Relationships Between Autonomic and Orthostatic Self-Report and Physician Ratings of Orthostatic Intolerance in Youth

Abstract

Purpose:

There is no known biological marker or physical assessment to diagnose Chronic Fatigue Syndrome (CFS), leaving physicians to heavily rely on self-report measures regarding the symptoms associated with CFS. Common symptoms of CFS include difficulty sleeping, joint pain, headaches, sore throat, cognitive dysfunction, physical exhaustion, dizziness, and nausea. Due to the overlap among CFS symptoms and autonomic functioning, we examined the relationship among two self-report measures of orthostatic and autonomic symptoms and a physician’s report of autonomic functioning (measures of changes in blood pressure and heartrate) to further understand the relationship among autonomic functioning within individuals endorsing symptoms of CFS.

Methods:

Utilizing data from an ongoing study, Independent t-tests and Pearson’s correlation tests were used to assess the relationship between the Orthostatic domain from the DePaul Symptom Questionnaire, Autonomic Symptom Checklist composite scores, and the Physician’s assessment of Orthostatic Intolerance obtained from a sample of 191 participants, 42 who were healthy controls.

Findings:

There were no significant demographic differences between the CFS-like group and the healthy controls. Results indicate a significant correlation between orthostatic and autonomic functioning (r=0.58), and showed a correlation with a low effect size among autonomic functioning and physician measures of orthostatic functioning (r=−.01—0.29). However, there were fewer correlations between self-reported symptoms of orthostatic functioning and the physician’s measures of orthostatic functioning.

Implications:

These results are suggestive that while orthostatic dysfunction is reported in child and adolescents with CFS-like symptoms, the physical measures of autonomic functioning in this study were unable to detect these symptoms.

Introduction

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a complex condition involving at least 6 months of severe fatigue and disabling musculoskeletal and cognitive symptoms (impairment of short-term memory/concentration, headache, tender lymphadenopathy, muscle or joint pain, unrefreshing sleep and post-exertional malaise lasting> 24 hours) without another explanation [1]. The disease has two age peaks, one in adolescence and one in older women [2]. Adolescents with chronic fatigue symptoms also suffer a high proportion of orthostatic intolerance [3]. The overlap of autonomic dysfunction and CFS/ME is a subject of investigation. For example, one study in adolescents showed that baseline autonomic function during a bout of infectious mononucleosis predicted CFS following infectious mononucleosis [4]. Symptoms related to autonomic dysfunction in CFS/ME include nausea, headaches, sleep disturbance, and cognitive problems [5]. Physical findings of autonomic dysfunction may be present in individuals with CFS/ME, such as a high resting heartrate, high systolic blood pressure, high mean arterial blood pressure, and lower stroke index [6]. Research also suggests other evidence of autonomic dysfunction in those with CFS/ME [7,8,9].

The most common sign of autonomic dysfunction seen in CFS/ME is orthostatic intolerance (OI), signifying abnormal dynamic blood pressure regulation, along with significant abnormalities in cardiovascular regulation in response to orthostatic stress [10, 11]. While there are many types of OI, two subtypes are commonly seen in individuals with CFS/ME: postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH). POTS results in increased heart rate when transitioning from the supine to upright position, and is thought to underlie many of the orthostatic symptoms observed in individuals with CFS/ME [12]. OH is characterized by a fall in blood pressure upon standing, which can cause blurred vision, dizziness, pain, and/or fainting [13]. While OI is not life-threatening, POTS and OH can cause unpleasant symptoms, and can contribute to an overall decrease in quality of life [3]. While there is a high prevalence of OI and autonomic dysfunction in adults with CFS/ME, there have been few studies that have looked at the role of OI in adolescents with CFS/ME. For example, Stewart et al. [14] found that OI occurred in most adolescents they studied who presented with CFS/ME.

The current study assessed the relationship between a self-report CFS/ME symptom questionnaire, the Autonomic Symptom Checklist (ASC) and a physician’s measurement of orthostatic intolerance on physical examination. It was hypothesized that there would be a significant positive correlation between the orthostatic domain on the self-report symptom questionnaire and the Autonomic Symptom Checklist and a significant positive correlation between all three measures of autonomic dysfunction (the orthostatic domain on the self-report symptom survey, the physician’s report of orthostatic intolerance and the ASC).

Method

Design

The present study utilized archival data from an ongoing, epidemiologic study of pediatric CFS/ME that began July 2013. This study utilized available participant data through October 2017, when this analysis was conducted. This study was approved by the DePaul University and Adler University IRB’s.

Sample Characteristics

Participants for this study were part of an epidemiological study of pediatric and adolescent CFS/ME. All participant data collected through October 2017 were utilized in this analysis. The age of eligible participants ranged from five to seventeen, and participants are part of a community-based sample that is reflective of the U.S Census of the Chicagoland area. Participants were recruited by contacting households by telephone in the Chicagoland area, followed by an initial screening for CFS/ME. We report on 191 total participants, 42 of which are healthy controls.

Screen-positive subjects were those who reported either significant fatigue or school problems (poor attendance, unable/unwilling to go to school, or school learning or memory problems) and endorsed the core symptoms of CFS/ME: headaches, sore throat, joint pain, muscle pain, abdominal pain, fever/chills/shivers, impaired memory/concentration, postexercise malaise. A matched subsample of participants who screened negative served as controls.

Exclusion Criteria

Exclusionary medical and psychiatric illnesses were assessed, and include organ failure, chronic infections, rheumatic and chronic inflammatory diseases, major neurological diseases, diseases requiring systemic treatment, major endocrine diseases, primary sleep disorders, morbid obesity, bipolar affective disorders, schizophrenia, delusional disorders, dementias, organic brain disorders, alcohol or substance abuse within the past 2 years, and major depressive disorder with psychotic or melancholic features, anorexia or bulimia nervosa within the past 5 years.

Procedures

Participants are recruited through a brief telephone screening for chronic fatigue like symptoms. During this initial telephone screening, a parent/legal guardian was asked for permission to screen any youth in the household for CFS and ME like symptoms. After verbal consent was obtained, parents/legal guardian respondents answered questions regarding the health status of the children and adolescents, ages 5–17, in the household. After the telephone screen, participants underwent an in-depth screening at the Ann & Robert H Lurie Children’s Hospital of Chicago, in which new parental consent and adolescent assent forms were obtained prior to further assessment. The in-depth screening consisted of symptom questionnaires, a semi-structured psychiatric interview, as well as a complete physical examination and laboratory screening (for more details, see [15]). Two of the questionnaires that assess autonomic function are the DePaul Symptom Questionnaire (DSQ) and the ASC. This report will focus on the response of screen positive and screen negative (control) adolescents to the two standardized questionnaires of autonomic functioning and physical findings consistent with a diagnosis of orthostatic intolerance

Instruments and Measures Used

DePaul Symptom Questionnaire.

The DePaul Symptom Questionnaire (DSQ) is a standardized, self-report questionnaire that assesses onset, frequency, and severity of symptoms related to CFS, as well as levels of physical and social functioning [16, 17]. The DSQ asks about 54 symptoms, in which the respondent rates both the frequency and severity of each symptom over the past six months. Responses are on a five-point Likert scale for both frequency (0= none of the time, 1= a little of the time, 2= about half the time, 3= most of the time, and 4= all of the time) and severity (0= symptom not present, 1= mild, 2=moderate, 3=severe, 4= very severe). The DSQ assesses demographics and health history as well [18]. The DSQ is available on Research Electronic Data Capture’s shared library (https://redcap.is.depaul.edu/surveys/index.php?s=tRxytSPVVw).

Brown and Jason [16] showed that the DSQ has good convergent validity as well as good test retest reliability, and moderate overall agreement with a physician assessment [17]. For the current analysis, the orthostatic domain from the DSQ was utilized, which includes questions assessing the frequency and severity of symptoms such as dizziness, chest pain, shortness of breath, feeling unsteady when standing, and irregular heartbeat.

Autonomic Symptom Checklist.

The ASC is a 30-item, self-report questionnaire, that is based on the Autonomic Symptom Profile (ASP) and the Compass 31. The Compass 31 is a well-established, validated questionnaire for assessing autonomic symptoms, in terms of both severity and distribution [19, 20, 21]. The Compass 31 has been shown to have good convergent validity (0.474) with “gold standard” autonomic function testing, high test-retest reliability (0.886), and Cronbach alpha coefficients ranging from 0.8–0.9 on orthostatic, vasomotor, gastrointestinal, and pupillomotor domains [20, 21]. While the psychometric properties of the ASC have not been vigorously researched, it has been shown to distinguish, on average two months after infectious mononucleosis (IM) between those who will and will not develop ME/CFS 6 months following IM [4]. Further, both the ASC and the Compass 31 are psychometrically sound [22, 21].

Physician’s report.

As part of their comprehensive physical examination, each participant was assessed for orthostatic intolerance. The exam included a variant of the Head-Up Tilt Test (HUTT) to assess for orthostatic intolerance. The HUTT assesses for multiple orthostatic indicators (heart rate, blood pressure, syncope, etc.) in a supine position and then at a tilted position, at approximately 60 degrees [10], and has been demonstrated as a viable instrument when assessing orthostatic variables in adolescents with CFS [22]. Further, the Head-Up Tilt-Test is considered the gold standard for assessing and measuring orthostatic intolerance [23].

During the physical exam, an appropriate sized cuff was placed on the upper arm of the participant and the participant was instructed to remain still and silent in a supine position for five minutes. At that time, blood pressure and pulse were measured with a sphygmomanometer. Then, the participant was asked to stand upright, and after one minute, blood pressure and pulse measurements were repeated.

In adults, OH is defined as a decrease of > 20mm Hg systolic blood pressure or a >10mm Hg decrease in diastolic pressure during orthostatic challenge. POTS is commonly defined as an increase in HR of 30 bpm or HR over 120 during orthostatic stress [24]. There is no standard OH or POTS definition for children and adolescents, and therefore, the adult diagnostic criteria are commonly utilized. We too utilized the adult definitions of OH and POTS in our study.

Statistical Analyses

Independent t-tests and Pearson’s correlation tests were used to assess the relationship between the Orthostatic domain from the DSQ, Autonomic Symptom Checklist composite scores, and the Physician’s assessment of OI. An alpha value of 0.05 was utilized, and t-tests were not adjusted for multiple comparisons. Pearson’s correlations were conducted for the screen positive and controls separately, and combined. Due to insignificant differences in results when separated, the combined Pearson’s correlation was presented in this analysis. Missing data from the analysis was adjusted for using the exclude case pairwise function within SPSS.

Results

Participants

We initially identified 194 participants. Three participants had missing physician report data, and were excluded, leaving 191 participants, 42 of whom were healthy controls. Mean age at the time of examination was 13.5 years (SD = 2.6) for the screen positive subjects, and 13.6 years (SD = 2.25) for the controls. There was no significant difference between the control and screen positive group based on gender, race or ethnicity.

Differentiating Screen-Positive and Controls

As shown in Table 1, there were significant differences between the two samples, as expected, on the ASC as well as on the DSQ Orthostatic composite scores. Each of the five individual items within the DSQ Orthostatic composite (chest pain, dizziness, shortness of breath, feeling unsteady, and irregular heartbeat), scored significantly higher in the screen-positive group, as expected.

Table 1.

Autonomic and Orthostatic Variables of Screen Positives and Controls

	Screen Positive (n=149)	Control (n=42)
	M (SD)	M (SD)	T-test	Sig. (2-tailed)
ASC	22.46 (17.37)	10.59 (9.4)	4.25	<.001
DSQ Orthostatic Composite	20.70 (17.88)	7.13 (10.81)	4.57	<.001
DSQ Chest Pain	20.4 (25.20)	4.26 (9.52)	4.01	<.001
DSQ Dizziness	28.66 (26.46)	8.04 (17.42)	4.76	<.001
DSQ Shortness of Breath	23.46 (27.1)	12.2 (18)	2.53	.012
DSQ Unsteady	20.6 (24.74)	7.14 (15.16)	3.36	.001
DSQ Heartbeat	10.07 (19.29)	2.44 (7.51)	2.46	.015
Pulse Supine	75.22 (14.17)	68.98 (10.38)	2.33	.009
Pulse Standing	92.12 (14.9)	83.74 (10.23)	3.41	.001
Change in Pulse	−16.98 (12.16)	−14.75 (12.84)	−1.03	.305
BP Systolic Supine	110.32 (11.56)	106.38 (12.46)	1.92	.057
BP Systolic Standing	113.52 (13.21)	107.31 (13.86)	2.66	.008
Change in BP Systolic	−3.2 (9.08)	−0.93 (10.76)	−1.37	.173
BP Diastolic Supine	67.22 (7.69)	63.5 (7.98)	2.75	.007
BP Diastolic Standing	73.84 (8.23)	70.4 (8.74)	2.35	.020
Change in BP Diastolic	−6.46 (7.04)	−6.9 (8.82)	0.34	.732
	1.16 (0.37)	1.21 (0.42)	−0.8	0.42

Note. ASC= Autonomic Symptom Checklist; DSQ= DePaul Symptom Questionnaire; BP= Blood Pressure

Physician Measures

For the physician measure of OI, pulse rate in the supine and standing positions were significantly higher among the screen-positive than the control group. However, the change in pulse rate was not significantly different. Systolic BP when standing was significantly different between the two groups, but Systolic BP in the supine position had only a trend towards being higher in the screen-positive group, while again, change in systolic BP was not significantly different. Diastolic BP in the supine position and standing was significantly higher among the screen-positive group than in the control group, but the change in diastolic BP was not significantly different. Twenty-four screen positive participants and nine control participants met criteria for either OH or POTS. See Table 2.

Table 2.

Correlation Matrix Among Autonomic and Orthostatic Variables

		1	2	3	4	5	6	7	8	9	10	11	12	13	14	15	16
1.	ASC	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
2.	DSQ Orthostatic Composite	.58**	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
3.	DSQ Chest Pain	.29**	.68**	—	—	—	—	—	—	—	—	—	—	—	—	—	—
4.	DSQ Dizziness	.64**	.83**	.38**	—	—	—	—	—	—	—	—	—	—	—	—	—
5.	DSQ Shortness of Breath	.30**	.71**	.31**	.48**	—	—	—	—	—	—	—	—	—	—	—	—
6.	DSQ Unsteady	.48**	.76**	.29**	.69**	.43**	—	—	—	—	—	—	—	—	—	—	—
7.	DSQ Heartbeat	.39**	.72**	.58**	.50**	.36**	.38**	—	—	—	—	—	—	—	—	—	—
8.	Pulse Supine	.11	.12	.02	.15*	.07	.13	.07	—	—	—	—	—	—	—	—	—
9.	Pulse Standing	.29**	.22**	.06	.31**	.10	.23**	.13	.61**	—	—	—	—	—	—	—	—
10.	Change in Pulse	−.22**	−.13	−.06	−.21**	−.04	−.13	−.07	.39**	−.48**	—	—	—	—	—	—	—
11.	BP Systolic Supine	−.01	.06	.11	.00	.05	−.01	−.04	.14	.09	.09	—	—	—	—	—	—
12.	BP Systolic Standing	.04	.08	.11	.08	.05	−.00	.03	.10	.13	.02	.73**	—	—	—	—	—
13.	Change in BP Systolic	−.08	−.04	−.01	−.11	−.02	−.02	−.09	.02	−.08	.08	.21**	−.52**	—	—	—	—
14.	BP Diastolic Supine	−.01	.08	.10	.07	.12	.04	.02	.32**	.22**	.12	73**	.54**	.14*	—	—	—
15.	BP Diastolic Standing	.06	.15*	.13	.15*	.12	.10	.08	.15*	.20**	−.01	.61**	.80**	−.36**	.58**	—	—
16.	Change in BP Diastolic	−.08	−.10	−.06	−.11	−.02	−.08	−.08	.15*	.02	.12	.06	−.38**	.57**	.38**	−.53**	—
17.	Normal/Abnormal Autonomic Function	.10	.02	−.02	.10	−.09	.07	−.01	.03	41**	−.45**	−.00	23**	23**	.00	−.14	.18**

Note. ASC=Autonomic Symptom Checklist; DSQ=DePaul Symptom Questionnaire; BP=Blood Pressure

^*correlation is significant at the 0.05 level (2 tailed);

^**correlation is significant at the 0.01 level (2 tailed)

Orthostatic Domain (DSQ) and Autonomic Symptom Checklist

The ASC was shown to be significantly correlated to the DSQ orthostatic domain (r = 0.575, p<0.01), indicating a moderate positive correlation. The ASC was also significantly correlated with each of the items within the DSQ Orthostatic domain: chest pain; dizziness; shortness of breath; feeling unsteady; irregular heartbeat). See Table 2.

Orthostatic Domain (DSQ) and Physician’s Report

There were few significant correlations shown between the DSQ Orthostatic Domain and the physician report of OI. The DSQ Orthostatic Domain was shown to be significantly correlated to pulse rate in the standing position, as well as with diastolic BP when standing, although the correlations among these variables were weak. Some of the individual items from the DSQ Orthostatic composite showed correlations with some of the physician report measures. Dizziness had a significant, but weak, correlation with pulse rate supine, pulse rate standing, change in pulse rate, and diastolic BP when standing. Further, feeling unsteady had a significant correlation with pulse rate standing. See Table 2.

Autonomic Symptom Checklist and Physician’s Report

The ASC was correlated with two of the physician’s measures. ASC had a significant, but weak correlation with both pulse rate standing and change in pulse rate. However, ASC was not significantly correlated with change in systolic or diastolic blood pressure. See Table 2.

Discussion

We found significant differences in standardized, measured orthostatic and autonomic functioning between individuals who did and did not screen positive for CFS/ME on a phone interview. Chest pain, dizziness, and feeling unsteady were commonly endorsed by those who were screen-positive. When comparing orthostatic specific symptoms to overall autonomic functioning as measured by the DSQ, there were moderate correlations. Dizziness and feeling unsteady were highly correlated with overall autonomic functioning as measured by the DSQ. In addition, these two domains were more commonly reported in children and adolescents who are screen positive, as has been previously reported [5, 12, 24].

There were fewer significant correlations between orthostatic domain on the DSQ and the physician’s measurement of OI. There was a higher incidence of reported orthostatic symptoms on the self-report measures than depicted through the physician’s measurements, as only 33 participants from the entire sample met criteria for OH/POTS. In addition, the ASC was only weakly correlated with changes in heartrate and was not significantly correlated with changes in blood pressure. Further, although correlated with significant changes in heartrate, the ASC was not shown to be significantly correlated with autonomic dysfunction, as depicted by having OH or POTS.

Despite the self-report of dizziness and unsteadiness when standing, we did not document any significant changes in blood pressure to account for these symptoms. However, formal tilt-test evaluation was not performed. In addition, the adult standards for measuring autonomic functioning may be too stringent to detect change in a child or adolescent with CFS/ME [24].

The results of this study highlight the utility of self-report measures when assessing symptoms of orthostatic intolerance in child and adolescent populations, as they correlated with more formal measures. Moving forward, it would be beneficial to further understand the role of OI in pediatric CFS/ME.

Due to symptom overlap with other autoimmune diseases, it would be beneficial to consider how other conditions might relate to chronic fatigue syndrome. Fibromyalgia, a condition of chronic pain often accompanied by fatigue, sleep, memory and mood symptoms, has been shown to be related to the sympathetic nervous system [25]. Specifically, mast cells have been shown to be involved in the inflammatory cytokines [25]. Due to the overlap of symptoms of fibromyalgia and chronic fatigue syndrome, it is plausible that a similar process of cell inflammation might be disrupting autonomic functioning within the CFS population. Further, research on myasthenia gravis, an autoimmune disease also characterized by fatigue and muscle weakness, has shown symptom improvement by regulating the balance of Th1 cells, TH17 cells, and Tregg cells with artemisinin in lab rats [26]. While not as much is currently known about the role TH1 cells, TH17 cells, and Tregg cells have with chronic fatigue syndrome, due to the overlap in presenting symptoms, further research regarding these cells could be informative.

A limitation of the study is that the physician’s measures of heartrate (pulse rate) and blood pressure were only at two points in time and did not include a tilt-table examination. Another limitation is the lack of a validated definition of OH/POTS in children and adolescence [24].

This study showed that self-report measures capture orthostatic and autonomic dysfunction that can be objectively measured. A more sensitive screening test for the presence of OI that can be easily performed in a physician’s office is needed.

Highlights.

• Self-report measures capture orthostatic and autonomic dysfunction.

• Moderate correlations between responses on a general autonomic symptom questionnaire and specific orthostatic symptoms.

• Physician assessment of orthostatic changes in blood pressure and heart rate did not correlate with self-report measures of autonomic dysfunction within the sample

• despite high report of dizziness in sample, no significant correlation between dizziness and other autonomic/orthostatic symptoms with physical measures of heart rate and blood pressure changes were detected.