Brain & Development xxx (2022) xxx–xxx

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The diagnostic values of red flags in pediatric patients with headache

Eu Gene Park a, Il Han Yoo b,⇑
a
Department of Pediatrics, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 56, Dongsu-ro, Bupyeong-gu,
Incheon 21431, Republic of Korea
b
Department of Pediatrics, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, 93, Joongbudae-ro, Paldal-gu,
Suwon-si, Gyeonggi-do 16247, Republic of Korea

Received 22 December 2021; received in revised form 8 April 2022; accepted 17 April 2022

Abstract

Background: Headache is a common complaint in childhood and adolescence. Differentiating benign primary headaches from
ominous secondary headaches is often difficult. Clinicians usually seek red flags to determine the need for neuroimaging. We aimed
to evaluate the diagnostic values of red flags in pediatric headaches.
Methods: We retrospectively reviewed the medical records of 1510 pediatric patients (1470 with primary headache, 40 with sec-
ondary headache) presenting with headache and underwent neuroimaging from two centers between March 2010 and December
2019.
Results: The secondary-headache group exhibited significantly higher frequencies of abnormal neurologic signs/symptoms
(40.0% vs 6.8%, p < 0.001), Valsalva maneuver/exercise-induced headache (15.0% vs 4.9%, p = 0.004), headache with vomiting
(35.0% vs 17.9%, p = 0.006), and onset under age 6 (25.0% vs 10.3%, p = 0.003) than the primary-headache group, with the follow-
ing positive likelihood ratio (PLR): 5.88, 3.06, 1.96, and 2.42, respectively. The sensitivity values were as follows: abnormal neuro-
logic signs/symptoms (16/40, 40.0%), headache with vomiting (14/40, 35.0%), onset under age 6 (10/40, 25.0%), and Valsalva
maneuver/exercise-induced headache (6/40, 15.0%). The overall sensitivity for ominous secondary headaches requiring surgical
treatment was 86.2% (25/29).
Conclusions: Certain red flags, including abnormal neurologic signs/symptoms, Valsalva maneuver/exercise-induced headache,
headache with vomiting, and onset under age 6, were more prevalent in the secondary-headache group; nonetheless, their sensitivity
values and PLR were relatively low. Notwithstanding, considering these red flags’ high overall sensitivity for ominous secondary
headaches, neuroimaging in patients presenting these red flags should rely on careful follow-up of symptom progression.
Ó 2022 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

Keywords: Headache; Children; Red flags; Neuroimaging; Computed tomography; Magnetic resonance imaging

1. Introduction adolescence [1,2]. The vast majority of pediatric head-

Headache is a common complaint in children and
adolescents, prompting referral to pediatric neurolo-
gists. The prevalence of headache in children ranges
from 37.0% to 51.0% and increases gradually during
⇑ Corresponding author.
E-mail address: dr_yooilhan@hanmail.net (I.H. Yoo).
aches are due to a primary headache disorder, such as
migraine and tension-type headaches, or due to sec-
ondary conditions related to respiratory infections
[3,4]. The incidences of brain tumors and other sinister
intracranial abnormalities requiring emergent identifica-
tion among children with headaches are considerably
low, ranging from 0.5% to 1.0% [3,5,6].

https://doi.org/10.1016/j.braindev.2022.04.008
0387-7604/Ó 2022 The Japanese Society of Child Neurology Published by Elsevier B.V. All rights reserved.

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Although serious or life-threatening causes of head-
ache in children are uncommon, neuroimaging studies
are frequently performed in clinical practice due to par-
ental anxiety and clinicians’ uncertainty regarding the
possibility of significant underlying structural lesions
[7]. However, neuroimaging is costly and entails the risk
of incidental findings, potentially leading to superfluous
testing and interventions as well as unwarranted patient
and parental concerns [8]. Furthermore, the overuse of
computed tomography (CT) may lead to unnecessary
radiation exposure, potentially inducing fatal malignan-
cies at an estimated rate of between 1 in 1000 and 1 in
5000 CT scans [9,10]. Magnetic resonance imaging
(MRI) may require procedural sedation, despite its asso-
ciated risks, and prove more time consuming and costly
to perform than other imaging modalities.
Red flags are clinical warning signs or symptoms that
suggest the requirement for neuroimaging studies to
identify secondary causes of headache [11]. Clinical
experience and large case studies of patients with specific
secondary headache disorders provide the basis for red
flags and direct clinicians toward conducting a thorough
investigation when red flags are present. However,
despite the use of red flags, most neuroimaging studies
reveal no significant abnormal findings. In a prospective
study of 3,655 patients with headache [12], red flags were
used to determine whether a patient should undergo
neuroimaging or not. After screening, 530 (14.5%)
patients underwent neuroimaging, and only 11 exhibited
significant abnormalities (2.1% of those imaged and
0.3% of the study population). Furthermore, data
regarding the choice of red flags to be used in determin-
ing the requirement for neuroimaging in pediatric head-
aches are limited.
In this study, we aimed to evaluate the diagnostic val-
ues of red flags in pediatric headaches to enable the
appropriate selection of candidates requiring neu-
roimaging, thus minimizing unnecessary testing.
2. Materials and methods
We performed a retrospective medical chart review of
pediatric patients who presented with headache and
underwent neuroimaging at Incheon St. Mary’s Hospi-
tal (Incheon, Korea) and St. Vincent’s Hospital (Suwon,
Korea), respectively. Subjects were recruited between
March 2010 and December 2019. Patients with systemic
diseases involving fever, known intracranial lesion, or
history of recent head trauma within the preceding
3 months were excluded. All neuroimaging studies were
interpreted by neuroradiologists at each institution.
Data obtained included age, sex, duration, location,
headache character and intensity, pain-relieving and
aggravating factors, history of headache coupled with
vomiting, additional symptoms, analgesic usage, preex-
isting illnesses, family history of migraine, neurologic
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examination findings, and neuroimaging results. Pain
intensity was measured using the visual analog scale.
Patient records were evaluated for the following 12
red flags: 1) recent onset (<6 months) of severe head-
ache; 2) change in headache type or pattern; 3) occipital
headache; 4) existence of atypical aura, such as hemiple-
gia, vertigo, lower cranial nerve symptoms, or visual dis-
tortion; 5) headache accompanied by vomiting; 6)
headache on awakening from sleep at night; 7) headache
on or soon after awakening in the morning; 8) headache
precipitated by Valsalva maneuver or exercise; 9) the
presence of abnormal neurologic signs or symptoms;
10) lack of response to medical therapy; 11) onset at
<6 years of age; and 12) lack of family history of
migraine.
Headaches were classified according to the Interna-
tional Classification of Headache Disorders, Third Edi-
tion (ICHD-3), proposed by the Committee of the
International Headache Society [13]. If a headache did
not clearly match a defined type of headache, it was
included under unclassified headaches. According to
the underlying cause of headache, patients were divided
into the following two groups: 1) primary-headache
group and 2) secondary-headache group. Differences in
the prevalence of red flags were compared between the
two groups. In addition, the prevalence of secondary
headache was assessed according to the frequency of
red flags.
All statistical analyses were performed using SPSS
21.0 for Windows (IBM Corp., Armonk, NY, USA).
Numerical data, including age, were compared using
Student’s t-test or the Mann–Whitney test. Categorical
data, such as the clinical characteristics of headache as
well as the distribution and frequency of red flags, were
analyzed using Fisher’s exact test or the chi-square test.
Fisher’s exact test was used when >20% of cells had
expected frequencies of < 5. Statistical significance was
set at p < 0.05. Additionally, to assess the validity and
reliability of red flags, we estimated their sensitivity,
specificity values and positive likelihood ratio (PLR) in
patients harboring more than one red flag.
2.1. Ethics
Ethical approval for this retrospective study was pro-
vided by the Institutional Review Board of the Catholic
Medical Center (IRB XC20WADI0010). The need for
informed consent was waived due to the retrospective
nature of this study.
3. Results
3.1. Patient characteristics
Of 4,032 patients who presented to the hospital with a
headache between March 2010 and December 2019,
 E.G. Park, I.H. Yoo / Brain & Development xxx (2022) xxx–xxx 3

1,510 pediatric patients (669 males and 841 females, modalities, and headache characteristics, including loca-
37.5%) underwent neuroimaging. The median age at tion, character, and clinical course prior to the neu-
the initial visit was 11 years (interquartile range (IQR), roimaging study.
8–14). Of the 1,510 patients, 1,460 patients exhibited The overall percentage of abnormal neuroimaging
more than one red flag, while 273 patients (18.1%) had findings that required treatment alterations was 2.0%
one, 496 (32.8%) had two, 390 (25.8%) had three, and (30/1,510 patients). Of the 30 patients, 29 (96.7%) under-
301 (19.9%) presented with more than four red flags. went surgery based on neuroimaging findings, and they
The remaining 50 patients (3.3%) underwent neuroimag- included 14 (48.3%) with brain tumor, 12 (41.4%) with
ing upon parental or physicians’ demands. Neuroimag- Moyamoya disease, and three (10.3%) with arteriove-
ing studies included brain MRI (n = 1089, 72.1%) and nous malformation. The remaining patient (3.4%) was
head CT (n = 421, 27.9%). Of the 1,510 patients, diagnosed with multiple sclerosis and received methyl-
1,470 (97.4%) presented with primary headache and 40 prednisolone pulse therapy.
(2.6%) with secondary headache. The most common pri-
mary diagnoses were migraine without aura (n = 599, 3.2. Distribution of red flags between the primary- and
40.7%), followed by unclassified headache (n = 533, secondary-headache groups
36.3%), tension-type headache (n = 203, 13.8%), and
migraine with aura (n = 135, 9.2%). The most common A comparison of red flags between patients with pri-
secondary diagnoses were brain tumor (ICHD-3 code 7; mary headache and those with secondary headache is
n = 14, 35%), followed by Moyamoya disease (ICHD-3 shown in Table 3. Patients with secondary headache
code 6; n = 12, 30%), sinusitis (ICHD-3 code 11; n = 8, exhibited significantly higher frequencies of abnormal
20%), and arteriovenous malformation (ICHD-3 code 6; neurologic signs or symptoms (40% vs 6.8%,
n = 3, 7.5%). The three remaining patients were diag- p < 0.001), headache accompanied by vomiting (35%
nosed with communicating hydrocephalus (ICHD-3 vs 17.9%, p = 0.006), headache precipitated by Valsalva
code 7), chronic subdural hematoma (ICHD-3 code 6), maneuver or exercise (15% vs 4.9%, p = 0.004), and
and multiple sclerosis (ICHD-3 code 7) (Table 1). The onset of headache at <6 years of age (25% vs 10.3%,
demographic and clinical characteristics of the p = 0.003) than those with primary headache. No signif-
primary-headache and secondary-headache groups are icant differences were observed between the two groups
shown in Table 2. The median age at the initial visit regarding headache characteristics, pattern change in
was 11 years (IQR, 8–14) and 8.5 years (IQR, 5.5–11) headache, the presence of atypical aura, headache on
in the primary and secondary headache groups, respec- awakening from sleep, morning headache, response to
tively (p < 0.001). No statistically significant between- medical therapy, and positive family history of migraine.
group differences were observed in sex, neuroimaging With regard to the presence of neurologic signs or
symptoms, patients with secondary headache had a sig-
nificantly higher proportion of those with abnormal
Table 1 neurologic examination findings, including papilledema,
Patient characteristics. asymmetric cranial nerve or motor function, ataxia, and
Number of patients a positive Romberg test (p = 0.020). The secondary-
(n = 1510) headache group exhibited a significantly greater likeli-
Male, n (%) 669 (44.3%) hood of having experienced a recent onset of double
Age (years) at initial visit, median 11 (8–14) vision or decreased visual acuity (p = 0.008) than the
(interquartile range) primary-headache group. The proportion of patients
Neuroimaging modalities
who experienced transient loss of consciousness was sig-
Computed tomography 421 (27.9%)
Magnetic resonance imaging 1,089 (72.1%) nificantly higher in the primary-headache group than in
Types of headaches the secondary-headache group (p = 0.039). No statisti-
Primary headache (n = 1,470, 97.4%) cally significant differences were observed between the
Migraine without aura 599 (40.7%) two groups in other transient or subjective neurologic
Unclassified 533 (36.3%)
symptoms, including motor weakness, sensory change,
Tension-type headache 203 (13.8%)
Migraine with aura 135 (9.2%) movement symptom, unsteadiness, dysarthria or sen-
Secondary headache (n = 40, 2.6%) sory aphasia, and hearing impairment, within 6 months
Brain tumor 14 (35.0%) prior to the visit (Table 3).
Moyamoya disease 12 (30.0%) The red flags’ sensitivity and specificity values were as
Sinusitis 8 (20.0%)
follows: negative family history of migraine (sensitivity
Arteriovenous malformation 3 (7.5%)
Communicating hydrocephalus 1 (2.5%) 80.0%, specificity 30.5%), the presence of abnormal neu-
Chronic subdural hematoma 1 (2.5%) rologic signs or symptoms (sensitivity 40.0%, specificity
Multiple sclerosis 1 (2.5%) 93.2%), recent onset of severe headache (sensitivity
37.5%, specificity 59.7%), headache accompanied by

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Table 2
Comparison of demographic and clinical characteristics of headache between the primary- and secondary-headache groups.
Primary headache Secondary headache (n = 40) p value
(n = 1,470)
Male, n (%)a 652 (44.4%) 17 (42.5%) 0.816
Age (years) at initial visit, median (interquartile range)b 11 (8–14) 8.5 (5.5–11) < 0.001
Neuroimaging modalities
Computed tomographya 413 (28.1%) 8 (20.0%) 0.260
Magnetic resonance imaginga 1,057 (71.9%) 32 (80.0%) 0.260
Clinical course
Acute (3 months)a 264 (18.0%) 11 (27.5%) 0.123
Acute recurrent (3 months)a 391 (26.6%) 10 (25.0%) 0.821
Chronic progressive (>3 months)a 400 (27.2%) 9 (22.5%) 0.508
Chronic nonprogressive (>3 months)a 408 (27.8%) 10 (25.0%) 0.701
Not availablec 8 (0.5%) 0 0.896
Localization
Frontala 269 (18.3%) 12 (30.0%) 0.061
Temporala 479 (32.6%) 9 (22.5%) 0.178
Parietalc 114 (7.8%) 1 (2.5%) 0.360
Occipitala 191 (13.0%) 6 (15.0%) 0.710
Not localized (diffuse)c 229 (15.6%) 3 (7.5%) 0.188
Region not mentioneda 366 (24.9%) 9 (22.5%) 0.729
Character
Throbbinga 356 (24.2%) 9 (22.5%) 0.802
Sharpc 81 (5.5%) 0 0.270
Crampingc 12 (0.8%) 0 1.00
Pricklingc 125 (8.5%) 4 (10.0%) 0.771
Constant/dullc 14 (1.0%) 0 1.00
Pressurec 258 (17.6%) 4 (10.0%) 0.290
Othersc 176 (12.0%) 2 (5.0%) 0.220
a
Chi-square test was used.
b
Independent t-test was used.
c
Fisher’s exact test was used.

vomiting (sensitivity 35.0%, specificity 82.1%), headache
on or soon after awakening in the morning (sensitivity
35.0%, specificity 77.8%), pattern change in headache
(sensitivity 25.0%, specificity 71.2%), onset at <6 years
of age (sensitivity 25.0%, specificity 89.7%), headache
on awakening from sleep (sensitivity 20.0%, specificity
83.9%), poor response to analgesics (sensitivity 17.5%,
specificity 87.1%), headache precipitated by Valsalva
maneuver or exercise (sensitivity 15.0%, specificity
95.1%), occipital headache (sensitivity 10.0%, specificity
88.6%), and the presence of atypical aura (sensitivity
7.5%, specificity 95.3%). The overall sensitivity of cer-
tain red flags, including abnormal neurologic signs or
symptoms, Valsalva maneuver or exercise-induced head-
ache, headache with vomiting, and onset under age 6,
for sinister secondary headaches which required surgical
treatment was estimated at 86.2% (25/29).
As shown in Table 3, the red flags yielding the highest
PLR for secondary headache were as follows: the pres-
ence of abnormal neurologic signs or symptoms (5.88,
95% confidence interval (CI): 3.56–8.65), followed by
headache precipitated by Valsalva maneuver or exercise
(3.06, 95% CI: 1.02–5.91), onset at <6 years of age (2.42,
95% CI: 1.20–3.94), and headache accompanied by vom-
iting (1.96, 95% CI: 1.14–2.87). Of the 116 patients with
abnormal neurologic signs or symptoms, a considerably
greater PLR (29.4, 95% CI: 7.02–172.21) was observed
in patients exhibiting abnormalities on neurologic exam-
ination (n = 9), except for those with transient or subjec-
tive neurologic symptoms with normal neurologic
examinations (n = 107). The PLR of the remaining
red flags for secondary headache were as follows: the
presence of atypical aura (1.60, 95% CI: 0.05–3.91),
headache on or soon after awakening in the morning
(1.58, 95% CI: 0.93–2.30), poor response to analgesics
(1.35, 95% CI: 0.55–2.41), headache on awakening from
sleep (1.25, 95% CI: 0.52–2.11), negative family history
of migraine (1.15, 95% CI: 0.95–1.32), recent onset of
severe headache (0.93, 95% CI: 0.57–1.32), occipital
headache (0.88, 95% CI: 0.21–1.88), and pattern change
in headache (0.87, 95% CI: 0.43–1.38). The overall PLR
of certain red flags, including abnormal neurologic signs
or symptoms, Valsalva maneuver or exercise-induced
headache, headache with vomiting, and onset under
age 6, for ominous secondary headaches which required
surgical treatment was estimated at 2.44 (95% CI: 2.00–
2.80).
Patients with secondary headache exhibited a signifi-
cantly greater likelihood of presenting with more than
four red flags than those with primary headache

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Table 3
Distribution of red flags between the primary- and secondary-headache groups.
Primary Secondary headache p value Positive likelihood ratio
headache (n = 40)
(n = 1,470)
Recent onset (<6 months) of severe headachea 593 (40.3%) 15 (37.5%) 0.718 0.93
Change in headache type or patterna 424 (28.8%) 10 (25.0%) 0.596 0.87
Occipital headacheb 168 (11.4%) 4 (10.0%) 1.00 0.88
Headache with atypical aurab 69 (4.7%) 3 (7.5%) 0.435 1.60
Headache accompanied by vomitinga 263 (17.9%) 14 (35.0%) 0.006 1.96
Headache awakening from sleep at nighta 236 (16.1%) 8 (20.0%) 0.504 1.25
Headache on or soon after wakening in the morninga 326 (22.2%) 14 (35.0%) 0.055 1.58
Precipitated by Valsalva maneuver or exercisea 72 (4.9%) 6 (15.0%) 0.004 3.06
Lack of response to medical therapya 190 (12.9%) 7 (17.5%) 0.397 1.35
Onset at <6 years of agea 152 (10.3%) 10 (25.0%) 0.003 2.42
Lack of family history of migrainea 1,022 (69.5%) 32 (80.0%) 0.154 1.15
Presence of abnormal neurologic signs or symptomsa 100 (6.8%) 16 (40.0%) <0.001 5.88

Abnormal neurologic examinationb 5 (5.0%) 4 (25.0%) 0.020

Focal motor weaknessc 32 (32.0%) 5 (31.3%) 0.952
Sensory changec 24 (24.0%) 2 (12.5%) 0.518
Seizurec 3 (3.0%) 1 (6.3%) 0.452
Movement symptomc 9 (9.0%) 0 0.357
Episode of loss of consciousnessc 23 (23.0%) 0 0.039
Unsteadinessc 0 1 (6.3%) 0.138
Double vision or decreased visual acuityc 1 (1.0%) 3 (18.8%) 0.008
Dysarthria or sensory aphasiac 1 (1.0%) 0 1.00
Hearing impairmentc 2 (2.0%) 0 1.00
a
Chi-square test was used.
b
Papilledema, asymmetric cranial nerve/motor function, ataxia, positive Romberg test.
c
Within 6 months prior to visit.

(37.5% vs 19.5%, p = 0.005). On the other hand, the pro- Table 4

portion of patients having one red flag was significantly Comparison of the number of red flags between the primary- and
secondary-headache groups.
higher in the primary-headache group (18.4% vs 5.0%,
p = 0.034) (Table 4). Among the 15 patients harboring Primary headache Secondary headache p value
(n = 1,470) (n = 40)
more than four red flags, negative family history of
migraine (13/15, 86.7%), headache on or soon after 0b 50 (3.4%) 0 0.399
1b 271 (18.4%) 2 (5.0%) 0.034
awakening in the morning (10/15, 66.7%), the presence
2a 487 (33.1%) 9 (22.5%) 0.158
of abnormal neurologic signs or symptoms (9/15, 3a 376 (25.6%) 14 (35.0%) 0.179
60.0%), and headache accompanied by vomiting (9/15, 4a 286 (19.5%) 15 (37.5%) 0.005
60.0%) were frequently observed. The proportions of a
Chi-square test was used.
patients presenting with the remaining red flags were b
Fisher’s exact test was used.
as follows: headache on awakening from sleep (7/15,
46.7%), recent onset of severe headache (7/15, 46.7%),
headache precipitated by Valsalva maneuver or exercise neuroimaging without detecting anything of clinical rel-
(5/15, 33.3%), pattern change in headache (4/15, 26.7%), evance. We observed a high rate (1,460/1,510, 96.7%) of
occipital headache (3/15, 20.0%), poor response to anal- patients reported to have red flags, with a low rate
gesics (3/15, 20.0%), onset at <6 years of age (3/15, (29/1,460, 2.0%) of severe neuroimaging abnormalities
20.0%), and the presence of atypical aura (1/15, 6.7%). which required surgical treatment. This study demon-
strated that abnormal neurologic signs or symptoms,
4. Discussion headache triggered by Valsalva maneuver or exertion,
headache accompanied by vomiting, and onset at
This was a relatively large-scale study regarding the <6 years of age were significantly more frequent in
diagnostic values of red flags in pediatric headaches. patients with secondary headache, as previously
Clinicians usually search for red flags when they encoun- reported in other studies. One prominent finding in this
ter patients with headache to determine their eligibility study is that the sensitivity values and PLR of the afore-
for neuroimaging. However, despite the presence of mentioned red flags were relatively low, suggesting the
red flags, numerous patients with headache undergo undesirability of routine neuroimaging in children

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exhibiting these features. However, considering the
aforementioned red flags’ high overall sensitivity for
ominous secondary headaches requiring surgical treat-
ment (25/29, 86.2%), this study emphasizes that the
presence of any of these red flags should be interpreted
meticulously through careful clinical follow-up of symp-
tom progression.
In the present study, patients with abnormal neuro-
logic examinations or those with neurologic symptoms
yielded the highest PLR for secondary headache (5.88)
compared to those with other red flags. Furthermore,
we performed a detailed analysis of patient distribution
according to the presence of abnormalities on neuro-
logic examinations. No statistically significant differ-
ences were observed between primary and secondary
headaches in transient or subjective neurologic symp-
toms, including motor weakness, change in sensation,
movement symptom, seizure, unsteadiness, speech diffi-
culty, or hearing impairment, with normal neurologic
examinations. These results are potentially attributable
to the possibility that patients confused certain migraine
features with the aforementioned symptoms. In this
regard, the clinical follow-up of patients with headache
involving transient or subjective neurologic symptoms
and normal neurologic examinations over time can
safely replace neuroimaging. As regards seizures, previ-
ous studies found headache combined with the presence
of new-onset seizures to be an indication for neuroimag-
ing, contrary to our study [14,15]. The discordant find-
ings may be related to the relatively small sample size
of patients with secondary headache in the present
study. Nonetheless, a high prevalence of recent-onset
double vision or decreased visual acuity in patients with
secondary headache was noted in this study, suggesting
that patients with headache involving recent visual
symptoms should be promptly investigated to identify
the potential causes of the headache. Additionally,
except for patients with transient or subjective neuro-
logic symptoms with normal neurologic examinations,
a considerably higher PLR (29.4) was observed in
patients exhibiting abnormalities on neurologic exami-
nations. These results revealed that recognizing the pres-
ence of abnormalities on neurologic examinations
potentially serves as the strongest predictive factor for
severe underlying intracranial abnormalities, consider-
ing that neurologic examination is the most reliable,
accurate, and objective clinical tool for assessing neuro-
logic function. The current findings are consistent with
those of previous studies, which demonstrated that con-
ducting routine neuroimaging studies is not recom-
mended for children with recurrent headache and
normal neurologic examinations [16,17].
Headache triggered by Valsalva maneuver or exertion
and that accompanied by vomiting have been regarded
as warning signs of headache attributable to cranial or
vascular disorder [18–20]. Similar to previous studies,
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our study noted statistically significant differences in
the aforementioned features between the primary- and
secondary-headache groups. Notwithstanding, the
PLR of headache precipitated by Valsalva maneuver
or exertion and that coupled with vomiting were 3.06
and 1.96, respectively, and they were relatively lower
than the PLR of headache with abnormal neurologic
signs or symptoms (5.88). This can be partly ascribed
to the limited acquisition of precise information on chil-
dren and the possibility of including patients with typi-
cal features of migraine, such as headache aggravated
by physical activity or that accompanied by nausea
and vomiting.
This study demonstrated that the secondary-
headache group had a significantly higher proportion
of children with headache onset prior to 6 years of age
than the primary-headache group, thus corroborating
the findings of previous studies [19,21]. On the contrary,
Chu et al. [22] stated that headaches in young children
are usually benign, and neuroimaging studies produce
a considerably low yield in the absence of other neuro-
logic symptoms and findings. However, in preschool
children, taking a detailed history and performing a neu-
rologic examination can be challenging and limited due
to inadequate cooperation and comprehension of ques-
tions asked. In that regard, the relatively low PLR
(2.42) in this study is apparently attributable to the lim-
ited acquisition of accurate and reliable information
regarding pain in preschool children.
Our data revealed that red flags associated with a sig-
nificantly higher prevalence of secondary headache, such
as abnormal neurologic examinations or symptoms,
headache precipitated by Valsalva maneuver or exercise,
headache coupled with vomiting, and onset at <6 years
of age, had relatively low sensitivity values and PLR.
The results indicate that each of these red flags cannot
be used individually to indicate the requirement for neu-
roimaging studies and that routine neuroimaging studies
in patients with these features are not recommended.
Nevertheless, except for patients with sinusitis-related
headache, which is a non-ominous type of secondary
headache, the overall sensitivity and PLR of the afore-
mentioned red flags for sinister secondary headaches
were estimated at 86.2% and 2.44, respectively. This rel-
atively high sensitivity value implies that determining
the requirement for neuroimaging in patients with any
of these red flags should be based on the clinical
follow-up of symptom progression.
In general, occipital headaches tend to raise alarm
among clinicians [23]. Previous studies have demon-
strated that pediatric patients presenting to the emer-
gency department with occipital headaches were more
likely to be associated with sinister underlying pathology
[5,24]. However, in both studies, all patients with an
occipital location and severe intracranial disorder exhib-
ited abnormal findings on neurologic examination.
 E.G. Park, I.H. Yoo / Brain & Development xxx (2022) xxx–xxx
Other studies have also reported that the occipital loca-
tion of headache alone is not more likely to be associ-
ated with intracranial pathology than other headache
locations, in the absence of any remarkable history or
abnormalities on examination [25–27]. Our data rein-
force the assertion that occipital headache with a normal
neurologic examination does not increase the risk of sec-
ondary pathology. In addition, headache on awakening
or sleep interruption secondary to headache has often
been deemed a potential sign of raised intracranial pres-
sure by clinicians. This is attributed to lying flat during
sleeping, which exacerbates elevated intracranial pres-
sure overnight [28]. However, Ahmed et al. [29] found
headache on awakening or sleep interruption secondary
to headache among neurologically normal pediatric
patients to be predominantly associated with primary
headaches, particularly migraine or tension-type head-
aches. Lanphear et al. [30] also noted that a minority
of pediatric patients with brain tumors (13.8%) pre-
sented with morning headaches. Similarly, our study
also revealed that headache on awakening or headache
interrupting the patient’s sleep is unlikely to be caused
by sinister etiologies. Therefore, routine neuroimaging
should not be arranged for neurologically normal chil-
dren with morning headache or those with headache
on awakening from sleep. Other possible causes of head-
ache on awakening or headache wakening an individual
from asleep, including sleep apnea, nocturnal hyperten-
sion, hypoglycemia, and medication-overuse headache,
should also be ruled out [29].
We found the frequency of red flags to be signifi-
cantly higher in the secondary-headache group than in
the primary-headache group. Consistent with our
results, a previous study reported a positive correlation
between the number of red flags and the risk of a
space-occupying intracranial lesion [20]. This positive
correlation was also observed in a consortium study
[31], in which two-thirds of the children with brain
tumors exhibited three or more neurologic symptoms
at diagnosis. In addition, Rossi et al. [32] found a higher
number of red flags to be associated with a higher risk of
sinister etiology. Hence, in clinical practice, identifying
the number of red flags can be beneficial in distinguish-
ing secondary headache from primary headache and
avoiding unnecessary testing.
Overall, we found that a small proportion of patients
(30/1,510, 2.0%) had clinically important intracranial
findings identified by neuroimaging that required treat-
ment alterations. Consistent with our findings, Schwedt
et al. [33] found neuroimaging findings that necessitate a
change in management to be rare, approximately 1.2%,
in neurologically normal patients. Rho et al. [7] also
reported that the overall rate of imaging abnormalities
requiring a neurosurgical procedure was 0.91%. The
low rates of significant intracranial abnormalities on
neuroimaging in our data and previously published
Please cite this article in press as: Park EG, Yoo IH. The diagnostic values of red flags in pediatric patients with headache. Brain Dev (2022),
https://doi.org/10.1016/j.braindev.2022.04.008
Descargado para Anonymous User (n/a) en University El Bosque de ClinicalKey.es por Elsevier en mayo 15, 2022. Para uso personal
exclusivamente. No se permiten otros usos sin autorización. Copyright ©2022. Elsevier Inc. Todos los derechos reservados.
7
studies revealed that primary headaches, predominantly
migraine and tension-type headaches, are common in
the pediatric population.
This study has certain limitations. First, due to the
retrospective nature of the study, not all data were avail-
able, which may have resulted in underreporting if the
data were missed on chart review. Thus, in some
patients, the temporal relation between headaches, brain
lesions, and headache response after treatment, which
included communicating hydrocephalus and chronic
subdural hematoma, could not be investigated. This
could also be attributed to the limited acquisition of
accurate information from preschool children. Never-
theless, in other patients (38/40, 95%) with surgical
space-occupying lesions, cerebrovascular or demyelinat-
ing diseases, or rhinosinusitis, we confirmed the tempo-
ral relation between headaches, brain lesions, and
headache improvement after treatment. Second, because
the data were collected from two referral hospitals, the
findings may not be representative of the general popu-
lation. Thus, larger prospective studies or collaborative
trials are warranted to further elucidate the diagnostic
values of red flags in children presenting with headache.
In conclusion, the prevalence of sinister headaches
requiring surgical treatment was low (2.0%), even in
the presence of documented red flags (96.7%), demon-
strating that the presence of commonly suggested indi-
cations for neuroimaging in pediatric headaches does
not always provide a true warning. Although children
with certain red flags, such as abnormal neurologic
examinations or symptoms, headache precipitated by
Valsalva maneuver or exercise, headache coupled with
vomiting, and onset at <6 years of age, were more likely
to have secondary headache, the sensitivity values and
PLR of these features were relatively low. In that regard,
routine neuroimaging in children with these red flags is
undesirable. However, considering that the overall sensi-
tivity of these features for sinister secondary headaches
was high, we propose that neuroimaging in patients with
any of these red flags be determined based on the careful
follow-up of symptom progression.
Acknowledgements
Not applicable.
Conflict of interest disclosures
The authors declare no competing interests.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-for-
profit sectors.
8 E.G. Park, I.H. Yoo / Brain & Development xxx (2022) xxx–xxx
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