A large group of patients diagnosed with CH were systematically evaluated in terms of demographics, diagnosis patterns, clinical characteristics, triggers, gender issues, treatment experiences and personal burden by headache experts. There is still a remarkable diagnostic delay of 4.9 years for these patients experiencing severe and disabling headaches in Turkey. Our male CH patients showed higher rates of smoking, and family history of heart disease, whereas female CH patients had more commonly a previous diagnosis with migraine and past preventive treatment experiences of CH (Fig. 1). In addition to that, females reported more migrainous associated features, nausea/vomiting and triptan usage during their longer CH attacks. Moreover, CCH patients reported more frequent oxygen usage, past preventive treatment experiences, higher usage of verapamil and corticosteroid in-bout, and medication overuse headache compared to ECH patients, as expected. Furthermore, a higher percentage of CCH patients reported that their illness was negatively affected their education, probably reducing career opportunities later.
Demographics
In our hospital based cohort, the mean age at onset was 28.6 years, similar to the previous studies and male-to-female ratio was 5.3:1. The gender ratio was more compatible with Asian studies (5.1:1) compared to recent European/North American studies (2-3.1:1) [10, 18, 19, 21–23, 25–27]. Research about the mean time from CH onset to correct diagnosis reported various times in different countries (in the UK: 2.6 years, in Flanders: 3.6 years, in Spain: 4.9 years, in Italy and East European countries: 5.3\(\pm\)6.4 years, in Denmark: 6.2-9 years, in the USA: 6.6–8.5 years, in Japan: 7.3\(\pm\)6.9 years) [20, 28–35]. In our study, diagnostic delay was 4.9 years. In Greece and Flanders, neurologists missed the diagnosis in 40% and 80% of the patients [34, 36]. Even though a majority of our patients were diagnosed by a neurologist in Turkey, a correct initial diagnosis of CH occurred in 42.1% of them. Indeed, this rate was still higher than a previous large internet American survey (21%) [24]. Our finding was probably related to the fact that neurology was the mostly consulted specialty for headache disorders in Turkey because of the health care organization [37]. Our rate of family history for CH (9.1%) was higher than Eastern countries (0-6.7%) and more similar to Western countries (5–17%) [10, 18, 21, 24, 38–40].
It is well-known that the rates of being a previous or current smoker were high in patients with CH, as 73–81% [14, 26, 41]. Our male CH patients had statistically higher rates of past and current smoking compared to females in line with the USA study [24]. The percentage of active smokers in the male CH patients was higher than the average rate of overall active smokers (29.3 %) in Turkey (2018) [42]. Current smokers had higher numbers of attacks with longer bouts than patients with CH who report never having smoked [26, 41]. Although there is no strong evidence between quitting smoking and improvement of CH, smoking may enhance alcohol consumption and alcohol may trigger CH attack [41, 43]. Therefore, it might be wise to advice to quitting smoking for CH patients. But even clinicians gave advice about quitting smoking, our CH patients seemed not to follow it. Thus more strong suggestions might be necessary for those patients.
Gender comparisons
Females with CH had a longer mean duration of untreated attacks than males (112.8 min vs 87.9 min), this finding was compatible with previous studies [44, 45]. Migraine and CH have overlapping features that they share as different primary headache disorders. It was understandable but still interesting to note that females with CH are more frequently misdiagnosed as migraine [31]. Migraine was the leading misdiagnosis regardless of gender differences in Turkey, a pattern similar with the USA findings (32.1% vs. 34%). An important confusing factor in misdiagnosis is the accompanying symptoms during attacks. There is a need for increased awareness, since CH patients can also experience the same accompanying symptoms well-known in migraine, as also seen in Table 2. Migrainous features and nausea/vomiting were frequently reported by females with CH in this study compatible with previous reports [14, 15, 25, 44, 46], explaining the increased misdiagnosis rate in women along with the well-known male dominance of CH.
We observed that female patients were statistically more likely to experience pain in the temple and in the ear compared to men, for unclarified reasons.
Menstruation was cited as a trigger for CH attack in females similar to migraine, but with a low rate of 3.3% of females, in this study. Moreover, autonomic features can also occur in migraine, but usually bilaterally. Hence the occurrence of either ipsilateral or bilateral autonomic features needs to be carefully questioned in headache patients.
Clinical features
In our study, the most common cranial autonomic symptoms were lacrimation (79.9 %), followed by nasal congestion (55%), and agitation (55 %). In the USA study, lacrimation (91%) and nasal congestion (84%) were also the leading two autonomic symptoms reported in more frequent rates [24]. On the other hand, in Asian studies, lacrimation, conjunctival injection and rhinorrhea were the most common cranial autonomic symptoms [10, 18, 21, 22]. In the USA study, men experienced more frequently lacrimation (92% vs. 88%, p = 0.03), while woman were more likely to experience nausea (41% vs. 34%, p = 0.03). In the Italian study, ptosis and nasal congestion were more prevalent in females [46]. In contrast to aforementioned studies, we did not see any statistical difference between two genders in regard to occurrence of autonomic symptoms. Moreover, we did not see any difference of these symptoms between episodic and chronic CH patients in contrast to previous studies [38, 47].
It is worth to emphasize that the presence of aura is not particularly helpful in the differentiation between migraine and CH. Intriguingly, aura occurs in 14–23% of Western CH patients, but only <%1 of Asian patients [10, 14, 18, 21, 22, 25, 38, 39, 48]. Our finding of 26.8% with aura was pretty similar with the Western cohort studies. Agitation is also the most striking difference between migraine and CH, it was reported up to 93% of patients in the USA population. More than half of our participants (55%) reported a sense of restlessness or agitation during their attacks, remarkably.
January and February were the most frequently reported months of the year that cluster bouts would start in Turkey. Seasonal propensity has been reported partly discordant in studies, this might be related to geographical location of countries [10, 22, 24]. Seasonal changing, stress and alcohol were the most common triggers for attacks in our study. Sleep deprivation was more likely to be reported by chronic CH patients. The chronobiological features of CH have been extensively studied [13, 49]. Higher risk was reported at 21.41, 02.02 and 06.23 [49]. However, the highest peak was during the afternoon in an Italian population [13]. In our cohort, 82.3% of the participants reported that they had the exact same time of the day for CH attacks and an increased risk peak was found at the night (57.7%). Many factors might be related to this timing like light exposition in different altitudes and different sociocultural habits [13]. In Western, Japan and Korean studies, nocturnal CH attacks were frequent (58–73%), whereas CH patients (65%) had both diurnal and nocturnal attacks in some Asian studies [10, 20, 22, 24, 38, 40, 47].
Treatment experiences
We noted that triptans were more widely preferred by our female patients with CH, partly explained by longer attack durations. In regard to the effectiveness of abortive treatment, only 42.1% of all participants reported satisfying treatment experience. CCH patients (33.3%) gave lower scores about effectiveness of acute therapies, as expected. But still the rates of oxygen use for attacks were statistically higher in CCH patients compared to episodic ones. Oxygen has been well-known as an acute treatment of CH since 1985 [50]. Studies have shown that oxygen therapy frequently was found to be effective by more than 75% of patients in both Western and Asian countries [19, 21, 51–54]. In the current study, 85.9 % of all participants reported that oxygen was efficient for an abortive treatment of CH; however only 22 % of them had oxygen tube in their home. In our hospital-based population, only 57.2% of all participants remembered that they had a previous advice for having an oxygen tube at home. Moreover 11% of all participants had been using a nasal cannula instead of a non-breather mask during oxygen treatment and 33.1% of our cohort did not know about an exact oxygen treatment protocol for CH attacks [55]. These findings may be related to insufficient patient education, difficulty to obtain durable medical equipment of home oxygen because of insurers and unreluctance of patients to have this equipment in spite of enough suggestion and encouragement from clinicians. Subcutaneous sumatriptan 6 mg has been shown to be effective as an abortive treatment of CH [55]. Zolmitriptan and sumatriptan spray can both be used as an alternative treatment of CH attacks, but they are not available in Turkey [55]. In the current study, efficacy of triptan treatment was reported by 39.2% of the participants. Indeed, females had statistically more frequently used triptans in their attacks and also reported to effectiveness of triptans more superior compared to males (54.4% vs. 36.4%; NS). In the USA study, females were significantly more likely to respond to sumatriptan than males (injectable sumatriptan 72% vs. 86%, p = 0.003; nasal spray 35% vs. 47%, p = 0.02). The response rates to triptan in Asian studies have been reported as 80-97.3% of the CH patients [19, 21, 52, 54]. Our response rates to triptan treatment seems to be lower than other studies. This finding might be related to genetic differences, wrong timing of usage or unavailability of some active drugs in Turkey.
Corticosteroids are commonly used as bridging therapy of CH [56, 57]. In our cohort, 36.4% of the participants had past experiences with steroid therapy. Another bridging therapy is suboccipitical nerve block injections with steroids [55]. In our study, only 10% of the participants were treated with nerve block injections.
In this study, 69.2% of the participants had been treated with preventive medicines. As expected, female participants as well as CCH patients reported higher likelihood of preventive treatment experiences. The average duration of bout treatment was 4.5 weeks in this study. Past experiences with other preventive treatment agents were lower (around 10% for lithium, melatonin, topiramate) in Turkey and verapamil (72.7%) was obviously many clinicians’ first choice in our country.
During the study enrollment, 24% of all participants were under treatment for CH, and female gender showed statistical significance compared to males (42.4% vs. 20.6%; p = 0.013). Medication overuse headache is another important, yet controversial topic in CH [58–60]. Ten percent of the participants and 25% of CCH patients reported usage of triptan or NSAI drugs every day. Despite the treatment efforts in the headache centers, in our study, at least 50% of the participants reported ER admission in the previous year, a finding indicating the need for more efforts in acute treatment of CH.
The disease burden of cluster headache
The burden of a disease has many dimensions such as symptom burden, disability burden, lost-productivity burden, interictal burden, cumulative burden and financial burden. Personal burden related to CH was reported by 49.3% of the patients in our study. CCH patients appeared to be more disabled by their headaches in terms of loss in their education (25% vs. 9.2%). Over one-quarter percent of our cohort reported job related burden. As expected, it was higher in CCH patients (45.8 vs. 33%). A consequence of lost school-time and/or recurring inability to work may reduce the probability of promotion and decreased career opportunities for those patients. Furthermore, these cumulative effects might be resulted in difficulties on relationships, love life and family dynamics.
Limitations and strengths
Several limitations were present in this study. Firstly, our cohort was hospital-based. For that reason, our findings and conclusions may not generalize to community-based patients. Secondly, we collected data retrospectively from patients’ files and from interviews. Hence, recall bias may obscure our results [61, 62]. Thirdly, it is possible that coexisting migraine diagnosis in our cohort may create problems. This comorbid condition might blur some our results such as the presence of aura, associated symptoms, and triggers. But investigation of the files and the interviews were realized by headache experts and we tried to isolate CH findings from migraine as far as we can. Fourth, it might be hard to precise conclusions regarding treatment experiences retrospectively without any established guide or previous consensus among the centers. Nevertheless, the study has some obvious strengths. This is the first large-sized multicenter study about CH from Turkey and our findings were gathered on face-to-face or detailed phone interviews due to pandemic by experienced headache specialists. Moreover, we compared results of two genders and two forms of CH to get more detailed picture of this ominous disease.
In conclusion, remarkable diagnostic delay is an ongoing problem for CH and migraine was the most common misdiagnosis, especially for females with CH due to longer attacks and higher rates of associated symptoms. Therefore females who have confounding features about a diagnosis of CH need to be examined in detail. In the treatment part, even though higher oxygen efficacy for attack treatment, only 22% of patients had oxygen tube in their homes. We think that the availability of oxygen tube may reduce ER utilization of the patients for abortive treatment. Finally, nearly half of the patients suffered from a personal burden of CH and at least one-third of them had job related burden in our country. Past treatment experiences of the patients underscore insufficient efficacy of available choices and need for more specific abortive and preventive treatment options.