Pupillography refines the diagnosis of diabetic autonomic neuropathy
Introduction
Autonomic neuropathy is one of the most disabling complications of diabetes mellitus with symptoms such as diarrhea or constipation, hypohidrosis or excessive gustatory sweating, erectile dysfunction or orthostatic hypotension [1], [2]. Several epidemologic studies demonstrate increased mortality rates in diabetic patients with autonomic neuropathy even if patients are still clinically asymptomatic [3], [4], [5], [6]. Early diagnosis of autonomic dysfunction in still asymptomatic patients and initiation of a more intense treatment might thus contribute to preventing a progression towards overt autonomic failure [1], [2], [7], [8]. Clinical diagnosis of autonomic dysfunction is largely based on the assessment of cardiac autonomic neuropathy by means of evaluation of heart rate variability (HRV) in response to challenge maneuvers such as metronomic breathing, Valsalva maneuver or active standing up [1], [2], [7], [8]. These tests primarily evaluate parasympathetic autonomic function [1], [9], [10], [11], [12], [13]. The additional evaluation of autonomic function of other organs might be relevant to identify autonomic dysfunction already in early stages of the disease.
The modulation of the pupillary diameter is known to be reduced in advanced stages of diabetes mellitus [14], [15]. Changes of the pupillary diameter, e.g. in response to light stimulation, are controlled by the sympathetic as well as the parasympathetic nervous system [14], [16], [17], [18], [19], [20], [21], [22], [23]. Several studies showed associations between abnormal autonomic control of the pupils and the prevalence of peripheral [14], [24] or cardiac autonomic neuropathy [15] in advanced stages of diabetes mellitus. However, the prevalence and severity of sympathetic versus parasympathetic dysfunction might be different at the eye and the heart. Diabetic neuropathy is a length-dependent dying-back neuropathy. The longer parasympathetic fibers innervating the heart are affected at earlier stages than the cardiac sympathetic fibers [1], [9], [10], [11], [12], [13] while sympathetic pupillary dysfunction might be more pronounced than parasympathetic pupillary dysfunction due to greater length of sympathetic than parasympathetic fibers innervating the eye [25]. Moreover, the vulnerability of the cardiac and pupillary autonomic nerve fibers might be different in diabetes mellitus.
So far, it has not been studied whether the prevalence of pupillary autonomic dysfunction differs from that of cardiac autonomic neuropathy or peripheral somatic neuropathy.
To evaluate whether the assessment of pupillary function refines the early diagnosis of diabetic autonomic neuropathy, we studied pupillary light reflex responses in diabetic patients and compared results to the evaluation of cardiac autonomic and peripheral somatic neuropathy.
Section snippets
Patients
Thirty-six type-II diabetic patients (16 female, 20 male, 39–84 years old [mean age: 57.3±23.5] with mean HbA1c values of 7.45±2.01 mg% and a disease duration ranging between 0.5 and 30 years [mean duration: 18.5±15.8]) and 36 healthy controls (16 female, 20 male, 34–78 years old [mean age: 55.1±19.7]) participated in the study. Informed consent was obtained according to the declaration of Helsinki. Patients with evidence of renal insufficiency, as defined by a serum creatinine of more than 2.2
Results
Fig. 2 demonstrates the number of patients with abnormal results of pupillary light reflexes alone and in combination with test results of cardiovascular autonomic function and/or peripheral nerve function. Overall, light reflex pupillography showed abnormal results in 28 of our 36 patients (77.8%). Seven of the 36 patients (19.4%) showed abnormal results with the tests of cardiac autonomic and/or peripheral neuropathy. Only 1 of the 36 patients (2.8%) had normal results with all of the three
Discussion
Our results demonstrate that impairment of light reflex responses occurs independently from peripheral diabetic neuropathy or from cardiovascular autonomic neuropathy. The prevalence of pupillary autonomic dysfunction was similar in patients with and those without signs of cardiac autonomic or peripheral neuropathy. Moreover, there is no correlation between parameters of cardiovascular and pupillary testing. More than 11% of our patients (4/36) had abnormal pupillary autonomic function but no
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