Are migraine and cluster headache one spectrum? Implications from cyclical migraine

doi:10.21203/rs.3.rs-3332938/v1

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Are migraine and cluster headache one spectrum? Implications from cyclical migraine

https://doi.org/10.21203/rs.3.rs-3332938/v1

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Background and Objectives: Cyclical migraines (C-M) are occasionally met in headache clinics, but not well studied. The aim of the study was to delineate the characteristics of C-M, and compared them with those of cluster headache (CH) and migraine without aura (MO).

Methods: We collected patients with C-M from our headache center, and patients with CH and MO from our cross-sectional standardized survey between 2014 and 2020. Data including demographics, headache characteristics, triggers, and relieving factors were recorded.

Results: Forty-seven patients with C-M were identified. Most of the characteristics of C-M were found to be intermediate between MO and CH, including gender, attack duration, headache degree, headache side, as well as both migraine-like and CH-like accompanying symptoms. C-M had a significant higher percentage of women, and less severe and lower percentages of most CH-like accompanying features compared to CH. On the other hand, C-M had a significant lower percentage of women, earlier onset, shorter duration of headache attacks, more severe, lower percentages of migraine-like accompanying features and higher percentages of CH-like accompanying features compared to MO. However, triggers and relieving factors in C-M were more similar to CH than MO.

Discussion: The largest C-M series defines it as a transition stage between MO and CH. Fewer differences were found between C-M and CH, indicating that C-M may be more similar to CH.

Cyclical migraine

cluster headache

migraine

migraine without aura

Cluster headache (CH) is a severe primary headache, typically accompanied by cranial autonomic symptoms (CAS). Its distinct features include an identifiable cluster period and a circadian rhythm, which account for its name. Although the majority of CH characteristics are typical, a minority presents with atypical symptoms (12.6% in Republic of Korea)[1]. In contrast, migraine, a common primary headache, occasionally exhibits CAS and is often accompanied by nausea and vomiting, rather than a cluster period.

Cyclical migraine (C-M) is a unique type of headache, which was initially report by Medina in 1981[2]. The headache should meet the criteria for migraine or probable migraine but have a regular attack cycle like CH. However, it is noteworthy that cyclical migraine is not contained in the International Classification of Headache Disorders[3], leading to challenges in its diagnosis and treatment. Notably, the treatment for migraine and CH prevention differs significantly. Delayed onset of relief and prolonged duration of discomfort for patients may result from the maintenance of treatment for an extended duration for the assessment of efficacy. In addition, the emergence of the intermediate state of C-M raises the possibility that CH and migraine may manifest a homologous mechanism and represent a continuous disease spectrum. These observations indicate the need for further research into C-M to establish its place in the classification criteria.

Therefore, we conducted this cross-sectional study to examine the clinical characteristics of C-M. We recruited C-M patients from headache center at the Chinese PLA General Hospital, and compared the similarities and differences among C-M, CH and migraine without aura (MO) in clinical characteristics, including headache location, pain nature, headache intensity, attack durations, concomitant symptoms, triggers and relieving factors. to elucidate the features of C-M and provide a basis for clinical practice.

Participants and data collection

Patients diagnosed with C-M were collected from the headache center at Chinese PLA General Hospital between 2014 to 2020. The headaches should meet the criteria of migraine or probable migraine according to the International Classification of Headache Disorders, Third Edition (ICHD-Ⅲ) or β vision (ICHD-Ⅲβ)[4] and had experienced at least two episodes of cluster periods. These C-M patients were compared to cohorts consisting of patients with episodic CH and episodic migraine without aura based on cross-sectional standardized survey data which was conducted in the headache center at PLA General Hospital and nine other neurology clinics between January 2014 to December 2020[5, 6]. This electronic survey was designed to be accessible online for all qualified researchers[7–9]. Data related to age, age of onset, gender, diagnosis, headache characteristics (location, pain nature, headache intensity on visual analogue score (VAS) from 0 to 10, mean headache duration, headache attack frequency, mean bout duration since the first cluster period, bout frequency per year), CH-like and migraine-like accompanying features, triggers and relieving factors were systematically collected. Migraine-like accompanying symptoms included nausea, vomiting, photophobia and phonophobia, aggravation by activity. CH-like accompanying symptoms included conjunctival injection and/or lacrimation (abbreviated as lacrimation in Table 1), nasal congestion and/or rhinorrhoea (abbreviated as nasal congestion in Table 1), ptosis, forehead and facial sweating (abbreviated as sweat in Table 1), miosis and eyelid oedema. The frequency of bouts was categorized into three levels: less than once per year, once per year and more than once per year. Headache attack frequency was divided into five grades: less than once per day, once per day, more than once but less than twice per day, twice per day, more than twice per day. Bout frequency, headache attack frequency, the bout duration, and the headache attack duration were determined by the mean value over the course of the condition. Triggers of C-M included alcohol, tiredness and sleep disturbance, hot or cold weather changes, stress, intense light, specific odor, noisy environments, hypo-oxygen or enclosed space, and hormonal fluctuations. Various relieving factors were identified, including rest or sleep, hot or cold compress, exercise, massage, pregnancy, and others miscellaneous interventions.

Standard protocol approvals, registration, and patient consents

The study was approved by the Ethics Committee of the Chinese PLA General Hospital. The study protocol complied with China’s regulations and Guidelines for Good Clinical Practice. The Institutional Review Board of each participating hospital approved this study. All patients must provide written informed consent to participate in the study.

Statistical analysis

The statistical analyses were performed using SPSS (version 23.0). For continuous data, normality test was performed first. If both groups met normality, mean (standard deviation) was used for statistical description, and t-test was used for analysis. Otherwise, median (P25-P75) was used for statistical description and the Mann–Whitney U test was used for analysis. The categorical data were analyzed using chi-square test. If an expected value was less than five, Fisher’s exact test was used. p < 0.05 was considered statistically significant. Subjects with missing data were excluded from the analyses.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request and with permission of Chinese PLA General Hospital.

Participation and description for C-M

This study comprised of 47 patients diagnosed with C-M. In addition to 401 cases of CH and 3628 cases of migraine without aura, as illustrated in Fig. 1.

Of the 47 C-M patients enrolled, 30 were male and 17 were female. Among these patients, 15 (32%) could be diagnosed as migraine, and 32 (68%) were classified as probable migraine. Moreover, 3 (6.4%) patients could be diagnosed with CH, while 41 (87.2%) exhibited symptoms indicative of probable CH. Notably, none of the C-M patients presented with aura. The median age of onset for headaches was 21 years old, with a median pain degree of 9 and attack duration of 180 minutes. Furthermore, 72.3% of patients experienced a migraine-like headache nature, which included throbbing headache, distending, and bursting headache).

Headaches were primarily localized in the temporal and orbital areas, with unilateral presentation noted in 85% of patients (Table 1, Fig. 2). The median duration of clusters were 30 days (Table 2). Specifically, 36.2% of clusters occurred less frequently than once a year, 40.4% occurred once a year, and 23.4% occurred more than once a year. Furthermore, 40.4% of patients suffered headache attack once daily, while 23.4% experienced attacks less than once a day or between once and twice per day. Merely 12.7% of patients reported two or more daily attacks (Table 2). Headache aggravation due to activity was noted in 63.8% of patients, and restlessness accompanied headaches in 25.5% of patients. More than half of the patients accompanied with migrainous symptoms, with nausea being the most common symptom. Over half of the patients also demonstrated cluster-associated symptoms, with lacrimation being the most commonly observed symptoms (Table 1, Fig. 3). Weather, tiredness, and alcohol were the most frequent triggers identified, while rest and massage were the most effective mitigating strategies reported.

Table 1

Clinical features of patients with CH, C-M and MO
	CH	C-M	MO
	(n = 401)	(n = 47)	(n = 3628)	p value
Demographics
Gender (female)	66 (16.5)	17 (36.2)	2940 (81.0)	< 0.001
Age (years old)	33(28–39)	30(27-36.5)	37(29–46)	< 0.001
Age at Onset (years old)	22(18-27.8)	21.1(17.8–25.9)	27(19.8–35.5)	< 0.001
Headache Features
Headache Course (years)	10(5–14)	10(6–14)	8(2.75–13.3)	0.009
Headache Intensity (VAS)	9(8–10)	9(7–10)	7(6–8)	< 0.001
Attack duration (minutes)	75(50–120)	180(82.5–240)	1440(480–1440)	< 0.001
Migraine-like Headache Type	318 (79.3)	34 (72.3)	3354 (92.4)	< 0.001
Main Headache Area
Frontal	88 (21.9)	6 (12.8)	787 (21.7)	0.331
Parietal	102 (25.4)	11 (23.4)	1399 (38.6)	< 0.001
Occipital	104 (25.9)	14 (29.8)	1193 (32.9)	0.017
Temporal	304 (75.8)	32 (68.1)	2526 (69.6)	0.035
Orbital	241 (60.1)	23 (48.9)	453 (12.5)	< 0.001
Others	132 (32.9)	10 (21.3)	253 (7.0)	< 0.001
Unilateral	401 (100)	40 (85.1)	1751 (48.3)	< 0.001
Bilateral	0 (0)	7 (14.9)	1877 (51.7)	< 0.001
Migraine-like accompanying features
Aggravation by activity	192 (47.9)	30 (63.8)	83 (76.9)	< 0.001
Nausea	254 (63.3)	35 (74.5)	3223 (88.8)	< 0.001
Vomiting	140 (34.9)	19 (40.4)	2201 (60.7)	< 0.001
Photophobia	162 (40.4)	24 (51.1)	2248 (62.0)	< 0.001
Phonophobia	184 (45.9)	26 (55.3)	2539 (70.0)	< 0.001
CH-like accompanying features
Restless	219 (54.6)	12 (25.5)	229 (6.3)	< 0.001
Lacrimation	354 (88.3)	30 (63.8)	83 (2.3)	< 0.001
Nasal congestion	270 (67.3)	19 (40.4)	56 (1.5)	< 0.001
Ptosis	158 (39.4)	10 (21.3)	9 (0.2)	< 0.001
Sweat	125 (31.2)	6 (12.8)	41 (1.1)	< 0.001
Miosis	6 (1.5)	0 (0)	3 (0.1)	1
Eyelid oedema	83 (20.7)	5 (10.6)	22 (0.6)	< 0.001

Median (P25-P75) for quantitative data; n (%) for qualitative data.

Migraine-like Headache Type including throbbing headache, distending headache, bursting headache

CH, cluster headache; C-M, cluster migraine; MO, migraine without aura; VAS, visual analogue score; CAS, cranial autonomic symptoms

Table 2

Cluster-related features of patients with CH and C-M
	CH	C-M
	(n = 401)	(n = 47)	p value
Duration of clusters (days)	30 (20–45)	30 (20.5–45)	0.417
Frequency of clusters			0.898
< 1 time/year	155 (38.7)	17 (36.2)
1 time/year	163 (40.6)	19 (40.4)
> 1 time /year	83 (20.7)	11 (23.4)
Attack frequency			0.105
< 1/day	47 (11.7)	11 (23.4)
1/day	159 (39.7)	19 (40.4)
> 1/day, < 2/day	93 (23.2)	11 (23.4)
2/day	34 (8.5)	1 (2.1)
> 2/day	68 (17.0)	5 (10.6)

Median (P25-P75) for quantitative data; n (%) for qualitative data.

C-M, cluster migraine; CH, cluster headache

Demography among C-M, CH and MO

Overall, statistically analysis revealed significant differences among the three groups in terms of demographic characteristics, headache features, headache areas, and accompanying features related to CH and migraines, with the exception of the forehead in the headache area and miosis in CH-like accompanying features (Table 1). It is possible that these differences are largely attributed to the distinctions between CH and MO, rather than the C-M subtype. Therefore, our subsequent analysis compared C-M to CH and MO independently. In terms of gender, the male-to-female ratio in the C-M subgroup was 1.8:1, which is significantly lower than that of CH (5:1; p = 0.001) and higher than that of MO (1:4.3; p < 0.001, Fig. 2a). There were no significant differences in the age (p = 0.172) or age of onset (p = 0.304) between individuals in the C-M and CH groups. However, when comparing C-M to MO, significant differences were found in term of age (p < 0.001) and age of onset (p < 0.001) as depicted in Fig. 2 (b-c).

Headache features among C-M, CH and MO

There were no significant differences observed in terms of headache course (p = 0.567) between individuals of C-M and CH and that of C-M and MO subjects (p = 0.159; Fig. 2d). However, attack duration showed significant differences among three groups (p < 0.001; Fig. 2e). The visual analogue scale (VAS) value was significantly lower in C-M compared to CH (p = 0.015), and significantly higher in C-M relative to MO (p < 0.001, Fig. 2f). Since solely C-M and CH exhibited cluster periods, only data pertaining to cluster periods were analyzed for these two groups. The results indicate no significant differences between the two groups in term of the frequency of cluster periods (p = 0.898), duration of cluster periods (p = 0.417), or headache attacks frequency (p = 0.105, Table 2).

Headache locations among C-M, CH and MO

No significant differences were observed in any of the headache locations between C-M and CH (Frontal, p = 0.144; Parietal, p = 0.762; Occipital, p = 0.571; Temporal, p = 0.247; Orbital, p = 0.141, Fig. 2g), while certain headache locations were found to exhibit no differences between C-M and MO (Frontal, p = 0.139; Occipital, p = 0. 0.653; Temporal, p = 0.82). Remarkably, C-M patients reported less pain in the parietal (p = 0.03) and more pain in the orbital (p < 0.001) compared to MO patients. A small proportion of C-M patients (15%) have bilateral headache, but almost half of all MO patients reported having bilateral headaches (p < 0.001, C-M vs MO, Fig. 2h).

Migraine-like and CH-like accompanying features among C-M, CH and MO

As expected, the prevalence of migraine-like accompanying features in C-M patients was between that of CH and MO patients. A greater proportion of C-M patients reported aggravation by activity as compared to CH patients (p = 0.039). MO patients, on the other hand, reported experiencing aggravation by activity, nausea, vomiting and phonophobia more often than C-M patients (aggravation by activity, p = 0.0346; nausea, p = 0.002; vomiting, p = 0.005, photophobia, p = 0.126, phonophobia, p = 0.030, Fig. 3a).

CAS were specific accompanying symptoms in CH, but can also manifest in migraine patients. With the exception of miosis and eyelid oedema, all other CAS and restless were found to be significantly more common in CH patients than in C-M (restless, p < 0.001; lacrimation, p < 0.001; nasal obstruction, p < 0.001; ptosis, p = 0.015; sweat, p = 0.009; miosis, p = 1; eyelid oedema, p = 0.101, as presented in Fig. 3b). Except for miosis, the prevalence of all other CAS and restless was significant higher in C-M patients when compared to MO patients (restless, p < 0.001; lacrimation, p < 0.001; nasal obstruction, p < 0.001; ptosis, p < 0.001; sweat, p < 0.001; miosis, p = 1; eyelid oedema, p < 0.001, as shown in Fig. 3b).

Triggers and mitigating factors among C-M, CH and MO

Stress, tiredness and weather were revealed as the top three triggers for MO patients, accounting for 29.8%, 26.1%, and 21.8%, separately. In contrast, weather, tiredness and alcohol emerged as the top three triggers for C-M and CH patients (32.5%, 27.5%, 25% for C-M; 24.4%, 22.7%, 20.0% for CH). Furthermore, alcohol was found to more frequently induce headaches in C-M and CH patients compared to MO (p < 0.001), whereas stress was more likely to trigger headaches in MO patients compared to CH and C-M patients (p < 0.001, p = 0.026, separately). Notably, hormones emerged as a common trigger for MO patients, yet they were not found to cause any C-M or CH. Moreover, a noisy environment and specific odors were also more commonly associated with MO than with CH (p = 0.013, p = 0.039) (as displayed in Fig. 3c).

Rest was found to be the most effective mitigating factor for both MO and C-M patients, with rest being significantly more effective in MO patients than in C-M and CH patients (p < 0.001). There were no particularly effective mitigating factors identified for CH, although massage was deemed the most effective (22.7%). Additionally, pregnancy and rest were found to be more useful for MO patients compared to CH patients (p = 0.006; p < 0.001, separately), and cold compress and exercises were more effective for CH patients compared to MO patients (p < 0.001; p < 0.001, separately) (Fig. 3d).

This study aimed to characterize a kind of headache that exhibits both migraine-like features and temporal patterns similar to CH. In general, the majority of the characteristics of C-M patients fell between those of MO and CH patients, including gender ratio, attack duration, headache severity, and headache location. Additionally, C-M patients reported exhibiting intermediate states for most migraine-like and CH-like accompanying symptoms. However, the triggers and mitigating factors for C-M were found to more closely resemble those of CH patients, thereby suggesting a greater similarity to CH.

Comparison of C-M to CH and MO

Differences in gender

Previous studies have shown the male to female ratio for CH ranged from 3.8-7:1 in Eastern populations, while between1.3-3.5:1 in Western populations [10]. By comparison, the male to female ratio for migraine was approximately 1:2–3 [9, 11],while that for MO was further reduced to 1:2.2-1:4.9[12–15]. In our study, the male to female ratio was 5:1 in CH, 1.8:1 in C-M and 1:4.3 in MO. It should be noted that although C-M still presents more commonly in men, the proportion of males has been significantly reduced compared with CH. As CH has been found to be typical and prone to be misdiagnosis in female [16], the atypical presentation is often conflated with migraine-like characteristics. Although the proportion of women with C-M has increased, hormone levels and pregnancy have not been reported as triggers or mitigating factors for C-M patients.

Differences in headache features

The pain intensity, attacks duration, and headache location for both CH and MO patients in this study were consistent with those reported in previous studies[17–21]. C-M patients exhibited headache features and locations that were largely intermediary between those of CH and MO patients, although C-M was found to be more similar to CH in terms of attack duration, headache characteristics, and certain headache location.

Remarkably, none of the patients with CH or C-M in this study reported experiencing aura, which contrasts with findings from Western countries, where it has been reported in approximately 7–23% of CH patients[22]. The incidence of aura in China is significantly low (0-0.7%)[23, 24]; therefore, we chose MO as a comparison group in this study.

Differences for accompanied symptoms

Our study has found that the prevalence of most CAS and restlessness was significantly lower in C-M patients as compared to CH patients. Similarly, MO patients also exhibited a lower prevalence of CAS as compared to C-M patients. Notably, CAS is a distinguishing characteristic of CH and is observed in approximately 90% of patients[25]. Among CH patients, the most frequent manifestations of CAS are conjunctival and larcrimation (more than 80%)[25, 26]. CAS is not unique to CH, however, has been reported in 56% of Caucasians and 42.4% of Asians who suffer from migraines[27, 28]. One probable mechanism underlying CAS symptoms is hypothalamus activation. The hypothalamus is known to initiate both CH and migraine by activating the trigeminal-autonomic reflex and descending trigeminal nuclei, thus producing CAS symptoms[29, 30]. Patients experiencing CAS have been reported to exhibit a significant level of central sensitization compared with those who do not experience such symptoms[31]. In this study, the prevalence of CAS in MO patients was substantially lower than what has been reported in previous researches, which may be due to recall bias among the patients.

The prevalence of migraine-like accompanying features was found to be high among CH patients, with approximately 50–65% of CH patients reporting the presence of these features, a proportion which is consistent with prior research[32]. Migraine-like accompanying features of C-M patients fell between those of CH and MO patients.

Differences in headache triggers and mitigating factors

CH and migraine have distinct triggers and mitigating factors. Weather changes and alcohol consumption are more commonly associated with CH, while mood, stress, sleep, and hormone levels are more typically related to migraine. It has been observed that patients with C-M exhibit more similarities with CH patients than MO patients. This finding suggests that the pathophysiological mechanisms underlying C-M may be more akin to CH.

Comparison of C-M in different studies

In 1981 and 1982, Medina reported a C-M cohort consisting of 27 individuals, which to date, remains the only reported cohort[2, 33]. Our study found similarities in age, age at onset, quality, intensity, and migraine-like accompanying features with Medina’s study. However, differences were observed in gender, CH-like accompanying features and aura. Medina reported a much higher proportion of females, with a male/female ratio of 1:0.29, which is lower than the ratio observed in our study of 1.8:1. Furthermore, only 3 patients (11.1%) in our study exhibited a congested nose. Medina reported 11 patients (40.7%) with aura, including 7 patients (25.9%) with scintillating scotomas. These findings suggest that the migraine features of C-M in our study were less pronounced than those observed in Medina's study. Interestingly, medications such as tricyclic antidepressants, propranolol, and methysergide maleate-which are effective in preventing migraines-did not show efficacy in C-M patients with features close to migraines; whereas lithium, known to be a first-line therapy for CH, showed the greatest response.

Implications from C-M that whether CH and migraine belong to one spectrum

It has been discussed whether migraine and cluster headaches should be considered as two distinct primary headaches or as a continuous spectrum disease[34]. Traditionally, they have been regarded as separate diseases due to differences in headache features, gender, attack duration and response to therapies such as β-blockers and verapamil. Nonetheless, both types of headaches are frequently accompanied by CAS, and share common triggers including histamine, glyceryl trinitrate and calcitonin gene-related peptide (CGRP), as well as a response to triptans and CGRP-mAb, indicating similar pathophysiological mechanisms[34]. In particular, some patients present with overlapping clinical features, complicating the nosological boundaries between the two headache types[35]. These occasions present diagnostic challenges, and in the past, tems such as “cyclical migraine”, “cyclic migraine”, “migraine-cluster headache symptoms”, and “cluster migraine” have been used to described these conditions[2, 33, 35–37]. “Migraine-cluster headache symptoms” and “cluster migraine” are broad terms that describe headaches with characteristics of both migraine and cluster headache, especially when one type of headache predominates and includes some features of the other[35, 37]. “Cyclical migraine” and “cyclic migraine” refer to headaches that met the criteria for migraine or probable migraine but occur in a regular, periodic pattern similar to CH, which is a common subtype of cluster migraine[2, 33]. The phenomenon of cluster-migraine was discussed in detail in the 1980s but appeared to receive less attention thereafter until recently. Chwolka, et al documented five cases of cluster-migraine earlier this year, thereby corroborating the existence of this phenomenon and underscoring the need for further investigation[38]. CH and migraine share a common anatomical structure known as the trigeminovascular system, which includes the trigeminocervical complex (TCC), the parasympathetic nerve fibers (trigeminal autonomic reflex, TAR), and the hypothalamus. The fibers from the TCC project to thalamic and sensory neurons, which transmit and regulate pain, while fibers connected to parasympathetic neurons in the superior salivatory nucleus activate autonomic symptoms[34]. The hypothalamus also participates in these processes., with the anterior hypothalamus contributing to circadian rhythm and the lateral and posterior parts generating restlessness[34]. These anatomical similarities form the basis for the overlaps observed between CH and migraine.

Previous studies, including our own, have indicated that the majority of features associated with C-M are situated between CH and migraine, effectively bridging the gap between the two diseases. On the other hand, our study revealed that C-M displayed greater similarity to CH, not only in terms of headache features but also in terms of common triggers and mitigating factors. The observed strong response of C-M patients to lithium treatment in Medina's studies and the cyclicity of C-M may represent a more fundamental mechanism, thereby suggesting that C-M may be more closely related to CH.

Sjöstrand and colleagues conducted a study involving 21 families, with a total of 55 patients diagnosed with CH[39]. Of these patients, 42 presented with episodic or chronic CH, while one exhibited probable CH. The remaining 12 patients were classified as atypical, due to low frequency and lengthy duration of headaches, as well as absence of CAS and restlessness, which prevented them from meeting the diagnostic for CH. Notably, despite the atypical presentation, these patients experienced severe to very severe strictly unilateral pain, strongly indicative of CH. Consequently, Sjöstrand and colleagues postulated that atypical CH represents an expanded spectrum of CH. Similarly, our study raises the question of whether C-M, despite not satisfying the complete diagnostic criteria for CH, may represent a manifestation of an expanded spectrum of this disease.

Strengths and limitations

This is the first cross-sectional study of C-M patients, with a focus on comparing and contrasting the similarities shared by CH and migraine patients. However, there exist certain limitations that should be acknowledged. Firstly, due to the methodical usage of patient diaries for data collection, recall bias may be unavoidable. Secondly, the C-M cohort was enrolled specifically from headache clinic, leading to the fact that some affected individuals may not have been identified. Finally, noteworthy therapeutic outcomes were not documented in this study. Consequently, there is a need to establish a C-M cohort for further investigation.

We have provided evidence for the existence of C-M, as an intermediate state between cluster headache and migraine, and have suggested that it may even be a subtype of CH. Moving forward, we plan to establish a cohort of patients with cluster migraine, with the goal of exploring possible mechanisms through long-term follow-up observation and functional magnetic resonance examination.

C-M: Cyclical migraine; CH: Cluster headache; MO: Migraine without aura; pCH: probable cluster headache; ICHD: International Classification of Headache Disorders; VAS: Visual analogue score; CAS: cranial autonomic symptoms; CGRP: Calcitonin gene-related peptide

Ethics approval and consent to participate

The research protocol was approved by the Ethics Committee of the Chinese PLA General Hospital. All patient provided written informed consent to participate in the study.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

None.

Authors’ contributions

MJZ analyzed and interpreted the data and results. MJZ and ZD drafted the manuscript. ZMY developed and maintained the software to collect clinical data. ZHZ, SHZ, KL, JRM, WZ, YJL, YMX, YJL, JLL, QG, FHY, ZLG, YL, DMH, SFC, XLW, RFW, XYC, ZHJ, JL, XH collected the data of patients. YR and HXL analyzed and interpreted the data and results. ZD and SYY proposed the concept and design of the study, and revised manuscript for critical intellectual content. All authors read and approved the final manuscript.

Acknowledgement

Thanks to doctors in Chinese PLA General Hospital and other 9 hospitals for their contribution in providing the cases and the participation of patients in this study.

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No competing interests reported.

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Are migraine and cluster headache one spectrum? Implications from cyclical migraine

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Abstract

Figures

Introduction

Methods

Participants and data collection

Standard protocol approvals, registration, and patient consents

Statistical analysis

Data Availability

Results

Participation and description for C-M

Demography among C-M, CH and MO

Headache features among C-M, CH and MO

Headache locations among C-M, CH and MO

Migraine-like and CH-like accompanying features among C-M, CH and MO

Triggers and mitigating factors among C-M, CH and MO

Discussion

Comparison of C-M to CH and MO

Differences in gender

Differences in headache features

Differences for accompanied symptoms

Differences in headache triggers and mitigating factors

Comparison of C-M in different studies

Implications from C-M that whether CH and migraine belong to one spectrum

Strengths and limitations

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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