Aaem minimonograph #48: Autonomic nervous system testing

The autonomic nervous system maintains internal homeostasis by regulating cardiovascular, thermoregulatory, gastrointestinal, genitourinary, exocrine, and pupillary function. Testing and quantifying autonomic nervous system function is an important but difficult area of clinical neurophysiology. Tests of parasympathetic cardiovagal regulation include heart rate analysis during standing (the 30:15 ratio), heart rate variation with deep breathing, and the Valsalva ratio. Tests of sympathetic adrenergic vascular regulation include blood pressure analysis while standing, the Valsalva maneuver, sustained handgrip, mental stress, and cold water immersion. Tests of sympathetic cholinergic sudomotor function include the sympathetic skin response, quantitative sudomotor axon reflex test, sweat box testing, and quantification of sweat imprints. Pupil function is tested pharmacologically and with pupillographic techniques. Tests of gastrointestinal and genitourinary function do not satisfactorily isolate autonomic regulation from their other functions. The available tests have various sensitivities and ease of administration. They are typically administered in a battery of multiple tests, which improves sensitivity and reliability, and allows probing of various autonomic functions. © 1997 American Association of Electrodiagnostic Medicine. Published by John Wiley & Sons, Inc. Muscle Nerve 20: 919–937 1997.     

Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes.

The purpose of this study was to evaluate sweating and cardiovascular autonomic function in patients with distal small fiber neuropathy (DSFN). Sweat testing by the quantitative sudomotor axon reflex test was abnormal in 32 of 40 (80%) patients. The thermoregulatory sweat test was abnormal in 18 of 25 (72%) patients; one or both tests were abnormal in 36 of 40 (90%). Minor heart rate abnormalities were present in 11 of 40 (28%) patients. We conclude that, in patients with DSFN: (a) the sympathetic sudomotor fibers are frequently affected, and that evaluation of sweating is a useful diagnostic test; (b) that the autonomic nerves controlling heart rate are less affected.     

Autonomic diabetic neuropathy: skin sympathetic response and neurovegetative cardiovascular functionality tests.

One hundred and twelve diabetic patients were submitted to several tests for evaluation of autonomic cardiovascular and sudomotor function. It was found that a patient could be positive to one test and negative to others, thus confirming the presence of sectorial lesions which do not affect the autonomic nervous system uniformly. The parasympathetic system is more frequently and precociously affected than the sympathetic system. The tests used for investigating the sympathetic component, the sympathetic skin response (SSR) gives results which are more frequently and precociously altered.     

Sweat testing to evaluate autonomic function

Sudomotor dysfunction is common in many subtypes of neuropathy but is one of the earliest detectable neurophysiologic abnormalities in distal small fiber neuropathy. Clinical assessments of sudomotor function include thermoregulatory sweat testing (TST), quantitative sudomotor axon reflex testing (QSART), silicone impressions, the sympathetic skin response (SSR), the acetylcholine sweat-spot test and quantitative direct and indirect axon reflex testing (QDIRT). These testing techniques, when used in combination, can detect and localize pre- and postganglionic lesions, can provide early diagnosis of sudomotor dysfunction and can monitor disease progression or disease recovery. In this article, we describe many of the common clinical tests available for evaluation of sudomotor function with focus on the testing methodology and limitations while providing concrete examples of test results.     

Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society,American Academy of Neurology,and the International Federation of Clinical Neurophysiology

Evaluation of disorders of the autonomic nervous system is both an art and a science, calling upon the physician’s most astute clinical skills as well as knowledge of autonomic neurology and physiology. Over the last three decades, the development of noninvasive clinical tests that assess the function of autonomic nerves, the validation and standardization of these tests, and the growth of a large body of literature characterizing test results in patients with autonomic disorders have equipped clinical practice further with a valuable set of objective tools to assist diagnosis and prognosis. This review, based on current evidence, outlines an international expert consensus set of recommendations to guide clinical electrodiagnostic autonomic testing. Grading and localization of autonomic deficits incorporates scores from sympathetic cardiovascular adrenergic, parasympathetic cardiovagal, and sudomotor testing, as no single test alone is sufficient to diagnose the degree or distribution of autonomic failure. The composite autonomic severity score (CASS) is a useful score of autonomic failure that is normalized for age and gender. Valid indications for autonomic testing include generalized autonomic failure, regional or selective system syndromes of autonomic impairment, peripheral autonomic neuropathy and ganglionopathy, small fiber neuropathy, orthostatic hypotension, orthostatic intolerance, syncope, neurodegenerative disorders, autonomic hyperactivity, and anhidrosis.     

Quantitative autonomic testing in the management of botulism

Even with mild neurological signs, patients with botulism frequently complain of autonomic symptoms. This study aimed at the evaluation of sudomotor and cardiovascular reflex functions by quantitative autonomic testing (QAT), which may identify patients with autonomic involvement but otherwise benign clinical presentation. Five patients with food-borne botulism were subjected to a structured questionnaire on autonomic symptoms, cardiac and neurological examination, and QAT after a median of 2 weeks (baseline) and 12 weeks (follow-up) post intoxication. For calculation of haemodynamic and cardiovascular autonomic parameters, we used the Task Force^® Monitor (Version 2.1, CNSystems, Graz, Austria). Cardiovagal function was assessed by Ewing’s test battery. Autonomic complaints were more pronounced than neurological symptoms. Baseline tests revealed widely abnormal sudomotor function and marked impairment of heart rate variation and blood pressure response to standing. Prominent features of cardiovascular failure were high resting heart rate, supine hypertension, orthostatic hypotension, and impaired baroreflex function. Three patients reported inability to keep up with their routine amount of physical work. Based on the baseline QAT results, these three patients were instructed to engage in physical activity but avoid physical strain until there was considerable improvement. On follow-up, fatigue was the most frequent residual complaint, sympathetic skin responses were present, and cardiovascular QAT results were significantly improved and did not differ from those of ten control subjects. QAT identified autonomic involvement in botulism patients with otherwise benign neurological presentation. Comprehensive evaluation of autonomic failure may provide useful information for the management of botulism.     

Sudomotor function in familial dysautonomia

BACKGROUND: Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity. METHODS: In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function. RESULTS: Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p<0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function. CONCLUSION: The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow.     

Cardiovascular autonomic function and sympathetic skin response in chronic inflammatory demyelinating polyradiculoneuropathy

Quantitative cardiovascular autonomic function tests (AFTs) and sympathetic skin response (SSR) were performed in 12 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Parasympathetic autonomic function was examined by Valsalva ratio and R-R interval variation during rest and deep breathing. Sympathetic autonomic function was evaluated by blood pressure responses to sustained handgrip and active standing. Using quantitative AFTs, subclinical autonomic dysfunction was demonstrated in three (25%) patients. Abnormal SSR was seen in six (50%) patients. Thus, mild autonomic dysfunction is present in many CIDP patients. The autonomic abnormalities involve parasympathetic or sympathetic components; in the sympathetic nervous system, both vasomotor and sudomotor fibers may be involved.     

Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease

BACKGROUND: Formal laboratory testing of autonomic function is reported to distinguish between patients with Parkinson's disease and those with multiple system atrophy (MSA), but such studies segregate patients according to clinical criteria that select those with autonomic dysfunction for the MSA category. OBJECTIVE: To characterise the profiles of autonomic disturbances in patients in whom the diagnosis of Parkinson's disease or MSA used criteria other than autonomic dysfunction. METHODS: 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features. They were classified clinically into three diagnostic groups: Parkinson's disease (19), MSA (14), and uncertain (14). The performance of the patients with Parkinson's disease was compared with that of the MSA patients on five autonomic tests: RR variation on deep breathing, heart rate changes with the Valsalva manoeuvre, tilt table testing, the sudomotor axon reflex test, and thermoregulatory sweat testing. RESULTS: None of the tests distinguished one group from the other with any statistical significance, alone or in combination. Parkinson's disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions. CONCLUSIONS: This study supports the clinical observation that Parkinson's disease is often indistinguishable from MSA when it involves the autonomic nervous system. The clinical combination of parkinsonism and dysautonomia is as likely to be caused by Parkinson's disease as by MSA. Current clinical criteria for Parkinson's disease and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.     

Impaired baroreflex function in temporal lobe epilepsy

Changes of cardiovascular function are frequent in temporal lobe epilepsy (TLE). The baroreflex – the most important reflex for cardiovascular stability – has not been studied systematically in TLE. We evaluated cardiovascular variability and baroreflex function in TLE. In 22 TLE patients and 20 controls, we continuously monitored heart rate (HR) and blood pressure (BP). Time-domain parameters were derived from recordings at rest and from standard cardiovascular reflex tests. Spectral analysis determined sympathetic and parasympathetic modulation of HR and BP in the low (LF-power) and high frequency range (HF-power). We calculated the relative LF- and HF-powers of HR in relation to the sum of LF- and HF-powers. LF/HF-ratio of HR was assessed as a parameter of sympatheticovagal balance. LF-transfer function gain between BP and HR determined baroreflex function. Time-domain parameters did not differ between TLE patients and controls. Spectral analysis showed decreased absolute LF- and HF-powers but increased relative LF-power and LF/HF-ratio of HR in TLE. LF-transfer function gain between BP and HR was reduced in TLE (p<0.05). The reduction of absolute LF- and HF-powers indicates decreased total autonomic variability in TLE. However, increased relative LF-power and LF/HF-ratio of HR in TLE show a relative increase of sympathetic tone. Most importantly, we demonstrate an impaired baroreflex function in TLE. These cardiovascular autonomic abnormalities may contribute to cardiac arrhythmia in TLE. Received in revised form: 15 February 2006     

Autonomic Function Tests: Some Clinical Applications

Modern autonomic function tests can non-invasively evaluate the severity and distribution of autonomic failure. They have sufficient sensitivity to detect even subclinical dysautonomia. Standard laboratory testing evaluates cardiovagal, sudomotor and adrenergic autonomic functions. Cardiovagal function is typically evaluated by testing heart rate response to deep breathing at a defined rate and to the Valsalva maneuver. Sudomotor function can be evaluated with the quantitative sudomotor axon reflex test and the thermoregulatory sweat test. Adrenergic function is evaluated by the blood pressure and heart rate responses to the Valsalva maneuver and to head-up tilt. Tests are useful in defining the presence of autonomic failure, their natural history, and response to treatment. They can also define patterns of dysautonomia that are useful in helping the clinician diagnose certain autonomic conditions. For example, the tests are useful in the diagnosis of the autonomic neuropathies and distal small fiber neuropathy. The autonomic neuropathies (such as those due to diabetes or amyloidosis) are characterized by severe generalized autonomic failure. Distal small fiber neuropathy is characterized by an absence of autonomic failure except for distal sudomotor failure. Selective autonomic failure (which only one system is affected) can be diagnosed by autonomic testing. An example is chronic idiopathic anhidrosis, where only sudomotor function is affected. Among the synucleinopathies, autonomic function tests can distinguish Parkinson''s disease (PD) from multiple system atrophy (MSA). There is a gradation of autonomic failure. PD is characterized by mild autonomic failure and a length-dependent pattern of sudomotor involvement. MSA and pure autonomic failure have severe generalized autonomic failure while DLB is intermediate.     

Autonomic nerve function in adults with cyclic vomiting syndrome: a prospective study

Background Cyclic vomiting syndrome (CVS) is a functional gastrointestinal disorder that is characterized by recurrent episodes of intense vomiting. There are several postulated mechanisms involved in its pathogenesis and one potential explanation for this disorder may be linked to autonomic dysfunction. The aim of our study was to evaluate autonomic nerve function in patients with CVS prospectively. Methods We tested the sympathetic nervous system through postural changes in heart rate (HR) and blood pressure and the thermoregulatory sweat test. The parasympathetic nervous system was tested through the HR response to deep breathing (R‐R variability on EKG). Key Results A total of 20 patients who met Rome III criteria for CVS, 14 (70%) women and 6 (30%) men, and 20 controls were enrolled in the study. A total of 17 (85%) CVS subjects and 2 (10%) controls had abnormalities on thermoregulatory sweat testing (P < 0.001). A total of 7 (35%) patients and one control subject had evidence of postural tachycardia (P = 0.04) with an increase in HR > 30 on standing. Of the subjects, 18 (90%) had either abnormal sudomotor function or postural tachycardia or both. The HR response to deep breathing was normal in 19 (95%) subjects with CVS and 18 (95%) controls. Conclusions & Inferences The results of this study suggest that the majority of subjects (90%) with CVS have impairment of the sympathetic nervous system with postural tachycardia and/or sudomotor dysfunction while parasympathetic nerve function appears to be intact. These findings of dysautonomia in CVS have implications in both the diagnosis and treatment of these patients.     

Coexpression of cholinergic and noradrenergic phenotypes in human and nonhuman autonomic nervous system

It has long been known that the sympathetic innervation of the sweat glands is cholinergic in most mammalian species and that, during development, rodent sympathetic cholinergic sweat gland innervation transiently expresses noradrenergic traits. We show here that some noradrenergic traits persist in cholinergic sympathetic innervation of the sweat glands in rodents but that lack of expression of the vesicular monoamine transporter renders these cells functionally nonnoradrenergic. Adult human sweat gland innervation, however, is not only cholinergic but coexpresses all of the proteins required for full noradrenergic function as well, including tyrosine hydroxylase, aromatic amino acid decarboxylase, dopamine beta-hydroxylase, and the vesicular monoamine transporter VMAT2. Thus, cholinergic/noradrenergic cotransmission is apparently a unique feature of the primate autonomic sympathetic nervous system. Furthermore, sympathetic neurons innervating specifically the cutaneous arteriovenous anastomoses (Hoyer-Grosser organs) in humans also possess a full cholinergic/noradrenergic cophenotype. Cholinergic/noradrenergic coexpression is absent from other portions of the human sympathetic nervous system but is extended in the parasympathetic nervous system to intrinsic neurons innervating the heart. These observations suggest a mode of autonomic regulation, based on corelease of norepinephrine and acetylcholine at parasympathocardiac, sudomotor, and selected vasomotor neuroeffector junctions, that is unique to the primate peripheral nervous system.     

Valsalva manoeuvre in patients with different Parkinsonian disorders

The valsalva manoeuvre (VM), used as an autonomic function test, can detect sympathetic and/or parasympathetic autonomic dysfunction. This study investigated the value of VM in patients with different Parkinsonian syndromes (PS). We continuously recorded blood pressure, ECG and respiration among 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson’s disease (PD) and in 27 healthy subjects matched in age and sex (Con). VM was performed in addition to metronomic breathing and tilt-table testing. VM could not be analysed in 26% of the ES patients. Valsalva ratio (VR), as a parameter of cardiovagal function, was pathologically decreased in all patient groups. Valsalva ratio (VR) was not able to discriminate parasympathetic dysfunction between patients and controls as well as E/I ratio of metronomic breathing. As a parameter of sympathetic dysfunction during VM, the physiological increase of blood pressure was more often missing during phase IV than phase II especially in PD and MSA patients. Correlation with orthostatic hypotension during tilt-table testing was only moderate. Although VM can demonstrate sympathetic and parasympathetic autonomic dysfunction, we cannot recommend VM as a first line autonomic test in PS patients. Metronomic breathing and tilt-table test seem more capable as parasympathetic resp. and sympathetic function tests to identify cardiovascular abnormalities in PS patients.     

Sudomotor dysfunction in autoimmune autonomic ganglionopathy: a follow-up study

Objective

We have previously shown that sudomotor dysfunction in autoimmune autonomic ganglionopathy is severe, widespread, and predominantly post-ganglionic. However, the long-term changes in sudomotor function have not been studied in detail. Our objective was to characterize the long-term changes in sudomotor dysfunction in patients with autoimmune autonomic ganglionopathy.

Methods

Changes in sudomotor function were compared in a cohort of nine ??3 nAChR antibody positive autoimmune autonomic ganglionopathy patients over an approximate 5-year period. Standard measurements of sudomotor function were used including the thermoregulatory sweat test and quantitative sudomotor axon reflex test.

Results

Total body anhidrosis on thermoregulatory sweat testing showed improvement in four of nine patients. Quantitative sudomotor axon reflex testing for both forearm and foot sites was variable with four of nine patients showing improvement in total sweat output. Distribution of sudomotor dysfunction at follow-up was post-ganglionic in seven of nine patients at the foot site and three of nine patients at the forearm site. Overall, sudomotor dysfunction was post-ganglionic in seven of nine patients throughout the follow-up period (62.4?±?19.4?months).

Interpretation

Sudomotor dysfunction in autoimmune autonomic ganglionopathy was severe and widespread throughout the follow-up period for the majority of patients studied. Sudomotor dysfunction was predominantly post-ganglionic throughout the follow-up period.     

Cardiovascular autonomic testing in extrapyramidal disorders

Various diagnostic tests are available to demonstrate autonomic failure in extrapyramidal disease. Autonomic function tests can identify parasympathetic and sympathetic dysfunction. While specialized tests are only available in autonomic labs, routine tests such as 24h ambulatory blood pressure measurements can be broadly used in clinical practice eg. as screening tests. In this review, we briefly introduce functional cardiovascular autonomic testing and propose a workup plan for patients with extrapyramidal disease. In all patients with extrapyramidal disease, screening for autonomic dysfunction should be performed. In the case of pathological findings, detailed autonomic testing should be considered with repeated measurements at follow up visits.     

Baroreflex sensitivity and power spectral analysis during autonomic testing in different extrapyramidal syndromes

Autonomic dysfunction has been frequently demonstrated in patients with extrapyramidal diseases by cardiovascular autonomic testing. In addition to classical testing, we applied the more detailed baroreflex and spectral analysis on three traditional cardiovascular tests in this study to get additional information on autonomic outflow. We recorded continuously blood pressure, electrocardiogram, and respiration in 35 patients with multiple system atrophy, 32 patients with progressive supranuclear palsy, 46 patients with idiopathic Parkinson's disease and in 27 corresponding healthy subjects during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head‐up tilt). Baroreflex and spectral analyses were performed by using trigonometric regressive spectral analysis between and during the manoeuvres. Consistent with previous interpretations, our data showed an increase of sympathetic activity in head‐up tilt and Valsalva test in healthy controls. This sympathetic activity was significantly decreased in patients with typical and atypical Parkinson syndromes. Significant modulation of baroreflex activity could be observed especially during metronomic breathing; again it was significantly lower in all patient groups. Baroreflex and spectral parameters could not only differentiate between patients and healthy controls, but also differentiate between clinically symptomatic (with autonomic dysfunction as eg. orthostatic hypotension) and asymptomatic patients. In conclusion, our approach allows the evaluation of autonomic variability during short and nonstationary periods of time and may constitute a useful advance in the assessment of autonomic function in both physiological and pathological conditions. © 2009 Movement Disorder Society     

A device to measure secretion of individual sweat glands for diagnosis of peripheral neuropathy

There is a need for quantitative, precise assessment of small fiber peripheral nerve function. We tested a customized camera device and protocol designed to quantify secretions of individual sweat glands (SGs). Testing was performed on 178 healthy controls and 20 neuropathy subjects. Sweating was stimulated on a 2.25 cm² skin area by iontophoresis of pilocarpine. The camera imaged sweat from 50 to 400 sweat ducts. We calculated secretion rate of individual SGs, total sweat volume, and number of secreting SGs at four body sites. Neuropathy subjects were tested at the two distal sites to demonstrate the device's capability to detect abnormal sudomotor function. Normal ranges were calculated for each body site. Neuropathy subjects had lower sweat rates per SG, lower total sweat, and lower SG density. The normal values decreased with advancing age, were lower in females, and differed between body sites. There was good agreement with repeat testing. The device provides reliable, precise quantitative measures of sweat secretion from single SGs for characterization of sudomotor nerve function in healthy control subjects and in subjects with known peripheral neuropathy. The test combines the capabilities of existing tests of sudomotor function while providing additional capabilities.     

Methods of quantitative evaluation of the autonomic nerve system

Dysfunction of the autonomic nervous system is a frequent finding in many neurological and internal diseases. The quantitative assessment of cardiovascular and sudomotor function is important for diagnosing the autonomic impairment. In this review article, we focus on standard tests that allow evaluation of cardiovascular and sudomotor autonomic functions and describe methods of quantitative assessment that are better suited for research.     

Autonomic dysfunction in Guillain-Barré syndrome.

The following tests of autonomic function were performed on seven patients with the Guillain-Barré syndrome and compared with controls: (1) measurement of heart rate and blood pressure in the supine and erect positions, (2) measurement of baroreflex sensitivity, (3) Valsalva's manoeuvre, (4) sweat test. In two patients the heart rates were fixed and greater than 100/min and in three there was postural hypotension. The baroflex sensitivity of four patients was abnormal and heart rate response to Valsalva's manoeuvre was impaired in two of the three patients who were able to perform the manoeuvre. Areas of anhidrosis were found in all seven patients. These abnormalities probably reflect pathological alterations of the sympathetic and parasympathetic components of the autonomic nervous system of patients with Guillain-Barré syndrome. The severity of autonomic involvement is not related to the degree of sensory and motor disturbance which is consistent with the patchy distribution of lesions throughout the peripheral and autonomic nervous systems.