HEADACHE, INCLUDING MIGRAINE 2

PRINCIPAL CLINICAL VARIETIES OF RECURRENT HEADACHE

There is usually little difficulty in diagnosing the serious types of headaches listed above because of the clues provided by the associated symptoms and signs. It is when headache is chronic, recurrent, and unattended by other important signs of disease that the physician faces a challenging and unique medical problem. The following sections describe a variety of headache types, ranging from the most common (e.g., tension-type headache) to rare causes of recurrent headache.

TENSION-TYPE HEADACHE

The term tension-type headache is still commonly used to describe a chronic head pain syndrome characterized by bilateral tight, bandlike discomfort. Patients may report that the head feels as if it is in a vise or that the posterior neck muscles are tight. The pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days. Exertion does not usually worsen the headache. The headache may be episodic or chronic (i.e., present more than 15 days per month). Tension-type headache is common in all age groups, and females tend to predominate. In some patients, anxiety or depression coexist with tension headache.

The pathophysiologic basis of tension-type headache remains unknown. Some investigators believe that periodic tension headache is biologically indistinguishable from migraine, whereas others believe that tension-type headache and migraine are two distinct clinical entities. Abnormalities of cervical and temporal muscle contraction are likely to exist, but the exact nature of the dysfunction has not yet been elucidated.

Relaxation almost always relieves tension-type headaches. Patients should be encouraged to find a means of relaxation, which, for a given individual, could include bed rest, massage, and/or formal biofeedback training. Pharmacologic treatment consists of either simple analgesics and/or muscle relaxants. Ibuprofen and naproxen sodium are useful treatments for most individuals. When simple over-the-counter analgesics such as acetaminophen, aspirin, ibuprofen, and/or other nonsteroidal anti-inflammatory drugs (NSAIDs) alone fail, the addition of butalbital and caffeine (in a combination compound such as Fiorinal, Fioricet) to these analgesics may be effective. A list of commonly used analgesics for tension-type headaches is presented in . For chronic tension-type headache, prophylactic therapy is recommended. Low doses of amitriptyline (10 to 50 mg at bedtime) can provide effective prophylaxis.

MIGRAINE

Migraine, the most common cause of vascular headache, afflicts approximately 15% of women and 6% of men. A useful definition of migraine is a benign and recurring syndrome of headache, nausea, vomiting, and/or other symptoms of neurologic dysfunction in varying admixtures. Migraine can often be recognized by its activators (red wine, menses, hunger, lack of sleep, glare, estrogen, worry, perfumes, let-down periods) and its deactivators (sleep, pregnancy, exhiliration, sumatriptan). A classification of the many subtypes of migraine, as defined by the International Headache Society, is shown in .

Severe headache attacks, regardless of cause, are more likely to be described as throbbing and associated with vomiting and scalp tenderness. Milder headaches tend to be nondescript¾tight, bandlike discomfort often involving the entire head¾the profile of tension-type headache.

Pathogenesis

Genetic Basis of Migraine Migraine has a definite genetic predisposition. Specific mutations leading to rare causes of vascular headache have been identified. For example, the MELAS syndrome consists of a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and is caused by an A ® G point mutation in the mitochondrial gene encoding for tRNALeu(UUR) at nucleotide position 3243. Episodic migraine-like headaches are another common clinical feature of this syndrome, especially early in the course of the disease. The genetic pattern of mitochondrial disorders is unique, since only mothers transmit mitochondrial DNA. Thus, all children of mothers with MELAS syndrome are affected with the disorder.

Familial hemiplegic migraine (FHM) is characterized by episodes of recurrent hemiparesis or hemiplegia during the aura phase of a migraine headache. Other associated symptoms may include hemianesthesia or paresthesia; hemianopic visual field disturbances; dysphasia; and variable degrees of drowsiness, confusion, and/or coma. In severe attacks, these symptoms can be quite prolonged and persist for days or weeks, but characteristically they last for only 30 to 60 min and are followed by a unilateral throbbing headache.

Approximately 50% of cases of FHM appear to be caused by mutations within the CACNL1A4 gene on chromosome 19, which encodes a P/Q type calcium channel subunit expressed only in the central nervous system. The gene is very large (>300 kb in length) and consists of 47 exons. Four distinct point mutations have been identified within the gene (in five different families) that cosegregate with the clinical diagnosis of FHM. Analysis of haplotypes in the two families with the same mutation suggest that each mutation arose independently rather than representing a founder effect. Thus, certain subtypes of FHM are caused by mutations in the CACNL1A4 gene. The function of the CACNL1A4 gene remains unknown, but it is likely to play a role in calcium-induced neurotransmitter release and/or contraction of smooth muscle. Different mutations within this gene are the cause of another neurogenetic disorder, episodic ataxia type 2.

In a genetic association study, a NcoI polymorphism in the gene encoding the D2 dopamine receptor (DRD2) was overrepresented in a population of patients with migraine with aura compared to a control group of nonmigraineurs, suggesting that susceptibility to migraine with aura is modified by certain DRD2 alleles. In a Sardinian population, an association between different DRD2 alleles and migraine has also been demonstrated. Therefore, these initial studies suggest that variations in dopamine receptor regulation and/or function may alter susceptibility to migraine since molecular variations within the DRD2 gene have been associated with variations in dopaminergic function. However, since not all individuals with certain DRD2 genotypes suffer from migraine with aura, additional genes or factors must also be involved. Migraine is likely to be a complex disorder with polygenic inheritance and a strong environmental component.

The Vascular Theory of Migraine It was widely held for many years that the headache phase of migrainous attacks was caused by extracranial vasodilatation and that the neurologic symptoms were produced by intracranial vasoconstriction (i.e., the "vascular" hypothesis of migraine). Regional cerebral blood flow studies have shown that in patients with classic migraine there is, during attacks, a modest cortical hypoperfusion that begins in the visual cortex and spreads forward at a rate of 2 to 3 mm/min. The decrease in blood flow averages 25 to 30% (insufficient to explain symptoms on the basis of ischemia) and progresses anteriorly in a wavelike fashion independent of the topography of cerebral arteries. The wave of hypoperfusion persists for 4 to 6 h, appears to follow the convolutions of the cortex, and does not cross the central or lateral sulcus, progressing to the frontal lobe via the insula. Perfusion of subcortical structures is normal. Contralateral neurologic symptoms appear during temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no flow abnormalities; an occasional patient has developed focal ischemia sufficient to cause symptoms. However, focal ischemia does not appear to be necessary for focal symptoms to occur.

The ability of these changes to induce the symptoms of migraine has been questioned. Specifically, the decrease in blood flow that is observed does not appear to be significant enough to cause focal neurologic symptoms. Second, the increase in blood flow per se is not painful, and vasodilatation alone cannot account for the local edema and focal tenderness often observed in migraineurs. Moreover, in migraine without aura, no flow abnormalities are usually seen. Thus, it is unlikely that simple vasoconstriction and vasodilatation are the fundamental pathophysiologic abnormalities in migraine. However, it is clear that cerebral blood flow is altered during certain migraine attacks, and these changes may explain some, but clearly not all, of the clinical syndrome of migraine.

The Neuronal Theory of Migraine In 1941, the psychologist KS Lashley charted his own fortification spectrum, which is a migraine aura characterized by a slowly enlarging visual scotoma with luminous edges (see below). He was able to estimate that the evolution of his own scotoma proceeded across the occipital cortex at a rate of 3 mm/min. He speculated that a wavefront of intense excitation followed by a wave of complete inhibition of activity were propagated across the visual cortex. In 1944, the phenomenon that has come to be known as spreading depression was described by the Brazilian physiologist Leao in the cerebral cortex of laboratory animals. It is a slowly moving (2 to 3 mm/min), potassium-liberating depression of cortical activity, preceded by a wavefront of increased metabolic activity that can be produced by a variety of experimental stimuli, including hypoxia, mechanical trauma, and the topical application of potassium. These observations suggest that neuronal abnormalities, most likely initiated in the brainstem, could be the cause of a migraine attack. More recently, both cortical and brainstem changes have been observed in positron emission tomography (PET) scan studies of migraine. Thus, the existence of a specific "brainstem generator" for migraine remains an intriguing possibility that might represent the pathophysiologic basis of migraine.

The Trigeminovascular System in Migraine Activation of cells in the trigeminal nucleus caudalis in the medulla (a pain-processing center for the head and face region) results in the release of vasoactive neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), at vascular terminations of the trigeminal nerve. These peptide neurotransmitters have been proposed to induce a sterile inflammation that activates trigeminal nociceptive afferents originating on the vessel wall, further contributing to the production of pain. This mechanism also provides a potential mechanism for the soft tissue swelling and tenderness of blood vessels that attend migraine attacks. However, numerous pharmacologic agents that are effective in preventing or reducing inflammation in this animal model (e.g., selective 5-HT1D agonists, NK-1 antagonists, endothelin antagonists) have failed to demonstrate any clinical efficacy in recent migraine trials.

5-Hydroxytryptamine in Migraine Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also know as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.

More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. Molecular cloning studies have demonstrated that at least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located both on blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.

Physiologically, electrical stimulation near dorsal raphe neurons can result in migraine-like headaches. Blood flow in the pons and midbrain increases focally during migraine headache episodes; this alteration probably results from increased activity of cells in the dorsal raphe and locus caeruleus. There are projections from the dorsal raphe that terminate on cerebral arteries and alter cerebral blood flow. There are also major projections from the dorsal raphe to important visual centers, including the lateral geniculate body, superior colliculus, retina, and visual cortex. These various serotonergic projections may represent the neural substrate for the circulatory and visual characteristics of migraine. The dorsal raphe cells stop firing during deep sleep, and sleep is known to ameliorate migraine; the antimigraine prophylactic drugs also inhibit activity of the dorsal raphe cells through a direct or indirect agonist effect.

Recent PET scan studies have demonstrated that midbrain structures near the dorsal raphe are differentially activated during a migraine attack. In one study of acute migraine, an injection of sumatriptan relieved the headache, but did not alter the brainstem changes noted on the PET scan. These data suggest that a "brainstem generator" may be the cause of migraine and that certain antimigraine medications may not interfere with the underlying pathologic process in migraine.

Dopamine in Migraine A growing body of biologic, pharmacologic, and genetic data support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. As noted above, recent genetic data also suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.

The Sympathetic Nervous System in Migraine Biochemical changes occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all trigger factors for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines [e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine (mCPP) and reserpine]. By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs) and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.

Clinical Features

Migraine without Aura (Common Migraine) In this syndrome no focal neurologic disturbance precedes the recurrent headaches. Migraine without aura is by far the more frequent type of vascular headache. The International Headache Society criteria for migraine include moderate to severe head pain, pulsating quality, unilateral location, aggravation by walking stairs or similar routine activity, attendant nausea and/or vomiting, photophobia and phonophobia, and multiple attacks, each lasting 4 to 72 h.

Migraine with Aura (Classic Migraine) In this syndrome headache is associated with characteristic premonitory sensory, motor, or visual symptoms. Focal neurologic disturbances are more common during headache attacks than as prodromal symptoms. Focal neurologic disturbances without headache or vomiting have come to be known as migraine equivalents or migraine accompaniments and appear to occur more commonly in patients between the ages of 40 and 70 years. The term complicated migraine has generally been used to describe migraine with dramatic transient focal neurologic features or a migraine attack that leaves a persisting residual neurologic deficit.

The most common premonitory symptoms reported by migraineurs are visual, arising from dysfunction of occipital lobe neurons. Scotomas and/or hallucinations occur in about one-third of migraineurs and usually appear in the central portions of the visual fields. A highly characteristic syndrome occurs in about 10% of patients; it usually begins as a small paracentral scotoma, which slowly expands into a "C" shape. Luminous angles appear at the enlarging outer edge, becoming colored as the scintillating scotoma expands and moves toward the periphery of the involved half of the visual field, eventually disappearing over the horizon of peripheral vision. The entire process lasts 20 to 25 min. This phenomenon is pathognomonic for migraine, and has never been described in association with a cerebral structural anomaly. It is commonly referred to as a fortification spectrum because the serrated edges of the hallucinated "C" seemed to resemble a "fortified town with bastions all round it"; "spectrum" is used in the sense of an apparition or specter.

Basilar Migraine Symptoms referable to a disturbance in brainstem function, such as vertigo, dysarthria, or diplopia, occur as the only neurologic symptoms of the attack in about 25% of patients. A dramatic form of basilar migraine (Bickerstaff's migraine) occurs primarily in adolescent females. Episodes begin with total blindness accompanied or followed by admixtures of vertigo, ataxia, dysarthria, tinnitus, and distal and perioral paresthesia. In about one-quarter of patients, a confusional state supervenes. The neurologic symptoms usually persist for 20 to 30 min and are generally followed by a throbbing occipital headache. This basilar migraine syndrome is now known also to occur in children and in adults over age 50. An altered sensorium may persist for as long as 5 days and may take the form of confusional states superficially resembling psychotic reactions. Full recovery after the episode is the rule.

Carotidynia The carotidynia syndrome, sometimes called lower- half headache or facial migraine, is most common among older patients, with the incidence peaking in the fourth through sixth decades. Pain is usually located at the jaw or neck, although sometimes periorbital or maxillary pain occurs; it may be continuous, deep, dull, and aching, and it becomes pounding or throbbing episodically. There are often superimposed sharp, ice pick-like jabs. Attacks occur one to several times per week, each lasting several minutes to hours. Tenderness and prominent pulsations of the cervical carotid artery and soft tissue swelling overlying the carotid are usually present ipsilateral to the pain; many patients also report throbbing ipsilateral headache concurrent with carotidynia attacks as well as between attacks. Dental trauma is a common precipitant of this syndrome. Carotid artery involvement also appears to be common in the more traditional forms of migraine; over 50% of patients with frequent migraine attacks are found to have carotid tenderness at several points on the side most often involved during hemicranial migraine attacks.