NEUROLOGICAL PROGRESS Disorders of the Autonomic Nervous System: Part 2. Investigation and Treatment* J. G. McLeod, PPhil, FRACP, and R. R. Tuck, PhD, FRACP Autonomic function may be adequately tested with noninvasive tests of sympathetic and parasympathetic pathways, including: the response of blood pressure to change in posture and isometric contraction, heart rate response to standing, variation in heart rate with respiration, Valsalva ratio, sweat tests, and plasma noradrenaline measurements. Abnormal results in two or more of these tests indicate autonomic dysfunction. Intraarterial catheterization and tests of vasomotor function are usually required only in doubtful cases or for research purposes. Treatment of autonomic dysfunction is focused primarily on bladder control and control of orthostatic hypotension. Orthostatic hypotension is best treated with physical measures, pharmacologically with 9-alpha-fluorohydrocortisone and dihydroergotamine mesylate. A number of other agents may be tried but results have been less effective. McLeod JG, Tuck RR: Disorders of the autonomic nervous system: Part 2. Investigation and treatment. Ann Neurol 21:519—529, 1987 When autonomic neuropathy is suspected, noninvasive BLOOD PRESSURE CHANGES. From a study in our tests may be used initially to confirm the diagnosis and laboratory of 76 control subjects aged 5 to 85 years, it to determine whether sympathetic or parasympathetic was concluded that a fall in systolic pressure of greater pathways, or both, are involved. In some cases, further than 30 mm Hg and a fall of diastolic pressure of studies requiring intraarterial catheterization may be greater than 15 mm Hg on standing is abnormal [58], required to localize more precisely the site of the le- although other authors have regarded falls of 20/10 sion in the autonomic nervous system (Table). mm Hg as being outside the normal (control) range [63, 122]. In our own study, and that of others [65], Noninvasive Tests the arterial blood pressure responses to a change in The noninvasive tests of blood pressure and heart rate posture did not alter significantly with age. When response to change in posture, blood pressure re- measuring blood pressure with an inflatable cuff it is sponse to isometric exercise, heart rate variation with important that the arm is extended horizontally when breathing, Valsalva ratio, sweat tests, and plasma the subject is vertical because the hydrostatic effect of noradrenaline levels are adequate screening tests ot the column in the dependent arm may give a falsely sympathetic and parasympathetic function (see Table). elevated blood pressure reading [144]. An abnormal Studies in our laboratory conducted by Ingall [58] fall in arterial blood pressure may occur in patients (which will be reported in detail elsewhere) have who are taking antihypertensive drugs and other medi- shown that abnormal results in two or more of these cations, and in patients with adrenal insufficiency and tests correlate well with abnormalities detected by in- hypovolemia, but if none of these conditions is present vasive tests and indicate autonomic dysfunction. the fall usually signifies the presence of a lesion or lesions in the baroreflex pathways, mainly affecting Blood Pressure and Heart Rate Response vasomotor sympathetic fibers. to Change in Posture The responses of heart rate and blood pressure to CHANGE IN HEART RATE. In resting healthy subjects, changing from the supine to standing position, or to heart rate is determined by the predominantly vagal tilting on a tilt table, are the simplest tests of auto- background autonomic activity [121];,changing from nomic function. the supine to the erect position causes an increase in From the Department of Neurology, Royal Prince Alfred Hospital, Received July 30, 1986, and in revised form Oct 21. Accepted for and the Department of Medicine, University of Sydney, Sydney, publication Oct 21, 1986. NSW 2006 Australia. Address correspondence to Dr McLeod. 'Part 1, "Disorders of the Autonomic Nervous System: Pathophys- iology and Clinical Features," appeared in the May issue. 519 Clinical Tests of Autonomic Function Test Normal Response Part of Reflex Arc Tested NONINVASIVE BEDSIDE TESTS Blood-pressure response to standing Fall in BP S30/15 mm Hg Afferent and efferent limbs or vertical tilt Heart rate response to standing Increase 11—29 beats/minute; 30:15 Afferent and efferent limbs ratio SI.04 Isometric exercise Increase in diastolic BP, 15 mm Hg Sympathetic efferent limb Vagal Heart rate variation with respiration Maximum—minimum heart rate =15 afferent and efferent limbs beats/minute; E:I ratio §1.2" Valsalva ratio S1.41 Afferent and efferent limbs Sweat tests Sweating all body and limbs Sympathetic efferent limb Postganglionic sympathetic efferent Axon reflex Local piloerection, sweating fibers Sympathetic Plasma noradrenaline level Rises on tilting from horizontal to efferent limb vertical Rise with induced Plasma vasopressin level hypotension Afferent limb INVASIVE TESTS Valsalva maneuver Phase I: Rise in BP Afferent and efferent limbs Phase II: Gradual reduction of BP to plateau; tachycardia Phase III: Fall in BP Phase IV: Overshoot of BP, bradycardiaa (1) Slowing of heart rate with induced Baroreflex sensitivity rise of BP* (1) Parasympathetic afferent and effe (2) Steady-state responses to induced rent limbs rise and fall of BP (2) Afferent and efferent limbs (l)Rise in BP Infusion of pressor drugs (2) Slowing of heart rate (1) Adrenergic receptors (2) Afferent and efferent parasympa- thetic limbs OTHER TESTS OF VASOMOTOR CONTROL Radiant heating of trunk Increased hand blood flow Sympathetic efferent limb Immersion of hand in hot water Increased blood flow of opposite hand Sympathetic efferent limb Cold pressor test Emotional Reduced blood flow Sympathetic efferent limb stress Inspiratory gasp Increased BP Sympathetic efferent limb Reduced hand blood flow Sympathetic efferent limb TESTS OF PUPILLARY INNERVATION 4% Cocaine Pupil dilates Sympathetic innervation 0.1% Adrenaline No response Postganglionic sympathetic innervation 1% Hydroxyamphetamine hydro- Pupil dilates Postganglionic sympathetic innervation bromide 2.5% Methacholine, 0.125% pilocar- No response Parasympathetic innervation pine "Age-dependent response. BP = blood pressure; E:I = expiration:inspiration. 520 Annals of Neurology Vol 21 No 6 June 1987 hean rate from 11 to 29 beats a minute [19, 121], but up to age of 40, ratios less than 1.2 may be re- which is independent of age [65]. garded as abnormal. Upon standing, heart rate increases until it reaches a maximum at about the fifteenth heart beat, after which Valsali'a Ratio it slows to a relatively stable rate at about the thirtieth The change in heart rate that occurs in response to a beat. The ratio of the R-R intervals corresponding to brief period of forced expiration against a closed glottis the thirtieth and fifteenth heart beats is known as the or mouthpiece (Valsalva's maneuver) is a useful 30:15 ratio [36], the magnitude of which decreases screening test for abnormalities of autonomic control with increasing age. In young adults, a ratio of less than of the cardiovascular system. During and after Valsal- 1.04 is abnormal. The biphasic heart rate response to va's maneuver, changes occur in cardiac vagal efferent standing is not observed during passive tilting [15] and and sympathetic vasomotor activity that are due to is blocked by atropine; this finding suggests that the stimulation of afferents from baroreceptors in the response is dependent upon normal parasympathetic hean, lungs, aorta, carotid sinuses, and possibly, innervation of the hean [36]. stretch receptors in the lung and muscles of the chest wall [30, 74, 81]. Lesions of any of these autonomic Isometric Exercise pathways or of their central connections are likely to An increase in heart rate, arterial blood pressure, and result in abnormal heart rate responses to Vaisalva's cardiac output occurs during sustained isometric con maneuver. The patient breathes forcefully into a traction of a group of muscles [85]. The cardiovascular mouthpiece attached to a mercury manometer, main- responses are mediated partly by central command taining an expiratory pressure of 40 mm Hg for 10 or [42, 45] and partly by metabolic and/or mechanical 15 seconds while an EKG recording of the hean rate is changes in contracting muscle that activate small fibers made. In normal young subjects, the ratio of the in the afferent limb of the reflex arc [45, 56]. An longest R-R interval to the shonest R-R interval dur- increase in diastolic pressure of less than 15 mm Hg ing the maneuver is at least 1.45 [84]. The response is after 5 minutes of sustained handgrip at 309£ of the age-dependent; a ratio lower than the age-matched maximum voluntary effort is abnormal [37]. The re control values is usually indicative of impaired auto- sponse is not affected by age. In patients with diabetic nomic nervous system control of the heart and blood or uremic neuropathy, the pressor response may be vessels, but low values may also be recorded in pa- reduced or absent [37, 38]. dents with hean and lung disease. Hean Rate Variation Tests of Sweating The increase in heart rate that occurs during inspira- In most normal subjects, a rise in body temperature tion (sinus arrhythmia) results from decreased cardiac causes sweating over the entire body, although small vagal activity; it is blocked by atropine but not by pro- areas of anhidrosis are sometimes observed [11, 86]. pranolol [145]. The vagal afferent fibers that are in- The thermal sweat test is usually performed by apply- volved in the reflex innervate pulmonary stretch re- ing radiant heat to the trunk until the oral temperature ceptors [111]. The magnitude of sinus arrhythmia has risen by 1°C. Sweat is detected by one of several decreases with age [134, 146] and is diminished or chemicals that change color when moist [51, 86, 93]. absent in diabetes and other disorders that affect cen- Large areas of anhidrosis are found in patients with tral or peripheral autonomic pathways [78, 80, 113, autonomic neuropathy due to central or peripheral 137, 145].