Of all the painful states that afflict humans, headache is undoubtedly the most frequent and rivals backache as the most common reason for seeking medical help. In fact, there are so many cases of headache that special headache clinics have been established in many medical centers. In addition to its frequency in general practice, many headaches are caused by general medical rather than neurologic diseases, and the subject is the legitimate concern of the general physician. Yet there is always the question of intracranial disease, so that it is difficult to approach the subject without a knowledge of neurologic medicine.

Why so many pains are centered in the head is a question of some interest. Several explanations come to mind. For one thing, the face and scalp are more richly supplied with pain receptors than many other parts of the body, perhaps to protect the precious contents of the skull. Also, the nasal and oral passages, the eye, and the ear—all delicate and highly sensitive structures—reside here and must be protected; when affected by disease, each is capable of inducing pain in its own way. Finally, there is greater concern about what happens to the head than to other parts of the body, since the former houses the brain, and headache frequently raises the specter of brain tumor or other cerebral disease.

Semantically, the term headache encompasses all aches and pains located in the head, but in practice, its application is restricted to discomfort in the region of the cranial vault. Facial, lingual, and pharyngeal pains are put aside as something different and are discussed separately in the latter part of this chapter and in Chap. 47, on the cranial nerves.

In the introductory chapter on pain, reference was made to the necessity, in dealing with any painful state, of determining its quality, severity, location, duration, and time course as well as the conditions that produce, exacerbate, or relieve it. In the case of headache, a detailed history following these lines will determine the diagnosis more often than will the physical examination or imaging. Although the examination is unlikely to be revealing, a few aspects are worth emphasis. Auscultation of the skull may disclose a bruit (with large arteriovenous malformations), and palpation may disclose the tender, hardened or elevated arteries of temporal arteritis, sensitive areas overlying a cranial metastasis, an inflamed paranasal sinus, or a tender occipital nerve, examination of neck flexion may reveal meningitis; however, apart from such special instances, examination of the head itself, although necessary, seldom discloses the diagnosis.

As to the quality of cephalic pain, the patient’s description may or may not be helpful. When asked to compare the pain to some other sensory experience, the patient may allude to tightness, aching, pressure, bursting, sharpness, or stabbing. The most important information to be obtained is whether the headache is pulsatile, but one must keep in mind that patients sometimes use the word throbbing to refer to a waxing and waning of the headache without any relation to the pulse, or simply use the term to transmit the severity of pain, whereas authentic pulsatile throbbing, is characteristic of migraine.

Similarly, statements about the intensity of the pain must be accepted with caution, as they reflect as much the patient’s temperament, attitudes and customary ways of experiencing and reacting to pain as its true severity. A better index of severity is the degree to which the pain has incapacitated the patient, especially if he is not prone to illness. A severe migraine attack seldom allows the migraineur to perform the day’s work. Another rough index of the severity of headache is its propensity to awaken the patient from sleep or to prevent sleep. The most intense cranial pains are those associated with meningitis and subarachnoid hemorrhage, which have grave implications, and with migraine, cluster headache, or tic douloureux, which do not.

Data regarding the location of a headache are apt to be more informative. Migraine headache is unilateral in two-thirds of attacks and is commonly associated with nausea, vomiting, and sensitivity to light, sound, and smells. Inflammation of an extracranial artery causes pain localized to the site of the vessel. Lesions of the paranasal sinuses, teeth, eyes, and upper cervical vertebrae induce a less sharply localized pain but still one that is referred to a certain region, usually the forehead or maxilla or around the eyes. Intracranial lesions in the posterior fossa generally cause pain in the occipitonuchal region and usually are homolateral if the lesion is one-sided. Supratentorial lesions induce frontotemporal pain, or approximate the site of the lesion. Localization, however, may also be deceiving. Pain in the frontal regions may be caused by such diverse lesions and mechanisms as glaucoma, sinusitis, thrombosis of the vertebral or basilar artery, pressure on the tentorium, and increased intracranial pressure. Similarly, ear pain may signify disease of the ear itself, but as often, it is referred from other regions, such as the throat, cervical muscles, spine, or structures in the posterior fossa. Periorbital and supraorbital pain, while usually indicative of local disease, may reflect dissection of the cervical portion of the internal carotid artery. Headaches localized to the vertex or biparietal regions are infrequent and should raise the suspicion of sphenoid or ethmoid sinus disease or thrombosis of the superior sagittal venous sinus.

The mode of onset, the variation of the pain over time, and duration of the headache, with respect both to a single attack and to the profile of the headache over a period of years, are also useful data. At one extreme, the headache of subarachnoid hemorrhage (caused by a ruptured aneurysm) occurs as an abrupt attack that attains its maximal severity in a matter of seconds or minutes, or, in the case of meningitis, it may come on more gradually, over several hours or days. Simulating the rapid onset, severe headache of subarachnoid hemorrhage are a group of “thunderclap headaches” of diverse causes but principally cerebral venous thrombosis and vasospasm syndromes. Brief sharp pain, lasting a few seconds, in the eyeball (ophthalmodynia) or cranium (“ice-pick” pain) and “ice-cream headache” caused by pharyngeal cooling is more common in migraineurs, with or without the characteristic headache, but otherwise cannot be interpreted and is significant only by reason of its benignity.

Migraine of the classic type usually has its onset in the early morning hours or in the daytime, reaches its peak of severity typically over several to 30 min, and lasts, unless treated, for 4 to 24 h, occasionally for as long as 72 h or more. Often, it is terminated by sleep. A migrainous patient having several attacks per week usually proves to have a combination of migraine and tension headaches, an analgesic “rebound headache,” or, rarely, some unexpected intracranial lesion. By contrast, the occurrence of unbearably severe unilateral orbitotemporal pain coming on within an hour or two after falling asleep or at predictable times during the day and recurring nightly or daily for a period of several weeks to months is typical of cluster headache; usually an individual attack of “cluster” dissipates in 30 to 45 min but some blend into more prolonged migraine. The headache of intracranial tumor may appear at any time of the day or night; it will interrupt sleep, vary in intensity, and last a few minutes to hours as the tumor raises intracranial pressure. With posterior fossa masses, the headache tends to be worse in the morning, on awakening. Tension headaches, described further on, may persist with varying intensity for weeks to months or even longer; when such headaches are protracted, there is usually an associated depressive illness. In general, headaches that have recurred regularly for many years prove to be migraine or tension in type.

The more or less constant relationship of headache to certain biologic events and also to certain precipitating or aggravating (or relieving) factors can be of great significance in diagnosis. Headaches that occur regularly in the premenstrual period are usually generalized and mild in degree, but attacks of migraine may also occur at this time (catamenial migraine). Headaches that have their origin in cervical spine disease are most typically intense after a period of inactivity, such as a night’s sleep, and the first movements of the neck are stiff and painful. Headache, or more often face ache, from infection of the nasal sinuses may appear, with clock-like regularity, upon awakening or in midmorning and is characteristically worsened by stooping and changes in atmospheric pressure; there is associated midfrontal or maxillary tenderness. On the other hand, the regular recurrence of migraine headache is often misdiagnosed as chronic sinusitis. Eyestrain headaches, of course, follow prolonged use of the eyes, as after long-sustained periods of reading, or exposure to the glare of video displays, but the pain is transient. In certain individuals, alcohol, intense exercise (such as weight lifting), stooping, straining, coughing, and sexual intercourse are known to initiate a special type of bursting headache, lasting a few seconds to minutes. If a headache is made worse by sudden movement or by coughing or straining, an intracranial source is tentatively suggested. Migraine often occurs several hours or a day following a period of intense activity and stress (“weekend”, or “letdown” migraine). Some patients have discovered that their migraine is relieved momentarily by gentle compression of the carotid or superficial temporal artery on the painful side, and others report that the carotid near the angle of the jaw is tender during the headache. Pain that is noticed when the scalp is stroked in combing or fixing the hair (allodynia) is common in migraine but could be a symptom of inflammation of the temporal arteries (temporal arteritis).

Pain-Sensitive Cranial Structures

Our understanding of headache has been augmented by observations made during operations on the brain (Ray and Wolff). These observations have informed us that only certain cranial structures are sensitive to noxious stimuli: (1) skin, subcutaneous tissue, muscles, extracranial arteries, and external periosteum of the skull; (2) the delicate structures of the eye, ear, nasal cavities, and paranasal sinuses; (3) intracranial venous sinuses and their large tributaries because they are intradural; (4) parts of the dura at the base of the brain and the arteries within the dura, particularly the proximal parts of the anterior and middle cerebral arteries and the intracranial segment of the internal carotid artery; (5) the middle meningeal and superficial temporal arteries; and (6) the first three cervical nerves and cranial nerves as they pass through the dura. Interestingly, pain is practically the only sensation produced by stimulation of these structures; the pain arises in the walls of blood vessels containing pain fibers (the nature of vascular pain is discussed further on). Much of the pia-arachnoid, the parenchyma of the brain, and the ependyma and choroid plexuses lack sensitivity.

The reference sites of pain from the aforementioned structures are important in understanding the genesis of cranial pain. Pain that arises from distention of the middle meningeal artery is projected to the back of the eye and temporal area. Pain from the intracranial segment of the internal carotid artery and proximal parts of the middle and anterior cerebral arteries is felt in the eye and orbitotemporal regions. The pathways whereby cephalic sensory stimuli are transmitted to the central nervous system (CNS) are the trigeminal nerves, particularly their first and, to some extent, second divisions, which convey impulses from the forehead, orbit, anterior and middle fossae of the skull, and the upper surface of the tentorium. The sphenopalatine branches of the facial nerve convey impulses from the nasoorbital region. The ninth and tenth cranial nerves and the first three cervical nerves transmit impulses from the inferior surface of the tentorium and all of the posterior fossa. Sympathetic fibers from the three cervical ganglia and parasympathetic fibers from the sphenopalatine and otic ganglia are mixed with the trigeminal and other sensory fibers. The tentorium roughly demarcates the trigeminal from the cervical–vagal–glossopharyngeal innervation zones. The central sensory connections, which ascend through the brainstem or the cervical spinal cord and brainstem to the thalamus, are described in Chaps. 8. and 9.

To summarize, pain from supratentorial structures is referred to the anterior two-thirds of the head, i.e., to the territory of sensory supply of the first and second divisions of the trigeminal nerve; pain from infratentorial structures is referred to the vertex and back of the head and neck predominantly by the second cervical roots. Trigeminal and cervical sensory inputs converge on the second order neurons at the C2 level, permitting pain from the neck and occipital regions to be referred to the forehead, and vice versa. The seventh, ninth, and tenth cranial nerves refer pain to the nasoorbital region, ear, and throat. There may be local tenderness of the scalp at the site of the referred pain. Dental or temporomandibular joint pain impulses are carried by the second and third divisions of the trigeminal nerve. With the exception of the cervical portion of the internal carotid artery, from which pain is referred to the eyebrow and supraorbital region, and the upper cervical spine, from which pain may be referred to the occiput, pain because of disease in extracranial parts of the body is not referred to the head. There are, however, rare instances of angina pectoris that may produce discomfort at the cranial vertex or adjacent sites and, of course, in the jaw.

Mechanisms of Cranial Pain

The studies of Ray and Wolff demonstrated that relatively few mechanisms are operative in the genesis of cranial pain. More specifically, intracranial mass lesions cause headache only if they deform, displace, or exert traction on vessels and dural structures at the base of the brain, and this may happen long before intracranial pressure rises. In fact, artificially raising the intraspinal and intracranial pressure by the subarachnoid or intraventricular injection of sterile saline solution does not consistently result in headache. This has been interpreted to mean that raised intracranial pressure does not cause headache—a questionable conclusion when one considers the relief of headache in some patients that follows lumbar puncture and lowering of the cerebrospinal fluid (CSF) pressure, particularly after subarachnoid hemorrhage. Actually, most patients with high intracranial pressure complain of bioccipital and bifrontal headaches that fluctuate in severity, probably because of traction on vessels or dura.

Dilatation of intracranial or extracranial arteries (and possibly sensitization of these vessels), of whatever cause, is likely to produce headache. The headaches that follow seizures and ingestion of alcohol are probably all caused by cerebral vasodilatation. Nitroglycerin, nitrites in cured meats (“hot-dog headache”), and monosodium glutamate in Chinese food may cause headache by the same mechanism. It is possible that the throbbing or steady headache that accompanies febrile illnesses has a vascular origin as well; it is likely that the increased pulsation of meningeal vessels activates pain-sensitive structures within their walls or around the base of the brain. Febrile headache may be generalized or predominate in the frontal or occipital regions and is relieved on one side by carotid or superficial temporal artery compression and on both sides by jugular vein compression. Like migraine, it is also increased by shaking the head. Certain systemic infectious agents, enumerated further on, have a tendency to cause severe headache.

A similar mechanism may be operative in the severe, bilateral, throbbing headaches associated with extremely rapid rises in blood pressure, as occurs with pheochromocytoma, malignant hypertension, sexual activity, and in patients being treated with monoamine oxidase inhibitors. Mild to moderate degrees of chronic hypertension, however, do not cause headaches despite a popular notion to the contrary. So-called cough and exertional headaches may also have their basis in the distention of intracranial vessels.

For many years, following the investigations of Harold Wolff, the headache of migraine was attributed to dilatation of the extracranial arteries. Now, it appears that this is not a constant relationship and that the headache is of complex intracranial as much as extracranial origin, perhaps related to the sensitization of blood vessels and their surrounding structures. Activation of the trigeminovascular system (the trigeminal nerves and the blood vessels they supply), leading to an inflammatory response that is generated by local neural mechanisms, “neurogenic inflammation,” has also been assigned a role in migraine headache. These and other theories of causation are summarized by Cutrer and discussed further on in this chapter in the section on migraine.

With regard to cerebrovascular diseases causing head pain, the extracranial temporal and occipital arteries, when involved in giant cell arteritis (cranial or “temporal” arteritis), give rise to severe, persistent headache, at first localized on the scalp and then more diffuse. Most strokes caused by vascular occlusion do not cause head pain. However, with occlusion or dissection of the vertebral artery, there may be pain in the upper neck or postauricular area; basilar artery thrombosis causes pain to be projected to the occiput and sometimes to the forehead; and the ipsilateral eye and brow, and the forehead above it are the most common sites of projected pain from dissection of the carotid artery and occlusion of the stem of the middle cerebral arteries. Expanding or ruptured intracranial aneurysms of the posterior communicating or distal internal carotid arteries very often cause pain projected to the eye.

Infection or blockage of paranasal sinuses is accompanied by pain over the affected maxillary or frontal sinuses. Usually it is associated with tenderness of the skin and cranium in the same distribution. Pain from the ethmoid and sphenoid sinuses is localized deep in the midline behind the root of the nose or occasionally at the vertex (especially with disease of the sphenoid sinus). The mechanism in these cases involves changes in pressure and irritation of pain-sensitive sinus walls.

With frontal and ethmoidal sinusitis, the pain tends to be worse on awakening and gradually subsides when the patient is upright; the opposite pertains with maxillary and sphenoidal sinusitis. These relationships are believed to disclose their mechanism; pain is ascribed to filling of the sinuses and its relief to their emptying, induced by the dependent position of the ostia. Bending over intensifies the pain by causing changes in pressure, as does blowing the nose and air travel, especially on descent, when the relative pressure in the blocked sinus rises. Sympathomimetic drugs, such as phenylephrine hydrochloride, which reduce swelling and congestion, tend to relieve the pain. However, the pain may persist after all purulent secretions have disappeared, probably because of blockage of the orifice by boggy membranes and absorption of air from the blocked sinus, so called vacuum sinus headaches.

Headache of ocular origin, located as a rule in the orbit, forehead, or temple, is of the steady, aching type and tends to follow prolonged use of the eyes in close work. The main faults are hypermetropia and astigmatism (rarely myopia), which result in sustained contraction of extraocular as well as frontal, temporal, and even occipital muscles. In the uncommon and overemphasized circumstance of a refractive error causing headache, correction rapidly ameliorates the headache. Traction on the extraocular muscles or the iris during eye surgery will evoke pain. Patients who develop diplopia from neurologic causes or are forced to use one eye because the other has been occluded by a patch often complain of frontal headache. Another mechanism is involved in iridocyclitis and in acute angle closure glaucoma, in which raised intraocular pressure causes steady, aching pain in the region of the eye, radiating to the forehead. When acute angle closure glaucoma causes headache, the sclera is invariably red. Dilating the pupil risks precipitating angle closure glaucoma, a situation that can be reversed by the administration of pilocarpine 1 percent drops.

Headaches that accompany disease of ligaments, muscles, and apophysial joints in the upper part of the cervical spine are referred to the occiput and nape of the neck on the same side and sometimes to the temple and forehead. These headaches have been reproduced by the injection of hypertonic saline solution into the affected ligaments, muscles, and facet joints and are comparable to the regions of sclerotogenous referred pain that is discussed in Chap. 8. Such pains are especially frequent in late life because of the prevalence of degenerative changes in the cervical spine and tend also to occur after whiplash injuries or other forms of sudden flexion, extension, or torsion of the head on the neck. If the pain is arthritic in origin, the first movements after the individual has been still for some hours are stiff and painful. The pain of fibromyalgia, a controversial entity, is characterized by tender areas near the cranial insertion of cervical and other muscles. There are no pathologic data as to the nature of these vaguely palpable and tender regions, and it is uncertain whether the pain actually arises in them. They may represent only the deep tenderness felt in the region of referred pain or the involuntary secondary protective spasm of muscles. Massage of muscles, heat, and injection of the tender spots with local anesthetic has unpredictable effects but relieves the pain in some cases. Unilateral occipital headache is often misinterpreted as occipital neuralgia (see further on).

The headache of meningeal irritation (usually due to infection or hemorrhage) is typically acute in onset, usually severe, generalized, deep seated, constant, and associated with stiffness of the neck, particularly on forward bending. It has been ascribed to increased intracranial pressure; indeed, the withdrawal of CSF may afford some relief. However, dilatation and inflammation of meningeal vessels and the chemical irritation of pain receptors in the large vessels and meninges by endogenous chemical agents, particularly serotonin and plasma kinins, are probably more important factors in the production of pain and spasm of the neck extensors. In the chemically induced meningitis from rupture of an epidermoid cyst, for example, the spinal fluid pressure is usually normal, but the headache is severe. Meningeal irritation or inflammation may also be chronic and have as its main feature a concurrently ongoing headache.

A distinctive type of headache is produced by subarachnoid hemorrhage; it is very intense and very sudden in onset and is usually associated with vomiting and neck stiffness. It is not uncommon for the rupture of an aneurysm that gives rise to subarachnoid hemorrhage to be precipitated by exertion, even of minor degree. Other causes of what has been called “thunderclap headache” discussed further on simulate this disease (see Chap. 34). Among them is a type of diffuse cerebrovascular spasm that may be spontaneous, the result of sympathomimetic drugs, and extracranial vascular dissection of the carotid or vertebral arteries. Another cause is cerebral venous thrombosis.

Lumbar puncture (LP) or spontaneous low CSF pressure headache, as elaborated in Chap. 2, is characterized by a steady occipitonuchal and frontal pain coming on within a few minutes after arising from a recumbent position (orthostatic headache) and is relieved within a minute or two by lying down. Its cause is a persistent leakage of CSF into the lumbar tissues through the needle track, or a tear of the meninges that may be spontaneous or induced by spinal trauma. The CSF pressure is low (often zero in the lateral decubitus position), and installation of an epidural “blood patch” relieves the headache. Usually this type of headache is increased by compression of the jugular veins but is unaffected by digital obliteration of the carotid artery. It is likely that, in the upright position, a low intraspinal and negative intracranial pressure permits caudal displacement of the brain, with traction on dural attachments and dural sinuses. Pannullo and colleagues, with MRI, have demonstrated this downward displacement of the cranial contents. “Spontaneous” low-pressure headache may follow a cough, sneeze, strain, or athletic injury, sometimes as a result of rupture of the arachnoid sleeve along a nerve root (see “Spontaneous Intracranial Hypotension” in Chap. 30). Less frequently, LP is complicated by severe stiffness of the neck and pain over the back of the neck and occiput (see “Lumbar Puncture Headache” in Chap. 2); a second spinal tap in some instances discloses slight pleocytosis but no decrease in glucose—a sterile meningitis. This benign reaction must be distinguished from the rare occurrence of meningitis caused by introduction of bacteria through a rent in the meninges that has allowed both escape of spinal fluid and ingress of bacteria.

Headaches that are aggravated by lying down or lying on one side occur with acute and chronic subdural hematoma and with some brain masses, particularly those in the posterior fossa. The headache of subdural hematoma, when it occurs, is dull and unilateral, perceived over most of the affected side of the head. The global and nuchal headaches of idiopathic intracranial hypertension (pseudotumor cerebri) are also generally worse in the supine position (Chap. 31). In all these states of raised intracranial pressure, headaches are typically worse in the early morning hours after a long period of recumbency. Further on, we discuss the relative infrequency of headache as a result of brain tumor.

Exertional headaches are usually benign, but they are sometimes related to pheochromocytoma, arteriovenous malformation, or other intracranial lesions, in addition to the aforementioned subarachnoid hemorrhage from ruptured aneurysm. The same applies to headaches induced by stooping, most of which are benign or, at worst, are accounted for by sinus infection but there are exceptions and subdural hematoma is a known cause (see further on).

The clinician’s first goal when confronted with a patient with cranial pain is to determine if the headache is primary or secondary. The main primary headache syndromes are migraine, tension-type headache, cluster headache, or one of the trigeminal–sympathetic migraine variants of migraine or cluster. These tend to be chronic, recurrent, and unattended by other symptoms and signs of neurologic disease. Familiarity with the variety of symptoms, temporal profiles, and accompanying features of the primary headache disorders, and the proclivity for most of them to be familial, assist in identifying them from the patient’s description. There should be little difficulty in recognizing the secondary headaches of diseases such as glaucoma, purulent sinusitis, subarachnoid hemorrhage, and bacterial or viral meningitis provided that these sources of headache are kept in mind. A fuller account of these types of “secondary” headache syndromes is given in later chapters of the book, where the underlying diseases are described. All other headaches that by their localization, quality of pain, and precipitating characteristics do not conform to one of the primary types should be suspected of being symptomatic of a cranial, cervical, or systemic disorder. Nonetheless, in many instances no such underlying cause will be found after investigation.

The following broad categories of headaches should be considered (Table 10-1). In general, the classification of these headaches and other types of craniofacial pain follow the plan outlined by the International Headache Society (see Olesen and http://ihs-classification.org/en/).

Migraine

Migraine is a highly prevalent and largely familial disorder characterized by periodic, commonly unilateral, often pulsatile headaches that begin in childhood, adolescence, or early adult life and recur with diminishing frequency during advancing years.

Two closely related clinical syndromes have been identified, the first called migraine with aura and the second, migraine without aura (terminology of the International Headache Society). For many years, the first syndrome was referred to as classic or neurologic migraine and the second as common migraine. The ratio of classic to common migraine is 1:5. Either type may be preceded by vague premonitory changes in mood and appetite. Migraine with aura is ushered in by a disturbance of nervous function, most often visual, followed in a few minutes to hours by hemicranial (or, in about one-third of cases, bilateral) headache, nausea, and sometimes vomiting, all of which last for hours or as long as a day or more. Migraine without aura is characterized by an unheralded onset over minutes or longer of increasing hemicranial headache or, less often, by generalized headache with or without nausea and vomiting, which then follows the same temporal pattern as the migraine with aura. Sensitivity to light, noise, and often smells (photophobia, phono- or sonophobia, and osmophobia) attends both types, and intensification with movement of the head is common. If the pain is severe, the patient prefers to lie down in a quiet, darkened room and tries to sleep. The hemicranial and the throbbing (pulsating) aspects of migraine are its most characteristic features in comparison to other headache types. Each patient displays a proclivity for the pain to affect one side or the other of the cranium, but not exclusively, so that some bouts are on the other side.

The heritable nature of classic migraine is apparent from its occurrence in several members of the family of the same and successive generations in 60 to 80 percent of cases; the familial frequency of common migraine is slightly lower. Twin and sibling studies have not revealed a consistent mendelian pattern in either the classic or common form. Certain special forms of migraine, such as familial hemiplegic migraine, appear to be monogenic disorders but the role of these genes, most of which code for ion channels, in classic and common migraine is speculative.

Migraine, with or without aura, is a remarkably common condition. A study by Stewart and colleagues in the United States showed differences in the prevalence of migraine between individuals of white, African, and Asian origin of approximately 20, 16, and 9 percent, respectively, among women, and 9, 7, and 4 percent for men (see also Lipton et al). One-third of migraineurs have more than three attacks monthly if untreated and many require bed rest or severe curtailment of daily activities. Migraine may have its onset in childhood but usually begins in adolescence or young adulthood; in more than 80 percent of patients, the onset is before 30 years of age, and the physician should be cautious in attributing headaches that appear for the first time after this age to migraine, although there are exceptions.

In younger women, the headaches often tend to occur during the premenstrual period; in approximately 15 percent of such migraineurs, the attacks are exclusively perimenstrual (also termed “catamenial migraine”). Menstrual migraine, discussed further on, had been considered to be solely related to the withdrawal of estradiol (based on the work of Somerville). It is now acknowledged that the influence of sex hormones on headache is more complex. Migraine tends to cease during the second and third trimesters of pregnancy in 75 to 80 percent of women, and in others they continue at a reduced frequency; less often, attacks of migraine or the associated neurologic symptoms first appear during pregnancy, usually in the first trimester.

Although migraine commonly diminishes in severity and frequency with age, it may actually worsen in some postmenopausal women, and estrogen therapy may either increase or, paradoxically, diminish the incidence of headaches. The use of birth control pills is associated with an increased frequency and severity of migraine and in rare instances has resulted in a permanent neurologic deficit (see further on and Chap 34).

Some patients link their attacks to certain dietary items—particularly chocolate, cheese, fatty foods, oranges, tomatoes, and onions—but these connections have proved invalid in controlled trials and, except in the occasional persuasive instance, they seem to us to be overrated. Some of these foods are rich in tyramine, which has been incriminated as a provocative factor in migraine. Alcohol, particularly red wine or port, regularly provokes an attack in some persons; in others, headaches are fairly consistently induced by exposure to glare or other strong sensory stimuli, sudden jarring of the head (“footballer’s migraine”), or by rapid changes in barometric pressure. A common trigger is excess caffeine intake or withdrawal of caffeine.

Migraine with aura frequently has its onset soon after awakening, but it may occur at any time of day. During the preceding day or so, there may have been mild changes in mood (sometimes a surge of energy or a feeling of well-being), hunger or anorexia, drowsiness, or frequent yawning. Then, abruptly, there is a disturbance of vision consisting usually of unformed flashes of white, or silver, or, rarely, of multicolored lights (photopsia). This may be followed by an enlarging blind spot with a shimmering edge (scintillating scotoma), or formations of dazzling zigzag lines (arranged like the battlements of a castle, hence the term fortification spectra, or teichopsia). Other patients complain instead of blurred or shimmering or cloudy vision, as though they were looking through thick or smoked glass or the wavy distortions produced by heat rising from asphalt. These luminous hallucinations move slowly across the visual field for several minutes and may leave an island of visual loss in their wake (scotoma); the latter is usually homonymous (involving corresponding parts of the field of vision of each eye), pointing to its origin in the visual cortex. Patients often attribute these visual symptoms to one eye rather than to parts of both fields. Ophthalmologic abnormalities of retinal and optic nerve vessels have been described in some cases but are not typical.

Other focal neurologic symptoms, much less common than visual ones, include numbness and tingling of the lips, face, and hand (on one or both sides); slight confusion of thinking; weakness of an arm or leg; mild aphasia or dysarthria, dizziness, and uncertainty of gait or drowsiness. Only one or a few neurologic phenomena are present in any given patient and they tend to occur in more or less the same combination in each attack. If weakness or paresthetic numbness spreads from one part of the body to another, or if one neurologic symptom follows another, this occurs relatively slowly over a period of minutes (not over seconds, as in a seizure, or simultaneously in all affected parts as in a transient ischemic attack).

The visual or neurologic symptoms usually last for less than 30 min, sometimes longer. As they recede, a unilateral dull pain develops of slowly increasing intensity that progresses to a throbbing headache (usually but not always on the side of the cerebral disturbance). At the peak of the pain, within minutes to an hour, the patient may be forced to lie down and to shun light (photophobia) and noise (phonophobia). Light is irritating and may be painful to the globes, or it is perceived as overly bright (dazzle) and strong odors are disagreeable. Nausea and, less often, vomiting may occur. The headache lasts for hours and sometimes for a day or even longer and is always the most unpleasant feature of the illness. The temporal scalp vessels may be tender and the headache is worsened by strain or jarring of the body or head. Pressure on the scalp vessels or carotid artery may momentarily reduce the pain and releasing pressure accentuates it.

Between attacks, the migrainous patient is normal. In the past, it was believed that a migrainous personality existed, characterized by tenseness, rigidity of attitudes and thinking, meticulousness, and perfectionism. Further analyses, however, have not established a particular personality type in the migraineur. A relationship of migraine to epilepsy in general is also tenuous; however, the incidence of seizures is slightly higher in migrainous patients and their relatives than in the general population, and there are syndromes that encompass both disorders.

Some patients note that their attacks of migraine tend to occur during the “let-down period,” after many days of hard work or tension. There is an overrepresentation of motion sickness or a vague instability of vision or accommodation, sensitivity to striped patterns, fainting, and of fleeting sensory symptoms on one side of the body in migraineurs. Moreover, as appreciated by Graham, migraine has a lifetime profile and is a familial disease that includes some or many of the following: colic in infancy, motion sickness, episodic abdominal pain, fainting, alcohol sensitivity, exercise-induced headaches, “sinus headaches,” “tension headaches,” and menstrual headaches. These are fairly dependable markers of the disease, and their absence in the patient or family members should at least cause the consideration of alternative explanations for cranial pain.

Migraine Variants

Much variation occurs in migraine. The headache may be exceptionally severe and abrupt in onset (“crash migraine” or “thunderclap headache”), raising the specter of subarachnoid hemorrhage. Careful questioning in these cases sometimes reveals that the headache did not truly attain its peak rapidly but evolved over several minutes. Nonetheless, the distinction of this type of “thunderclap headache” from subarachnoid hemorrhage can be made only by examination of the CSF and imaging of the brain (see further on, under “Special Varieties of Headache“).

A headache may at times precede or accompany, rather than follow, the neurologic abnormalities of migraine with aura. Although typically hemicranial (the French word migraine is said to be derived from megrim, which, in turn, is from the Latin hemicrania, and its corrupted forms hemigranea and migranea), the pain may be frontal, temporal, or, quite often, generalized.

Any two of the three principal components—neurologic abnormality, headache, and gastrointestinal upset—may be absent. With advancing age, for example, there is a tendency for the headache and nausea to become less severe, finally leaving only the neurologic abnormality, which itself recurs with decreasing frequency. This is also subject to great variation. One common configuration is a full-blown visual aura without subsequent headache (migraine without headache, or migraine dissocié). Visual disturbances differ in detail from patient to patient; numbness and tingling of the lips and the fingers of one hand are probably next in frequency, followed by transient dysphasia or a thickness of speech and hemiparesis as mentioned earlier. Rarely, there is sudden but transient blindness or a hemianopia at the onset of a migraine attack, accompanied by only a mild headache.

Basilar Migraine

A less-common form of the migraine syndrome with prominent brainstem symptoms was described by Bickerstaff. The patients, usually children with a family history of migraine, first develop visual phenomena like those of typical migraine except that they occupy much or the whole of both visual fields (temporary cortical blindness may occur). There may be associated vertigo, staggering, incoordination of the limbs, dysarthria, and tingling in both hands and feet, and sometimes around both sides of the mouth. These symptoms last 10 to 30 min and are followed by headache, which is usually occipital. Some patients, at the stage when the headache would have been likely to begin, may faint, and others become confused or stuporous, a state that may persist for several hours or longer. Exceptionally, there is an alarming period of coma or quadriplegia. The symptoms closely resemble those caused by ischemia in the territory of the basilar-posterior cerebral arteries—hence the name basilar artery or vertebrobasilar migraine. Subsequent studies have indicated that basilar migraine, although more common in children and adolescents, affects men and women more or less equally over a wide age range, and that the condition is not always benign and transient.

Ophthalmoplegic and Retinal Migraine

The ophthalmoplegic migraines are recurrent unilateral headaches associated with weakness of extraocular muscles. A transient third-nerve palsy with ptosis, with or without involvement of the pupil, is the usual picture; rarely, the sixth nerve is affected. This disorder is more common in children. The ocular paresis often outlasts the headache by days or weeks; after many attacks, a slight mydriasis and, rarely, ophthalmoparesis may remain permanently.

In some cases of uniocular visual disturbance with scotoma, the retinal arterioles have been reported to be attenuated and, rarely, there are retinal hemorrhages as described by Berger and colleagues. More often, there are no funduscopic changes. Such events are referred to as retinal migraine, or, more accurately, ocular migraine, as either the retinal or the ciliary circulation may be involved. However, in adults the syndrome of headache, unilateral ophthalmoparesis, and loss of vision may have more serious causes, including temporal (cranial) arteritis.

Migraine Following Head Injury

Cranial trauma of almost any degree may precipitate a migraine headache in persons prone to the condition. A particularly troublesome migraine variant occurs in a child or adolescent who, after a trivial or mild head injury, may lose vision, suffer severe headache or be plunged into a state of confusion, with belligerent and irrational behavior that lasts for hours or several days before clearing. In yet another variant, there is an abrupt onset of either one-sided paralysis or aphasia after virtually every minor head injury (we have seen this condition several times in college athletes) but without visual symptoms and little or no headache. Although a family history of migraine is frequent in such cases, there has been no history of hemiplegia in other family members.

Migraine in Young Children

This may present special difficulties in diagnosis, as a young child’s capacity for accurate description is limited. Instead of complaining of headache, the child appears limp and pale and complains of abdominal pain; vomiting is more frequent than in the adult, and there may be slight fever. Recurrent attacks were referred to in the past by pediatricians as the “periodic syndrome.” Another variant in the child is episodic vertigo and staggering (paroxysmal disequilibrium) followed by headache, probably a type of basilar migraine (see Watson and Steele). Also, there are puzzling patients with bouts of fever or transient disturbances in mood (“psychic equivalents”) and abdominal pain (abdominal migraine), that had been attributed to migraine but are dubious entities at best. We have seen several infants and young children who have had attacks of hemiplegia (without headache), first on one side then the other, every few weeks. Recovery was complete, and arteriography in one child, after more than 70 attacks, was normal. Alternating hemiplegia of childhood may terminate in a dystonic state. The relationship of this condition to familial hemiplegic migraine (see below) remains uncertain. The only advantage of considering such attacks as migrainous is that it may protect some patients from unnecessary diagnostic procedures and surgical intervention; but, by the same token, it may delay appropriate investigation and treatment.

Familial Hemiplegic Migraine

In a related disorder, known as hemiplegic migraine, a condition mostly of infants and children (rarely adults), there are episodes of unilateral paralysis that may long outlast the headache. Several families have been described in which this condition is the result of a mutation in an ion channel (familial hemiplegic migraine; alternating hemiplegia of childhood). Of the known loci, which together account for approximately 50 percent of cases, the most common one is in the gene coding for the P/Q-type calcium channel α subunit (CACNA1A). A second locus is in the gene for the Na+/K+–adenosine triphosphatase (ATPase) channel and a rarer subtype is caused by mutations in a sodium channel α-subunit gene, SCNA1. These do not account for all cases, indicating that there are other mutations that will inevitably be discovered. It is reasonable to surmise that many of the nonfamilial cases of hemiplegic migraine are also caused by these mutations. By their nature, these channelopathies would be expected to have clinical and genetic overlap with other neurologic diseases. Indeed, there are shared traits between some of the genetic forms of familial hemiplegic migraine and both episodic and degenerative cerebellar diseases (Goadsby, 2007). Ducros and colleagues have found a variety of other neurologic features in these families, including persistent cerebellar ataxia and nystagmus in 20 percent; others had attacks of coma and hemiplegia from which they recovered.

Complicating the situation is the undoubted existence of sporadic migraine with transient hemiplegia that has no familial trait. Neurologic symptoms lasting more than an hour or so should prompt investigation for alternative causes, but none may be found. Instances of hemiplegic migraine may account for some of the inexplicable strokes in young women and older adults of both sexes, as discussed below.

Transient Ischemic Attacks and Stroke with Migraine (See Also Chap. 34.)

Attacks of migraine, instead of beginning in childhood, may have their onset later in life, and Fisher provided support for the hypothesis that some of the transient aphasic, hemianesthetic, or hemiplegic attacks of later life may be of migrainous origin (“transient migrainous accompaniment”).

Rarely, migrainous neurologic symptoms, instead of being transitory, leave a prolonged or even permanent deficit (e.g., homonymous hemianopia), indicative of an ischemic stroke. This has been called complicated migraine and a small number of these prove to be migrainous infarctions. Platelet aggregation, edema of the arterial wall, increased coagulability, dehydration from vomiting, and intense, prolonged spasms of vessels have all been implicated (on rather uncertain grounds) in the pathogenesis of arterial occlusion and strokes that complicate migraine (Rascol et al).

The reported incidence of this complication has varied. At the Mayo Clinic, in a group of 4,874 patients ages 50 years or younger with a diagnosis of migraine, migraine equivalent, or vascular headache, 20 patients had migraine-associated infarctions (Broderick and Swanson). Caplan described 7 patients in whom attacks of migraine were complicated by strokes in the vertebrobasilar territory. A more recent study by Wolf and colleagues collected 17 instances of stroke and migraine. Most had a prolonged aura, either visual, sensory or aphasic and over two-thirds of the strokes, demonstrated by diffusion restriction on MRI, were in the posterior circulation territory and occurred in younger women. There is, nonetheless, a paucity of useful pathology by which to interpret the mechanism of migraine-associated stroke. The uncertain but potential role of antimigraine medications in producing stroke is discussed further on in the section on treatment. Estrogen medications have also been implicated in stroke in some women migraineurs.

In children and young adults with the mitochondrial disease MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and in adults with the rare cerebral vasculopathy CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), migraine may be a prominent feature. Chap. 34 addresses these issues further.

The special problem of focal cerebral disorders associated with segmental or diffuse vasospasm, including the form that follows treatment with the “triptan” (serotonin agonist) drugs and Call-Fleming syndrome, is discussed further on in the section on treatment and under “Diffuse and Focal Cerebral Vasospasm” in Chap. 34.

A separate set of observations, mainly epidemiologic, pertain to the risk of mundane strokes in women with both migraine and cardiovascular disease later in life, and the related issue of imaging changes in migraineurs that are suggestive of small ischemic lesions. Regarding the last problem, a number of cross-sectional population studies, such as the ones by Kurth and colleagues, Scher et al, and Kruit and coworkers, indicated that MRI changes in both the deep and subcortical white matter were more frequent in women migraine patients who experienced auras than in those without auras and in the general population. A high frequency of migraine headaches was also associated in some studies with an increased number of white matter lesions. Some series have emphasized lesions in the cerebellar white matter.

In contrast, a meta-analysis of case control and cohort studies conducted by Schurks and colleagues were unable to demonstrate an increased risk for cardiovascular events. Other investigators, again depending on various population databases and few patient level studies, have come to the opposite conclusion (Bigal et al) and suggested that all cause mortality is increased in migraine patients (Gudmundsson et al).

The implications of the ubiquitous small white matter lesions in MRI that are now familiar to neurologists are unclear. Several studies indicate that migraineurs with these changes have no greater cognitive decline over time than those in the general population. The lesions are a frequent cause for neurological consultation, sometimes with the question of multiple sclerosis having been raised. We tend to underemphasize these lesions and the risk of stroke in discussion with patients but point out that the usual stroke risk factors, smoking, hypertension, hyperlipidemia, and cardiac rhythm abnormalities should be attended to assiduously.

The issue of oral contraceptives as a risk for stroke is a more complicated matter that has not been resolved. All that can be said at the moment is that this factor did not appear to be consistent in the above discussed epidemiologic surveys, and it is the population of young women who are likely to have both exposures. The pills are not interdicted in migraineurs but perhaps lower estrogen compounds are advisable as formulations with high estrogen concentrations have been associated with clotting in the venous circulation.

Patent Foramen Ovale and Migraine

Finally, there has long been discussion of an association between migraine and patent foramen ovale. A few physicians continue to favor a causal role and have advocated closure of the foramen in an attempt to alleviate migraine. Migraine with aura has been especially associated with an open foramen. However, the largest cross-sectional (Rundek et al) and case-control (Garg et al) studies have not affirmed these associations and the issue, while still under discussion, has been of waning interest.

Status Migrainosus

In some individuals, migraine attacks, for unaccountable reasons, may increase in frequency for several months. As many as three or four attacks may occur each week, leaving the scalp on one side continuously tender. An even more difficult clinical problem is posed by migraine that lapses into a condition of daily or virtually severe continuous headache (status migrainosus). The pain is initially unilateral, later more generalized, more or less throbbing, but with a constant superimposed ache and is disabling; vomiting or nausea is common at the outset but abates. Almost without exception, there is a preceding history compatible with migraine; in fact, the absence of prior headaches should raise concern about a more serious cause. Status migrainosus sometimes follows a head injury or a viral infection, but most cases have no explanation. Relief is sought by increasing the intake of ergot or serotonin agonist preparations or even opiates, often to an alarming degree, but with only temporary relief, serving at times to perpetuate the condition through a rebound mechanism.

In the diagnosis of such cases, the possibility should be considered that migraine has been combined with tension headache (migraine-tension or mixed-pattern headache) or transformed to so-called analgesia-rebound headache, or ergotamine, or serotonin agonist-dependency headache, as described by Taimi and colleagues. Narcotic addiction is another consideration. Although not generally popular, it is our practice to admit such patients to the hospital, discontinue all narcotic medications, and administer intravenous hydration, corticosteroids, one of the serotonin agonist medications, or dihydroergotamine intravenous infusion in selected patients (see further on for details of treatment). When admission is not possible or practical, the same therapeutic plan may be pursued in an ambulatory infusion center.

Migraine with CSF Pleocytosis (HaNDL)

An intriguing problem arises in the patient with migraine who is found to have a lymphocytic pleocytosis in the spinal fluid. Most of these cases in our experience have turned out to be simply instances of aseptic meningitis that have precipitated migraine in susceptible individuals. In others, a few cells are found in the spinal fluid during an attack of migraine without obvious explanation; probably a minor cellular reaction of 3 to 10 white blood cells (WBCs)/mL can be ignored if there is no fever or meningismus.

A more extensive syndrome was originally described by Bartleson, Swanson, and Whisnant under the title “A migrainous syndrome with cerebrospinal fluid pleocytosis”. A series reported by Gomez-Aranda and colleagues gave the syndrome the name, “Pseudomigraine with Temporary Neurological Symptoms and Lymphocytic Pleocytosis”, also called HaNDL (Headache with Neurological Deficits and CSF Lymphocytosis) by Berg and Williams, together describing what is probably yet another migraine variant. Gomez-Aranda’s series comprised 50 adolescents and young adults, predominantly males, who developed several separate episodes of transient neurologic deficits lasting hours, accompanied by migraine-like headaches, sometimes with slight fever but no stiff neck. One-quarter of this group had a history of past migraine and a similar number had a viral-like illness within 3 weeks of the neurologic problem. The CSF contained from 10 to 760 lymphocytes per cubic millimeter, and the total protein was elevated. The transient neurologic deficits were mainly sensorimotor and aphasic; only 6 patients had visual symptoms. The patients were asymptomatic between attacks and in none did the entire illness persist beyond 7 weeks.

The causation and pathophysiology of this syndrome and its relation to migraine are obscure. We have observed several cases, all in otherwise healthy middle-aged men, none related to the use of nonsteroidal medications, which may cause an aseptic meningeal reaction, and we found corticosteroids to be helpful. The distinction between this syndrome and the recurrent aseptic meningitis of Mollaret and other chronic meningitic syndromes as well as cerebral vasospasm or vasculitis is difficult (see “Chronic Persistent and Recurrent Meningitis” in Chap. 32).

Cause and Pathogenesis of Migraine

So far, it has not been possible to determine from the many clinical observations and investigations, a unifying theory as to the cause and pathogenesis of migraine. Tension and other emotional states, which are claimed by some migraineurs to precede their attacks, are so inconsistent as to be no more than potential aggravating factors. Clearly, an underlying genetic factor is implicated, although it is expressed in a recognizable mendelian pattern in only a small number of families (see above). The puzzle is how this genetic predisposition is translated periodically into a regional neurologic deficit, unilateral headache, or both. For many years, our thinking about the pathogenesis of migraine was dominated by the views of Harold Wolff and others—that the headache was caused by the distention and excessive pulsation of branches of the external carotid artery. Certainly, the throbbing, pulsating quality of the headache and its relief by compression of the common carotid artery supported this view, as did the early observation of Graham and Wolff that the headache and amplitude of pulsation of the extracranial arteries diminished after the intravenous administration of ergotamine.

The importance of vascular factors continues to be emphasized by more recent findings but not in the way envisaged by Wolff. For example, in a group of 11 patients with classic migraine, Olsen and colleagues, using the xenon inhalation method, noted a regional reduction in cerebral circulation spreading forward from the occipital region during the period when neurologic symptoms appear. They concluded that the reduction in blood flow was consistent with the cortical spreading depression syndrome described below. In a subsequent study, Woods and colleagues

Related posts:

Chapter 12. Disorders of Smell and Taste Chapter 14. Disorders of Ocular Movement and Pupillary Function Chapter 22. Neurologic Disorders Caused by Lesions in Specific Parts of the Cerebrum Chapter 26. Disorders of the Autonomic Nervous System, Respiration, and Swallowing Chapter 39. Degenerative Diseases of the Nervous System Chapter 38. Developmental Diseases of the Nervous System

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