To describe the frequency and number of
premonitory symptoms (PS) in migraine, the
co-occurrence of different PS, and their
association with migraine-related factors.
In this cross-sectional study, a validated
questionnaire was sent to Finnish migraine
families between 2002 and 2013 to obtain data on
14 predefined PS, migraine diagnoses,
demographic factors, and migraine
characteristics. The estimated response rate was
Out of 2714 persons, 2223 were diagnosed
with migraine. Among these, 77% reported PS,
with a mean number of 3.0 symptoms compared to
30% (p<0.001) and 0.5 symptoms (p<0.001)
among 491 persons with non-migraine headaches.
Yawning was the most commonly reported symptom
(34%) among migraineurs. Females reported PS
more frequently than males (81 versus 64%,
p<_0.001) and experienced a higher number of
different symptoms (mean 3.3 versus 1.8,
p<0.001). All measures of migraine severity
were associated with a higher burden of PS.
Light and sound sensitivity showed the highest
co-occurrence (kappa_=0.51, 95% CI 0.47-0.55).
In a generalized linear model, age, gender,
higher frequency, duration and intensity of
headache, reduced working capacity, most aura
symptoms, and associated symptoms of the
headache phase were significantly associated
with an increased in the number of PS.
PS are experienced by a majority of
migraineurs. More severe migraine is associated
with a higher burden of PS. Since the material
was not entirely representative of the general
population of migraineurs, caution should be
exercised in generalizing the results.
Migraine is the most common neurological
disease and is characterized by intermittent
headache accompanied by nausea, vomiting,
photophobia, and phonophobia (1). The
premonitory symptoms (PS) of migraine are
defined forewarning of a migraine attack by 2-48
hours, occurring before the aura in migraine
with aura and before the onset of pain in
migraine without aura,'' with fatigue, elation,
depression, unusual hunger, and craving for
certain foods given as examples (1). However,
various PS and timespans have been used in
previous studies (2-8).
The pathophysiologic basis to the PS is
incompletely understood, but the involvement of
hypothalamic and dopaminergic mechanisms has
been suggested (9,10). Recently, glyceryl
trinitrate has been used to provoke
migraine-like attacks as well as PS, allowing
them to be studied directly, which might
increase our insight into the pathophysiology of
Previous studies have reported that between
8% and 87% of adult migraineurs (4-7) and 67% of
child migraineurs (8) experience PS. Varying
study populations and definitions of PS might
have contributed to the wide range of reported
In a prospective study, it was shown that,
in migraineurs with PS, the onset of headache
attacks can be pre- dicted several hours in
advance (3). Early treatment guided by PS might
be beneficial (13,14). Our objectives were to
determine the frequency and number of PS among
persons from Finnish migraine families, to
explore the co-occurrence of different PS, and
to examine the association between PS and age,
gender, and migraine characteristics.
This study is, to date, the largest study of
PS, including altogether 2714 persons with
headache. The frequency of PS of 77% among
migraineurs in this material is within the
previously reported range of 8-87% (4-7),
comparable to the frequency found in 100 persons
seek- ing a general practitioner for migraine
headache (84%) (5) and 374 migraine patients
from a neurology out- patient clinic (87%) (7),
but higher than in a study of 484 migraineurs in
the general population (8%) (4) and 893 at a
tertiary care clinic (33%) (6). Among the 137
persons below 18 years of age, the frequency of
PS was 71%, which is in line with a previous
report of 67% in 103 pediatric-adolescent
migraine patients (8). The mean number of
different PS per person of 3.0 out of a possible
14 is similar to a previously reported mean of
3.2 symptoms out of 12 (7).
The most commonly reported individual
symptoms in the present study, namely
yawning, mood changes, lethargy, neck
symptoms, and light sensitivity, have all
previously been shown to be frequent, with some
vari- ation between studies (3,5-8).
As expected, PS were more than twice as
common in migraine headaches as in non-migraine
headaches. Persons with MwA reported PS
significantly more often and experienced a
higher number of PS compared to those with MwoA,
which has not been reported pre- viously
(4,5,7,8). The differences were much larger
between the subtypes of MwA, with hemiplegic
migraine having by far the highest frequency and
number of PS. This is in agreement with
hemiplegic migraine being at the very end of the
spectrum of migraine severity.
Sound and light sensitivity showed the
highest co-occurrence, which might represent a
common origin, as both symptoms are aspects of
sensory hypersensitivity. Yawning showed a high
co-occurrence with several other symptoms; for
instance, lethargy, craving, and mood changes.
In a previous study exploring co-occurrences of
PS, associations between these symptoms were not
as strong as those between depression and
irritability, concentration problems, and
All measures of severity (frequency,
duration, inten- sity, working capacity, attacks
requiring bed rest, and presence of associated
symptoms) were related to a higher burden of PS.
This is in accordance with clinical impressions
and previous findings that severe pain is
associated with a higher number of PS than
mild-moderate pain (5) and that those who
experience PS have a longer duration of headache
and more nausea (i.e. more is more in migraine)
(6). These factors also significantly and
greatly affected the PS as predictors in the
regression analyses. An unpredicted exception
was that scintillating scotoma was associated
with a lesser burden of PS.
In this material, a relatively large number
of participants reported a typical headache
duration of less than 4 hours. This may be due
to the large number of children (in whom a
shorter duration is more common) (16), the
effects of successful treatment, or the
uncertainty of self-reported time estimates. In
addition, the ICHD criteria for MwA do not
include a minimum duration (1).
The number of PS differed across age groups
and age was a significant predictor in both
regression analyses. Previously, in smaller
studies, age has not been asso- ciated with PS
As in this study, females have been
associated with a higher number of PS previously
(7), while there have been no gender differences
in other studies (4-6,8). In the generalized
linear model, females reported a 16% higher
number of PS. Females have a higher prevalence
of migraine and more severe migraines than males
(17), thus our findings might be explained by a
stronger migraine phenotype in females.
Strengths of the study include the vast
material, the large pediatric-adolescent subset,
and ample information on other characteristics
of the migraines.
In terms of the limitations of the study,
firstly, the material did not represent the
general population because the questionnaire was
only distributed to migraine patients and their
relatives. While the study population did
consist of persons from a wide range of ages
with both genders being well represented, our
sampling strategy caused the material to be
skewed towards those with a larger hereditary
burden and more severe migraine, which was shown
in that MwA was more common than MwoA and in
that hemiplegic migraine was considerably more
prevalent than expected, at approximately
one-tenth of all migraineurs compared to an
estimated 1 in 10,000 in the general population
However, this allowed us to study the
relationship between PS and measurements of
migraine severity across their entire
Secondly, retrospective questions have the
drawback of potential recall bias and lack the
prospective recordings of the frequency and
temporal aspects of the symptoms. We did not
determine the frequency of the symptoms we
considered to be PS during headache-free
intervals, which is more readily done with a
prospective approach, and this might have led to
an overestimation of their rate, as several such
symptoms have been shown also to be common
outside the migraine attack (5).
Furthermore, all of the PS in the study were
prede- fined, which could result in a lower
reported frequency than with open questions in
which participants are able to add their other
observed symptoms. For instance, ''face
changes'', which in a previous report was the
most common individual PS among children, was
not included (8). However, open questions might
have introduced unspecific symptoms and been
unfavorable for determining co-occurrences.
In conclusion, PS are experienced by
a majority of migraineurs, more commonly in
females. A higher burden of PS is associated
with a more severe migraine. Thus, further
understanding of the pathophysiology of the
premonitory phase is desired to enable the
development of specific therapy for this early
phase of migraine that might alleviate the
. Increased knowledge of the occurrence of
premonitory symptoms (PS) could help in
understanding the pathophysiologic basis of
. Among 2223 individuals with migraine, 77%
. More severe migraine was associated with a
higher burden of PS.
1. Headache Classification Committee of the
International Headache Society. The
International Classification of Headache
Disorders, 3rd edition (beta version).
Cephalalgia 2013; 33: 629-808.
2. Houtveen JH and Sorbi MJ. Prodromal
functioning of migraine patients relative to
their interictal state - an ecological momentary
assessment study. PLoS One 2013; 8: e72827.
3. Giffin NJ, Ruggiero L, Lipton RB, et al.
Premonitory symptoms in migraine: an electronic
diary study. Neurology 2003; 60: 935-940.
4. Russell MB, Rasmussen BK, Fenger K, et
al. Migraine without aura and migraine with aura
are distinct clinical entities: a study of four
hundred and eighty-four male and female
migraineurs from the general population.
Cephalalgia 1996; 16: 239-245.
5. Quintela E, Castillo J, Munoz P, et al.
Premonitory and resolution symptoms in migraine:
a prospective study in 100 unselected patients.
Cephalalgia 2006; 26: 1051-1060.
6. Kelman L. The premonitory symptoms
(prodrome): a tertiary care study of 893
migraineurs. Headache 2004; 44: 865-872.
7. Schoonman GG, Evers DJ, Terwindt GM, et
al. The prevalence of premonitory symptoms in
migraine: a ques- tionnaire study in 461
patients. Cephalalgia 2006; 26: 1209-1213.
8. Cuvellier JC, Mars A and Vallee L. The
prevalence of premonitory symptoms in paediatric
migraine: a ques- tionnaire study in 103
children and adolescents. Cephalalgia 2009; 29:
9. Alstadhaug KB. Migraine and the
hypothalamus. Cephalalgia 2009; 29:
10. Akerman S and Goadsby PJ. Dopamine and
migraine: biology and clinical implications.
Cephalalgia 2007; 27: 1308-1314.
11. Afridi SK, Kaube H and Goadsby PJ.
Glyceryl trinitrate triggers premonitory
symptoms in migraineurs. Pain 2004; 110:
12. Maniyar FH, Sprenger T, Monteith T, et
al. Brain acti- vations in the premonitory phase
of nitroglycerin- triggered migraine attacks.
Brain 2014; 137: 232-241.
13. Cady RK, Voirin J, Farmer K, et al. Two
center, rando- mized pilot study of migraine
prophylaxis comparing paradigms using
pre-emptive frovatriptan or daily topir- amate:
research and clinical implications. Headache
2012; 52: 749-764.
14. Luciani R, Carter D, Mannix L, et al.
Prevention of migraine during prodrome with
naratriptan. Cephalalgia 2000; 20: 122-126.
15. Kallela M, Wessman M and Farkkila M.
Validation of a migraine-specific questionnaire
for use in family studies. Eur J Neurol 2001; 8:
16. Laurell K, Larsson B and Eeg-Olofsson O.
Prevalence of headache in Swedish
schoolchildren, with a focus on ten- sion-type
headache. Cephalalgia 2004; 24: 380-388.
17. Buse DC, Loder EW, Gorman JA, et al. Sex
differences in the prevalence, symptoms, and
associated features of migraine, probable
migraine and other severe headache: results of
the American Migraine Prevalence and Preven-
tion (AMPP) study. Headache 2013; 53:
18. Lykke Thomsen L, Kirchmann Eriksen M,
Faerch Romer S, et al. An epidemiological survey
of hemiplegic migraine. Cephalalgia 2002; 22: