When you're lying awake

With a dismal headache

And repose is taboo'd by anxiety,

I conceive you may use

Any language you choose

To indulge in without impropriety.

“Iolanthe” by W.S. Gilbert

A headache, in a variety of forms, is one of the most common complaints presented to the clinician. A new classification of headache has been proposed by the International Headache Society (IHS) and is summarized in Table 1.¹ This chapter addresses the neuro-ophthalmologic aspects of migraines and provides a brief review of other common headaches, facial and ocular pains.

A Migraine is a periodic and paroxysmal protean disorder that affects more than 17% of women and 6% of men in the United States.^2,3 It is estimated that the lifetime prevalence of migraine in women is 99% and the lifetime prevalence in men is 93%.⁴ Neuro-ophthalmologic symptoms and signs are common in migraines and should be recognized by the clinician. The term hemicrania evolved from a variety of older descriptions and was one of the first names for this disorder; this was later contracted by the French in the thirteen century to the word “migraine.” More than 300 years ago, Thomas Willis wrote the first modern description of a migraine and its possible causes. Historical figures believed to have had migraines include Julius Caesar, Emmanuel Kant, Alexander Pope, Isaac Newton, and Sigmund Freud. Throughout the eighteenth and nineteenth centuries, descriptions of the clinical phenomena and suggestions for therapy continued to appear in the writings of many prominent men in the medical professions. Sacks⁵ pays homage to Edward's masterful treatise On Megrim, Sick Headache, and Some Allied Disorders (1873) as an unequaled description of the disorder. Further detailed clinical descriptions are found in the writings of Gowers.⁶

In contemporary medicine, Dalessio, Goadsby, Raskin, Sacks, Silberstein, Lipton, Stewart, Saper, and Welch are among those who could be singled out for their contributions to the study of migraines. One central theme seems to decry the simplistic view that a migraine is defined by a unilateral (hemicranial) headache. As Sacks⁵ wrote, “It is necessary to state that headache is never the sole symptom of a migraine, nor indeed is it the necessary feature of migraine attacks.” Another quote emphasizes this belief: “Migraine is diagnosed by the entire history, not by physical findings or by the presence of headache alone.”⁷ It is unfortunate that many have limited their concept of migraine to a stereotyped syndrome of visual disturbance followed by unilateral throbbing headache, which is diagnosed by the response to ergot preparations. Migraine gives rise to a number of well-recognized syndromes, as well as a variety of “equivalents” less commonly considered as migraine. The symptom-complexes or syndromes of migraine include migraine without aura, migraine with aura, ophthalmoplegic migraine, retinal migraine, as well as the others listed in Table 1. The clinical features of migraine will be discussed according to the formal criteria published by the IHS in 2004.¹

Other conditions and syndromes discussed include cluster headache, trigeminal neuralgia, atypical facial pain, temporal arteritis, and the headaches produced by intracranial mass lesions, muscle contraction, trauma, vascular anomalies, and ocular lesions.

TABLE 1. New International Headache Society Classifications of Headaches

PRODROME

Premonitory phenomena occur in approximately 60% of migraineurs, often hours to days before the onset of headache. These phenomena include psychologic, neurologic, constitutional, and autonomic features. Psychologic symptoms include depression, euphoria, irritability, restlessness, mental slowness, hyperactivity, fatigue, and drowsiness. Neurologic phenomena include photophobia, phonophobia, and hyperosmia. The generalized or constitutional symptoms include a stiff neck, a cold feeling, sluggishness, increased thirst, increased urination, anorexia, diarrhea, constipation, fluid retention, and food cravings. Some patients just report a poorly characterized premonition that a migraine attack is coming.

AURA

An aura refers to the appearance of focal neurologic symptoms that proceed or even accompany an attack of migraine. Approximately 20% of migraine sufferers experience auras. Most aura symptoms develop over a course of 5 to 20 minutes and usually last less than 60 minutes. The aura can be characterized by visual, sensory, or motor phenomena, and may also involve language or brainstem disturbances. When a headache follows, it most often occurs within 60 minutes of the end of the aura. The appearance of isolated auras without headache is known as migraine dissociée. The most common aura is visual, previously termed classic migraine. It usually has a distribution in the right or left homonymous hemifields.

Sensory disturbances involve one side of the body and are characterized by descriptions of numbness or tingling on the face and in the hand. Further neurologic symptomatology is discussed under the heading of migraine with prolonged aura and migrainous infarction.

HEADACHE PHASE

The typical migraine headache is unilateral and throbbing. It may be bilateral and constant at first and later become throbbing. As pointed out by Lipton and Stewart,¹⁰ pain is characterized as throbbing in 85% of patients. However, it should be noted that a throbbing headache is described in other types of headache.¹¹ The pain of migraine is almost always accompanied by other features such as anorexia. Nausea occurs in up to 90% of patients and vomiting occurs in approximately one-third of migraineurs.¹⁰

Many patients experience photophobia, phonophobia, and osmophobia, and seek seclusion in a dark, quiet room. Additional generalized symptoms include blurry vision, nasal stuffiness, anorexia, hunger, tenesmus, diarrhea, abdominal cramps, polyuria (followed by decreased urinary output after the attack), facial pallor (or, less commonly, redness), sensations of heat or cold, and sweating.⁹ Localized edema of the scalp, the face, or the periorbital regions may occur; tenderness may occur and be particularly prominent. There may also be tenderness of the scalp, a special prominence of a vein or artery in the temple, or a stiffness or tenderness of the neck. Impaired concentration is common; memory impairment occurs less frequently. Depression, fatigue, anxiety, nervousness, and irritability are common. A sensation of faintness may be experienced. The IHS selects particular associated features as cardinal manifestations for diagnosis.

TERMINATION AND POSTDROME

In the termination phase, the pain diminishes. Thereafter the patient may be listless, tired, or “washed out” and not feel well for 24 to 48 hours. Rarely patients feel unusually refreshed or euphoric after an attack, whereas it is more common to note depression and malaise.⁹

According to Goadsby et al.,^16,17 a migraine is best understood as a primary disorder of the brain. A migraine is a polygenetic disorder believed to have a primary problem in the abnormal function of an ion channel in the brain-stem nuclei that modulates sensory input.¹⁷ Specific gene abnormalities have been found in patients with familial hemiplegic migraine, that is a missense mutation in the α₁ subunit of the voltage-gated P/Q-type calcium channels.¹⁸ As pointed out by Goadsby,¹⁶ it is likely that the aura of migraine is separate from the headache as cases of migraine with aura have been linked to the familial-hemiplegic-migraine locus.¹⁹

It was primarily through the work of Wolff and colleagues¹⁵ that vascular phenomenon were recognized as a mechanism responsible for the headache of migraine. Research to date suggests that the initiation of a migraine attack is primarily a neuronal phenomenon with secondary hemodynamic consequences.^17,23–26 Wolff divided the migraine attack into four phases: preheadache, headache, late headache, and postheadache. The preheadache phase is characterized by the constriction of certain blood vessels that supply the brain. Then, the beginning of the headache phase is characterized by vascular dilatation, particularly involving branches of the external carotid such as the temporal, occipital, and middle meningeal arteries. Local tenderness of the scalp ensues, and the scalp vessels may become rigid. The nature of the headache then changes from a pulsatile type to a more constant dull ache. Alleviation of the early headache phase with vasoconstrictors (e.g., ergotamine) is cited as evidence that this pain is related to vasodilatation. In their most simplistic form these concepts can be reduced to the idea that the cerebral symptomatology, including the auras of classic migraine, is the result of cerebral ischemia secondary to intracranial vessel spasm, and the ensuing headache phase is initiated by vasodilatation. However, vasodilatation may occur without pain, and additional factors are involved in the production of the headache. Local tissue changes take place (e.g., vessel edema, scalp swelling, and conjunctival chemosis) that may continue after vasodilatation has ceased. A wide variety of substances have causative roles in the production of large and small vessel dilatation as well as local tissue changes. Among the substances most frequently considered are the kinins (neurokinin and bradykinin), acetylcholine, histamine, serotonin, and reserpine. Migraine, then, may result from dysfunction of brain stem or diencephalic nuclei involved in nocieceptive modulation of afferents from the trigeminal vascular system.¹⁶ Positron emission tomography has detected activation in the brain stem during attacks of migraine.^27,28

Sicuteri et al.²⁹ hypothesized that the following sequence occurs: the initial event is a local release of catecholamines (with vasoconstriction and increased urinary excretion of vanillylmandelic acid); during subsequent reactive hyperemia serotonin is released (documented by plasma serotonin decrease³⁰ and increased urinary 5-hydroxy indoleacetic acid³¹), presumably from platelets or mast cells, which sensitizes cranial pain receptors perhaps also affected by the kinins. Additional evidence suggests that there are nervous system connections between the trigeminal ganglia and cerebral blood vessels, termed the trigeminovascular system.³² Trigeminovascular neurons and their peripheral unmyelinated nerve fibers contain the neurotransmitter peptide, substance P. Stimulation of this system by a variety of mechanisms would cause the release of substance P, which is postulated to increase vascular permeability and dilate cerebral blood vessels. The role of this system in the generation of human vascular headache may account for the effects of hormones or other circulating substances that change the receptive field properties of trigeminal ganglion cells. Individuals prone to chemically induced headaches from ingestion of tyramine, alcohol, phenylethyamine, monosodium glutamate, nitroglycerine, wine, or chocolate also experience spontaneous headaches.³³ Extensive studies of the reactivity of blood vessels in migraine³⁴ and cerebral blood flow^24,25,35,36 suggest that abnormal vasomotor responses may be present in patients with migraine between, as well as during, migraine attacks.

There are several lines of indirect evidence that suggest a relationship between serotonin and migraine, making the understanding of the pharmacology of serotonin important for understanding the pharmacology of the new serotonin agonist in migraine therapy.⁹ The serotonin or 5-HT receptors consist of at least three distinct types of molecular structures: guanine nucleotide G protein-coupled receptors, ligand-gated ion channels, and transporters. At least five 5-HT₁ receptor subtypes are present in humans. Headaches resembling migraine can be triggered by serotonergic drugs such as reserpine (a 5-HT releaser and depleter) and m-chlorophenylpiperazine (a serotonin agonist).^37,38

Other metabolic and endocrine factors also influence migraine attacks. According to Friedman and Merritt,³⁹ 80% of pregnant women previously prone to migraines either lose the headaches or experience improvement. Callaghan,⁴⁰ however, found an increase in the severity of migraine in pregnancy. The use of oral contraceptives appears to increase the incidence and severity of migraine.^41,42 Whitty⁴³ felt that migraine might be precipitated by withdrawal of progesterone, while Somerville⁴⁴ found from a study of three women with regular menstrual migraine that their attacks were related to estradiol withdrawal rather than to decreasing levels of progesterone. Tyramine has also been invoked as a precipitating factor, especially in the so-called allergic migraine,⁴⁵ however, only approximately 5% of migraine subjects notice headaches precipitated by food. Some patients, however, are unusually sensitive to chocolate or alcohol, particularly red wines. Recent therapeutic trials with dietary therapy designed to avoid hypoglycemia suggest that glucose and/or insulin metabolism may play a role in the generation of vascular headache.

The role of trauma in the production or exacerbation of a preexisting migrainous tendency is still incompletely defined. Many individuals experience vascular headaches of the common migraine type after even minor head trauma.⁴⁶ A previously well-controlled migraineur can experience a recrudescence of prior symptomatology after a head trauma. Such exacerbations are usually short-lived with a return to the preinjury status in weeks to a few months. However, there are some patients who experience posttraumatic migraine headaches for years after a head injury. Other triggering events preceeding migraine attacks include bright light, especially sunlight reflected from water, exercise or exertion, and high altitude. Vascular headache of the migraine type may also follow orgasm.⁴⁷ The role of stress is less clear. It appears more likely that migraine headache follows a period of psychologic stress than occurring during the time of stress.

The pathophysiology of the migraine aura itself also has been studied extensively. Wolff showed that the use of a potent vasodilator, amylnitrate, could abort the migraine scotoma (Fig. 1), supporting the vasoconstrictor hypothesis. Milner⁴⁸ suggested that the scotomas of migraine and the neurophysiologic phenomenon, Leão's spreading depression, may be related. The spreading depression progresses across the cortex at approximately 3 mm/min, similar to the slow evolution of the visual phenomenon that had been detailed by Lashley,⁴⁹ and estimated to spread over the occipital cortex at a rate of 3 mm/min.

It is currently believed that the aura of migraine may be the human counterpart of the animal phenomenon of Leão's spreading depression.⁵⁰ The aura is characterized by a wave of decreased blood flow or oligemia passing across the cortex^24,51–53 at a slow rate (2 to 6 mm/min) consistent with the spread of the visual phenomenon through the visual cortex, as mentioned above.⁵⁴ There is a short phase of hyperemia preceding the oligemia that may be a correlate of the scintillating scatoma, also a characteristic of migraine with aura.⁵⁵ However, persistent oligemia is probably a response to depressed neuronal function and is present when the headache starts, as noted by Goadsby.^16,53,56 Such findings coupled with the direct evidence of adequate local oxygen supply⁵⁷ vitiate the theory that migraine is just a vascular headache.¹⁶

Three cardinal factors are important in the pathogenesis of migraine, according to Goadsby.¹⁶ These include the cranial blood vessels, the trigeminal innervation of these vessels, and the reflex connection of the trigeminal system with a cranial parasympathetic outflow. The pain sensitive structures within the cranium, such as large blood vessels or the dura mater, are innervated by branches of the ophthalmic division of the trigeminal nerve⁵⁸ and the posterior fossa structures are innervated by branches of C2 nerve roots.⁵⁹ As indicated by Goadsby,¹⁶ involvement of the ophthalmic division of the trigeminal nerve and the overlap with structures innervated by C2 explain the common distribution of the pain of migraine in the frontal and temporal regions, as well as involvement of parietal occipital and high cervical regions, by referred pain. Peripherally, the trigeminal afferents are activated in migraine by the release of calcitonin gene-related peptide (CGRP) a vasodilator,⁶⁰ and while the mechanism of pain generation is not entirely clear, animal studies suggest that pain is caused by a sterile neurogenic inflammation in the dura mater.⁶¹ This may, in part, explain the prevention of migraine pain by substances such as botulinum toxin type A, which inhibit the release of CGRP.⁶² As stated by Goadsby,¹⁶ the pain may be a combination of an altered perception—as a result of peripheral or central sensitization—of craniovascular input that is not usually painful⁶³ and the activation of feed-forward neurovascular dialator mechanism that is functioning specific to the first ophthalmic division of the trigeminal nerve.⁶⁴ Again, the effect of botulinum toxin type A in reducing migraine pain may interfere with this peripheral activation and, therefore, function to provide peripheral desensitization.⁶²

TABLE 2. Migraine Without Aura

Migraine usually lasts several hours or the entire day. When the migraine persists for longer than 3 days, the term “status migrainosis” is used. Frequency of attacks varies widely from a few per lifetime to several per week.⁹ The average migraineur experiences from one to three headaches per month.³ A precise location ascribed to migraine, such as unilateral or temporal, is misleading, for as Wolff³⁴ wrote:

The sites of migraine are notably temporal, supraorbital, frontal, retrobulbar, parietal, postauricular, and occipital… They may as well occur in the malar region, in the upper and lower teeth, at the base of the nose, in the median wall of the orbit, in the neck, and in the region of the common carotid arteries and down as far as the tip of the shoulder.

The prodromes of common migraine are vague, preceding the attack by hours or days, and include psychic disturbances (such as depression or hypomania), gastrointestinal manifestations and changes in fluid balance. Usually the onset of the common migraine headache is unilateral, but the pain often becomes holocephalic. In an individual patient the headache is commonly more prominent on a single side, with occasional or rare alternation. Some individuals always experience a unilateral headache, while in approximately one-third the headache is diffuse from onset. Traditionally, the character of the headache is described as throbbing but this may be a feature only at onset, with the discomfort soon changing to a steady ache. The victim can often relieve unilateral headache by carotid artery or temporal artery compression, only to experience resurgence of the pain after release.

Nausea in some degree almost always accompanies common migraine. Vomiting can occur at the height of an attack, sometimes with relief of the headache, but more often only signals an intensifying phase of the episode, which continues for many minutes or hours. Usually the migraine sufferer becomes pallid and seeks seclusion, darkness, quiet, and a cold towel or ice bag for the head. Frequently at the time of nausea with vomiting, a diuretic phase with polyuria ensues, the consequence of fluid retention that occurred in the hours or days preceding the acute headache.

Ocular signs and symptoms may occur in common migraine, such as conjunctival injection, periorbital swelling, excessive tearing, foreign body sensation, and photophobia; however, these phenomena are more prominent in cluster headache.

TABLE 3. Migraine with Aura

Many general characteristics are shared by common and classic migraine. Both varieties affect men and women and can occur at any age, often seemingly triggered by a significant event such as puberty, school graduation, or marriage. A family history is usually present both in classic and common migraine and there may be an earlier history of colic as a baby or car illness as a small child. The full history of a complete migraineur would include migraine with aura in the teens, migraine without aura with nausea and vomiting in the second and third decades, followed by simple periodic headache or isolated migrainous auras in later life.

Migraine with aura is subclassified into migraine with typical aura (homonymous visual disturbance, unilateral numbness or weakness, or aphasia); migraine with prolonged aura (or lasting longer than 60 minutes); familial hemiplegic migraine; basilar migraine; migraine without headache and migraine with acute-onset aura.

The primary feature of migraine with aura is the visual aura. Extensive reviews of this phenomenon are found throughout the literature.^{5,6,34,65–67} While many variations occur, the following description by Richards⁴⁴ summarizes the most common type of visual phenomena (Figs. 2 and 3):

The visual disturbance usually precedes the headache… [it] begins near the center of the visual field as a small gray area with indefinite boundaries. If this area first appears during reading, as it often does, then the migraine is first noticed when words are lost in a region of “shaded darkness.” During the next few minutes the gray area slowly expands into a horseshoe with bright zigzag lines appearing at the expanding outer edge. These lines are small at first and grow as the blind area expands and moves outward toward the periphery of the visual field.

One important aspect of the visual disturbance just described, is that it expands slowly, over a period of 10 to 20 minutes. The initial region of visual abnormality is most often near fixation and then, as described by Lashley,⁴⁹ with increase in size the disturbed area moves or “drifts” across the visual field so that its central margin withdraws from the macular region as its peripheral margin invades the temporal; the area may be totally blind (negative scotoma), amblyopic or outlined by scintillations.

The scintillations surrounding the negative scotoma make “fortification” figures or spectrums, so called by the appearance of a “map of the bastions of a fortified town.”⁴⁹ The scintillations are brilliant, with the intensity of a bright fluorescent bulb flickering at a rate of 5 to 10 cycles per second (Figs. 4 and 5).

Gowers,⁶⁸ commenting on the descriptions by the British astronomer, Sir George Airy, and his physician son, Dr. Hubert Airy (both migraineurs), was particularly impressed with the intensity of the visual sensation. Many migraine sufferers can precisely recall their own vivid visual experiences well enough to describe them precisely or even on occasion to paint them (Fig. 6 and 7). Not all migraine visual disturbances begin near the fixation point; some patients consistently experience scotomas starting eccentrically in the visual field, and these sensations can appear alternately or simultaneously in both hemifields (Fig. 8). Other less dramatic visual auras also occur: just the sensation of peripheral brightness or awareness of a rhythmicity or pulsating character in the intensity of the ambient light. The duration of these visual symptoms is measured in minutes rather than the brief few seconds of flashing, bright moving spots, or transient flickering phenomena characteristic of occipital epileptic discharges.^7,68 Additional visual disturbances are categorized by Klee and Willanger,⁶⁶ consisting of metamorphopsia, diplopia, polyopia, and apparent movement of stationary objects. Variations in the scotomas of migraine, including their occurrence in patients with acquired blindness, are well described.^65,69 The auras of migraine, although most commonly only visual, have many other associated manifestations, such as hemihypesthesias, perioral anesthesia, vertigo, and transient aphasia. The aura or prodromes of classic migraine may be precipitated by intense stimuli: bright lights, loud noises, head trauma, or the intake of certain foods in susceptible individuals.

In the usual sequence of migraine with aura the sensory prodrome precedes the onset of the headache (in accord with the traditional concept of vasoconstriction followed by vasodilatation). The visual disturbance rarely may have a simultaneous onset with headache or, once having disappeared, may recur following the onset of headache. Such unusual patterns, or strict unilaterality for all attacks, should increase suspicion of a mass lesion or vascular malformation. As opposed to definite periodicity with symptom-free intervals and predictable circumstances, as in migraine without aura, migraine with aura may occur “out of the blue” and in multiple attacks over a few days.

Migraine-with-aura attacks tend to diminish in the third and fourth decades. While most migraine patients experience a stereotyped clinical pattern, there is a well-recognized group in which both classic and common migraine attacks are admixed.⁷⁰ Some patients with classic migraine may lose the headache component eventually and suffer only isolated auras thereafter. This monosymptomatic pattern stresses the importance of accurate history-taking when confronted by a patient with isolated visual phenomena (migraine dissociée). Haas⁷¹ emphasized the occurrence of “migraine aura status”. The differential diagnosis should include consideration of vertebro-basilar transient ischemic attacks. Symptomatology that favors migraine has been reviewed by Fisher,⁷² and includes luminous visual images, build-up of images, progression from one aura to another, and benign outcome.

Focal symptoms and signs of the aura may persist beyond a headache phase. In the previous classification, this was termed complicated migraine. It is now defined by the IHS classification with two labels with increased specificity. If the aura lasts for longer than 1 hour but less than 1 week, the term migraine with prolonged aura is applied. If the signs persist for more than 1 week or a neuroimaging procedure demonstrates a stroke, a migrainous infarction has occurred. As pointed out previously, in mid or later life the aura may not be followed by headache and has been termed migraine accompagnée or migraine associée. Migraine with aura (classic) in early reports was sometimes referred to as “ophthalmic migraine” (to be differentiated from ophthalmoplegic migraine, a subtype of migraine with aura). Migraine with aura is further reviewed in sections Cerebral, Ophthalmoplegic, Retinal, Basilar, and Other Varieties.

CEREBRAL

A variety of cerebral symptoms may occur in migraine with aura, including motor, visual, and other sensory defects. As pointed out previously, if the aura lasts for more than 1 hour but less than 1 week, the term migraine with prolonged aura is applied. However, if the signs persist for more than 1 week or a neuroimaging procedure shows a stroke the term used is migrainous infarction. The HIS classification of migraine-related stroke is presented in Table 4. Welch²³ has classified migraine-related stroke into four subtypes. These are described briefly.

TABLE 4. Classification of Migraine-Related Stroke

1. Coexisting Stroke and Migraine

A clearly defined clinical stroke syndrome must occur remotely in time from a typical migraine attack. Stoke in the young is rare; in contrast, migraine is common. As pointed out by Welch, the two conditions should coexist without migraine being a contributing risk factor for stroke.

2. Stroke with Clinical Features of Migraine

A structural lesion that is unrelated to migraine pathogenesis presents with clinical features of a migraine attack. Subtype A is symptomatic and in these patients, established structural central nervous system (CNS) lesions or cerebral vessels cause episodic symptoms typical of migraine with neurologic aura, although infrequently. Such cases could be termed symptomatic migraine. Cases of cerebral arteriovenous malformation exemplify this concept and may masquerade as migraine with aura.^7,73

Welch's second subtype is a migraine mimic. In this category, stroke caused by acute and progressive structural disease is accompanied by headache and a constellation of progressive neurologic signs and symptoms. These situations are difficult to distinguish from those of migraine, hence the term migraine mimic. The diagnosis can be most difficult in patients who continue to have migraine late in life, when the incident of cerebrovascular disease increases.²³

3. Migraine-Induced Stroke

Migraine-induced stroke must meet the following criteria: neurologic deficit must be identical to the migraine symptoms of previous attacks; the stroke must occur during the course of a typical migraine attack; and all other causes of stroke have been excluded, although stroke risk factors may be present.

4. Uncertain Classification

Welch has indicated that many migraine-related strokes cannot be categorized with certainty. For example, the IHS definition of migraine-induced stroke does not prevent the diagnosis in patients with migraine without aura. Migraine-induced stroke associated with treatment of the attack is appropriately classified in category. In addition, there are occasional cases of migraine-like symptoms and persistent neurologic deficit associated with cerebrospinal fluid (CSF) protein and pleocytosis.^74,75 Other rare syndromes and migraine-related stroke include migraine associated with mitochondrial encephalopathies⁷⁶ and “migraine coma.”⁷⁷ Intracerebral hemorrhage has been reported,⁷⁸ with most cases, according to Welch, being migraine mimics. Whether there is a role of antiphospholipid antibodies is still to be determined.⁷⁹ Permanent homonymous visual field defects are well documented in migraine patients.^67,80–82 The defects almost always occur in patients who have previously had migrainous attacks with transient scintillating scotomas. Computed cranial tomography (CT) or magnetic resonance imaging (MRI) has now documented a number of cerebral infarctions usually in the occipital and parietal regions. Rothrock and colleagues⁸³ evaluated 22 patients with migraine-associated stroke finding that 91 percent were women and 23% had a prior history of presumed migrainous stroke. They concluded that extracranial and intracranial vasospasm played a major role in some cases that they were able to document angiographically. One controlled study of migraine with aura reported that 91% of patients who had stroke during an attack had no arterial lesions. This was as opposed to 9% of migraine with patients with aura who suffered stroke remote from a migraine attack and 18% of patients with stroke without a migraine history.⁸⁴ In a rigorous case controlled study no overall association between migraine and ischemic stroke was found, but among women younger than 45 years, migraine and stroke were significantly associated; the risk was increased fourfold and it became even greater in women who smoked.⁸⁵

According to Hollenhorst,⁸⁶ approximately 4% of patients who have a typical sequence of visual aura followed by hemicranial headache experience transient hemianopsia lasting up to 15 minutes. Much rarer are patients with permanent hemianopia. Bilateral upper quadrantic defects have been reported.^87,88

Other sensory disturbances such as paresthesias particularly involve hands, fingers, and

lips.^87–89 Various aspects of cerebral migraine with aura are illustrated by the following case history.

A 26-year-old woman was seen with a complaint of difficulty with vision. She had a history of migraine since the age of 12, characterized by an aura of “black spots” slowly spreading over the field of vision for 20 minutes, occasionally accompanied by numbness in the right hand and arm. Thereafter throbbing headache would occur that was left-sided 90% of the time. Her father had a history of classic migraine as a young man. Ten days prior to first being seen, she had a typical attack of migraine but with persistent difficulty in vision after the episode. Examination was entirely normal except for a congruous right homonymous visual field defect (Fig. 9). Ten days later she again developed her visual aura, but with a moderate right hemiparesis as well, during her headache. Brain scan and cerebral arteriography were normal. During the next week all neurologic abnormality including her visual field defect cleared completely.

Frequently a disturbance of language occurs with migraine, as pointed out by Sir George Airy in 1865, who described his own inability to speak during an attack. A typical history related to the author by his brother is as follows.

While reading, I become aware that I am unable to understand what I have just read. After rereading a paragraph two or three times, I begin to realize that I cannot understand the sense of words. The letters can be identified but the words are unintelligible… At this point a numb feeling occurs in my right hand and I finally realize that I am at the start of another migraine attack.

A wide variety of language difficulties, sensory defects, and motor abnormalities have been described (most often transient but rarely permanent) from presumed cerebral infarction. Caplan et al.⁹⁰ reported 12 patients with transient global amnesia and prior migraine. In 3 patients, the classic migrainous phenomenon accompanied the amnestic attack.

Variable electroencephalographic (EEG) findings occur.^89,91,92 There is general lack of agreement as to the incidence and significance of abnormalities in the EEGs of patients with migraine. Some authors report a normal EEG,⁹³ but various abnormal patterns have been recorded.^91,92 A detailed review by Hockaday and Whitty⁹⁴ indicated an incidence of EEG abnormality in 61% of 560 migraine patients. The highest frequency of abnormality occurred in patients with transient lateralized motor or sensory auras.

Friedman⁹⁵ first reported the results of angiography during an attack of migraine; there were no abnormalities. While the majority of patients in reported cases show normal arteriograms, others have demonstrated some abnormality during an attack (see Cluster Headache). However, angiography is considered by some to have increased risk in patients with migraine^67,96 and has not yet provided useful information on the pathophysiology of complicated migraine.^97–99

Hemiplegic migraine occurs both sporadically and as a familial syndrome. This entity is defined as “vascular headache” featuring sensory and motor phenomena that persist during and (for a brief time) after the headache.¹⁰⁰ A narrower view would be to use the term hemiplegic migraine when only motor involvement (i.e., weakness or paralysis) occurs.

The first mention of transient hemiparesis during an attack of migraine was by Liveing,⁵ and multiple reviews and case reports have appeared since.^101,102 Heyck¹⁰³ reviewed the neurologic complications of 980 of 3890 patients with migraine. The majority of these patients complained of unilateral tingling or numbness that invariably involved the hand and sometimes spread to the arm, face, tongue, and, rarely, to the leg. The symptoms seldom lasted more than 30 minutes and could occur before or at the peak of the headache. Twelve of these patients had unilateral motor disturbances ranging from minimal loss of function to complete paralysis. There have been few permanent sequelae attributed to hemiplegic migraine; progressive dementia was noted by Symonds, and permanent hemiplegia has been reported.^89,97,103

Reports of hemiplegic migraine in the literature seem to indicate that most cases are familial. However, Heyck⁹⁷ pointed out the tendency to report familial cases; if unselected patients with the syndrome are reviewed, most do not occur in families with hemiplegic migraine but rather in “families with ordinary migraine as often as common or classic migraine.” Familial hemiplegic migraine is well documented,^101,104,105 at times in kindred with associated neuro-ophthalmologic findings such as retinal degeneration and nystagmus.¹⁰⁶ One interesting report is that of Dooling and Sweeney,¹⁰⁷ who describe a blind woman whose attacks were precipitated by breast feeding her infant. This led to the speculation that oxytocin (chemically similar to ergotamine) could exercise a complex effect on cerebral vessels predisposed to vasospasm.

OPHTHALMOPLEGIC

So-called ophthalmoplegic migraine has now been changed in the official Classification of Headache of the International Headache Society.¹ This is because many reports have shown abnormalities of the oculomotor nerve using MRI in children with recurrent painful ophthalmoplegia fulfilling the previous criteria for ophthalmoplegic “migraine.”^108,109 It is now believed that all modern cases show MRI enhancement of the third nerve, which may represent a type of inflammation and, therefore, more characteristic of what is seen with facial nerve palsy than with any form of migraine.¹¹⁰ In this rare variety of what was formerly termed “complicated migraine” the headaches were associated with oculomotor nerve palsies.^111,112 Usually the ophthalmoplegia is transient, however, it can become permanent especially after repeated attacks. Major controversy has surrounded the diagnostic and nosologic position of ophthalmoplegic “migraine” since its initial recognition in the mid 1880s. Until the 1930s and 1940s when angiography was introduced and practiced, it was impossible in many cases to rule out aneurysms and other lesions in the vicinity of the cavernous sinus. Multiple etiologies were cited as underlying causes of ophthalmoplegic “migraine” including aneurysm, basilar arachnoiditis, and tumors; indeed, many physicians believed that no separate clinical syndrome of ophthalmoplegic migraine existed but that all patients had specific organic lesions.

Woody and Blaw¹¹³ reported two cases of ophthalmoplegic “migraine” occurring in infants who were 5 and 7 months old. The infants had recurrent attacks with almost complete clearing between episodes. Both children were treated with prednisone during subsequent attacks, which seemed to shorten the duration of the episodes.

In ophthalmoplegic “migraine” the third nerve is most frequently involved. Walsh and Hoyt⁶⁷ state that abducens palsy occurs 1:10 as frequently as third-nerve palsy, with even rarer affliction of the fourth nerve. In most cases positive family history is not present. Thus, a typical clinical syndrome emerges: a child or young adult with periodic headache has ophthalmoplegia involving all functions of the third nerve, beginning at the height of an attack of cephalgia, which is primarily unilateral and in the orbital region; the paresis lasts for days to weeks after the cessation of headache; recovery is gradual and tends to be less complete after repeated attacks. The following case report is considered exemplary.

A 3-year-old boy presented with a complete left oculomotor palsy. The day before he had complained of headache, was lethargic, and went to bed early. The following morning he awakened with complete ptosis of the left upper lid but his headache was gone. On examination the left pupil was 6 mm and slightly reactive to light; all muscles supplied by the left third nerve were profoundly affected (Fig. 10), The neurologic examination and plain skull x-rays were entirely normal. The child recovered completely in 3 weeks' time. An exactly similar episode occurred 20 months later, also with rapid spontaneous resolution, and a third episode occurred 1 year after that. The child is now well and suffers only occasional headaches.

In the differential diagnosis, consideration should be given to aneurysm, tumor, diabetes, and sphenoid sinus mucocele. The age at onset, negative glucose tolerance test, and radiologic studies will usually rule out the listed possibilities. Other clinical entities confused with ophthalmoplegic “migraine” have included myasthenia gravis and the Tolosa-Hunt syndrome. The former condition is ruled out if the pupil is involved (and actually should not be considered in the presence of pain) and with response to edrophonium chloride (Tensilon); the latter possibility should be considered if pain persists. On rare occasions only limited involvement of the third nerve occurs.

Reports of transient, otherwise unexplained unilateral pupillary mydriasis have been tentatively attributed to migraine in young patients.^114,115 One should be careful to exclude intermittent angle-closure glaucoma with mydriasis as pointed out by Sarkies and colleagues.¹¹⁶ They reported a 31-year-old man with an 18-month history of episodic periorbital pain who, during an attack, noted blurred vision and a dilated pupil. He was found to have a sector palsy in the upper nasal quadrant of the left iris, an intraocular pressure of 16 mm Hg between attacks and on gonioscopy, and narrow angle with a plateau-type iris. During an attack his intraocular pressure increased to 26 mm Hg. After a provocative dark-room test, the patient developed a typical headache and was found to have an intraocular pressure of 45 mm Hg and a closed-angle on gonioscopy. This report is important because it points out a condition that must be eliminated before considering episodic mydriasis with ocular pain to be a part of ophthalmoplegic “migraine.”

Rarely, ophthalmoplegic “migraine” may occur without headache. Durkan et al.¹¹⁷ described two children with isolated recurrent painless oculomotor palsy in whom neurodiagnostic investigations were all normal.

In the differential diagnosis, suspicion would be raised by (1) the absence of a migraine history; (2) severe persistent headache with total ophthalmoplegia; (3) onset after age 20; and (4) symptoms and signs of subarachnoid hemorrhage. Angiography is not warranted in a young patient strictly fulfilling the clinical criteria.

Now, however, ophthalmoplegic “migraine” is a diagnosis of exclusion, and noninvasive imaging tests such as MRI or magnetic resonance angiography (MRA) should be performed in all cases to exclude the possibility of aneurysm.¹¹² The finding of an entirely normal MRI, except for nerve enhancement, in a child with a third cranial nerve palsy after a 4 day history of headache, who is otherwise well, should complete the workup. This is because aneurysmal third-nerve palsies are extremely rare in children under age 14 years.¹¹⁸ However, in third nerve palsy involving pupillomotor function, serious consideration should be given to angiography. The usual cause will be a posterior communicating artery aneurysm, which is best excluded by conventional angiography. However, newer techniques such as MRA or spiral contrast-enhanced computed tomographic scanning may soon provide sufficient resolution to exclude aneurysm as a cause.¹¹²

The pathophysiology of ophthalmoplegic “migraine” remains obscure. Theories include swelling of the posterior cerebral artery, pituitary swelling, vascular anomaly with compression of the third nerve, and unilateral brain swelling. None of these theories has been documented, and cerebral angiography is unrevealing. Walsh and O'Doherty¹¹⁹ suggested that a swollen intracavernous carotid artery compressed adjacent cranial nerves within the cavernous sinus. Such swelling would also narrow the vessel, which they attempted to document angiographically. However, subsequent negative arteriograms during attacks do not support this theory.¹²⁰ In Nigeria, ophthalmoplegic “migraine” has been associated with an abnormal hemoglobin.¹²¹

Ideally, prophylactic therapy would prevent the occurrence of repeated episodes and prevent the development of permanent eye muscle palsies, but reports suggest that therapy has met with only limited success.¹²⁰ A trial with calcium channel blocking drugs such as verapamil or β-blocking drugs such as propranolol or even methysergide may be warranted if the attacks are frequent.

RETINAL

The IHS code is 1.4 for retinal migraine (Table 5). A short description from the Headache Classification Committee is the following: repeated attacks of monocular scotoma or blindness lasting less than 1 hour and associated with headache. Other ocular or structural vascular disorder must be ruled out. Additional terms include: ocular migraine, anterior visual pathway migraine, and ophthalmic migraine. This condition may be broadly defined as a transient or permanent monocular visual disturbance accompanying a migraine attack or occurring in an individual with a strong history of migrainous episodes.¹¹⁰ One term applicable to all such attacks would be “ocular migraine, “however, to include optic nerve dysfunction as well, a more general phrase (i.e,, “anterior visual pathway migraine)” may be preferable. This last phrase would include reported defects, such as ischemic papillitis, retinal hemorrhage, vitreous hemorrhage, central serous retinopathy, pigmentary changes of the retina, and optic nerve atrophy.

TABLE 5. Retinal Migraine

Retinal migraine occurs more frequently than ophthalmoplegic ‘migraine.’ We estimate the frequency of strictly monocular visual phenomena occurring in conjunction with migraine to be 1 in 200 migraine sufferers. Frequently, however, homonymous visual field phenomena in migraineurs is incorrectly attributed to a single eye. For example, a patient with transient right homonymous hemianopia might think that the right eye is affected, because normally the right temporal hemifield is 30 to 40 degrees larger than the left nasal hemifield.¹²²

The exact genetic predisposition to this subtype of migraine headache is unknown. The familial occurrence is similar to that expected in all patients with migraine preceded by visual aura, with an estimated 25% positive familial history. Retinal migraine is expected to be more common in women than men, which is true of migraine headaches in general, but this also has not been documented.

One may consider two forms of anterior visual pathway migraine: transient monocular blindness and permanent unilateral visual loss, a much less common occurrence.

The transient form has a relatively stereotyped presentation, consistent with retinal or optic nerve hypoperfusion from spasm of the central retinal or ophthalmic artery. For example, 10 of 24 patients reported by Tomsak and Jergens¹²³ described concentric contraction of vision, and only 5 of their patients had an altitudinal or quadratic visual change consistent with spasm of retinal artery branch. Kline and Kelley¹²⁴ studied a patient with a history of cluster headache and documented a reduction in central retinal artery blood flow during an attack of ocular migraine by intravenous fluorescein angiography. They noted no change in choroidal perfusion, also suggesting selective spasm of the central retinal artery. Others have noted retinal artery constriction during episodes of migrainous transient monocular blindness^125,126 or normal arterial caliber.¹²⁷ It is of interest to note that in the case reported by Wolter and Burchfield,¹²⁷ a review of the fundus photographs depicts venous vasoconstriction as well as retinal opacification during an episode (Fig. 11). Recently Burger and co-workers¹²⁸ reported amaurosis fugax episodes caused by documented vascular constriction in the retina. Their patients did not have retinal migraine, but showed the ability of retinal vascular constriction to produce monocular episodes of amaurosis in the absence of embolic phenomena.

Permanent unilateral visual loss from anterior visual path migraine is well documented but uncommon. In addition to arterial or venous retinal vascular occlusions,^{95,126,129,130} central serous retinopathy, vitreous hemorrhage, retinal hemorrhage, and ischemic optic neuropathy have been noted.^131,132 Newman et al.¹³³ reported bilateral central retinal artery occlusions, disk drusen, and migraine, and other descriptions of anterior visual path migraine and vascular retinopathy are reported.^134,135 A recent unconfirmed report suggests that up to one-third of migraineurs have retinal or optic nerve type visual field defects when tested with automated perimetry.¹³⁶

A typical history is that of a young adult with a pattern of common or classic migraine, who has recurrent episodes of monocular visual loss or monocular scintillating scatomas. The visual loss is often one-sided, stereotyped in nature, and tends to affect the entire monocular visual field,¹²³ although any of the visual patterns described in migraine with aura may occur on a monocular basis in “retinal” migraine. Carrol¹³⁷ suggested that such transient episodes never have a preceding fortification spectra, that the absence of accompanying headache was invariable, and that the visual disturbance never lasted more than 10 minutes. Permanent visual loss is the exception rather than the rule. Transient anterior visual pathway migraine is not associated with other neurologic symptoms but may be precipitated by postural change or exercise. Approximately one-third of patients have a prior history of migraine.¹²³

Ocular migraine as a cause of transient monocular blindness should be a diagnosis of exclusion. This was highlighted by a recent case¹³⁸ in which a young medical student had episodes of amaurosis fugax, occasionally accompanied by headache, and was considered to have retinal migraine. In actuality he was found to have a large pituitary tumor.

Walsh and Hoyt⁶⁷ state that “the eye itself can be involved in the angiospastic circulatory disturbance of a migraine attack,” and that subsequent visual disturbance is caused by retinal hypoxia. The retinal arterioles have been reported to be constricted during such an episode by some authors^67,125 or to be normal despite an ischemic retina.¹²⁷

Ischemic papillopathy in migraine was presented by McDonald and Sanders,¹³⁹ with sudden monocular visual loss in a migraine patient who had experienced multiple bouts of transient amaurosis of the same eye. A typical nerve fiber bundle defect was present on visual field testing, and fluorescein angiography showed areas of delayed choroidal filling in the peripapillary region.

Typical case histories of “retinal migraine” are presented here.

The patient was a 22-year-old college student who complained of decreased vision in the left eye. He had a 7-year history of classic migraine headaches, which had been much less frequent in the previous 3 years. Three years prior to examination he awakened to discover decreased vision in the temporal quadrant of the left eye. One year later he again noticed an abrupt onset of a negative scotoma in the inferior nasal periphery of the same eye. Neuro-ophthalmologic examination was normal except for a slight afferent pupillary defect in the left eye and the visual fields (Fig. 12A). Fundus photography revealed an absence of the nerve fiber bundle layer in the superior portion of the left optic disc corresponding to the inferior visual field defect demonstrated on perimetry (Fig. 12B).

Fig. 12 Patient with permanent retinal nerve fiber bundle defect attributed to migraine. A. Visual field. B. Visible attenuation of retinal nerve fiber layer (between arrows) corresponding to field defect. Compare with visible nerve fibers entering inferior aspect of disc.

A 24-year-old right-handed carpenter complained of “blackouts” in the right eye occurring over the previous 3 months. The patient stated that he had nine episodes of diminished vision in the right eye unassociated with other neuro-ophthalmologic signs. These episodes began as a “blur” starting in the right temporal field and characterized by distinct “lines and angles,” or like “a fish net.” There was a subjective appreciation of increased brightness during the phenomenon but no particular color. As the effect intensified, the entire field of the right eye became gray such that the patient “could not see anything,” and the vision subsequently diminished to bare perception of light. This sensation lasted 10 to 15 minutes and then slowly cleared in reverse fashion. There was no previous history of migraine, transient neurologic phenomena, or family history of migraine. His neurologic and neuro-ophthalmologic examinations were entirely normal. The impression was that the patient suffered from the retinal form of migraine.

The pathogenesis of such episodes is not well defined. It would appear in most instances that the visual disturbances are the result of constriction in either the central retinal artery or the ophthalmic artery, with resultant ischemia of the optic nerve or retina. One argument that vasoconstriction occurs in vessels proximal to the retina itself is the work of Laties,¹⁴⁰ who showed the absence of adrenergic innervation to the intraocular branches of the central retinal artery. Additional clinical descriptions of anterior visual pathway migraine and vascular retinopathy associated with this condition are presented by Corbett¹³⁴ and Coppeto et al.¹⁴¹

In general, the prognosis for retinal migraine is similar to that of migraine headache with typical aura. Recurrent attacks are expected with a variable interval. Because the true incidence of retinal migraine is unknown, it is uncertain whether there is a higher incidence of permanent neuroretinal injury. The visual field data presented previously¹³⁶ suggests that there is a higher incidence of end arteriolar distribution infarction and a higher incidence of permanent visual field defects in retinal migraine than in clinically manifest cerebral infarctions in migraine with aura. However, there may be a higher incidence than expected of cerebral infarctions in migraineurs with visual aura who are studied by MRI. These would, in effect, be silent strokes revealed by neuroimaging that were clinically unsuspected. An infarction in the retina, however, is usually apparent to the patient.

A recent study of transient ischemic attacks in young patients, containing a large proportion of migraineurs, suggests a benign prognosis for stroke and myocardial infarction as long as other cardiovascular risk factors are not present.¹⁴² Another study of retinal strokes in people under 30 found that 8 of 27 had migraine. Only 2 patients, however, had migraine as the only association, the others having other systemic and/or ocular risk factor as well.¹⁴³

We believe that all patients with retinal migraine should be placed on prophylactic antimigrainous therapy such as calcium channel blocking or β-blocking agents. There is a report of the salutary effects of isoproterenol inhalation on anterior visual pathway migraine and other migrainous visual phenomena,¹⁴⁴ but we have not had personal experience with this treatment. Newman et al¹³³ reported bilateral central retinal artery occlusions, disk drusen, and migraine.

BASILAR-TYPE MIGRAINE

What was formerly known as “basilar artery migraine” or “basilar migraine” is now termed “basilar-type migraine” and is listed as 1.2.6 in the new IHS classification.¹ A description of this condition is listed in Table 6. Basilar-type attacks are mostly seen in young adults. While originally the terms “basilar artery migraine” or “basilar migraine” were used, the involvement of the basilar artery territory was uncertain, and therefore, it is now preferred to use the term “basilar-type migraine.”^145,146

TABLE 6. Basilar-Type Migraine

Bickerstaff¹⁴⁷ introduced the concept of “basilar artery migraine,” with symptomatology including bilateral disturbance of vision, ataxia, dysarthria, vertigo, tinnitus, and face or limb paresthesias, followed by severe throbbing headache usually in the occipital region. While a definite diagnosis of migraine was impossible to prove, the mode of onset, the associated headache, the relatively brief duration of the attack, the family history of migraine, the occurrence of other attacks more typically migrainous, and the absence of all neurologic abnormality between episodes made the diagnosis of migraine most likely. Twenty-six of 34 described patients were adolescent girls. The symptoms lasted from 2 to 45 minutes with rapid disappearance of symptoms; however, if there had been complete loss of vision, this symptom disappeared more gradually with a period of “graying” of vision. The attacks occurred infrequently but tended to be associated with menses in the young girls; the episodes subside over ensuing years and are replaced by more common varieties of migraine.

The visual symptoms described included vivid flashes of light throughout the entire visual field, intense enough to obscure vision completely, and sudden bilateral visual loss occurring over seconds and persisting up to 15 minutes, with a gradual return to normal vision. None of these patients had their symptoms of brain stem ischemia accompanied by the characteristic fortification spectra of classic migraine.

Later, Bickerstaff¹⁴⁸ described a group of patients in whom consciousness was impaired during attacks of migraine, and he suggested that the mechanism was transient ischemia of the reticular activating system of the brain stem secondary to vasomotor disturbance in the distribution of the basilar artery. Loss of consciousness in migraine was reviewed by Lees and Watkins,¹⁴⁹ with particular reference to the association of migraine and epilepsy. Basser,¹⁵⁰ in an analysis of 1800 migraine patients demonstrated an increased incidence of epilepsy compared to a control group. Bickerstaff¹⁵¹ suggested that two mechanisms could lead to loss of consciousness in migraine: (1) brain stem ischemia of the reticular activating system and (2) ischemia producing seizure in a potentially epileptic brain, the latter being much less common.

Basilar-type migraine is regarded as a rare but definite clinical variant of the migraine spectrum, with signs and symptoms similar to those seen in transient ischemic attacks of the posterior circulation as observed in elderly individuals with cerebrovascular disease. This syndrome occurs primarily in young women and usually has a benign prognosis. However, one reported fatality with migraine was probably due to a complicated basilar artery attack.¹⁵²

Basilar artery migraine was reviewed by Swanson and Vick.¹⁵³ Ten of the 12 patients reported were female with age of onset from 8 to 46 years. All but 1 had onset before age 25. Symptoms included typical classic migraine visual auras, diplopia, ptosis, ataxia and brief (1 to 10 minute) episodes of unconsciousness. One illustrative case is abstracted as follows.

The patient had cyclic vomiting and car-sickness as a young girl. At age 20 she had episodes of bilateral loss of vision associated with vertigo, but no headaches or other migrainous symptoms. At age 21, and twice at age 23, she became unconscious without warning. Two attacks occurred in a brightly lighted environment while she was standing at the foot of an upward moving elevator. The third attack occurred at home while she was reading quietly. In each attack she suddenly lost vision and quickly became unconscious, slumping to the floor. Upon awakening she had severe, generalized throbbing headache, nausea, and vomiting. Truncal ataxia was severe and lasted 15 minutes. Her father had common migraine and her mother had classic migraine. At age 24, photic stimulation during an EEG induced a fourth attack similar to the others.

Therapy for these patients included ergonovine maleate, propranolol, phenytoin, and primidone. It is of interest that anticonvulsants were effective in half the patients.

OTHER VARIETIES

Less common varieties of migraine are the so-called migraine equivalents and unusual varieties of complicated migraine. “Migraine equivalent” is a term used to denote conditions or symptomatology believed to be migrainous in origin but without the typical history of either classic or common migraine headache. While the idea of migraine equivalents has not always been well received, according to Sacks⁵ the concentrated experience of working with migraine patients must convince the physician, whatever his previous beliefs, that many patients do suffer repeated, discrete, paroxysmal attacks of abdominal pain, chest pain, fever, etc., which will fill every clinical criteria of migraine save for the presence of headache.

The most well-recognized type of migraine equivalent is abdominal migraine, in which cyclical vomiting, periodic attacks of nausea, or abdominal pain occur, usually in children or in adolescents. These patients experience more typical attacks of migraine in later life. If the past history of migraine patients is investigated, a history of cyclical vomiting is far more commonly found than in a control headache population.¹⁵⁴ Very rarely true abdominal migraine occurs in adult life. In this situation there may be sudden severe abdominal pain with vomiting and even abdominal rigidity. The usual brevity of the attack or previous similar benign episodes or strong history of migraine help confirm the diagnosis.¹⁵⁵ Other migraine equivalents include periodic diarrhea, fever, mood changes, and possibly attacks of chest pain known as precordial migraine. Acute confusional states have been attributed to migraine in juveniles.¹⁵⁶

Migraine attacks may clearly occur without headache. Whitty¹⁵⁷ detailed the case histories of 16 patients who experienced auras of different varieties, with and without headache, in whom strong family histories of migraine, other migraine attacks, or otherwise asymptomatic follow-up allowed the diagnosis of migraine. Other atypical symptoms of complicated migraine have been separated into subgroups such as facioplegic migraine, cerebellar migraine, dysphrenic migraine, and migraine with involuntary movements.⁸⁸ Such unusual cases must be reviewed individually and evaluated carefully before concluding that such episodes truly are migrainous.

TABLE 7. Cluster headache

TABLE 8. Episodic Headache

The phrase “cluster headache” denotes a characteristic type of cephalgia defined as a severe unilateral head or facial pain, which lasts minutes to hours. It is often associated with ipsilateral lacrimation, nasal congestion, and facial flushing. The headaches tend to occur in separate bouts or clusters in one or more attacks daily for periods of weeks to months.^162–167 Often during an attack, and sometimes persisting after the episode, there is ipsilateral miosis and ptosis (i.e., and oculosympathetic paresis or Horner syndrome).

In 1840, Romberg¹⁶⁸ described “ciliary neuralgia” as recurrent pain in the eye with injection and pupillary constriction. Harris described the same syndrome in 1926 as “periodic migrainous neuralgia”¹⁶⁹ and later (1928) as ciliary (migrainous) neuralgia.¹⁷⁰ Multiple redescriptions and rediscoveries of the syndrome have resulted in a host of synonymous terms as well as confusion with other entities not related to this particular headache syndrome (Table 9).

TABLE 9. Cluster Headache and Variants

The pain in cluster headache is severe, being described as “boring,” “sharp,” “unbearable,” and “the worst pain I have ever felt.” The headache usually appears in or around one eye or on the cheek and then can spread to the temple, frontal region, occiput, or the ipsilateral neck. It rapidly builds to a peak within a few minutes, with an intensity greater than most other headache varieties. The usual duration is from 30 minutes to a few hours. Rather than lying down in seclusion, as preferred by most migraine sufferers, the cluster victim often paces about, holds onto his face, or applies hot or cold water to the affected region, even to the point of injury. The attacks usually occur once in a 24-hour period, often at a specific time, and frequently in the early morning hours, awakening the patient from sleep. Men are affected much more commonly than women, in a ratio of approximately 5:1. Usually the episodes begin in the second or third decade and, according to Bickerstaff,¹⁶³ frequently are ipsilateral to previous head trauma. The headache tends to remain on the same side in a given cluster but rarely may alternate in subsequent clusters. Typical migraine headache is frequently found in family members. While most patients have clusters occurring over weeks or months (often at the same season of year), other patients have sporadic attacks or irregular episodes for indeterminate periods of time.

Typical migraine headaches may occur in the same individual with cluster, sometimes waning as the cluster commences. In the cluster attacks as described, it is extremely rare that any organic pathology is ever demonstrated, however, the variants of the syndrome require more detailed analysis. When the pain becomes persistent, bilateral, or additional neurologic abnormalities are present (such as fifth-nerve or optic nerve involvement), other conditions must be ruled out.

Regarding the mechanism of cluster headache, few specifics are known. However, Ekbom and Greitz¹⁷¹ have demonstrated a localized narrowing of the extradural portion of the internal carotid artery distal to its exit from the carotid canal in a patient during an attack of cluster headache. They speculated that, in addition to the headache, the partial Horner syndrome might be the result of repeated dilatation and edema of the internal carotid artery resulting in damage to the sympathetic nerves surrounding the vessel.

Bickerstaff¹⁶³ has reviewed the variety of terms used to describe cluster headache and the relationship to other types of facial and cranial neuralgias. Vidian neuralgia as described by Vail¹⁷² referred to recurrent aching pain affecting the nose, eye, face, neck, and shoulder on one side, but he also included recurrent episodes which would clearly conform to the cluster headache syndrome. The facial pain described originally by Sluder included clinical variants but primarily referred to a constant pain affecting eye, upper jaw, hard palate, and teeth on one side, usually in menopausal women.¹⁷³

In 1924, Raeder described five patients with Horner syndrome (oculosympathetic paresis), but without facial anhydrosis, with pain or numbness in the distribution of the ophthalmic branch of the trigeminal nerve, which he designated as “paratrigeminal neuralgia”¹⁷⁴; however, some of his patients had other cranial nerve signs. Additional findings suggested specific intracranial lesions.

Boniuk and Schlezinger¹⁷⁵ divided Raeder syndrome into two groups: (1) characterized by hemicrania, ipsilateral oculosympathetic paresis, and parasellar cranial nerve (III, IV, V, and VI) involvement, these additional cranial nerve signs suggesting disease in the middle cranial fossa and indicating appropriate diagnostic studies and (2) hemicrania and group the most common cause is a cluster headache variant,^162,176,177 and further diagnostic studies including arteriography are unwarranted. However, in Raeder type 2 neuralgia, aneurysm,^178,179 and fibromuscular dysplasia of the carotid artery¹⁸⁰ have been reported. In the patients with such demonstrable lesions, unilateral facial pain was persistent rather than the episodic excruciating variety described in the classic cluster headache syndrome.

Headaches with similar characteristics of cluster and associated signs and symptoms similar to cluster but with a shorter burst of pain, occurring more frequently, and responding to indomethacine are known as paroxysmal hemicrania headaches (Table 10). The usual dose of indomethacine is 25 to 50 mg/d. Failure to respond makes the diagnosis questionable. Therapy recommended for cluster headache has been quite variable and often was tailored to the suspected condition. Harris' method¹⁷⁰ was to inject the gasserian ganglion. Horton¹⁸¹ tried to desensitize his patients to histamine, and others have recommended sphenopalatine ganglionectomy.¹⁸² Histamine is indeed elevated in serum during a cluster attack, with minimal change in serotonin (as contrasted to depressed levels of serotonin in typical migrainous episodes).¹⁸³ Ergotamine preparations have been widely used, parenterally in the acute attack and orally as a prophylactic agent.¹⁸³ The prophylactic use of methysergide (Sansert) has been used successfully,¹⁸⁴ and currently propranolol (Inderal), 20 to 40 mg, two to four times per day, may serve as an effective preventive.¹⁸⁵ Calcium channel blocking agents may also be effective in cluster headache, particularly nimodipine.¹⁸⁶ Therapy of cluster headache and their relationship to other forms of vascular headache has been reviewed by Lance.¹⁶⁰

TABLE 10. Paroxysmal Hemicrania

SUNCT SYNDROME

The SUNCT syndrome is an unusual and severe condition characterized by short-lasting unilateral neuralgiform headache with conjunctival injection and tearing, hence the abbreviation SUNCT.^187–189 The SUNCT syndrome can be idiopathic or secondary to prolactin-producing tumors¹⁹⁰ and with brain stem infarction¹⁸⁹ (Table 11).

TABLE 11. SUNCT Syndrome

A particularly unusual type of migraine, with recurrent attacks of impairment of time sense, body image, and visual analysis of the environment, has been termed “Alice in Wonderland” syndrome. Golden¹⁹⁶ reported two such children who retained a clear state of consciousness during recurrent episodes. An excerpt from the description an 11-year-old girl is included.

As I started to go into Mommy's room I grabbed my door—it felt about one foot thick in my hand. As I went through the hall, it felt as if I was going too fast. (Like you want to stop but energy is keening up inside of you. You feel like you're going to burst and your eyes are going to pop out—like you're going to explode.) Things were going too fast. I felt like my hands were made of tiny twigs with a little mushy flesh on the outside. I felt like I was holding things in my hands.

Migraine may be triggered by head trauma in children¹⁹⁷ and some of the posttraumatic syndromes may be related to migraine. The suggestion has been made that transient blindness after head injury in childhood¹⁹⁸ may occur primarily in children with a history of migraine.¹⁹⁹ Acute confusional states in juveniles may also represent migraine.¹⁵⁶

The treatment of childhood migraine is similar to that of adult migraine (see Therapy) and is theoretically directed toward preventing vascular dilatation.²⁰⁰ The prognosis in childhood migraine is thought to be good,²⁰¹ but a complete follow-up study has not been reported.¹⁹⁵

FACIAL PAIN

Trigeminal neuralgia or tic douloureux is a facial pain characterized by repetitive attacks of lightening-like jabs of lancinating pain in the maxillary and mandibular divisions of the trigeminal nerve. The ophthalmic division may be involved but is rarely the sole location. The onset is usually in the sixth or seventh decade with women being affected slightly more than men (3:2). The usual cause is vascular cross compression of the sensory root entry zone of the fifth nerve as it enters the pons, but multiple sclerosis and cerebellopontine angle tumors may also produce the syndrome. Both sides of the face may rarely be involved with pains occurring asynchronously on opposite sides. Bilaterality in a person under 50 suggests multiple sclerosis. The paroxysmal attacks last only seconds reaching maximal intensity immediately, often with a deep aching pain persisting between the paroxysms. The pain is often described as “electric” and is frequently triggered by talking, chewing, touching the lips, or by cold exposure. The neurologic examination is normal in most patients, but some, even with classic tic, have a small area of numbness medially on the upper lip. Any neurologic deficit or the presence of the condition in a patient under 50 necessitates a magnetic resonance scan to rule out tumor or multiple sclerosis.

Medical therapy is successful in the majority of patients and includes carbamazepine, baclofen, phenytoin, clonazepan and valproic acid alone or in combination.^14,206 Surgical therapy includes vascular decompression^207–209 and a variety of percutaneous procedures aimed at destruction of the pain fibers of the trigeminal nerve.^14,209,210

Atypical facial pain is a less well-defined complex involving pain in the face. The pain tends to be deep, aching, more diffuse, sometime superficial but longer in duration than attacks of trigeminal neuralgia. There may or may not be alterations of facial sensation. The pain is not necessarily localized to the sensory distribution of the trigeminal nerve and is often poorly characterized by the patient. The pain responds poorly to medical or surgical therapy and is usually accompanied by various degrees of psychologic impairment. Such patients should be thoroughly evaluated to rule out organic causes such as nasopharyngeal neoplasm and dental abnormality, but in the absence of defined pathology may be treated symptomatically with nonaddicting analgesics, antidepressants, and psychotherapy.

TEMPORAL ARTERITIS

Temporal arteritis or giant-cell arteritis is a systemic disorder of unknown cause characterized by an inflammatory obliterative arteritis particularly, but not exclusively involving branches of the external carotid and ophthalmic arteries. It is well known as a cause of anterior ischemic optic neuropathy (see Chapter 5) and less well recognized as a cause of ophthalmoplegia (see Chapter 12). The most common initial symptom is headache, often accompanied by diffuse aches and pains (polymyalgia rheumatica).²¹¹ Other common symptoms include jaw claudication, fever, anemia, and weight loss. In the study by Vilaseca et al.,²¹² the simultaneous presence of recent onset headache, jaw claudication and abnormalities of the temporal arteries on physical examination had a specificity of 94.8% compared to the histologic diagnosis and 100% with respect to the final diagnosis.

Solomon and Cappa²¹³ point out that the headache of temporal arteritis may clearly involve more than the temporal area and include pain in the temporal, frontal, vertex and occipital regions. The headache is characterized by gradual onset, progressing to a diffuse, often severe, aching. The headache may be intermittent, but usually becomes a prominent, if not daily, feature of patients with the disorder. The headache usually is constant and perceived as superficial in the scalp. There may be exquisite tenderness of the scalp and blood vessels particularly in the temporal region. The headache is usually worse at night and may be especially aggravated by exposure to cold.¹⁴

Sixty-five percent of patients are women with the average age at onset of 70 (range, 50–85). It is a common disorder and must be actively sought in any headache patient presenting after the age of 50 particularly in those with systemic symptoms. Allen and Studenski²¹⁴ emphasize additional symptoms such as extremity and tongue claudication, ear pain, stroke, and angina as well as systemic panarteritis involving the peripheral nervous system and abdominal or pelvic viscera.

Other ocular complaints with temporal arteritis include tonic pupils from ischemia of the ciliary ganglia²¹⁵ and bilateral uveitic glaucoma that may be on an immunologic basis.¹³⁵ While most attention has been drawn to vascular complications in the distribution of the external carotid and ophthalmic arteries, rarely do patients present with vertebral basilar symptomatology.²¹⁶ Among the protean manifestations of temporal arteritis are those described in the following reports: bilateral carotid artery occlusion,²¹⁷ renal disease,²¹⁸ aortic arch arteritis,²¹⁹ temporal mandibular joint pain,²²⁰ painful facial swelling,²²¹ jaw claudication,²²² and sudden death from arteritis in the coronary arteries, dissection of the aorta, and major cerebrovascular accident.²²³

An elevated sedimentation rate has been considered by some indispensable in diagnosing temporal arteritis. Without an elevated sedimentation rate, even in patients with a classic history and clinical findings, the diagnosis might be abandoned without proceeding to a temporal artery biopsy.

Nonetheless, it is now estimated that up to 9% of patients with temporal arteritis may have normal sedimentation rates.^224,225 Wong and Korn²²⁴ have identified 37 reported cases of biopsy-proven temporal arteritis with a normal Westergren sedimentation rate (< 40 mm/hr in patients older than than 50 years old).

Up to one-third of temporal artery biopsies may be falsely negative, especially when one fails to examine a long segment of vessel by serial sections. As has been stated, “because of the danger to vision, most authorities would start steroid treatment when they suspect the diagnosis clinically. Any response other than prompt and striking improvement in clinical well-being and symptoms, however, speaks against the diagnosis.”²²⁶ Raskin¹⁴ and Allen and Studenski,²¹⁴ as well as others believe steroid therapy should start immediately, before confirmation by laboratory and pathologic determinations. They suggest in very ill patients, intravenous methylprednisolone may be better.

INTRACRANIAL MASS LESIONS

The headache associated with an intracranial mass is nonspecific and often not localizing. It is estimated that almost two-thirds of patients with brain tumors complain of headache and that half consider headache to be the primary complaint.¹⁴ The headache of intracranial mass lesion is believed to be caused by traction on pain-sensitive structures within the cranium including the meninges and dural venous sinuses. The typical headache has a dull, nonthrobbing quality, is of moderate intensity, is worsened by physical activity, especially change in posture, and is intermittent. The headache is often associated with nausea and vomiting as is typical migraine headache. Ten percent of adults and two-thirds of children with brain tumors are awoken from sleep by headache. Brain tumor headache may be more prominent upon arising. Supratentorial headaches tend to have some localization to the side of the tumor and posterior fossa tumor headache tends to be bilateral, especially posterior. Any focal finding on neurologic examination or presence of papilledema in a patient with new onset headache requires neuroimaging and follow-up.

Cough headache describes the sudden transient occurrence of diffuse often severe headache precipitated by a valsalva maneuver that occurs on coughing, sneezing, bending, lifting, etc. It is usually benign, but approximately 10% of such patients have intracranial abnormalities usually in the posterior fossa. The Arnold-Chiari malformation, in particular, may present with cough headache, and therefore all patients with this condition must have magnetic resonance scans.

Increased intracranial pressure alone, without the presence of a mass lesion may be responsible for headache as in the syndrome of benign increased intracranial pressure or pseudotumor cerebri (see Chapter 5). These headaches tend to be diffuse, daily, of mild to moderate severity and are usually relieved following reduction of the increased intracranial pressure either by drugs such as acetazolamide or lumbar puncture. Raskin¹⁴ is impressed by the frequency of “migrainous” symptoms in individuals with pseudotumor cerebri and indicates that many persist with headache after papilledema and increased intracranial pressure have resolved. It is my experience that headache improvement is a good guide to efficacy of therapy in most patients. Given the overall frequency of migraine in young women it is not surprising that many with pseudotumor may have migraine as a concomitant condition.

MUSCLE CONTRACTION

Tension-type headache is classified as headache type 2.0 in the IHS classification and is further subclassified into 2.1: episodic tension-type headache, 2.2: chronic tension-type headache, and 2.3: tension-type headache not fulfilling the above criteria.

Muscle contraction or tension headache has been characterized as head pain without migrainous features. Typically, the headache is described as bilateral, commonly in an occipital or posterior neck location, variable in intensity, dull, with pressure and tightness in muscles and in association with emotional conflict.^14,227 They tend to occur on a daily basis but may be intermittent or periodic. On careful analysis there are many overlapping features common to migraine. Features at one time believed to be specific for tension headache, such as neck muscle contraction and precipitation by stress and anxiety, are know known to occur just as often in migraine.²²⁸ Indeed many patients with daily constant headache, without throbbing and having a “band-like” tightness, may respond to antimigrainous therapy. At one point an Ad Hoc Committee on Classification of Headache recommended separate categories for “Headaches of Delusional, Conversion, or Hyperchondriacal States” and for “Muscle-Contraction Headache” but others prefer to combine these into a category of “psychogenic headaches” under which there are the subtypes: depression (overt or masked), delusional (in a psychotic), somatoform disorder, chronic posttraumatic, chronic atypical facial pain, and muscle contraction pain (when caused by psychogenic factors and not unusual postures or strains).²²⁷ In the 2004 IHS Classification,¹ these headaches are classified as 12: headaches attributed to psychiatric disorder.

Clearly there are patients with major psychologic problems who have psychogenic headaches as a feature of their disorder, but in a majority without features which permit a diagnosis of probable or definite migraine, the distinction is often difficult. Muscle contraction or tension headaches do overlap significantly with migraine, as indicated above, and may respond to similar therapy. Antidepressant therapy in the form of tricyclics may be helpful in both muscle contraction and migraine headaches.

POSTTRAUMATIC

In the IHS Classification, Section 5.0 is for headache associated with head or neck trauma. This is further subdivided into 5.1: acute posttraumatic headache, and 5.2: chronic posttraumatic headache. Posttraumatic headaches are a regular feature of the posttraumatic or postconcussion syndrome, which follows significant head injury. The syndrome is not necessarily associated with definable central nervous system injury and can occur whether or not unconsciousness occurred at the time of trauma.¹⁴ The syndrome is characterized by headache, vertigo, impairment of memory and concentration, and variable degrees of emotional impairment. Headache lasting more than 2 months occurs in up to 60% of patients hospitalized after head injury.²²⁹ The degree of apparent disability may seem to outweigh the amount of objective evidence of central nervous system or musculoskeletal injury. Some believe that persistent symptoms relate to the patient's desire to seek compensation, but most believe that this occurs only in a small percent. There is evidence that an organic mechanism is operative in a large proportion of these patients.^14,230

The headache in postconcussional states usually occurs within a day of the injury but may be delayed for weeks. It is characterized by a dull, aching, generalized discomfort with localized exacerbation in bifrontal, bioccipital, or bitemporal locations, which may last for hours. The headache tends to be on a daily basis, but may be periodic and throbbing, quite characteristic of migraine. The usual course is one of gradual improvement in all symptoms when there is not severe organic impairment, but the headache may persist for many months.

Both common and classic migraine may have a significant exacerbation after closed head injury; uncommonly typical migraine attacks may follow injury in a previously headache-free individual. The incidence of posttraumatic migraine is higher in people with a strong family history of migraine headache.

ANEURYSM AND ARTERIOVENOUS MALFORMATIONS

Headaches associated with vascular disorders in the IHS classification are category 6.0 (see Table 1). Sudden, severe, “blinding,” excruciating headache, with stiff neck, vomiting, and altered mental status is the classic presentation for ruptured berry aneurysm. Subarachnoid blood is usually found on lumbar puncture, if it is performed, and the majority of CT scans reveal evidence of blood. Focal neurologic deficits may occur after rupture of berry aneurysms, such as the third-nerve palsy that often follows rupture of a posterior communicating artery aneurysm or hemiparesis after middle cerebral artery aneurysm rupture. The syndrome of “occipital apoplexy”: sudden headache, stiff neck, and a homonymous field defect is almost pathognomonic for a ruptured occipital lobe arteriovenous malformations (AVM).⁷ Any patient, with sudden severe headache, with or without stiff neck or focal neurologic signs must be evaluated with the possibility of ruptured or unruptured vascular anomaly such as aneurysm or AVM. The other neuro-ophthalmologic signs and symptoms of aneurysms, AVMs, and related vascular anomalies are detailed in Chapter 17.

Unruptured aneurysms and AVMs may also produce headache. When the headache pattern is completely stereotyped throughout life, strong suspicion should be raised as to the possibility of an arteriovenous malformation rather than migraine with aura.⁷³ Sentinel headaches are reported to occur in approximately 50% of patients days to weeks preceding subarachnoid hemorrhage from berry aneurysm.⁷⁰ Approximately half such headaches are reported to be abrupt in onset and severe and have been believed to be the result of an initial leak caused by partial rupture. Such patients should probably be evaluated with arteriography even if the cerebrospinal fluid does not disclose blood as Day and Raskin⁷⁰ have documented that thunderclap headache episodes may occur as symptoms of an unruptured aneurysm.

OCULAR

There are several ocular lesions that are important and treatable as causes of headache, including conjunctivitis, corneal lesions, anterior uveitis, angle closure glaucoma, optic neuritis, metastatic orbital tumors, orbital pseudotumors and the Tolosa-Hunt syndrome. The symptoms of paratrigeminal syndrome, ocular motor nerve paralysis, small vessel disease, carotid cavernous fistulas, and nasopharyngeal carcinomas may all have eye pain as a presenting symptom. Dissection of the internal carotid artery can also present with eye pain (see below). Photophobia is often seen with subarachnoid hemorrhage, meningitis, retrobulbar neuritis, and migraine and probably has its basis in central cortical and brainstem reflexes.²³¹

Carlow²³² notes that the eye and periorbital regions are common points of headache, but that the eye is rarely responsible if ophthalmic signs are not obvious. He also believes that refractive disorders and muscle imbalance are overemphasized as the cause of headache and that correction of these problems seldom provides resolution, the exception being convergence insufficiency. Ocular neurosis is the usual cause of eye strain headache that begins abruptly with use of the eyes in which there is a normal ophthalmologic examination.

CAROTID DISSECTION

Another type of unusual facial pain that initially may be thought to be temporal arteritis is that caused by spontaneous dissection of the carotid and/or vertebral arteries.²³³ The vascular dissection may occur spontaneously, especially in those with unsuspected fibromuscular dysplasia. Carotid and/or vertebral artery dissection may follow head and neck injury is in “whiplash,” blows to the neck, and after neck manipulation. The clues to making the diagnosis include pain over the angle of the jaw and hemicranium, oculosympathetic paresis, dysgeusia, and altered facial sensation, as in the following case:

A 46-year old mildly hypertensive woman developed “lightening pains” that radiated to her face from the left side of her neck. The following day the pain had become dull and was localized behind her left eye. She noted slight drooping of her left eyelid, a strange persistent metallic taste, and discomfort over the left side of her forehead. Her unilateral neck and face pain then increase in intensity, and the entire left side of her face became “numb and disagreeable.” Examination showed a left oculosympathetic paresis and marked decrease in sensation to light touch and pinprick over all three divisions of the left trigeminal nerve. Testing facial sensation evoked an unpleasant sensation. The remainder of her examination was normal as were CT and MRI. Cerebral angiography demonstrated a dissection of the left internal carotid artery extending intracranially to the cavernous sinus and a 2-cm dissection of the left vertebral artery.²³⁴

Carotid dissection can mimic Raeder's paratrigeminal syndrome (see above), but requires angiography for diagnosis.

Headaches in general should be considered as a serious medical problem only when they become continuous or recur frequently, because almost everyone suffers from occasional headache. Dalessio²³⁵ discusses the approach to diagnosing a severe headache: “Although headache remains one of the most common medical complaints, even its most severe and chronic manifestations are rarely caused by organic disease. In a given year, nearly three-quarters of Americans have headaches, but of these, only 5% seek medical help.”²³⁵ When the complaint is of a persistent or recurrent headache, the history becomes of primary importance in establishing the proper diagnosis. Additional description of the characteristics of the nonmigrainous headaches are found in standard references on headache.^14,15,203 The question arises as to which conditions are confused with migraine and when should one reasonably proceed to a more detailed investigation or referral to a specialist.

In assessing the specific history of the headache, important facts to determine are onset, duration, periodicity, timing, localization, intensity, character, precipitating factors, accompanying symptoms and signs, and response to therapy. Often the exact description alone of the nature, duration, and timing of the headache permits the correct diagnosis. This is particularly true with migraine headache characterized by periodicity and associated symptoms.

When a new headache occurs, particularly in an adult who has never been prone to headache and in whom atypical features are present, such as persistent focal pain, then disorders other than migraine should be carefully ruled out. When obvious disease of cranial or extracranial structures accompanies the headache, little diagnostic confusion results. However, when cephalgia persists without readily apparent reason, further evaluation is needed.

General physical and neurologic examination in patients with migraine, aside from the complicated varieties, is normal. Conditions that may be confused with each of the migraine syndromes described previously are reviewed briefly.

Migraine without aura, as emphasized earlier, should not be diagnosed simply by the presence of headache. Tension or muscle contraction headache alone or in combination with a vascular component is most often confused with common migraine. The periodicity, associated symptoms (nausea, photophobia, and fluid retention), and family history all weigh in favor of migraine. Persistent pain, absent family history, muscle tenderness, and bizarre descriptions such as “a knife being driven through the skull” raise the possibility of muscle contraction or psychogenic headache. Any neurologic abnormality on examination, such as mild hemiparesis, consistent sensory defect, or reflex asymmetry, again suggests the possibility of intracranial disease and traction headache. Headache from intracranial sources is produced most often by inflammation, traction and displacement, or distension of pain-sensitive structures, usually dura and blood vessels. Exact correlation of headache site with intracranial mass lesions is often misleading; but in general, lesions of the posterior fossa produce occipital headache, and hemispheric tumors produce more anterior, frontal headache. In the absence of increased intracranial pressure, the headache tends to be localized to the side of the lesion.

Cranial arteritis, a disorder of the elderly, often produces headache, frequently without overt signs. The headache can be severe and accompanied by tenderness of the extra cranial arteries. In the older patient the investigation of a new headache should always include an erythrocyte sedimentation rate as a screening test for cranial arteritis.

Migraine with aura (classic migraine), in its complete form with slowly progressive visual aura, is virtually never caused by an organic process. A question is frequently raised as to the possibility of AVM. While headaches may indeed be present with AVM, such vascular lesions more commonly present as subarachnoid hemorrhage or seizure. In a review of occipital lobe AVMs, Troost and Newton⁷ determined that the characteristic visual phenomena represent occipital epilepsy, and the nonalternating, unilateral character of the headache, as well as the history of a seizure, always distinguished these vascular malformations from migraine. Rarely, an arteriovenous malformation may produce clinical symptomatology, which in a single episode is indistinguishable from an episode of classic migraine.⁷³ The invariant nature of the attack, lack of response to therapy, and presence of abnormality on examination, such as a cranial bruit, should lead to additional diagnostic studies in these unusual patients. A normal physical examination, family history, and response to therapy should eliminate the need to perform neuroradiologic studies in the vast majority of patients with migraine.

Common, classic, and complicated migraine may be precipitated by trauma. If the typical clinical pattern of one of the migraine syndromes follows head trauma, other additional causes such as subdural hematoma need not be sought. Complicated migraine can present some of the most difficult diagnostic problems, particularly in the absence of prior episodes or family history. The acute onset of neurologic dysfunction and headache in this setting must always be regarded initially as caused by another process, such as cerebrovascular disease or rapidly growing tumor, and must be investigated fully. Again the prior history of uncomplicated common or classic migraine may lessen the suspicion of another process in a given individual.

Ophthalmoplegic “migraine” should be diagnosed only in the typical clinical setting described in the previous section: a young individual with history of recurrent ophthalmoplegic episodes or known migraine. Sudden oculomotor nerve palsy associated with previous chronic headache, or with new acute severe headache, should be considered caused by aneurysm until proved otherwise. With aneurysm, the history is not one of recurrent episodes of ophthalmoplegia with full recovery. Occasionally other congenital vascular anomalies, meningeal inflammation, or neoplastic disease may produce painful ophthalmoplegia. Diabetic oculomotor palsy usually occurs in older individuals with diabetes, spares the pupil, and is rarely recurrent. Sphenoid sinus mucocele may present as a recurrent headache and third-nerve palsy;²³⁶ radiologic studies should clarify the diagnostic dilemma.

Cranial nerve abnormality other than oculosympathetic paresis in a patient with “cluster” headaches should alert the physician to an intracranial mass lesion (Rader paratrigeminal neuralgia, type 1). Persistent localized pain most often makes this cluster atypical and points to a different etiology.

In general, knowledge of the different headache varieties other than migraine and a careful history and examination will lead to the appropriate diagnosis.

Medications used in acute headache treatment include analgesics, antiemedics, antianxiety agents, nonsteroidal anti-inflammatory drugs (NSAIDs), ergots, steroids, major tranquillizers, narcotics, and the selective 5-HT₁ (serotonin) agonists, the triptans. The original triptan was sumatriptan, initially introduced in the United States in subcutaneous form but later in oral dosage.^238–241 There are now six triptans with different pharmacokinetic profiles and half-lives.¹⁶ Preventive therapy include a broad range of medications, most notably, anticonvulsants, calcium channel blockers, β-blockers, antidepressants, serotonin antagonists, and the botulinum neurotoxins.^62,242–244

SYMPTOMATIC TREATMENT

There are a wide variety of acute treatments available for migraine (Table 12). A further listing of abortive and symptomatic therapies for migraine is adapted from Baumel²³⁷ (Tables 13 and 14). As pointed out by Silberstein and Lipton, the choice of acute treatment depends on the severity and frequency of headaches, the pattern of associated symptoms, comorbid illnesses, and the patient's treatment response profile. The simplest treatment is with nonprescription or prescription analgesics. Many individuals find headache relief with compounds such as aspirin or acetaminophen either alone or in combination with caffeine. Butalbitol, a short-acting barbiturate is often added to the combination of simple analgesics and caffeine. The combination of acetaminophen, isometheptene, a sympathomimetic; and dichloralphenazone, a chloral hydrate derivative, is also safe and effective in headache treatment.^245,246 When simple analgesics fail, consideration may be given to combination with more potentially habit forming medication. Combinations are available with codeine. The nausea is often effectively treated with prochloperazine.

TABLE 12. Drugs Used for Acute Migraine Therapy

TABLE 13. Abortive Therapy for Migraine

TABLE 14. Symptomatic Therapy for Migraine

More potent narcotic analgesics such as propoxyphene, meperidine, morphine, hydromophone, and oxycodone are available alone and in combination. However, because of medication overuse and rebound, these agents should be used sparingly and only for patients who experience infrequent headaches.¹⁴ Further discussion about the use of opioids and transnasal opioids are discussed by Silberstein and Lipton.⁹

Headaches similar to migraine can be triggered by serotonergic drugs such as reserpine and m-chloralphenalpiprazine (serotonergic agonist).^37,38 Two agents effective in the acute treatment of migraine, sumatriptan,^247–249 a serotonin analogue, and dihydroergotamine (DHE),^250,251 an ergot derivative. These agents block the development of neurogenically induced inflammation in rat dura mater. This in turn blocks the release of neuropeptides including substance P and calcitonin gene-related peptide, preventing neurogenic inflammation.⁹ The NSAIDs may also block neurogenic inflammation; the mechanism of this action, however, is less certain.

Ergotamine and DHE can be used to treat moderate to severe migraine.²⁵² It was once the mainstay of acute therapy. It was once said that “if a headache does not respond to ergotamine tartrate, it is not true migraine.”²⁵³ This agent, derived from Claviceps purpurea, a fungus that grows in rye and other grains, is the major compound effective as a specific agent in an acute migraine attack. Ergotamine is one of the naturally occurring alkaloids in crude ergot; all the ergot alkaloids are derivatives of lysergic acid.²⁵⁴ Ergotamine has as one of its major pharmacologic properties the ability to produce a peripheral vasoconstriction and, in higher doses, damages capillary endothelium. Inasmuch as ergotamine is neither sedative nor analgesic and other forms of pain are not relieved by the drug, its action is believed to directly related to the pathophysiology of migraine. In the classic experiments of Graham and Wolff,²⁵⁵ the intensity of pain was directly related to the amplitude of the temporal artery pulsation, and both decline in response to intravenous ergotamine tartrate (Fig. 13).

DHE is available in 1 mg/mL ampules, which can be administered intramuscularly, subcutaneuously, or intravenously.¹⁴ DHE nasal spray with 40% bioavailability is also available. Dosage for individual attacks should be limited to 1 mg intramuscularly or intravenously, with a maximum of 3 mg/d. Monthly limits, according to Silberstein and Lipton, are 18 ampules or 12 events.

The oral combination for ergotamine tartrate with caffeine (Cafergot: 1 mg ergotamine tartrate and 100 mg of caffeine) remains widely used. The oral absorption of ergotamine is erratic. While often effective, it shares the disadvantage of most of the oral ergotamine preparations in that it can produce nausea and vomiting itself. However, patients who cannot tolerate ergotamine because of nausea can be pretreated with metoclopramide ²⁵⁶ Proclorperazine, promethazine²⁵⁷ or a mixture of a barbiturate and a belladonna alkaloid for patients with intractable migraine intravenous DHE has been recommended.²⁵⁸

It should be noted that pregnant women should not use ergot preparations because of their potent oxytocic effects. Fortunately, pregnancy usually brings a diminution in the symptoms of migraine. Ergot preparations in high doses may cause peripheral capillary endothelial damage, peripheral paresthesias, pain, and even gangrene. These preparations are generally not recommended for patients in septic states or who have coronary artery disease, obliterative peripheral vascular disease, or cardiac conditions. As indicated by Goadsby,¹⁶ the main advantage of the ergotamines is low cost and long experience with use; however, their pharmacology is complex and they have generalized vasoconstrictor effects that may be associated with vascular vents, high risk of overuse syndrome, and rebound headaches.²⁵⁹

Is it advisable to use vasoconstricting agents during a complicated migraine prodrome, such as mild hemiparesis or dysphasia? If the cerebral event is indeed vasoconstriction, will ergot preparations potentiate the possibility of permanent cerebral infarction? Theoretically, the preparations act only peripherally and not on the intracranial vasculature. However, since little is really known of the actual central nervous system effects of the ergot alkaloids,²⁵⁴ it may be wise to be cautious with their use if prominent central nervous system symptoms precede the headache attack.

THE TRIPTANS

The triptans have now been available for over 10 years, the initial agent being sumatriptan. There are now six other triptans with varying forms including oral dosing, subcutaneous injection, nasal spray, and rapid oral disintegrating tablets (Table 15). As noted by Goadsby,¹⁶ compared to the ergot medications, the triptans have significant advantages— notably, very selective pharmacology, simple and consistent pharmacokinetics, and established efficacy based on well-designed controlled trials and a well-established safety record.^260,261 The triptans are serotonin 5-HT_1b/1D-receptor agonists. It is believed this agonist activity is the primary mechanism of the therapeutic effect of the drugs which have three potential mechanisms of action: cranial vasoconstriction, peripheral neuronal inhibition, and inhibition of transmission through second-order neurons in the trigeminocervical complex.^16,262 Specific contraindications to the use of the triptans include ischemic heart disease, sustained hypertension, Prinzmetal's angina, and hemiplegic and basilar-type migraine. Side effects of the triptans include: tingling, parasthesias, and sensations of warmth in the head, neck, chest, and limbs. There are less frequent side effects such as dizziness, flushing, and neck pain or stiffness. It should be noted that triptans can constrict coronary arteries and can cause chest symptoms which may mimic angina. There has been extensive use of the triptans and they are regarded generally as being quite safe, however, they all are 5-HT_1b/1D agonists and these receptors are present on the coronary arteries, thus it is quite reasonable to avoid the use of triptans in ischemic heart disease, uncontrolled hypertension, and cerebrovascular disease.

TABLE 15. Triptans

Comparisons between the main pharmacologic and clinical characteristics of newer oral triptans compared to 100 mg of oral sumatriptan are reviewed elsewhere.^16,263 In other comparative trials, 40 mg of eletriptan was found to be superior to 100 mg of sumatriptan.^264,265 In selecting the initial treatment for an acute attack, it should be recognized that migraine is a polygenetic heterogeneous disorder and, therefore, treatment of the initial attacks depend on the severity and frequency of the attacks and the prior history of treatment. Patients who do not respond to one triptan may respond to another. In patients with significant disability, a triptan should be prescribed early in the course of treatment in keeping with a stratified approach to care.^16,266

PROPHYLACTIC TREATMENT

Preventive therapy should be based on general principles including the following (Silberstein and Lipton⁹):

1. When two or more attacks occur per month and produce disability lasting more than 3 days.
   
2. When symptomatic medications are contraindicated or ineffective.
   
3. When abortive medication is required more than twice per week or when special circumstances that exist, that is, a rare headache attack that produces profound disruption.
   

In general, when headaches are causing significant disability or are interfering with work, prophylactic treatment is indicated. Similarly, patients who have severe migraine attacks, unresponsive to acute medications, would be candidates for preventive therapy. As pointed out by Goadsby, if the headaches occur 1 to 2 days per month, there is usually no need for preventive therapy; if they occur 3 to 4 days per month, preventive therapy should be considered; and if the patient has 5 or more attacks per month, preventive therapy should be seriously considered.¹⁶

The major medication groups include: anticonvulsants, calcium channel agonists, beta adrenergic blockers, antidepressants, serotonin agonists, and botulinum toxin (Table 16). For cluster headache, if these drugs fail, methysergide or lithium may be utilized. Methysergide is an extremely effective agent for cluster headache. It is related chemically to ergotamine tartrate and closely to lysergic acid, but it is relatively free of vasoconstrictor effect and is believed to be an antagonist of serotonin. Acutely, it may rarely cause a confusional state requiring its withdrawal. The major concern as to its long-term use is the development of retroperitoneal fibrosis.^267,268 This complication develops after long-term (usually more than 1 year) continuous methysergide therapy, often at doses of 8 to 16 mg/d. It is currently believed that such complications can be avoided by gradually discontinuing the drug (to avoid rebound) over 2 to 3 weeks and stopping it for 3 to 4 weeks every 6 months.

TABLE 16. Preventive Therapy for Migraine

ANTICONVULSANTS

A variety of anticonvulsants may be very effective in reducing migraine attacks. The only anticonvulsant currently approved for migraine prophylaxis is valproate, which has significant side effects such as weight gain, drowsiness, tremor, and hair loss. Fetal abnormalities and hematologic and liver abnormalities are also noted. The second anticonvulsant, which will be approved in 2004, is topiramate. A small percentage of patients using topiramate experience cognitive side effects such as memory loss and mild confusion. Other side effects include hair loss and peripheral tingling of the hands and feet. Topiramate is also a potent appetite suppressor in approximately 50% of individuals who take it and it is also a blocker of carbonic and hydrase, which makes it a medication of choice in the headache of pseudotumor cerebri. Levetiracetam is also an agent useful in the management of migraine.²⁶⁹ Levetiracetam is weight neutral and does not have significant cognitive side effects, although drowsiness is sometimes noted unless the dose is increased quite slowly. Other anticonvulsants useful in the prevention of migraine include zonisamide and neurontin.

CALCIUM CHANNEL BLOCKERS

Specific calcium channel blockers were originally intended for use in cardiovascular disease but show great promise as prophylactic agents in the treatment of migraine. Diltiezam,²⁷⁰ verapamil,²⁷¹ nifedipine,²⁷² nimodipine,^273–275 and flunarizine²⁷⁶ have all been reported to be effective in migraineurs. The mechanism of action of this class of drug in headache is unknown but may relate to their antivasoconstrictor activity²⁷⁷ or to nonvascular processes such as inhibition of platelet aggregation, serotonin release,²⁷¹ or serotonin and histamine receptor blockade. Calcium entry blockers do not necessarily share common molecular structures and may act at different sites on the calcium channel. For instance, nimodipine, nifedipine and nitrendipine are dihydropyridines, flunarizine is a piperazine derivative and verapamil is structurally related to papaverine. It is now known that many other drugs have calcium channel blocking activity including some useful for migraine, such as amitriptyline and cyproheptadine.²⁷⁷

Data suggest that there may be a delay of up to 8 weeks before any response to these agents is seen.^270,273,274 Verapamil may be an exception with improvement occurring within 1 or 2 weeks of initiation. At the current time verapamil is my first choice for most patients with migraine headaches. Therapy is initiated with 80 mg/d for 2 days, then 80 mg 2/d for 2 days, and then 80 mg 3/d for 2 days, and then switch to the 240-mg sustained release form. Sometimes patients report an initial increase in headache and headache improvement often requires weeks of treatment. The dose of verapamil may then be increased to 240-mg sustained release in the morning and 120-mg sustained release in the evening, and later to 240-mg sustained release twice per day. The primary side effect of verapamil is constipation which may be avoided with the use of stool softeners. Other side effects vary and depend upon the individual drug, but include dizziness, headache (particularly with nifedipine), depression, vasomotor changes, tremor, orthostatic hypotension, and bradycardia. Calcium channelers are especially useful in patients with comorbid hypertension and in patients with a contraindication to β-blockers, such as asthma and Raynaud's disease. These agents, particularly verapamil, may have a particular advantage in patients with prolonged aura or vertibular vascular migraine. There is little comparative data on the efficacy of various calcium channel blockers.

β-BLOCKERS

β-blockers, particularly propranolol, have been the most widely used prophylactic agents in migraine. They have shown to be 60% to 80% effective in producing greater than 50% reduction in attack frequencies. Many controlled studies²⁷⁸ have shown that propranolol, metoprolol, timolol, nadolol, and atenolol reduce the frequency of attacks in patients who have migraine with and without aura.^185,252 All β-blockers have side effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression and, rarely, esophageal spasm. Less common side effects include orthostatic hypotension, significant bradycardia, impotence, and aggravation of intrinsic muscle disease. Such drugs have specific contraindications including asthma, heart block and congestive heart failure. Long-acting forms of propranalol may be helpful in some patients, but are significantly more expensive and less flexible in dosage. Studies have been carried out with other β-blocking agents but none has been superior to propranalol. There are clearly some patients who are responsive to one and not to other drugs in this class, so if a patient does not respond to propranalol it is reasonable to proceed with nadolol, (80–240 mg), atenolol (50–100 mg), or timolol (20–100 mg). Determination of plasma propranolol concentrations have demonstrated that different responses to the same oral dose do not depend on different plasma levels of the drug.²⁷⁹ Therefore, clinical response to such agents would seem to be linked to individual sensitivity. Several articles and text discuss the overall approach to the treatment of vascular headaches.^{14,15,237,279}

TRICYCLIC ANTIDEPRESSANTS

Propranolol was compared to amitriptyline by Zieglar et al.²⁸⁰ and found to be equally effective, however, many regard amitriptyline to be the drug of choice in mixed headache particularly when there is a muscle contraction and depression factor. Time and experience will indicate whether tricyclic antidepressants are really as effective as the β-blocking drugs in pure vascular headaches. “The ideal prophylactic agents for the therapy of migraines should be early active, possess long-term efficacy with few side effects and a convenient dosing schedule, and truly prevent attacks from occurring rather than merely decreasing their severity.”²⁸¹ The fact is that no such ideal agent has been found.

The tricyclic antidepressants most commonly used for migraine and tension-type headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protryptyline.²⁵² Side effects of tricyclic antidepressants are common and involve antimuscarinic effects such as dry mouth and sedation. These drugs also increase appetite and therefore produce weight gain. One should also be aware of potential cardiac toxicity and orthostatic hypotension. Tricyclics have also been used cautiously in combination with monoamine oxidase inhibitors and with β-blockers. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline are the newest types of antidepressants that may be effective in some headache patients.

SEROTONIN ANTAGONISTS

Methysergide is a semisynthetic ergot 5-HT₂ receptor antagonist that displays affinity for the 5-HT₁ receptor.⁹ Methysergide (Sansert) is an effective migraine prophylactic in 60% or more of migraineurs and may be especially effective in cluster headache. The side effects of methysergide include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucination. The major complication is the rare (1 in 5000) development of retroperitoneal, pulmonary, or endocardial fibrosis.^282,283 It is believed that this major complication may be prevented by having a medication-free interval of 4 weeks after each 6 months of continuous treatment. The dosage should not exceed three of the 2-mg pills (6 mg total daily dose).

Other agents such as cyproheptadine, pizotifen, and the use of anticonvulsant medications are discussed further elsewhere.^9,237

Another approach to migraine therapy is that of vigorous bilateral compression and massage of the frontal branch of the superficial temporal artery, started at the first sign of visual aura. The technique was successful in blocking 81% of attacks in 15 patients.²⁸⁴ The authors speculated that the blood vessels of the extracranial circulation as well as those of the circle of Willis have perivascular nerve fibers of trigeminal origin. It may well be that these nerve fibers, rather than the dilation of blood vessels with release of vasoactive substances mediate the pain syndrome of migraine. Digital massage might stimulate the nerve endings and for some reason stop the ensuing pain phase of the headache.

BOTULINUM TOXIN TYPE A

Botulinum toxins are neurotoxins that inhibit the release of acetylcholine from presynaptic nerve terminals resulting in muscle relaxation. Another mechanism of action is blocking the release of CGRP and substance P from nerve terminals, thereby inhibiting the sterile neurogenic inflammation. Botulinum toxin type A was discovered serendipitously by Dr. William Binder, who was using it to treat wrinkles. Many patients returned and reported a significant amelioration of their headaches. Thereafter, small controlled trials were performed showing moderate efficacy.²⁸⁵

Botulinum toxin type A shows significant promise in the management of a variety of headache types. Pivotal double-blind placebo-controlled trials are currently underway to establish the potential efficacy in the management of headache. It is now recognized that botulinum toxin type A is an effective prophylactic treatment in the primary headache disorders.^243,244

My personal experience^62,242,286 is based on experience with over 600 patients and 2200 injection cycles. The majority of these patients (> 95%) had previously failed three or more of the preventive pharmacologic therapies for migraine previously discussed. Outcome was measured on a 1 to 5 scale from no change to excellent improvement. Overall, 91% of the patients noted some level of improvement and, after three treatments, 75% of the patients reported improvement as good to excellent.⁶² The mechanism of action is based upon two factors: botulinum toxin type A is a focally acting neurotoxin that inhibits release of acetylcholine and other neurotransmitters from presynaptic nerve endings. At the neuromuscular junction this results in reduced muscle tone, but there is good evidence now that botulinum toxin type A affects pain signaling and reduces the local release of nociceptive neuropeptides.^287–289

In my experience, patients with migraine with aura usually experience reduction in headaches along with reduction in aura. Menstrual-associated migraine headache is also reduced after the use of botulinum toxin, prompting us to consider whether there is central desensitization from the peripheral muscle and scalp injections of botulinum toxin.

Our results and those of others suggest that botulinum toxin type A may be an effective and safe prophylactic treatment variety of moderate to severe chronic headache types.²⁴³As pointed out by Silberstein and Lipton,⁹ the goals of treatment are to relieve or prevent pain in the associated symptoms of migraine and optimize the patient's ability to function normally. The patient should learn to identify and avoid headache triggers. The wide variety of drug therapies available, numbering over 400, attest to the fact that no particular therapy or combination of drugs is completely effective. The management of the patient with migraine is a complex problem requiring evaluation and elimination of possible precipitating factors, including psychogenic ones, as well as vigorous management of the acute attack and attempts at prevention of recurrent episodes. The care of the migraine patient continues to represent, in many instances, a major therapeutic challenge.

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