Edited by: Tim P. Jürgens, Universitätsmedizin Rostock, Germany
Reviewed by: Mads Barløse, Hvidovre Hospital, Denmark; Marco Carotenuto, Università degli Studi della Campania “Luigi Vanvitelli” Caserta, Italy
This article was submitted to Headache Medicine and Facial Pain, a section of the journal Frontiers in Neurology
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Cluster headache (CH), which is characterized by severe headache localized in or around the eye and accompanied by cranial autonomic symptoms (CAS), is the most painful form of primary headache disorder. Based on epidemiological surveys from the USA and Europe, CH has a prevalence of 0.1% in the general population (
Probable CH is diagnosed when a patient's headache fulfills all but one criterion for CH based on the International Classification of Headache Disorder (ICHD) (
Here, we sought to assess the proportion of probable CH diagnoses and to clarify the diagnostic profile of individuals with probable CH. In addition, the clinical characteristics of probable CH patients were compared with those of patients diagnosed with definite CH.
This study was performed using data obtained from the Korean Cluster Headache Registry (KCHR) study, a multicenter, cross-sectional headache registry that used prospectively collected data from consecutive patients with CH treated at the neurology outpatient departments of 15 hospitals in Korea between August 2016 and May 2018. This study was conducted at 13 university hospitals (8 tertiary referral hospitals and 5 secondary referral hospitals) and 2 secondary referral general hospitals throughout Korea in accordance with the Declaration of Helsinki and good clinical practice. Board-certified neurologists with a special interest in headache conducted the study, and all investigators were Directors on the Korean Headache Society Board.
All participants were examined by each investigator to confirm that the diagnosis fulfilled the criteria set forth in the International Classification of Headache Disorders, 3rd Edition, beta version (ICHD-3β) (
Investigators assessed the demographic features of and recorded the clinical information about each patient's current and previous bouts of CH. Clinical information regarding the current headache episode included location, severity, duration, and frequency of pain, associated symptoms, and duration of bout period. Previous history of CH included the time since the first bout of CH, the total frequency of the cluster period, and the pattern of recurrence.
Each patient completed a self-administered Headache Impact Test-6 (HIT-6) questionnaire to measure headache-related impact, the Patient Health Questionnaire-9 (PHQ-9) to assess depression, the Generalized Anxiety Dirorder-7 (GAD-7) to assess anxiety, the EQ-5D to measure of health-related quality of life, and the Short Form Perceived Stress Scale-4 (PSS-4) to assess psychological stress. The impact of headaches on an individual's quality of life, as determined based on HIT-6 scores, was defined as mild (≤49), some (50–55), substantial (56–59), and severe (≥60) impact. Cut-off points for depression and anxiety were defined as PHQ-9 scores ≥8 and GAD-7 scores ≥6, respectively.
For continuous variables, the Kolmogorov–Smirnov test was used to assess the normality of the distribution. After normality was confirmed, chi-square and student's
In total, 159 patients, 20 (12.6%) of whom were diagnosed with probable CH, 114 (71.7%) with episodic CH, 5 (3.1%) with chronic CH, and 20 (12.6%) with unclassified CH, were enrolled in this study. The most commonly unfulfilled criterion in patients with probable CH was the duration of attack, which was found in eight (40%) patients with probable CH. The duration of the attack of probable CH (163.0 ± 164 min) tended to be longer than that of definite CH (94.3 ± 52.9 min), but the difference was not significant (
The reason for failure of definite cluster headache diagnosis.
No significant differences in the clinical characteristics of patients with definite and probable CH were observed, including with regard to mean age, male to female ratio, body mass index (BMI), alcohol use, and smoking status. Among the headache characteristics, patients with probable CH showed a tendency toward fewer CAS compared to those with definite CH (1.7 ± 1.2 vs. 2.4 ± 1.5,
Comparison of demographics and clinical features between definite and probable cluster headache.
Age (years) | 39.1 ± 10.7(19–76) | 42.5 ± 12.7(22–80) | 0.197 |
Male sex (%) | 117 (84.2%) | 17 (85.0%) | 1.000 |
BMI (kg/m2) | 24.0 ± 3.4(14–35) | 24.7 ± 3.4(20–34) | 0.343 |
Current smoker (%) | 65 (44.8%) | 7 (35.0%) | 0.455 |
Alcohol drinking (%) | 71 (51.1%) | 8 (40.0%) | 0.492 |
Age of onset (years) | 29.1 ± 13.2(9–78) | 30.9 ± 11.7(16–59) | 0.549 |
Total period of cluster headache (years) | 8.7 ± 8.4(0–48) | 8.2 ± 7.9(0–24) | 0.815 |
Duration of bout (weeks) | 7.5 ± 10.3(1–57) | 5.9 ± 4.7(1–22) | 0.329 |
Total bout number | 8.2 ± 12.2(1–100) | 9.0 ± 11.5(1–50) | 0.778 |
Presence of seasonal variation | 62 (48.1%) | 5 (26.3%) | 0.126 |
Presence of diurnal variation | 71 (52.2%) | 8 (40.0%) | 0.435 |
Number of autonomic symptom | 2.4 ± 1.5(0–7) | 1.7 ± 1.2(0–4) | 0.051 |
Frequency of headache (day) | 2.2 ± 1.9(0.1–10) | 1.8 ± 1.3(0.3–5) | 0.336 |
Duration of headache (min) | 94.3 ± 52.9(12–270) | 163.0 ± 164.0(10–600) | 0.078 |
Intensity of headache (NRS) | 9.1 ± 1.1(5–10) | 8.6 ± 1.8(4–10) | 0.223 |
Univariable odds ratios for definite and probable cluster headache as function of clinical characteristics.
Headache location | Orbital, supraorbital, temporal | 107 (85.0%) | 17 (85.0%) | 0.423 | 1.69 | 0.53–7.58 |
Unilaterality | 136 (97.8%) | 19 (95.0%) | 0.461 | 2.39 | 0.11–19.14 | |
Headache intensity | Severe intensity | 128 (92.1%) | 17 (85.0%) | 0.304 | 2.05 | 0.43–7.40 |
Associated symptoms | Conjunctival injection/lacrimation | 118 (84.9%) | 13 (65.0%) | 0.035 | 3.03 | 1.03–8.33 |
Nasal congestion/rhinorrhea | 79 (55.8%) | 11 (55.0%) | 0.877 | 1.08 | 0.41–2.77 | |
Eyelid edema | 32 (23.0%) | 4 (20.0%) | 0.763 | 1.20 | 0.40–4.40 | |
Forehead and facial sweating | 39 (28.1%) | 1 (5.0%) | 0.055 | 7.41 | 1.46–135.38 | |
Forehead and facial flushing | 22 (15.8%) | 2 (10.0%) | 0.500 | 1.69 | 0.44–11.12 | |
Ear fullness | 13 (9.4%) | 1 (5.0%) | 0.528 | 1.96 | 0.36–36.61 | |
Miosis/ptosis | 29 (20.9%) | 2 (10.0%) | 0.264 | 2.37 | 0.63–15.46 | |
Restlessness/agitation | 63 (45.3%) | 7 (35.0%) | 0.387 | 1.54 | 0.43–7.40 |
Next, we assessed psychosomatic comorbidities, including anxiety, depression, and stress using GAD-7, PHQ-9, and PSS-4 scores, respectively. No significant differences were evident between patients with definite and probable CH. Similarly, the headache-related disabilities, as determined based on HIT-6 and EQ-5D scores, of patients with probable and definite CH (Table
Psychiatric comorbidity and headache-related disability of individuals with definite and probable cluster headache.
GAD-7 scores | 7.6 ± 5.5(0–21) | 6.1 ± 5.6(0–21) | 0.297 |
Presence of anxiety (%) | 82 (61.2%) | 7 (38.9%) | 0.121 |
PHQ-9 scores | 7.2 ± 6.0(0–27) | 7.9 ± 7.9(0–25) | 0.605 |
Presence of depression (%) | 56 (41.8%) | 7 (36.8%) | 0.872 |
PSS-4 scores | 6.6 ± 2.8(0–16) | 6.0 ± 3.2(0–11) | 0.385 |
EQ-5D scores | 0.85 ± 0.14(0.54–0.95) | 0.84 ± 0.14(0.55–0.95) | 0.640 |
HIT-6 scores | 68.1 ± 7.7(42–78) | 63.9 ± 11.2(42–78) | 0.117 |
Presence of severe impact | 112 (83.6%) | 13 (65.0%) | 0.094 |
ASC-12 scores | 2.5 ± 3.9(0–20) | 2.9 ± 4.1(0–16) | 0.670 |
Presence of cutaneous allodynia | 40 (33.6%) | 8 (42.1%) | 0.644 |
Comparison of treatment response between definite and probable cluster headache.
Oxygen | 12/14 (85.7%) | 1/1 (100.0%) | 1.000 |
NSAIDs | 13/55 (23.6%) | 5/11 (45.5%) | 0.301 |
Combination analgesics | 3/9 (33.3%) | 2/4 (50.0%) | 1.000 |
Triptans | 83/95 (87.4%) | 9/10 (90.0%) | 0.476 |
Steroid | 55/62 (88.7%) | 8/9 (88.9%) | 0.184 |
Occipital nerve block | 13/18 (68.4%) | 0/0 | |
Verapamil | 69/86 (74.2%) | 5/7 (71.4%) | 0.743 |
Lithium | 20/30 (66.7%) | 2/4(50.0%) | 0.471 |
Three major outcomes were observed in this study. First, the prevalence of probable CH within our patient cohort was 12.6%, and duration of attack was the most common unfulfilled criterion differentiating probable and definite CH. Second, no differences in demographics characteristics, disability, or treatment response were observed between patients with probable and definite CH. Finally, we observed a tendency toward fewer CAS in patients with probable CH, whereas the presence of conjunctival injection and lacrimation was identified as a positive predictor of definite CH.
A previous multicenter, cross-sectional registry study found that a diagnosis of probable primary headache disorder, based on ICHD-3β, was given to 21.3% of first-visit patients due to incomplete or atypical presentations of the headaches. The proportions of probable primary headache disorders differed among the subtypes as follows: migraines (16.1%), tension-type headaches (33%), TACs (40.9%), and other primary headache disorders (14%) (
According to two population-based surveys, the most common unmet criterion preventing a definitive migraine diagnosis was headache duration (61.1 and 82.0%, respectively); a separate multicenter study identified the number of attacks (41.9%) and associated symptoms (33%) as the most common unmet symptoms (
Some of the characteristics of patients with probable CH differed from those with definite CH. Definite CH was characterized by more CAS compared to probable CH. According to the univariate regression analyses, patients with definite CH showed an increased OR for CAS accompanied by conjunctival injection and lacrimation. Of the CAS, lacrimation and conjunctival injection were the most frequent and consistently reported autonomic features in CH (
CH is frequently associated with psychiatric comorbidities. Depression, anxiety, and aggressive behavior are among the most commonly observed psychiatric comorbidities in CH patients (
We also assessed headache-related disability and impact on quality of life among patients with probable and definite CH. Previous studies reported disability and reduced quality of life in probable migraine patients relative to controls, and these rates were similar to those of migraine sufferers (
Like migraine headaches, probable migraines are often sub-optimally treated, even in those with access to medical care and prescription drugs (
Recently, the new ICHD-3 criteria were published (
In conclusion, probable CH is a prevalent condition among CH disorders, with a similar disability and impact on quality of life as definite CH. Therefore, both probable and definite CH, which have similar clinical characteristics and impact, deserve similar medical, and therapeutic management.
JW-P and J-HS conceived the idea for this article. Y-JC, B-KK, P-WC, ML, J-WP, MC, J-YA, B-SK, T-JS, J-HS, KO, K-SL, S-KK, JC, and H-SM contributed the acquisition of the data. K-YP and J-WP performed the data analyses and data interpretations. P-WC, J-WP, MC, J-YA, B-SK, T-JS, J-HS, KO, K-SL, S-KK, JC, H-SM, and C-SC contributed with inputs to this article. J-HS and J-WP drafted the work and paper. B-KK, P-WC, ML, J-WP, MC, J-YA, B-SK, T-JS, J-HS, KO, K-SL, S-KK, K-YP, JC, H-SM, and C-SC revised the paper for important intellectual content. All authors reviewed and approved the final manuscript. All authors agreed to be accountable aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
MC was involved as a site investigator for a multicenter trial sponsored by Eli Lilly, worked an advisory member for Teva, and received lecture honoraria from Allergan Korea and Yuyu Pharmaceutical Company. S-JC was involved as a site investigator of multicenter trial sponsored by Otsuka Korea, Eli Lilly and Company, Korea BMS, and Parexel Korea Co., Ltd., and received research support from Hallym University Research Fund 2016 and Myungin Research Fund 2016. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Cluster headache
Cranial Autonomic Symptom
International Classification of Headache Disorder
Trigeminal Autonomic Cephalalgia
International Classification of Headache Disorder, 3rd Edition, beta version
Headache Impact Test-6
Patient Health Questionnare-9
Generalized Anxiety Dirorder-7
Perceived Stress Scale-4.