Autonomic dysfunction in migraineurs

Objective.—To evaluate autonomic function and sympathovagal balance in migraineurs and healthy controls.
Background.—The pathophysiology of migraine is still largely unknown. An imbalance of the autonomic nervous system could explain many of the clinical manifestations of the disorder.
Materials and Methods.—We undertook autonomic function tests in 17 women suffering from migraine (8 with aura) (average age 36 ± 7 years) and 16 healthy women (average age 34 ± 7 years). Autonomic nervous system studies consisted of tests of sympathetic function (the quantitative sudomotor axon reflex test, beat-to-beat blood pressure responses to the Valsalva maneuver, sustained handgrip, cold pressor test, and head-up tilt and tests of parasympathetic function (heart rate responses to deep breathing and the Valsalva maneuver). The data from the tilt test were further evaluated by time-frequency analysis (Wigner distribution).
Results.—Subjects with migraine with aura had a smaller increase of mean blood pressure during phase IV of the Valsalva maneuver ( P <0.05) and a lower blood pressure increment during the handgrip test ( P =0.08); their time-frequency distribution showed reduced power at the nonrespiratory frequencies in the R-R interval at both minutes 1 ( P <0.03) and 5 ( P <0.04) of head-up tilt. Sympathovagal balance (a ratio of spectral power of nonrespiratory frequency variations in blood pressure to that at respiratory frequency variations in the R-R interval) was significantly increased in migraineurs, both with and without aura, by 10 minutes of head-up tilt.
Conclusion.—Subjects with migraine with aura had resting supine sympathetic hypofunction and intact parasympathetic function. With head-up tilt, sympathovagal balance is increased. The dynamic alterations in autonomic nervous system function may contribute to the development of aura in patients with migraine.     

Autonomic Nervous System Function in Migraine Without Aura

Autonomic nervous system functions were studied in 13 females with migraine without aura during headache-free intervals, using physiological, pharmacological and biochemical methods. Heart-rate in the resting condition and blood pressure rises in the cold-face and isometric handgrip tests were higher than in controls. Normal cardiovascular responses to the Valsalva manoeuvre and to noradrenaline infusion suggest that the baroreflex arc is intact. Normal heart rate responses to the Valsalva manoeuvre, to the cold-face test and to deep breathing confirmed a normal cardiac parasympathetic function. Clonidine infusion showed a sedative and depressor effect and an inhibition of plasma NA similar to those occurring in controls, suggesting a normal central sympathetic tone. As a whole, the physiological, pharmacological and biochemical tests were consistent with a non-specific sympathetic hyperactivity, but do not confirm any impairment of the autonomic control of the cardiovascular system in migraine patients in headache-free intervals.     

Altered Cardiovascular Reactivity to Mental Stress But Not to Cold Pressure Test in Migraine

(Headache 2010;50:133‐137) Objectives.— This study assessed cardiovascular reactivity to mental stress and cold pressure test in migraineurs and controls. It compared the cardiovascular reactivity between patients with migraine with aura and patients with migraine without aura. Background.— Several studies have assessed the autonomic nervous system functioning and cardiovascular responses to stressor stimuli in migraine. Cold pressure test and sustained attention tasks are distinct forms of induced stress. It is still unknown if patients with migraine have distinct patterns of response to sustained attention tasks and cold pressure test, since no previous studies have evaluated the cardiovascular responses to these 2 distinct types of stress in the same population of migraine patients. Methods.— Two distinct protocols were used to induce cardiovascular reactivity. Mental stress was induced by using a Stroop test card, a procedure involving the maintenance of the attention control. The other protocol was the cold pressure test. The blood pressure and heart rate were digitally recorded in rest and test phases. The mean elevation and the variance of blood pressure and heart rate were compared between groups. Results.— Patients with migraine had higher rest systolic blood pressure and lower heart rate induced by mental stress than controls. There were no differences between migraineurs and controls with cold pressure test. There were no differences between migraineurs with and without aura. Conclusion.— There was a significantly different pattern of cardiovascular reactivity between migraineurs and controls with mental stress but not with cold pressure test. Distinct central nervous system structures are involved in these 2 types of stress. A distinct pattern of activation of the prefrontal cortex—periaqueductal gray matter circuit in migraine may explain a singular autonomic reactivity to mental stress in this disease.     

Autonomic Function Testing in Patients with Migraine

SYNOPSIS
Autonomic nervous system function was studied in 62 patients with migraine. The Valsalva maneuver, deep breathing test, sustained handgrip test, orthostatic test and spectral analysis of heart rate variability in the supine and standing positions were performed in a group of 62 patients of both sexes, aged 21 to 50 years, and in an age-matched control group of 45 healthy volunteers.
Heart rate increase during sustained handgrip was significantly reduced in the headache group, when compared to the control group, while the results of the remaining cardiovascular tests did not significantly differ between the control and headache groups. In standing patients, the integrals of middle frequency bands of amplitude spectra were smaller in patients than in controls because the increase induced by standing was smaller in migraine patients. The results in patients with migraine with aura (21 patients) and migraine without aura (41 patients) did not differ significantly from each other. The same was true for the results of the female and male patients.
It is concluded that sympathetic function is impaired in migraine patients.     

Neuropeptide Y in Juvenile Migraine and Tension-Type Headache

SYNOPSIS
Neuropeptide Y (NPY) is widely distributed throughout sympathetic nerve endings where it is co-stored and co-secreted with noradrenaline. It is considered a marker of noradrenergic function. To determine the role of NPY in the pathogenesis of juvenile headache, we determined its plasma levels in two groups of young migraine patients (with and without aura), in a group of episodic tension-type headache patients and in a group of age and sex-matched healthy subjects. Significantly lower plasma levels of NPY were evident in the migraine patients with aura (P<0.001) and, to lesser extent, in the migraine patients without aura (P<0.02), both assessed in the interictal period, with respect to the control group. Plasma NPY levels tended to significantly increase during attacks in migraine patients with aura (P<0.0009). A less evident, though significant increase was also present during attacks in migraine patients without aura (P<0.02). No significant variations were observed between headache-free periods and attacks in tension-type headache patients. Reduced NPY levels in the interictal period can be considered further evidence of the derangement of the sympathetic function in the course of migraine, particularly that with aura. The increase in NPY levels during migraine attacks could be an expression of sympathetic activation, even though the functional status of this system is less efficient.     

Cardiorespiratory regulation in migraine. Results in children and adolescents and review of the literature

To investigate autonomic regulation in juvenile migraine we studied 70 children and adolescents with migraine during the headache-free period and 81 healthy controls by cardiorespiratory function tests. Heart rate variability was analysed with time and frequency domain indices during spontaneous breathing at rest and during metronomic breathing. Changes of heart rate and blood pressure were studied during tilt-table test, active standing, Valsalva manoeuvre and sustained handgrip. We found significant differences in metronomic breathing, tilt-table test and Valsalva manoeuvre. We interpret our findings and results reported in the literature as pointing to a restricted ability of the system to rest, which supports therapies intending to further this ability. In autonomic tests, hyperreactivity in juvenile migraineurs changes to hyporeactivity and passive coping in adults. This might be explained by disturbances of raphe nuclei and the periaqueductal grey. It corresponds to psychological findings in juvenile migraineurs reporting hypersensitivity and repressed aggression and claiming learned helplessness.     

Cardiovascular Reflex Responses During Migraine Attack

SYNOPSIS
The cardiovascular reflex responses of 10 migraine patients were recorded during both migraine attacks andheadache-free intervals. Ten healthy subjects of similar age and sex served as a control group.When the results of the measurements for migraine patients performing an isometric work test duringmigraine attacks and during headache-free intervals were compared, during migraine attacks a statisticallysignificant smaller increase in diastolic B.P. was encountered than interictally (p<0.05).When the results for migraine patients during migraine attack, and controls, were compared, statisticallysignificant differences were encountered in the pulse rate variation in Valsalva manoeuvre, in an orthostatictest, and in the systolic and diastolic blood pressure reactions in an isometric work test. The mean Valsalvaratio and R-R-interval ratio during the orthostatic test were lower in migraine patients during migraine attackthan in controls, and the mean blood pressure rise in the isometric work test was also lower in the migrainepatients group during attacks.There were no statistically significant differences between the results of the migraine patients duringheadache-free intervals and those of the control subjects.     

Platelet levels of dopamine are increased in migraine and cluster headache

OBJECTIVE: To measure plasma and platelet levels of dopamine in patients with migraine with aura, migraine without aura, and cluster headache. BACKGROUND: Clinical, genetic, and pharmacological evidences suggest that an abnormality of dopaminergic system plays a role in migraine pathogenesis. Direct evidence of an abnormal metabolism of dopamine in migraine, however, is lacking. METHODS: Plasma and platelet levels of dopamine were measured in patients with migraine with aura or migraine without aura during headache-free periods and in patients with cluster headache during the remission and active periods, as compared with healthy control subjects, using a multichannel electrochemical high-performance liquid chromatography system. RESULTS: Plasma levels of dopamine were not detectable with our methodology. Platelet levels of dopamine were higher in both types of migraine (migraine without aura = .20 +/- .17 ng/10(8) platelets; migraine with aura = .16 +/- .19 ng/10(8) platelets) than in control subjects (.10 +/- .11 ng/10(8) platelets), although in migraine with aura patients the difference was not significant. Patients with cluster headache showed the highest levels of platelet dopamine (.34 +/- .36 ng/10(8) platelets). CONCLUSIONS: Our results support the hypothesis that the dopaminergic system is impaired in migraine and cluster headache and suggest that high platelet levels of dopamine may represent an abnormal biochemical phenotypic trait of these primary headaches.     

Migraine with and without aura in the same patient: expression of a single clinical entity?

Migraine with aura and migraine without aura may be different clinical expressions of one disease. This theory is debated, however. In order to further address the issue, we administered a standardized questionnaire to 45 migraineurs. The results indicate a significant overlap between migraine with and without aura, most importantly with respect to response to therapy; 70% of patients had similar responses.     

Hungarian migraine epidemiology

OBJECTIVE: A population-based epidemiological survey of migraine without aura and migraine with aura completed by mailed questionnaire in Hungary. The diagnosis and classification of migraine was according to the criteria of the International Headache Society. METHODS: The validity of the self-administered headache questionnaire was evaluated by a neurologist using clinical interviews. The study population was a random sample of 2000 men and women aged between 15 and 80 years. The questionnaire was completed by 813 of 1910 people (392 men and 421 women), providing a 42.6% participation rate. RESULTS: Sixty-seven percent of these people experienced some kind of headache during their lives. The 1-year prevalence of migraine without aura was 7.6% (the female/male ratio was 3:1), while the 1-year prevalence of migraine with aura was 2% (female/male ratio was 2:1). Most migraineurs experienced headache attacks 1 to 4 times monthly, which lasted 24 hours. The most characteristic accompanying signs were nausea and phonophobia. Stress, sleep deprivation, hot weather, and fasting were the most common precipitating factors of a migraine attack. In the migraine with aura group, the most common aura was a visual disturbance. Only 43% of migraineurs had ever consulted a physician for headache, and only 15% of patients had missed work or school because of a migraine attack in the previous year. Most of the patients suffering from migraine without aura were between 20 and 40 years old, while migraineurs with aura were over 40 years old. According to this investigation, the prevalence of migraine was not lower than in Western countries.     

Cerebrovascular reactivity in migraine during headache-free intervals

Alterations of intracranial vessel tone have been implicated in the pathophysiology of migraine. The cerebrovascular reactivity was measured by means of transcranial Doppler in 60 migraine patients with ( n =30) or without aura ( n =30) during the headache-free interval and in 30 healthy controls. The vasomotor response was evaluated during hypercapnia induced by inhalation of a mixture of CO_z 5% and O₂ 95% and during hypocapnia obtained after voluntary hyperventilation. To improve the power of the study in detecting possible abnormalities of cerebrovascular reactivity, two different measures were performed at 1 week intervals in migraine patients and controls. Reactivity index values during CO₂ inhalation were significantly different ( p =0.01) among the three groups during the first and second measurements; in particular, lower values were found in patients suffering from migraine without aura with respect to controls ( p <0.05, Scheffe's test). Values of reactivity index obtained following induction of hypocapnia did not differ between migraine patients and controls (all p values >0.05). Our data suggest a reduced vasodilatory response to hypercapnia of cerebral arterioles in patients suffering from migraine without aura with respect to controls that might be related to baseline arteriolar vasodilation.     

Magnesium Content of Mononuclear Blood Cells in Migraine Patients

SYNOPSIS
Recent research has shown that magnesium levels in serum, salivary secretions and red blood cells are reduced in migraine patients with and without aura, both ictally and interictally. This suggests that lower magnesium levels can contribute to the etiopathogenetic mechanisms underlying migraine attacks. It has been suggested that mononuclear magnesium content is a reliable index of magnesium nutritional status, as it is more closely related to the total body stores than other biochemical indices. Therefore we determined mononuclear magnesium content in adult migraine patients with and without aura, in headache-free periods and, in a number of patients, during attacks. Migraine patients with and without aura, assessed in interictal periods, had a reduced mononuclear magnesium content compared to age-matched healthy control subjects. No significant variations were observed between ictal and interictal periods in migraine patients with aura and without aura. The lower magnesium content in mononuclear cells could indirectly indicate the reduction of brain magnesium concentration, which has recently been demonstrated in the course of migraine.     

Persistent and Repetitive Visual Disturbances in Migraine: A Review

Visual disturbances in migraineurs, such as visual aura, are typically episodic, that is, associated with the headache attack, and overlaid by head pain and other symptoms that impact the patient. In some patients, however, visual symptoms are dominant due to frequency (migraine aura status), duration (persistent migraine aura and other persistent positive visual phenomena), or complexity (visual snow syndrome). These syndromes are more rare and challenging to classify in clinical practice resulting in a lack of systematic studies on pathophysiology and treatment. We aim at describing clinical features and pathophysiological concepts of typical migraine aura with a focus on cortical spreading depression and differentiation from non‐typical migraine aura. Additionally, we discuss nomenclature and the specifics of migraine aura status, persistent migraine aura, persistent positive visual phenomena, visual snow, and other migrainous visual disturbances. The term migraine with prolonged aura might be a useful bridge between typical aura and persistent aura. Further studies would be necessary to assess whether a return of the classification category eventually helps diagnosing or treating patients more effectively. A practical approach is presented to help the treating physician to assign the correct diagnosis and to choose a medication for treatment that has been successful in case reports of these rare but disabling conditions.     

Autonomic Dysfunction in Adult Migraineurs

SYNOPSIS
The autonomic nervous system (ANS) functions of 60 migraine patients, aged from 23 to 50 years, wereinvestigated during headache-free intervals by utilizing a number of cardiovascular reflexes as indices.Thirty-five healthy subjects of similar age served as a control group. The pulse rate (R-R-interval) variationwas recorded in normal and deep breathing, in the Valsalva manoeuvre, and in an orthostatic test (a tilttable was used); and the blood pressure reactions were recorded in an orthostatic test and in an isometricwork (hand grip) test.There were significant differences in the results between migraine patients and control subjects in theR-R-interval variation ratio, both in normal and deep breathing tests and in the Valsalva manoeuvre. Thedifferences between migraine patients and controls in pulse rate variation in orthostatic test and in bloodpressure reactions in isometric work test were highly significant (p < 0.001 ). There were no statisticallysignificant differences in cardiovascular reflex responses of various subgroups of migraine patients(common-classic, frequent-infrequent attacks, normal-abnormal EEGs). These results suggest mildparasympathetic hypo function, but more definite sympathetic hypofunction (Valsalva manoeuvre,orthostatic test and isometric work test) in adult migraine patients during headache-free intervals.     

Red blood cell magnesium levels in migraine patients

In the last few years, it has been suggested that magnesium plays a central role in establishing a threshold for migraine attacks and in intervening with the pathogenetic mechanisms involved in their onset. Accordingly, we determined red blood cell magnesium levels in adult migraine patients with and without aura interictally and in some of them also ictally. In comparison with normal subjects, migraineurs with and without aura had significantly lower red blood cell magnesium levels in the interictal period. Ictal red blood cell magnesium levels did not differ from the interictal values. Low red blood cell magnesium levels could be a peripheral expression of the reduced brain magnesium concentration observed in migraine patients.     

Pattern reversal visual evoked potentials in migraine with aura and migraine aura without headache

Pattern reversal visual evoked potentials (PVEPs) were recorded in 20 patients with migraine with aura (MA), 19 patients with migraine without headache (migraine equivalent; ME.) during interictal periods, and 34 normal subjects. All migraine patients had hemianopsia or fortification spectra during attacks. In both MA and ME patients of less than 49 years of age, there were significant ( p <0.01) differences in amplitude of PVEPs at the mid-occipital and contralateral to visual aura electrode sites compared to normal subjects. Amplitude of PVEPs in MA and ME showed significant ( p <0.001) increases when recorded soon after attacks, especially within 10 days. There was a significant ( p <0.0l) correlation between percentage asymmetries and the duration of illness in both MA and ME. We conclude from our PVEP findings that cortical spreading depression remains the most likely explanation for the migraine visual aura.     

Migraine with aura versus migraine without aura: pain intensity and associated symptom intensities after placebo

OBJECTIVE: To compare the intensity of pain and associated symptoms after placebo administration in patients with migraine with aura and migraine without aura. BACKGROUND: Studies that evaluate drugs used in the acute treatment of migraine ideally should include a placebo arm. The International Headache Society also recommends stratification according to age and sex but not by the presence versus absence of aura. METHODS: The study was conducted as part of a placebo controlled randomized survey comparing four active drugs against placebo in the acute treatment of migraine. Patients were blinded as to treatment received. Placebo consisted of 10 mL of normal saline (0.9%) intravenously. Pain intensity was evaluated by a 10-point analogical-verbal scale. Nausea, photophobia, and phonophobia were evaluated by a four-point analogical-verbal scale. For statistical analysis, unpaired t-test with Welch correction was used. RESULTS: After placebo administration, reduction of symptom intensity (pain, nausea, photophobia, and phonophobia) in patients with migraine without aura was significantly greater than that observed in patients with migraine with aura. CONCLUSIONS: Our findings suggest that studies comparing placebo against an active drug should use stratification according to the presence versus absence of aura.     

Perfusion weighted imaging during migraine: spontaneous visual aura and headache

Using perfusion weighted imaging, we studied 28 spontaneous migraine episodes; 7 during visual aura (n = 6), 7 during the headache phase following visual aura (n = 3), and 14 cases of migraine without aura (n = 13). The data were analyzed using a region-of-interest-based approach. During aura, relative cerebral blood flow (rCBF) was significantly decreased (27% +/- 0.07) in occipital cortex contralateral to the affected hemifield. rCBV was decreased (15% +/- 0.12) and mean transit time increased (32% +/- 0.3), persisting up to 2.5 h into the headache phase. Other brain regions did not show significant perfusion changes. During migraine without aura, no significant hemodynamic changes were observed. In one patient who experienced both migraine with and without aura, perfusion deficits were observed only during migraine with aura. These findings suggest that decremental blood flow changes in occipital lobe are most characteristic of migraine with aura.     

Headache in 25 consecutive patients with atrial septal defects before and after percutaneous closure--a prospective case series

(Headache 2011;51:1297‐1304) In contrast to patent foramen ovale that is highly prevalent in the general population, atrial septal defect (ASD) is a rare congenital heart defect. The effect of ASD closure on headache and migraine remains a matter of controversy. The objectives of our study were (1) to determine headache prevalence in consecutive patients with ASD scheduled for percutaneous closure for cardiologic indications, using the International Classification of Headache Disorders and (2) to compare headache characteristics before and after closure of ASD. In this observational case series no a priori power analysis was performed. Twenty‐five consecutive patients were prospectively included over 27 months. Median duration of follow‐up was 12 months [interquartile range 0]. Prevalence of active headache seemed to be higher compared with the general population: any headaches 88% (95% confidence interval 70‐96), migraine without aura 28% (14‐48), migraine with aura 16% (6‐35). After ASD closure, we observed a slightly lower headache frequency (median frequency 1.0 [2.6] vs 0.3 [1.5] headaches per month; P = .067). In patients with ongoing headaches, a significant decrease in headache intensity (median VAS 7 [3] vs 5 [4]; P = .036) was reported. Three patients reporting migraine with aura before the intervention noted no migraine with aura attacks at follow‐up, 2 of them reported ongoing tension‐type headache, 1 migraine without aura. In summary, this prospective observational study confirms the high prevalence of headache, particularly migraine, in ASD patients and suggests a possible small beneficial effect of ASD closure.     

A prospective study of migraine with aura attacks in a headache clinic population

In order to investigate the prevalence of migraine with aura (MA) attacks according to the criteria set by the International Headache Society (IHS) for diagnosis down to the three-digit level of classification, and to determine the recurrence and possible variability of MA attacks over time, we conducted a 6-15-month-long prospective study on 64 MA patients (42 women and 22 men) consecutively referred for the first time to the University of Parma Headache Centre. At the end of the follow-up period, diagnosis was the same as at the first visit for 80.0% of patients, while it was changed for 20.0%. Throughout the duration of the study, the average number of attacks for each patient was 5.3 +/- 6.2 (range 0-30). Attacks of migraine with typical aura were the most frequent (69.1% of patients), but migraine aura without headache (29.1%) and migraine with prolonged aura (20.0%) were also common; by contrast, basilar migraine and migraine with acute onset aura were reported only by one patient in either case. Migraine aura without headache was statistically significantly more frequent in males than in females. Our study results suggest that in most cases the frequency of recurrent MA attacks is relatively low and provide interesting indications about the prevalence of the different MA subtypes listed in the IHS classification, albeit in a headache clinic population.