Treatment

Neurologists generally first assure themselves and their patients that the headache does not represent a brain tumor or other potentially fatal illness, which is frequently an unspoken fear. On the other hand, these headaches are liable to become a chronic, intractable, demoralizing painful condition. Risk factors for chronicity or other poor outcome include comorbid migraine, being unmarried, and sleep disorders.

For headaches that occur less than twice a week, neurologists usually suggest “acute therapy” – medicines taken at the headache’s onset to abort an incipient attack or reverse a full-blown one. Over-the-counter medicines, such as aspirin, aspirin–caffeine compounds, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs), usually suffice. Patients keep these medicines readily available in the car, at work, and in pocketbooks to take at any inkling of a headache. However, physicians should be mindful that their daily use often leads to chronic daily headache (see later).

Neurologists often recommend “preventive therapy” – medicines taken daily – under several circumstances: if headaches occur more frequently than two or three times per week, acute therapy is ineffective, or analgesic consumption becomes excessive. For example, even if patients have no history of depression, neurologists often prescribe small nighttime doses of a tricyclic antidepressant (TCA). Similarly, even if patients have no history of epilepsy, neurologists often prescribe certain antiepileptic drugs (AEDs), such as valproate/divalproex (Depakote) or topiramate (Topamax). However, they usually avoid prescribing benzodiazepines. As if to confirm that muscle contraction does not cause TTH, botulinum toxin injections into scalp and cervical muscles, even though they reduce muscle spasm, fail to alleviate these headaches.

In children and adolescents, relaxation and cognitive-behavioral therapy (CBT) reduce the frequency and severity of chronic headache. In adults, insight-oriented psychotherapy and psychoanalysis, when directed toward headaches, do not alleviate them, but may provide insight, reduce anxiety, treat depression, and offer other benefits. Stress management therapy, especially when combined with a TCA, provides modest help.

Migraine with Aura

Migraine with aura, previously labeled classic migraine, affects only about 20–30% of migraine patients. The aura, which can represent almost any symptom of cortex or brain dysfunction, typically precedes or accompanies the headache (Box 9-2). The headache itself is similar to the headache in migraine without an aura (see later).

Auras usually appear gradually and then evolve over 5–20 minutes, persist for less than 1 hour, and evaporate with the headache’s onset. They characteristically consist of a transient visual phenomenon, but sometimes a simple olfactory hallucination. Instead of a disturbance in one of the special senses, aura occasionally consists of language impairment similar to aphasia, sensory misperception, or personality change. In children, but not adults, recurrent colic or “cyclic abdominal pain” with nausea and vomiting may constitute a migraine variant, but not technically an aura.

By far the commonest migraine auras are visual hallucinations (see Chapter 12). They usually consist of a graying of a region of the visual field (scotoma) (Fig. 9-2, A), flashing zigzag lines (scintillating or fortification scotomata) (Fig. 9-2, B), crescents of brilliant colors (Fig. 9-2, C), tubular vision, or distortion of objects (metamorphopsia). Unlike visual auras that represent several different neurologic conditions (see Box 12-1), migraine auras most often involve the simultaneous appearance of positive phenomena, such as scintillations, and negative ones, such as opaque areas. Finally, instead of sensory auras, some migraineurs experience premonitory somatic symptoms, such as fatigue, stiff neck, yawning, hunger, and thirst. These patients can frequently predict their impending migraine hours to days before onset.

FIGURE 9-2 A, These drawings by an artist who suffers from migraine show the typical visual obscurations of a scotoma that precedes the headache phase of her migraines. In both cases, she loses a small circular area near the center of vision. As occurs with most migraineurs, she says that, although the aura is only gray and has a simple shape, it mesmerizes her. B, The patient who drew this aura, a scintillating scotoma, wrote, “In the early stages, the area within the lights is somewhat shaded. Later, as the figure widens, you can peer right through the area. Eventually, it gets so wide that it disappears.” This typical scotoma consists of an angular, brightly lit margin and an opaque interior that begins as a star and expands into a crescent. She somehow calculated that it scintillated at 8–12 Hz. Neurologists refer to auras with angular edges as fortification scotomas because of their similarity to ancient military fortresses. C, A 30-year-old woman artist in her first trimester of pregnancy had several migraine headaches that were heralded by this scotoma. Each began as a blue dot and, over 20 minutes, enlarged to a crescent of brightly shimmering, multicolored dots. When the crescent’s intensity peaked, she was so dazzled that she lost her vision and was unable to think clearly. D, Having patients, especially children, draw what they “see” before a headache has great diagnostic value. One adolescent reconstructed this “visual hallucination” using his computer.

Migraine without Aura

Previously labeled common migraine, migraine without aura affects about 75% of migraine patients. In other words, most individuals with migraine do not have an aura. Arising without warning, their headaches are initially throbbing and located predominantly behind a temple (temporal) or around or behind one eye (periorbital or retro-orbital), but usually on only one side of the head (hemicranial) (Fig. 9-3). In the majority of cases, the side of the headache switches within and between attacks. Individual attacks usually occur episodically and last 4–72 hours. Frequent attacks may evolve into a dull, symmetric, and continual pain – chronic daily headache – that mimics TTH.

FIGURE 9-3 Patients with migraine usually have throbbing hemicranial headaches that may either move to the other side of the head or become generalized.

For patients and neurologists, what really distinguishes migraine from TTH are migraine’s nonheadache symptoms, including sensory hypersensitivity (photophobia and phonophobia), autonomic dysfunction (nausea and vomiting), and disability. In common terms, people with migraine typically have episodes of moderately severe headaches accompanied by nausea; and during a painful attack, they gravitate to dark, quiet places.

During migraine attacks, patients often have dysphoria and inattentiveness that can mimic depression, complex partial seizures, and other neurologic disturbances (Box 9-3). Most patients withdraw during an attack, but some become feverishly active. Many then tend to drink large quantities of water or crave certain foods or sweets, particularly chocolate. Children often become confused and overactive. After an attack clears, especially when it ends with sleep, migraine sufferers may experience a sense of tranquility or even euphoria.

An additional point of contrast to TTH is that migraine attacks typically begin in the early morning rather than the afternoon. In fact, they often have their onset during rapid eye movement (REM) sleep, which predominates in the several hours before awakening (see Chapter 17). Sometimes migraines begin exclusively during sleep (nocturnal migraine). No matter when a migraine attack has begun, naturally occurring or medication-induced sleep characteristically cures it.

In women, migraine often first develops at menarche, recurs premenstrually, and is aggravated by some oral contraceptives. Most women with migraine report that their attacks are most likely to occur immediately before or at the beginning of their menses, and about 10% of them suffer migraines exclusively at this time. During pregnancy, about 70% of women with migraine experience dramatic relief, but usually only during their second or third trimesters. However, pregnancy can also have adverse effects. About 10% of women with migraine experience their first attack during pregnancy. Furthermore, 10–20% of pregnant women with migraine have more frequent or more severe attacks than usual. Nevertheless, pregnant women beset by migraine are no more likely than ones free of migraine to suffer miscarriage, eclampsia, or fetal malformations. Although postpartum headaches may represent a recurrence of migraine, they may instead represent more serious conditions, such as cortical vein thrombosis, complication of epidural anesthesia, or pituitary infarction. Postmenopausal women usually enjoy improvement in their migraine frequency and severity.

Another important characteristic of migraine is that it can be precipitated – in susceptible individuals – by certain factors or “triggers,” such as skipping meals or fasting on religious holidays, too little or excessive sleep, menses, psychologic or occupational stress, overexertion, head trauma, and alcoholic drinks. (Alcohol can also provoke attacks of cluster headaches [see later].) Red wine and brandy are the alcoholic drinks most likely to trigger an attack, with vodka and white wine the least likely.

To the chagrin of many patients, migraine attacks often coincide with weekends and the start of a vacation. Many of the factors associated with these holidays likely contribute to this paradox: withdrawal from work-related stress, anxieties associated with leisure periods, too little sleep, sleeping later than usual (which extends REM periods and does not allow the customary morning cup of coffee [see later]), and lavish meals, which typically include foods spiced with monosodium glutamate (MSG) accompanied by wine.

Psychiatric Comorbidity

Contrary to old views, migraine is not restricted to individuals in upper-income brackets or among those who are rigid, perfectionist, and competitive. Neurologists consider “migraine personality” an outmoded concept.

Depression is strongly comorbid with migraine and the conditions appear reciprocal. Major depression increases the risk of migraine but not of other severe headaches. Similarly, unlike other headache disorders, migraine increases the risk of major depression up to four times the normal population. Migraineurs are also more likely to carry the diagnosis of generalized anxiety disorder, panic disorder, and bipolar disorder. Studies differ as to the effect of comorbid depression on the frequency or disability of migraine. In an effect that seems to be restricted to women, adverse life events increase headache frequency.

Therapy for patients with migraine and comorbid depression should start with simple behavioral advice, such as getting sufficient sleep on a regular schedule, exercising moderately, avoiding alcohol and drugs, and keeping a “headache diary” (see later). CBT and biofeedback, as an adjunct to medication, may be helpful.

TCAs are not only effective for treating migraine comorbid with depression, they are more effective than selective serotonin or norepinephrine reuptake inhibitors (SSRIs or SNRIs) for treating migraine with or without comorbid depression. SSRIs and SNRIs are less effective than TCAs, and, when administered concurrently with one of the popular anti-migraine serotonin (5-hydroxytryptamine [5HT]) agonists, such as a “triptan” (see later) or dihydroergotamine (DHE), they carry a low but often-cited risk of producing the serotonin syndrome (see Chapter 6).

Recognizing the neurologic basis of migraine, the preliminary version of the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) would place headaches on Axis III. If patients fabricate reports of migraine to obtain opioids or other tangible benefit, the diagnosis would be Factitious Disorder or Malingering.

Other Subtypes of Migraine

Childhood migraine is not simply migraine in “short adults.” Compared to migraine in adults, in childhood migraine the headache is more severe, but briefer (frequently less than 2 hours), and less likely to be unilateral (only one-third of cases). However, as with migraine in adults, the nonheadache components may overshadow the headache. For example, childhood migraine often produces episodes of confusion, incoherence, or agitation. In addition, it frequently leaves children incapacitated by nausea and vomiting. Physicians caring for children with such episodes may consider mitochondrial encephalopathy as an alternative, although rare, diagnosis (see Chapter 6). Pediatric neurologists also consider mitochondrial encephalopathy, along with hemiplegic migraine (see later), in the differential diagnosis of transient hemiparesis in a child with headaches.

Children are particularly susceptible to migraine variants. In basilar-type migraine, the headache is accompanied or even overshadowed by ataxia, vertigo, dysarthria, or diplopia – symptoms that reflect brain dysfunction in the basilar artery distribution (the cerebellum, brainstem, and posterior cerebrum [see Fig. 11-2]). In addition, when basilar migraine impairs the temporal lobes, children as well as adults may experience temporary generalized memory impairment, e.g., transient global amnesia (see Chapter 11). Hemiplegic migraine, another variant, is defined by hemiparesis of various grades often accompanied by hemiparesthesia, aphasia, or other cortical symptoms. All these symptoms usually precede or occur with an otherwise typical migraine headache, but they may also develop without any headache or other migraine symptom. Thus, in evaluating a patient who has had transient hemiparesis, the physician might consider hemiplegic migraine along with transient ischemic attacks, stroke, postictal (Todd’s) hemiparesis, and conversion disorder.

In familial hemiplegic migraine, patients develop transient hemiparesis before or during the headache. This variant of migraine is transmitted in an autosomal dominant pattern by a genetic abnormality on chromosome 19. The basic mechanism is a calcium channel abnormality – a “channelopathy.” Other channelopathies include myotonic dystrophy, spinocerebellar ataxia type 6 (also transmitted by a mutation on chromosome 19), and varieties of epilepsy.

Stroke occasionally complicates migraine. Of its variants, migraine with aura serves as the most powerful risk factor for stroke. Female migraine patients who both smoke cigarettes and use oral contraceptives are particularly at risk of stroke.

Migraine-Like Conditions: Food-Induced Headaches

Neurologists look at certain foods and medications as both a cause of nonspecific headache and a trigger of migraine. However, other than alcohol, the role of food is overemphasized. It precipitates migraine or other headache in only about 15% of patients.

The two clearest examples of foods precipitating headaches occur in the Chinese restaurant syndrome, where the offending agent is MSG, and the hot dog headache, where nitrites, used in many processed meats, are the offending agent. A different situation is the icecream headache, where any very cold food that touches the pharynx triggers a headache. Some people – but fewer than generally assumed – develop migraine-like headaches after eating foods containing tyramine, such as ripened cheese, or ones containing phenylethylamine, such as chocolate. In view of chocolate’s tendency in some individuals to precipitate attacks, migraine sufferers’ frequent chocolate craving before an attack is ironic. Nevertheless, migraine sufferers should probably avoid the “four Cs”: chocolate, cheese, Chinese food, and alcohol (C₃H₅OH).

On the other hand, people who miss their customary morning coffee typically develop the caffeine withdrawal syndrome that consists of moderate to severe headache often accompanied by anxiety and depression. Although this syndrome is almost synonymous with coffee deprivation, withdrawal of other caffeine-containing beverages or caffeine-containing medications can precipitate it (see Chapter 17). Herein lies a dilemma: sudden withdrawal of caffeine can cause the withdrawal syndrome, but excessive caffeine leads to irritability, palpitations, and gastric acidity. Moreover, excessive caffeine also is a risk factor for transforming migraine to chronic daily headache.

Medication-Induced Headaches

Similarly, neurologists look at certain medications as playing both roles. Antianginal medicines, such as nitroglycerin or isosorbide (Isordil), perhaps because they contain nitrites that dilate cerebral as well as cardiac arteries, cause headaches. Elderly patients who have cerebrovascular atherosclerosis are particularly vulnerable. Curiously, whereas some calcium channel blockers, such as nifedipine (Procardia), trigger headaches, others, such as verapamil (Calan), may prevent them. For the psychiatrist, the most notorious iatrogenic headache, which is often complicated by cerebral hemorrhage, is produced by the interaction of monoamine oxidase inhibitor (MAOI) antidepressants with other medications or foods (see later).

Sex-Related Headaches

Sexual intercourse or masturbation, with or without orgasm, may trigger a migraine-like headache. Currently termed Primary Headache Associated with Sexual Activity, these headaches were previously termed coital cephalalgia or orgasmic headache, depending on the circumstances. Sex-related headaches, which are especially common in individuals with migraine, typically last for several minutes to several hours. The pain may be severe and incapacitating, but the neurologic problem is almost always benign. Nevertheless, before analyzing headaches occurring during sex, physicians might consider intracerebral or subarachnoid hemorrhage (see later). When the diagnosis of sex-related headaches is secure, taking propranolol or indometacin before sex usually prevents an ensuing headache.

Proposed Causes of Migraine

A once-popular theory postulated that constriction of muscles of the cerebral arteries first caused an aura and then, when the muscles fatigued, the arteries dilated and allowed pulsations to pound the interior of the arterial walls. In this theory, the unsuppressed pounding produced the typical throbbing headache.

A current, more credible theory attributes migraine to “spreading neuronal depression.” This theory postulates that impaired metabolism of cerebral neurons spreads – first as increased neuronal activity and then as inhibited neuronal activity – from the posterior to anterior cerebral cortex. The impaired metabolism, according to the theory, produces the aura and activates the trigeminal nucleus, which innervates the meninges, triggering the release of vasoactive neuropeptides, including serotonin, substance P, and neurokinin. Then these neuropeptides incite painful vasodilation and perivascular inflammation. Related theories propose that the relationship between serotonin and migraine headaches explains why migraineurs have relatively high rates of epilepsy, major depression, and anxiety.

Other theories postulate faulty serotonin neurotransmission because several serotonin-related observations stand out. For example, at the onset of migraine, platelet serotonin concentration falls. Triptans, which are an effective and specific treatment for migraine, act primarily as serotonin 5HT_1B and 5HT_1D receptor agonists in the cerebral vessels’ trigeminal nerve endings. They most likely relieve migraine by blocking the release of the vasoactive neuropeptides.

Whatever the biochemical mechanism, a genetic abnormality predisposes certain individuals to migraine. About 70% of migraine patients have a close relative with the disorder, and studies of twins show a high concordance. The risk of migraine is 50% or greater in relatives of an individual with migraine, and this risk increases with the severity of attacks. In the case of hemiplegic migraine, the genetic basis is well established.

Acute Treatment

In attempting to identify triggers, neurologists usually suggest that patients create a headache diary to note migraine days, meals, menses, school examinations, stressful episodes, and other potential precipitants. If patients cannot avoid triggers, they should at least anticipate attacks. For some patients, relaxation techniques or other forms of CBT may be helpful. In contrast, scientific studies have not documented benefits from hypnosis, acupuncture, transcutaneous electrical stimulation, or spinal manipulation.

Successful treatment of migraine usually requires medications to dampen the headache and ameliorate the accompanying nausea and vomiting. Treatment regimens for children and adolescents differ from those for adults. As with TTH, patients take medications on an acute basis to abort an incipient migraine or reverse a full-blown one. For acute treatment of occasional mild attacks, simple analgesics, NSAIDs, and other over-the-counter medicines may suffice.

Although opioids may suppress headaches, neurologists have remained wary of their leading to drug-seeking behavior (see Chapter 14). In the majority of patients receiving opioid treatment, emergency room visits and hospitalizations decrease, but their headaches and disability persist. Nevertheless, neurologists often prescribe them in limited, controlled doses when vasoactive or serotoninergic medications carry too many risks, such as for pregnant or elderly patients.

Triptans, the 5HT_1B/1D serotonin receptor agonists, include eletriptan (Relpax), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig). They are rapidly effective for moderate to severe migraine and some are available as injections, sublingual wafers, and nasal sprays. The variety of forms allows patients to administer their medicines without delay, even when in public or beset by nausea. Women with menstrually related migraine might suppress attacks by taking a triptan or NSAID for the several days before menses commence or during the days of their cycle when their headaches occur – catamenial migraine.

Ergotamine and DHE, which are primarily vasoconstrictors, are also rapidly effective. Although widely used decades ago, triptans have supplanted them. Excessive use of the vasoconstrictors may lead to persistent, excessive vasoconstriction (ergotism) in the coronary arteries, digits, and elsewhere. In another caveat, because vasoconstrictors might precipitate a miscarriage or cause fetal malformations, ergotamine and DHE, unlike triptans, are unequivocally contraindicated in pregnant women. Finally, administration of either a triptan or vasoconstrictor to patients already under treatment with an SSRI or SNRI risks causing the serotonin syndrome.

Many of these migraine medications have the same worrisome side effect as those used to treat TTH. Their frequent use – as little as two to three times a week – may lead not to cure but to chronic daily headache.

Nausea and vomiting not only constitute symptoms of migraine, but they may also be side effects of DHE or another antimigraine medicine. Whatever their cause or severity, nausea and vomiting prevent gastric absorption of orally administered medicines. Many migraine sufferers thus require a parenterally administered antiemetic, such as metoclopramide (Reglan). One caveat remains: dopamine-blocking antiemetics may cause dystonic reactions identical to those induced by dopamine-blocking antipsychotics (see Chapter 18). Thus, neurologists often prophylactically administer diphenhydramine (Benadryl) along with those antiemetics.

Migraine attacks lasting more than 3 days (status migrainosus) usually lead to prostration, prolonged painful distress, and dehydration. Patients suffering from such prolonged, refractory illness benefit substantially from parenteral medication, intravenous fluids, antiemetics, and a quiet, dark refuge. Neurologists must often hospitalize patients in status migrainosus. Medically supervised withdrawal from over-the-counter medications, opioids, or even excessive conventional antimigraine medicines may also require hospitalization.

Preventive Treatment

Neurologists prescribe preventive treatment under several circumstances: migraine occurring more than four times a month; migraine causing 3–4 days of disability per month; acute medicines losing their effectiveness; or patients taking excessive medicine. For realistic purposes, neurologists expect to decrease their patients’ migraine frequency and intensity by 50%. Most preventive medicines fall into three categories: antidepressants, antihypertensives, and antiepileptics.

TCAs, particularly amitriptyline and nortriptyline, reduce the severity, frequency, and duration of migraine. Apart from their mood-elevating effect, TCAs may ameliorate migraine because they suppress REM sleep, which is the phase when migraine attacks tend to develop. In addition, because TCAs enhance serotonin, they are analgesic (see Chapter 14). As most migraine patients are young and require only small doses of TCAs compared to those used to treat depression, the side effects of TCAs in this situation are rarely a problem. Interestingly, for preventing migraine, SSRIs are ineffective compared to TCAs.

Neurologists often prescribe β-blockers for migraine prophylaxis, as well as for treatment of essential tremor (see Chapter 18). However, they avoid prescribing β-blockers to migraine patients with comorbid depression because of their tendency to precipitate or exacerbate mood disorders.

Certain AEDs, such as topiramate and valproate, offer preventive treatment for migraine, as well as for neuropathic pain and epilepsy. Valproate is suitable for migraine sufferers with or without mood disorders. It may suppress migraine by reducing 5-HT neurons firing in the dorsal raphe nucleus or by altering trigeminal GABA_A receptors in the meningeal blood vessels. However, its side effects, especially weight gain, often preclude its use.

Numerous medications in other categories show some benefit for chronic migraine. Among them, botulinum toxin injections reduce the frequency or severity of migraines that both last 4 hours or longer and occur at least 15 times a month. Indeed, botulinum toxin injections reduce the impact of migraines and improve a patient’s quality of life. Finally, naturopaths have long hailed acupuncture as a successful preventive treatment for migraines. While there is no difference between the efficacies of the “true” acupuncture group in comparison to the “sham” acupuncture control group, up to 50% of patients in both groups can have improvement in their headache frequency and severity.