The burden of headache following aneurysmal subarachnoid hemorrhage: a prospective single-center cross-sectional analysis

Aneurysmal subarachnoid hemorrhage (SAH) is a frequently devastating condition which constitutes about 5% of all strokes with a variable annual incidence between 0.7 and 23.9 cases per 100,000 inhabitants among different regions of the world with slight decline over the past decades [16, 29, 56, 57]. Despite of its relatively rare occurrence, SAH contributes significantly to stroke-associated reduction of health-related quality of life, morbidity, and mortality mainly due to the severity of the condition and the young average age of the affected patients [4, 9, 43, 66]. A decrease in case fatality rates could be determined over the past decades due to improved therapeutic management, but the long-term health-related quality of life (HR-QOL) of these patients resulting from physical, cognitive, and psychological impairment as well as associated medical conditions like chronic headache has not been sufficiently elucidated so far [2, 31, 37, 41, 56]. This study aims to characterize the long-term burden of headache and its influence on HR-QOL after aneurysmal subarachnoid hemorrhage.

Protocol and patient consent forms of this prospective single-center cross-sectional investigation were approved by the Ethics Committee of the Hamburg Medical Council (reference number PV5584). The study was conducted in accordance with the Declaration of Helsinki adopted by the World Medical Association General Assembly in 1964 and its later amendments. Study conception, data collection, and presentation strictly adhere to the principles of good practice in the conduct and reporting of survey research proposed by Kelley et al. in 2003 [35].

A total of 145 patients treated for newly diagnosed SAH at our tertiary referral center between January 2014 and December 2016 fulfilled the beforehand specified eligibility criteria of an age of 18 years or older and favorable neurological status defined as Glasgow Outcome Scale Score (GOS) ≥ 3 at hospital discharge [33]. All cases were either direct admissions or early transfers from surrounding clinics within the catchment area of our institution. The diagnosis of SAH was based on cranial computed tomography and/or magnetic resonance imaging and/or lumbar puncture. A four-vessel digital subtraction angiography was utilized to determine the location and morphological aspects of the underlying aneurysm in all cases. Patients suffering from hemorrhages due to non-aneurysmal pathologies were excluded. To improve the overall participation rate and reduce the bias effects of non-response, all patients or their legal guardians were contacted by phone in advance and informed briefly about the scope and expected time requirement in case of voluntary study participation. All telephone interviews were performed personally by the principal investigator (TH). After exclusion of 52 cases due to various reasons set out in Flowchart 1, questionnaires including detailed study descriptions and informed consent forms were sent by mail to all 93 patients (31 males, 62 females) willing to take part in the survey in 2018 (mean follow-up after SAH 32.6 months ±9.3 SD).

We used the German version of the 12-Item Short-Form Health Survey (SF-12) as a well-established generic measure of physical and mental health [67]. Multidimensional headache assessment was achieved by the combined implementation of the German pain questionnaire (DSF) of the German Society for the Study of Pain containing among other tools a 10-point numeric pain rating scale (NRS) ranging from 0 (=no pain) to 10 (maximum pain) and the depression, anxiety, and stress scale (DASS) [21, 47, 49], the short-form McGill Pain Questionnaire (SF-MPQ), and the German version of the Henry Ford Hospital Headache Disability Inventory (HDI-G) [6, 32, 44].

All patients were initially asked whether they suffered from continuous or recurrent burdensome headache for 6 months or longer at the time of the interview. This kind of headache differs from the so-called headache attributed to SAH (International Classification of Headache Disorders of the International Headache Society 2nd Edition Code 6.2.2) which develops, by definition, simultaneously with the bleeding and resolves within 1 month thereafter [26]. According to their reply to the previous question, all cases were separated into two groups: SAH with (HA+; n = 38) or without (HA-; n = 55) burdensome headache.

Additionally, clinical and radiographic data concerning the initial inpatient course was obtained from the electronic medical records of our institution. Clinical information comprises the epidemiological data, aneurysm features including size and location (by definition, anterior circulation consists of the following four vessels: internal carotid artery, middle cerebral artery, anterior cerebral, and anterior communicating artery), SAH severity was defined using the World Federation of Neurological Surgeons Grading (WFNS) [50], the latter of whom containing the Glasgow Coma Scale as main component [63], treatment mode (endovascular vs. microsurgical clipping), hospital and intensive care unit (ICU) length of stay as well as functional outcome (GOS). Fisher, Graeb, and Hijdra Scores were utilized to quantify the amount of subarachnoid and intraventricular blood [18, 23, 27].

All clinical and radiographic parameters as well as questionnaire-derived scores were calculated separately for both collectives and group comparisons were performed. Variables are presented utilizing descriptive statistics, inter alia, fractions, central tendency (mean/median), and appropriate dispersion measures (e.g., standard deviation (SD)). Fisher’s exact test was applied with regard to categorical variables, and Mann-Whitney test as well as unpaired t-test was utilized depending on whether non-parametric or parametric data was available for comparison. Multivariate logistic regression was performed to determine the predictive value of epidemiological and clinical variables showing a p value < 1 in the univariate analysis (patient age at bleeding onset, initial WFNS grade, and GOS score at discharge) with regard to headache occurrence at follow-up. Results are displayed in the form of odds ratios (OR) with 95% confidence intervals (CI). All statistical procedures were carried out with GraphPad Prism (version 7.0, GraphPad Software, La Jolla California, USA) and SPSS (version 22.0, International Business Machines Corporation (IBM), Armonk, USA). A p value < 05 was considered to indicate statistical significance. A biostatistician was involved in the planning and realization of all statistical procedures.

Data on the incidence and impact of chronic headache after SAH is sparse. Here, we demonstrate that a significant number of the SAH patients suffer from burdensome headaches with a profound negative impact on the HR-QOL. Our SAH study collective presented with a mean age of 52.5 years and two out of three cases were of female gender. Previous studies on SAH reported on average patient ages between 50 and 57 years with males in general being affected earlier [7, 39, 66, 69]. Throughout the body of literature, females suffer more frequently from SAH than their male counterparts after their late thirties [39, 69]. With respect to the above-mentioned preceding investigations, our patient sample is in line with the main epidemiological SAH characteristics and, therefore, representative. A total of 78.5% of our patients suffered from bleeding as a result of an aneurysm located at the anterior cerebral circulation with a mean aneurysm size of 5.9 ± 3.2 mm, which is in line with other studies [2, 19, 28, 69]. The SAH severity distribution of the study population differed significantly from other surveys which generally give account of lower percentages of patients grouped into neurologically favorable low SAH grades [2, 39]. The higher percentage of lower scores determined in this study may be explained by the predefined inclusion criterion of a GOS ≥ 3 at discharge, because a positive correlation between advantageous neurological condition at hospital admission and good functional outcome has been proven for patients suffering from SAH [15]. In our series a minority of patients (28%) underwent microsurgical clipping. Historically, the major share of SAH cases were allocated to open surgical procedures [39], but over the past decades, the ratio of patients treated with endovascular devices (e.g., coiling embolization) grew continuously forming nowadays the treatment of choice for the majority of cases [37, 59]. Our results suggest that long-term prevalence of headache does not seem to be dependent on the chosen treatment modality with similar coiling-clipping quota in both groups (HA+ and HA-). This conclusion contradicts the findings of a recent study reporting lower pain scores after open surgical intervention at 6 months follow-up [10]. Of note, apart from a divergent follow-up period and a small patient sample, this study refers to pain in general and is therefore not headache-specific. Younger SAH patients were more likely to develop headache at follow-up, which is in conformity with the findings of a recently published meta-analysis suggesting younger patients to be more prone to suffer from headache following ischemic stroke [25]. A possible reason for the higher prevalence of burdensome headache in SAH patients without major deficits (WFNS I/II) could be the fact that these patients generally are aware of the potentially traumatizing treatment course while being in intensive care. Roper and colleagues found a correlation between post-traumatic stress disorder and headache-related limitations following traumatic brain injury [58]. Preexisting comorbidities and early in-hospital complications such as rebleeding or delayed cerebral ischemia were not significantly different between patients with and without headache. Our SAH cases showed equivalent cardiopulmonary comorbidity rates as well as similar ratios for alcohol and tobacco consumption compared to previous studies, but diabetes mellitus was less frequently encountered in our cohort [2, 39]. Interestingly, all three SAH patients with anamnestic prior rheumatic condition reported on burdensome headache at follow-up, but this association narrowly failed the statistical significance. Being described already in 1938 by Cyriax, many recent reports chronicle headache in conjunction with various rheumatic conditions like polymyalgia rheumatica, systemic lupus erythematosus, and antiphospholipid syndrome [11, 14, 53, 64]. Conversely, people with headache had a higher prevalence of rheumatic disorders in an Austrian general population-based study [55]. Cavestro et al. gave additional insight into the linkage between headache and various systemic autoimmune diseases [13]. Fatigue, a common feature in rheumatic disorders, could be a factor contributing to the occurrence of chronic headache in this setting and has already been recognized as a risk factor for persistent headache after ischemic stroke [38]. The HA+ group comprising 40.9% (38/93) of good-grade SAH patients suffered from an average headache intensity of 3.7/10 NRS at long-term follow-up, which came along with approximately 9 days of significant restrictions of daily living activities within the last 3 months. According to other empirical surveys, 77% of good-grade SAH patients and 16–22% of SAH long-term survivors presented with higher headache burden several years after the bleeding event [12, 30, 51]. A Danish study reported on persistent primarily tension-type or migraine-like headache 3 years after stroke in about 10% of patients with a comparable mean intensity of 4.5/10 NRS during the last weeks [24]. The body of evidence suggests SAH to be a subtype of stroke with especially high propensity toward headache in the acute and chronic setting [22]. Even though episodic tension-type headache and migraine are known to show a high lifetime prevalence [52], a relatively low headache point prevalence of 5.7% was stated in a Central European population-based study [55]. Hence, persistent headache seems to be much more prevalent in SAH survivors compared to the general population, which also contributes to elevated health-related expenditures mainly by means of indirect costs [17]. Interestingly, one recent case-control study revealed an increased migraine frequency also in patients with unruptured intracranial aneurysms [68]. The pathophysiology behind the development of persistent post-stroke headache is principally not understood so far and thus speculative. One possible mode of action could be the central sensitization of nociceptive pathways [38]. Another possible mechanism could be chronic hyperreactivity of the cerebral vasculature, as it is also seen in the so-called reversible cerebral vasoconstriction syndrome, which is typically characterized by chronic headache with intermittent thunderclap attacks [46]. Headache tends to be more frequent after cortical ischemic strokes as compared to subcortical events. Moreover, headache is more likely present following a large vessel than small vessel occlusion [25]. The subarachnoid space, which is the region of interest in SAH, is directly adjacent to the cortex. Therefore, ischemic and hemorrhagic vascular events may affect the same anatomical cortical structures by means of different mechanisms (ischemia, aseptic inflammation, delayed cerebral ischemia). Currently, there is a lack of knowledge with regard to the pathophysiological key processes leading to post-SAH headache preventing specific target-oriented treatment measures. Generally speaking, an essential step in chronic headache management besides analgesic medication is the increase in patient resiliency. This can be primarily achieved by cognitive-behavioral approaches and relaxation training [61]. A multidisciplinary approach including physiotherapy seems to be the most preferable therapeutic strategy [20]. We found long-lasting headache after SAH in association with pronounced weariness, sleep disturbance, and concentration problems. Numerous authors reported on high rates of chronic tiredness, motivational impairment, sleep disorder, and various cognitive limitations in patients who were treated for SAH beforehand [3, 30, 40, 51, 56], but there are also contradictory findings suggesting sufficient neuropsychological recovery following hemorrhage [36, 54]. In line with our findings, a recent comprehensive literature review also identified reduced well-being related to diminished energy level as well as sleep impairment in patients with primary headache disorders [1]. The etiology of reduced vitality following SAH has not been fully elucidated yet, but development of hypothyroidism could be a contributing factor with partial recovery of cognitive dysfunction after hormone replacement therapy [42]. In our study, HR-QOL was significantly decreased in HA+ patients along with increased levels of anxiety and stress indicating a profound impact of burdensome headache on patient’s quality of life perception. Despite a general lack of neuropsychological and QOL endpoints in most interventional SAH trials [5], there is a growing body of evidence regarding anxiety, stress, and depression as frequently encountered phenomena in long-term SAH survivors, which may subsequently contribute to reduced HR-QOL and social isolation [30, 34, 36, 56]. The HR-QOL restrictions in SAH patients seem to be stable over at least two years post hemorrhage [65]. Bodily, social, and role functioning limitations are well-known factors undermining HR-QOL in patients suffering from any type of chronic headache [1, 8]. One out of two of the whole SAH sample in this study presented with an officially certified degree of disability, and almost one out of three patients were incapacitated for work at follow-up which states the enormous socioeconomic importance of this certain subtype of stroke affecting preferentially people of younger ages. Our findings concerning long-term disability and occupational reintegration difficulties agree with the current state of scientific knowledge [36, 51, 60, 70]. The HA+ patients revealed slightly higher, but non-significant levels of disability and unemployability. Monzani et al. determined a correlation between headache intensity and loss of workers’ productivity in patients suffering from tension-type headache [45]. A recent comprehensive meta-ethnographic systematic analysis describes chronic headache as “driver of behavior’ which subsequently provokes a feeling of “a loss of control” in patient’s life. This loss of control significantly contributes to the self-experienced limitations [48]. For migraineurs it has been shown that these patients are less physically active and mobile than controls even in their interictal (pain-free) phases [62]. This finding underlines an intensity-independent disabling effect of headache conditions. The main strengths of this investigation are the prospective data collection of a large and up-to-date consecutive patient sample (n = 93) from an extensive catchment area, a long follow-up period (mean 32.6 months, range between 14 and 50 months), and the utilization of a comprehensive multidimensional set of validated pain and physical as well as mental health measures. Standardized pain questionnaires are not designed to establish a specific headache diagnosis, and therefore, we are incapable of making clear statements regarding the distribution of different headache entities with respect to the International Classification of Headache Disorders of the International Headache Society. We are aware of the potential bias due to the refusal to participate of a fraction of patients and the per-protocol exclusion of poor-grade SAH patients. Another possible limitation, which should be mentioned here, is the monocentric study design.

Our results suggest that a considerable proportion of good-grade SAH patients suffers from sustained burdensome headache at long-term follow-up with significant pain-related impairment of everyday activities. Furthermore, persistent headache seems to be associated with increased weariness, sleep disturbance, cognitive dysfunction, as well as anxiety and stress levels, which may altogether contribute to a relevant reduction in the quality of life in SAH cases. Consequently, there is an urgent need for further basic and clinical research in this field to elucidate the underlying pathophysiological and psychophysiological mechanisms, characterize the specific phenotype of long-term post-SAH headache, and also develop preventive as well as therapeutic pain reduction strategies following SAH.