Current Pain and Headache Reports (2021) 25: 80

https://doi.org/10.1007/s11916-021-00995-8

SECONDARY HEADACHE (M ROBBINS, SECTION EDITORS)

Updates in the Diagnostic Approach of Headache

Thien Phu Do1 · Nikolaj Folke la Cour Karottki1 · Messoud Ashina1,2,3,4

Accepted: 4 October 2021 / Published online: 11 December 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review In this review, we summarize updates in the diagnostic approach of headaches with the aim of facilitating
the distinction between primary and secondary etiology in headaches.
Recent Findings In the USA, headache is the fifth most common complaint in the emergency department, but only a minority
will have a secondary etiology. Initial suspicion and diagnostic workup of secondary headache relies on a patient’s medical
history due to a scarcity of validated biomarkers. A special interest group under the International Headache Society recently
synthesized information on red flags (information that indicates a secondary etiology) and green flags (information that
indicates a primary etiology). A systematic diagnostic approach using red flags and green flags can help reduce unnecessary
testing and shift attention to patient care.
Summary Going forward, further validation of these concepts is needed to properly introduce them for clinical use.

Keywords Headache · Emergency department · Red flag · Green flag · SNNOOP10 · Primary · Secondary ·
Neuroimaging · Lumbar puncture · Biomarker

Abbreviations for presentation to the emergency department; a pattern

CT Computerized tomography which has remained consistent over the past decade [3]. Only
ICHD International Classification of Headache a minority of these cases of headache will have a secondary
Disorders etiology, and as a result, wastage will occur due to unneces-
MRI Magnetic resonance imaging sary referrals to further diagnostic workup. For instance,
SNNOOP10 A mnemonic covering 15 red flags in less than 6% of neuroimaging conducted due to headache
headache in emergency departments in the USA reveal pathological
findings [4]. Furthermore, not every relevant pathology can
Introduction
be detected with neuroimaging or biochemistry due to scar-
city of validated biomarkers. As such, the initial suspicion
Headache is a leading contributor to global disease burden
and diagnostic workup of secondary headache rely on the
and negative changes in health-adjusted life expectancy [1,
medical history. In principle, these unnecessary escalations
2]. In the USA, headache is the fifth most common reason
could be prevented if reliable and cost-effective screening
This article is part of the Topical Collection on Secondary procedures were used during the initial clinical presentation.
Headache However, such validated algorithms are not yet available for
general headache and exist only for specific indications, e.g.,
* Messoud Ashina
[email protected] thunderclap headache and subarachnoid hemorrhage. One
difficulty with the development of validated algorithms is
1
Danish Headache Center, Department of Neurology, that most of the literature on secondary headache is largely
Rigshospitalet Glostrup, Faculty of Health and Medical based on case series of patients with a known etiology, and
Sciences, University of Copenhagen, Copenhagen, Denmark
it is challenging to run large prospective multicenter studies.
2
Danish Knowledge Center On Headache Disorders, Glostrup, Recently, a special interest group under the International
Denmark
Headache Society, an organization of healthcare providers
3
Department of Nervous Diseases of the Institute who are professionally involved in the study and manage-
of Professional Education, IM Sechenov First Moscow State
Medical University, Moscow, Russia
ment of headache disorders, synthesized data on red flags
4
(information that indicate a secondary etiology) and green
Department of Neurology, Azerbaijan Medical University,
Baku, Azerbaijan
flags (information that indicate a primary etiology) [5••,

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6•]. In this review, we summarize updates in the diagnostic is needed. Nevertheless, a secondary headache disorder
approach of headache with a focus on red flags and green is suspected more often than detected. Even with the use
flags with the aim of facilitating the distinction between pri- of red flags, neuroimaging of patients presenting with red
mary and secondary etiology in headache. flags often reveals no clinically relevant findings [14, 15].
Several initiatives have over time sought to improve the
Methods use and detection rate of red flags in headache. Two dec-
ades ago, the SNOOP mnemonic (systemic symptoms/
We searched MEDLINE for articles published from data- signs and disease, neurologic symptoms or signs, onset
base inception up to May 1, 2021. We used the search sudden or onset after the age of 40 years, and change
terms “headache” with the terms “primary,” “secondary,” of headache pattern) was promoted as a systematic red
“red flags,” and/or “green flags.” Publications were largely flag detection tool in clinical practice [16]. National and
selected from the past 5 years but commonly referenced, and regional guidelines have since provided other potential
highly regarded older publications were not excluded. Ref- screening items [5••]. A special interest group under the
erence lists of relevant primary articles, reviews, and book International Headache Society reviewed and synthesized
chapters were also reviewed to identify studies that may have this information, which has led to the updated SNNOOP10
been missed in the search process. list of red flags for secondary headaches (Table 1) [5••].
The SNNOOP10 list covers 15 red flags in headache, their
Epidemiology related secondary etiology, and contextualizes usage with
brief clinical information. Unfortunately, large case series
In a survey conducted by the World Health Organization in of patients with a known secondary headache generally
2011, neurologists globally estimate 18% of individuals with form the basis of many red flags [5••], which only allows
headache have a secondary etiology [7]. The actual propor- for the sensitivity to be known, while specificity and
tion of patients with a secondary headache depends on sev- predictivity are unknown. Consequently, much remains
eral factors including level of systems of care (e.g., tertiary unclear as large-scale prospective studies are lacking.
headache center vs. emergency department) and whether the
headache is a chronic or acute condition. In a Norwegian
population-based study of individuals aged 30–44 years old, Green Flags
the 1-year prevalence of a chronic secondary headache was
2.14% [8]. In more selective clinic-based cohorts, the pro- To date, no studies have identified reliable biomarkers for
portion is higher; two studies conducted at tertiary headache primary headache disorders in humans. As an alternative, the
centers reported proportions ranging from ~13 to ~20% of concept of green flags was introduced in 2021 [6•]. Green
individuals with headache [9, 10]. Headache is one of the flags are information indicative of a primary headache dis-
most common reasons for visits to the emergency depart- order. Since red flags are not pathognomonic for their related
ment in the USA; however, only ~2% of these cases are disorders, the absence of these does not exclude a secondary
secondary to pathology in the central nervous system [4]. etiology, and green flags must be screened in addition to red
Evidently, this number depends on the characteristics of the flags. The purpose of red flags and green flags is different.
headache with estimates of > 14% for sudden onset severe The aim of red flags is to have a high sensitivity for a second-
headache (thunderclap headache) [11–13]. Nonetheless, ary headache; the higher the sensitivity, the lower the num-
less than 6% of neuroimaging conducted due to headache in ber of missed cases. Conversely, the aim of green flags is to
emergency departments in the USA reveal pathological find- have a high specificity; the higher the specificity, the higher
ings [4]; likewise, only 11% of patients in the same cohort the number of identified primary headache disorders with-
who underwent lumbar puncture due to headache received out overlooking a secondary cause. The presence of a green
a pathological diagnosis [4]. In general, there is much room flag with a high specificity increases the likelihood of a pri-
for improvement in assessing which patients with headache mary headache disorder. The same International Headache
should be referred to further investigations. Society special interest group presented a list of green flags
in secondary headache derived through the Delphi method
Red Flags (SNNOOP10) (Table 2) [6•]. In parallel with the SNNOOP10 list of red
flags, these green flags need to be validated in prospective
Red flags are information indicative of a secondary etiol- studies as they in the end derive from expert opinion [6•].
ogy. The presence of red flags should encourage the clini- Nonetheless, they may be used in cases where the clinician
cian to initiate further investigations while the absence of needs reassurance that the headache is a primary headache
red flags may indicate that no further diagnostic workup disorder in the absence of red flags.

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 Table 1  The SNNOOP10 list of red flags for secondary headaches
Sign or symptom Related secondary etiology Key points

1 Systemic symptoms including fever Headache attributed to infection or non-vascular intracranial Headache with fever is primarily alarming when accompa-
disorders, carcinoid, or pheochromocytoma nied by relevant symptoms (e.g., neck stiffness, decreased
consciousness, and neurologic deficit)
2 Neoplasm in history Neoplasms of the brain; metastasis A newly developed headache in a patient with neoplasm is
highly suspect for an intracranial metastasis
3 Neurological deficit or dysfunction (including decreased Headaches attributed to vascular, non-vascular intracranial Headache occurs in one-fourth of episodes of acute stroke.
consciousness) disorders The severity of headache is not related to the size of the
Brain abscess and other infections lesion
4 Onset of headache is sudden or abrupt (thunderclap head- Subarachnoid hemorrhage and other headaches attributed to Thunderclap headache can be the only initial symptom of
ache) cranial or cervical vascular disorders subarachnoid hemorrhage
5 Older age (after 50 years) Giant cell arteritis and other headache attributed to cranial or Older individuals with headache have a higher frequency of
Current Pain and Headache Reports (2021) 25: 80

cervical vascular disorders secondary etiology. The incidence of primary headache

Neoplasms and other non-vascular intracranial disorders disorders is also lower in this age group
6 Pattern change or recent onset of headache Neoplasms, headaches attributed to vascular, non-vascular A recent change of pattern or a newly developed headache can
intracranial disorders be the only signs of a secondary etiology. Diagnosis is often
delayed in these cases
7 Positional headache Intracranial hypertension or hypotension Positional headache is the trademark of intracranial hypoten-
sion, and the most common cause is cerebrospinal fluid leak
at the spinal level
8 Precipitated by sneezing, coughing or exercise Posterior fossa lesions, Chiari malformation Cough headache is highly predictive of Chiari malformations
and posterior fossa lesions
9 Papilledema Neoplasms and other non-vascular intracranial disorders; A high prevalence of patients with papilledema has a serious
intracranial hypertension underlying pathology
10 Progressive headache and atypical presentations Neoplasms and other non-vascular intracranial disorders Progressive headache and atypical headache presentation can
be the only signs of serious underlying pathology
11 Pregnancy or puerperium Headaches attributed to cranial or cervical vascular disor- Headache during pregnancy and puerperium has a higher risk
ders; post-dural puncture headache; hypertension related of severe pathology. More than one-third of individuals pre-
disorders (e.g., preeclampsia); cerebral venous thrombosis; senting to acute care with headache during pregnancy will
hypothyroidism; anemia; diabetes have a secondary etiology. Most common causes are hyper-
tensive disorders followed by pituitary adenoma or stroke
Other risk factors are no prior headache history, occurring
during third trimester, seizures, hypertension, and fever
12 Painful eye with autonomic features Pathology in posterior fossa, pituitary region or cavernous Patients with presentations of painful eye with autonomic
sinus features should undergo neuroimaging as it can be due to a
Tolosa-Hunt syndrome structural lesion. Even typical presentations of cluster head-
Ophthalmic causes ache (or other trigeminal autonomic cephalalgias) can derive
from a structural lesion
13 Posttraumatic onset of headache Acute and chronic posttraumatic headache; subdural hema- Headache related to trauma should always be explored
toma and other headache attributed to vascular disorders

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Diagnostic Workup

Red flags are information that encourages further investigation of a secondary etiology. Reference: Do TP, Remmers A, Schytz HW, Schankin C, Nelson SE, Obermann M, Hansen JM, Sinclair
AJ, Gantenbein AR, Schoonman GG. Red and orange flags for secondary headaches in clinical practice: SNNOOP10 list. Neurology. 2019 Jan 15;92(3):134–144. https://​doi.​org/​10.​1212/​WNL.​
Risk of severe pathology is dependent on the degree of immu-

Medication overuse is the most common cause of secondary

headache. Onset of headache due to a new drug can be a
A thorough medical history is the most important diagnostic
tool for headache as individuals with headache often have
no abnormal findings during their physical examination. In
most cases, patients will have a primary headache disor-
sign of incompatibility with the given drug der; however, serious secondary pathology should always
be excluded [4]. This should be seen in the context of that
secondary etiology can be indistinguishable from and mimic
primary headache disorders with significant overlap in symp-
tomatology, e.g., in a clinic-based study of 111 consecutive
individuals with a primary or metastatic intracranial tumor,
the phenotype of the headache was tension-type headache-
nosuppression

like in 77%, migraine-like in 9%, and other in 14% [17]. An

isolated clinical presentation of headache in a patient with
Key points

a brain tumor is rare, but as it often meets the diagnostic

criteria for a primary headache, this raises the importance
of assessing accompanying symptoms [18]. Furthermore,
patients may simultaneously have a primary headache dis-
order and new onset of a secondary cause, emphasizing
the need for a thorough investigation. Using a standardized
Medication overuse headache; drug incompatibility

approach for headache diagnosis likely reduces the risk of

overlooking a secondary etiology (Fig. 1), improves care,
and reduces costs through wastage avoidance.
It is recommended that all new patients with headache
undergo screening with the SNNOOP10 list as this will
presumably increase the likelihood of detecting a second-
Related secondary etiology

ary etiology. Patients should be inquired about a thorough,

Opportunistic infections

chronological description of onset, severity, frequency,

duration, location, characteristics, and associated symp-
toms. This should be accompanied by asking questions
about systemic symptoms, medication use, familial dis-
positions, and previous medical history. Individuals with
a pre-existing primary headache disorder should be care-
fully evaluated for change in headache patterns or fre-
quency. There can be several pitfalls when trying to obtain
Pathology of the immune system such as AIDS (acquired
immunodeficiency syndrome)) or medical immunosup-

a thorough history. Patients may have varying degrees of

insight into their symptoms and often need to be asked sys-
Painkiller overuse or new drug at onset of headache

tematically in a direct or visual manner. The terminology

“thunderclap” in thunderclap headache already implies an
instantaneous onset, but patients can simply refer to the
first perceived sensation of headache regardless of sever-
ity. Since the change from pain-free to painful often will be
considered as sudden, it is essential to inform patients that
sudden onset in this case means the progression from no
headache to maximum intensity, either from onset or within
00000​00000​006697 [5••]

a minute; this could be visualized with a handclap or other

Sign or symptom

cues to represent an instantaneous onset. It may also be rel-

Table 1  (continued)

evant to determine the circumstances in which the headache

pression

occurred and how it affected current or daily tasks, further

giving an indication of associated symptoms, or exacerbat-
ing factors. Patients with a pre-existing primary headache
can be challenging, but a general approach is to interview
14

15

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Table 2  Proposed green flags for secondary headaches

Sign or symptom Key points

1 The current headache has already been present during childhood Viral infections are the most common cause of secondary headache
in children. In children with chronic headache, the pain is rarely
secondary. A life-threatening headache is very unlikely in adults
in whom that headache type has already been present during
childhood
2 The patient has headache-free days Most primary headache disorders are paroxysmal. Although
recurring secondary headache also occur, they are often caused
by trigger factors, such as injury to the head, cerebral ischemia,
intracranial hemorrhage, arteritis, arterial dissection, or exposure
to a substance, e.g., phosphodiesterase inhibitors or nitric oxide
donors. An important exception is intracranial tumors that can
also present with recurring headache
3 The headache occurs in temporal relationship with the menstrual The relationship between pain and menstrual cycle has been
cycle validated with a headache diary. Migraine attacks associated with
fluctuations in the menstrual cycle is common
4 Close family members have the same headache phenotype There is a genetic disposition to migraine, cluster headache, and
medication overuse headache. The prevalence of genetic vascu-
lopathies is lower than the beforementioned headache disorders
5 Headache occurred or stopped more than 1 week ago Life-threatening secondary headache generally present within few
days. Consequently, the more time passed since the headache, the
smaller the probability of a life-threatening cause. However, time
passed since onset is unlikely to influence the likelihood of other
non-life-threatening secondary causes, e.g., temporomandibular
disorder, persistent post-traumatic headache

Green flags are information that may suggest that no further investigations for a secondary etiology are needed. Reference: Pohl H, Do TP,
García-Azorín D, Hansen JM, Kristoffersen ES, Nelson SE, Obermann M, Sandor PS, Schankin CJ, Schytz HW, Sinclair A, Schoonman GG,
Gantenbein AR. Green Flags and headache: A concept study using the Delphi method. Headache. 2021 Feb;61(2):300–309. https://​doi.​org/​10.​
1111/​head.​14054 [6•]

how the new headache may or may not differ from their of a secondary etiology is very low when combined with
usual phenotype. Asking what prompted a patient to seek the absence of red flags [20, 21]. If a secondary etiology
help from healthcare professionals at the specific moment has been excluded, it is good clinical practice to diagnose
can often clarify relevant deviations. the type of primary headache disorder or initiate relevant
As the absence of a red flag does not rule out a second- workups and follow-ups, e.g., starting a headache diary. This
ary cause, patients who do not have red flags in the initial can be daunting due to the many different possible diagno-
evaluation should be screened for green flags and whether ses, but it should be kept in mind that tension-type headache
diagnostic criteria for a primary headache disorder are met and migraine account for most presentations of headache
according to the International Classification of Headache [22, 23].
Disorders (ICHD) [19]. The recently proposed green flags
can be used to increase the likelihood of a primary pathol- Clinical Implications
ogy. In the absence of red flags and the presence of green
flags, the pre-test probability of a primary cause is higher Further work to improve and validate this diagnostic
than a secondary etiology, and patients can be symptomati- approach will enable clinicians, particularly in primary
cally treated in the acute phase and referred for further diag- care, to correctly assess and refer patients with headache.
nostic evaluation later. In the case of absence of both red In Europe, estimates project that primary care can meet
and green flags without fulfilment of ICHD-criteria for a the needs of 90% of patients consulting for headache [24].
primary headache disorder, a concerned clinician should Approximate 10% of cases will require referral to special-
consider consulting a senior colleague or specialist (Fig. 1). ist care; only 1% will require referral to tertiary care in
In primary care, this systematic approach can help when countries who offer these services. As such, most headache
deciding whether to refer patients to specialist care for fur- care should be initiated and maintained in primary care to
ther workup. Furthermore, since fulfilling the ICHD-criteria optimize resource usage. However, patients with headache
of a primary headache disorder is highly indicative of the consulting primary care continue to be affected by diagnostic
disease even in an emergency department setting, the chance delay and misdiagnosis [7]. A similar pattern is observed

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Fig. 1  Usage of red flags

(SNNOOP10) and green
flags in clinical practice. The
SNNOOP10 list can be used to
screen patients with headache
for red flags. Absence of red
flags indicates a primary head-
ache disorder if ICHD-3 criteria
are fulfilled and/or a green flag
is present. ICHD International
Classification of Headache
Disorders

among specialists; in an international survey of neurolo- sensitivity [26]. Initial MRI, in the absence of thunderclap
gists, explicit diagnostic criteria are only used in 56% of headache or trauma, is both easier to compare to follow-up
cases [7]. More than a quarter of individuals with migraine scans and limits overuse of neuroimaging overall. How-
revisit the emergency department within 6 months, a fre- ever, the average cost of neuroimaging conducted with
quency which can be reduced with targeted interventions MRI in the USA is US$517 [27]. Up to 50% of referred
[25]. A more systematic diagnostic approach is needed for patients will have positive findings on neuroimaging, but
resource optimization, as this constitutes the basis for clini- only a minority, ~0.5%, have clinically significant findings
cal management. if the primary reason for referral is headache. As such, the
Red and green flags can be used by clinicians at all cost per clinically significant finding for neuroimaging for
levels and are with a little practice not time-consuming. headache has been estimated up to US$34,535. By providing
They may also work to increase the awareness of sec- the means to accurately categorize headache and improve
ondary headaches in patients where further evaluation is stratification of referrals to neuroimaging, the burden on
indicated. As the prevalence of primary headaches is high the healthcare system is likely to be reduced. In the USA,
compared to secondary headaches, a systematic approach patients without insurance or presenting during the evening,
using red and green flags can help reduce unnecessary test- night-time, or weekends are less likely to be scanned, and
ing and shift attention to treating the patient adequately. a systematic tool to evaluate the need for further investi-
Diagnostic workups can be expensive and time consuming, gation may lead to a better distribution of these resources
depending on the modality used and further exacerbated [4]. Furthermore, patients will avoid unnecessary tests
by the low number of positive findings. Neuroimaging is and scans, which are not always harmless or painless, and
essential in diagnosing many secondary headaches, but in anxiety due to eventual incidental findings. Finally, while
cases of limited accessibility, better approaches are needed the radiation exposure of non-contrast CT scans of the
to evaluate the need for scans. Computerized tomography head is rather low, an abundant use of CT scans can result
(CT) scans are the gold standard in excluding subarach- in an increased amount of unnecessary exposure. This is
noid hemorrhage or skull fractures in the acute setting, of particular concern for children and young adults, where
but most other secondary causes of headache warrant a it can accumulate and increase the risk of malignancy later
follow-up magnetic resonance imaging (MRI) due to higher in life [28, 29].

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Current Pain and Headache Reports (2021) 25: 80 Page 7 of 8 80

Conclusions and Future Perspectives References

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