The Autonomic Symptom Profile
A new instrument to assess autonomic symptoms
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Abstract
Objective: To develop a new specific instrument called the Autonomic Symptom Profile to measure autonomic symptoms and test its validity.
Background: Measuring symptoms is important in the evaluation of quality of life outcomes. There is no validated, self-completed questionnaire on the symptoms of patients with autonomic disorders.
Methods: The questionnaire is 169 items concerning different aspects of autonomic symptoms. The Composite Autonomic Symptom Scale (COMPASS) with item-weighting was established; higher scores indicate more or worse symptoms. Autonomic function tests were performed to generate the Composite Autonomic Scoring Scale (CASS) and to quantify autonomic deficits. We compared the results of the COMPASS with the CASS derived from the Autonomic Reflex Screen to evaluate validity.
Results: The instrument was tested in 41 healthy controls (mean age 46.6 years), 33 patients with nonautonomic peripheral neuropathies (mean age 59.5 years), and 39 patients with autonomic failure (mean age 61.1 years). COMPASS scores correlated well with the CASS, demonstrating an acceptable level of content and criterion validity. The mean (±SD) overall COMPASS score was 9.8 (±9) in controls, 25.9 (±17.9) in the patients with nonautonomic peripheral neuropathies, and 52.3 (±24.2) in the autonomic failure group. Scores of symptoms of orthostatic intolerance and secretomotor dysfunction best predicted the CASS on multiple stepwise regression analysis.
Conclusions: We describe a questionnaire that measures autonomic symptoms and present evidence for its validity. The instrument shows promise in assessing autonomic symptoms in clinical trials and epidemiologic studies.
Because there is no validated, self-completed questionnaire to assess autonomic symptoms, we developed and tested a questionnaire, the Autonomic Symptom Profile, as an instrument to assess autonomic symptoms in three groups of patients: normal controls, patients with nonautonomic peripheral neuropathies, and patients with neurogenic autonomic failure. Our objectives were to determine the frequency of symptoms of autonomic dysfunction, to assess if symptom frequency correlated with quantitative assessment of autonomic deficits, and to test if subscores of symptoms are helpful in differentiating between control and disease groups.
Methods.
Questionnaire design.
The questionnaire was designed to address the following criteria:
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1. Items should reflect domains or systems (i.e., orthostatic, secretomotor, gastrointestinal) that are relevant to patients with autonomic disorders.
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2. Summary quantitative scores should be provided by domain and overall for each person.
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3. The scale scores should be clinically meaningful and accurate.
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4. The questionnaire should demonstrate face, content, and criterion validity.
Questions.
We asked questions used routinely in practice. We specifically asked questions about onset and evolution of symptoms as well as their frequency and severity, exacerbating and relieving factors, and possible relationship to meals, standing, exercise, and other factors influencing autonomic function.
Questionnaire.
The questionnaire was 169 items, including demographic questions. The items were generated by seeing patients with autonomic disorders, having experience in the design of other questionnaires, engaging in discussion with clinicians specializing in autonomic disorders, reviewing other questionnaires, and conducting extensive and unstructured interviews with patients with autonomic disorders and peripheral neuropathy.1 From this set of questions, 73 items emerged as the most important and frequently asked questions about autonomic symptoms. This profile is an expansion of an earlier questionnaire used to evaluate symptoms of orthostatic hypotension.2 These 73 questions assess the following nine domains of autonomic symptoms: orthostatic (9 items); secretomotor, including sudomotor symptoms (8 items); male sexual dysfunction (8 items); urinary (3 items); gastrointestinal, including gastroparesis, diarrhea, and constipation (14 items); pupillomotor, including visual symptoms (7 items); vasomotor (11 items); reflex syncope (5 items); and sleep function (8 items). Some categories consisted of primary questions followed by conditional modifying questions. This approach was helpful in saving time for those patients with few or no symptoms. The nine domains were chosen because they are commonly affected in autonomic disorders and because they have the potential to aid in recognizing patterns or systems involved with possible diagnostic implications. The following is a sample question from the orthostatic domain: “In the past year, have you ever felt faint, dizzy, or ‘goofy’ or had difficulty thinking soon after standing up from a sitting or lying down position?” A group of 12 questions aimed at detecting psychosomatic indices (6 items) and understatement indices (6 items) were mixed with the autonomic items. An example of such an understatement question is: “Have you ever in your adult life had difficulty keeping your mind on your job or task?”
Composite Autonomic Symptom Scale (COMPASS).
Seventy-three questions were grouped into key scorable areas of the autonomic nervous system. Each area was scored based on presence, severity, distribution, frequency, and progression of symptoms. Based on our clinical judgment, a positive response was given a value of 1, but responses with better predictability for disease were given a value of 2 or 3. Examples of responses are as follows: Answering yes to question #18 (“In the past year, have you ever felt faint, dizzy, or ‘goofy’ or had difficulty thinking soon after standing up from a sitting or lying down position?”) was given a score of 2, and answering no was given a score of 0. An answer of “almost always” to question #19 (“When standing up, how frequently do you get these feelings or symptoms?”) was given a weighting of 3. Based on our current perception of the importance of symptoms, an aggregate score incorporating individual items, with weighting according to clinical relevance, was established. The weighted maximum scores per autonomic domain were as follows: orthostatic, 40; secretomotor, 20; male sexual dysfunction, 30; urinary, 20; gastrointestinal, 40; pupillomotor, 5; vasomotor, 10; reflex syncope, 20; sleep disorder, 15. An example of the weighting scale for the orthostatic domain is shown in table 1. The highest possible overall score for men was 200 and for women was 170. The smaller overall score for women was due to the lack of questions addressing sexual dysfunction in women. The psychosomatic and understatement scales are scored separately and are not included in the COMPASS scores.
Orthostatic intolerance
Validation.
Assessing the degree of criterion validity was accomplished by correlating the COMPASS scores with the scores of the Composite Autonomic Scoring Scale (CASS).3 We selected the CASS, which objectively quantitates autonomic deficits derived from the Autonomic Reflex Screen (ARS), as our criterion “gold standard” assessment. The ARS consists of a comprehensive battery of noninvasive autonomic tests that are quantitative, sensitive, specific, reproducible, and standardized.4 Autonomic tests were performed as previously described,5 and the elements of the ARS include the Quantitative Sudomotor Axon Reflex Test, which evaluates one upper and three lower limb sites; orthostatic blood pressure and heart rate response to tilt; heart rate response to deep breathing; the Valsalva ratio; and beat-to-beat blood pressure measurements during the Valsalva maneuver, tilt, and deep breathing. The CASS is a 10-point scoring system of autonomic function. The scale rates adrenergic deficits by one of four grades and sudomotor and cardiovagal deficits each by one of three grades. Each score is normalized for the compounding effects of age and sex. This score ranges from 0 (no deficit) to 10 (maximal deficit).
Study subjects.
Three subject groups were studied: normal controls (NMLs), patients with peripheral neuropathy (PN), and patients with neurogenic autonomic failure (NAF). We consecutively recruited patients referred for evaluation of PN and autonomic dysfunction. Normal subjects were recruited from the community and healthy controls from a longitudinal population-based study (Rochester Diabetic Neuropathy Study). All NMLs received medical care at Mayo Clinic Rochester, and their medical records were reviewed to exclude those with neurologic or autonomic disorders. None of the control subjects were taking medications known to influence the results of autonomic tests. When medically permissible, we asked patients in the PN and NAF groups to discontinue medications that could alter the results of autonomic tests for 24 to 48 hours before testing.5
A total of 113 subjects completed a self-administered questionnaire before undergoing autonomic tests. To ensure compliance and minimize missing items, the questionnaire was assessed for completeness by the study coordinator before autonomic studies. The diagnoses of patients in the PN and NAF groups were determined before analyzing the responses to the questionnaire.
Statistical analysis.
Nonparametric methods were used for data analysis because of skewness in the overall COMPASS score and subscores. The Wilcoxon rank sum test was used to make pairwise comparisons between the three subject groups and between the sexes. Univariate and age- and sex-adjusted Spearman rank correlations were used to describe the overall association between the CASS score and the COMPASS subscores. Stepwise regression using Kendall’s τb from the correlation matrix6 was used to assess the association of the COMPASS scores, age, and sex with the CASS. Statistical significance was defined as a two-tailed p value ≤ 0.05.
Results.
General observations.
The questionnaire was well received and was completed in approximately 20 minutes in most cases.
Clinical features of groups.
Demographic details of the subjects are summarized in table 2. Individuals in the NML group tended to be younger than those in PN and NAF groups. The age and sex distribution of patients in the PN and NAF groups were not significantly different. The etiology of the nonautonomic neuropathies was as follows: distal small fiber neuropathy (10), monoclonal gammopathy-associated neuropathy (5), diabetic neuropathy (3), chronic inflammatory demyelinating polyradiculoneuropathy (3), hereditary motor and sensory neuropathy (2), multiple mononeuropathies and immune-mediated neuropathies (6), neuropathy associated with osteosclerotic myeloma (2), idiopathic sensory neuropathy (2). The causes of generalized autonomic failure in 39 patients of the NAF group were as follows: idiopathic autonomic neuropathy (17), pure autonomic failure (9), parkinsonism-plus (4), diabetic autonomic neuropathy (3), multiple system atrophy/Shy Drager syndrome (2), amyloidosis (2), system degeneration (1), chronic neuropathy (1). The clinical characteristics of patients with idiopathic autonomic neuropathy have been recently reported.7
Age and sex distribution of controls and patients with peripheral neuropathy and neurogenic autonomic failure
Score profiles in healthy subjects and in patients with peripheral neuropathy and neurogenic autonomic failure.
Patients in the NAF group had significantly higher overall COMPASS scores (52.3 ± 24.2 [mean ± SD]) than did NMLs (9.8 ± 9) and PN patients (25.9 ± 17.9). The figure illustrates the distribution of COMPASS scores in the three groups and by sex. Table 3 shows the COMPASS scores for the different domains in the three groups. The orthostatic domain included symptoms such as feeling dizzy or “goofy” and difficulty thinking upon standing. There were additional questions aimed at identifying the presence of aggravating factors such as relationship with meals, prolonged standing, exercise, and increased body temperature. Orthostatic intolerance scores were higher in NAF and PN patients than they were in NMLs. There was also a statistically significant difference for orthostatic intolerance between the NAF and PN groups. The secretomotor domain included symptoms characteristic of thermoregulatory impairment such as heat intolerance, changes in general and specific areas of body sweating, and dry eyes and mouth. These scores were also consistently higher in PN and NAF patients than they were in NMLs and statistically significant when compared among the different groups. Symptoms of sexual difficulty were more common in NAF patients than they were in any other group. This subscore of the questionnaire applied only to 60 men because there were no questions addressing sexual function in women. There was no statistical difference between NAF and PN patients.
Figure. The distribution of Composite Autonomic Symptom Scale (COMPASS) scores by sex, control, nonautonomic peripheral neuropathy (PN), and neurogenic autonomic failure (NAF). The box and whisker figures represent the extremes and the 25th, 50th, and 75th percentile values. ○ = mean value.
COMPASS and validity subscores in the three subject groups
Scores for urinary symptoms consisted of data regarding difficulty voiding, urinary retention, and loss of control of bladder function. These scores were higher in the NAF and PN groups than they were in NMLs and were statis-tically significant between NAF and PN patients. The domain for gastrointestinal symptoms included gastroparesis, diarrhea, and constipation as the most frequently reported gastrointestinal symptoms in NAF and PN patients. COMPASS subscores assessing pupillomotor and visual symptoms such as blurred vision, photophobia, trouble focusing, and difficulty seeing at night were higher in the NAF group than they were in the PN and NML groups. Vasomotor symptoms subscores, such as color changes in the skin, were not significantly different between NAF and PN patients but were more frequent in both of these groups than they were in NMLs. Scores for reflex syncope were obtained from questions such as, “Have you ever fainted while passing urine or coughing?” This mean domain score was significantly higher in the NAF group compared with the NML group and marginally significantly different between NAF and PN groups. Items assessing the sleep domain included questions to identify symptoms associated with obstructive sleep apnea, narcolepsy, and abnormal or disordered sleep patterns. Sleep domain scores were significantly higher in NAF and PN patients than they were in NMLs, but the difference between NAF and PN patients was not statistically significant.
The understatement index, for which high scores would be indicative of a more stoic personality, included questions such as, “Have you ever in your adult life had difficulty keeping your mind on your job or task?” There was a higher mean score in NAF and PN patients than there was in NMLs. The difference was not statistically significant between NAF and PN subjects and was borderline between the NAF and NML groups. The psychosomatic index for which higher scores would be reflective of neurotic, hypochondriac, or suggestible respondents included questions such as “In the past 5 years, how would you rate the amount of trouble, if any, you have had with feelings of complete weakness all over the body?” and “in the past 5 years, how would you rate the amount of trouble, if any, you have had with oversensitive hearing?” The mean score was slightly higher in NAF patients than it was in the PN and NML groups, but there was no statistically significant difference between NAF and PN groups.
Severity of autonomic failure.
We evaluated the presence and severity of autonomic deficits in all groups using the CASS. The CASS was significantly increased in the NAF group (6.9 ± 2; p < 0.001) and in the PN group (3.1 ± 2.3; p < 0.001) over NMLs (mean = 0). The mean overall score for NAF patients was more than two times higher than the score for patients in the PN group.
Validity.
Criterion validity was assessed by the degree of association between the COMPASS overall and domain-specific scores with the CASS overall score. Table 4 presents the Spearman rank correlation coefficients and the partial Spearman rank correlation, adjusting for age and sex, of CASS with COMPASS subscores, in which the independent variable (x) was the COMPASS total score and the dependent variable (y) was the CASS score. For the overall total COMPASS score, the rank correlation was 0.67. A good correlation was observed with the orthostatic intolerance and secretomotor subscores. A modest correlation was found with pupillomotor, male sexual dysfunction, gastroparesis, reflex syncope, urinary symptoms, vasomotor, diarrhea, and constipation domain-specific subscores. No correlation was noted between the sleep disorder COMPASS score and the CASS score. In addition, the two validity scores for psychosomatic and understatement indices were not found to be associated with the CASS score.
Correlation of Composite Autonomic Scoring Scale (CASS) with Composite Autonomic Symptom Scale (COMPASS) subscores and validity scales
We performed stepwise linear regression with Kendall’s τb correlations to examine the relationship between CASS and the domain-specific COMPASS scores. Combining all three subject groups, the COMPASS domain-specific scores for orthostatic intolerance (p < 0.001) and secretomotor symptoms (p < 0.001) were the variables that in combination best predicted the CASS. Overall, the analysis demonstrated an acceptable level of criterion validity of the questionnaire compared with the standard instrument, the ARS.
Discussion.
We have developed and tested a new method for assessing autonomic symptoms, the Autonomic Symptom Profile. The questions were easily understood, and the questionnaire was easy to complete in less than 30 minutes. We judged that its content and criterion validity were acceptable.
We designed the Autonomic Symptom Profile as a specific questionnaire because of the potential of increased responsiveness resulting from selecting only a determined area of function and the advantage of relating closely to areas assessed by clinicians.
The questionnaire was designed and pretested and underwent several revisions before reaching its current form. A limited subset of items was used in a recent prospective study of the clinical characteristics of orthostatic hypotension.2 The Autonomic Symptom Profile has several domains to comprehensively evaluate all the different areas that may account for autonomic symptoms. In addition, we added psychosomatic and understatement indices to provide information on these areas. For example, higher scores in the psychosomatic domain may indicate symptoms of physical illness, preoccupation with bodily functions, and excessive concerns about general health, which may not have an organic basis. Higher scores may alert the physician to consider the role of emotional factors in the assessment of organic aspects of the illness. We are not implying that one should assume a neurotic basis for patients’ symptoms simply because of higher scores in the psychosomatic scale. The overall judgment of the clinician should prevail.
A new scale is usually compared with established measures (concurrent validity). To our knowledge, no well-validated self-reported autonomic questionnaire exists. Thus, we could not test for concurrent validity. We decided to compare the results of the COMPASS scores with the CASS and use this to test for criterion validity. The CASS is derived from a group of noninvasive autonomic tests that are sensitive, specific, reproducible, and standardized. In a previous report3 the CASS was found to be sensitive and specific for detecting and quantitating symptomatic autonomic failure. Patients with symptomatic autonomic failure were easily separated from asymptomatic patients without significant overlap.
Previous studies,8,9 mainly on diabetic autonomic neuropathy, have described some associations between autonomic symptoms and abnormal test of autonomic function. However, these reports have been limited by several flaws, including 1) failure to comprehensively evaluate and quantitate autonomic symptoms and deficits using validated tests, 2) lack of a control group of healthy subjects, and 3) failure to stage different degrees of autonomic failure. Our study provides some insight into the relationship between autonomic symptoms and the severity of autonomic deficits (CASS). COMPASS subscores for symptoms of orthostatic intolerance as well as secretomotor and pupillomotor function had high correlation with the CASS score. Orthostatic intolerance (p < 0.001) and secretomotor subscores (p < 0.001) were the variables that best correlated with the CASS using stepwise multiple regression analyses. As noted,2 when symptoms of orthostatic intolerance are analyzed separately in NAF and PN patients, the results show a greater symptom-to-autonomic deficit (CASS) relationship in NAF patients. NAF patients had on average moderate autonomic failure (mean CASS score = 6.9) compared with mild autonomic failure (mean CASS score = 3.1) in PN patients. Interestingly, COMPASS subscores were consistently higher in NAF patients even though the correlation with the CASS was not strong.
Symptomatic autonomic failure is important to detect and quantitate because 1) it may be associated with increased morbidity and mortality and 2) it may improve with treatment. Patients with symptomatic autonomic failure have a poorer prognosis than patients with normal autonomic function. Patients with diabetic autonomic neuropathy and autonomic failure may have increased instability of blood pressure and increased intraoperative mortality.10-13 In addition, the function of small myelinated and unmyelinated fibers may improve with treatment. For instance, Fagius et al.14 found improvement in heart rate deep breathing in diabetics treated with aldose reductase inhibitors. McEvoy et al.15 reported improvement in cholinergic function in patients with myasthenic syndrome treated with 3,4-diaminopyridine.
The questionnaire systematically explores a wide range of autonomic domains, providing a comprehensive scoring system (COMPASS) with an overall score and subscores for nine subscales useful for quantitation of autonomic symptoms. Another important feature of the scales is the potential ability to recognize clinically important changes (improvement or worsening of symptoms) which may translate into scores useful to monitor the progression of disease and to evaluate the response to treatment. However, this feature was not explored in the current study. Furthermore, the questionnaire may also be applicable to exploring the presence of autonomic symptoms in other neurologic disorders in which autonomic symptoms may occur such as MS, CNS lesions, and other neurologic conditions.
Although we have found the Autonomic Symptom Profile helpful in the detection and measurement of autonomic symptoms, we must emphasize the preliminary stage of these results. Further testing is needed to assess its reproducibility, sensitivity, and specificity. This will require the development of normative percentiles appropriately adjusted for age and sex using a large and randomly selected healthy cohort. To address these issues, we have expanded the profile’s responses in more than 400 healthy subjects, and the results will be reported separately.
Acknowledgments
Supported in part by grants from NINDS (P01 NS32352, NS22352, NS30534), MDA, NASA, and Mayo Funds.
Acknowledgment
The authors thank Anita Zeller for her outstanding secretarial assistance.
Footnotes
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Presented in part at the Conjoint Meeting of the VI International Symposium of the Autonomic Nervous System and XXII International Congress of Neurovegetative Research; Phoenix, AZ; November 17–19, 1995.
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A copy of the questionnaire is available upon request.
- Received April 22, 1998.
- Accepted October 17, 1998.
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