Orthostatic Intolerance and Autonomic Dysfunction in Youth With Persistent Postconcussion Symptoms

A Head-Upright Tilt Table Study

Abstract

Objective: 

To explore head-upright tilt table (HUT) signs of autonomic dysfunction in a cohort of youth with persistent postconcussion symptoms (PCSs) that include light-headedness and to correlate repeat tilt table results with symptom improvements for those patients found to have postural tachycardia syndrome (POTS) on initial testing.

Design: 

Prospective cohort design.

Setting: 

Nationwide Children's Hospital, Neurology Clinic.

Participants: 

Thirty-four patients (13-18 years of age) with persistent PCSs.

Main Outcome Measures: 

All patients underwent at least 1 tilt table test. The PCS Interview (PCS-I) and patient ratings of light-headedness and vertigo were used to measure symptom burden. Patients found to have POTS were asked to repeat tilt table testing when PCSs improved or 3 to 6 months after the initial test if symptoms persisted.

Results: 

Twenty-four of the 34 (70.6%) patients had abnormal tilt table results with patients categorized as normal (n = 10), isolated syncope (n = 10), and POTS (n = 14). Patients with POTS had higher PCS-I scores than normal patients (P < 0.001) and higher ratings of light-headedness than both normal patients (P = 0.015) and syncope patients (P = 0.04). Twelve POTS patients underwent repeat tilt table testing, and 9 of 12 (75%) no longer met POTS diagnostic criteria. All patients with resolution of POTS had corresponding improvements in PCSs, including light-headedness and vertigo.

Conclusions: 

Our study demonstrates a high rate of tilt table abnormalities among youth with persistent PCSs. Several patients with POTS had normalization of tilt table testing when PCSs improved. These findings warrant further research of autonomic dysfunction related to concussion.

Clinical Relevance: 

Our study is the first to prospectively characterize autonomic dysfunction in patients with persistent PCSs using HUT testing and to show that the tilt test abnormalities normalize in some patients as PCSs improve.

INTRODUCTION

Traumatic brain injury (TBI) is an important public health problem. It has been estimated that 1.6 to 3.8 million TBIs occur annually in the United States.¹ Mild forms of TBI account for 80% to 90% of these injuries.² Concussion is often regarded as a subset of mild TBI and is defined as a complex pathophysiologic process affecting brain function and resulting from direct or indirect biomechanical forces transmitted to the head.³

Concussions are a common occurrence in children and adolescents. Approximately 1 in every 220 pediatric patients seen in an emergency department is diagnosed with concussion.⁴ Most concussion patients recover within a brief period of 7 to 10 days;³ however, some patients develop protracted postconcussion symptoms (PCSs) that can persist for months and sometimes years.^5–7 An epidemiologic study in Alberta, Canada, demonstrated that 13.7% of school-aged children had persistent PCSs 3 months after injury and 2.3% reported symptoms at 1 year.⁸

The cause of persistent PCSs remains controversial. Factors related to premorbid adjustment, postinjury psychological distress, poor patient and parent coping strategies, and outright malingering may lead to amplified symptom ratings and protracted recovery in some youth after mild TBI.^5,9,10 However, recent evidence suggests that injury-related factors also may impact clinical course and outcome.

Associations have been found between specific concussion symptoms and protracted recovery, with dizziness emerging as a potential predictor of persistent PCSs.^6,11–17 In their prospective study of adults with PCSs, Yang et al¹² assessed patients at 1, 2, 4, and 8 weeks after injury and found dizziness to be the most persistent symptom adversely affecting both early and late stages of disease. A study of high school football players demonstrated that athletes who reported on-field dizziness immediately after concussion were more likely to experience protracted recovery (>21 days) than athletes without dizziness postconcussion.¹¹ An investigation of diagnostic criteria for postconcussion syndrome demonstrated that dizziness and fatigue were the only 2 symptoms that distinguished concussion patients from nonconcussed controls at 3 months after brain injury.¹⁷

Unfortunately, although dizziness may play a key role in predicting the clinical course, dizziness as a PCS has not been well characterized. Many of the studies assessing clinical predictors of protracted recovery did not distinguish between the different types of dizziness, particularly vertigo (the abnormal perception of movement) and light-headedness. Orthostatic intolerance is a term used to describe symptoms that occur while standing and that are completely or partially relieved with recumbency.¹⁸ Light-headedness is probably the most common complaint associated with orthostatic intolerance. Some patients with orthostatic intolerance meet diagnostic criteria for postural tachycardia syndrome (POTS), which represents a symptomatic elevation in heart rate related to upright position and without hypotension.

The aim of this study was to characterize orthostatic intolerance among a cohort of youth with persistent PCSs that included light-headedness. We conducted head-upright tilt table (HUT) testing in all cohort patients and explored the associations between symptom burden and HUT results. Those patients found to have POTS were asked to repeat tilt testing when their PCSs improved or 3 to 6 months after the initial procedure if symptoms persisted.

SUBJECTS AND METHODS

Subjects

We conducted a prospective cohort study using HUT testing to characterize orthostatic intolerance in a cohort of youth with persistent PCS. All patients were referred to a pediatric neurology headache clinic between May 2012 and June 2013 for evaluation and management of PCSs, particularly posttraumatic headache. Study eligibility criteria included (1) age group of 13 to 18 years, (2) at least 1 concussion between 21 days and 6 months before clinic evaluation, (3) ongoing PCSs that included light-headedness, and (4) the absence of light-headedness or syncope before concussion. Patients who reported syncope as the cause of concussion were excluded.

Of the 38 consecutive patients eligible for study, 4 (10.5%) refused to participate. The most common reason for study refusal was reluctance to undergo HUT testing due to fear of syncope. Among the 34 study participants, 26 (76.5%) were female, 28 (82.4%) were white, and the average age was 16 years (range, 13-18 years).

Ethics

The study was approved by the Institutional Review Board at Nationwide Children's Hospital. Informed consent (parents and subjects 18 years of age) and assent (subjects <18 years) were obtained in all cases.

Data and Measures

Demographic information and relevant concussion histories were obtained using a standardized study template. The operational definition of concussion was adapted from the Zurich Consensus Statement on Concussion in Sport, 2008.³ Data collected included concussion date(s), concussion mechanism(s), symptoms at the time of injury (including loss of consciousness and posttraumatic amnesia), symptoms at the time of evaluation, and numbers of prior concussions. We defined persistent PCSs as ≥3 somatic, cognitive, and/or emotional complaints attributed to concussion and lasting ≥21 days but not more than 6 months. We chose a minimum symptom duration of 21 days based on the definition of protracted recovery used by Lau et al.¹¹ The 6-month maximum for symptom duration was chosen arbitrarily with the intent to minimize the role of noninjury factors as contributors to symptom ratings.¹⁹

All symptom scales were completed on the day of HUT, before the procedure. Patients were asked to report their levels of light-headedness and vertigo over the past 7 days using a 6-point scale, ranking the frequency of symptoms from 0 (not present) to 5 (occurring daily). Light-headedness was defined as the sensation of dizziness, cloudiness, and/or visual changes caused by standing (or sitting upright) and relieved by recumbency; vertigo was defined as the sensation that the room was spinning or moving (or the individual was spinning or moving within the room). Based on eligibility criteria, all study participants had light-headedness scores ≥1.

The PCS Interview (PCS-I) measures the presence or absence of somatic, cognitive, and emotional symptoms attributed to concussion.⁵ The total instrument score equals the number of symptoms present over the preceding week (range 0 to 15). Both patients and parents completed the PCS-I before each HUT test. Parents completed a retrospective version of the PCS-I rating symptoms present over the week before concussion to establish the premorbid symptom baseline. The instrument has been shown to be reliable and valid in pediatric concussion patients.⁵ Item-level correlation between patient and parent ratings has been shown to be significant.²⁰

Head-Upright Tilt Table Protocol

In preparation for HUT, medicines that could cause orthostatic intolerance were discontinued for a minimum of 5 half-lives. Amitriptyline (prescribed for headache prophylaxis) was the most commonly held medicine. Patients were encouraged to eat and drink the morning of testing but to fast 3 hours before the appointment. Cardiac evaluations including 12-lead electrocardiogram (EKG) were normal in all subjects. Immediately before each HUT, urine specific gravity was obtained from all patients and urine pregnancy testing was performed for females. We used the urine specific gravity as a measure of relative hydration status.

An abbreviated HUT protocol was performed. The patient rested quietly in the supine position, lights dimmed, for a minimum of 30 minutes. Heart rate and blood pressure were monitored continuously by Portapres (Finapres Medical Systems, Amsterdam, the Netherlands) and by automated arm cuff (CARESCAPE V100; GE Healthcare, Milwaukee, Wisconsin) at 1-minute intervals. The electrocardiogram (Mac 1200; GE Healthcare) was monitored continuously. After 30-minute resting, the patient was tilted head-upright to 70°. They were encouraged to report all symptoms. At frequent intervals, they were asked about symptoms and examined for signs of acrocyanosis, pallor, and diaphoresis. The HUT test concluded when syncope or imminent syncope (defined below) occurred or after 10 minutes.

The POTS diagnostic criteria were defined as (1) a sustained heart rate increment of >30 beats per minute (bpm) or a total heart rate elevation >120 bpm while tilted, (2) orthostatic symptoms (light-headedness and at least one of the following: headache, dimming or blurring of vision, nausea, fatigue, diaphoresis, or confusion) that corresponded with heart rate changes and resolved with recumbency, and (3) the absence of orthostatic hypotension, defined as a drop of systolic blood pressure by 20 mm Hg and/or diastolic blood pressure by 10 mm Hg.¹⁸ We diagnosed POTS in subjects who maintained blood pressures for a minimum of 5 minutes and fulfilled all diagnostic criteria but before 10 minutes developed neurally mediated hypotension with syncope or imminent syncope. Syncope was defined as hypotension (>30 mm Hg drop in systolic blood pressure) with or without bradycardia (>25% drop in resting heart rate), accompanied by loss of postural tone and loss of consciousness. Imminent syncope was defined as hypotension with or without bradycardia, accompanied by loss of postural tone but with retained consciousness. Patients were categorized based on HUT results as normal, POTS (with and without syncope), or syncope (without POTS). The syncope designation included non-POTS patients with imminent syncope.

Subjects meeting POTS criteria were asked to repeat the HUT study after PCS improved or 3 to 6 months after the initial procedure if symptoms persisted. Symptom improvement was assessed at regular follow-up intervals and defined using patient and parent reports of return to premorbid baseline (or near premorbid baseline). We can compare abbreviated HUT procedures for the presence or absence of POTS because the diagnostic criteria are met within the first 10 minutes of study. In contrast, the diagnostic sensitivity for syncope from an abbreviated HUT is not well characterized, and the absence of syncope on repeat testing would not prove that the predisposition to syncope had resolved. For this reason, we did not repeat HUT testing for patients found to have isolated syncope during the initial procedure.

Statistics

All statistical analyses were performed using SPSS (version 19; SPSS Inc, Chicago, Illinois). The Kruskal–Wallis test and the χ² test were used to compare continuous and categorical variables for independent groups based on initial HUT results (normal, syncope, and POTS). To further characterize between-group differences, post hoc testing was performed using the Mann–Whitney U test. The Wilcoxon signed-rank test was used to compare continuous variables associated with repeat HUT. Two-tailed test statistics were calculated and the significance was set at 5%.

RESULTS

Twenty-four of the 34 (70.6%) study patients had abnormal HUT results. Based on results, patients were categorized as normal (n = 10; 29.4%), isolated syncope (n = 10; 29.4%), or POTS (n = 14; 41.2%). Seven of the 14 (50%) POTS patients also had syncope or imminent syncope between 5 and 10 minutes of HUT testing.

Table 1 compares demographics, concussion data, PCS-I ratings, and data from initial HUT testing between patient groups. Between-group differences were found for 3 variables: light-headedness ratings (P = 0.03), patient PCS-I scores (P = 0.03), and heart rate increments during HUT (P < 0.001). Post hoc comparisons between groups demonstrated that patients with POTS had higher light-headedness ratings than both the normal group (P = 0.015) and the syncope group (P = 0.044). The patients with POTS had higher patient PCS-I scores compared with those with normal HUT testing (P < 0.001), whereas PCS-I score did not differ between POTS and syncope patients (P = 0.44). Heart rate elevation during HUT represents a principal diagnostic feature of POTS. The POTS patients had higher heart rate increments compared with the normal group (P = 0.004) and compared with the syncope group (P < 0.001). Although the study cohort was predominantly female, there were no differences in sex ratios between groups. Vertigo ratings, parental PCS-I scores (current and retrospective), and urine specific gravity did not differ between groups. The lack of differences in urine specific gravities suggests that relative hydration status did not play a prominent role in determining HUT diagnoses.

TABLE 1: Demographics, Concussion Data, Postconcussion Symptom Ratings, and Initial HUT Data for All Patients

All patients meeting POTS diagnostic criteria on initial HUT were asked to repeat the procedure when symptoms improved or within 3 to 6 months if symptoms persisted. Of the 14 patients diagnosed with POTS initially, 2 were lost to follow-up and 12 repeated the procedure. Nine of the 12 patients no longer met POTS diagnostic criteria (POTS resolved) on subsequent HUT, whereas 3 patients continued to have POTS (POTS persisted). Table 2 compares symptom burden and HUT data between initial and subsequent HUT procedures for the 9 patients with resolved POTS. Urine specific gravity did not differ between tests. All patients with resolution of POTS also had corresponding improvements in symptom burden: PCS-I scores, light-headedness, and vertigo.

TABLE 2: POTS Resolved (n = 9), Comparison of Data Between the First and Second HUT

In contrast, the small group of patients with persistent POTS continued to acknowledge PCSs and light-headedness at the time of repeat HUT testing. Compared with the patients with resolved POTS, the 3 individuals with persistent POTS had significantly higher self-reported light-headedness (2.3 ± 0.6 vs 0.3 ± 0.5, P = 0.007), higher patient PCS-I scores (6 ± 1.7 vs 2 ± 1.7, P = 0.02), higher parental premorbid PCS-I scores (4.3 ± 2.1 vs 1 ± 1.1, P = 0.03), and higher heart rate increments during repeat HUT (46.3 ± 9 bpm vs 25.8 ± 2.5 bpm, P = 0.01). The higher parental ratings of preconcussion symptoms were not related to the numbers of prior concussions. Interval days between the first and second HUT procedures did not differ statistically between those with resolved POTS and those with persistent POTS (77.7 ± 28 days vs 122.3 ± 8.5 days, P = 0.052).

DISCUSSION

The results of this study indicate that HUT abnormalities are common among adolescents and young adults with persistent PCSs that include light-headedness. In our cohort, we found that over 70% of study patients had POTS (with or without syncope) or isolated syncope during abbreviated HUT testing. Patients with POTS diagnosed at initial HUT testing rated PCS and light-headedness higher than patients with normal HUT tests, whereas smaller differences in symptom ratings were detected between syncope patients and normal patients. Although differences in sex ratios were not detected between groups, over 76% of our cohort was female. This female predominance in our persistent PCS cohort mirrors data that female patients may take longer to recover after concussion than male patients.^21–23

Both POTS and syncope represent forms of autonomic dysfunction. Limited data exist on the effects of concussion on the autonomic nervous system. During the acute phase of concussion, patients can have changes in heart rate variability,²⁴ heart rate complexity,²⁵ and cerebral blood flow autoregulation.²⁶ Keren et al²⁷ demonstrated that changes in heart rate variability occur in patients with moderate and severe forms of TBI and that these changes normalize after an average of 70 days after injury. We are aware of a single retrospective study that identified a relationship between TBI and POTS.²⁸ Kanjwal et al reported 8 adult patients who developed orthostatic intolerance after TBI with intervals ranging from 3 months to 3 years between brain injury and the HUT diagnosis of POTS.

Several of our patients who met POTS diagnostic criteria initially had normalization of the HUT on subsequent testing. Kimpinski et al²⁹ found that 37% of POTS patients aged 13 to 50 years no longer met diagnostic criteria for POTS at 1-year follow-up. Traumatic brain injury was not listed among the antecedents to symptom onset in their study. In our study, resolution of POTS corresponded with lower ratings of light-headedness and PCSs, including symptoms unrelated to dizziness, whereas those individuals with persistent POTS continued to acknowledge multiple symptom types and higher symptom burdens. Interestingly, the patients with persistent POTS also had higher parental ratings of premorbid symptoms, which were not related to the numbers of prior concussions.

Is light-headedness the form of dizziness that predicts protracted postconcussion recovery? Our study participants developed new-onset light-headedness after mild TBI. In the setting of persistent PCSs and light-headedness, patients had high rates of syncope and POTS; and when PCS and light-headedness improved, POTS resolved. Unfortunately, we cannot prove that orthostatic intolerance was present during the acute postconcussion period because we limited our recruitment to youth with persistent symptoms (≥3 weeks). It is possible that autonomic dysfunction developed in relation to recovery from concussion rather than the injury itself. We encourage further research during the acute postconcussion period to determine whether orthostatic intolerance is a PCS. Future studies of postconcussion dizziness as a predictor of protracted recovery should distinguish vertigo symptoms from symptoms of light-headedness and orthostatic intolerance. Confirmation that some patients develop a reversible form of autonomic dysfunction as a consequence of concussion would have important diagnostic and treatment implications, among which include an objective measure of symptoms through HUT testing. Furthermore, a postconcussion model of reversible POTS may help to broaden our understanding of the causes of POTS in nonconcussed patients.

We recognize several potential study limitations. The sample size for this exploratory study was small, and the study population was highly selected for age, persistent PCSs, the presence of light-headedness, and referral to a pediatric headache clinic. Given that recruitment was limited to youth with persistent PCSs, we cannot prove that autonomic dysfunction was present during the acute postconcussion period. Also, syncope patients did not have repeat HUT assessments, so we do not know if these patients exhibit normalization of HUT testing that coincides with improvement in PCS burden as was demonstrated for POTS patients. Unfortunately, the diagnostic sensitivity for syncope during an abbreviated HUT is not well characterized. The absence of syncope on repeat testing would not prove that the predisposition for syncope had resolved. This lack of diagnostic sensitivity also means that we may have underestimated the syncope rate in our cohort. Patients designated as normal based on initial HUT results may have developed syncope if the procedure had been longer in duration. Finally, our study did not include a control group. We recommend that future studies use longer HUT protocols when assessing syncope and that syncope rates among cases be compared against a control population. We also recommend studying a broader age range of patients during the acute and chronic postconcussion periods to allow more extensive generalization of results.

CONCLUSIONS

Our exploratory study demonstrates that youth with persistent PCSs including light-headedness have high rates of POTS and syncope during abbreviated HUT testing. Several patients found to have POTS initially had resolution of POTS on repeat testing that corresponded with improvements in PCS-I and light-headedness ratings. Further study of orthostatic intolerance and autonomic dysfunction in the setting of acute and chronic PCS is warranted.

ACKNOWLEDGMENTS

The authors thank Aggie LeGros, RN, for her coordination of this study. They also acknowledge Dr. E. Steve Roach and Dr. Keith O. Yeates for their helpful recommendations regarding the manuscript preparation.