Cluster headache in Greece: an observational clinical and demographic study of 302 patients
© The Author(s). 2016
Received: 13 August 2016
Accepted: 22 September 2016
Published: 26 September 2016
Cluster headache (CH) is considered the most excruciating primary headache syndrome; although much less prevalent than migraine, it is not rare as it affects more than 1/1000 people. While its clinical presentation is considered stereotypic, atypical features are often encountered. Internationally, cluster headache is often misdiagnosed, undertreated and mistreated.
We prospectively studied 302 CH patients, all examined by the same headache specialist. The aim of our study was to describe the demographic and clinical characteristics of CH patients in Greece and draw attention to under-management, under-treatment and mis-treatment often encountered in clinical practice; our purpose is to improve recognition and successful treatment of cluster patients by Greek neurologists and other physicians.
In the present cohort, clinical characteristics of CH are similar to those described in other populations. Beyond the standard clinical characteristics, features like side shifts (12.6 %), location of maximal pain intensity outside the first trigeminal branch division (10.2 %), lack of autonomic features (7 %), presence of associated features of migraine and aggravation by physical activity (10 %) were encountered. Four out of five patients had consulted a physician prior to diagnosis. The median number of physicians seen prior to diagnosis was 3 and the median time to diagnosis was 5 years, though it improved for patients with recent onset. Chronic cluster headache, side shifts, pain location in the face or the back of the head and aggravation by physical activity were found, among others, to be statistically significantly related to delayed diagnosis or more physicians seen prior to diagnosis. Even properly diagnosed patients were often undertreated or mistreated.
Cluster headache, in a large cohort of Greek patients, has the same phenotypic characteristics as described internationally. Uncommon clinical features do exist and physicians should be aware of those, since they may eventuate in diagnostic problems. Most CH patients in Greece remain misdiagnosed or undiagnosed for rather lengthy periods of time, but time to diagnosis has improved recently. Even after diagnosis, treatment received was suboptimal.
KeywordsCluster headache Episodic cluster headache Chronic cluster headache Cluster headache phenotype Cluster headache demographics Error Delay Misdiagnosis Mismanagement Mistreatment
Cluster headache (CH), the most common trigeminal autonomic cephalalgia, is considered to be the most excruciating form of primary headache, causing profound ictal disability to sufferers [1, 2]. Although cluster headache was described long ago by a variety of names, systematic study of its clinical characteristics and significant advances in understanding its pathophysiology, began taking place only in the last 40–50 years, pioneered by the work of Dr. Lee Kudrow [3, 4]. He studied oxygen inhalation therapy as a way to abort attacks; the importance of light and flying through time zones as triggers; and predicted that the hypothalamus was a critically important area of the brain involved in its pathophysiology [3, 4]. From a clinical, pathogenic and therapeutic point of view, CH is distinct from other primary head syndromes such as migraine [1–6]. Cluster headache attacks are stereotypical and the usual clinical characteristics include side-locked pain episodes that are accompanied by ipsilateral cranial autonomic symptoms, most often lacrimation, conjunctival injection and rhinorrhea. The attacks are relatively short-lasting, usually 45–90 min and may differ in duration, frequency, intensity of pain and presence of autonomic symptoms [1–7]. Cluster headache is well described and characterized within the International Classification of Headache Disorders and may be diagnosed as episodic or chronic, the latter one characterized by CH attacks for more than a year with no remission or with remission for less than a month . The disorder is more prevalent in men, although the male to female varies across studies .
Although often described by the word “rare” , CH is not actually rare, as its prevalence in population-based samples is estimated to be about 1/1000 , which is comparable to that of multiple sclerosis . Still, worldwide, CH is considered to be largely underdiagnosed and undertreated, as a significant percentage of CH patients are not treated according to existing guidelines or evidence-based treatment recommendations [12, 13].
Characteristics of CH patients in various countries [7, 14–17] and diagnostic and therapeutic trends and issues [7, 18–21] have been described in a number of publications, but so far no epidemiologic data have been published from Greece. We prospectively studied a large number of CH patients visiting two specialized headache clinics, located in Glyfada, Greece, and examined by the same headache specialist. The aim of our study was to describe the demographic and clinical characteristics of CH patients in Greece; in so doing, we hoped to draw attention to under-management and under-treatment often encountered in clinical practice, with the purpose of improving recognition and successful treatment by Greek neurologists and other physicians.
This study was a prospective clinical study, conducted in accordance with the principles of the Helsinki Declaration. Written informed consent was obtained from every patient. The study was approved by the first author’s Institutional Review Board (Mediterraneo Hospital, protocol no. 1640). Data on consecutive CH patients (n = 302) were prospectively recorded in Glyfada Headache Clinic and in Mediterraneo Hospital Headache Clinic from February 2007 until June 2015. Patients came from all geographical regions of Greece, mainly through self-referral (84.7 %), although we did get referrals from other physicians, including neurologists. All patients were examined by the same headache specialist (MV). A detailed history was obtained through a semi-structured questionnaire, a complete neurological examination was performed, further examinations assessed or requested when needed and patients were finally assigned a diagnosis according to the International Headache Society (IHS) diagnostic criteria. After the publication of the last version of the International Classification of Headache Disorders (ICHD-III beta) , all previous cases were revisited and the IHS-III beta criteria were used for reconfirming diagnosis. All data were inserted in a database, double-checking for typing errors. Only data from patients diagnosed with cluster headache according to the IHS-III beta criteria (digit codes 3.1.1 and 3.1.2) were entered into the database and further analyzed. X2 test of independence or Fisher’s exact test was used to evaluate the association between two qualitative variables. Kruskal-Wallis or Mann-Whitney test was used to evaluate the association between groups and the continuous characteristics of the sample (eg. age, etc.). Nominal variables are presented in absolute and relative (%) frequencies, while continuous variables are presented by median and range or mean and standard deviation. The 5 % significance level (alpha = 0.05) was considered as statistically significant. All statistical analyses were performed with version 20 of the SPSS package (SPSS Inc, Chicago, Il, USA).
Demographics and CH types
Male to female ratio by decade of onset
Decade of onset
Males (N = 237)
Females (N = 65)
Male to female ratio
CH family history and social habits
A positive family history of CH was reported by 17.5 % of patients (16.7 % in ECH and 20.6 % in CCH) and in most cases involved a parent with similar symptoms (usually undiagnosed, but with typical witnessed clinical description). Smoking was quite common, with the majority of our patients reporting being current (61.3 %) or past smokers (12.9 %). Current alcohol consumption was reported by 58.3 % of the patients, while 16.9 % of them were former alcohol users. Alcohol was reported as a trigger for CH attacks by 84,8 % of males and 45,3 % of females (p = 0.001). Use of recreational illegal substances was reported by 14.9 % as current and by 15.6 % as prior. Most of CH patients in our series worked on a regular basis (or were full-time students) (63 %), but 21 % were unemployed and 16 % worked occasionally.
CH onset and course
The median age at onset of CH in our series was 29 years of age (mean: 32 years), with the youngest patient reporting disease onset at the age of 8 and the oldest at the age of 67 (both were ECH patients). In the ECH group, median age of onset was 29 years (mean 31.5 years), while in the CCH group, the median age of onset was 30 years (mean 33.2 years). The youngest and oldest age at onset was 8 and 68 years for men and 12 and 67 years for women, respectively. In CCH the youngest reported age of onset was 13 years and the oldest was 66 years of age. In ECH, the vast majority started as episodic, but 8 patients out of 234 (3.3 %) evolved from an initially chronic form. In CCH, 50 out of 68 patients (73.5 %) patients experienced CCH since onset, while in 18 of them (26.5 %) CH evolved from an initially episodic form.
Site of pain (%, N = 302, unless otherwise indicated)
Upper teeth (%)
Lower teeth (%)
Nose (%) (N = 299)
Ear (%) (N = 301)
Shoulder (%) (N = 300)
Vertex (%) (N = 293)
Side of pain, laterality, side shifts
Side of pain, laterality, side shifts (%, N = 302, unless otherwise indicated)
Strictly unilateral (%)
Strictly left (%)
Strictly right (%)
Side shift between bouts (%) (N = 299)
Side shift within bouts (%) (N = 301)
Side shift within attacks (%)
Autonomic and associated features, character of pain
Autonomic features (%, N = 302, unless otherwise indicated)
Conjunctival injection (%)
Nasal congestion and/or rhinorrhea (%)
Eyelid oedema (%)
Forehead and facial sweating (%)
Miosis and/or ptosis (%)
None of the above (%)
Forehead and facial flushing (%) (N = 133)
Sensation of fullness in the ear (%) (N = 128)
Associated features and character of pain (%, N = 302, unless otherwise indicated)
Vomiting (%) (N = 301)
Belching (%) (N = 300)
Sense of restlessness or agitation (%) (N = 301)
Pain aggravation by physical activity (N = 301)
Stabbing/lancinating pain (%)
Throbbing pain (%)
Pressing pain (%)
Other type of pain (%)
Attacks triggered by alcohol (n = 301)
Attack duration and frequency, bout duration, periodicity
Attack duration and frequency
Usual attack duration (min)
Usual minimum attack duration (min)
Usual maximum attack duration (min)
Usual attack frequency/24 h
Usual maximum attack frequency/24 h
Usual bout duration (weeks)
Usual minimum bout duration (weeks)
Usual maximum bout duration (weeks)
Diagnostic and therapeutic issues
Years from disease onset to diagnosis, correlated to decade of onset
Tota Median (range)
ECH Median (range)
CCH Median (range)
Men Median (range)
Women Median (range)
Decade of onset of CH
Diagnoses made and physicians seen prior to CH diagnosis
A. Diagnoses made prior to CH diagnosis (%)
B. Physicians seen prior CH to diagnosis (%)
Primary care physician
Dental or jaw disease
Cervical spine disease
Factors correlated with more years to diagnosis
Years to diagnosis
Decade of onset
Side shift between bouts
Jaw location of pain
Cheek location of pain
Lower teeth location of pain
Ear location of pain
Aggravation by physical activity
Forehead and facial sweating
Absence of autonomic features
Factors correlated with seeing increased number of physicians prior to diagnosis
Number of physicians
Decade of onset
Upper teeth location of pain
Jaw location of pain
Cheek location of pain
Lower teeth location of pain
Neck location of pain
Nose location of pain
Ear location of pain
Shoulder location of pain
Vertex location of pain
Aggravation by physical activity
Miosis and/or ptosis
Usual maximum duration of bout
Usual duration of bout
Usual attack frequency
Usual maximum attack frequency
Treatments offered to previously diagnosed patients, (%)
Overall % (N = 127)
Previously diagnosed by a neurologist % (N = 89)
Although less common than other primary headaches, cluster headache is not rare per se [9, 12, 13]. Still, worldwide it is reported to remain largely under-recognized and sub-optimally or poorly treated both in primary care and by specialists, despite the fact that its severity would warrant prompt diagnosis and treatment [7, 12, 18–21, 30]. Therefore, it is critical that all physicians be familiar with diagnosing and managing cluster headache. In order to improve recognition and successful treatment of CH by Greek neurologists and general physicians, we undertook the task of describing the demographic, clinical characteristics, diagnostic and treatment paths of a large cohort of CH patients, seen over a lengthy period of time by the same headache specialist.
Overall, our data are in line with previously published data from different countries [5, 7, 14–17, 31]. As expected, the typical presentation of cluster headache in Greece is indisputably stereotyped and distinct from other primary headache syndromes. Still, our data show that CH is not a male disorder, as the female to male ratio for patients with disease onset during this decade has fallen to 2.3:1 from 6:1 twenty years ago, a finding that has been noticed long ago . Clinical presentation of the disease was largely similar in both genders.
Features often considered uncommon or atypical were encountered in a significant percentage of patients in our cohort. Those included side shifts, maximal pain intensity outside the first division of the trigeminal nerve, lack of all autonomic features or lack of a sense of restlessness or agitation, as other studies have also shown [5, 7, 16, 33]. Some of the atypical features, including side shifts, pain located in jaw, cheek, teeth, shoulder, vertex or neck area, were found in our study to be coexistent with, and maybe the cause of, delayed diagnosis and/or a larger number of physicians being consulted prior to diagnosis. In addition, migraine associated symptoms and autonomic features were often encountered, with photophobia being the most common, but not the only one reported in our series. This is in line with previously published data [7, 34, 35]. In our cohort, among migraine associated symptoms, aggravation by physical activity, reported by 10 % of our patients, was related both to delayed diagnosis and a greater number of physicians being consulted prior to diagnosis. It is worth mentioning that even though the autonomic features added in criterion C of the revised criteria of the International Headache Society (ICHD-III beta) for CH, (−namely ipsilateral sensation of fullness in the ear and ipsilateral forehead/facial flushing) were rather commonly reported in our group, there was not a single case of a patient without the presence of any of the autonomic features included in ICHD-II (conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid oedema, forehead and facial sweating) in whom forehead and facial flushing or sensation of fullness in the ear was reported. This supports the opinion that adding forehead and facial flushing and sensation of fullness in the ear in ICHD-III beta provides no added diagnostic value .
Concerning diagnostic delays, our data are in line with other published studies, which have already shown that CH patients are often misdiagnosed and mistreated [7, 19, 20, 30, 37]. In our cohort, eight out of ten CH patients have consulted at least one physician without been diagnosed and more than 40 % have consulted a neurologist. Furthermore, even in diagnosed patients, and despite the existence of evidence-based treatment options [10, 13, 22–26, 37, 38], use of guidelines or recommended treatments is quite low. These facts clearly point out the need for Continuous Medical Education in the field of cluster headache. Still, our study demonstrates that time to diagnosis is improving in Greece, something that might have to do with increasing access to specialized neurologic care and headache specialists. The role of medical information found mainly on the internet is increasingly important, as a significant percentage of patients in our group, despite having seen physicians, were actually self-diagnosed and self-referred to our center. In addition, despite these improvements, the typical sufferer still waits five years for a correct diagnosis and sees three physicians prior to it, having received one or more incorrect diagnoses, inappropriate treatments or having undergone unnecessary invasive procedures, as has also been described in other series [19–21].
This study does not come without limitations. The main one is the design of the study and the setting. It could be argued that a population-based study, resulting in a random sample of CH patients would be more appropriate and that CH patients who reach a specialist may represent an enriched population who would have atypical features or be more difficult to treat correctly. We believe our data do not point towards a highly enriched population. Patients visited us from all geographical regions of Greece, most patients came through self-referral (84.7 %), something quite common in Greece. Additionally, the majority of our cohort (57.9 %) were undiagnosed prior to visiting our clinic. Furthermore, extrapolating from the international CH prevalence data  to the Greek population (10.816.286 according to the last census) , an estimation of around 13.400 CH patients are expected to live in Greece. In this case, our sample would represent a little more that 2 % of the total CH patients in Greece.
Cluster headache, studied in a large cohort of Greek patients, has the well-documented general characteristics described in all Western populations. Despite the concept of a stereotyped clinical picture, atypical features are quite often present and physicians should be aware of those, as they usually may result in diagnostic problems. Most patients remain undiagnosed for a lengthy period of time; even when diagnosed, the treatment they receive remains far from optimal. On the other hand, our data show that time to diagnosis is improving, reaching a median period of one year for patients with recent onset. Educational activities for neurologists and other medical specialties that treat headache patients are critically important and should result in better recognition and treatment of cluster headache patients.
Chronic cluster headache
Episodic cluster headache
The authors would like to thank Ms Evie Delicha for performing the statistical analysis and Dr. Georgios S. Vlachos for kindly reviewing the manuscript and providing fruitful comments.
No funding source had a role in the preparation and conduction of this study or in the preparation of the manuscript and the decision to submit it for publication.
MV designed the protocol, conducted the study and drafted the manuscript. Alan M. Rapoport critically reviewed the manuscript. Both authors approved the final manuscript.
MV has received honoraria and travel grants from Allergan, Greece, Brain Therapeutics, Greece and is an investigator in an Amgen-sponsored clinical trial on migraine prophylaxis. AMR has received honoraria for Ad Boards and consulting from several companies, but nothing related to this study.
Neither the authors or any immediate family member has financial relationships with commercial organizations that might appear to present a potential conflict of interest with the material presented.
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