31 Sympathetic adrenergic tests BP response to a Valsalva maneuver: During the Valsalva maneuver, increased HR occurs in response to decreased BP. The baroreflex response is responsible for the compensatory bradycardia. Patients with autonomic dysfunction show absent overshoot in BP and bradycardia reflex.109 BP response to postural change: Sympathetic nerve function can be tested by measuring the BP response to postural change. Redistribution of blood volume, results into a compensatory tachycardia. In healthy individuals BP increases with approximately 10 mmHg. 1-2 minutes after postural change, BP starts to decrease. In patients with severe autonomic dysfunction, BP abnormalities are seen until 5-10 minutes after postural change.108–110 BP response to sustained handgrip: Sustained muscle contraction results in a reflex rise in BP. During the sustained handgrip, the subject holds a dynamometer for 3-5 min. BP is measured every minute. The difference between diastolic BP just before contraction and just before release of handgrip, is used as measure of BP response. Patients with autonomic dysfunction, show absent rise in BP. Although this is a valuable research tool, many confounders are responsible for a low sensitivity and specificity. Confounders include poor standardization of muscle effort, reduced muscle afferent activity in trained muscles and reduced muscle chemoreceptor afferent activity due to decreased metabolite accumulation.106,108 Cold pressor and mental stress test: Immersing one hand into ice water results into increased BP. This reflex is linearly related with increase in muscle sympathetic nerve activity and venous plasma norepinephrine. Mental stress is created by subtracting seven series from 100 or by applying the Stroop color word-naming test. Mental stress also increases the sympathetic outflow. During sympathetic dysfunction, BP increase is lowered or absent.110 This test is not part of the Ewing test106 or mentioned in the recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.105 Sensitivity and specificity are low and inter-subject variability is high.108 Combined parasympathetic and sympathetic adrenergic tests Pupillometry Pupillometry is the study of changes in pupil diameter as function of cognitive arousal.111 The pupil light reflex is mediated by both, sympathetic and parasympathetic autonomic nerve fibers. This reflex controls the pupil radius as response to environmental light. The parasympathetic system stimulates dilation of the pupil (mydriasis) and the sympathetic system stimulates constriction of the pupil (miosis). The pupil reflex serves as measure for arousal and emotional responses112, sensory pain113 and an index for mental load112. Selective parasympathetic denervation results in relative mydriasis in light. Selective sympathetic denervation results in relative miosis in darkness and diminution of the startle reflex as seen in Horner’s syndrome.114 Therefore, the size of the pupil can be used as indicator for several autonomic neuropathies.115 However, changes of pupil diameter due to arousal or cognitive load, will not exceed 0.5 mm,111 while switching from light to dark can result into an increase from 1.5 to 9 mm. Bladder function test Bladder function depends on learned behavior and is under voluntary control in contrast to other visceral organs. Voluntary control is possible due to complex interactions between autonomic and somatic efferent pathways. Afferent components of the sensory input from the bladder neck and urethra consist of Aδ and C-fibers.116,117 The Aδ fibers are thought to be the primary functional nerves during normal micturition. In contradiction, the C fibers are responsive for pathologic or noxious stimuli, such as chemical irritation or cooling.118,119 Bladder dysfunction may develop as consequence of SFN.120,121 Bladder function tests consist of cystometry, uroflowmetry, sphincter electromyography and urethral pressure profilometry. Cystometry: Cystometry is usually used to test the passive filling component of the bladder. It evaluates sensation, capacity and involuntary detrusor activity. During the test, bladder pressure is 2 33 2
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