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
Overveiw
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.
MENINGITIS
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.
INTRACRANIAL HEMORRHAGE
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.
BRAIN TUMOR
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
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
OTHER CAUSES OF HEADACHE
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.
TENSION-TYPE HEADACHE
The term tension-type headache is still commonly used to describe a chronic
head pain syndrome characterized by bilateral tight, bandlike discomfort. Patients
may report that the head feels as if it is in a vise or that the posterior neck
muscles are tight. The pain typically builds slowly, fluctuates in severity,
and may persist more or less continuously for many days. Exertion does not usually
worsen the headache. The headache may be episodic or chronic (i.e., present
more than 15 days per month). Tension-type headache is common in all age groups,
and females tend to predominate. In some patients, anxiety or depression coexist
with tension headache.
The pathophysiologic basis of tension-type headache remains unknown. Some investigators
believe that periodic tension headache is biologically indistinguishable from
migraine, whereas others believe that tension-type headache and migraine are
two distinct clinical entities. Abnormalities of cervical and temporal muscle
contraction are likely to exist, but the exact nature of the dysfunction has
not yet been elucidated.
Relaxation almost always relieves tension-type headaches. Patients should be
encouraged to find a means of relaxation, which, for a given individual, could
include bed rest, massage, and/or formal biofeedback training. Pharmacologic
treatment consists of either simple analgesics and/or muscle relaxants. Ibuprofen
and naproxen sodium are useful treatments for most individuals. When simple
over-the-counter analgesics such as acetaminophen, aspirin, ibuprofen, and/or
other nonsteroidal anti-inflammatory drugs (NSAIDs) alone fail, the addition
of butalbital and caffeine (in a combination compound such as Fiorinal, Fioricet)
to these analgesics may be effective. A list of commonly used analgesics for
tension-type headaches is presented in 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
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.
TREATMENT OF MIGRAINE
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 cyprohe
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