ISSN 0017-8748

Headache doi: 10.1111/head.13382

© 2018 American Headache Society Published by Wiley Periodicals, Inc.

Views and Perspectives

A Narrative Review of Persistent Post-Stroke Headache – A
New Entry in the International Classification of Headache
Disorders, 3rd Edition
Joshua Lai, MD; Rebecca A. Harrison, MD; Alyson Plecash, MD; Thalia S. Field, MD, MSc

Background.—Persistent post-stroke headache is a clinical entity that has recently entered the International Classification
of Headache Disorders, 3rd edition. In contrast to acute headache attributed to stroke, the epidemiology, clinical features,
­potential pathophysiology, and management of persistent post-stroke headache have not been reviewed.
Methods.—We summarize the literature describing persistent headache attributed to stroke.
Results.—Persistent headache after ischemic or hemorrhagic stroke affects up to 23% of patients. These persistent headaches
tend to have tension-type features and are more frequent and severe than acute stroke-related headaches. Risk factors include
younger age, female sex, pre-existing headache disorder, and comorbid post-stroke fatigue or depression. Other factors including
obstructive sleep apnea or musculoskeletal imbalances may contribute to headache persistence. Although more evidence is needed,
it may be reasonable to treat persistent post-stroke headache according to headache semiology.
Conclusion.—Recognition of persistent post-stroke headache as a separate clinical entity from acute stroke-attributed head-
ache is the first step toward better defining its natural history and most effective treatment strategies.

Key words: h eadache, persistent headache, stroke, post-stroke pain, post-stroke complications, International Classification
of Headache Disorders

(Headache. 2018;00:00-00)

INTRODUCTION classify the entity of persistent post-stroke headaches.

The 2018 International Classification of
Headache Disorders, 3rd edition (ICHD-3) has up-
dated its criteria for “Headache attributed to cranial
and/or cervical vascular disorders.”1 These new crite-
ria more accurately reflect the timeline for resolution
of headaches associated with stroke onset, and better
From the Division of Neurology, University of British Columbia,
Vancouver, BC, Canada (J. Lai, A. Plecash and T. Field);
Department of Neuro-Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA (R. Harrison).
Address all correspondence to J. Lai, Gordon and Leslie
Diamond Health Care Centre, 8th Floor, 2775 Laurel Street,
Vancouver, BC, Canada V5Z 1M9.
Accepted for publication May 19, 2018.
These new criteria may help to promote improved
knowledge and understanding around the entity of
post-stroke headache.
Headache around the time of stroke onset is well
described. However, persistent post-stroke headache,
despite being a common post-stroke pain syndrome
affecting up to 1 in 5 stroke survivors, is less well
characterized in the literature and under-recognized
in clinical practice.2,3
Conflict of Interest: The authors declare that there is no conflict
of interest.
Funding: Funding for both J. Lai and R. Harrison was provided
by the Barbara Allen Scholarship for Pain Research from the UBC
Division of Neurology.

1
2 XX 2018
Here, we review the epidemiology, clinical fea-
tures, potential pathophysiology, and management of
persistent post-stroke headache. We provide contrast
with the more well-known entity of acute headache
at stroke onset and identify future directions for re-
search and therapy. Improved recognition and treat-
ment of post-stroke pain syndromes improves both
pain outcomes and quality of life.
METHODS
A literature search including PubMed, MEDLINE,
Embase, and the Cochrane Library was performed to
identify articles pertaining to post-stroke headache and
its comorbidities. The reference lists of relevant articles
were then hand-searched for other references. Relevant
articles underwent a “cited reference search” (ISI Web
of Science). All English-language articles in the past 30
years (1988 to present) were considered. Included ref-
erences were observational studies, randomized con-
trolled trials, systematic reviews, narrative reviews,
meta-analyses, scale validation studies, and basic sci-
ence research. Case reports were not included. Specific
search terms included: “post stroke headache,” “per-
sistent post stroke headache,” “post stroke pain,” “post
stroke depression,” “post stroke fatigue,” “post stroke
complications,” “stroke,” “ischemic stroke,” “intrac-
erebral hemorrhage,” “headache,” “International
Classification of Headache Disorders,” “reversible cer-
ebral vasoconstriction syndrome,” “cerebral venous
sinus thrombosis,” and “dissection.”
DEFINING POST-STROKE HEADACHE –
CURRENT FRAMEWORKS AND
CHALLENGES
Timing.—Headache is a common complaint with
stroke onset, usually reported in the period shortly
preceding, during, or following stroke onset. The
new ICHD-3 criteria identify this entity as “acute
headache” attributed to stroke. The time window
encompassing the “acute” period in most recent
studies is development of headache within the first 72
hours after stroke onset.4–8 However, this window is
arbitrary, and in other studies ranges from as little as 12
hours to up to 7 days.9–12 The ICHD-3 criteria describe
headache that “has developed in very close temporal
relation to other symptoms and/or clinical signs of
stroke,” and resolves within 3 months as an acute
stroke-attributed headache.1 A 72-hour window before
onset of focal neurological symptoms has also been
used in studies examining “sentinel” headaches,5 but
ranges from up to 7 days prior to stroke to immediately
preceding the stroke.12,13 Differences in study design
account for this variation, and some studies do not
clearly define this window.14–16 In a prospective study
(n = 124) examining the presence of new headache from
day 1 to day 8 after stroke, no patients had new onset
headache beyond day 5.9 We propose standardization
of this time window to include headache onset between
72 hours before focal neurological symptoms to up to
7 days after, in order to better facilitate comparisons
between study populations.
The ICHD-3 has recently acknowledged an im-
portant subset of patients with new headache begin-
ning at stroke onset that continue to have persistent
new headache, months to years after stroke.1 A time
window of 3 months was used to define “persistent”
headache related to past ischemic stroke, nontrau-
matic intracranial hemorrhage, cervical artery dis-
section, and reversible cerebral vasoconstriction
syndrome (RCVS).1 Other stroke types that may be
associated with persistent headache, such as cerebral
venous thrombosis, were not included. These defini-
tions have also excluded patients who did not have
acute stroke-attributed headache, but had delayed
onset of a new persistent headache.2,3,10,17
Stroke Subtype and Acute Headache.—In certain
stroke subtypes, such as cerebral venous thrombosis,
cervical and intracranial artery dissection, and re-
versible cerebral vasoconstriction syndrome, head-
ache (and/or, in the case of dissection, facial pain) is
the commonest presenting feature.1,18 Even excluding
these stroke types, new headache associated with
acute stroke is common (Table 1).1,17
Acute headache associated with ischemic stroke
tends to present concurrently with focal neurological
signs, have tension-type features, have a mean dura-
tion of 3–4 days, and are mild to moderate in inten-
sity.9,17 Risk factors include younger age, female sex,
pre-existing headache disorder, and posterior circula-
tion stroke.4,5,10,17
Acute headache associated with non-traumatic
intracerebral hemorrhage (ICH) tends to present be-
fore other focal neurological signs, with thunderclap
onset and moderate to severe intensity.9,13 Risk factors
Headache 3

Table 1.—Prevalence of Acute Stroke-Attributed Headache than 3 months, would be classified as having “per-
by Stroke Subtype
sistent headache attributed to past stroke” according
to ICHD-3 criteria. Second, a patient with a pre-ex-
Peri-Stroke Headache isting primary headache disorder may experience a
Prevalence Range (%) change in headache severity, frequency, or quality
Stroke Etiology
after stroke. The criteria have not yet included this
Extracranial cervical artery 55–100 group of patients. In either scenario, headache onset
dissection1,17 or change in headache pattern occurs around the time
Large artery atherosclerosis7,9,16 15–41 of stroke and might be attributable to stroke.
Small vessel disease12,13 13–33
Delayed Post-Stroke Headache.—More contro-
Cardioembolic7,16 9–39
TIA7,10 16–36
versial are the subset of patients without a primary
Intracerebral nontraumatic 34–65 headache history who develop persistent headaches
hemorrhage8,10,11 with delayed onset following a stroke. Early studies
Cerebral venous sinus thrombosis1 80–90 cast doubt on whether these headaches were in fact
Reversible cerebral 95–100
attributable to the stroke event.20 Even recent stud-
vasoconstriction syndrome
(RCVS)4 ies on prevalence of post-stroke headache do not de-
fine timing of headache onset, potentially leading to
include younger age, female sex, hematoma volume, inclusion of patients with coincidental primary head-
and cerebellar or lobar hemorrhage.19 Duration of the ache disorders.8,21–23 Although the ICHD-3 criteria
headache appears to be similar to that of ischemic stipulate that headache due to stroke occurs “in close
stroke.9 temporal relation” to stroke symptoms,1 it is plausible
Characterizing the Relationship Between Stroke that persistent headaches may develop in a delayed
and Pre-Existing Headache Syndromes.—Defining fashion, akin to other delayed post-stroke complica-
and attributing a persistent headache to stroke can tions, including central post-stroke pain syndrome,
be difficult. Patients may fall into different categories post-stroke movement disorders, or post-stroke
(Fig. 1). First, a patient without a pre-stroke headache epilepsy. Up to 24% of patients report onset of head-
disorder may experience a new acute stroke-attributed ache between 1 and 7 days after stroke,5,9,12,20 and
secondary headache disorder that persists for months in one prospective cohort study, a subset of patients
to years. This patient, if headache persisted more reported headache onset between 3 and 6 months

Fig. 1.—Trajectories of headache after stroke and proposed terminology.

4 XX 2018
after stroke.3 More studies are needed to clarify
whether headaches with onset delayed by months or
even years after stroke might be attributable.
“PERSISTENT” POST-STROKE HEADACHE
Epidemiology.—Prevalence of any persistent post-
stroke headache in the literature ranges from 7–23%,
with follow-up times ranging from 3 months to 3 years
after stroke.2,3,8,21–24 However, prevalence studies of
persistent post-stroke headache are uncommon, and
most are part of broader studies examining preva-
lence of all post-stroke pain (Table 2). A few studies
have focused specifically on risk factors and clinical
features for persistent post-stroke headache (Table 3).
Stroke Mechanisms Commonly Associated With
Persistent Headache.—For uncommon stroke mecha-
nisms such as cerebral venous thrombosis (CVT) and
cervical artery dissection that are highly associated
with headache at onset, headache is often persistent
beyond 3 months (Table 1). In patients with CVT,
headache persisted in 14–53% of patients, as long
as 5 years after the event, with up to 43% reporting
that headache caused significant impact on quality
of life.25,26 Persistent headache in this population was
also related to high depression and fatigue scores, and
had significant impact on return to work.25 Similarly,
approximately a quarter of patients with cervical ar-
tery dissection had persistent headache at 6 and 36
month follow-up.27,28 However, these studies do not
account for history of primary headache disorder,
which is common in both of these young cohorts, with
migraine history being an additional risk factor for
cervical artery dissection.29
Ischemic Stroke and Intracerebral Hemorrhage.—
Persistent post-stroke headache is also prevalent fol-
lowing other, more common, stroke mechanisms.
Most studies do not separately consider persistent
headache prevalence or risk factors between patients
with ischemic stroke versus ICH. One retrospective
population-based study (n = 608, stroke type un-
specified) found a 10.5% prevalence of new persistent
headache in stroke survivors 2 years following their
event, compared to 2.3% in an age-matched refer-
ence population.21 Risk factors for headache included
younger age and pre-stroke headaches. In stroke pa-
tients with new headache, headache was severe in
47% and occurred on more than 7 days per month in
63.5%. Similarly, post-stroke headache prevalence in
a prospective cohort study (n = 408, 80.4% ischemic
stroke, 12.5% TIA, 7.1% ICH) was 10.8% at 6 months
post-stroke.22 In this cohort, risk factors for headache
included female sex, younger age, pain in the pa-
retic limb, and post-stroke fatigue. NIH Stroke Scale
(NIHSS) score, modified Rankin Scale (mRS) score,
prior depression, and stroke location were not signifi-
cantly associated. Interestingly, patients with head-
ache were significantly more likely to use analgesics
than patients with post-stroke pain affecting a limb
or another location (32% vs 17%). One retrospective
study (n = 90) in a post-ICH cohort found that 35% of
this cohort had headache at ICH onset, and 11% had
new headaches within 2 years of ICH.8 These head-
aches were usually probable tension-type and were
not associated with new intracranial lesions on repeat
neuroimaging. Post-ICH headaches were more com-
mon in females, those with pre-ICH headaches, and
those with high post-stroke depression scores.
The most detailed information on persistent
post-stroke headache comes from a cohort study by
Hansen et al2,3 (n = 275, 90.5% ischemic stroke, 9.5%
ICH). Patients were assessed prospectively at stroke
onset, 3 months, 6 months, and 3 years post-stroke
for newly developed headache. One-third (33.5%) re-
ported headache at stroke onset. At 3 and 6 months,
23% and 23.4% of patients had persistent headache,
respectively. Persistent headache was newly developed
in 15.3% and 13.1% of patients. Interestingly, a small
number of these patients reported delayed headache
onset between 3 and 6 months. At 3 years, 11.7%
(26/222) endorsed new persistent headache. Of these
26 patients, 16 had also reported headache at stroke
onset. The authors labeled these “stroke-attributed”
headaches, whereas the remaining 10 patients had
“non-stroke-attributed” headache because of lack
of headache at stroke onset. Younger age and female
sex were headache risk factors at 3 and 6 months but
were not significant at 3 years. At 3 years, antidepres-
sant use, absence of atrial fibrillation, and right-sided
stroke were associated with headache. These findings
suggest that although most headaches at stroke onset
will resolve, persistent headache is a real entity even
years after stroke.
 Headache

Table 2.—Prevalence of Persistent Post-Stroke Headache

Risk Factors for Persistent

Study Design/Population Follow-Up Period Prevalence Headache Headache Classification
Author/year

Hansen et al (2012)3 Prospective cohort (n = 275) Onset (<4 days) Onset: 33.5% Young age Not specified
90.5% infarct 3 months 3 months: 23%
9.5% ICH 6 months 6 months: 23.4%
Hansen et al (2015)2 Prospective cohort 3 years 3 years: 11.7% Pre-stroke headache Tension: 50%
Same cohort at 3 years (n = 222/275) “Stroke attributed”: 61.5% Right-sided stroke Migraine: 31.3%
84.6% infarct “Non-stroke attributed”: Lack of atrial fibrillation Mixed: 7.7%
15.4% ICH 38.5% Med overuse: 3.8%
Other: 3.8%
Klit et al (2011)21 Retrospective population- Median follow-up: Follow-up period: 10.5% vs Young age Not specified
based survey (n = 608 stroke 794.5 days 2.3% (reference population)
patients/1127) Range (588–1099)
Stroke type unspecified
Naess et al (2010)22 Prospective cohort (n = 408) Median follow-up: Follow-up period: 10.8% Younger age Not specified
80.4% infarct 372 days Female sex
12.5% TIA Range (185–757 days) Post-stroke fatigue
7.1% ICH Pain in paretic limb
Jonsson et al (2006)23 Prospective cohort (n = 297) 4 months 4 months: 7% Headache-specific risk Not specified
89.2% infarct 6 months 6 months: 10% factors not reported
6.4% ICH
4% SAH
0.3% undefined
Melo et al (1996)11 – Prospective cohort (n = 289 at Onset Onset: 57% Female sex At 2 years: 20 patients
cohort at onset onset, n = 90 at 2 years) 2 years 2 years: 11% Pre-ICH headache with new tension type
Ferro et al (1998)14 – 100% ICH Depression headache, 1 patient with
same cohort at 2 years new migraine headache
5
6 XX 2018
Table 3.—Risk Factors for Persistent Post-Stroke Headache
Risk factors for persistent post-stroke headache
Demographic
•  Younger age
•  Female sex
Clinical
•  Pre-existing headache disorder
•  Headache at stroke onset
• Stroke mechanism: Dissection, cerebral
venous thrombosis
Psychosocial
•  Post-stroke fatigue
•  Post-stroke depression
CLINICAL FEATURES
Severity.—The Hansen study also explored clinical
features of persistent post-stroke headache.2,3 At both
3 and 6 months, mean headache severity was moderate
(graded 5/10 in severity), with ~10% of patients
reporting constant headache and 25–31% reporting
daily headache. At 3 years, in those with persistent
post-stroke headache (11.7% of the original cohort,
n  =  26), 62–70% reported moderate to severe
headaches (>4/10), while ~12% reported constant
headache. This suggests that persistent post-stroke
headaches may be more frequent and severe than
headaches associated with acute stroke, which are
generally mild to moderate in intensity and decrease
in severity and frequency over time.9 Neither acute nor
persistent post-stroke headache severity has been
linked to clinical stroke severity.2,17
Location and Headache Type.—In those with ischemic
stroke, acute stroke-attributed headache location tends
to be ipsilesional in anterior circulation stroke, and
occipital in posterior circulation stroke.17,30 Although
19/26 patients with persistent headache at 3 years had
right-sided strokes, this may reflect a selection bias
against aphasic patients who could not complete the
survey.2 Persistent headaches were more likely to be
probable-tension type (50%) than probable-migraine
(31%), using ICHD-3 criteria.2 This is consistent with
a study on acute stroke-associated headache that
found an equal proportion of probable tension type vs
probable migraine on day 1 post-stroke, but a higher
proportion of tension-type headaches by day 8.9
However, using classification criteria developed for
primary headache disorders to describe a post-stroke
headache should be done with caution, as underlying
pathophysiology may be distinct.
INTERACTION BETWEEN PRE-EXISTING
PRIMARY HEADACHE AND POST-STROKE
HEADACHE
Primary headaches are a consistent risk factor for
both acute stroke-attributed and persistent post-
stroke headache. A headache history is present in
22–57% of patients with acute stroke-attributed head-
ache across several large studies.4,5,9,12 When studied
prospectively, patients with any pre-stroke headache
disorder had a 20% probability of acute headache at
stroke onset, compared to 6.5% in patients without
pre-stroke headaches.3 Patients with a pre-existing
history of migraine were 1.7 times more likely to de-
velop acute stroke-attributed headache than patients
without migraine.4 Twenty-three percent of patients
with persistent headache at 3 years had pre-stroke
headaches.2
Interestingly, improvement and even remission of
pre-existing headache disorders after stroke is also re-
ported. At our own center, headache remission after
ischemic or hemorrhagic stroke has been observed in
5/53 (9.4%) of patients in a pilot study assessing head-
ache between 1 and 6 months post-stroke. In the ret-
rospective ICH cohort, 14% of patients with pre-ICH
headaches were headache-free 2 years following their
event.8 A proportion were attributed to stopping alco-
hol use. However, they found that almost all patients
had a headache-free interval of weeks to months,
even if pre-ICH headache returned or a delayed post-
ICH headache developed. Furthermore, post-ICH
headaches were generally less frequent or severe than
pre-ICH headaches. At 3 years after ischemic stroke,
post-stroke headache was milder than pre-stroke
headache in 48%.2
PROPOSED PATHOPHYSIOLOGY
The potential mechanisms behind the development
of headache associated with acute stroke have been
reviewed, and may differ depending on stroke sub-
type.17,31 Proposed mechanisms include: 1) mechani-
cal or chemical stimulation of trigeminovascular
Headache
afferents innervating extra- and intracranial vessels,
particularly in the posterior circulation, 2) ischemia
to brainstem nuclei or the pain-sensitive dura, 3) dural
stretch due to massive infarction or hemorrhage.
The pathophysiology behind the development
of a persistent post-stroke headache or worsening
of pre-existing headache are speculative (Fig. 2).
Infarction may disrupt central pain modulation,
particularly in the brainstem, insula, or somatosen-
sory cortex.32 Notably, structural and functional al-
terations in these regions, as well as cingulate and
orbitofrontal cortex, have been implicated in chronic
migraine and chronic tension-type headache.33,34
Central sensitization of nociceptive pathways may
also contribute to persistence of headache associ-
ated with acute stroke. In patients with poor posture
or altered biomechanics following stroke, for exam-
ple, prolonged stimulation of pericranial myofascial
structures may trigger sensitization of second-order
spinal and supraspinal central neurons, resulting in
chronic tension-type headaches.35 Finally, comor-
bid depression, fatigue, and sleep apnea may ex-
acerbate or perpetuate headache. Further studies
are required to explore these clinical-pathologic
hypotheses.
In those patients who experience post-stroke
improvement of their primary headache disorder,
Fig. 2.—Proposed pathophysiological factors underlying persistent post-stroke headache.
7
several pathophysiological mechanisms have been
suggested, though it is possible that headache im-
provement is coincidental. One patient with “cured”
migraine following ICH had a brainstem hemorrhage
in the area of the trigeminal nucleus caudalis.8 Other
proposed mechanisms include a transient depletion
of calcium gene-related peptide (CGRP) or arterial
sympathetic denervation after leakage of blood into
the subarachnoid space.8 Infarction or reinnervation
of pain generators or networks may also account for
headache improvement.
COMORBID POST-STROKE
COMPLICATIONS
Although post-stroke mood disorders and post-
stroke fatigue have been linked to post-stroke pain
in general, there is a paucity of literature describing
the relationship between these comorbidities and
post-stroke headache specifically.23,36 However,
both mood disorders and fatigue are well described
in chronic migraine patients.37,38 One study found
that post-stroke fatigue was a significant risk factor
for headache at 6 months post-stroke.22 Higher
depression scores were found in patients with post-
ICH headaches than for patients whose headaches
had resolved.8
8 XX 2018
In meta-analyses, the incidence of post-stroke
depression and post-stroke generalized anxiety is
33% (range 11–61%) and 24% (range 19–29%), re-
spectively.39,40 Post-stroke fatigue, an under-recog-
nized phenomenon, affects 23–75% of patients.41,42
Systematic reviews have demonstrated co-occur-
rence of these post-stroke disorders.43 One challenge
in relating these comorbidities to pain syndromes
such as headache is the time it takes for screening
and diagnosis, both in clinic and in the research set-
ting. Multiple scales, including the Hospital Anxiety
and Depression Scale (HADS), Beck Depression
Inventory (BDI), Hamilton Depression Rating Scale
(HDRS), System Checklist (SCL-90), Montgomery
and Ashberg Depression Rating Scale (MADRS),
Personal Health Questionnaire (PHQ-2, PHQ-9), and
Center for Epidemiological Diseases Depression Scale
(CES-D) have been validated in stroke.44‒46 The Post-
stroke Depression Rating Scale was developed spe-
cifically for stroke patients.47 Optimal cut-off scores
for screening vary between studies. No specific fa-
tigue scale has been developed for post-stroke fatigue.
However, a systematic review identified the Fatigue
Assessment Scale (FAS), SF-36v2 Health survey (vi-
tality component), Profile of Mood States (POMS-f),
and Multidimensional Fatigue Symptom Inventory
(MFSI) as scales with the best face validity.48 The
Fatigue Severity Scale (FSS) is commonly used, and
a shortened version (FSS-7) is validated in stroke.49
The directionality of the relationship between post-
stroke headache and post-stroke comorbidities such
as mood issues and fatigue may be complex. These
common issues should be screened for at follow-up.
As with other chronic headache disorders, treatment
of mood and fatigue may be integral to successful
treatment of headache.
Obstructive sleep apnea, which is associated with
morning headache in particular, is both an indepen-
dent risk factor for stroke, as well as a potential post-
stroke complication.50,51 Obstructive sleep apnea in
stroke and TIA patients is common, with up to 72%
of patients screening positive for sleep disordered
breathing (apnea-hypopnea index >5) in a recent
meta-analysis.52 Central sleep apnea was reported
in only 7% of patients.50 Risk factors for obstructive
sleep apnea in stroke patients include male sex, recur-
rent stroke, and severe stroke.50,53 In our clinical expe-
rience, some patients with post-stroke headache have
a significant improvement or resolution of their head-
aches following diagnosis of OSA and subsequent ini-
tiation of CPAP; this diagnosis should be considered
in the context of post-stroke headache.
Musculoskeletal issues following stroke are com-
mon and under-reported.54 Though shoulder sublux-
ation and pain are well-known complications of stroke
affecting the upper extremity,55 other musculoskeletal
issues such as mechanical back or joint pain may arise
as patients begin to mobilize, given altered stance,
weight distribution, compensatory movements, use of
gait aids, and proprioceptive and other sensory defi-
cits.56 Musculoskeletal issues – including cervicogenic
or other referred pain patterns – may also contribute
to new post-stroke headaches. A population-based
survey (n = 16,222, 415 with prior stroke) in partic-
ipants over the age of 55 found self-reported joint
pain in 47% of stroke patients compared to 39% of
controls.56 Risk factors included older age and female
sex; stroke factors were not reported. Physiotherapy
and occupational therapy to address musculoskeletal
issues arising from altered posture and biomechanics
after stroke may identify reversible factors contribut-
ing to cervicogenic headache.
Stroke patients may have vascular risk factors as-
sociated with headache including uncontrolled hyper-
tension and obesity, or may take multiple medications
that may exacerbate headache.57‒59 Dipyridamole has
been associated with headache but was not a risk fac-
tor for post-stroke headache at 3 years post-stroke.2
Additional vasodilatory medications associated with
headache may be indicated for comorbid coronary
artery disease or congestive heart failure, including
nitroglycerin or sacubitril.60
MANAGEMENT
There are no evidence-based guidelines for the treat-
ment of persistent post-stroke headache. Headache
associated with acute stroke is usually a self-limited
disorder that responds to simple analgesics.61 On the
other hand, persistent headache may be more chal-
lenging to manage. Secondary causes such as recur-
rent stroke, hemorrhage, cerebral venous thrombosis,
dissection, posterior reversible leukoencephalopathy
(PRES), reversible cerebral vasospasm (RCVS), infec-
tious and inflammatory processes should be consid-
ered in the appropriate clinical contexts.
Headache
It may be reasonable to treat persistent post-
stroke headache according to headache semiology,
although this approach lacks evidence. For instance,
persistent post-stroke headache with migrainous fea-
tures may be treated with similar strategies, although
without contraindicated vasoactive agents such as
triptans and dihydroergotamine (DHE). Choice of
migraine prophylaxis should consider stroke-related
comorbidities. Botulinum toxin A is indicated for
chronic migraine and is sometimes trialled in refrac-
tory tension-type headaches.62 Its role in persistent
post-stroke headache is unclear. Non-pharmacologic
strategies that may be effective in other post-stroke
pain syndromes including exercise, cognitive behav-
ioral therapy (CBT), and biofeedback are low-risk
strategies to consider for persistent post-stroke head-
ache. Cognitive behavioral therapy, proven bene-
ficial for management of mental health and certain
chronic pain conditions involves developing strategies
to problem solve and alter unhelpful thoughts and
beliefs.63 Biofeedback uses specific relaxation tech-
niques to help control certain autonomic-type func-
tions (such as heart rate, muscle tension, etc) in order
to reduce headache pain.64 Finally, it is reasonable to
screen patients for medication overuse (as defined by
the ICHD-3). Medication overuse is a treatable phe-
nomenon that may also worsen post-stroke headache.
FUTURE DIRECTIONS AND
RECOMMENDATIONS FOR COMMON DATA
ELEMENTS IN FUTURE RESEARCH
Further long-term prospective cohort studies are re-
quired to explore this entity of persistent post-stroke
headache. Although long-term follow-up data are
available for some post-stroke complications such as
anxiety, depression and fatigue, the natural history
of persistent post-stroke headache is poorly charac-
terized. Further, more research separating persistent
headache in patients with ischemic stroke and ICH is
needed, as these different subtypes may have distinct
risk factors, mechanisms, and prognoses.
Hansen et al. were the first to address the challenge
of attributing persistent headache to stroke.2 They
focused on the group of patients with “stroke-
attributed” headache who reported headache at both
stroke onset and at 3 years post-event. However, it is
unclear if these patients with acute stroke-headache
9
had persistence of this headache for 3 years, or if
the acute headache resolved, and another headache
disorder developed.
Ideally, headache characteristics would be
­recorded at onset and compared at various follow-up
points to identify the group that truly has a per-
sistent headache disorder that occurred around the
time of stroke. The ICHD-3 standardizes the tem-
poral definition for persistent post-stroke headache
to 3 months, allowing for more optimal comparison
between studies. Although patients with persistent
but delayed-onset headaches after stroke are not
included in this definition, it remains plausible that
delayed headaches may relate to stroke. However,
these patients should be reported as a separate group
in future studies. We also propose standardization of
the “acute” period to include 72 hours before and 7
days after stroke symptoms. “Delayed” onset head-
aches would then be defined as occurring more than
7 days after stroke.
Headache, like other post-stroke pain syndromes,
affects rehabilitation potential, functional outcome,
and quality of life.56 Like other forms of post-stroke
pain, post-stroke headache should be screened for in
stroke patients, acknowledged, and treated. In our clin-
ical experience, headache following stroke can cause
significant anxiety in stroke survivors, who may worry
that their headache is a harbinger of another stroke
event. Even in the absence of effective pain treatment,
reassurance that post-stroke headache is common, and
does not signify a new or imminent vascular event, can
alleviate distress.
Addressing this problem as a separate entity from
both (a) acute stroke-associated headache and (b)
other forms of post-stroke pain is the first step to an-
swering clinically relevant questions such as: (1) What
are the risk factors for transformation of acute head-
ache to persistent headache in stroke? (2) What is the
natural history and prognosis of persistent headache
after stroke? (3) How is persistent post-stroke head-
ache best treated?
CONCLUSION
Persistent post-stroke headache is a common issue that
is underrepresented in the current literature. It has only
recently been recognized this year as a separate entity
from acute stroke-attributed headache in the ICHD-3,
10
for certain stroke types. Further characterization of
its epidemiology, natural history, and options for ef-
fective treatment are unmet needs for stroke survivors.
Screening, acknowledgment, and therapy may lead to
improved rehabilitation outcomes and quality of life.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Joshua Lai, Thalia S. Field
(b) Acquisition of Data
Joshua Lai
(c) Analysis and Interpretation of Data
Joshua Lai
Category 2
(a) Drafting the Manuscript
Joshua Lai, Thalia S. Field
(b) Revising It for Intellectual Content
Rebecca A. Harrison, Alyson Plecash
Category 3
(a) Final Approval of the Completed Manuscript
Joshua Lai, Thalia S. Field, Rebecca A. Harrison,
Alyson Plecash
REFERENCES
1. Cephalalgia. Headache Classification Committee
of the International Headache Society (IHS). The
International Classification of Headache Disorders.
2018;38:1-211.
2. Hansen AP, Marcussen NS, Klit H, et al. Development
of persistent headache following stroke: A 3-year fol-
low-up. Cephalalgia. 2015;35:399-409.
3. Hansen AP, Marcussen NS, Klit H, et al. Pain fol-
lowing stroke: A prospective study. Eur J Pain.
2012;16:1128-1136.
4. Tentschert S, Wimmer R, Greisenegger S, et al.
Headache at stroke onset in 2196 patients with isch-
emic stroke or transient ischemic attack. Stroke.
2005;36:e1-3.
5. Vestergaard K, Andersen G, Nielsen M, et al.
Headache in stroke. Stroke. 1993;24:1621-1624.
6. Arboix A, Grau-Olivares M, Garcia-Eroles L,
et al. Clinical implications of headache in lacu-
nar stroke: Relevance of site of infarct. Headache.
2006;46:1172-1180.
XX 2018
7. Arboix A, Garcia-Trallero O, Garcia-Eroles L,
et al. Stroke-related headache: A clinical study
in lacunar infarction. Headache. 2005;45:
1345-1352.
8. Ferro JM, Melo T, Guerreio M. Headache in in-
tracerebral hemorrhage survivors. Neurology.
1998;50:203-207.
9. Verdelho A, Ferro JM, Melo T, et al. Headache in
acute stroke. A prospective study in the first 8 days.
Cephalalgia. 2008;28:346-354.
10. Mitsias PD, Ramadan NM, Levine SR, et al. Factors
determining headache at onset of acute ischemic
stroke. Cephalalgia. 2006;26:150-157.
11. Kumral E, Bougousslavsky J, Van Melle G, et
al. Headache at stroke onset: The Lausanne
Stroke Registry. J Neurol Neurosurg Psychiatry.
1995;58:490-492.
12. Paciaroni M, Parnetti L, Sarchielli P, et al. Headache
associated with acute ischemic stroke. J Headache
Pain. 2001;2:25-29.
13. Arboix A, Oliveres M, Titus A. Headache in acute
cerebrovascular disease: A prospective clinical study
in 240 patients. Cephalalgia. 1994;14:37-40.
14. Chen PK, Chiu PY, Tsai IJ, et al. Onset headache
predicts good outcome in patients with first-ever
ischemic stroke. Stroke. 2013;44:1852-1858.
15. Koudstaal P, van Gijn J, Kappelle L. Headache in
transient or permanent cerebral ischemia. Stroke.
1991;22:754-759.
16. Kropp P, Holzhausen M, Kolodny E, et al. Headache
as a symptom at stroke onset in 4,431 young isch-
aemic stroke patients. Results from the “Stroke in
Young Fabry Patients (SIFAP1) study.” J Neural
Transm. 2013;120:1433-1440.
17. Evans RW, Mitsias PD. Headache at onset of acute
cerebral ischemia. Headache. 2009;49:902-908.
18. Cheng Y-C, Kuo K-H, Lai T-H. A common cause of
sudden and thunderclap headaches: Reversible cere-
bral vasoconstriction syndrome. J Headache Pain.
2014;15:1-10.
19. Melo T, Pinto AN, Ferro JM. Headache in intracere-
bral hematom. Neurology. 1996;47:494-500.
20. Mitsias PD, Ramadan NM. Headache in ischemic
cerebrovascular disease. Part I: Clinical features.
Cephalalgia. 1992;12:269-274.
21. Klit H, Finnerup NB, Overvad K, et al. Pain fol-
lowing stroke: A population-based follow-up study.
PLoS One. 2011;6:e27607.
22. Naess H, Lunde L, Brogger J, et al. Post-stroke pain
on long-term follow-up: The Bergen stroke study. J
Neurol. 2010;257:1446-1452.
Headache
23. Jonsson AC, Lindgren I, Hallstrom B, et al.
Prevalence and intensity of pain after stroke: A popu-
lation based study focusing on patients’ perspectives.
J Neurol Neurosurg Psychiatry. 2006;77:590-595.
24. Widar M, Samuelsson L, Karlsson-Tivenius S, et al.
Long term pain conditions after stroke. J Rehabil
Med. 2002;34:165-170.
25. Koopman K, Uyttenboogaart M, Vroomen PC, et
al. Long-term sequelae after cerebral venous throm-
bosis in functionally independent patients. J Stroke
Cerebrovasc Dis. 2009;18:198-202.
26. Ferro JM, Canhao P. Cerebral venous sinus throm-
bosis: Update on diagnosis and management. Curr
Cardiol Rep. 2014;16:523.
27. Schytz HW, Ashina M, Magyari M, et al. Acute
headache and persistent headache attributed to cer-
vical artery dissection: Field testing of ICHD-III
beta. Cephalalgia. 2014;34:712-716.
28. Leys D, Moulin T, Stojkovic T, et al. Follow-up of
patients with history of cervical artery dissection.
Cerebrovasc Dis. 1995;5:43-49.
29. Metso TM, Tatlisumak T, Debette S, et al. Migraine
in cervical artery dissection and ischemic stroke pa-
tients. Neurology. 2012;78:1221-1228.
30. Jamieson DG, Cheng NT, Skliut M. Headache and
acute stroke. Curr Pain Headache Rep. 2014;18:444.
31. Mitsias PD, Ramadan NM. Headache in ischemic
cerebrovascular disease. Part II: Mechanisms and
predictive value. Cephalalgia. 1992;12:341-344.
32. Seifert CL, Schonbach EM, Magon S, et al. Headache
in acute ischaemic stroke: A lesion mapping study.
Brain. 2016;139(Pt 1):217-226.
33. Schmidt-Wilcke T, Leinisch E, Straube A, et al. Gray
matter decrease in patients with chronic tension type
headache. Neurology. 2005;65:1483-1486.
34. Kim JH, Suh SI, Seol HY, et al. Regional grey mat-
ter changes in patients with migraine: A voxel-based
morphometry study. Cephalalgia. 2008;28:598-604.
35. Bendtsen L, Fernandez-de-la-Penas C. The role
of muscles in tension-type headache. Curr Pain
Headache Rep. 2011;15:451-458.
36. Appelros P. Prevalence and predictors of pain and
fatigue after stroke: A population-based study. Int J
Rehabil Res. 2006;29:329-333.
37. Peres M, Zukerman E, Young W, et al. Fatigue
in chronic migraine patients. Cephalalgia.
2002;22:720-724.
38. Antonaci F, Nappi G, Galli F, et al. Migraine and
psychiatric comorbidity: A review of clinical find-
ings. J Headache Pain. 2011;12:115-125.
11
39. Hackett ML, Yapa C, Parag V, et al. Frequency of
depression after stroke: A systematic review of obser-
vational studies. Stroke. 2005;36:1330-1340.
40. Campbell Burton CA, Murray J, Holmes J, et al.
Frequency of anxiety after stroke: A systematic re-
view and meta-analysis of observational studies. Int
J Stroke. 2013;8:545-559.
41. Lerdal A, Bakken LN, Kouwenhoven SE, et al.
Poststroke fatigue-a review. J Pain Symptom Manage.
2009;38:928-949.
42. Duncan F, Wu S, Mead GE. Frequency and natural
history of fatigue after stroke: A systematic review
of longitudinal studies. J Psychosom Res. 2012;73:
18-27.
43. Wu S, Barugh A, Macleod M, et al. Psychological as-
sociations of poststroke fatigue: A systematic review
and meta-analysis. Stroke. 2014;45:1778-1783.
44. Sagen U, Vik TG, Moum T, et al. Screening for
anxiety and depression after stroke: Comparison
of the hospital anxiety and depression scale and the
Montgomery and Asberg depression rating scale. J
Psychosom Res. 2009;67:325-332.
45. Aben I, Verhey F, Lousberg R, et al. Validity of the
Beck depression inventory, hospital anxiety and de-
pression scale, SCL-90, and Hamilton depression
rating scale as screening instruments for depression
in stroke patients. Psychosomatics. 2002;43:386-393.
46. Meader N, Moe-Byrne T, Llwellyn A, et al. Screening
for poststroke major depression: A meta-analysis
of diagnostic validity studies. J Neurol Neurosurg
Psychiatry. 2013;1-9.
47. Gainotti G, Azzoni A, Razzano C, et al. The post-
stroke depression rating scale: A test specifically
devised to investigate affective disorders of stroke
patients. J Clin Exp Neuropsychol. 1997;19:340-356.
48. Mead G, Lynch J, Greig C, et al. Evaluation of fatigue
scales in stroke patients. Stroke. 2007;38:2090-2095.
49. Lerdal A, Kottorp A. Psychometric properties of the
Fatigue Severity Scale-Rasch analyses of individual
responses in a Norwegian stroke cohort. Int J Nurs
Stud. 2011;48:1258-1265.
50. Johnson KG, Johnson DC. Frequency of sleep apnea
in stroke and TIA patients: A meta-analysis. J Clin
Sleep Med. 2010;6:131-137.
51. Dyken ME, Somers VK, Yamada T, et al.
Investigating the relationship between stroke and
obstructive sleep apnea. Stroke. 1996;996:401-407.
52. Ramachandran SK, Josephs LA. A Meta-analysis of
clinical screening tests for obstructive sleep apnea.
Anesthesiology. 2009;110:928-939.
12
53. Bassetti C, Aldrich MS, Chervin RD, et al. Sleep
apnea in patients with transient ischemic attack and
stroke: A prospective study of 59 patients. Neurology.
1996;47:1167-1173.
54. Harrison RA, Field TS. Post stroke pain:
Identification, assessment, and therapy. Cerebrovasc
Dis. 2015;39(3-4):190-201.
55. Kalichman L, Ratmansky M. Underlying pathology
and associated factors of hemiplegic shoulder pain.
Am J Phys Med Rehabil. 2011;90:768-780.
56. Hettiarachchi C, Conaghan P, Tennant A, et al.
Prevalence and impact of joint symptoms in people
with stroke aged 55 years and over. J Rehabil Med.
2011;43:197-203.
57. Cirillo M, Stellato D, Lombardi C, et al. Headache
and cardiovascular risk factors: Positive association
with hypertension. Headache. 1999;39:409-416.
58. Chai NC, Scher AI, Moghekar A, et al. Obesity
and headache: Part I–a systematic review of the
epidemiology of obesity and headache. Headache.
2014;54:219-234.
XX 2018
59. Fuchs FD, Gus M, Moreira LB, et al. Headache is
not more frequent among patients with moderate
to severe hypertension. J Hum Hypertens. 2003;17:
787-790.
60. Menendez JT. The mechanism of action of LCZ696.
Cardiac Failure Review. 2016;2:40.
61. Balami JS, Chen R-L, Grunwald IQ, et al.
Neurological complications of acute ischaemic
stroke. Lancet Neurol. 2011;10:357-371.
62. Diener HC, Dodick DW, Aurora SK, et al.
OnabotulinumtoxinA for treatment of chronic mi-
graine: Results from the double-blind, randomized,
placebo-controlled phase of the PREEMPT 2 trial.
Cephalalgia. 2010;30:804-814.
63. Eller-Smith OC, Nicol AL, Christianson JA.
Potential mechanisms underlying centralized pain
and emerging therapeutic interventions. Front Cell
Neurosci. 2018;12:35.
64. Thomas DA, Maslin B, Legler A, et al. Role of al-
ternative therapies for chronic pain syndromes. Curr
Pain Headache Rep. 2016;20:29.