Abstract : The nosology of migraine
premonitory (PS) and resolution (RS) symptoms
was studied in 100 migraineurs consulting their
general physician. They were asked to fill in,
for three attacks, a PS and RS questionnaire.
'True' PS/RS were those experienced the day
before (or the day after) the headache had
started only if they were not present in a
questionnaire completed in a pain-free
period.
True PS and RS were experienced by 84% and
80%, respectively, of subjects for the first
attack. The mean and range (per patient) of PS
were 6.8 and 0-21 and of RS 4.7 and 0-15.
Anxiety, phonophobia, irritability, unhappiness
and yawning were the commonest PS,
whereas asthenia, tiredness, somnolence and
concentration difficulties were the most common
RS. Gender, age and Migraine Disability
Assessment scores did not influence PS and
RS.
Both PS and RS were more frequent in
migraine with aura subjects. Patients on
preventatives showed a decreased frequency of PS
and, to a lesser degree, of RS. Severity of
headache was associated with a higher frequency
of RS. Individual RS and especially PS were
quite consistent after three attacks. Almost
two-thirds of the symptoms were noticed in at
least two out of three attacks, while more than
a half of PS and more than a quarter of RS
repeated in three out of three attacks.
In conclusion, around 80% of unselected
migraineurs experience RS and PS. Migraine with
aura and severe pain are risk factors for
experiencing PS and RS, while preventatives were
protective, especially for PS.
Introduction
Migraine is a frequent disorder
characterized by attacks of unilateral,
pulsating headache often accompanied by a
constellation of non-headache symptoms, of which
nausea, phono- and photophobia are an
established part of the International Headache
Society (IHS) criteria for migraine diagnosis.
Leaving migraine aura aside, non-headache
symptoms have been associated with the three
stages of the attack: the premonitory symptoms
(PS), the headache and the resolution symptoms
(RS) phases.
Little attention has been paid to the
variety of PS preceding the headache phase,
while RS, though clinically recognized (9),
remain almost unstudied. In the 1980s, Blau
published the first results of a clinical
assessment of the PS. He studied 50 patients who
had only migraine without any additional
symptoms, such as tension-type headache. He
found that 17 patients had early PS, such as
mood changes, somnolence, changed mental state,
unusual appetite or fluid disregulations from 1
h to 1 day before the attack. He proposed the
term 'complete migraine' for those migraine
patients also experiencing PS. Isler has since
1970 evaluated the answers of 100 migraine
patients to the specific queries about prodromes
in his questionnaire. He found that 65 patients
had mentioned prodromes which were different
from focal aura symptoms, occurring from within
minutes to within several days before the
headache. In 1985, Waelkens described the
characteristic warning symptoms in 49 selected
migraine patients with 'complete migraine'.
Fewer than 10% of his patients spontaneously
reported the existence of PS symptoms. He
distinguished evolutive symptoms appearing from
a few minutes up to a few hours before the
headache and including visual aura from the
non-evolutive early warning symptoms beginning
up to 48 h before the attack, which he found in
88% of his patients. A 30-mg dose of
domperidone, but not an equivalent dose of
cisapride, a nonantidopaminergic stimulant of
gastrointestinal motility, taken at the first
appearance of the PS prevented two-thirds of the
attacks in a doubleblind, placebo-controlled
crossover study. The question of whether PS
accurately predict headache, with relevant
implications in the pathophysiology and
management of migraine, was addressed in 120
patients who reported PS that they believed
predicted migraine headache in at least two out
of three attacks. Using electronic diaries,
patients correctly predicted 72% of migraine
headaches (12). Finally, a retrospective review
of the frequency of PS in 893 headache patients
seen consecutively at a tertiary Headache Clinic
showed that 39.2% of 627 IHS migraine patients
had PS.
The heterogeneous studies reviewed above do
not allow us to define the actual frequency of
PS and especially of RS. In addition, it is far
from clear how clinically to classify PS and RS
and their nature and pattern. These vary
considerably among the different studies
regarding both the clinical pattern of these
symptoms and their number, which has ranged from
59 to 21 potential PS. One crucial point is that
many of these symptoms are experienced outside
of the attacks and none of these studies has
recorded the background to these symptoms
interictally. As an example, estimates for
fatigue in the general population are high,
around 35%. [n the only study analysing
migraine postctromes, a total of 255 RS were
reported by 40 migraineurs who were asked to
complete a questionnaire the day after the
attack.
To sum up, the few studies which have
examined PS and RS in migraine have been flawed
for many methodological reasons, such as
retrospective data collection, absence of
diaries, scarcity of patients, heterogeneous
classification or by the lack of interictal
testing. Our study was undertaken to clarify the
nosology of PS and RS in the standard migraine
patient.
Discussion
The present study is the first nosographic
analysis of migraine PS and RS in a group of
non-selected migraineurs after the appearance of
the revised IHS Classification. Key
methodological aspect of our study was that, to
be considered as true PS or true RS, we
carefully discounted, in the same patient, the
symptoms experienced by these subjects when they
were headache-free. No previous studies had
e recorded the background prevalence of
these symp:1 toms interictally, which could be
methodologically 10 compared to offering the
results of a clinical trial t without taking
into account a placebo arm. This approach turned
out to be crucial when interpreting e the final
results, as the frequency of some interictal
symptoms was in fact relevant. As shown in Table
1, symptoms such as asthenia, fatigue, anxiety,
speech difficulties, yawning or
irritability were referred to by 15% or more of
our patients in a headache-free period. The
questionnaire, comprising 28 items (see Table
1), included the PS symptoms already and
consistently described in the literature in
migraine patients. In order to avoid repetition
and to increase the clarity of results, we made
an effort not to include: items with the same
meaning (e.g. headache tension, headache
tightness), anecdotal PS (e.g. irritated by
collar, aversion from menstruation) or untrue PS
(e.g. pain above the eyes, typical aura), which
has been one of the reasons for the variability
of the results among previous studies.
Collection of exact information about migraine
PS and RS, however, is complicated by different
kinds of bias. Recording may be biased by the
individual's difficulties in describing
important characteristics, especially if the
patient is confused or sleeps during the attack,
and towards the more severe or recent episodes.
The present data were collected using a complete
and easy to answer questionnaire, but are
limited by the memory of the participants. In
this regard and to avoid including interictal
and not true PS, we decided to consider PS/RS
only those experienced by the patient the 24 h
before/after the headache had started. Even
though PS have been described several days
before the headache phase, most PS have been
shown to occur up to 24 h before the
aura/headache phases appear (1-4). This was
confirmed in the prospective electronic diary
study, where most headaches were predicted
within 24 h, in spite of a 72-h limit for PS
(12).
This study shows that both PS and RS are
very prevalent and numerous in migraine attacks.
Even after discounting headache-free symptoms
and considering the 24-h period, PS and RS were
noticed in 84% and 80% of the attacks,
respectively. The average was seven PS and five
RS per migraine attack (1, 16). The prevalence
of RS is largely unknown, while the prevalence
of PS in previous studies has ranged from 7% to
88%, depending largely on study methodology
(1-8, 12). Even though the symptoms were
collected after 24 h and not exactly
prospectively with electronic diaries, the high
frequency of the symptoms found here probably
reflects our improved methodology, with specific
and immediate data collection, a clear and easy
questionnaire and experienced together with
personalized interview. Anxiety, phonophobia,
irritability, unhappiness and yawning
were the most common PS, being noticed in
between almost one-half and more than one-third
of the attacks, whereas asthenia and tiredness
and, to a lesser degree, somnolence and
concentration difficulties were the most common
RS. We arbitrarily grouped the individual
symptoms into four categories: neuropsychiatric
(encompassing 'pure' psychiatric symptoms),
sensory (symptoms due to 'neurological'
hypersensitivity), digestive and general.
Neuropsychiatric (82%) were the most frequent
PS, while general (69%) were the most frequent
RS.
These data illustrate differences in the
clinical profile of RS compared with PS,
probably reflecting different pathophysiological
mechanisms, at least for some of these symptoms.
Of interest is the high proportion of symptoms
typically associated with the headache phase,
such as nausea, phono- and photophobia, in the
premonitory phenomenon continuing through to the
resolution phase. Assuming that PS are an
integral part of a migraine attack and taking
into account the PS profile, these results agree
with the proposal that an attack probably begins
with a rather diffuse cerebral disturbance,
which spreads to the hypothalamus or to the
brainstem dopaminergic nuclei (19, 20) and
carries on through the headache and into the
resolution phase, giving clinical weight to
evidence of electrophysiological changes
beginning 24 h before the headache.
Neurophysiological techniques have shown
interictal loss of cognitive
habituation which increases continuously
during the migraine interval until sudden
normalization on the first day of the attack.
Other studies have shown an increase in early
contingent negative variation amplitude the day
before an attack which is associated with
changes in EEG power spectrum from 4 days before
the attack. This increasing interictal
abnormality in cortical hyperexcitability may
reflect a neurophysiological readiness to
generate an attack and an increasing
susceptibility of the migrainous brain to
precipitating factors. A further study has shown
normalization of visual and auditory evoked
potentials just before and during migraine
attacks compared with interictally, which may
represent the brain's attempt to abort the
impending attacks by activation of appropriate
sensory-modulating systems.
Individual RS, and especially PS, were quite
consistent after three attacks. Almost
two-thirds of the symptoms were noticed in at
least two out of the three attacks, while more
than one-half and a quarter of PS and RS,
respectively, repeated in three out of three
attacks. This high consistency agrees with
previous data obtained in more selected migraine
patients and may allow us to investigate in more
detail the therapeutic potential for the
management of migraine in the premonitory phase.
Non-randomized trials have suggested that
naratriptan and dopamine antagonists may be
effective in preventing the development of
migraine attacks when given during the PS phase.
There is also evidence that the dopamine
antagonist domperidone can prevent migraine, but
only if taken at least 6 h before the expected
attack. The type of symptoms reported may also
give us some insight into migraine
pathophysiology. For example, excessive
yawning, which is associated with
dopamine release, was one of the most common and
consistent PS, which again suggests that
dopaminergic mechanisms, possibly involving
brainstem nuclei, may play a role in the
premonitory phase.
With regard to the influence of clinical and
demographic variables, gender, age, severity of
headache and MIDAS scores did not clearly
influence the frequency or the profile of PS.
Even though the global numbers were not
significant due to the low proportion of aura
attacks in this series, migraine with aura
patients experienced more PS and RS than
migraine without aura patients. Interestingly,
the individual symptoms which were significantly
more frequent in migraine with aura patients
were those usually associated with the headache
phase, such as nausea and phono- and
photophobia, raising the question as to when
'headache phase' really begins. Other authors
have noticed that some patients added
voluntarily 'headache of different quality or
severity' as a PS although they had been
instructed to record only non-headache symptoms.
They considered that headache evolves from the
PS phase over a variable period, with full-blown
migraine headache finally developing when a
critical physiological threshold is reached. It
seems logical to propose that patients with
migraine with aura attacks experience more
relevant CNS changes and cross this
physiological threshold more easily and
intensely compared with migraine without aura
subjects. Future studies with a greater and more
balanced number of migraine with and without
aura patients are therefore necessary. Of
interest is the finding that patients on
preventatives showed a significantly decreased
frequency of PS, and to a lesser degree of RS,
compared with those not on these medications.
This suggests that preventatives, known to
reduce the frequency and sometimes the intensity
of the headache phase, are also able to reduce
the non-headache symptoms and that these
medications can reduce in some way the CNS
activation occurring before the headache phase.
In line with this, the use of preventatives has
been shown to revert the increased intensity
dependence of auditory evoked potentials seen in
migraineurs. Finally, severity of headache was
significantly associated with a higher frequency
of RS, which suggests that, together with
specific nonheadache symptoms beginning before
and remaining after the headache through to the
resolution phase, at least some of the RS may be
non-specific transient sequels of a severe,
full-blown migraine attack.
