Estimation of Cerebrovascular Reactivity in Migraine Without Aura
Background and Purpose The nature and role of vascular abnormalities in migraine are controversial. In this study we evaluated cerebrovascular reactivity to hypercapnia in patients suffering from migraine without aura with unilateral headache.
Methods Using bilateral transcranial Doppler ultrasound, we studied the changes of flow velocity after hypercapnia in the anterior, middle, and posterior cerebral arteries of 16 migraine patients and 16 healthy control subjects. All patients were studied during an attack-free interval and during a migraine attack. Cerebrovascular reactivity was evaluated with the breath-holding index, obtained by dividing the percent increase in mean flow velocity occurring during breath-holding by the time (seconds) in which the subjects held their breath after a normal inspiration.
Results The response to breath-holding was similar for all arteries considered in both control subjects and patients during the attack-free interval. During the migraine attack, the breath-holding index in patients was significantly lower than the migraine-free interval in all arteries (P<.001). No side-to-side difference in cerebrovascular reactivity was detected in migraine patients either outside or during attacks.
Conclusions These results suggest that a failure of cerebrovascular regulation occurs during attacks of migraine without aura.
Transcranial Doppler ultrasound (TCD) has been used extensively to study the vascular feature of migraine.1 This method provides information about flow velocity changes in individual cerebral arteries as representation of cerebral blood flow.2 Studies investigating the diagnostic value of ultrasonic features in migraine have not provided encouraging results because of their low sensitivity.3 However, preliminary results suggest that the study of cerebrovascular reactivity may enhance the diagnostic yield of TCD and provide information on the pathophysiology of migraine.4 5
We report here the results of a study investigating the reactivity of the intracranial large vessels to hypercapnia in patients suffering from migraine without aura both outside and during attacks. A simultaneous bilateral TCD recording has been used to evaluate the possible side-to-side asymmetries of flow velocity changes.
Subjects and Methods
Sixteen patients with migraine without aura6 (6 males and 10 females; mean age, 25.8 years; range, 17 to 36 years) were included in the study under informed consent conditions. In all patients the headache was always unilateral during attacks. Endocrinologic, neuropsychiatric, and systemic disorders were excluded by careful clinical and laboratory examinations. No patient was using prophylactic antimigraine medication or had used analgesic drugs for 72 hours before examination. Attack frequency ranged from 1 to 6 per month. All patients were examined during an attack-free interval and during a migraine attack. Attack-free investigations were made between 3 and 6 days after an attack.
The evaluation of the migraine attack was made within 8 hours (mean±SD, 6.56±1.1 hours) from the headache onset in all patients. The headache was on the right side in 7 patients and on the left in 9. For the evaluation during the attack-free interval, the headache side was considered the same as that observed during the migraine attack. The intensity of the headache at the time of the examination was moderate in all patients. After the examination all patients were allowed to take analgesic drugs. Sixteen healthy volunteers, matched for age and sex, composed the control group. These subjects were examined twice, with an interval of at least 10 days between the two examinations.
Bilateral simultaneous flow velocity recording of the intracranial arteries was obtained by means of a Multi-Dop X/TCD transcranial Doppler instrument (DWL Elektronische Systeme GmbH, Esaote Biomedica). Two dual 2-MHz transducers fitted on a headband and placed on the temporal bone window were used to obtain a bilateral continuous measurement of homologous vessels. The signal from the anterior cerebral arteries (ACAs), middle cerebral arteries (MCAs), and posterior cerebral arteries (PCAs) was obtained by changing the depth of the sample volume and the inclination of the probes. Compression tests were also used to recognize the different arteries. The sequence for examining the vessels was random. The reactivity of each pair of homologous vessels was examined by calculating the breath-holding index (BHI). This index is obtained by dividing the percent increase in mean flow velocity (MFV) occurring during breath-holding by the length of time (seconds) the subjects hold their breath after a normal inspiration. This method has recently been introduced and was shown to be at least as effective as methods requiring CO2 inhalation.7 8
The study was carried out in a quiet room with the subjects lying in a comfortable supine position. The MFV at rest was obtained by the continuous recording of a 1-minute period of normal room air breathing. After a breath-holding period, the MFV over 4 seconds was recorded. A fixed period of 30 seconds for the breath-holding was arbitrarily chosen. Between the examination of a pair of vessels and the following, we refrained from recording for at least 10 minutes. All examinations were performed by the same TCD ultrasonographer, who was blinded to the subjects’ clinical status.
Mean blood pressure and heart rate were continuously monitored by means of a blood pressure monitor (2300 Finapress Ohmeda).
Data for the analysis consisted of the values of the BHI of each pair of homologous intracranial arteries. Each pair of arteries (ACAs, MCAs, and PCAs) was compared with the corresponding ones in the different groups of subjects examined (control subjects, patients outside attack, and patients during attack).
Data from control subjects were analyzed by means of a two-way ANOVA (dependent factor: BHI) with status (first exam, second exam) and side (right, left) as within-subject factors. The four values (right/left side×first/second exam) of BHI for each examined artery were not statistically different. Therefore, one of the four values for each subject was randomly selected, and this data set was separately compared with the BHI in the arteries homolateral and contralateral to the headache side of patients in the migraine-interval period by performing a one-way ANOVA with group (control subjects, patients [headache side], patients [nonheadache side]) as the between factor.
To compare cerebrovascular reactivity outside and during the migraine attacks, values of the BHI for each pair of cerebral arteries were analyzed by means of a two-way ANOVA (dependent factor: BHI) with status (outside and during attack) and side (headache and nonheadache side) as within factors.
Baseline MFV in control subjects and in patients outside and during attack were compared by the same statistical analyses used for the BHI. The considered values of MFV were those recorded during the 1-minute normal breath period.
MFV values at rest were not statistically different in any of the examined arteries in control subjects and in patients outside and during migraine attack on either the headache or the nonheadache side (Table 1⇓).
Table 2⇓ shows the mean values of the BHI in the different cerebral arteries of control subjects and patients outside and during attack.
The Figure⇓ shows the individual values of the BHI in the MCA of the headache side outside and during the migraine attack.
When comparing control subjects with patients in the attack-free interval (headache and nonheadache sides), no significant difference in the BHI was found in the ACAs (F=0.11), MCAs (F=0.7), or PCAs (F=0.37).
When comparing the BHI of patients outside and during migraine attack, the status effect was significant in the ACAs (F=31.6; P<.001 with 1 and 60 df), MCAs (F=41.7; P<.001 with 1 and 60 df), and PCAs (F=65.7; P<.001 with 1 and 60 df). This was due to the fact that the BHI (considering both headache and nonheadache sides) in each pair of cerebral arteries was significantly higher outside (ACAs, 1.04; MCAs, 1.11; PCAs, 0.94) than during the attacks (ACAs, 0.44; MCAs, 0.45; PCAs, 0.30). The side effect was not significant in any of the arteries (ACAs, F=0.85; MCAs, F=0.67; PCAs, F=0.78). In fact, no side-to-side difference of the BHI values of each pair of arteries was present either outside or during the attacks. Finally, the interaction between status and side was not significant (ACAs, F=0.15; MCAs, F=0.01; PCAs, F=0.16). This was due to the fact that the decrease of BHI values during the migraine attack with respect to the migraine-free interval was similar in the symptomatic and asymptomatic sides in all arteries considered.
There were no significant differences in mean blood pressure and heart rate in the baseline condition between control subjects and patients either outside or during attack. Moreover, no significant modification of the two variables occurred during the breath-holding.
Recent studies with TCD have suggested an alteration of vascular response to visual3 5 and motor5 stimulation as well as to CO2 both outside4 9 and during4 attacks. Overlap of individual responses greatly limits the clinical usefulness of these findings. In these studies patients suffering from different forms of migraine and with unilateral or bilateral headache have all been considered together.
In our study we considered only patients suffering from migraine without aura since these patients are considered the most appropriate ones for studying vascular hemodynamics because of the lack of potentially confounding aura-related vascular changes of migraine with aura.10 All patients had unilateral headache during migraine attacks. Finally, all the large intracranial arteries were investigated by means of a bilateral TCD that permits simultaneous recording of flow velocity changes and an evaluation of possible side-to-side asymmetries. With this kind of approach we found reduced reactivity to hypercapnia in all the intracranial vessels without side-to-side differences in the patients examined during the migraine attack. This result suggests that hemodynamic alterations during migraine without aura attacks are generalized even if the headache is unilateral. No difference in the vascular response to hypercapnia was found between control subjects and patients in the attack-free interval. This last result does not agree with the results of previous studies4 9 in which an increased reactivity to hypercapnia induced by inhalation of a gas mixture containing 5% CO2 was reported in patients suffering from migraine with and without aura outside the attack. This disagreement may be due to the fact that we limited our investigation to patients with migraine without aura and used a different method for the induction of hypercapnia.
We are not able to provide a definitive explanation of the reduced vascular reactivity during migraine attacks. In fact, TCD does not permit complete understanding of the pathophysiological mechanisms of flow changes. On the other hand, the purpose of our study was not to obtain information on migraine pathogenesis but only to show the possibility of acquiring functional information with a simple, completely noninvasive approach combining a breath-holding test (recently introduced to evaluate the hemodynamic effects of carotid stenosis7 8 ) to produce hypercapnia and a bilateral TCD recording of flow velocity changes.
The reliability of the findings obtained with this kind of approach is suggested by the good reproducibility of our measurements in control subjects in the two sequential examinations performed and by the constant pattern of the vascular response found in the patients. During the migraine attack, the BHI was reduced in every single patient (Figure⇑). Moreover, the extent of the reduction of reactivity in each artery was quite similar in all patients.
Further work is needed to fully clarify the relations between migraine and hemodynamic abnormalities. The noninvasiveness of TCD and the possibility it provides for obtaining instantaneous information about cerebral blood flow changes may indicate its usefulness in the study of vascular changes in different types of migraine.
- Received February 25, 1994.
- Revision received September 14, 1994.
- Accepted September 16, 1994.
- Copyright © 1995 by American Heart Association
Headache Classification Commission of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8(suppl 7):1-96.
Markus HS, Harrison MJG. Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke. 1992;23:668-673.
Thomas TD, Harpold GJ, Troost BT. Cerebrovascular reactivity in migraineurs as measured by transcranial Doppler. Cephalalgia. 1990;10:95-99.