Understanding the Patient With Migraine: The Evolution From Episodic Headache to Chronic Neurologic Disease. A Proposed Classification of Patients With Headache

Roger K. Cady, MD; Curtis P. Schreiber, MD; Kathleen U. Farmer, PsyD


Headache. 2004;44(5) 

In This Article

Clinical and Pathophysiological Anatomy of a Migraine Attack

Preheadache Phases: Prodrome and Aura Prodrome

Symptoms occurring before the onset of headache associated with migraine have been acknowledged since ancient times. Numerous eminent clinicians have described the occurrence of preheadache symptomatology, including Willis, Liveing, Babinski, Charcot, Graham, and Wolff. Blau, however, described these symptoms as a prodrome implying that it was an integral component of the migraine process. He reported that many patients have a period early in the migraine process of "headache awareness" where the headache has yet to declare its path of evolution.[13] Consequently, patients may delay therapy as they "wait and see" which presentation of the migraine process will unfold. This prompts patients to postpone treatment or to employ treatment beyond the point when it is likely to be effective. Patients then may experience unnecessary disability and unwarranted risk from utilizing medications when they are unlikely to provide therapeutic value.

Prodromal or premonitory symptoms can range widely from patient to patient or even from headache to headache within the same patient. These symptoms often begin hours to days before the onset of the headache phase of migraine. Prodromes are nonfocal neurologic changes that represent the earliest symptoms of migraine. Not all prodromal symptoms progress to the headache phase of migraine.[15] Frequency and consistency with which prodrome symptoms occur before the headache phase of migraine are generally unknown. In the American Migraine Study II, approximately 70% of migraineurs reported at least one premonitory symptom occurring before the onset of headache.[2] In an electronic diary study with subjects who reported having prodromes predictive of most of their migraines, 82% predicted over 50% of their headaches by the presence of premonitory symptoms.[17]

Impact of the premonitory period has also been evaluated. Using visual analog scales, Giffin et al found that many patients experienced significant impact of migraine during the premonitory period.[17] Farmer et al, using a modification of the Automated Neuropsychological Assessment Metrics, demonstrated significant reduction in cognitive performance associated with the premonitory period.[18] These studies, while not conclusive, support the concept that the prodrome is a valid phase of migraine that can create a significant impact for some migraineurs.

The pathophysiology of the prodrome is largely unstudied. The varied nature of symptoms associated with prodrome, however, suggests that central disruption occurs at both cortical and subcortical levels. For example, changes in water metabolism or appetite would implicate hypothalamic involvement, and the presence of cognitive slowing suggests cortical level disruption.


Aura is one of the most dramatic neurologic events associated with migraine. It is distinguished from prodrome by the focal nature of the neurologic symptoms. Historically, aura was considered to be the consequence of migraine-associated vasoconstriction of cerebral vessels that resulted in focal areas of reduced cerebral blood flow leading to oligemia or even ischemia. These symptoms were historically considered as evidence for a vascular model of migraine. In 1944, however, Leão reported on a neuronal phenomenon termed spreading cortical depression resulting from noxious substances being applied to the brain of rabbits.[19] The resulting wave of neuronal depression spread at a rate similar to the progression of the aura symptoms observed clinically.[20] Though direct confirmation of spreading depression causing aura remains somewhat speculative, considerable evidence does support aura to be a neuronal rather than a vascular event.[21,22] Whether neuronal depression occurs as a phase of all migraine attacks or just those with the clinical event of aura is unknown, but it is tempting to speculate that spreading cortical depression may be an important mechanism by which the trigeminovascular system can be activated.[23]

Aura is most commonly visual, though it can be sensory or, more rarely, motor. Occasionally, auras can produce impressive distortions of perception that are hallucinogenic in nature. These auras have been named the Alice in Wonderland syndrome.[24] According to IHS diagnostic criteria, a single aura symptom should last less than 60 minutes and most evolve slowly over several minutes. Classically, aura occurs before the onset of the headache phase of migraine, but perhaps as many as 40% of patients experiencing migraine with aura report its continuation into or recurrence during the headache phase.[25] According to IHS diagnostic criteria (1988), after experiencing 2 previous episodes of migraine with aura, any headache following an aura is migraine regardless of its characteristics or associated symptoms.[10]

Headache Phases

Mild, Moderate, and Severe. The headache of migraine typically begins as a mild pain that is nonthrobbing in character and may be diffuse. Duration of the mild pain phase is variable, lasting from minutes to hours or even days. The headache frequently progresses to moderate or severe intensity, though only approximately 8% of headaches are reported to remain at mild intensity even in a population receiving prescribed treatment for migraine.[26] On average, the duration of the moderate to severe headache phase ranges from 4 to 72 hours.[10] As the headache process progresses from mild to moderate or severe, the headache characteristically localizes, becomes increasingly aggravated by routine physical activity, and may become throbbing. Many associated symptoms are common during the headache phase of migraine. Those selected as part of the IHS diagnostic criteria for migraine without aura are nausea, vomiting, photophobia, and phonophobia. A multitude of other symptoms, however, are commonly observed such as fatigue, drowsiness, osmophobia, cognitive slowing, muscle pain, diarrhea, and mood changes ( Table ).[8,27,28] Cranial autonomic symptoms such as nasal congestion, rhinorrhea, and lacrimation commonly occur as part of the migraine process.[29] It is felt that the occurrence of these autonomic symptoms often leads to an erroneous association of headache to "sinus" disease rather than migraine.[9]

The pathophysiology of the mild headache phase of migraine has not been studied rigorously. Given the diffuse and often subtle nature of symptoms commonly witnessed during early headache, however, it is likely that there is insufficient inhibition of sensory input entering the trigeminal nucleus caudalis (TNC) in the brain stem. This may be due to central factors disinhibiting the TNC or from accelerated sensory traffic from the trigeminal nerve or upper cervical dermatomes that have input into the rostral nuclei of the TNC. As the headache process progresses and intensifies to moderate to severe levels of pain, the initial underlying pathophysiology is probably related to trigeminovascular activation with the release of inflammatory peptides such as the calcitonin gene-related peptide in the trigeminal vascular system. This, in turn, results in vasodilation and lowering of the sensory threshold required to activate trigeminal afferents. Consequently, there is an overabundance of sensory traffic entering the brain stem. Once centralized, these stimuli are amplified through disinhibition of central sensory processing mechanisms, and migraine can rapidly escalate into an allodynic pain state. This process has been termed central sensitization.

Postheadache Phases: Resolution and Postdrome Resolution

The mechanism by which the cascade of migraine resolves and the nervous system recovers is unknown. Migraine resolution commonly occurs during sleep. Further, it has been observed that events such as vomiting or a strong emotional stimulus can occasionally result in rapid resolution of migraine.[5] Serotonin and serotonin receptor agonists can rapidly terminate migraine, thus suggesting a role for serotonergic mechanisms in migraine resolution.[30]


The postdrome is a constellation of symptoms that persist beyond the resolution of headache. Many of these symptoms appear initially during the prodrome or with the headache phase. Commonly, patients report anorexia, nausea, muscle tension, fatigue, and cognitive impairment. This phase has been termed the migraine hangover and can last and produce disability up to 1 to 2 days beyond the headache phase. The pathophysiology of the postdrome is unknown, but likely represents a gradual recovery phase from the extreme neurologic disruption that occurs during migraine.


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