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 Table of Contents  
Year : 2022  |  Volume : 39  |  Issue : 3  |  Page : 146-150

Understanding pathophysiology of cluster headache: Heart rate variability and parasympathetic activation

1 Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
2 Department of Cardiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

Date of Submission16-Aug-2021
Date of Decision24-Dec-2021
Date of Acceptance26-Dec-2021
Date of Web Publication30-Sep-2022

Correspondence Address:
Erdi Sahin
Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Capa-Fatih, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/nsn.nsn_154_21

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Aim: The underlying mechanisms of cluster headache (CH) have not been fully understood yet. The cranial autonomic activation suggests that both sympathetic and parasympathetic systems are impaired in the clinical presentation; however, the systemic autonomic involvement during pain-free episodes is not well-known. Methods: Thirty-five subjects were included in 24 h Holter monitoring and electrophysiological studies in this controlled study. Results: In Holter monitoring, heart rate variability parameters, RMSSD (P = 0.001), and pNN50 (P = 0.024) were significantly higher in patients compared to age and gender-matched controls. The R-R variations during breathing and deep breathing and sympathetic skin responses of all patients were normal. Conclusions: High RMSSD and pNN50 levels are the two indicators of increased parasympathetic activity in CH patients. Considering the intense stress because of severe pain of the CH patients, who are mostly adult men and smokers, there is an urgent need for broader studies with prospective follow-up in terms of cardiac health.

Keywords: Autonomic, cluster, headache, pathophysiology

How to cite this article:
Sahin E, Ekizoglu E, Orhan EK, Bilge AK, Baykan B. Understanding pathophysiology of cluster headache: Heart rate variability and parasympathetic activation. Neurol Sci Neurophysiol 2022;39:146-50

How to cite this URL:
Sahin E, Ekizoglu E, Orhan EK, Bilge AK, Baykan B. Understanding pathophysiology of cluster headache: Heart rate variability and parasympathetic activation. Neurol Sci Neurophysiol [serial online] 2022 [cited 2022 Dec 2];39:146-50. Available from: http://www.nsnjournal.org/text.asp?2022/39/3/146/357499

  Introduction Top

Cluster headache (CH) is the most common trigeminal autonomic cephalalgia, which causes severe disability and was even previously known as “suicide headache.”[1],[2] The underlying mechanism has not been fully understood yet. The presence of cranial autonomic activation, which is known because of the typical accompanying symptoms, suggests that sympathetic and parasympathetic systems are impaired during the attacks. Autonomic symptoms of CH include lacrimation and rhinorrhoea because of increased local parasympathetic activity and are associated with the autonomic activity of the face. However, sweating and flushing occur as a result of sympathetic activation because of vasodilation. Moreover, the complaints of patients such as palpitations and chest pain that accompany pain and a history of cardiac disease suggest that this disruption causes systemic effects.[3] Oral cavity, tongue, lower lip, and nasal structures are innervated by the facial nerve. Upper lip, nose, lacrimal glands, and forehead are innervated by postganglionic fibers of the sphenopalatine ganglion. Secretion of the glands is the result of these innervations and complex connections between them. Sympathetic activity of the face is controlled by the cervical sympathetic chain. Clinical signs of CH showed that sympathetic and parasympathetic impairment are both involved in pathogenesis. All these findings showed that autonomic system impairment is one of the defining features of CH and could be related to the pathophysiology of the disease that may persist during the interictal period in a hidden way.

Sympathetic skin responses (SSR) and R-R interval variations (RRIV) were mostly used to evaluate the autonomic nervous system. Sympathetic hypofunction and hyperfunction have been reported in CH and migraine patients by recording SSR from the neck area.[4],[5] Variations in the heart rhythm from one beat to the other are called heart rate variability (HRV) occurring because of the sympathetic and parasympathetic activity changes with variable assigned parameters. Low HRV is associated with cardiovascular diseases and mortality,[6] and a decrease in HRV is shown in some neurological disorders.[7],[8] Studies on HRV without using the specific HRV parameters in CH revealed autonomic involvement during only attack periods.[9] Given that most of the patients are middle-aged male smokers, their screening for cardiac problems is vital; but there are no systematic studies with Holter monitoring and electromyography yet.

We hypothesized that autonomic dysregulation has a role in the pathophysiology of CH and conducted HRV and electrophysiological tests to underline this point.

  Methods Top

Subjects with CH were diagnosed according to the third edition of the International Classification of Headache Disorders.[3] A total of 35 subjects with a mean age of 37.26 ± 13.318 were included. Sixteen episodic CH patients during pain-free episodes (No CH attack in the past 6 weeks) and four chronic CH patients were selected for each group according to their availability during testing as described in figure [Figure 1]. Patients with other nervous system disorders, heart and respiratory diseases, and severe rhythm disturbances were excluded, and none of our patients were on medication during the study. Gender and age-matched healthy individuals without painful conditions like migraine participated in the study as the control group. These healthy controls neither have medical history nor use of prescription drugs. All subjects were included after signing the informed consent form and ethical approval.
Figure 1: Flow chart of patient selection

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For measuring HRV, patients were recorded with a 12-channel electrocardiogram Holter device that performed 24-h ambulatory measurement. All results were evaluated blindly by an experienced cardiologist. Moreover, mean and maximum heart rate values were analyzed along with 24-h mean HRV parameters (SDNN-24: Standard deviation of normal to normal (NN) intervals, SDNN-index: Mean of the standard deviations of all the NN intervals for each 5 min segment of a 24-h HRV recording, SDANN-index: Standard deviation of the average NN intervals for each 5 min segment of a 24-h HRV recording, RMSSD: Root mean square of successive RR interval differences, and pNN50: Percentage of successive RR interval differences). Sympathetic skin response and RRIV (normal and deep breathing) were performed in a ventilated, quiet, and normally illuminated room while patients were lying on their backs and their skin temperatures were maintained at >32°C. The subjects were evaluated regarding diseases that could lead to dysautonomia, and history of orthostasis, syncope, gastrointestinal dysfunction, and sweating were investigated. To ensure standardization, all examinations were made by an experienced clinical neurophysiologist using the same electromyography device (keypoint 9033A07, Alpine Biomed ApS, DK-2740 Skovlunde, Denmark).

Statistical analyses

SPSS v22.0 (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA) was used for statistical evaluation and Prism 8 for drawing graphs. Kolmogorov–Smirnov test was used for testing the normality of the data, and Kruskal–Wallis test was applied to compare nonparametric data obtained from analysis of the HRV and electrophysiological examinations. Student's t or Mann–Whitney U test was performed to compare the significant results between two groups. Moreover, Chi-square and t-tests were used to compare clinical characteristics between the groups, and the Spearman correlation test was used for correlation analyses. P < 0.05 was considered to be statistically significant in all tests. Study size is determined by the power analysis of the results. Binomial logistic regression was performed to ascertain the effects.

  Results Top

[Table 1] summarizes the demographics, general disease information, clinical features, and test results of the patients with a disease duration of 7.89 ± 7.34 [Table 1]. Most common autonomic features were lacrimation (n = 31, 88%), rhinorrhoea (n = 22, 62%), myosis/ptosis (n = 17, 48%), and eyelid edema (n = 14, %40) in attack period and there was no systemic autonomic symptom.
Table 1: Demographics, general disease information, and test results of the patients

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Heart rate variability

Sixteen patients in the attack-free period and four chronic CH patients (but without pain during the study for convenience and due to ethical issues) (15 men; mean age: 38.45 ± 12.845 years), 20 controls (15 men; mean age: 38.45 ± 9.467 years) were monitored for 24 h with a Holter monitor. The normal heart rhythm, mean sinus rate, as well as minimum and maximum heart rate values of all patients and controls were reported to be within normal limits. There was no significant difference between the patients and controls for analyzing SDNN-24, SDNN-index, and SDANN-index values reflecting sympathetic system regulation. The mean heart rate (P = 0.046) was significantly higher in 11 cases with more autonomic manifestations (at least four autonomic symptoms that occurred during the attacks). RMSSD (P < 0.001) and pNN50 (P = 0.024), short-term HRV parameters reflecting parasympathetic system activity, were significantly higher in CH patients [Figure 2]. Binomial logistic regression was performed to ascertain the effects of rMSDD and pNN50 on the likelihood that participants have CH. Of the two predictor variables, none was found to be statistically significant.
Figure 2: Values of RMSSD and pNN50 in patients compared to controls

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Electrophysiological findings

SSR and RRIV examinations were performed in 20 patients (15 men, mean age: 37.40 ± 12.663 years) and 20 controls (15 men, mean age: 37.40 ± 5.725 years). All recorded RRIV during normal breathing and deep breathing as well as SSR of all patients were within normal limits based on age and gender [Figure 3], without showing any interictal autonomic dysfunction. Moreover, no significant difference was reported in terms of latency and amplitude of SSR recorded from the hands and feet and the RRIV at rest and during deep breathing between the patient and control groups. The amplitudes of the responses recorded from the hands (P = 0.012) and the RRIV at rest (P = 0.046) were significantly lower in nine subjects with late onset.
Figure 3: Normal sympathetic skin responses result of a patient

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  Discussion Top

Results of HRV tests are the most striking part of our study. We showed autonomic dysregulation in these studies, but the results of electrophysiological tests were nonsignificant in our study.

The most important result of this study is the significantly higher RMSSD and pNN50 levels, which are two main indicators of increased parasympathetic activity in CH patients compared to the controls. There are no published data on these parameters in patients with CH yet, and our study is the first to show this interesting result.

On the other hand, notable studies on low RMSSD levels associated it with sudden death and myocardial infarction in other groups.[10],[11] Low RMSSD values vary during the day and night; however, in light of recent studies, they have become more important because of increased cardiac risk. The high RMSSD values observed in this study suggest an autonomic involvement specific to the CH group; however, its clinical significance is unknown. In a study conducted in subjects with multiple sclerosis, although there was no significant relationship between HRV parameters and the disease, a positive correlation between relapse and SDNN and RMSSD values were noted as a possible inflammatory marker.[12] Moreover, we would like to emphasize that these data should be considered a warning for careful monitoring of CH patients regarding the risk of heart disease, especially at older ages. Considering the intense stress because of severe pain in CH patients who may have hyperlipidemia and other risk factors, there is a requirement for broader studies with prospective follow-up in terms of cardiac health. The data we obtained during the nonattack period suggest that CH is associated with a disturbance in the regulation of the autonomic nervous system regardless of the painful period of the disorder. Questioning interictal cardiac symptoms in CH patients is vital to understanding the clinical meaning of this data. A multidisciplinary approach and a closer link between neurologists and cardiologists are needed to reveal the cardiac and systemic involvements of disease. This involvement showed structural effects of CH beyond our knowledge, and broader studies are needed to investigate the possible effects of autonomic impairment on the human body. The balance was disturbed in the parasympathetic direction and guided in terms of the effects of the disorder on the autonomic nervous system. In patients with migraine, unlike our CH cases, the results of reduced parasympathetic activity and predominance of sympathetic activity at night, particularly in migraine with aura, are striking.[13] This difference in HRV findings of different forms of primary headaches can be interpreted to be clinically in line with their variable effects on the autonomic system.

We found no significant differences in SSR and RRIV between the patient and control groups in the electrophysiological examinations, demonstrating that the pathophysiology of CH did not exert prominent effects on the autonomic nervous system during the nonattack period. The lower amplitudes of SSR recorded from the hands in subjects with late onset and lower RRIV at rest were considered age-related symptoms and not associated with the disorder.[14]

  Conclusion Top

These findings have significant implications for a better understanding of CH disease. The increased parasympathetic activity we detected in the nonattack period added value to the present study because of the tips it has provided to understand the pathophysiology of the disorder. Furthermore, HRV findings showing autonomic impairment in a group consisting of primarily men and smokers could lead us to know the cardiovascular effects of the disease. Our study had a few limitations. First, the number of patients included in our study was sufficient for an uncommon disease, but we would like to include more patients. Long attack periods and logistic problems were the main reasons for patient exclusion. Second, adding ictal data would enrich the findings, but 24-h ambulatory measurement was not suitable for painful attack periods.

This controlled study, which investigated various autonomic mechanisms of CH, is important because of its multifaceted approach. Our analysis suggested that the changes of RMSSD and pNN50 were not reliable predictors for CH diagnosis, but this result should be tested in a larger study. We showed that analysis of HRV in CH patients might be clinically significant and provide information about the disorder. More comprehensive analyses of CH with a higher number of subjects can guide understanding the underlying mechanisms.


We would like to thank all participants.

Financial support and sponsorship

This work was supported by the Istanbul University Scientific Research Fund (grant number BAP-TTU-2017-26478).

Conflicts of interest

There are no conflicts of interest.

  References Top

Rozen TD. Cluster headache: Diagnosis and treatment. Curr Pain Headache Rep 2005;9:135-40.  Back to cited text no. 1
Snoer A, Lund N, Beske R, Jensen R, Barloese M. Pre-attack signs and symptoms in cluster headache: Characteristics and time profile. Cephalalgia 2018;38:1128-37.  Back to cited text no. 2
Headache Classification Committee of the International Headache Society (IHS) The international classification of headache disorders, 3rd edition. Cephalalgia 2018;38:1-211.  Back to cited text no. 3
Korkmaz B, Yildiz S, Yildiz N. Sympathetic skin responses from the neck area in patients with unilateral migraine. Noro Psikiyatr Ars 2015;52:151-6.  Back to cited text no. 4
Altiokka O, Mutluay B, Koksal A, Ciftci-Kavaklioglu B, Ozturk M, Altunkaynak Y, et al. Evaluation of interictal autonomic function during attack and remission periods in cluster headaches. Cephalalgia 2016;36:37-43.  Back to cited text no. 5
La Rovere MT, Bigger JT Jr., Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998;351:478-84.  Back to cited text no. 6
Maetzler W, Karam M, Berger MF, Heger T, Maetzler C, Ruediger H, et al. Time- and frequency-domain parameters of heart rate variability and sympathetic skin response in Parkinson's disease. J Neural Transm (Vienna) 2015;122:419-25.  Back to cited text no. 7
Kasanuki K, Iseki E, Fujishiro H, Ando S, Sugiyama H, Kitazawa M, et al. Impaired heart rate variability in patients with dementia with Lewy bodies: Efficacy of electrocardiogram as a supporting diagnostic marker. Parkinsonism Relat Disord 2015;21:749-54.  Back to cited text no. 8
Barloese MC. A review of cardiovascular autonomic control in cluster headache. Headache 2016;56:225-39.  Back to cited text no. 9
Jarczok MN, Koenig J, Wittling A, Fischer JE, Thayer JF. First evaluation of an index of low vagally-mediated heart rate variability as a marker of health risks in human adults: Proof of concept. J Clin Med 2019;8:1940.  Back to cited text no. 10
Buccelletti E, Gilardi E, Scaini E, Galiuto L, Persiani R, Biondi A, et al. Heart rate variability and myocardial infarction: Systematic literature review and metanalysis. Eur Rev Med Pharmacol Sci 2009;13:299-307.  Back to cited text no. 11
Reynders T, Gidron Y, De Ville J, Bjerke M, Weets I, Van Remoortel A, et al. Relation between heart rate variability and disease course in multiple sclerosis. J Clin Med 2019;9:3.  Back to cited text no. 12
Matei D, Constantinescu V, Corciova C, Ignat B, Matei R, Popescu CD. Autonomic impairment in patients with migraine. Eur Rev Med Pharmacol Sci 2015;19:3922-7.  Back to cited text no. 13
Kucera P, Goldenberg Z, Kurca E. Sympathetic skin response: Review of the method and its clinical use. Bratisl Lek Listy 2004;105:108-16.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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