomatic autonomic neuropathy and mortality in adults with type 1 diabetes. Deaths 5 years later were predominantly due to associated vascular disease (1), which other authors (2) have considered to be an explanation for the increased mortality related to abnormal cardiac autonomic tests. Deaths were also due to hypoglycemia and "sudden death" (1). Owing to the era of the Ewing et al. study, A1C was not measured; therefore, it was not controlled for, and questions remained unanswered. These questions include whether increased mortality was directly related to glycemic control (i.e., a shared mechanism of damage causing both neuropathy and cardiovascular disease by accumulation of advanced glycation end products) or whether there may be...

Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

“…In smaller studies of type 1 diabetes, autonomic dysfunction was associated with increased albuminuria and higher rates of eGFR loss, although cases of abnormal eGFR were rare (16,34). The long-term temporal relationship between the presence of autonomic dysfunction and the development of complications observed in these studies and the current analysis supports the view that the relationship between autonomic neuropathy and future CKD is causal in type 1 diabetes.…”

Cardiac Autonomic Dysfunction Is Associated With High-Risk Albumin-to-Creatinine Ratio in Young Adolescents With Type 1 Diabetes in AdDIT (Adolescent Type 1 Diabetes Cardio-Renal Interventional Trial)

“…+Reference group is lower tertiles. response, a marker of autonomic dysfunction, preceded development of microalbuminuria and diabetic retinopathy 12 years later (33). A limitation of this study is its crosssectional nature; thus, it cannot examine causative and temporal relationships between albumin excretion and the autonomic function.…”

Dysfunction of the pupillary light reflex in experimental autoimmune autonomic ganglionopathy

“…Pupillometry can detect subtle abnormalities when the pupil response appears normal or may demonstrate a small pupillary light reflex when no pupil response is apparent clinically. Pupillometry may also be utilized in assessment of primary autonomic disorders, and in some instances; it is more sensitive than cardiovascular function tests to investigate autonomic dysfunction (Maguire et al, 2007, Micieli et al, 1995, Pena et al, 1995.…”