Abstract
We aimed to describe and classify headaches associated with acute stroke, by interviewing patients consecutively admitted to a stroke unit using a validated headache questionnaire and the International Classification of Headache Disorders of the International Headache Society (IHS). One hundred and twenty-four patients (61% ischaemic and 39% haemorrhagic stroke) reported headache. Headaches started mostly on the day of stroke, were more often continuous, pressure-type, bilateral and located in the anterior region, were increased by movement and by cough and lasted for a mean of 3.8 days. Tension-type was the most frequent type of headache. Eleven per cent of headaches could not be classified using the criteria of the IHS. Previous primary headache was documented in 71 patients. The presence of nausea/vomiting due to acute stroke can confound headache classification using the IHS criteria. In up to half of the patients, headache seems to be a reactivation of previous primary headache.
Introduction
Headache is frequent in the setting of acute stroke (1–6), but many of its characteristics remain to be reliably described. Prevalence varies widely (18–64.5%) (2, 4, 6–10), with higher frequency reported in haemorrhagic strokes (50–64.5%) (3, 4, 11, 12). Headache can start before (43–60%), simultaneously (25–30%) or after (14–27%) focal signs (3, 13). Headache quality is scarcely described, with few studies reporting higher frequency of either pulsating or throbbing type (3, 4, 13). Location of pain is an unreliable predictor of stroke topography (7, 13, 14). Location also varies, with more prevalence of diffuse than lateralized and of ipsilesional than contralesional headache (3, 4, 6, 11, 12). The discrepancies in results among studies are mostly due to methodological differences and variation in stroke type and stroke samples (1, 2, 4). Few studies were designed prospectively. Even in those with prospective design, retrospective recall of headache was required, as a cross-sectional evaluation was usually performed at a variable time elapsed since stroke (2, 4, 7, 8, 11, 12). Retrospective recall of the characteristics of headache due to stroke is probably not reliable, as the patient is usually more concerned with other neurological signs than with characteristics of headache in the acute phase. Moreover, data on presence of headache were collected simultaneously with other variables related with stroke (2, 4, 7, 11, 12). Specific queries about headache and its diverse characteristics were not well defined. Last, several studies did not use clear, uniform and accepted tools to classify headache type (2, 4, 6–8, 11–13). With few exceptions (3, 7), previous headache was not recorded according to any operational diagnostic definition.
The International Headache Society (IHS) has established criteria to identify headache associated with stroke, which include headache as a new symptom or of a new type and a close temporal relationship with the onset of other neurological signs (15). These criteria were retained by the last revision of headache classification (16).
The purpose of our study was to describe the characteristics, duration, evolution and type of headache associated with stroke during the first days of acute stroke, using the classification criteria of the IHS (15, 16), and to define how often stroke-associated headache was a reactivation of a previous primary headache.
Patients and methods
Patients
The study population was selected among all consecutive acute haemorrhagic or ischaemic stroke patients who were admitted to the Stroke Unit, Santa Maria Hospital, over a 2-year period. Patients with headache for at least 1 day during hospitalization due to acute stroke were included in the study. During the daily visit to the stroke unit, patients were routinely questioned about complaints, including the presence of headache. Exclusion criteria were (i) drowsiness [Unified Neurological Stroke Scale (UNS) item 1], consciousness < 4 (17); (ii) moderate to severe aphasia (UNS item 2), speech/verbal communication < 2 (17); (iii) delirium [according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria] (18); (iv) diagnosis of dementia prior to stroke, according to DSM-IV criteria (18); (v) diagnosis of cerebral venous thrombosis; (vi) subarachnoid haemorrhage; and (vii) transitory ischaemic attack. Patients who could not be interviewed prospectively from day 1 to day 8 (due to delay in hospital admission, or because they were admitted during weekends or holidays) were also excluded.
Methods
Demographic data, vascular risk factors, symptoms and signs of the current stroke as well as the results of ancillary procedures were collected in standardized form by the group of neurologists working in the Stroke Unit, according to the procedure of the Stroke Unit registry. For the purpose of the present research, we also registered other clinical variables that could be implicated in the origin of headache, for each of the 8 days of the study: uncontrolled hypertension [defined as diastolic blood pressure (BP) ≥ 120 mmHg], fever (≥ 38 °C), infections, intake of nitrite/nitrate or calcium antagonists. Previous hypertension was defined according to the World Health Organization guidelines for the management of hypertension (current antihypertensive treatment or BP values ≥ 140/90 mmHg in subjects not taking antihypertensive medication, based on multiple BP measurements on several separate occasions) (19).
Assessment of stroke patients was performed according to the usual procedures of the Stroke Unit, which include electrocardiogram, ultrasound study of extracranial (triplex) and intracranial (transcranial Doppler) vessels, echocardiogram and routine laboratory investigations. All patients had a computed tomography (CT) scan performed at admission. Repeated CT scan or magnetic resonance imaging were performed only when neurological deterioration or further clinical/aetiological investigation was needed.
Patients included in the study were interviewed daily from the day of stroke onset until day 8 (or until discharge, if sooner) by one of the neurologists involved in the study using a validated headache questionnaire (20, 21), enabling the classification of headache following the IHS classification. Headaches were classified according to the IHS classification (15, 16). Headache onset was defined as sudden (maximal intensity from onset) or progressive. Relationship between headache onset and the onset of other neurological signs was defined as previous, concomitant, or following other neurological signs. Severity of headache was defined as mild, moderate or severe, according to patient description. Use of analgesic therapy was also registered. Headache location was defined as unilateral or bilateral, anterior (defined as located in the orbicular, frontal and temple regions), posterior (defined as occipital), in the vertex, diffuse or multiple sites. Other locations were also registered.
Quality was defined as pressure, throbbing, stabbing and other qualities (registered using the description of the patient). A history of lifelong headaches was also collected, using the same questionnaire, usually after the first days of stroke. Lifelong headaches were also classified according to the IHS criteria. Frequency of headache that occurred in the year before stroke was registered and classified as frequent if the patient had had more than one episode of headache per month, or sporadic if less than one episode of headache had occurred per month in the previous year.
For each included patient and for each day they reported headache, daily headache classification was performed independently by two neurologists using the IHS criteria. Discordant classifications were discussed to reach consensus. Classification of stroke-associated headache and of previous headache was also made independently, in order to avoid the influence of the diagnosis of stroke-associated headache on previous headache classification and vice versa.
Haemorrhagic strokes were classified based on CT location as lobar (frontal, parietal, temporal, occipital or multiple lobes), deep (thalamic, capsular, lenticular and lesions that originated in the basal ganglia and extended into the adjacent white matter), brainstem, cerebellar, multiple haematomas and primary intraventricular haemorrhage. Presence and location of secondary subarachnoid and intraventricular blood were also recorded.
Ischaemic strokes were classified based on CT locations as anterior cerebral artery, total middle cerebral artery (MCA), cortical middle cerebral artery, large subcortical MCA, lacunar, cortical junctional territory, posterior cerebral artery (PCA), brainstem, cerebellar and multiple territories. When the stroke lesion was not visible on the CT scan, the stroke location was presumed on the basis of clinical data, using the Oxford Community Stroke Project (OCSP) classification (22).
Data analysis
We performed descriptive statistics of the study population's characteristics and of the onset, frequency, duration, severity, location and quality of stroke-associated headache over the 8 days of the study. Headache associated with stroke and previous headache classification according to the IHS criteria were subsequently described.
Bivariate analyses were performed comparing headache characteristics between patients with ischaemic strokes and patients with haemorrhagic strokes, using χ2 test with continuity correction when necessary, difference between proportions and 5% confidence intervals (CI). Variables considered were onset, severity, location, associated nausea and vomiting, as well as headache classification according to IHS criteria.
Results
During the study period, 668 patients were admitted to the Stroke Unit. Two hundred and six acute stroke patients (31%) had a complaint of headache at stroke onset or during the first 8 days of stroke. A total of 82 patients that referred headache did not meet the inclusion criteria for the study, due to severe aphasia, drowsiness, delayed admission in the stroke unit and stroke type (cerebral venous thrombosis, subarachnoid haemorrhage, and transitory ischaemic attack). One hundred and twenty-four patients, 60 women (48%) and 64 men (52%) with a median age of 58 years (range 20–84 years), were eligible for the study.
Strokes were ischaemic in 76 patients (61%) and haemorrhagic in 48 patients (39%). Ischaemic strokes were in the following locations: four total MCA, 10 cortical MCA, 10 large subcortical MCA, five lacunar, one cortical junctional territory, 13 PCA, three brainstem, three cerebellar, one brainstem and cerebellar and one multiple territories (PCA and cortical MCA). In 25 patients (20.2%), CT scan performed at admission showed no acute lesion related to stroke. Based on clinical data, stroke location (according to the OCSP classification) was presumed to be: vertebrobasilar in 13 patients, lacunar in nine patients and partial territorial strokes in the carotid distribution in three patients.
The location of the intracerebral haemorrhages was as follows: 21 lobar; 19 deep; two intraventricular; and six brainstem/cerebellar.
Eighty-one patients had previous arterial hypertension. During the study period, uncontrolled hypertension was observed in 42 patients, 10 patients had fever/infections, 10 took nitrite/nitrate and calcium antagonists were prescribed in 22 patients.
Fourteen patients (11%) were discharged from hospital before the 8 days necessary for the completion of the study, and follow-up was not done. In four patients, subsequent evaluation before the 8 days of the study was not possible due to worsening of neurological status because of increasing drowsiness.
Day of onset and duration
For 107 patients (86%), the headache started on the day of stroke onset. For the remaining 17 patients, headache started between the day 2 and day 5. The proportion of patients with headache decreased progressively from day 1 to day 8. On the 8th day of stroke, 18 patients (14.6%) still complained of headache (Table 1).
Characteristics of headache associated with stroke
Day 1, First day of other neurological signs/symptoms. Number of patients (%).
Headache lasted a mean of 3.8 days (S.D. 2.1; median 3 days). In 12 patients, headache lasted 8 days and in other 12 patients headache lasted just 1 day.
Headaches were mainly continuous and not episodic with headache-free intervals. On day 1, 72% of patients had continuous headaches.
All 14 patients discharged before the 8 days had mild headache at the time of discharge.
Type of headache onset and relationship between headache onset and onset of other neurological signs
In 26 patients (21%), headache onset was sudden, whereas in 23 patients (19%) it was progressive. Seventy-six (60%) patients could not recall headache onset as sudden or progressive. Headache started before other neurological signs in 32 patients (26%), concomitant to other neurological signs in 37 patients (30%) and after other neurological signs in 33 patients (27%).
Severity
Headache was more severe on the first day of stroke (Table 1). Headache that started after day 1 (17 patients) was more often mild (seven patients) or moderate (seven patients) than severe (three patients). Severity was not related with stroke location. Unilateral and bilateral headache had similar severity. Severity of headache was not related to other clinical variables [uncontrolled hypertension (diastolic BP > 120 mmHg), fever (> 38°C) and infections, nitrite/nitrate and calcium antagonists' intake] or vascular risk factors (data available if requested).
Location
Headache was more often bilateral than unilateral (59 patients vs. 45 patients on day 1). In 11 of the 45 patients with unilateral headache on day 1, headache became bilateral on day 2. When unilateral, headache was more often ipsilesional than contralesional (32 vs. 13 patients, among 101 patients with unilateral strokes).
Headache was more frequently located in the anterior cranial region (Table 1). Diffuse headache, posterior headache and headache referred to multiple sites were infrequent (Table 1). Other locations were rare, as lateral cervical (one patient), parietal (one patient), hemicranial (one patient) and located in the ear (one patient).
On day 1, headache involved the posterior region (isolated posterior headache or headache located in multiple sites with involvement of the posterior cranial region) in 18 patients. Fourteen of these patients had posterior lesions (brainstem/cerebellar 11; PCA one; occipital haematoma two).
Quality
Pressure was the most frequently described quality, followed by throbbing type. Stabbing was infrequent, as were other qualities of pain (burning type, dull feeling, wet, ‘wind’ or cold, ‘glass inside the head’) (Table 1).
Nausea and vomiting, relation with cough and movement
Nausea and vomiting were present in 40% of the patients complaining of headache on day 1, but the proportion of subjects with headache who vomited decreased after day 2. Headache severity increased with cough and with movement (Table 1). This relationship was observed throughout the 8 days of the study.
Headache classification according to the IHS criteria
According to the IHS criteria, on day 1, headache could be classified in similar proportions to tension-type and migraine-type (Table 2), but on the other 7 days, tension-type headache was the most frequent type of headache referred (Table 2). In all 8 days, a substantial number of patients had headache that could not be classified according to the IHS criteria (Table 1).
Headache classification according to the International Headache Society criteria
Number of headaches (%). Total of headaches on day 1 is 115 because eight patients had two types of headache on day 1.
Headache associated with acute stroke and previous headache
Previous headache type could be reliably described by 71 patients on the first day of admission. Tension-type was referred by 41 patients and migraine-type by 26 patients. Other types of headache were referred by four patients (headache associated with substance use/withdrawal, two; acute sinus headache, one; and unclassified, one). Nine patients had two different types of previous headache and one patient complained of three different types of previous headache. Twenty-five patients (20%) denied any headache prior to stroke. In 28 patients (23%), it was not possible to define previous headache characteristics reliably because of language/mental status change due to stroke.
When stroke headache was compared with previous headache, patients with past history of sporadic headache (defined as one episode per month, or less) were more prone to have a different type of headache (62% with new headache type vs. 38% with same type), whereas patients with previous frequent episodes of headache (defined as more than one episode of headache per month in the year before stroke) had a trend to complain of the same headache type (53% with the same headache vs. 47% with new headache type, P = 0.053). Re-activation of headache was independent of the type of previous headache (migraine- or tension-type). Headache that started after day 1 (17 patients) was a reactivation of previous headache in 29% (five patients).
Headache in patients with no previous history of headache
Patients with no previous headache history (n = 25) referred tension-type headache more frequently (59% of these patients on day 1). This group of patients also had a relevant number of unclassifiable headaches (11% of the patients on day 1).
Differences of headache characteristics according to stroke type
Onset
Comparing haemorrhagic with ischaemic stroke, headache associated with haemorrhagic stroke began more frequently before other focal signs (29% vs. 11%, difference 0.18; 95% CI 0.04, 0.33), and there was a trend to have more frequently a sudden onset even though the difference did not reach statistical significance. Headache associated with ischaemic stroke was more frequently concomitant to other neurological signs (36% vs. 19%, difference 0.17; 95% CI 0.07, 0.34) and progressive in onset (26% vs. 8%, difference 0.18; 95% CI 0.24, 0.29). Days of onset and duration were similar (mean of 3.94 days on haemorrhagic stroke vs. mean of 3.75 days on ischaemic stroke, median 3 days for both ischaemic and haemorrhagic stroke).
Severity
Headache associated with haemorrhagic strokes was more severe than headache associated with ischaemic stroke. This difference persisted on the first days of stroke (Table 3). Patients with ischaemic stroke were more frequently headache-free or had mild headache on day 2 than patients with haemorrhagic stroke (59% vs. 35%, difference 24; 95% CI 0.06, 0.40).
Differences in proportions of patients with headache and headache characteristics in ischaemic and haemorrhagic strokes
On day 1, mild/moderate headache is significantly more frequent on ischaemic stroke than in haemorrhagic stroke, 55% vs. 29%, 95% CI 0.08, 0.43; P < 0.01.
On day 2, the same difference persists, 61% (mild/moderate headache on ischaemic stroke) vs. 40% (moderate/slight headache on haemorrhagic stroke), 95% CI 0.04, 0.39, P < 0.01.
Non-significant difference.
Difference −0.22, 95% CI −0.4, −0.05.
Headache was more severe/moderate in posterior ischaemic strokes (20 posterior circulation strokes plus 13 vertebrobasilar strokes based on clinical data) than in anterior ischaemic strokes (24 MCA strokes plus three carotid stroke based on clinical data; 85% vs. 61%, difference 0.24; 95% CI 0.02, 0.46). Headache had shorter duration (≤ 5 days) in posterior than in anterior ischaemic strokes (91% vs. 71%, difference 0.20; 95% CI 0.001, 0.38). There was no difference between sides or location of the headache when considering anterior vs. posterior ischaemic strokes. Severity was similar between cortical and subcortical strokes (superficial/deep locations). Severity was not different between deep and lobar haemorrhages.
Headache severity increased with movement and cough more frequently in haemorrhagic than in ischaemic stroke, but the difference did not reach statistical significance (Table 3).
Location
Even though bilateral headache was more frequent in both types of stroke, unilateral headache was significantly more frequently associated with ischaemic stroke (difference 0.17; 95% CI 0.01, 0.32, on day 1) than with haemorrhages.
In lobar haemorrhages, there was a predominance of bilateral headache (11/21). Less frequently lobar haemorrhages were associated with ipsilesional headache (7/21), and rarely with contralesional side, but the differences did not have statistical significance. Deep haematomas were more frequently associated with bilateral headaches (10/19).
Headache classification according to IHS criteria
On day 1, migraine-type was the most frequent type of headache associated with haemorrhagic strokes (40% of haemorrhagic strokes with migraine-type vs. 25% of haemorrhagic strokes with tension-type). Ischaemic strokes were always more frequently associated with tension-type (49% with tension-type vs. 37% with migraine-type). In fact, tension-type headache was significantly associated with ischaemic stroke (difference 24; 95% CI 7.4, 41) on day 1. Both stroke types were associated with a relevant number of unclassifiable headaches (14% of haemorrhagic stroke vs. 8% of ischaemic stroke on day 1).
There was no difference in headache type between posterior and anterior ischaemic stroke.
Nausea and vomiting
Nausea and vomiting were more frequently associated with haemorrhagic than with ischaemic stroke in the first 2 days. On the second day, there was a relevant reduction in vomiting associated with ischaemic stroke, whereas the association persisted with haemorrhages (Table 3).
Discussion
Our study has shown that: (i) headache associated with acute stroke is frequent, starts usually on the first day of stroke, lasts for a median of 3 days, is most frequently continuous, pressure-type, more often located in the anterior cranial region and bilateral, and is consistently aggravated by movement and cough; (ii) headache is more severe on the first day of stroke, and on the same day association with nausea and vomiting is frequent; (iii) headache in acute stroke is a reactivation of previous headache in 38–53% of the patients, depending on the frequency of previous headache.
Forty per cent of patients admitted to the Stroke Unit with headache in acute stroke could not be included in the study due to drowsiness, severe aphasia and evaluation later than the first day of stroke. This fact probably led to an underestimation of headache frequency. We found headache in 31% of acute stroke patients, similar to previous studies (3, 4, 6, 7, 10, 11, 13), a number that probably underestimates the real frequency. So far, studies reporting higher frequencies (1, 4) have included also subarachnoid haemorrhages or included only haemorrhages (12).
In the majority of previous studies, data were collected retrospectively: a variable number of days elapsed between recall of headache and stroke; data were collected only on admission day and no prospective daily evaluation was performed. Recalling headache's characteristics in acute stroke appears to be a difficult task for patients. In fact, 63% of patients could not recall the type of onset of headache, while 19% could not describe the temporal relationship between headache onset and the onset of other neurological signs. We minimized recall bias of the characteristics of headache by collecting them daily.
No influence was found of uncontrolled hypertension, fever and infections, intake of nitrite/nitrate and calcium antagonists on the severity of headache. Previous studies also failed to find a consistent relation with vascular risk factors (2, 3, 6–11).
Despite the general conviction that haemorrhagic stroke is associated with more severe headache than is ischaemic stroke, few studies (1, 4) have explored severity of headache according to stroke type. We found headache to be more severe and to start more frequently before other neurological signs in haemorrhagic strokes, whereas headache in ischaemic stroke started more frequently concomitantly to other focal signs and was more progressive in its onset.
We found headache associated with ischaemic and haemorrhagic strokes to have similar duration. A previous study reported longer headache in haemorrhagic stroke (4), but this study also included subarachnoid haemorrhages.
Headache was more often bilateral in haemorrhagic stroke, unilateral in ischaemic stroke and more often anterior, bilateral and ipsilesional, as reported by previous studies (3, 4, 11, 12).
Some studies have reported more frequent headache related to stroke in vertebrobasilar strokes (2–4, 6, 7, 10, 11). We found ischaemic strokes located in the posterior circulation associated with more severe and shorter headaches. The few patients with posterior located headaches had mostly posterior strokes. However, anterior headache location was also associated with posterior stroke. We did not find a relation between severity and location of headache, similarly to previous studies (7, 8, 13, 14).
According to the IHS criteria, headache associated with stroke must occur simultaneously or in very close temporal relationship with the onset of other neurological signs and should be a new type of headache and not an exacerbation of a pre-existing type of headache. The recent revision of the Headache Classification has introduced a new item: improvement or disappearance of headache within a defined period (16). However, it is stated that this criterion is not indicated in some vascular disorders, and ‘chronic postvascular-disorder headache’ is also considered for longstanding headaches (after 3 months). Very scant information is given concerning other headache characteristics associated with acute stroke.
We found that 38–53% of stroke patients had a reactivation of previous headache in acute stroke, depending on the frequency of previous headache, and irrespective of headache type prior to stroke. Patients with previous frequent episodes of headache were more prone to complain of the same type of headache, whereas patients with previous sporadic headache had more frequently a new type of headache. Patients with no previous headache had tension headache more frequently. Reactivation of previous headache was found in 54% of patients in other series (3), mainly for migraine in vertebrobasilar strokes. Other studies have found headache related to ischaemic stroke more frequent in patients with previous migraine (7, 8, 11), but the classification and frequency of other previous headaches and stroke-associated headaches were not evaluated in those studies. Some authors have proposed that migraine and stroke-associated headache could be triggered by similar mechanisms (8, 13). We found that tension headache is also reactivated by stroke, suggesting that the vascular insult is able to trigger the usual individual pain response for each patient.
In previous studies, with one exception (3), no uniform and accepted tools were used to define and describe headache related to stroke. In our study, using the IHS classification, headache could be classified either as tension-type or migraine-type on the first day of stroke, and tension-type on the following days. In fact, on day 1, association with nausea and vomiting probably confounds the application of the IHS criteria, and increases migraine-type on day 1. After day 2, as nausea and vomiting frequency decrease, tension-type becomes the most frequent headache type. Even for patients without previous headache, tension-like headache was the most frequent headache type associated with acute stroke (59%).
Headache could not be classified using the IHS criteria in 11% of the cases, even for those patients who had no previous history of headache. Vestergaard et al. (3) have also found 23.2% of patients with unclassifiable headaches.
This observational study was not designed to investigate the pathophysiological mechanism of headache associated with stroke. However, these results provide support for some mechanisms. Whereas in some patients previous headache is triggered by vascular insult, ischaemia or blood products and/or an acute stressful situation (severe acute illness and hospital admission), in others they activate the novo the trigeminovascular system. A third mechanism is suggested from the association between headache in acute stroke, movement and cough that remained consistent over the first week of stroke. This association has not been previously reported and could be related to a higher susceptibility to stretching from pain-sensitive structures, in response to the mechanical effect of intracerebral haemorrhage or ischaemia related to cerebral oedema. In conclusion, this study has identified the most common characteristics of headache associated with stroke in the first days after onset, the temporal change in such characteristics and the usual duration of these headaches.