Headache
OVERVEIW
WHAT CAUSES HEADACHE
GENERAL CLINICAL CONSIDERATIONS
MENINGITIS
INTRACRANIAL HEMORRHAGE
BRAIN TUMOR
TEMPORAL ARTERITIS
GLAUCOMA
OTHER CAUSES OF HEADACHE
PRINCIPAL CLINICAL VARIETIES OF RECURRENT HEADACHE
TENSION-TYPE HEADACHE
MIGRAINE
CLINICAL FEATURES OF MIGRAINE
TREATMENT OF MIGRAINE
CLUSTER HEADACHE
TREATMENT OF CLUSTER HEADACHE
Many of us has expreinced of head pain. As many as 90% of individuals have at least one headache per year.
What Causes headache
Headache can occur as the result of
(1) distention, traction, or dilation of intracranial or extracranial arteries
(2) traction or displacement of large intracranial veins or their dural envelope;
(3) compression, traction, or inflammation of cranial and spinal nerves;
(4) spasm, inflammation, or trauma to cranial and cervical muscles;
(5) meningeal irritation and raised intracranial pressure; or (6) other possible
mechanisms such as activation of brainstem structures.
GENERAL CLINICAL CONSIDERATIONS
(1) quality,
(2) location,
(3) duration,
(4) trigger or exacerbate factors
(5) relieveing factors
Tension-type headaches are described as tight pain or as dull, deeply located,
pounding, brief, sharp pain. A throbbing quality and tight muscles about the
head, neck, and shoulder girdle are common nonspecific accompaniments of vascular
headaches. Pain intensity rarely has diagnostic value, although from the patient's
perspective, it is the single aspect of pain that is most important.
Meningitis, subarachnoid hemorrhage, and cluster headache produce intense cranial pain (most severe headache of mu life). (rule out migranine.
Brain tumor is not usually distinctive or severe. location of headache is informative. If the source is an extracranial structure, as in giant cell arteritis, the correspondence with the site of pain is fairly precise. Inflammation of an extracranial artery causes pain and exquisite tenderness localized to the site of the vessel. Lesions of paranasal sinuses, teeth, eyes, and upper cervical vertebrae induce less sharply localized pain, but pain that is still referred in a regional distribution. Intracranial lesions in the posterior fossa cause pain that is usually occipitonuchal, and supratentorial lesions most often induce frontotemporal pain.
Duration and time-intensity curves of headaches are diagnostically useful. A ruptured aneurysm results in head pain that peaks in an instant, thunderclap-like; much less often, unruptured aneurysms may signal their presence in the same way. Cluster headache attacks reach their peak over 3 to 5 min, remain at maximal levels for about 45 min, and then taper off. Migraine attacks build up over hours, are maintained for several hours to days, and are characteristically relieved by sleep. Sleep disruption and early morning headaches that improve during the day are characteristics of headaches produced by brain tumors.
The analysis of facial pain requires a different approach. Trigeminal and, less commonly, glossopharyngeal neuralgia are frequent causes of facial pain "Neuralgias" are painful disorders characterized by paroxysmal, fleeting, often electric shock-like episodes that are frequently caused by demyelinating lesions of nerves (the trigeminal or glossopharyngeal nerves in cranial neuralgias). Certain maneuvers characteristically trigger paroxysms of pain. However, the most common cause of facial pain by far is dental; provocation by hot, cold, or sweet foods is typical. The application of a cold stimulus will repeatedly induce dental pain, whereas in neuralgic disorders, a refractory period usually occurs after the initial response so that pain cannot be repeatedly induced.
The effect of eating on facial pain may provide insight into its cause. Is it the chewing, swallowing, or taste of the food that elicits pain? Chewing points toward trigeminal neuralgia, temporomandibular joint dysfunction, or giant cell arteritis ("jaw claudication"), whereas swallowing and taste provocation point toward glossopharyngeal neuralgia. Pain upon swallowing is common among patients with carotidynia (see below) because the inflamed, tender carotid artery abuts the esophagus during deglutition.
Many patients with facial pain do not experience stereotypic neuralgias; the term atypical facial pain has been used in this setting. Vague, poorly localized, continuous facial pain is characteristic of nasopharyngeal carcinoma; a burning pain often develops as deafferentation occurs and evidence of cranial neuropathy appears. Burning facial pain may also occur with tumors of the fifth cranial nerve (meningioma or schwannoma) or with lesions of the pons that interrupt the dorsal root entry zone of the nerve (multiple sclerosis). In patients with facial pain, the finding of objective sensory loss is an important clue to a serious underlying disorder. Occasionally, the cause of a pain problem cannot be resolved promptly, necessitating periodic follow- up until further signs appear.
Patients who present with their first severe headache raise entirely different
diagnostic possibilities than those with recurrent headaches over many years.
In new-onset and severe headaches, the probability of finding a potentially
serious cause is considerably greater than in recurrent headache. When a patient
complains of an acute, new-onset headache, a number of causes should be considered
including meningitis, subarachnoid hemorrhage, epidural or subdural hematoma,
glaucoma, and purulent sinusitis. Clinical features of acute, new-onset headache
caused by serious underlying conditions are summarized as follow:
"Worst" headache ever
First severe headache
Subacute worsening over days or weeks
Abnormal neurologic examination
Fever or unexplained systemic signs
Vomiting precedes headache
Induced by bending, lifting, cough
Disturbs sleep or present immediately upon awakening
Known systemic illness
Onset after age 55
A complete neurologic examination is an essential first step in the evaluation. In most cases, an abnormal examination should be followed by a computed tomography (CT) or a magnetic resonance imaging (MRI) study. As a screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. A general evaluation of acute headache might include the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; eyes by fundoscopy, intraocular pressure measurement, and refraction; cranial arteries by palpation; and cervical spine by the effect of passive movement of the head and imaging.
The psychological state of the patient should also be evaluated since a relationship exists between head pain and depression. Many patients in chronic daily pain cycles become depressed; moreover, there is a greater-than-chance coincidence of migraine with both bipolar (manic depressive) and unipolar major depressive disorders. Drugs with antidepressant actions are also effective in the prophylactic treatment of both tension-type headache and migraine.
Underlying recurrent headache disorders may be activated by pain that follows otologic or endodontic surgical procedures. Treatment of the headache problem is largely ineffective until the cause of the primary problem is addressed. Thus, pain about the head as the result of diseased tissue or trauma may reawaken an otherwise quiescent migrainous syndrome.
In general, acute, severe headache with stiff neck and fever suggests meningitis. Lumbar puncture is mandatory. Often there is striking accentuation of pain with eye movement. Meningitis is particularly easy to mistake for migraine in that the cardinal symptoms of pounding headache, photophobia, nausea, and vomiting are present. ®A detailed discussion of meningitis can be found in Chaps. 372 to 374.
In general, acute, severe headache with stiff neck but without fever suggests subarachnoid hemorrhage. A ruptured aneurysm, arteriovenous malformation, or intraparenchymal hemorrhage may also present with only headache. Rarely, if the hemorrhage is small or below the foramen magnum, the head CT scan can be normal. Therefore, a lumbar puncture may be required to make the definitive diagnosis of a subarachnoid hemorrhage.
Approximately 30% of patients with brain tumors consider headache to be their
chief complaint. The head pain is usually nondescript¾an intermittent
deep, dull aching of moderate intensity, which may worsen with exertion or change
in position and may be associated with nausea and vomiting. This pattern of
symptoms results from migraine far more often than from brain tumor. Headache
of brain tumor disturbs sleep in about 10% of patients. Vomiting that precedes
the appearance of headache by weeks is highly characteristic of posterior fossa
brain tumors. A history of amenorrhea or galactorrhea should lead one to question
whether a prolactin-secreting pituitary adenoma (or the polycystic ovary syndrome)
is the source of headache. Headache arising de novo in a patient with known
malignancy suggests either cerebral metastases and/or carcinomatous meningitis.
Head pain appearing abruptly after bending, lifting, or coughing can be the
clue to a posterior fossa mass (or a Chiari malformation).
TEMPORAL ARTERITIS
Temporal (giant cell) arteritis is an inflammatory disorder of arteries that frequently involves the extracranial carotid circulation. This is a common disorder of the elderly; its annual incidence is 77:100,000 in individuals aged 50 and older. The average age of onset is 70 years, and women account for 65% of cases. About half of patients with untreated temporal arteritis develop blindness due to involvement of the ophthalmic artery and its branches; indeed, the ischemic optic neuropathy induced by giant cell arteritis is the major cause of rapidly developing bilateral blindness in patients over 60 years of age. Because treatment with glucocorticoids is effective in preventing this complication, prompt recognition of this disorder is important.
Typical presenting symptoms include headache, polymyalgia rheumatica, jaw claudication, fever, and weight loss. Headache is the dominant symptom and often appears in association with malaise and muscle aches. Head pain may be unilateral or bilateral and is located temporally in 50% of patients but may involve any and all aspects of the cranium. Pain usually appears gradually over a few hours before peak intensity is reached; occasionally, it is explosive in onset. The quality of pain is only seldom throbbing; it is almost invariably described as dull and boring with superimposed episodic ice pick-like lancinating pains similar to the sharp pains that appear in migraine. Most patients can recognize that the origin of their head pain is superficial, external to the skull, rather than originating deep within the cranium (the pain site for migraineurs). Scalp tenderness is present, often to a marked degree; brushing the hair or resting the head on a pillow may be impossible because of pain. Headache is usually worse at night and is often aggravated by exposure to cold. Reddened, tender nodules or red streaking of the skin overlying the temporal arteries may be found in patients with headache, as is tenderness of the temporal or, less commonly, the occipital arteries.
The erythrocyte sedimentation rate (ESR) is often, though not always, elevated; a normal ESR does not exclude giant cell arteritis. A temporal artery biopsy and the initiation of prednisone at 80 mg daily for the first 4 to 6 weeks should be instituted when clinical suspicion is high. The prevalence of migraine among the elderly is substantial, considerably higher than that of giant cell arteritis. Migraineurs often report amelioration of their headaches with prednisone, so that one must be cautious about interpreting the therapeutic response.
Glaucoma may present with a prostrating headache associated with nausea and vomiting. The history will usually reveal that the headache started with severe eye pain. On physical examination, the eye is often red with a fixed, moderately dilated pupil
Systemic Illness There is hardly any illness that is never manifested by headache; however, some illnesses are frequently associated with headache. These include infectious mononucleosis, systemic lupus erythematosus, chronic pulmonary failure with hypercapnia (early morning headaches), Hashimoto's thyroiditis, inflammatory bowel disease, many of the illnesses associated with HIV, and the acute blood pressure elevations that occur in pheochromocytoma and in malignant hypertension. The last two examples are the exceptions to the generalization that hypertension per se is a very uncommon cause of headache; diastolic pressures of at least 120 mmHg are requisite for hypertension to cause headache. Persistent headache and fever are often the manifestations of an acute systemic viral infection; if the neck is supple in such a patient, lumbar puncture may be deferred. Some drugs and drug-withdrawal states, e.g., oral contraceptives, ovulation-promoting medications, and glucocorticoid withdrawal, are also associated with headache in some individuals.
Idiopathic Intracranial Hypertension (Pseudotumor Cerebri) Headache, clinically
resembling that of brain tumor, is a common presenting symptom of pseudotumor
cerebri, a disorder of raised intracranial pressure probably resulting from
impaired cerebrospinal fluid CSF absorption by the arachnoid villi. Transient
visual obscurations and papilledema with enlarged blind spots and loss of peripheral
visual fields are additional manifestations. Most patients are young, female,
and obese. They often have a history of exposure to provoking agents such as
vitamin A and glucocorticoids.
Cough A male-dominated (4:1) syndrome, cough headache is characterized by transient,
severe head pain upon coughing, bending, lifting, sneezing, or stooping. Head
pain persists for seconds to a few minutes. Many patients date the origins of
the syndrome to a lower respiratory infection accompanied by severe coughing
or to strenuous weight-lifting programs. Headache is usually diffuse but is
lateralized in about one-third of patients. The incidence of serious intracranial
structural anomalies causing this condition is about 25%; the Chiari malformation
is a common cause. Thus, MRI is indicated for most patients with cough headache.
The benign disorder may persist for a few years; it responds dramatically to
indomethacin at doses ranging from 50 to 200 mg daily. Approximately half of
patients will also show a response to therapeutic lumbar puncture with removal
of 40 mL of CSF.
Many patients with migraine note that attacks of headache may be provoked by sustained physical exertion, such as during the third mile of a 5-mile run. Such headaches build up over hours, in contrast to cough headache. The term effort migraine has been used for this syndrome to avoid the ambiguous term exertional headache.
Lumbar Puncture Headache following lumbar puncture usually begins within 48 h but may be delayed for up to 12 days. Its incidence is between 10 and 30%. Head pain is dramatically positional; it begins when the patient sits or stands upright; there is relief upon reclining or with abdominal compression. The longer the patient is upright, the longer the latency before head pain subsides. It is worsened by head shaking and jugular vein compression. The pain is usually a dull ache but may be throbbing; its location is occipitofrontal. Nausea and stiff neck often accompany headache, and occasional patients report blurred vision, photophobia, tinnitus, and vertigo. The symptoms resolve over a few days but may on occasion persist for weeks to months.
Loss of CSF volume decreases the brain's supportive cushion, so that when a patient is upright there is probably dilation and tension placed on the brain's anchoring structures, the pain-sensitive dural sinuses, resulting in pain. Intracranial hypotension often occurs, but severe lumbar puncture headache may be present even in patients who have normal CSF pressure.
Treatment with intravenous caffeine sodium benzoate given over a few minutes as a 500-mg dose will promptly terminate headache in 75% of patients; a second dose given in 1 h brings the total success rate to 85%. An epidural blood patch accomplished by injection of 15 mL of autologous whole blood rarely fails for those who do not respond to caffeine. The mechanism for these treatment effects is not straightforward. The blood patch has an immediate effect, making it unlikely that sealing off a dural hole with blood clot is its mechanism of action.
Postconcussion Following seemingly trivial head injuries and particularly after rear-end motor vehicle collisions, many patients report varying combinations of headache, dizziness, vertigo, and impaired memory. Anxiety, irritability and difficulty with concentration are other hallmarks of this syndrome. Symptoms may remit after several weeks or persist for months and even years after the injury. Postconcussion headaches may occur whether or not a person was rendered unconscious by head trauma. Typically, the neurologic examination is normal with the exception of the behavioral abnormalities, and CT or MRI studies are unrevealing. Chronic subdural hematoma may on occasion mimic this disorder. Although the cause of postconcussive headache disorder is not known, it should not in general be viewed as a primary psychological disturbance. It often persists long after the settlement of pending lawsuits. The treatment is symptomatic support. Repeated encouragement that the syndrome eventually remits is important.
Coital Headache This is another male-dominated (4:1) syndrome. Attacks occur periorgasmically, are very abrupt in onset, and subside in a few minutes if coitus is interrupted. These are nearly always benign events and usually occur sporadically; if they persist for hours or are accompanied by vomiting, subarachnoid hemorrhage must be excluded.
PRINCIPAL CLINICAL VARIETIES OF RECURRENT HEADACHE
There is usually little difficulty in diagnosing the serious types of headaches listed above because of the clues provided by the associated symptoms and signs. It is when headache is chronic, recurrent, and unattended by other important signs of disease that the physician faces a challenging and unique medical problem. The following sections describe a variety of headache types, ranging from the most common (e.g., tension-type headache) to rare causes of recurrent headache.
The term tension-type headache is still commonly used to describe a chronic head pain syndrome characterized by bilateral tight, bandlike discomfort. Patients may report that the head feels as if it is in a vise or that the posterior neck muscles are tight. The pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days. Exertion does not usually worsen the headache. The headache may be episodic or chronic (i.e., present more than 15 days per month). Tension-type headache is common in all age groups, and females tend to predominate. In some patients, anxiety or depression coexist with tension headache.
The pathophysiologic basis of tension-type headache remains unknown. Some investigators believe that periodic tension headache is biologically indistinguishable from migraine, whereas others believe that tension-type headache and migraine are two distinct clinical entities. Abnormalities of cervical and temporal muscle contraction are likely to exist, but the exact nature of the dysfunction has not yet been elucidated.
Relaxation almost always relieves tension-type headaches. Patients should be encouraged to find a means of relaxation, which, for a given individual, could include bed rest, massage, and/or formal biofeedback training. Pharmacologic treatment consists of either simple analgesics and/or muscle relaxants. Ibuprofen and naproxen sodium are useful treatments for most individuals. When simple over-the-counter analgesics such as acetaminophen, aspirin, ibuprofen, and/or other nonsteroidal anti-inflammatory drugs (NSAIDs) alone fail, the addition of butalbital and caffeine (in a combination compound such as Fiorinal, Fioricet) to these analgesics may be effective. A list of commonly used analgesics for tension-type headaches is presented in Table 15-4. For chronic tension-type headache, prophylactic therapy is recommended. Low doses of amitriptyline (10 to 50 mg at bedtime) can provide effective prophylaxis.
Migraine, the most common cause of vascular headache, afflicts approximately 15% of women and 6% of men. A useful definition of migraine is a benign and recurring syndrome of headache, nausea, vomiting, and/or other symptoms of neurologic dysfunction in varying admixtures (Table 15-5). Migraine can often be recognized by its activators (red wine, menses, hunger, lack of sleep, glare, estrogen, worry, perfumes, let-down periods) and its deactivators (sleep, pregnancy, exhiliration, sumatriptan). A classification of the many subtypes of migraine, as defined by the International Headache Society, is shown in Table 15-1.
Severe headache attacks, regardless of cause, are more likely to be described as throbbing and associated with vomiting and scalp tenderness. Milder headaches tend to be nondescript¾tight, bandlike discomfort often involving the entire head¾the profile of tension-type headache.
Pathogenesis
Genetic Basis of Migraine Migraine has a definite genetic predisposition. Specific mutations leading to rare causes of vascular headache have been identified (Table 15-6). For example, the MELAS syndrome consists of a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and is caused by an A ® G point mutation in the mitochondrial gene encoding for tRNALeu(UUR) at nucleotide position 3243. Episodic migraine-like headaches are another common clinical feature of this syndrome, especially early in the course of the disease. The genetic pattern of mitochondrial disorders is unique, since only mothers transmit mitochondrial DNA. Thus, all children of mothers with MELAS syndrome are affected with the disorder.
Familial hemiplegic migraine (FHM) is characterized by episodes of recurrent hemiparesis or hemiplegia during the aura phase of a migraine headache. Other associated symptoms may include hemianesthesia or paresthesia; hemianopic visual field disturbances; dysphasia; and variable degrees of drowsiness, confusion, and/or coma. In severe attacks, these symptoms can be quite prolonged and persist for days or weeks, but characteristically they last for only 30 to 60 min and are followed by a unilateral throbbing headache.
Approximately 50% of cases of FHM appear to be caused by mutations within the CACNL1A4 gene on chromosome 19, which encodes a P/Q type calcium channel subunit expressed only in the central nervous system. The gene is very large (>300 kb in length) and consists of 47 exons. Four distinct point mutations have been identified within the gene (in five different families) that cosegregate with the clinical diagnosis of FHM. Analysis of haplotypes in the two families with the same mutation suggest that each mutation arose independently rather than representing a founder effect. Thus, certain subtypes of FHM are caused by mutations in the CACNL1A4 gene. The function of the CACNL1A4 gene remains unknown, but it is likely to play a role in calcium-induced neurotransmitter release and/or contraction of smooth muscle. Different mutations within this gene are the cause of another neurogenetic disorder, episodic ataxia type 2.
In a genetic association study, a NcoI polymorphism in the gene encoding the D2 dopamine receptor (DRD2) was overrepresented in a population of patients with migraine with aura compared to a control group of nonmigraineurs, suggesting that susceptibility to migraine with aura is modified by certain DRD2 alleles. In a Sardinian population, an association between different DRD2 alleles and migraine has also been demonstrated. Therefore, these initial studies suggest that variations in dopamine receptor regulation and/or function may alter susceptibility to migraine since molecular variations within the DRD2 gene have been associated with variations in dopaminergic function. However, since not all individuals with certain DRD2 genotypes suffer from migraine with aura, additional genes or factors must also be involved. Migraine is likely to be a complex disorder with polygenic inheritance and a strong environmental component.
The Vascular Theory of Migraine It was widely held for many years that the headache phase of migrainous attacks was caused by extracranial vasodilatation and that the neurologic symptoms were produced by intracranial vasoconstriction (i.e., the "vascular" hypothesis of migraine). Regional cerebral blood flow studies have shown that in patients with classic migraine there is, during attacks, a modest cortical hypoperfusion that begins in the visual cortex and spreads forward at a rate of 2 to 3 mm/min. The decrease in blood flow averages 25 to 30% (insufficient to explain symptoms on the basis of ischemia) and progresses anteriorly in a wavelike fashion independent of the topography of cerebral arteries. The wave of hypoperfusion persists for 4 to 6 h, appears to follow the convolutions of the cortex, and does not cross the central or lateral sulcus, progressing to the frontal lobe via the insula. Perfusion of subcortical structures is normal. Contralateral neurologic symptoms appear during temporoparietal hypoperfusion; at times, hypoperfusion persists in these regions after symptoms cease. More often, frontal spread continues as the headache phase begins. A few patients with classic migraine show no flow abnormalities; an occasional patient has developed focal ischemia sufficient to cause symptoms. However, focal ischemia does not appear to be necessary for focal symptoms to occur.
The ability of these changes to induce the symptoms of migraine has been questioned. Specifically, the decrease in blood flow that is observed does not appear to be significant enough to cause focal neurologic symptoms. Second, the increase in blood flow per se is not painful, and vasodilatation alone cannot account for the local edema and focal tenderness often observed in migraineurs. Moreover, in migraine without aura, no flow abnormalities are usually seen. Thus, it is unlikely that simple vasoconstriction and vasodilatation are the fundamental pathophysiologic abnormalities in migraine. However, it is clear that cerebral blood flow is altered during certain migraine attacks, and these changes may explain some, but clearly not all, of the clinical syndrome of migraine.
The Neuronal Theory of Migraine In 1941, the psychologist KS Lashley charted his own fortification spectrum, which is a migraine aura characterized by a slowly enlarging visual scotoma with luminous edges (see below). He was able to estimate that the evolution of his own scotoma proceeded across the occipital cortex at a rate of 3 mm/min. He speculated that a wavefront of intense excitation followed by a wave of complete inhibition of activity were propagated across the visual cortex. In 1944, the phenomenon that has come to be known as spreading depression was described by the Brazilian physiologist Leao in the cerebral cortex of laboratory animals. It is a slowly moving (2 to 3 mm/min), potassium-liberating depression of cortical activity, preceded by a wavefront of increased metabolic activity that can be produced by a variety of experimental stimuli, including hypoxia, mechanical trauma, and the topical application of potassium. These observations suggest that neuronal abnormalities, most likely initiated in the brainstem, could be the cause of a migraine attack. More recently, both cortical and brainstem changes have been observed in positron emission tomography (PET) scan studies of migraine. Thus, the existence of a specific "brainstem generator" for migraine remains an intriguing possibility that might represent the pathophysiologic basis of migraine.
The Trigeminovascular System in Migraine Activation of cells in the trigeminal nucleus caudalis in the medulla (a pain-processing center for the head and face region) results in the release of vasoactive neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), at vascular terminations of the trigeminal nerve. These peptide neurotransmitters have been proposed to induce a sterile inflammation that activates trigeminal nociceptive afferents originating on the vessel wall, further contributing to the production of pain. This mechanism also provides a potential mechanism for the soft tissue swelling and tenderness of blood vessels that attend migraine attacks. However, numerous pharmacologic agents that are effective in preventing or reducing inflammation in this animal model (e.g., selective 5-HT1D agonists, NK-1 antagonists, endothelin antagonists) have failed to demonstrate any clinical efficacy in recent migraine trials.
5-Hydroxytryptamine in Migraine Pharmacologic and other data point to the involvement of the neurotransmitter 5-hydroxytryptamine (5-HT; also know as serotonin) in migraine. Approximately 40 years ago, methysergide was found to antagonize certain peripheral actions of 5-HT and was introduced as the first drug capable of preventing migraine attacks. Subsequently, it was found that platelet levels of 5-HT fall consistently at the onset of headache and that drugs that cause 5-HT to be released may trigger migrainous episodes. Such changes in circulating 5-HT levels proved to be pharmacologically trivial, however, and interest in the humoral role of 5-HT in migraine declined.
More recently, interest in the role of 5-HT in migraine has been renewed due to the introduction of the triptan class of antimigraine drugs. The triptans are designed to stimulate selectively a particular subpopulation of 5-HT receptors. Molecular cloning studies have demonstrated that at least 14 specific 5-HT receptors exist in humans. The triptans (e.g., naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are potent agonists of 5-HT1B, 5-HT1D, and 5-HT1F receptors and are less potent at 5-HT1A and 5-HT1E receptors. A growing body of data indicates that the antimigraine efficacy of the triptans relates to their ability to stimulate 5-HT1B receptors, which are located both on blood vessels and nerve terminals. Selective 5-HT1D receptor agonists have, thus far, failed to demonstrate clinical efficacy in migraine. Triptans that are weak 5-HT1F agonists are also effective in migraine; however, only 5-HT1B efficacy is currently thought to be essential for antimigraine efficacy.
Physiologically, electrical stimulation near dorsal raphe neurons can result in migraine-like headaches. Blood flow in the pons and midbrain increases focally during migraine headache episodes; this alteration probably results from increased activity of cells in the dorsal raphe and locus caeruleus. There are projections from the dorsal raphe that terminate on cerebral arteries and alter cerebral blood flow. There are also major projections from the dorsal raphe to important visual centers, including the lateral geniculate body, superior colliculus, retina, and visual cortex. These various serotonergic projections may represent the neural substrate for the circulatory and visual characteristics of migraine. The dorsal raphe cells stop firing during deep sleep, and sleep is known to ameliorate migraine; the antimigraine prophylactic drugs also inhibit activity of the dorsal raphe cells through a direct or indirect agonist effect.
Recent PET scan studies have demonstrated that midbrain structures near the dorsal raphe are differentially activated during a migraine attack. In one study of acute migraine, an injection of sumatriptan relieved the headache, but did not alter the brainstem changes noted on the PET scan. These data suggest that a "brainstem generator" may be the cause of migraine and that certain antimigraine medications may not interfere with the underlying pathologic process in migraine.
Dopamine in Migraine A growing body of biologic, pharmacologic, and genetic data support a role for dopamine in the pathophysiology of certain subtypes of migraine. Most migraine symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Conversely, dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. As noted above, recent genetic data also suggest that molecular variations within dopamine receptor genes play a modifying role in the pathophysiology of migraine with aura. Therefore, modulation of dopaminergic neurotransmission should be considered in the therapeutic management of migraine.
The Sympathetic Nervous System in Migraine Biochemical changes occur within the sympathetic nervous system (SNS) of migraineurs before, during, and between migraine attacks. Factors that activate the SNS are all trigger factors for migraine. Specific examples include environmental changes (e.g., stress, sleep patterns, hormonal shifts, hypoglycemia) and agents that cause release and a secondary depletion of peripheral catecholamines [e.g., tyramine, phenylethylamine, fenfluramine, m-chlorophenylpiperazine (mCPP) and reserpine]. By contrast, effective therapeutic approaches to migraine share an ability to mimic and/or enhance the effects of norepinephrine in the peripheral SNS. For example, norepinephrine itself, sympathomimetics (e.g., isometheptene), monoamine oxidase inhibitors (MAOIs) and reuptake blockers alleviate migraine. Dopamine antagonists, prostaglandin synthesis inhibitors, and adenosine antagonists are pharmacologic agents effective in the acute treatment of migraine. These drugs block the negative feedback inhibition or norepinephrine release induced by endogenous dopamine, prostaglandins, and adenosine. Therefore, migraine susceptibility may relate to genetically based variations in the ability to maintain adequate concentrations of certain neurotransmitters within postganglionic sympathetic nerve terminals. This hypothesis has been called the empty neuron theory of migraine.
Clinical Features of Mirgraine
Migraine without Aura (Common Migraine) In this syndrome no focal neurologic disturbance precedes the recurrent headaches. Migraine without aura is by far the more frequent type of vascular headache. The International Headache Society criteria for migraine include moderate to severe head pain, pulsating quality, unilateral location, aggravation by walking stairs or similar routine activity, attendant nausea and/or vomiting, photophobia and phonophobia, and multiple attacks, each lasting 4 to 72 h.
Migraine with Aura (Classic Migraine) In this syndrome headache is associated with characteristic premonitory sensory, motor, or visual symptoms. Focal neurologic disturbances are more common during headache attacks than as prodromal symptoms. Focal neurologic disturbances without headache or vomiting have come to be known as migraine equivalents or migraine accompaniments and appear to occur more commonly in patients between the ages of 40 and 70 years. The term complicated migraine has generally been used to describe migraine with dramatic transient focal neurologic features or a migraine attack that leaves a persisting residual neurologic deficit.
The most common premonitory symptoms reported by migraineurs are visual, arising from dysfunction of occipital lobe neurons. Scotomas and/or hallucinations occur in about one-third of migraineurs and usually appear in the central portions of the visual fields. A highly characteristic syndrome occurs in about 10% of patients; it usually begins as a small paracentral scotoma, which slowly expands into a "C" shape. Luminous angles appear at the enlarging outer edge, becoming colored as the scintillating scotoma expands and moves toward the periphery of the involved half of the visual field, eventually disappearing over the horizon of peripheral vision. The entire process lasts 20 to 25 min. This phenomenon is pathognomonic for migraine, and has never been described in association with a cerebral structural anomaly. It is commonly referred to as a fortification spectrum because the serrated edges of the hallucinated "C" seemed to resemble a "fortified town with bastions all round it"; "spectrum" is used in the sense of an apparition or specter.
Basilar Migraine Symptoms referable to a disturbance in brainstem function, such as vertigo, dysarthria, or diplopia, occur as the only neurologic symptoms of the attack in about 25% of patients. A dramatic form of basilar migraine (Bickerstaff's migraine) occurs primarily in adolescent females. Episodes begin with total blindness accompanied or followed by admixtures of vertigo, ataxia, dysarthria, tinnitus, and distal and perioral paresthesia. In about one-quarter of patients, a confusional state supervenes. The neurologic symptoms usually persist for 20 to 30 min and are generally followed by a throbbing occipital headache. This basilar migraine syndrome is now known also to occur in children and in adults over age 50. An altered sensorium may persist for as long as 5 days and may take the form of confusional states superficially resembling psychotic reactions. Full recovery after the episode is the rule.
Carotidynia The carotidynia syndrome, sometimes called lower- half headache or facial migraine, is most common among older patients, with the incidence peaking in the fourth through sixth decades. Pain is usually located at the jaw or neck, although sometimes periorbital or maxillary pain occurs; it may be continuous, deep, dull, and aching, and it becomes pounding or throbbing episodically. There are often superimposed sharp, ice pick-like jabs. Attacks occur one to several times per week, each lasting several minutes to hours. Tenderness and prominent pulsations of the cervical carotid artery and soft tissue swelling overlying the carotid are usually present ipsilateral to the pain; many patients also report throbbing ipsilateral headache concurrent with carotidynia attacks as well as between attacks. Dental trauma is a common precipitant of this syndrome. Carotid artery involvement also appears to be common in the more traditional forms of migraine; over 50% of patients with frequent migraine attacks are found to have carotid tenderness at several points on the side most often involved during hemicranial migraine attacks.
Nonpharmacologic Approaches for All Migraineurs Migraine can often be managed to some degree by a variety of nonpharmacologic approaches (Table 15-7). The measures that apply to a given individual should be used routinely since they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; overresponsiveness to stress appears to be the issue. Since the stresses of everyday living cannot be eliminated, lessening one's response to stress by various techniques is helpful for many patients. These include yoga, transcendental meditation, hypnosis, and conditioning techniques such as biofeedback. For most patients, this approach is, at best, an adjunct to pharmacotherapy. Avoidance of migraine trigger factors may also provide significant prophylactic benefits (Table 15-7). Unfortunately, these measures are unlikely to prevent all migraine attacks. When these measures fail to prevent an attack, then pharmacologic approaches are needed to abort an attack.
Pharmacologic Treatment of Acute Migraine The mainstay of pharmacologic therapy is the judicious use of one or more of the many drugs that are effective in migraine. The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack (Table 15-8). Mild migraine attacks can usually be managed by oral agents; the average efficacy rate is 50-70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of three major pharmacologic classes: anti-inflammatory agents, 5-HT1 agonists, and dopamine antagonists.
Table 15-9 lists specific drugs effective in migraine. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks. Migraine therapy must be individualized for each patient; a standard approach for all patients is not possible. A therapeutic regimen may need to be constantly refined and personalized until one is identified that provides the patient with rapid, complete, and consistent relief with minimal side effects.
Nonsteroidal anti-inflammatory agents Both the severity and duration of a migraine attack can be reduced significantly by anti- inflammatory agents. Indeed, many undiagnosed migraineurs are self- treated with nonprescription anti-inflammatory agents (Table 15-4). A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of anti-inflammatory agents in migraine is usually less than optimal in moderate or severe migraine attacks. The combination of acetaminophen, aspirin, and caffeine (Excedrin Migraine) has been approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been show to be equivalent to a single dose of sumatriptan. Major side effects of NSAIDs include dyspepsia and gastrointestinal irritation.
5-HT1 agonists
ORAL Stimulation of 5-HT1 receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective receptor agonists, while the series of drugs known as triptans are selective 5-HT1 receptor agonists. A variety of triptans (e.g., naratriptan, rizatriptan, sumatriptan, zolmitriptan) are now available for the treatment of migraine (Table 15-9).
Each of the triptan class of drugs has similar pharmacologic properties, but varies slightly in terms of clinical efficacy. Rizatriptan appears to be the fastest acting and most efficacious of the triptans currently available in the United States. Sumatriptan and zolmitriptan have similar rates of efficacy as well as time to onset, whereas naratriptan is the slowest acting and the least efficacious. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability (Table 15-10). This observation is in keeping with a significant body of data indicating that faster-acting analgesics are more efficacious than slower-acting agents.
Unfortunately, monotherapy with a selective oral 5-HT1 agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are not effective in migraine with aura unless given after the aura is completed and the headache initiated. Side effects, although often mild and transient, occur in up to 89% of patients. Moreover, 5-HT1 agonists are contraindicated in individuals with a history of cardiovascular disease. Recurrence of headache is a major limitation of triptan use, and occurs at least occasionally in 40 to 78% of patients.
Ergotamine preparations offer a nonselective means of stimulating 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought since a dose that provokes nausea is too high and may intensify head pain. Except for a sublingual formulation of ergotamine (Ergomar), oral formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional vasoconstrictor activity). The average oral ergotamine dose for a migraine attack is 2 mg. Since the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of ergotamine versus the triptans. In general, ergotamine appears to have a much higher incidence of nausea than triptans, but less headache recurrence.
NASAL The fastest acting nonparenteral antimigraine therapies that can be self-administered include nasal formulations of dihydroergotamine (Migranal) or sumatriptan (Imitrex Nasal). The nasal sprays result in substantial blood levels within 30 to 60 min. However, the nasal formulations suffer from inconsistent dosing, poor taste, and variable efficacy. Although in theory the nasal sprays might provide faster and more effective relief of a migraine attack than oral formulations, their reported efficacy is only approximately 50 to 60%.
PARENTERAL Parenteral administration of drugs such as dihydroergotamine (DHE-45 Injectable) and sumatriptan (Imitrex SC) is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after intravenous dosing, 30 min after intramuscular dosing, and 45 min after subcutaneous dosing. If an attack has not already peaked, subcutaneous or intramuscular administration of 1 mg dihydroergotamine suffices for about 80 to 90% of patients. Sumatriptan, 6 mg subcutaneously is effective in approximately 70 to 80% of patients.
Dopamine Antagonists
ORAL Oral dopamine antagonists should be considered as adjunctive therapy in migraine. Drug absorption is impaired during migrainous attacks because of reduced gastrointestinal motility. Delayed absorption occurs in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine antagonist such as metoclopramide, 10 mg, should be considered to enhance gastric absorption. In addition, dopamine antagonists decrease nausea/vomiting and restore normal gastric motility.
PARENTERAL Parenteral dopamine antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1 agonists. A common intravenous protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine.
Other Medications for Acute Migraine
ORAL The combination of acetaminophen, dichloralphenazone, and isometheptene (i.e., Midrin, Duradrin, generic), one to two capsules, has been classified by the FDA as "possibly" effective in the treatment of migraine. Since the clinical studies demonstrating the efficacy of this combination analgesic in migraine predated the clinical trial methodologies used with the triptans, it is difficult to assess the clinical efficacy of this sympathomimetic compound in comparison to other agents.
NASAL A nasal preparation of butorphanol is available for the treatment of acute pain. As with all narcotics, the use of nasal butorphanol should be limited to a select group of migraineurs, as described below.
PARENTERAL Narcotics are effective in the acute treatment of migraine. For example, intravenous meperidene (Demerol), 50 to 100 mg, is given frequently in the emergency room. This regimen "works" in the sense that the pain of migraine is eliminated. However, this regimen is clearly suboptimal in patients with recurrent headache for two major reasons. First, narcotics do not treat the underlying headache mechanism; rather, they act at the thalamic level to alter pain sensation. Second, the recurrent use of narcotics can lead to significant problems. In patients taking oral narcotics such as oxycodone (Percodan) or hydrocodone (Vicoden), narcotic addiction can greatly confuse the treatment of migraine. The headache that results from narcotic craving and/ or withdrawal can be difficult to distinguish from chronic migraine. Therefore, it is recommended that narcotic use in migraine be limited to patients with severe, but infrequent, headaches that are unresponsive to other pharmacologic approaches.
Prophylactic Treatment of Migraine A substantial number of drugs are now available that have the capacity to stabilize migraine (Table 15-11). The decision of whether to use this approach depends on the frequency of attacks and on how well acute treatment is working. The occurrence of at least three attacks per month could be an indication for this approach. Drugs must be taken daily and there is usually a lag of at least 2 to 6 weeks before an effect is seen. The drugs that have been approved by the FDA for the prophylactic treatment of migraine include propranolol, timolol, sodium valproate, and methysergide. In addition, a number of other drugs appear to display prophylactic efficacy. This group of drugs includes amitriptyline, nortriptyline, verapamil, phenelzine, isocarbazid, and cyproheptadine. Phenelzine and methysergide are usually reserved for recalcitrant cases because of their serious potential side effects. Phenelzine is an MAOI; therefore, tyramine-containing foods, decongestants, and meperidine are contraindicated. Methysergide may cause retroperitoneal or cardiac valvular fibrosis when it is used for more than 8 months, thus monitoring is required for patients using this drug; the risk of the fibrotic complication is about 1:1500 and is likely to reverse after the drug is stopped.
The probability of success with any one of the antimigraine drugs is 50 to 75%; thus, if one drug is assessed each month, there is a good chance that effective stabilization will be achieved within a few months. Many patients are managed adequately with low-dose amitriptyline, propranolol, or valproate. If these agents fail or lead to unacceptable side effects, then methysergide or phenelzine can be used. Once effective stabilization is achieved, the drug is continued for 5 to 6 months and then slowly tapered to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods, suggesting that these drugs may alter the natural history of migraine.
A variety of names have been used for this condition, including Raeder's syndrome, histamine cephalalgia, and sphenopalatine neuralgia. Cluster headache is a distinctive and treatable vascular headache syndrome. The episodic type is most common and is characterized by one to three short-lived attacks of periorbital pain per day over a 4- to 8-week period, followed by a pain- free interval that averages 1 year. The chronic form, which may begin de novo or several years after an episodic pattern has become established, is characterized by the absence of sustained periods of remission. Each type may transform into the other. Men are affected seven to eight times more often than women; hereditary factors are usually absent. Although the onset is generally between ages 20 and 50, it may occur as early as the first decade of life. Propranolol and amitriptyline are largely ineffective. Lithium is beneficial for cluster headache and ineffective in migraine. The cluster syndrome is thus clinically, genetically, and therapeutically different from migraine. Nevertheless, mixed features of the two disorders are occasionally present, suggesting some common elements to their pathogenesis.
Clinical Features Periorbital or, less commonly, temporal pain begins without warning and reaches a crescendo within 5 min. It is often excruciating in intensity and is deep, nonfluctuating, and explosive in quality; only rarely is it pulsatile. Pain is strictly unilateral and usually affects the same side in subsequent months. Attacks last from 30 min to 2 h; there are often associated symptoms of homolateral lacrimation, reddening of the eye, nasal stuffiness, lid ptosis, and nausea. Alcohol provokes attacks in about 70% of patients but ceases to be provocative when the bout remits; this on-off vulnerability to alcohol is pathognomonic of cluster headache. Only rarely do foods or emotional factors precipitate pain, in contrast to migraine.
There is a striking periodicity of attacks in at least 85% of patients. At least one of the daily attacks of pain recurs at about the same hour each day for the duration of a cluster bout. Onset is nocturnal in about 50% of the cases, and then the pain usually awakens the patient within 2 h of falling asleep.
Pathogenesis No consistent cerebral blood flow changes accompany attacks of pain. Perhaps the strongest evidence for a central mechanism is the periodicity of attacks; the existence of a central mechanism is also suggested by the observation that autonomic symptoms that accompany the pain are bilateral and are more severe on the painful side. The hypothalamus may be the site of activation in this disorder. The posterior hypothalamus contains cells that regulate autonomic functions, and the anterior hypothalamus contains cells (in the suprachiasmatic nuclei) that constitute the principal circadian pacemaker in mammals. Activation of both is necessary to explain the symptoms of cluster headache. The pacemaker is modulated via serotonergic dorsal raphe projections. It can be concluded tentatively that both migraine and cluster headache result from abnormal serotonergic neurotransmission, albeit at different loci.
The most satisfactory treatment is the administration of drugs to prevent cluster attacks until the bout is over. Effective prophylactic drugs are prednisone, lithium, methysergide, ergotamine, sodium valproate, and verapamil. Lithium (600 to 900 mg daily) appears to be particularly useful for the chronic form of the disorder. A 10-day course of prednisone, beginning at 60 mg daily for 7 days followed by a rapid taper, may interrupt the pain bout for many patients. When ergotamine is used, it is most effective when given 1 to 2 h before an expected attack. Patients must be educated regarding the early symptoms of ergotism when ergotamine is used daily; a weekly limit of 14 mg should be adhered to.
For the attacks themselves, oxygen inhalation (9 L/min via a loose mask) is the most effective modality; 15 min of inhalation of 100% oxygen is often necessary. Sumatriptan, 6 mg subcutaneously, will usually shorten an attack to 10 to 15 min.
source: harrison's internal medicine
neurology