mise à jour du
10 septembre 2006
Premonitory and resolution symptoms in migraine:
a prospective study in 100 unselected patients
Quintela E, Castillo J, Munoz P, Pascual J
Health Centre of Astillero, University Hospital, Salamanca, Spain


Yawning and migraine
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.

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.
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.
-Schoonman GG, Evers DJ, Terwindt GM, van Dijk JG, Ferrari MD.The prevalence of premonitory symptoms in migraine: a questionnaire study in 461 patients. Cephalalgia. 2006;26(10):1209-1213