The premonitory phase of migraine is defined
as the presence of nonpainful symptomatology
occurring hours to days before the onset of
headache. Symptoms can include neck stiffness,
yawning, thirst, and increased frequency of
micturition. Clinical recognition of these
symptoms is important to ensure early and
effective attack management. Further
understanding of the clinical phenotype and
neurobiological mediation of these symptoms is
important in the advancement of therapeutics
research in both acute and preventive treatments
of migraine.
Since 2014, functional imaging studies have
been conducted during the premonitory stage of
migraine and have provided novel insights into
the early neurobiology and anatomy of the
earliest stage of the migraine attack. These
studies have shown early involvement of
subcortical brain areas including the
hypothalamus, substantia nigra, dorsal pons, and
various limbic cortical areas, including the
anterior cingulate cortex during the premonitory
phase. More recent work has revealed altered
hypothalamic-brainstem functional connectivity
during migraine, which starts before the onset
of pain. These exciting findings have provided
functional correlation of the symptoms
experienced by patients and changes seen on
functional brain imaging.
Les symptômes
prémonitoires de la
migraine
La phase prémonitoire de la migraine
est définie par la présence d'une
symptomatologie non douloureuse survenant
plusieurs heures à plusieurs jours avant
l'apparition du mal de tête. Les
symptômes peuvent inclure de la raideur de
la nuque, des bâillements, de la
soif et une fréquence accrue de mictions.
La reconnaissance clinique de ces
symptômes est importante pour assurer une
gestion d'attaque précoce et efficace.
Une meilleure compréhension du
phénotype clinique et de la
médiation neurobiologique de ces
symptômes est importante pour faire
avancer la recherche thérapeutique dans
le traitement tant aigu que préventif de
la migraine.
Bien que décrites dans la
littérature depuis des décennies,
la pertinence physiopathologique et les
implications cliniques de ces symptômes
prémonitoires ont été
largement négligées. Ces
symptômes, qui peuvent
précéder la phase du mal de
tête jusqu'à 72 heures, comprennent
des changements d'humeur et d'activité,
d'irritabilité, de fatigue, de fringales,
de bâillements
répétitifs, de raideurs au cou
et de phonophobie. Ces symptômes peuvent
persister longtemps durant l'aura, la
période de maux de tête et
même la phase dites de postdromes.
Depuis 2014, des études d'imagerie
fonctionnelle ont été
menées au stade prémonitoire de la
migraine et ont permis de mieux comprendre les
débuts de la séquence
neurobiologique et de
l'anatomo-physio-pathologie du stade le plus
précoce de la crise de migraine. Ces
études ont montré une implication
précoce des zones
cérébrales sous-corticales, y
compris l'hypothalamus, la substance noire, le
tronc cérébral et diverses zones
corticales limbiques, y compris le cortex
cingulaire antérieur.
Ces travaux ont révélé
une altération de la connectivité
fonctionnelle du tronc cérébral
à la région
hypothalamo-cérébral au cours de
la migraine commençant avant l'apparition
de la douleur. Ces découvertes
intéressantes ont permis d'établir
une corrélation fonctionnelle entre les
symptômes ressentis par les patients et
les modifications observées lors de
l'imagerie cérébrale
fonctionnelle.
The premonitory phase of migraine is defined
as the presence of nonpainful symptomatology
occurring hours to days before the onset of
headache. Symptoms can include neck stiffness,
yawning, thirst,
and increased frequency of micturition. Clinical
recognition of these symptoms is important to
ensure early and effective attack management.
Further understanding of the clinical phenotype
and neurobiological mediation of these symptoms
is important in the advancement of therapeutics
research in both acute and preventive treatments
of migraine.
Plaguing humans for more than two millennia,
manifest on every continent studied, and with
more than one billion patients having an attack
in any year, migraine stands as the sixth most
common cause of disability on the planet. The
pathophysiology of migraine has emerged from a
historical consideration of the "humors" through
mid-20th century distraction of the now defunct
Vascular Theory to a clear place as a
neurological disorder.
It could be said there are three questions:
why, how, and when?
Why: migraine is largely accepted to be an
inherited tendency for the brain to lose control
of its inputs.
How: the now classical trigeminal
durovascular afferent pathway has been explored
in laboratory and clinic; interrogated with
immunohistochemistry to functional brain imaging
to offer a roadmap of the attack.
When: migraine attacks emerge due to a
disorder of brain sensory processing that itself
likely cycles, influenced by genetics and the
environment.
In the first, premonitory, phase that
precedes headache, brainstem and diencephalic
systems modulating afferent signals,
light-photophobia or sound-phonophobia, begin to
dysfunction and eventually to evolve to the pain
phase and with time the resolution or postdromal
phase.
Understanding the biology of migraine
through careful bench-based research has led to
major classes of therapeutics being identified:
triptans, serotonin 5-HT1B/1D receptor agonists;
gepants, calcitonin gene-related peptide (CGRP)
receptor antagonists; ditans, 5-HT1F receptor
agonists, CGRP mechanisms monoclonal antibodies;
and glurants, mGlu5 modulators; with the promise
of more to come. Investment in understanding
migraine has been very successful and leaves us
at a new dawn, able to transform its impact on a
global scale, as well as understand fundamental
aspects of human biology.
Premonitory phase is characterized by
attacks of unilateral, throbbing head pain, with
sensitivity to movement, visual, auditory, and
other afferents inputs. Other symptoms such as
tiredness, irritability, reduced concentration,
and yawning can
precede the headache by up to 48 h: the
premonitory phase. Most attacks are followed by
hours or a day of feeling unwell, usually with
tiredness called the postdrome. Additionally, in
approximately onethird of migraine patients,
their attacks are associated by neurological
deficits, which include cortical perturbations,
collectively termed migraine aura.
The majority of migraineurs experience a
range of premonitory symptoms well before the
typical migraine headache initiates. Despite
being described in the literature for decades,
their pathophysiological relevance and their
clinical implications have been largely
neglected. Premonitory symptoms of a migraine
attack, which may precede the headache phase by
up to 72 h, include changes in mood and
activity, irritability, fatigue, food cravings,
repetitive
yawning, stiff
neck, and phonophobia. These symptoms may endure
well into the aura, headache (373), and even
postdrome phases. The current ICHD- 3 precludes
the existence of premonitory symptoms within 2 h
of headache onset; this clearly has no logical
basis and needs attention.
The consistency of these symptoms allows
some migraineurs to reliably predict their
migraine attacks. The fact that these symptoms
are to a large extent of hypothalamic origin and
imaging studies using H2O PET show an increase
in hypothalamic blood flow during the presence
of premonitory symptoms suggests a prominent
role of the hypothalamus in the early stages of
the attack.
Interestingly many of the trigger factors
described by migraineurs, such as for example
sleep deprivation, hunger, or bright light, may
in fact represent premonitory symptoms of an
already ongoing attack. This relationship
explains why observations in clinical studies
that aimed at prospectively identifying and
validating trigger factors of migraine commonly
differ from findings obtained from
questionnairebased studies in which patients
merely describe their own perception of factors
triggering their migraine attacks.
Understanding the pathophysiological
mechanisms underlying the premonitory symptoms
may offer insights in the structures of the
central nervous system involved in the early
phases of a migraine attack and ultimately
contribute to identifying a novel therapeutic
approach that would exert its action before the
headache begins.
The application of neurophysiological
methods in migraine patients has offered
important insights into the condition. These
approaches offer temporal over spatial
discrimination and prior to MRI, and still to
some extent, better opportunities for
repetition. What has emerged very clearly from
studies in visual, somatosensory, auditory, and
nociceptive domains is activation that differs
from controls reliably.
A prevailing synthesis of the data is to
consider thalamocortical dysrhythmia (185, 819)
to be key to migraine pathophysiology. It has
been observed for some time that migraine
patients fail to habituate normally between
attacks, for example, the intensity dependence
auditory evoked potentials is augmented between
attacks in migraine patients. Remarkably this
normalizes in the days before an attack.
Interestingly, this measure has a serotonin
dependence that can be altered by triptans,
serotonin 5-HT1B/1D receptor agonists.
Potentiation of the passive "oddball" auditory
event-related potential similarly suggests
migraineur's brains do not habituate as
non-migraineurs do, as does an interical
habituation deficit as measured by the
nociceptive blink reflex in migraineurs. This
has led to the concept that the migraine brain
over-responds, as distinct from being
hyperexcitable.
C. Premonitory Phase
From a clinical perspective, the premonitory
phase that connects the asymptomatic interictal
phase with the headache attack has to be crucial
for understanding the mechanism of migraine
ignition. One of the most important fMRI studies
in this respect assessed the (de-)activation
pattern elicited by trigemino-nociceptive
stimulation of the nasal mucosa as the headache
day approached (749). Compared with control
subjects, interictal migraineurs have reduced
activation of the spinal trigeminal nuclei. This
deactivation had a cyclic behavior over the
course of a migraine interval: there was
normalization prior to the next attack and a
significant reduction of deactivation during the
attack (FIGURE 1). This cyclic behavior might
thus reflect the increased susceptibility of the
brain to generate the next attack, and the
identification of its pacemaker would be crucial
for our understanding of the start of a migraine
attack.
The earliest clinical signs of a migraine
attack are so-called premonitory symptoms, which
occur prior to head pain but already tell the
patient that a headache is on its way. Based on
their manifestation, they are likely related to
the hypothalamus (56, 482) and include
concentration problems, tiredness, irritability,
or depression. Compared with the headache phase,
they typically resemble some of the nonheadache
symptoms of a migraine attack and thus might
persist during the headache phase. Recently,
Maniyar et al. (559) triggered migraine attacks
in eight patients with migraine without aura who
could predict the occurrence of headache by a
pronounced premonitory phase. During the
premonitory phase, i.e., still in the absence of
head pain, H2 15O-PET demonstrated activation of
the hypothalamus, the midbrain ventral tegmental
area, and the PAG. This functional correlate of
premonitory symptoms suggests a possible role of
the hypothalamus in generating migraine attacks.
Of great interest in this regard are data from a
single patient whose responses to trigeminal
nociceptive stimuli were tracked with BOLD-fMRI
over a 30-day period. Hypothalamic responses
were increased as the attack neared, and there
was coupling of the effects with the
dorsolateral pons (715). In addition, the
hypothalamus might be important for the
non-headache symptoms during the pain phase
since when studied in seven spontaneous migraine
attacks with H2 15O-PET activation of the
hypothalamus was seen (209), although the
locations of both activations were distinct. It
is noteworthy that activations seen in the
trigeminal-autonomic cephalalgias (575, 576,
581, 582, 748) are more posterior than reported
in migraine.
