Flashcards in Chapter 38 Migraine Headache and Cluster Deck (97):
represents a very common benign headache syndrome; it is sometimes referred to as a vascular headache
The pain-generating structures of the head include
venous sinuses, meningeal and large cerebral arteries, basal meninges, muscles, skin, and cranial nerves V, IX, and X.
A plexus of largely unmyelinated fibers arises from the
trigeminal ganglion (cranial nerve V) and innervates the
cerebral and pial arteries, the venous sinuses, and the dura
The neurons in the trigeminovascular
substance P, one of the major nociceptive neurotransmitters of primary sensory neurons; calcitonin gene-related peptide (CGRP), which causes vasodilatation and when infused intravenously into susceptible individuals triggers headache; and neurokinin A, which is similar in structure and function to substance P.
When the trigeminal ganglion is stimulated and causes antidromic activation of the trigeminovascular system,
these peptide neurotransmitters are released near the
blood vessels they innervate; this results in vasodilatation
with consequent extravasation of plasma, or so-called sterile
Leakage of plasma proteins
from the dilated blood vessels in turn stimulates
the trigeminal nerve endings and causes nociceptive orthodromic signals to the trigeminal ganglion—the end result of this sterile neurogenic inflammation is the perception of pain in and around the head.
Neurogenic inflammation is
substances that act as agonists on a subset of serotonin (5-hydroxytryptamine, or 5-HT) receptors: the 5-HT1D and 5-HT1B receptors.
The major drugs used to
abort acute migraine attacks
agonists at the 5-HT1D/1B receptors. Drugs that act as agonists at these sites are thought to reduce neurogenic inflammation by inhibiting the trigeminal nerve endings and by their actions on blood vessels
Agonists at the 5-HT1D/1B receptors
ergot alkaloids (ergotamine, dihydroergotamine) and triptans (sumatriptan and others).
stimulation of the trigeminal ganglion, through antidromic release of neurotransmitters, results in
increased cerebral and extracerebral blood flow.
Stimulation of the
dorsal raphe nucleus
serotonergic nucleus in the midbrain, also increases cerebral blood flow.
stimulation of the nucleus caeruleus
the major source of central noradrenergic input, causes a decrease in cerebral blood flow.
Interneurons in the spinal cord and brainstem that are part of the descending pain modulation system use what as neurotransmitters?
enkephalins and g-aminobutyric acid (GABA) as neurotransmitters
ascending serotonergic pathway in the midbrain raphe region
relays painful stimuli to the
ventroposteromedial (VPM) thalamus via the quintothalamic tract.
A descending endogenous
pain modulating system originates in the
periaqueductal gray region of the midbrain, one of whose major relay structures is the nucleus raphe magnus in the medulla. After this relay, the descending pain modulating system connects with the spinal tract of the trigeminal nerve and the dorsal horns of the first through third cervical nerves.
Stimulation of the periaqueductal gray region causes
headache. The major neurotransmitters of this pain-modulating system are norepinephrine, serotonin, and enkephalins
migraine with aura it is thought that the cortex,
particularly the occipital cortex, is hyperexcitable. The cause of this hyperexcitability is
may relate to decreased intracellular magnesium levels, to a dysfunction of brain mitochondria, or to abnormal calcium channels.
The aura phase of migraine begins as
a wave of cortical neural excitation, accompanied by hyperemia, and is followed by an electrical wave of spreading neural depression and oligemia that advances at a rate of 2 to 6 mm/minute (a rate similar to that of the developing aura). During the oligemic phase, blood
flow remains above the ischemic threshold.
Dopamine receptor hypersensitivity
may be responsible for the
nausea, vomiting, hypotension, and dizziness that frequently accompany, and sometimes characterize, attacks of migraine. Antiemetics, most of which are dopamine receptor antagonists (especially at the D2 receptor), are frequently useful, and sometimes
effective in and of themselves in treating migraine
The diagnosis of migraine is made by
a suggestive clinical history and a normal neurologic examination
The classic description of migraine
that of a recurrent headache lasting 2 to 72 hr, of moderate to severe intensity, pulsating, aggravated by routine physical activity, and associated with nausea, emesis, photophobia, phonophobia, and/or osmophobia.
The major subtypes of migraine are
migraine with aura and migraine without aura
The most frequent migrainous aura consists of
visual symptoms such as bright spots, dark spots, tunnel vision, or zigzag lines (fortification spectra). Other common auras include numbness or paresthesias in one arm or side of the body
The aura is followed (or sometimes accompanied) by
an intense, crescendo head pain, frequently unilateral or retro-ocular; it may be described as pounding, throbbing, pressure-like, exploding, stabbing, or vise-like
the headache becomes intractable and lasts a week or longer
A migraine whose aura seems to originate in the brainstem
or involve both hemispheres
A typical aura in basilar migraine might present
with bilateral visual loss or blindness
basilar migraine patients may complain
vertigo, dysarthria, diplopia, tinnitus, ataxia, a decreased
level of consciousness, or bilateral sensory (paresthesias)
or subjective motor symptoms (there should be no objective weakness); sometimes nausea and emesis are
prominent. Some patients present with other types of
auras such as a dysphasia, and as such may resemble a
transient ischemic attack (TIA), a stroke, or an evolving
Some patients develop severe headache, sometimes described as exploding, related to exertion
a severe ocular headache that presents with
ophthalmoplegia (usually of the oculomotor nerve and
includes a dilated pupil. The ophthalmoplegia can last
hours to months and is now believed to represent an inflammatory neuritis or the Tolosa–Hunt syndrome.10
Painful ophthalmoplegia usually has a dramatic presentation and always warrants a careful evaluation.
Migraine without Aura
At least five headache attacks: Headaches last 4–72 hr if untreated. Has at least two of the following, but not weakness: Unilateral pain, Pulsating, Intensity is moderate to severe. Aggravated by routine physical activity
Has at least one of the following: Phonophobia, Photophobia, Nausea, Emesis
Migraine with Aura
At least two headache attacks that also fulfill the characteristics of migraine without aura. Headaches usually follow the aura but may begin with it and last 4–72 hr if untreated. Has at least one of the following reversible symptoms (lasting 4 min to 60 min), but no weakness
Positive or negative visual symptoms such as scintillating scotomas, blind spot (scotoma), blurred vision, zigzag lines, homonymous hemianopsia. Positive or negative sensory symptoms such as tingling or numbness
At least two attacks of migraine with an aura whose symptoms are reversible and localize to the brainstem or are bihemispheric, but without weakness
Symptoms can include: Dysarthria, Dizziness or vertigo
Bilateral visual symptoms, including temporary blindness
Diplopia, Nystagmus, Ataxia, Decreased level of consciousness, Bilateral paresthesiae, Tinnitus with or without decreased hearing
Aura without Headache
At least two attacks of symptoms typical of auras, but not weakness, such as visual, sensory or speech disturbances that resolve within 1 hr and are
not followed by a headache
At least two attacks of migraine with a reversible aura of motor weakness that can last 1 hr to days
Also includes one of the following: Positive or negative visual symptoms, Positive or negative sensory symptoms
Dysphasia or dysarthria, Frequently accompanied by symptoms typical of basilar migraine. If at least one first- or second-degree relative has a migrainous aura that includes motor weakness, it is familial hemiplegic migraine and is associated with a mutation in the neuronal calcium channel. If no first- or second-degree relative has a migrainous aura that includes motor weakness, it is sporadic hemiplegic migraine
Migraines can be treated
abortively (after they start) or
prophylactically (with daily medication aimed at reducing
the frequency or intensity of the headaches).
Triptans (Imitrex, Maxalt, Zomig, Frova, Relpax,
Amerge, and others)
5-HT1D/1B receptor agonists
How are Triptans dosed?
A second dose of the same preparation, taken 2 to 24 hr after the first, may again provide significant relief. A
triptan should not be used again for at least 24 hr after
the second dose
Triptans should not be administered
within 24 hr of another substance with
properties (e.g., another triptan, ergotamine, dihydroergotamine,
Triptans should not be
administered within 2 weeks of discontinuation of a
monoamine oxidase inhibitor or methysergide.
Triptans should not be prescribed to patients with
ischemic or other heart disease or uncontrolled hypertension; they should be avoided in patients with complicated auras such as dysphasias and confusional states and in basilar migraine
major side effects of triptans
sensation of chest pressure, flushing, tingling,
dizziness, and dysphoria. These usually resolve in less than 1 hr.
older drug with 5-HT agonist activity that also is very effective for migraine.
One to 2 tablets are taken at the onset of the headache or aura, followed by 1 tablet every 30 min until the headache is gone or until a maximum of 5 tablets per headache or 10 tablets per week have been consumed
effective drug with 5-HT agonist and sympathomimetic (vasoconstrictive) activity. Midrin also contains dichloralphenazone,
a mild sedative-hypnotic drug similar to chloral hydrate. One to 2 capsules are taken at the onset of the headache or aura, followed by 1 capsule every hour until the headache is gone or until a maximum of 5 capsules per headache or 10 capsules per week have been consumed
If consumed in excess, ergotamine-containing preparations can cause
vasospastic complications and are emetogenic.
Preparations containing butalbital (such as Fioricet,
which also contains acetaminophen and caffeine, or Fiorinal, which contains aspirin and caffeine
One to two tablets can be taken every 4 hr as needed. Barbiturate-containing preparations
cause drowsiness and can be habit forming if used
Narcotic-containing preparations, such as those with codeine, hydromorphone, or hydrocodone (in combination with aspirin or acetaminophen)
should be used only as drugs of last resort. Narcotics bind opiate receptors and mask pain, but they do not bind serotonin receptors and therefore do not interrupt
the putative pathophysiologic mechanism of migraine.
or metoclopramide, by virtue of their effect on
serotonin receptors, are effective against migraine pain. Their action as antagonists of the D2 dopamine receptor helps control the associated gastrointestinal symptoms
and this makes them excellent adjuvant drugs
parenterally but also is available as a 4 mg/mL nasal spray. Administered by the intravenous or intramuscular route, the dose should not exceed 2 to 3 mg in 24 hr.
Dihydroergotamine (DHE) indication
the drug of choice for treatment of status
Nonsteroidal anti-inflammatory drugs (NSAIDs)
work for some patients with mild to moderate
migraine pain. Ketorolac, which can be administered
intramuscularly, and indomethacin, which also is
available as a suppository, may be particularly useful.
Aspirin, particularly combined with acetaminophen and caffeine (Excedrin),
remains an effective and inexpensive over-the-counter
combined with potassium bicarbonate. use for
the treatment of migraine.
It is a drug worth considering
in patients in whom vasoconstricting drugs are
contraindicated or who cannot tolerate the side effects
of vasoconstricting drugs.
The chronic use (averaging at least 10 times per month
over a prolonged period of time) of any of the triptans,
NSAIDs, acetaminophen, butalbital, narcotics, ergotamine, DHE, and isometheptane can lead to
development of a medication overuse, or rebound, headache syndrome.
propranolol (60 to 80 mg once per day), metoprolol,
atenolol, timolol, and nadolol, are frequently effective first-line prophylactic drugs; propranolol and timolol are FDA approved for migraine prophylaxis
Beta-blockers Side effects
dizziness from bradycardia or hypotension, fatigue,
depression, worsening of symptoms in patients with
asthma or chronic obstructive pulmonary disease, gastrointestinal
distress, blunting of hypoglycemic symptoms
in patients with diabetes, and vivid dreams.
valproic acid (Depakote and
Depakote ER) and carbamazepine have been used as prophylaxis against migraine. Depakote
and Topamax are FDA approved for migraine
The usual starting dose for Depakote ER
is 500 mg per day; the dose should be adjusted as necessary
at 2- to 4-week intervals
Valproic acid Side Effects
weight gain, hair loss, tremor, abdominal distress, and easy bruisability.
an inhibitor of carbonic anhydrase and it has been reported to be useful in treating the syndrome of idiopathic increased intracranial pressure
(previously called pseudotumor cerebri).
Frequent side effects of Topamax
mental confusion and paresthesia; another is weight loss
Antidepressants, particularly amitriptyline
at a starting dose of 10 to 25 mg at bedtime, are very active prophylactic drugs. Most patients who respond to tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, or desipramine) usually do so at doses of 25 to
200 mg at bedtime; occasionally a patient may require more
The major side effects from tricyclics relate to
their anticholinergic action and include a dry mouth,
excessive daytime sleepiness, dizziness, urinary retention, glaucoma, cardiac arrhythmias, and photosensitization.
The specific serotonin reuptake inhibitors
(SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)
tried in patients who do not respond or who develop intolerable side effects from tricyclic drugs.
The major side effects of the SSRIs and SNRIs
jitteriness, tremors, gastrointestinal distress,
decreased libido, and occasionally headaches
SSRIs and SNRIs are relatively contraindicated in
patients who use
triptans, as they may suffer from excessive
serotonin stimulation (serotonin syndrome).
Calcium channel blockers
verapamil, are occasionally
useful as prophylactic agents. Calcium channel blockers are worth a try when firstline agents fail; they also appear to be more useful in patients with cluster headaches.
useful in patients with frequent
migraines who do not respond to more traditional prophylactic regimens
The major indication for lithium
treatment of an ongoing cluster headache.
Individualized injections of botulinum toxin A into the
pericranial muscles (frontalis, temporalis, and glabellar muscles)
has been reported to increase significantly the
number of headache-free days in some patients with
chronic migraine. The beneficial effect may last up to 90 days postinjection
self-help strategies that can minimize the incidence of migraines
If the patient consumes caffeinated beverages (coffee, tea, soda, cocoa), total caffeine should be limited to less than 400 mg per day (to avoid caffeinism) and the intake should include weekends, vacations, and holidays
(to avoid a caffeine withdrawal headache).
foods high in tyramine
(a substance metabolized to serotonin), which is thought to play a role as a migraine trigger, can be avoided.
chocolate, aged cheeses,
yogurt, sour cream, soy sauce, chicken liver, banana, avocado, nuts, and yeast extracts (including beer).
Foods high in nitrates can be avoided, as these might
precipitate a migraine by virtue of their vasodilating
Some foods high in nitrates include processed
meats (hot dogs, salami, bacon, ham, sausage,
corned beef) and other canned, smoked, or aged meats.
patients are sensitive to certain food additives
monosodium glutamate, frequently
used in restaurants and added to cooked,
packaged, and canned foods as a flavor enhancer, and
aspartame (NutraSweet). These substances contain
glutamate, an excitatory neurotransmitter.
migraneurs are sensitive to alcoholic beverages.
Alcohol tends to dilate blood vessels.
trigeminal autonomic cephalalgias (TAC)
group of three headache disorders characterized by the occurrence
of pain in the distribution of the first division of
the trigeminal nerve accompanied by prominent parasympathetic
autonomic features in the same distribution.
trigeminal autonomic cephalalgias (TAC) examples
These headaches are: cluster, hemicrania (paroxysmal hemicrania
and hemicrania continua), and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).
trigeminal autonomic cephalalgias (TAC) presents
with some combination of ocular redness, tearing, swelling, miosis, or ptosis; additional symptoms can include
forehead sweating and rhinorrhea
trigeminal autonomic cephalalgias (TAC) durations
Cluster headache lasts longest and presents with circadian periodicity but, overall clusters tend to occur relatively infrequently, such as yearly. SUNCT have the shortest duration but a high frequency of attacks. The duration and frequency of paroxysmal hemicrania is intermediate. Hemicrania continua is characterized by continuous pain with exacerbations.
Cluster headache is diagnosed by
suggestive clinical history
and a normal neurologic examination. Typically, severe pain, which lasts between 15 and 90 min, awakens the patient. The pain is unilateral and periorbital; it may include
the temple, forehead, and cheek (the distribution of
the first division of the trigeminal nerve).
Cluster headache accompanied by
lacrimation, conjunctival injection, nasal stuffiness, ptosis (with or without eyelid edema), and miosis ipsilateral to the pain.
Unlike patients with migraine, who seek
a dark, quiet environment, patients with cluster tend to
pace, scream, or appear agitated; nausea and vomiting are uncommon.
The major limitation of drugs aimed at interrupting the cluster (drugs used in migraine prophylaxis) is
their slow onset of action, with most requiring 2 to 4 weeks to demonstrate
activity at the initial dose, and similar intervals for
subsequent dose adjustments.
drugs are useful for interrupting the cluster-
Calcium channel blockers
Calcium channel blockers, such as verapamil (Verapamil usually requires administration at relatively high doses, 240 to 480 mg/day, to be effective.)
drugs are useful for interrupting the cluster - Anticonvulsants
valproic acid (Depakote and
Depakote ER) and carbamazepine can be useful to help abort a cluster. The usual starting dose for Depakote ER is 500 mg per day; the dose should be adjusted as
necessary at 2- to 6-week intervals. Valproic acid can
cause weight gain, hair loss, tremor, and abdominal distress.
drugs are useful for interrupting the cluster - Lithium carbonate
can be useful in patients with cluster;
in fact, cluster remains the major indication for
lithium in the treatment of headaches.
drugs are useful for interrupting the cluster -Antidepressants
amitriptyline at a starting
dose of 10 to 25 mg at bedtime. Tricyclics help induce sleep, which
may constitute one of the mechanisms by which they
help patients with cluster.
The major side effects from
relate to their anticholinergic effects and include a dry mouth, excessive daytime sleepiness, dizziness,
urinary retention, glaucoma, cardiac arrhythmias,
drugs are useful for interrupting the cluster - Beta-blockers
propranolol, metoprolol, atenolol, timolol, and nadolol, are also used frequently for cluster. In most healthy people 60 to 80 mg once per day of a long-acting propranolol preparation can be started and the dosage can be adjusted as necessary
Beta-blockers Side Effects
dizziness from bradycardia or hypotension, fatigue, depression, worsening of symptoms in patients with asthma or chronic obstructive pulmonary
disease, gastrointestinal distress, blunting of hypoglycemic symptoms in patients with diabetes, and vivid dreams.
Corticosteroids are useful as adjuvants to other drugs in breaking a cluster
They should be started simultaneously with one of the other prophylactic drugs. Corticosteroids
are to be used for a limited time
drugs are useful for interrupting the cluster -NSAIDs
indomethacin appears to be more
active than others. It also can be used in anticipation of a
headache to block its onset. Indomethacin can be administered
in doses up to 150 mg/day but tends to irritate the
Treatment of an Acute Cluster Headache
inhaled oxygen remains the standard
for treatment of an acute cluster headache.31 Oxygen
should be administered at 12 L/minute through a nonrebreather mask for 15 min as soon after the onset of the attack as feasible.
The syndrome consists of frequent, unremitting, unilateral headaches exhibiting a frequency of a few to more than 20 per day; the headaches last 5 to 45 min each. The pain, throbbing or boring, is localized on one side of the
head, around the eye and temple (in the distribution of
the first division of the trigeminal nerve). As in cluster, the pain is accompanied by autonomic (parasympathetic) phenomena: redness and tearing of the eye, eyelid swelling, nasal congestion, and/or rhinorrhea.
The hallmark of hemicrania
it responds completely and dramatically to indomethacin, which can be administered in doses up
to 150 mg/day and, as long as it is tolerated, can be used for long periods of time.
short-lasting unilateral neuralgiform headache with conjunctival injection (SUNCT)
Bursts of stabbing, throbbing, or burning
pain around the eye or temple, lasts 5 seconds to 5 min and occurs in paroxysms of up to 30 per hr (with an average of 5 to 6/hr). Here too, the pain is accompanied by autonomic (parasympathetic) phenomena in the distribution of the first division of the trigeminal nerve: redness and tearing of the eye, eyelid swelling, nasal congestion, and/or rhinorrhea