Unanswered Questions in Headache: How Does a Migraine Attack Stop?

Much research in migraine focuses on understanding its initiation. But as migraine is typically self‐limited, its offset may be as important as its onset. We pose the question “how does migraine stop?” to three investigators with different backgrounds. The consensus is that the termination of a migraine attack, rather than being the passive loss of a trigger, must itself be an active biologic process.     

Acephalgic Migraine

SYNOPSIS
Acephalgic migraine is a term used interchangeably with the term migraine equivalents. These terms by definition refer to any migrainous phenomena that may occur in the absence of a migraine headache.¹ Perhaps 20% of migraineurs may experience acephalgic attacks of migraine at one time or another. The idea that various symptoms can occur in the absence of any headache has been noted for hundreds of years, but very little has been written about this condition recently. Some people do not believe the symptoms that are often classified as migraine equivalents are in actuality part of the migraine syndrome. Because there is as yet no specific test for migraine, there is no proof that these various symptoms are due to the same neurovascular dysfunction we know as migraine. The diagnosis of migraine is based only on the patient's history and the exclusion of other diagnoses. It is not unusual for a headache patient to see several headache "specialists" and be given different diagnoses.
Some prefer the term "migraine accompaniments" for neurological or visual symptoms occurring with or without a headache.² The aura of the classic migraine attack may linger into the painful phase and thus "accompany" rather than just precede the headache. At times, symptoms typical of the aura may occur and may not be followed by a headache (acephalgic migraine). The term "complicated migraine"should probably be reserved for those neural and/or visual symptoms that outlast the headache by at least 24 hours and should not be used when referring to symptoms of shorter duration which may accompany the headache or which occur in the absence of migraine headache. Although non-visual migraine equivalents are not nearly as common as visual symptoms, it is important to recognize the fact that migraine may account for almost any recurrent, transient, episodic organ dysfunction.     

Migraine and cerebrovascular disease

Migraine and cerebrovascular disease are linked in different ways: migraine may be a potential cause of stroke as in migrainous infarction, headache may be a symptom of cerebrovascular disease and also a risk factor for stroke, the association of migraine and stroke may constitute specific syndromes such as CADASIL and MELAS. The new IHS 2003 criteria, though preserving their main structure, have changed the terminology regarding secondary headaches, now described as “attributed to” another disease rather than “associated with” it. The more detailed knowledge of causal links between the underlying disorder and headache, has allowed to strengthen the terminology. Many cerebrovascular disorders as cerebral haemorrhage, venous sinus thrombosis, carotid or vertebral dissections and ischaemic stroke may present with a headache or be followed by it. In subarachnoid haemorrhage (SAH) headache may constitute an important warning sign before the bleeding. An interesting issue is the hypothesis that migraine may be a potential risk factor for stroke. Recent studies have underlined the increased relative risk of ischemic stroke in female migraineurs. Many potential mechanisms have been hypothesized: (1) alterations of vasoreactivity due to vessel wall dysfunction, (2) release of vasoactive substances during migraine, (3) platelet hyperactivity as expression of serotoninergic dysfunction in migraineurs, (4) intriguing studies have described a high prevalence of migraine with aura in stroke patients with patent foramen ovale (PFO). Differential diagnosis between migraine and stroke remains fundamental: some types of migraine can mimic cerebrovascular disease such as familial hemiplegic migraine, and basilar migraine. Migraine and stroke may be part of syndromic complexes as in CADASIL and MELAS. In conclusion migraine is a risk factor for cerebrovascular disease, it may be the cause of stroke as in migrainous infarctions, stroke may induce headache which may be a relevant symptom of cerebrovascular disease, yet migraine remains an essentially benign condition.     

Posttraumatic Migraine

The term posttraumatic migraine has been used in several contexts. The purpose of this discussion is to outline the different circumstances in which migraine may follow trauma. Cases from the literature and from the Headache Unit of Montefiore Medical Center are reviewed.
Although trauma may be one of many triggers of migraine, trauma is sometimes the sole or predominant precipitating factor; eg, footballer's migraine. In the posttraumatic syndrome, some exacerbations of headache upon a background of chronic daily headache often fulfill the criteria of migraine. Trauma may trigger the first attack of migraine in a susceptible individual. Biochemical and epidemiologic studies suggest that trauma may be the main etiologic factor of migraine in some cases. Migraine may also follow trauma on the basis of chance.
Differentiating the different types of posttraumatic migraine has diagnostic, therapeutic, and legal implications.     

John Graham Senior Clinicians Award Lecture. Posttraumatic migraine

The term posttraumatic migraine has been used in several contexts. The purpose of this discussion is to outline the different circumstances in which migraine may follow trauma. Cases from the literature and from the Headache Unit of Montefiore Medical Center are reviewed. Although trauma may be one of many triggers of migraine, trauma is sometimes the sole or predominant precipitating factor; e.g., footballer's migraine. In the posttraumatic syndrome, some exacerbations of headache upon a background of chronic daily headache often fulfill the criteria of migraine. Trauma may trigger the first attack of migraine in a susceptible individual. Biochemical and epidemiologic studies suggest that trauma may be the main etiologic factor of migraine in some cases. Migraine may also follow trauma on the basis of chance. Differentiating the different types of posttraumatic migraine has diagnostic, therapeutic, and legal implications.     

Comorbid neuropathologies in migraine

The identification of comorbid disorders in migraineurs is important since it may impose therapeutic challenges and limit treatment options. Moreover, the study of comorbidity might lead to improve our knowledge about causes and consequences of migraine. Comorbid neuropathologies in migraine may involve mood disorders (depression, mania, anxiety, panic attacks), epilepsy, essential tremor, stroke, and white matter abnormalities. Particularly, a complex bidirectional relation exists between migraine and stroke, including migraine as a risk factor for cerebral ischemia, migraine caused by cerebral ischemia, migraine as a cause of stroke, migraine mimicking cerebral ischemia, migraine and cerebral ischemia sharing a common cause, and migraine associated with subclinical vascular brain lesions.     

Platelets in migraine

Modification in platelet activation and aggregation has been demonstrated in migraine patients both during and between attacks. A different pattern in the secretion of platelet products has also been observed in patients affected by migraine compared with controls. The most important variation concerns a hyposecretion of dense body products. Platelets share structural and functional analogies with monoaminergic neurons, in particular serotoninergic neurons, and have been used as a peripheral model to study monaminergic function in migraine patients. A reduced turnover of serotonin has been shown in migraine patients in the interictal period, whereas a reduced content of this monoamine was detected in patients with chronic daily headache (CDH), particularly in those with analgesic abuse. Nitric oxide metabolism was also studied in platelets of migraine patients between and during attacks. An increased activity of nitric oxide synthase (NOS), which was more accentuated during attacks, was found in these patients compared to healthy individuals. The increase in platelet NOS activity was also confirmed in CDH patients in association with a reduction of serotonin content and increased calcium levels. Variations in aggregation to different agents and secretion may not, at the moment, be indicative of similar changes in cerebral circulation of migraine patients. Its occurrence should be confirmed in samples of jugular venous blood during attacks to establish a definite link with migraine pathogenesis. Moreover changes in serotonin and NO metabolism observed in platelets of migraine patients may only indirectly suggest similar modifications in the neuronal pathways involved in inducing and maintaining head pain in migraineurs.     

Platelet glutamate uptake and release in migraine with and without aura

Glutamate may play an important role in the pathogenesis of migraine: glutamate release in the brain may be involved in the development of spreading depression and increased concentrations of this amino acid have been reported in plasma and platelets from migraine patients. Here we assessed platelet glutamate uptake and release in 25 patients affected by migraine with aura (MA) and 25 patients affected by migraine without aura (MoA), comparing the results with a group of 20 healthy matched controls. Both glutamate release from stimulated platelets and plasma concentrations of the amino acid were assessed by high-performance liquid chromatography, and were increased in both types of migraine, although more markedly in MA. Platelet glutamate uptake, assessed as 3H-glutamate intake, was increased in MA, while it was reduced in MoA with respect to the control group. These results support the view that MA might involve different pathophysiological mechanisms from MoA and, specifically, up-regulation of the glutamatergic metabolism. Understanding these dysfunctional pathways could lead to new, possibly more successful therapeutic approaches to the management of migraine.     

The serotonergic system in migraine

Serotonin (5–HT) and serotonin receptors play an important role in migraine pathophysiology. Changes in platelet 5–HT content are not casually related, but they may reflect similar changes at a neuronal level. Seven different classes of serotoninergic receptors are known, nevertheless only 5–HT2B–2C and 5HT1B–1D are related to migraine syndrome. Pharmacological evidences suggest that migraine is due to an hypersensitivity of 5–HT2B–2C receptors. m–Chlorophenylpiperazine (mCPP), a 5–HT2B–2C agonist, may induce migraine attacks. Moreover different pharmacological preventive therapies (pizotifen, cyproheptadine and methysergide) are antagonist of the same receptor class. On the other side the activation of 5–HT1B–1D receptors (triptans and ergotamines) induce a vasocostriction, a block of neurogenic inflammation and pain transmission.     

The Stress and Migraine Interaction

There are several ways in which stress may interact with migraine in those predisposed to migraine attacks. These interactions may result from biochemical changes related to the physiological stress response, as, for example, the release of corticotrophin releasing hormone, or from changes induced by the psychological response to stressors. Stress is the factor listed most often by migraine sufferers as a trigger for their attacks, but in addition there is evidence that stress can help initiate migraine in those predisposed to the disorder, and may also contribute to migraine chronification. Migraine attacks themselves can act as a stressor, thereby potentially leading to a vicious circle of increasing migraine frequency. Since the important factor in the stress–migraine interaction is likely the individual's responses to stressors, rather than the stressors themselves, the acquisition of effective stress management skills has the potential to reduce the impact of stressors on those with migraine.     

What is the evolutionary advantage of migraine?

Susceptibility to migraine is determined by genetic factors and is therefore subject to the forces of natural selection. Migraine is a common and ancient disorder whose prevalence may be increasing, suggesting that a migraine-prone nervous system may be associated with reproductive or survival advantages. Five evolutionary explanations are reviewed that might account for the persistence of migraine: (i). migraine as a defence mechanism; (ii). migraine as a result of conflict with other organisms; (iii). migraine as result of novel environmental factors; (iv). migraine as a trade-off between genetic harms and benefits; and (v). migraine as a design constraint. An evolutionary perspective on migraine allows the generation of important hypotheses about the disorder and suggests rewarding possibilities for further research.     

Increased nitrosative and oxidative stress in platelets of migraine patients

The molecular mechanisms of migraine have not been fully clarified yet. Increased nitrosative and oxidative stress may be associated with migraine attacks. Platelets may play an important role in migraine patients and they can reflect the lability of tissues to nitrosative/oxidative stress. In the present study, we aimed to determine the levels of nitrosative and oxidative stress markers in platelets of migraine patients during headache-free and attack periods. A total of 56 subjects (22 migraine without aura, 14 migraine with aura, and 20 age- and sex-matched healthy controls) were included in the study and nitric oxide (NO) metabolites, malondialdehyde (MDA), and thiol (SH) groups were measured in platelets. During migraine attacks, platelet levels of nitrate, nitrite and MDA were significantly higher in migraineurs than these in control subjects (p = 0.042, p = 0.005 and p = 0.042, respectively). By contrast, during headache-free period, no statistically significant differences were found in the platelet levels of nitrate, nitrite and MDA between migraineurs and controls (p > 0.05), although the marginal increases were detected in migraineurs. These results suggest that increased biomarkers of nitrosative and oxidative stress in platelets may be important in migraine patients, especially during attacks; increase of NO metabolites in platelets during attacks supports the opinion that NO may play a modulatory role in biological processes particularly by vasodilatation in migraine attacks. Therefore, MDA and NO metabolites may serve as useful markers to show the increased vulnerability to nitrosative and oxidative stress in migraine patients.     

Topiramate in migraine progression

Increasing evidence shows that migraine, typically considered as an episodic disease, is a chronic and, in some patients, progressive disorder. Among neuromodulators used for migraine prevention, topiramate has a high level of evidence-based efficacy. Through its wide range of mechanisms of action topiramate increases the activation threshold resulting in neuronal stabilization and thereby reducing cortical neurons hyperexcitability, which is believed to be an important electrophysiological feature underlying the pathogenesis of epilepsy and migraine. Recent studies show that migraineurs have subclinical structural brain changes and persistent alteration of pain perception, in some cases correlated with the duration of the disease and the frequency of attacks that might play a role in the transformation of episodic migraine to chronic forms. An early and prolonged preventive treatment might reduce the risk of such transformation. Recent evidence suggests that topiramate, by reducing migraine frequency and use of acute medication, may prevent the negative progression of migraine. Furthermore, two recently completed multicenter, randomised, placebo-controlled trials have shown that treatment with topiramate 100 mg/day is effective and well tolerated in patients already progressed to chronic migraine and difficult to treat conditions associated with medication-overuse. Topiramate seems to be a preventive treatment, which might be able to act at different levels of the migraine cycle: reduction of frequency in episodic migraine, prevention, and treatment of chronic migraine.     

Mechanism of Chronic Migraine

Chronic migraine typically evolves from episodic migraine over months to years in susceptible individuals. Headaches increase in frequency over time, becoming less intense but more disabling and less responsive to treatment. Results of electrophysiologic and functional imaging studies indicate that chronic migraine is associated with abnormalities in the brainstem that may be progressive. Additionally, chronic migraine is associated with a greater degree of impairment in cortical processing of sensory stimuli than is episodic migraine, perhaps due to a more pervasive or persistent cortical hyperexcitability. These findings fit with the model of migraine as a spectrum disorder, in which the clinical and pathophysiological features of migraine may progress over time. This progression is postulated to result from changes in nociceptive thresholds and ensuing central sensitization caused by recurrent migraine in susceptible individuals, for whom a variety of risk factors have been described. This may lead to changes in baseline neurologic function between episodes of headache, evident not only in electrophysiologic and functional imaging studies, but also as an increase in depression, anxiety, nonhead pain, fatigue, gastrointestinal disorders, and other somatic complaints that may occur after years of episodic migraine. From the current research and migraine models, a conceptualization of chronic migraine, in which relatively permanent and pervasive central changes that warrant novel and tolerable treatments have occurred, is emerging. This model also implies that prevention of chronic migraine is an important goal in the management of episodic migraine, particularly in individuals who exhibit risk factors for chronic transformation.     

Beyond Neurovascular: Migraine as a Dysfunctional Neurolimbic Pain Network

No single model of migraine explains all of the known features of the disorder. Migraine has recently been characterized as an abnormality in pain‐modulating circuits in the brainstem. The periaqueductal gray appears to have a critical role in migraine genesis and has been labeled the “migraine generator.” The concept of a “pain matrix,” rather than a specific locus of pain, is widely accepted in the pain literature and offers a new dimension to understanding migraine. Recent neuroimaging studies of migraineurs suggest altered functional connectivity between brainstem pain‐modulating circuits and cortical (limbic) centers. Numerous clinical observations suggest that limbic influences play an important role in migraine expression. We propose a model of migraine as a dysfunction of a “neurolimbic” pain network. The influence between brainstem and cortical centers is bidirectional, reflecting the bidirectional interaction of pain and mood. Neurolimbic dysfunction may increase as migraine becomes more chronic or refractory. The neurolimbic model expands the model of migraine as a dysfunction of brainstem nuclei. A neurolimbic model may help bridge a gap in understanding the migraine attack, the interictal dysfunctions of episodic migraine, the progression to chronic migraine, and the common comorbidities with other disorders (such as fibromyalgia, irritable bowel syndrome, and mood and anxiety disorders), which may also be considered neurolimbic. A neurolimbic model of migraine may be a useful heuristic that would impact both clinical treatment and research agendas, as well as education of physicians and patients.     

Molecular mechanisms of antimigraine drugs: past,present, and future

Pharmacotherapeutic treatments for migraine have been documented for more than a century. Drugs that are effective in aborting an ongoing migraine attack exhibit a diversity of molecular mechanisms of action, but usually produce constriction of cranial arterial blood vessels, reversal of neurogenic inflammatory processes, and/or inhibition of sensory neuronal firing. This general understanding of drug action has led to the development of a unitary hypothesis for migraine pathophysiology, in which the onset of migraine is associated with activation of the trigemino-vascular system. Drugs which inhibit or reverse the activation of this system are effective acute treatments for migraine. Drugs useful in migraine prophylaxis have been discovered largely serendipitously, and display a fundamentally different pharmacology to the acutely effective agents. These drugs act at membrane receptors and ion channels, or by targeting intracellular biochemical pathways, and tend to reduce neuronal excitability in higher centers of the CNS. However, other than to suggest that this inhibits various migraine trigger events, it is not yet possible to delineate precisely how these drugs act to decrease the frequency and severity of migraine attacks. More recently, it has been observed that migraine is accompanied by sensory neuronal central sensitization that manifests as cutaneous allodynia in territory innervated by the trigeminal nerve. Although little is presently known about the ability of prophylactic drugs to modulate this process, it was recently shown that acute relief of migraine with triptan drugs is only reliably achieved when the drugs are given prior to the development of central sensitization. This important observation suggests that inhibition of migraine-related central sensitization could be an important new focus for future drug discovery, and may, for the first time, provide a rational target for the development of preventative medicines.     

GABA and glutamate in migraine

GABA and glutamic acid are the main inhibitory and excitatory neurotransmitters of central nervous system. Among other functions they modulate the pain threshold in the CNS. For this reason it has been hypothesized that anomalies of GABA and glutamate turn–over may play a role in migraine pathogenesis. In this review are discussed the evidences in favour of this hypothesis. A derangement of GABA may be an important factor in the occurrence of migraine attacks and their recurrence, whereas high level of glutamic acid may represent a biochemical marker of the neuronal hyperexcitability that may be the underlying cause of the aura. The pharmacological modulation of metabolism of both neurotransmitters is a promising approach to improve migraine therapy. In particular the studies presented here suggest that gabaergic drugs may be useful in migraine without aura, antiglutamatergic drugs are indicated to treat migraine with aura.     

Pathophysiology,epidemiology, and impact of migraine

Despite a decade of progress, migraine headache remains prevalent, disabling, underdiagnosed, and undertreated in the United States. Migraine affects ∼12% of the population, and the economic burden in terms of annual cost of labor lost to migraine disability is between $5.6 and $17.2 billion. The threshold for migraine may be genetically determined, although recent genetic and neurophysiologic studies point to migraine as possibly a channelopathy. Cerebral cortical and brain stem changes occur in migraine. Head pain and associated symptoms of migraine can be explained by activation of the trigeminal vascular system. Evidence has also been accumulated that suggests the release of nitric oxide is an important trigger mechanism. Introduction of the triptans has dramatically advanced acute migraine pharmacotherapy, and preventive therapy has greatly improved; however, public health initiatives may be needed to further advance diagnosis and treatment of this common and disabling disorder.     

Migraine prevention: what patients want from medication and their physicians (a headache specialty clinic perspective)

OBJECTIVE: To document the results of a migraine patients survey, from a headache specialty clinic, in which patients were asked to rank, in order of importance, certain characteristics of migraine preventive treatment. METHODS: A 10-question survey was completed by 150 patients (114 females and 36 males) with a history of migraine who presented to the Michigan Head Pain & Neurological Institute. The patients were asked to rank, in order of importance, characteristics of migraine preventive treatment. Each characteristic was rated individually on a 1 to 10 scale (1 being of little importance and 10 being extremely important). The mean rating of each characteristic was then calculated and the results analyzed. RESULTS/DISCUSSION: From this migraine preventive treatment survey, the most important thing to migraineurs, from a headache specialty clinic population, is that the prescribing physician involves them in the decision making of choosing a preventive agent. The physician taking time to explain the possible medication side effects is the second most highly ranked characteristic. Migraine preventives with published efficacy in the medical literature are also deemed very important. Migraineurs do not mind using more than 1 preventive agent at one time if greater efficacy can be achieved. Agents that may affect weight and/or cause sedation may be important factors as to why patients (especially females) may not want to take a preventive medication. Natural therapies and once-daily dosing are ranked lower overall but still are important characteristics of preventive treatment. Some gender differences are noted in the ranking of migraine preventive characteristics.     

Pathophysiology,epidemiology, and impact of migraine

Despite a decade of progress, migraine headache remains prevalent, disabling, underdiagnosed, and undertreated in the United States. Migraine affects approximately 12% of the population, and the economic burden in terms of annual cost of labor lost to migraine disability is between $5.6 and $17.2 billion. The threshold for migraine may be genetically determined, although recent genetic and neurophysiologic studies point to migraine as possibly a channelopathy. Cerebral cortical and brain stem changes occur in migraine. Head pain and associated symptoms of migraine can be explained by activation of the trigeminal vascular system. Evidence has also been accumulated that suggests the release of nitric oxide is an important trigger mechanism. Introduction of the triptans has dramatically advanced acute migraine pharmacotherapy, and preventive therapy has greatly improved; however, public health initiatives may be needed to further advance diagnosis and treatment of this common and disabling disorder.