Background
Reversible cerebral vasoconstriction syndrome (RCVS) is a unifying term for a variety of clinical-radiological syndromes characterized by recurrent thunderclap headaches and reversible multifocal cerebral vasoconstrictions [
1‐
4]. Many secondary causes have been identified [
1,
3,
4]; however, in a substantial group of patients, RCVS occurs spontaneously without any precipitating factors [
2,
3]. RCVS is not uncommon and potentially devastating because of high risks of complications such as posterior reversible encephalopathy syndrome (PRES), ischemic stroke, intracerebral hemorrhage (ICH) or cortical subarachnoid hemorrhage (SAH) [
3,
5‐
9]. The severity of vasoconstrictions is associated with PRES or ischemic stroke [
6,
7].
Despite gradual delineation of the clinical presentation, the underlying pathophysiology of RCVS remains enigmatic. An aberrant central sympathetic response has been proposed to play an important role [
10], which can be partly supported by the fact that RCVS can occur in some patients with pheochromocytoma [
11] and after the use of sympathomimetics [
12,
13]. Besides, the observations of blood pressure surge and/or the Valsalva maneuver-like triggers with elevated sympathetic tone also heightened the role of autonomic dysregulation in the pathogenesis [
2]. However, to our knowledge no study has directly investigated the roles of the autonomic system in the pathogenesis of RCVS.
Analysis of heart rate variability (HRV), an established method to study abnormalities of the autonomic function [
14], is an appropriate and easily applicable method to validate these speculations. Therefore, the present study employed standardized HRV measures to investigate the autonomic function in patients with RCVS and attempted to provide plausible pathophysiological mechanisms for this unique disorder.
Results
Clinical characteristics
During the study period, we prospectively recruited 39 patients with RCVS who had both eligible ictal and remission ECG monitoring. Thirty-nine subjects without major medical and psychiatric disorders were recruited as controls. The comparisons of demographics and associated medical conditions between patients and controls are listed in Table
1. The ictal ECG monitoring was conducted at a median of 12.5 (range 3–45) days after headache onset. The remission ECG monitoring was performed at a median of 178 (range 43–247) days after headache remission, at a time point that the MRA vasoconstrictions of the participants had normalized for 107.5 (range 33–158) days.
Table 1
The comparison of demographics, menopausal status and current medical illness between patients with RCVS and controls
|
(N = 39)
|
(N = 39)
| |
Mean age ± SD, years | 49.5 ± 10.4 | 50.0 ± 4.7 | 0.56 |
Sex (M/F) | 0/39 | 0/39 | 1.00 |
Hypertension, n (%) | 3 (7.7) | 3 (7.7) | 1.00 |
Diabetes, n (%) | 0 (0) | 0 (0) | 1.00 |
Migraine, n (%) | 8 (20.5) | 6 (15.3) | 0.77 |
Menopause, n (%) | 18 (46.2) | 19 (48.7) | 1.00 |
Headaches in 79% of the patients with RCVS were explosive at onset, 69% reported throbbing headache after onset. Fifty-six percent reported nausea as an accompanying symptom, followed by phonophobia (38%), photophobia (38%), and vomiting (36%). Triggers were noted in 79% of study patients with the leading ones being: Defecation (41%), exertion (31%), bathing (28%), sex (26%), cough (18%) and rage (10%). The headaches remitted at a median of 14 (range 5–45) days. Three patients developed PRES and one patient developed acute ischemic stroke.
The parasympathetic-related HRV indices including RMSSD, pNN50, and HF power were significantly lower in patients during the ictal stage compared with the controls (Table
2). These indices improved partially during the remission stage when compared with indexes during the ictal stage (paired
t-test), but remained lower than those of controls (Table
2). In fact, an ascending trend was observed in patients during the ictal stage, followed by the remission stage and controls.
Table 2
Comparison of heart rate variability profiles between patients with RCVS in ictal and remission stages and controls
Time domain variables
|
SDNN, ms | 129.4 ± 34.7 | 109.9 ± 24.8 | 0.006 | 120.7 ± 24.9 | 0.207 | 0.041 |
RMSSD, ms | 35.2 ± 14.2 | 22.1 ± 7.0 | <0.001 | 26.7 ± 11.1 | 0.005 | 0.019 |
pNN 50,% | 10.6 ± 8.1 | 3.7 ± 3.4 | <0.001 | 5.6 ± 6.3 | 0.003 | 0.070 |
Frequency domain variables
|
Total power, ln (ms2/Hz) | 9.01 ± 0.50 | 8.47 ± 0.48 | <0.001 | 8.71 ± 0.40 | 0.005 | 0.008 |
VLF (0.003 – 0.04 Hz), ln (ms2/Hz) | 8.66 ± 0.48 | 8.21 ± 0.46 | <0.001 | 8.43 ± 0.37 | 0.017 | 0.011 |
LF (0.04 – 0.15 Hz), ln (ms2/Hz) | 7.32 ± 0.60 | 6.63 ± 0.62 | <0.001 | 6.90 ± 0.53 | 0.001 | 0.020 |
HF (0.15 – 0.4 Hz), ln (ms2/Hz) | 6.77 ± 0.74 | 5.82 ± 0.73 | <0.001 | 6.21 ± 0.75 | 0.001 | 0.016 |
LF/HF, ratio | 2.48 ± 1.07 | 3.38 ± 1.32 | 0.001 | 2.97 ± 1.25 | 0.067 | 0.013 |
The LF/HF ratios were significantly higher in patients during the ictal stage compared with the controls based on 24-hour HRV measures (Table
2). The consistent finding was found when diurnal or nocturnal HRV was compared between controls and patients during the ictal stage. These higher LF/HF ratios partially normalized during the remission stage (a nominal difference was noted when compared with that of controls) (Table
2).
Other HRV indices
As the data in Table
2 demonstrated, patients during the ictal stage had significant reductions in SDNN, the total power and VLF, which were partially reversed but not normalized when patients were in the remission stage.
The correlations of clinical variables and HRV indices
Because of small case number of patients with PRES (n = 3) and ischemic stroke (n = 1) in our study participants, statistics were not conducted to correlate the HRV indices with these complications. Nevertheless, patients with PRES had nominally lower total power and VLF of HRV (total power: 8.04 ± 0.58 vs. 8.52 ± 0.47; VLF: 7.83 ± 0.55 vs. 8.26 ± 0.46), lower parasympathetic indices (RMSSD: 16.3 ± 6.4 vs. 22.5 ± 6.7; pNN50: 1.8 ± 2.0 vs. 3.82 ± 3.41; HF power: 5.21 ± 1.05 vs. 5.86 ± 0.70) and elevated LF/HF ratio (4.13 ± 1.54 vs. 3.36 ± 1.25) than those without PRES (n = 36). The other clinical variables such as blood pressure surge, types and numbers of triggers, headache duration, date of ECG performance from headache onset (the ictal stage and the remission stage were calculated separately), history of hypertension or migraine, or menopausal status did not correlate with any HRV indices.
Discussion
The study showed that patients with RCVS had markedly decreased heart rate variability, attenuated parasympathetic modulations and heightened sympathetic activity during the ictal stage. These autonomic aberrancies improved partially after disease remission, but were still abnormal in comparison with that of controls. These findings suggested that the autonomic dysfunction is not simply an accompanying phenomenon during the diseased stage but a biological trait marker in patients with RCVS.
The proposed pathophysiology of RCVS has been linked to sympathetic overactivity based on clinical observations or hypotheses including central vascular tone changes [
8,
24], aberrant sympathetic response [
10], blood pressure surge [
5], triggers [
3,
5], sympathomimetic agents [
3,
12,
13], pheochromocytoma and hypertensive crises [
25], and autonomic dysreflexia [
26], etc. Our findings provided more direct evidence in support of these speculations. A remarkably decreased parasympathetic modulation was unexpected from clinical observations, but not irrational. Actually, the balance between the sympathetic and parasympathetic systems is like the balance of yin and yang [
27]. For example, one arm weakened could actually make the other arm unantagonized and prone to a diseased state. It is thus possible that a dysfunctional autonomic nervous system renders the individual more susceptible to thunderclap headaches by exaggeratedly reacting to certain triggers, especially Valsalva maneuver-like triggers, and at a lower threshold. Cerebral blood vessels which were richly innervated by sympathetic nerve fibers [
28,
29], might also react to the heightened and unantagonized sympathetic activities and exhibit features of multifocal vasoconstrictions. Although it is likely that the pathophysiology of RCVS is multifactorial, we believe that central autonomic dysregulation plays a crucial role based on the distinct clinical presentations and the findings of this study.
It has been observed that during sympathetic activation the resulting tachycardia is usually accompanied by a marked reduction in total power, which may influence the change in HF and LF power in the same direction and thus lead to a less prominent ratio of LF over HF [
14,
30]. Hence, the higher LF/HF ratio observed in patients was still underestimated by the presence of decreased total power of HRV. Such sympathetic overactivity exactly coincided with the previously proposed neurogenic mechanism [
10] and the foregoing deduction. Admittedly, one could speculate that an alternative explanation may be that the sympathetic overactivity was the consequence rather than the cause of severe headaches since similar trends have been observed in certain painful conditions [
31‐
35]. However, such autonomic dysfunction should normalize after removal of the inciting factors. The persistently abnormal autonomic modulation during the remission stage effectively argues against this speculation.
Because all the enrolled patients had spontaneous RCVS, this study avoided the influence of HRV from exogenous factors, such as sympathomimetic agents, thus allowing us to examine the genuine endogenous autonomic derangements in these patients. It is noteworthy that low HRV measures are associated with onset and poor prognosis of cardiovascular diseases [
36,
37]. Since the case number of patients exhibiting PRES or ischemic stroke is limited, we were unable to accredit the prognostic value of HRV in predicting complications in patients with RCVS although a trend of lower HRV in found in patients with complications. However, given that the extent of lower HRV was not as severe as those with cardiovascular diseases, the prognosis of RCVS might not be as grave using similar criteria [
36,
37].
Our study had limitations. First, naturally one cannot study RCVS before it happens so that whether the abnormal cardiovascular autonomic responses in the RCVS group are the result of the event or causal to it could not be answered by the data. Second, HRV is highly variable among individuals and can be affected by confounders such as age, gender, medical conditions including hypertension [
38] and migraine [
35], as well as menopausal status [
39], etc. However, our study design had attempted to exclude possible confounders by enrolling matched controls and excluding subjects with extreme ages and secondary RCVS. One study had shown that migraineurs with disabling attacks may be prone to hypofunction of autonomic nervous system, but the causality between the autonomic hypofunction and migraine was unknown [
40]. It is possible that autonomic dysfunction is a common finding in patients with migraine or other severe headaches; however, the difference in study design and employed parameters made it difficult to directly compare our findings with those of previous studies. Whether there is difference in the severity of autonomic dysfunction between RCVS and migraine or other severe headaches requires further sophisticatedly designed studies which also take disease course into accounts. Of note, RCVS is known as a monophasic disorder; whereas, it might be difficult to define a true remission stage and the effects of therapeutics of primary headache disorders, such as migraine. Third, we are uncertain whether the use of nimodipine in our patients might have contributed to the changes in HRV during follow-up since calcium channel blockers had been reported to affect HRV [
41,
42]. To reduce the interference from this effect, we structured this study to allow a wash-out period from the use of the nimodipine. Finally, the nature of our study method reflected the autonomic controls on heart rates instead of directly on the control of cerebral vascular tone. More exploratory studies are required to investigate the relationship between central autonomic regulation and cerebral vasoconstrictions.
Acknowledgements
This study was supported in part by grants from National Science Council of Taiwan (NSC 95-2314-B-075 -111, 97-2628-B-010-007-MY3, and 99-2314-B-075-036-MY3), Taipei-Veterans General Hospital (VGHUST102-G7-6-1, V102C-118 , V102E9-001), NSC support for Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 101-2911-I-008-001), Brain Research Center, National Yang-Ming University and a grant from Ministry of Education, Aim for the Top University Plan. No additional external funding received for this study.
Disclosure
The authors have reported no conflicts of interest.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SPC participated in study design, acquisition of data, analysis and interpretation, as well as manuscript writing. ACY carried out data aquisition, analysis, interpretation, and manuscript writing. JLF participated in study design, study supervision, and critical revision of the manuscript for important intellectual content. SJW conceived of the study, participated in its design, coordination, supervision, and helped to draft and revise the manuscript. All authors read and approved the final manuscript.