Spontaneous Migraine Attacks Research Articles

Reversible Imaging Abnormalities Consistent With CSD During Migraine Without Aura Attack

An 18-year-old man with a history of migraine without aura and normal neurological examination carried out a cerebral CT scan during a spontaneous typical migraine attack. While the CT scan demonstrated left temporal-parietal-occipital low attenuation, a brain magnetic resonance imaging, performed 5 days later, did not show any lesions. Based on this evidence, we can speculate that the dysfunction of the cerebrovascular system, either in the cerebral cortex or in the subcortical regions, is an important mechanism in the pathophysiology of migraine.

Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis

Altered serotonin (5-HT) neurotransmission has been implicated in the pathophysiology of migraine headache. To test this hypothesis in migraine patients in vivo using PET and alpha-[(11)C]methyl-l-tryptophan as a surrogate marker of brain 5-HT synthetic rate during different phases of their migraine attack and after acute antimigraine therapy with sumatriptan, and to compare them with normal controls. Six patients were scanned 1) within 6 hours after the onset of a spontaneous migraine attack, 2) 2 hours after subcutaneous sumatriptan, and 3) interictally when migraine free for at least 3 days. Head pain was rated before each scan, and before and every 15 minutes after sumatriptan. Brain 5-HT synthesis was highest during attacks, lowest after sumatriptan, and intermediate when patients were migraine free. All states were statistically different from the others in virtually all brain regions examined. 5-HT synthetic rates in patients during migraine attacks did not differ from those of age- and sex-matched controls, whereas they were significantly lower after sumatriptan in a majority of regions. Interictally, global brain 5-HT synthetic rate was slightly, albeit not significantly, lower (-14%) in migraine patients than in controls, with specific cortical areas exhibiting proportionally more severe reductions (-28% to 31%). These findings point to a low cortical serotonergic tone in migraine patients interictally. Further, they demonstrate widespread increases in brain serotonin (5-HT) synthetic rate in migraine patients during attacks, and that triptans exert a negative feedback regulation of brain 5-HT synthesis concurrently with modulation of pain pathways.

Hypothalamic Activation in Spontaneous Migraine Attacks

Migraine sufferers experience premonitory symptoms which suggest that primary hypothalamic dysfunction is a likely trigger of the attacks. Neuroendocrine and laboratory data also support this hypothesis. To date, positron emission tomography (PET) scans of migraine sufferers have demonstrated activation of brainstem nuclei, but not of the hypothalamus. To record cerebral activations withH2 15OPET during spontaneous migraine without aura attacks. We scanned 7 patients with migraine without aura (6 females and 1 male) in each of 3 situations: within 4 hours of headache onset, after headache relief by sumatriptan injection (between the fourth and the sixth hour after headache onset), and during an attack-free period. During the headache we found not only significant activations in the midbrain and pons, but also in the hypothalamus, all persisting after headache relief by sumatriptan. Hypothalamic activity, long suspected by clinical and experimental arguments as a possible trigger for migraine, is demonstrated for the first time during spontaneous attacks.

Transcranial Doppler measurements in migraine and nitroglycerin headache.

The objective of this study was to examine the cerebral circulation during spontaneous migraine attacks and to compare changes to an experimental headache model induced by nitroglycerin (NTG) infusion. This prospective study was carried out in a tertiary care hospital on migraineurs with or without aura. Healthy volunteers served as controls. There were no interventions. Flow velocity (FV) and pulsatility index (PI) were measured in migraineurs between and during headache attacks. In controls, FV and PI of the middle cerebral arteries were performed at baseline and after each IV infusion of 0.125, 0.25 and 0.5 μg/kg/min of NTG. In migraineurs, a significant increase in the mean flow velocity (MFV) in the left vertebral artery (VA) and the PI of the right VA during spontaneous migraine headache was found. In controls, all FV significantly decreased after infusion of NTG. The NTG model produces expected and substantially different vascular effects than those seen with spontaneous migraine headache.

Is stress a trigger factor for migraine?

Although mental stress is commonly considered to be an important trigger factor for migraine, experimental evidence for this belief is yet lacking. To study the temporal relationship between changes in stress-related parameters (both subjective and objective) and the onset of a migraine attack. This was a prospective, ambulatory study in 17 migraine patients. We assessed changes in perceived stress and objective biological measures for stress (saliva cortisol, heart rate average [HRA], and heart rate variability [low-frequency power and high-frequency power]) over 4 days prior to the onset of spontaneous migraine attacks. Analyses were repeated for subgroups of patients according to whether or not they felt their migraine to be triggered by stress. There were no significant temporal changes over time for the whole group in perceived stress (p=0.50), morning cortisol (p=0.73), evening cortisol (p=0.55), HRA (p=0.83), low-frequency power (p=0.99) and high-frequency power (p=0.97) prior to or during an attack. Post hoc analysis of the subgroup of nine stress-sensitive patients who felt that >2/3 of their migraine attacks were triggered by psychosocial stress, revealed an increase for perceived stress (p=0.04) but no changes in objective stress response measures. At baseline, this group also showed higher scores on the Penn State Worry Questionnaire (p=0.003) and the Cohen Perceived Stress Scale (p=0.001) compared to non-stress-sensitive patients. Although stress-sensitive patients, in contrast to non-stress-sensitive patients, may perceive more stress in the days before an impending migraine attack, we failed to detect any objective evidence for a biological stress response before or during migraine attacks.

Influence of sumatriptan on the autonomic system during migraine attacks

gy of migraine provided evidence that the autonomic nervous system may contribute to the development of the headache phase [1, 2]. Although the effectiveness of the 5HT 1B/1D receptor agonists (triptans) on pain relief is thought to be due to their specific action on the trigeminovascular system, a potential effect on the autonomic system, though unproven, may also be speculated [3]. Because of its effectiveness in investigating skin microcirculation by detecting thermic changes of a specific cutaneous area, infrared imaging may be a useful tool to test the functional effects of triptans on the autonomic system in physiological and pathophysiological conditions. The typical infrared pattern of migraine is the forehead cold patch, an asymmetrical focus of temperature decrease of 0.5°C within the external carotid territory, which represents the end result of the haemodynamic changes due to the activity of the autonomic and the trigeminovascular systems [4, 5]. In a pilot study, we tested a sample of 40 consecutive patients who met the diagnosis of migraine without aura and who reported a monthly frequency of one to six attacks. All the patients underwent clinical and infrared evaluation (PM395 Thermacam, Inframetrics, Inc., Billerica, MA) within 30 min of the onset of a spontaneous migraine attack and before treatment (t0), and 5 (t1), 30 (t2) and 120 min (t3) after treatment. Subjects were randomly assigned to receive 6 mg of injectable sumatriptan (n=30) or the same volume of placebo (n=10) within 30 min of the attack onset. Efficacy endpoint consisted of improvement in headache intensity to mild or painfree levels (optimal response) and a complete disappearance of the asymmetric infrared pattern at t3. Twentythree subjects (57.5%) had an optimal response to treatment and a complete disappearance of the asymmetric pattern at infrared imaging. All these were in the subgroup of individuals who received sumatriptan. In contrast, no substantial modification of the asymmetric pattern was observed in the remaining 7 subjects (23.3%) who did not have an optimal response after treatment. The same findings were also observed in the subgroup of subjects receiving placebo: none of them had an optimal response to treatment and none showed any significant modification of the asymmetric infrared pattern. These results demonstrate that the beneficial clinical effect of sumatriptan on pain relief is associated with the disappearance of the cold patch at the infrared investigation. As the mechanism underlying the disappearJ Headache Pain (2006) 7:116–117 DOI 10.1007/s10194-006-0289-z

Tomographie par émission de positons dans la migraine

Due to technical constraints and randomness of migraine attacks, studies using PET are scarce. Nevertheless, these studies have given new insights into migraine pathogenesis. One of the main facts revealed by PET studies is that posterior cerebral hypoperfusion accompanying migraine auras could also be present in migraine attacks without aura. This hypoperfusion is probably due to an increase of intrinsic vasoconstrictive tone in the cerebral circulation. Using PET within 6 hours after the onset of a spontaneous migraine attack, significant activations of brainstem (midbrain and pons) and of hypothalamus, persisting after headache relief by sumatriptan have been shown. These structures could play the role of migraine attack generators, modulating intrinsic vascular tone and central pain transmission.

Rizatriptan does not change cerebral blood flow velocity during migraine attacks

Rizatriptan represents a major advance in the treatment of migraine attack: inhibition of peripheral trigeminal nerve and constriction of intracranial extracerebral blood vessels have been proposed as its main antimigraine mechanisms of action. Although many studies may suggest that rizatriptan causes highly selective vasoconstriction within intracranial extracerebral vessels (i.e., meningeal arteries), no literature data are available to date on possible cerebral hemodynamic changes in humans after treatment with rizatriptan. The aim of this study was to evaluate the effect of rizatriptan on cerebral blood flow velocity performing transcranial Doppler during spontaneous attacks of migraine without aura. Fourteen patients suffering from migraine without aura were monitored to evaluate mean flow velocity changes on both middle cerebral arteries during migraine attack 30 min before and 120 min after oral administration of rizatriptan 10 mg. Monitoring was repeated for 30 min during the pain-free period. All patients turned out to be drug responders and no significant mean flow velocity changes were observed between the pain-free period and pre-treatment phase; besides no significant difference in mean flow velocity value have been detected between the periods after the drug administration during the attack versus both pre-treatment period and pain-free phase. These findings indicate that the antimigraine action of rizatriptan is not associated with clear intracranial cerebral hemodynamic changes and may support its cerebrovascular safety.

Pharmacological treatment of attacks in juvenile migraine

Although migraine is a common complaint in childhood and adolescence, there is a lack of controlled clinical studies regarding treatment. In the young patient, the pharmacological approach should be preceded by setting up non-pharmacological measures which include behavioural intervention. The sole use of symptomatic therapies should be limited to patients who complain of up to four partially or totally disabling attacks, or those who suffer from headache for more than 4 days per month. The therapeutic armamentarium includes non-specific symptomatic drugs, such as analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), as well as anti-emetics and specific drugs, such as the triptans. Analgesics and NSAIDs are the most frequently used drugs in childhood and adolescence for the symptomatic treatment of migraine attacks of slight or moderate intensity. The first-choice drug for those under 12 years of age is acetaminophen. Among NSAIDs, two double-blind, randomized, placebo-controlled studies were conducted for ibuprofen, supporting its efficacy. In the past, ergot derivatives played an important role in the treatment of spontaneous migraine attacks, particularly in adults, but after the triptan revolution their role was strongly confined to a small number of patients. Although they are considered first-choice drugs for moderate and severe migraine attacks in adults, triptans are still under study in migraine patients under 18 years of age. The Health Ministry rules do not approve their use in patients under 18 years. They can only be given legally if the therapeutic plan for their use is previously approved by the Ethics Committee and after informed consent from the patient/parents. Promising results have been obtained, particularly for sumatriptan in nasal spray formulation as well as for zolmitriptan and rizatriptan, showing a high tolerability and safety profile.

Nitroglycerin induces migraine headache and central sensitization phenomena in patients with migraine without aura: a study of laser evoked potentials

In migraineurs nitroglycerin (NTG) induces severe delayed headache, resembling spontaneous migraine attacks. The aim of the present study was to evaluate NTG laser evoked potentials (LEP) features amplitude and pain sensation to laser stimuli during NTG-induced headache. Nine patients were selected. Headache was induced by oral administration of 0.6 mg of NTG; signals were recorded through disk electrodes placed at the vertex and referred to linked earlobes. CO 2-LEPs delivered by stimulation of the dorsum of both hands and the right and left supraorbital zones were evaluated after the onset of moderate or severe headache resembling spontaneous migraine and at least 72 h after the end of the headache phase. Patients exhibited a significant heat pain threshold reduction and an LEPs amplitude increment during headache when both the supraorbital zones were stimulated. NTG appeared to support a reliable experimental model of migraine, based on the neuronal effects on the integrative-nociceptive structures. The LEPs facilitation during NTG-induced headache may be subtended by a hyperactivity of nociceptive cortex as well as by a failure of pain-inhibitory control.

Cgrp May Play A Causative Role in Migraine

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.

Non-linear electroencephalogram dynamics in patients with spontaneous nocturnal migraine attacks

The present study was conducted to examine non-linear electroencephalogram (EEG) measures during the development of a spontaneous migraine attack. We investigated the sleep EEG of five patients with migraine without aura in the pain-free interval and at the onset of a nocturnal attack. Sleep EEG recordings were analysed using the method of global dimensional complexity compared to conventional sleep scoring techniques. We found no divergence between classical sleep architecture and the estimated dimensional course nor any relevant short-term changes related to the onset of headache. There was, however, a loss of dimensional complexity in the first two non-rapid eye movement sleep states in the migraine night, with statistical significance during the second sleep cycle. For the first time, these results provide evidence of a global dimension decrease that is related to cortical network changes during a migraine attack.

Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks.

Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the L-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be confirmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of five patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha, the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the first hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (ANOVA, statistical significance: P<0.001; P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha, as well as cAMP levels also significantly increased at the first hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively). Our results support early activation of the L-arginine/NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase.

Nitric oxide in primary headaches

Nitric oxide (NO) has been proposed to be a key molecule in migraine. Experimental evidence suggests its intervention in vasodilatation and activation of the trigeminovascular system as well as its involvement in the supraspinal pathways implicated in head and pain processing. Other findings suggest the implication of NO in coupling neuronal and vascular changes during spreading depression. A potential role for NO has also been proposed in the pathophysiological mechanisms underlying cluster headache and chronic tension-type headache. The most relevant evidence for an increased response to exogenous NO in all primary headaches emerges from the experimental model of nitroglycerin-induced headache. Moreover, the effectiveness of non-selective NO synthase inhibitor L-N-monomethylarginine (L-NMMA) further supports the involvement of NO in migraine and chronic tension-type headache. The endogenous increase in NO production has been shown only in studies carried out during spontaneous migraine attacks which demonstrated increased levels of nitrites and cGMP in peripheral blood and internal jugular blood; the latter was followed by an increased production of algogenic and vasodilatatory prostanoids. These data suggest the potential activation of cyclooxygenase (COX) due to NO. Additional evidence suggests the increased activity of L-arginine/NO pathway in the platelet model in migraine patients. This increase was also evident between attacks, more accentuated during attacks and expressed to a greater extent during late luteal phase in menstrual migraine. Higher NO production in platelet was also demonstrated in patients affected by chronic daily headache and they are accompanied by significant lower serotonin content and higher levels of intracellular calcium. Whether these changes may be expressed in the central nervous system is a matter of discussion. These data taken together suggest a crucial role played by NO in neurovascular headaches and chronic headaches. Further research concerning NO in all primary headaches will be aimed at verifying changes of reliable markers of NO metabolism and NO effects, to better understand the complex COX/NO synthase (NOS) interactions, to investigate the effectiveness of selective NOS inhibitors in discriminating neural versus vascular involvement of NO.

Investigations into the role of nitric oxide and the large intracranial arteries in migraine headache.

Previous studies suggest that nitric oxide (NO) is involved in headaches induced by i.v. infusion of the vasodilator and NO donor glyceryl trinitrate (GTN) in healthy subjects. Extending these studies to sufferers of migraine without aura, it was found that migraineurs experienced a stronger headache than non-migraineurs. In addition, most migraineurs experienced a delayed migraine attack at variable times (mean 5.5 h) after GTN provocation. This biphasic headache response in migraineurs may be linked to hypersensitivity in the NO-cGMP pathway. Thus, compared to controls, migraineurs were found to be more sensitive to GTN-induced intracranial arterial dilatation, which is known to be mediated via liberation of NO and subsequent synthesis of cGMP Furthermore, histamine infusions in migraineurs induced headache responses and intracranial arterial responses resembling those induced by GTN in migraineurs. Histamine is known to liberate NO from the endothelium via stimulation of the H1 receptor, which is present in the large intracranial arteries in man. Because both immediate histamine-induced headache and intracranial arterial dilatation and delayed histamine-induced migraine are blocked by H1-receptor blockade, a likely common pathway for GTN and histamine-induced headaches/migraines and intracranial arterial responses may be via activation of the NO-cGMP pathway. The delay in the development of these experimental migraines may reflect activation of multiple physiological processes. The intracranial arteries of migraineurs were found supersensitive to the vasodilating effect of GTN (exogenous NO). This relates to clinical findings suggesting dilatation of the large intracranial arteries on the headache side during spontaneous migraine attacks. The function of arterial regulatory mechanisms involving NO in migraine was therefore studied. In peripheral arteries, no endothelial dysfunction of NO was found and cardiovascular and intracranial arterial sympathetic function was normal. A mild parasympathetic dysfunction may be involved and may, via denervation supersensitivity, be responsible for the observed supersensitivity to NO. Another possibility is that NO initiates a perivascular neurogenic inflammation with liberation of vasoactive peptides. NO also mediates a variety of other physiological phenomena. One of these, the pain-modulating effect observed in animals, was evaluated in a human study using GTN infusion and measurements of pain thresholds. No definite effects of GTN were demonstrated. The precise mechanisms involved in NO-triggered migraines and which part of the NO-activated cascade that is involved remain to be determined. The possibilities for pharmacological stimulation and/or inhibition of several steps of the NO-activated cascade increase rapidly and soon may be available for human studies.

Nitric oxide synthase inhibition in migraine

The nitric oxide (NO) donor, glyceryl trinitrate, and histamine, a stimulator of endogenous nitric oxide formation, have both been shown to trigger migraine attacks indistinguishable from patients' spontaneous attacks. 1 Thomsen LL Kruuse C Iversen HK Olesen J A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol. 1994; 1: 73-80 Crossref PubMed Scopus (264) Google Scholar , 2 Lassen LH Thomsen LL Olesen J Histamine induces migraine via the H1-receptor: support for the NO hypothesis of migraine. Neuroreport. 1995; 6: 1475-1479 Crossref PubMed Scopus (145) Google Scholar These studies have led us to propose the so-called nitric oxide hypothesis of migraine. 3 Olesen J Thomsen LL Lasssen LH Olesen IJ The nitic oxide hypothesis of migraine and other vascular headaches. Cephalalgia. 1995; 15: 94-100 Crossref PubMed Scopus (205) Google Scholar However, it remains unknown whether NO is involved throughout the entire attack. This was explored by studying the effect of the nitric oxide synthase (NOS) inhibitor L-NG methylarginine hydrochloride (546C88) on spontaneous migraine attacks.

Dopamine Hypersensitivity in Migraine

We investigated the effects of apomorphine administration at two different doses (2-10 micrograms/kg, s.c.) in 35 migraineurs in headache-free period and in 20 age-matched healthy control subjects, with and without pretreatment with domperidone. Neither patients or controls complained of headache at either dose, whereas at the dose of 10 micrograms/kg migraineurs showed a statistically significant higher incidence of dopaminergic symptoms (nausea, vomiting, drowsiness, yawning, dizziness, sweating) than controls. Furthermore, symptoms due to postsynaptic dopamine receptors activation (i.e., nausea and vomiting) only appeared in migraineurs. No symptom, however, resembled those characterizing a spontaneous migraine attack. In conclusion, migraineurs show a lower threshold for dopamine receptor activation than normal subjects.

Arterial mechanisms in the pathophysiology of migraine headache—implications for modern therapy

Studies of the cephalic vascular system have markedly contributed towards an understanding of the mechanisms of migraine pain. Whereas cerebral blood flow changes, and thereby changes in the arterioles, correlate poorly with migraine headache, abnormal regulation of the large cranial arteries seems to play a significant role in relation to migraine pain. Thus, vasodilation of extra- and intracranial conductance arteries has been described both during spontaneous migraine attacks and during experimentally provoked vascular headaches. Whether dilation of these arteries is the key mechanism of migraine nociception or is merely associated with another more important nociceptive mechanism remains to be shown. Studies of vascular regulatory mechanisms have not only pointed towards a possible locus of migraine pain, but have also been helpful in demonstrating a new molecular mechanism of migraine-the key effect of the small messenger molecule nitric oxide. It is likely that nitric oxide is the most important molecule responsible for the induction of migraine attacks.

The autonomic nervous system and the regulation of arterial tone in migraine.

Abnormal regulation of the large cranial arteries seems to play a significant role in the mechanisms of migraine pain. Thus, vasodilatation of extra- and intracranial conductance arteries has been described both during spontaneous migraine attacks and during experimentally provoked vascular headaches. The regulation of the diameter of these arteries is complex and involves autonomic, trigeminovascular, endothelial and humoral mechanisms. Studies concerned with the function of the autonomic nervous system in migraine suggest that a mild parasympathetic dysfunction may be present. Cerebral arteries in migraineurs are hypersensitive to nitric oxide, which may induce migraine attacks. As the enzyme responsible for nitric oxide synthesis is present in parasympathetic nerve endings around cerebral arteries, this supports a role for the parasympathetic nervous system in migraine. In addition, vasoactive transmitters released from perivascular trigeminal nerve endings may be implicated. Several of these aspects are closely linked to the presumed mechanisms of action of modern migraine therapeutics.

Neuropeptides in the cerebral circulation: relevance to headache.

The article briefly describe the innervation of the human cerebral circulation by nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP). The neuropeptides in human cerebral arteries were characterized by radioimmunoassay in combination with HPLC. These neuropeptides mediate contraction (NPY) and dilation (VIP, SP, CGRP). In conjunction with spontaneous attacks of migraine or cluster headache, release of CGRP is seen. With the associated symptoms of nasal congestion and rhinorrhea, VIP is released. Successful treatment may abort the peptide release in parallel with disappearance of headache.