CAQ 2019 EXAM PREPARATION

MIGRAINE&
HEADACHE
OVERVIEW

Introduction
The National Headache Foundation (NHF) offers a Certificate In Added Qualification (GAG) in Headache
Medicine to validate your expertise in this field. Earning your GAG will enable you to be recognized
for your special expertise by your colleagues and patients. Participants may also receive the added
benefit of more patient referrals in the future, as those who complete the exam will be listed in the
Healthcare Practitioner Finder database on the NHF website. The upcoming GAG examination dates
are September 16 - October 1, 2019. Additional information on eligibility and fees, and the application
forms and procedure for fees are available here: https://headaches.org/caq/.

This overview of headache covers selected topics that are addressed in the certification process. While
it is not meant to be a comprehensive discussion of headache, this article does provide a synopsis of
the types of information that are addressed in the GAG examination. We encourage readers who are
interested in taking the exam to look at Diamond et al and the third edition of the International Glassification
of Headache Disorders (IGHD-3), which are the primary references cited in this overview, The NHF GAG
website listed above also provides additional resources for exam preparation, including several videos and
recommendations for further reading.

Cover image: © Glaus Lunau/Science Source

© 2019 Frontline Medical Communications Inc.

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CAO 2019 1: - AI/ F REPARATION
MIGRAINES
HEADACHE
OVERVIEW
Migraine
Epidemiology
Migraine is among the World Health Organization's 20
most disabling conditions.' Migraine with and without aura
occurs in approximately 12% of American adults, a number
that seems to be consistent across western countries.- In the
United States, the prevalence of migraine is about 18% in
adult females and 5% to 6% in adult males.^These numbers
translate to approximately 25 to 45 million migraine sufferers
in the United States, with a societal burden of approximately
$14 billion per year."'
The most frequent type of migraine is episodic, which
is defined as less than 15 days of headache per month in a
person with migraine. Some have chronic migraine, which
is defined as 15 or more headache days per month, of which
8 or more days have characteristics of migraine, for more
than 3 months.- Chronic migraine affects 1% to 2% of the
United States population, or approximately 5 million people
in a given year, with the same female preponderance seen in
episodic migraine.-
Migraines run in families, and approximately 80%
of all migraine sufferers have a first-degree relative with
migraine.-'^ Identical twins are twice as likely to both
have migraine compared to fraternal twins." Several gene
polymorphisms have been found in patients with migraine
without aura."
More definite genetic links have been discovered in
familial hemiplegic migraine, an autosomal-dominant
form of migraine with hemiplegia.- Four types of famil
ial hemiplegic migraine have gene defects identified by
genomic typing, including mutations in the CACNAJA,
ATP1A2, SCNIA,and PRRT2 genes.=
While the most prevalent primary headache disor
der presenting in a clinical setting is migraine (including
migraine variants), the most prevalent primary headache
disorder in the general population is tension-type headache,
with a lifetime prevalence between 30% and 78% depend
ing on population, age, and sex.-" Similar to migraine, it
can be categorized into episodic and chronic tension-type
headache. Those with episodic tension-type headache have
greater than 15 headache days per month.
Women report more tension-type headaches than men,
with gender ratios reported between 1.04 and 1.8.- A familial
association has been noted, with first-degree relatives hav
ing a 2- to 4-times increased risk of chronic tension head
aches.- An annual prevalence of 38% has been reported for
the United States general population, with a much lower
2.2% annual prevalence for chronic tension-type headache.-
S6 May 2019
Episodic tension-type headache is characterized by at least
10 episodes of headache occurring between 1 and 14 days per
month for more than 3 months, while chronic tension-type
headache is defined as headache occurring on 15 or more days
per month on average for more than 3 months." Both episodic
and chronic tension-type headaches are common in children
and adolescents, with prevalence rates reported between 10%
and 25% for episodic tension-type headache and between
0.1% to 5.9% for chronic tension-type headache.-
Because of the high prevalence in the population,
tension-type headache has a greater economic impact than
migraine or other primary headache disorders, with sub
stantial contributions from direct costs of medical service
and indirect costs such as lost work productivity.-
Cluster headache is a rarer primary headache,estimated to
affect 0.1% to 0.4% of the population, with a higher prevalence
in males (M:F ratios of 2:1 to 4:1).- Most cluster headaches are
episodic, defined as lasting 7 to 365 days.- However, approxi
mately 15% of patients have chronic cluster headache, defined
as lasting more than 1 year without remission.- Various inves
tigators estimate first-degree relatives as having a 5- to 39-fold
risk of developing cluster headache, depending on the study-
Types of migraine
Episodic migraine without aura
The International Classification of Headache Disorders third
edition (ICHD-3) identifies 2 major types of migraine: with
TABLE 1. Migraine without aura
Migraine without aura is a clinical syndrome whose
diagnosis requires at least 5 attacks that fulfill the
following criteria (ICHD-3 1.1)®;
• Headache lasting 4 to 72 hours (without successful
treatment). However, one notable difference
between children or adolescents and adults Is that
the length of a migraine may be as short as 2 hours
• Has at least 2 of the following characteristics:
unilateral location, pulsating, moderate or severe
pain, aggravated by or causes avoidance of routine
physical activity
• Nausea and/or vomiting, or both photophobia and
phonophobia during the attack.
(Note: Each set of diagnostic criteria in the ICHD-3 also
contains the comment "Not better accounted for by another
ICHD-3 diagnosis;" these are not repeated further here.)

and without aura (Tables 1 and 2).^ Not all migraines fit
the classic picture of unilateral, pulsating pain; a headache
can be bilateral and not pulsating and still be considered
a migraine if the other features are present.- On the other
hand, patients who complain of self-diagnosed recurrent
episodes of "sinus" headaches may actually have migraine,
since migraines can be associated with eye tearing and nasal
congestion, and this complaint should alert clinicians to
take careful histories to screen for migraine. Also, migraine
is often associated with neck pain, which erroneously can
trigger a diagnosis of tension-type headaches, even when
they fulfill the criteria for the diagnosis of migraine.-
Migraine attacks arise from a combination of genetics
and internal and/or external triggers, including stress, men
struation or ovulation, too much or too little sleep, alcohol,
changes in weather, dehydration, glare, flickering lights, or
certain foods.-
Prodrome
Migraines may be preceded by symptoms known collectively
as a prodrome, which can occur hours or days before the
headache.-'^ Some patients experience a postdrome phase
following the resolution of headache, either in addition to
or without a prodrome.'' Symptoms that can occur in either
prodrome or postdrome include hyperactivity, hypoactivity,
depression, cravings for particular foods, repetitive yawning,
fatigue, neck stillness and/or pain, and cold hands and feet.-'"
Comorbidities
Comorbidities of migraine include psychiatric disorders
such as depression, bipolar disorder, anxiety, and social pho
bias.- Additional comorbidities include Raynaud's phenom
enon, asthma, rhinitis, irritable bowel syndrome, epilepsy,
and stroke.- Stroke risk has been reported to be double in
migraineurs but this increase in risk is largely confined to
those with migraine with aura and correlates with frequency
but not severity of headache.Women, even those younger
than age 45, are particularly at a higher risk of stroke asso
ciated with migraine." However, out of the roughly 800,000
strokes that occur each year, only about 2000 to 3000 are
related to migraine.
Migraine with aura
Migraine with aura is defined as migraine with tran
sient focal neurological symptoms; these usually precede
the headache but sometimes occur during the migraine."
Cortical spreading depression (CSD) is considered to
be the basis for migraine aura.- CSD is a wave of electrical
CAQ 2019 ■^ARATION
MIGRAINES
HEADACHE
OVERVIEW
excitation that propagates across the cerebral cortex at a rate
of 2 to 5 mm/min. Following the excitation is a time period
of suppression or inactivity of cortical neurons.
Stroke risk has been reported to be double in
migraineurs but this increase in risk is largely confined
to those with migraine with aura and correlates with
frequency but not severity of headache. Women, even
those younger than age 45, are particularly at a higher
risk of stroke associated with migraine.
Up to 99% of reported auras involve visual changes,-
These are fully reversible, and individual symptoms typically
last 5 to 60 minutes." The visual features of aura have both
positive features (like photopsia and scintillations) and nega
tive ones (such as scotomata).- Neurologic symptoms of aura
also typically include both positive (eg, tingling) and negative
(eg, numbness) symptoms.- The neurologic deficits related to
migraine aura tend to march across a homuncular distribution
with dysfunction followed by a wave of resolution."
Chronic migraine
Chronic migraine headache is distinguished from episodic
migraine (with or without aura). The definition requires head
ache occurring on at least 15 days a month for more than
3 months, and the features of migraine occurring for at least
8 days a month (ICHD-3 1.3)."
Risk factors for converting from episodic to chronic
migraine include obesity, suboptimal response to acute
TABLE 2. Migraine with aura
Classification as migraine with aura requires at least
2 attacks that fulfill the following criteria (ICHD-3 1.2f\
• One or more of these reversible symptoms:
visual, sensory, speech and/or language, motor,
brainstem, retinal.
• At least 3 of these 6 characteristics:
- At least 1 aura symptom that spreads gradually
over at least 5 minutes
- Two or more aura symptoms occur in succession
- Each individual symptom lasts 5 to 60 minutes
- At least 1 symptom is unilateral
- At least 1 symptom is positive
- Headache accompanies or foilows within
60 minutes of aura.
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CAQ 2019 LXAM I^Ri'-PARATION
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OVERVIEW
treatment, asthma, depression, stress, cigarette smoking, and
medication overuse.-'"'
Comorbidities associated with chronic migraine include
allergies, sinusitis, depression, high cholesterol, high blood
pressure, arthritis, chronic pain, anxiety, obesity, asthma,
bronchitis, fibromyalgia, and epilepsy.- ''
A patient with symptoms that initially appear to be
chronic migraine may have medication overuse headache
(MOH), and about 50% of patients with what appears to be
chronic migraine will revert to episodic migraine after drug
withdrawal." MOH occurs 15 or more days per month in
patients with a pre-existing primary headache, and develops
because the patient has been overusing acute or symptom
atic headache medication for 10 to 15 days a month (depend
ing on the medication) for more than 3 months." It usually
resolves once the medication overuse stops, but not always."
Weaning off medication that is causing MOH can happen
slowly, or with the use of some intravenous agents adminis
tered as an inpatient.- Physicians may choose to initiate preven
tive medications for migraine before starting the withdrawal.-
Additionally, bridge therapies may be used for 5 to 14 days to
limit the anticipated worsening of the underlying headache.-
These include nonsteroidal agents such as naproxen, steroids,
triptans, ergotamines, and antidopaminergic agents.-
To avoid the development of MOH in patients being
treated for migraine headache, the general recommendation
is to have patients use acute headache medications no more
than 2 to 3 days a week.-
A patient with symptoms that initially appear to be
chronic migraine may have medication overuse
headache(MOH), and about 50% of patients with what
appears to be chronic migraine will revert to episodic
migraine after drug withdrawal.
An additional concern for clinicians is the role of sex
hormones in females with migraine. More than half of
women link a menstrual cycle relationship with their head
aches, although a careful headache diary is needed to con
firm this link in individuals.-" Hormonally linked migraines
are affected by hormone changes due to menses, pregnancy,
contraception, and menopause, or during transgender
transitions.- The definition of menstrual migraine ([CHD-3
Al.1.2) states that these attacks occur 2 days before to 3 days
after the onset of menstrua! bleeding (5-day time period)
during at least 2 out of 3 menstrual cycles and at other times
in the cycle." Acute therapies such as triptans, non-steroidal
anti-inflammatory drugs (NSAIDs) and dihydroergotamine
S8 May 2019
(DHE) can be used to treat the acute pain of migraine. Mini-
prophylaxis is a preventive therapy in which medications are
used only during the perimenstrual time period and not during
other times of the month.The medication is started 1 to 2 days
before the expected onset of menstrual migraine and is con
tinued for 4 to 12 days. Medications used for mini-prophylaxis
include triptans, naproxen, DHE,and magnesium.- Pregnancy
often decreases the frequency of attacks of migraine particu
larly during the second and third trimesters; the high levels
of estrogen and progesterone experienced during pregnancy
may actually be preventive for migraine.
Abdominal migraine,another type of recurring migraine,
occurs mainly in children with repeated attacks of moderate
to severe abdominal pain accompanied by vasomotor symp
toms, nausea and vomiting, but without headache." These
attacks typically last up to 72 hours." Many children with this
disorder will develop migraine headache as they get older.-
Recent Advancements
Many advances have occurred in recent years, particularly
in the understanding and treatment of migraine headache.^
The potential roles of several molecules have been investi
gated for their potential effects in the pathophysiology of
migraine, including calcitonin gene-related peptide (CGRP),
nitric oxide, and pituitary adenylate cyclase-activating pep
tide (PACAP-38).^
Calcitonin gene-related peptide
The peptide CGRP has been extensively studied in the
pathogenesis of migraine headache.- Synthesized within the
trigeminal afferents, CGRP is also found in other sections of
the trigeminal pain network, and considerable evidence has
accumulated linking CGRP release to the development of
migraine headache.^ Serum levels of CGRP increase during
a migraine attack. Also, intravenous infusions have triggered
migraine-like headache. This, in turn, has led to the target
ing of CGRP receptors as potential acute and preventive
therapies for migraine, an idea supported by the fact that
the CGRP receptor is located in much of the trigeminal pain
network linked to migraine development.-
Nitric oxide
Nitric oxide is known to trigger immediate headache in some
individuals, including migraineurs, and has been linked to
vasodilation of the middle cerebral artery.- Serum concentra
tions of CGRP do not increase with nitroglycerin infusion and
CGRP receptor antagonists do not block nitrous oxide-induced
headache, so these are not considered CGRP-dependent.^

Investigators reported mixed results \^^th nitric oxide synthase
(NOS) inhibitors and more research is needed to determine
if any of the newer types of NOS inhibitors will be beneficial
for migraine.-
PACAP-38 and PAC, receptor
The neuropeptide PACAP-38 is synthesized in the trigemi-
nal afferents, the trigeminal nucleus caudalis, the spheno-
palatine ganglion, and parasympathetic neurons.- It binds to
3 receptors, one of which, the PAC, receptor, binds only to
PACAP-38.- Immediate-type headaches are produced when
PACAP-38 is infused into either healthy controls or patients
with a history of migraine.- It also produces a headache
approximately 6 hours after infusion in 75% of migraine
patients that fits the criteria for migraine without aura.-These
and other results highlight a potentially important role for
PACAP-38 and its PAC, receptor in long-lasting vasodilation
in migraine headache, making the peptide and its receptor
potential targets for migraine therapy.-
Other new developments include discoveries from
neuroimaging studies that the hypothalamus is activated
during the prodrome of a migraine attack and may be an
important contributor to migraine generation.- Some stud
ies have noted differences in gray and white matter, corti
cal thickness and functional connectivity when comparing
the brains of migraine patients with healthy individuals.-
Advances have also been made in the area of treatment
using medical devices, including transcutaneous electrical
and transmagnetic stimulation and occipital and vagal nerve
stimulation.- Research is also advancing in the delineation of
genetic loci and single nucleotide polymorphisms linked to
migraine, including migraine with and without aura.^
Other Primary Headache Disorders
IMS international Classification
of Headache Disorders
The ICHD-3 offers a systematic, standardized classification
with explicit diagnostic criteria for the various known types
of headache."'
Primary headaches are headaches that lack a structural,
infectious, or metabolic cause.-They are identified by clini
cal symptomatology, and the diagnosis is based primarily on
an accurate and thorough history.- The ICHD-3 lists
3 major categories of primary headache: migraine,
tension-type headache (Table 3), and trigeminal auto-
nomic cephalalgias (TACs); and also includes a grouping
of 10 others, including primary cough headache, primary
exercise headache, primary headache associated with
CAQ 2019 I '-.AI-/ l-1^EPAnATI0N
MIGRAINES
HEADACHE
OVERVIEW
sexual activity, primaiy thunderclap headache, cold-stimulus
headache, external-pressure headache, primary stabbing
headache, nummular headache, hypnic headache, and new
daily persistent headache."'
Primary headache disorders
Tension-type headache
ICHD-3 diagnostic criteria for frequent episodic
tension-type headache specify at least 10 past episodes of
headache occurring on 1 to 14 days per month, on average,
for more than 3 months(between 12 and 179 days per year)."
Diagnostic criteria for the chronic form specifies headache
occurring on at least 15 days a month, on average, for more
than 3 months (at least 180 days per year)." One of the
characteristics that best differentiates episodic forms of
tension-type headache from migraine headache is the fact
the former does not typically alter daily function. With
both migraines, which typically improve following meno
pause, and tension-type headaches, negative emotions such
as anxiety, depression, and anger can impact the probability
of experiencing an attack as well as the disabling impact of
the migraine or headache attack.'" '^
The most commonly cited triggers for tension-type
headache are mental or physical stressors, with the head
ache developing during the exposure to the stressor. Other
triggers include hunger, dehydration, lack of sleep, and
excessive alcohol or caffeine consumption (or withdrawal).-
Some individuals have tension-type headaches linked to
female hormonal changes or weather changes.-
TABLE 3. Infrequent episodic tension-type headache
The ICHD-3 diagnostic criteria for infrequent, episodic
tension-type headache include the following^:
• Ten or more past episodes of headache
• Less than 12 days per year, each lasting from
30 minutes to a week
• At least 2 of the following:
- Bilateral location
- Nonpulsating (pressing or tightening) quality
- Mild-to-moderate intensity
- Not aggravated by routine physical activity
• Both of the following:
- No nausea or vomiting
- No more than 1 of these: photophobia or phonophobia.
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CAQ 2019 opEPARATION
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OVERVIEW
Trigeminal autonomic cephalalgias
TACs comprise a third group of primary headaches, includ
ing cluster, parox)'smal hemicranias, short-lasting unilateral
neuralgiform headache attacks (SUNCT), hemicrania conti-
nua, and probable TAC.^These are typically unilateral head
aches with prominent cranial parasympathetic autonomic
features that are ipsiiateral to the headache.'
Cluster headache
Cluster headache is a form of TAG (Table 4). Cluster head
ache occurs more often in men than women (M:F ratio 3:1),
with a typical age of onset of 20 to 40 years.' These head
aches typically occur at night, awakening the sufferer out of
sleep, but can occur at any time.- Some patients experience
a link in headache pattern to summer or winter solstice or
to spring or fall, with individual patients tending to demon
strate their own specific annual patterns.-
Paroxysmal hemicranias
Patients experiencing paroxysmal hemicranias have attacks
of severe unilateral pain that is orbital, supraorbital, tempo
ral, or any combination, lasting 2 to 30 minutes, occurring
several-to-many times a day. Responsive to indomethacin,
these headaches are also linked to conjunctival injection,
lacrimation, nasal congestion, rhinorrhea, forehead/facial
swelling, miosis, ptosis, and/or eyelid edema.'
Short-lasting unilateral neuralgiform headaches
Classification of short-lasting unilateral neuralgiform head
aches according to the lCHD-3 requires at least 20 attacks,
with the following criteria (ICHD-3 3.3.1)':
TABLE 4. Cluster headache
The diagnostic criteria for ciuster headache
(ICHD-3 3.1) include the following^:
• At least 5 attacks that fulfill the remaining criteria
• Severe unilateral orbital, supraorbital, and/or temporal
pain lasting 15 minutes to 3 hours when untreated
• Either or both of the following:
- At least 1 of the following, ipsiiateral to the
headache: conjunctival injection and/or lacrimation,
nasal congestion and/or rhinorrhea, eyelid edema,
forehead and facial sweating, miosis and/or ptosis
- Restlessness or agitation
• Occurring between once every other day and 8 per day.
S10 May 2019
• Moderate-to-severe unilateral pain with orbital,
supraorbital, temporal and/or other trigeminal distri
bution, lasting for 1 to 600 seconds and occurring as
single stabs, series of stabs, or in a saw-tooth pattern
• One or more of the following, ipsiiateral to the pain:
- Conjunctival injection and/or lacrimation
- Nasal congestion and/or rhinorrhea
- Eyelid edema
- Forehead and facial sweating
- Miosis and/or ptosis
• At least 1 headache occurs each day.
There are 2 different subtypes of short-lived neural
giform headaches. The first, SUNCT, only has conjunctival
injection and lacrimation as its autonomic symptoms. The
other is called short-lived neuralgiform headache attacks
with cranial autonomic symptoms (SUNA). SUNA can have
conjunctival injection and lacrimation as well as the other
autonomic symptoms listed above.'
Hemicrania continue
Hemicrania continua is a persistent unilateral headache
that has been present for at least 3 months, but which
responds to therapeutic doses of indomethacin.'There are
remitting and unremitting subtypes. The remitting subtype
is a persistent, continuous headache that is interrupted
by 24 hours or more of headache-free time periods. The
unremitting subtype is a daily and continuous headache
without any headache-free time periods. Classification
under ICHD-3 requires either the presence of 1 or both of
the following':
• A sense of restlessness or agitation, or aggravation of
the pain by movement
• One or more of these:
- Conjunctival injection and/or lacrimation
- Nasal congestion and/or rhinorrhea
- Eyelid edema
-Forehead and facial sweating
- Miosis and/or ptosis.
Additional types of primary headache are discussed in
detail in section 4 of ICHD-3.They include':
• Hypnic headache(ICHD-3 4.9) is a frequent headache
that causes the patient to awaken from sleep with
bilateral head pain.
• Primary stabbing headache (ICHD-3 4.7), often called
icepick headache, involves brief, stabbing pain in the
head, 1 to many times per day.
• Other primary headaches are linked to cough, exer
cise, sexual activity, cold stimulus, etc.

Secondary headache disorders
Secondar)' headaches are new headaches that are caused
by another disorder (Table 5).'^ Screening for secondary
headache can include consideration of a number of causes,
including brain tumors, abscesses or hematomas, central
nervous system infections, vascular disorders, and structural
abnormalities such as Chiari malformations, aneurysms, or
high or low cerebrospinal fluid (CSF) pressure.-
High- or low-pressure headache
One type of secondary headache is caused by changes in CSF
pressure, either high (ICHD-3 7.1) or low (lCHD-3 7.2).'^
High CSF pressure may or may not have an identifiable
cause. If no cause is found then it is termed idiopathic intra-
cranial hypertension. If it has a cause then it is referred to as
intracranial hypertension attributed to a metabolic, toxic or
hormonal cause.These headaches are worse with lying down,
bending forward, coughing, bearing down or sneezing. A seri
ous potential complication of persistent elevated intracranial
hypertension with papilledema is permanent loss of vision.^
Headache attributed to low CSF pressure includes
post lumbar puncture (LP) headache, CSF fistula headache,
and headache due to spontaneous intracranial hypotension.^
These headaches are generally worse with standing and
improved with lying down, but over time the postural fea
tures may disappear.They are called orthostatic headaches.
Additional headache classifications
Many additional types of secondary headache are described
in the ICHD-3.These include^:
• Headaches attributed to colloid cyst of the third
ventricle often appear as recurrent headache trig
gered by postural change or Valsalva-like maneuver
(ICHD-3 7.4.1.1).
TABLE 5. Secondary headache
The ICHD-3 classification of a secondary headache
requires the presence of another disorder that has
been documented scientifically to cause headache,
with evidence of causation, including at least 2 of the
following conditions^
• Headache onset has temporal relation to the onset
of causative disorder
• Headache worsening in parallel with worsening of
causative disorder and/or improvement in parallel
with improvement in causative disorder.
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• Headache, facial pain, or neck pain caused by cervical
carotid or vertebral artery dissection (ICHD-3 6.5.1).
A partial Homer's syndrome may occur with a carotid
dissection along with cranial nerve palsies, monocular
blindness and tinnitus.
• Sleep apnea headache (ICHD-3 10.1.4), a morning
headache that resolves with successful treatment of
the sleep apnea.
•Trigeminal neuralgia (ICHD-3 13.1.1) characterized by
recurrent, brief, unilateral, "electric shock-like" pains.
Diagnostic Considerations
While the clinician must differentiate between primary and
secondary headache and identify a specific diagnosis for the
patient presenting with headache, many headaches can be
diagnosed based on a complete history and physical exam
ination without additional diagnostic testing.- Neuroimag-
ing is not necessary if the patient presents with probably
migraine with a normal neurological examination and no red
flags of a secondary headache disorder.-
However, if red flags for secondary headache disorders
are present then one should consider neuroimaging or other
diagnostic tests. These red flags include:-
• First or worst headache or "thunderclap"headache
• New or unexplained neurologic signs or symptoms,or
a recent, significant alteration in the pattern of head
ache, including frequency and severity
• A headache that always involves the same side
• A new daily persistent headache
• Headache that does not respond to therapeutic
interventions
• New-onset headache in patients over age 50 or who
have cancer or HIV infection
• Headache associated with fever, stiff neck, papill
edema, cognitive impairment, or personality change
•The combination of seizure and headache
• Papilledema
• Postural worsening of headaches
• Progression of headaches including clear progression
of a preexisting headache type.
A detailed discussion of when to use computed
tomography (CT) versus magnetic resonance imaging (MRI)
scanning is beyond the scope of this article, but noncontrast
CT can be useful to examine sinus pathology, to exclude space-
occupying lesions, and for the diagnosis of acute subarachnoid
hemorrhage and bony abnormalities for acute head trauma.^
For a patient presenting emergently with "thunderclap" head
ache and mild encephalopathy, the most appropriate imaging
May2019 Sll
CAQ 2019 f-XAM PRhPARATiON
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Study to perform is a CT without contrast.'® The best initial
imaging study for low CSF pressure headache is MRI of brain
with and without contrast. MRI, on the other hand,is the test of
choice for most headache disorders as it is more sensitive than
CT in many settings, particularly in identifying ischemia and
posterior and cervicomedullary lesions.-
LP should be considered in patients with signs or symp
toms that suggest an underlying infectious cause for head
ache, or if the patient describes the headache as the first or
worst of their life, if the headache is not typical of primary
headache, or when intracranial hypertension or hypoten
sion is suspected." When bloody CSF is obtained during LP,
differentiating subarachnoid hemorrhage from traumatic
LP involves comparing the red cell count in tubes 1 and 4
and immediate centrifugation to detect hemoglobin degra
dation products called xanthrochromia.- While factors such
as the volume of CSF removed, intravenous hydration, CSF
opening pressure or the duration of bed rest after LP do not
affect whether the patient develops a headache from LP,
incorrect bevel orientation of the LP needle can be a con
tributing factor.'" Atraumatic needles reduce the incidence
of this complication.
CSF rhinorrhea results from a leakage of spinal fluid
through the bones of the skull base. Sometimes those with
IIH can develop CSF rhinorrhea when their pressures get
too high. Persons present with rhinorrhea or otorrhea. The
beta-2 transferrin analysis may be necessary to distinguish
whether the rhinorrhea is composed of CSF or nasal secre
tions. The presence of beta-2 transferrin in nasal or ear fluid
is highly sensitive for a CSF.-"
Treatment Options
There are 2 types of therapies used to treat migraine: acute
and preventive therapies. Acute therapies are used to treat
migraine attacks when they occur to relieve the pain and
associated symptoms of migraine. Preventive therapies are
used to reduce the number of attacks.
Acute Medications
Triptans
Triptans are serotonin receptor agonists with a high affinity
for the 5-HTjg and S-FTTjp receptors located in the trigeminal
vasculature and trigeminal neurons.-Triptans appear to work via
both vasoconstriction and by inhibiting the release of CGRP and
other neuropeptides from the trigeminal nerve.-
Orai formulations are useful for treatment of acute
episodic migraine during the initial mild headache phase.-
However, their use should be limited to no more than 2 days
SI 2 May 2019
per week; if further treatment is required, consideration should
be given to other classes of medications, preventive treat
ments, and nonpharmacological interventions,- While the
various triptans work by the same mechanisms, differences
in half-life may be clinically important for oral formulations.-
Among the frequently prescribed triptans, sumatriptan and
zolmitriptan have shorter half-lives, while frovatriptan has a
longer half-life.-
There are 2 types of therapies used to treat migraine:
acute and preventive therapies. Acute therapies are
used to treat migraine attacks when they occur
to relieve the pain and associated symptoms of
migraine. Preventive therapies are used to reduce
the number of attacks.
Because many patients with migraine experience nau
sea, gastric atony and/or gastric stasis, they might say they
have gastric stasis even outside of their attacks.- Additional
formulations of triptans include subcutaneous sumatriptan
(described as the fastest and most effective treatment for
acute migraine), nasal spray formulations of sumatriptan and
zolmitriptan, and dry nasal powder delivery of sumatriptan.-
Side effects associated with triptan use include dizzi
ness, sensations of warmth or heat, sleepiness, paresthe-
sias, numbness, and pressure or tightness/heaviness in the
chest, neck or throat.^ In addition to use in acute and chronic
migraine, triptans are also used in treating acute cluster
headache, specifically with subcutaneous sumatriptan, and
in the treatment of menstrual migraine if the use is modest.-
Nonsteroidal anti-inflammatory drugs
NSAIDs provide pain relief as well as anti-inflammatory
activity through inhibition of prostaglandin and thromboxane
production, and are used as monotherapy or in combination
with acute agents such as triptans to treat migraine.- In par
ticular, ibuprofen, naproxen sodium, and a combination of
aspirin-acetaminophen-caffeine have demonstrated efficacy
in reducing pain in acute migraine.- While these are popular
over-the-counter NSAID options for treating migraine, the US
Food and Drug Administration (FDA) has approved an oral
solution of potassium dicoflenac for acute migraine.- NSAIDs
may also reduce the risk of developing chronic migraine if the
use is modest.-
Dihydroergotamine(DHE)
DHE has been used for many years to interrupt migraine
headache." It is now known to be a 5-HT..Q receptor

agonist that inhibits the release of CGRP, but it also has
agonist activity against the S-HT,,, receptor and affinity for
many additional receptors.- It is available as a nasal spray
and for injection.- Nausea is the most common side effect
of DHE.-'
Neuroleptics
Phenothiazine neuroleptics, including prochlorperazine,
chlorpromazine, promethazine and metoclopramide, are used
as anti-emetics in the treatment of migraine-associated
nausea and vomiting.- Prochlorperazine and metoclopramide
arc also commonly employed in emergency departments to
abort an acute migraine.-
While the various triptans work by the same
mechanisms, differences in haif-iife may be
ciinicaiiy important for oral formulations. Among
the frequently prescribed triptans, sumatriptan
and zolmitriptan have shorter half-lives, while
frovatriptan has a longer half-life.
Opioids and butalbital
Most headache physicians would not recommend using
opioids or butalbital for the acute treatment of migraine with
the exception of rare circumstances. If used, they should be
prescribed in very small quantities.
Preventive Medications
Beta-blockers
Propranolol and timolol arc 2 beta-blockers that have FDA
indications for preventing migraines, with propranolol
carrying a lower risk in pregnancy than many other com
mon migraine therapies.- Metoprolol and atenolol, while
not FDA-approved for migraine prevention, are also
beta-blockers commonly used for this purpose.- Nadolol,
also in this group, is effective for reducing frequency and
severit)' of migraine and for treating chronic migraine.-
Tricyclic antidepressants
The tricyclic antidepressant amitript)'line is useful as a pre
ventive medication for tension-type headache and episodic
migraine.- Adverse events include anticholinergic effects such
as dry mouth and constipation, as well as tinnitus, weight
gain, drowsiness, and arrhythmias.- Adding antiepileptic
drugs (AEDs) or beta-blockers, which improve migraine,
to a tricyclic antidepressant has been recommended as
second-line therapy for migraine prevention.
CAO 2019 PD=°i.RATiON
MIGRAINES
HEADACHE
r:VL=RVIEW
Antiepileptic drugs
Some AEDs arc thought to act to inhibit both peripheral and
central nerve pain pathways.-Topiramate has been approved
for preventing episodic migraine headache.- Common side
effects for topiramate include kidney stones, memory loss,
paresthesias, weight loss, and teratogenicit)'. Osteoporosis
is associated with long-term use of topiramate.-- Divalproex
sodium is FDA approved as a migraine preventive. Its side
effects include weight gain, tremor, hepatotoxicit)', teratoge-
nicity, and pancreatitis.-'
OnabotulinumtoxinA
OnabotulinumtoxinA is approved for the prophylactic
treatment of chronic migraine based on 2 placebo-
controlled double-blind studies called PREEMPT,-
OnabotulinumtoxinA is an acetylcholine release inhib
itor, which is not likely related to its mechanisms of action
in migraine, but there is evidence of CGRP inhibition
in its mechanism of action. It is administered intramus
cularly, divided across multiple head and neck muscles as
specified in the prescribing information.-"' Neck pain and
headache, and ptosis are the most common adverse events
associated with this drug, when used for chronic migraine,
but OnabotulinumtoxinA also carries a boxed warning
noting the potential effects of distant spread of the toxin.-"*
CGRP
Three monoclonal antibodies that target CGRP (eptine-
zumab, galcanezumab, and fremanezumab) and 1 directed
against the CGRP receptor (erenumab) have been developed.-
Of these, erenumab is a fully human monoclonal antibody,
while the others are humanized.
The 3 CGRP receptor antagonists currently approved
by the FDA and indicated for the prevention of migraine in
adults are fremanezumab, galcanezumab, and erenumab.-'"-'
The most common adverse reactions in clinical trials were
injection site reactions.''
Fremanezumab is delivered as a subcutaneous
dose (225 mg monthly or 675 mg quarterly). Hyper-
sensitivit)' reactions have been reported within clinical trials
of fremanezumab."
Galcanezumab is delivered as a loading dose (2 consec
utive injections) followed by monthly doses.'"
Erenumab is delivered in monthly injections of 70 mg
or 140 mg (ie, 2 doses). In clinical trials, other than injec
tion site reactions, the only adverse event to occur in 3% or
more of patients and significantly more than placebo
was constipation."
May 2019 S13
CAQ 2019 FXAM PHrPARATION
MIGRAINES
HEADACHE
OVERVIEW
Angiotensin receptor blockers and
angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers (ARB) (eg, candesartan) and
angiotensin-converting en2yme (ACE) inhibitors (eg, lisinoprii)
have demonstrated efficacy in preventing migraine,although the
mechanisms of action in migraine are not clear.- A small study
of treatment with lisinoprii showed that patients experience fewer
hours with headache and fewer days with headache compared
to placebo, while another small study of treatment with cande
sartan showed fewer headache days, hours with migraine, hours
with headache, days with migraine, and days of sick leave.-" •''
Behavioral therapies
The combination of behavioral treatment and medication has
evidence to support its superiority to either type of therapy
alone.^- Mind-body therapies for headache include biofeed-
back training, mindfulness training, cognitive behavioral
training, acupuncture, imagery and visualization, and pro
gressive relaxation.
Summary
As this brief overview indicates, headache is a complex
topic involving many primary and secondary subtypes,
diagnostic issues, and potential treatments. While episodic
tension-type headache is the most prevalent primary head
ache disorder in the general population, the life-altering
symptoms of migraine and cluster headache are more likely
to bring patients to the specialist setting for treatment. The
number of individuals affected by headache and the potential
costs to the US economy of headaches that are untreated or
poorly controlled are staggering to consider.
The third edition of the ICHD has been published, pro
viding a systematic, standardized classification with diagnos
tic criteria. Unraveling some of the genetics of headache as
well as molecular pathways involved in the pathophysiol-
ogy of headache has highlighted key roles played by CGRP,
nitric oxide, and PACAP-38. Recommendations for diagnostic
procedures are evolving as well, and the array of treatment
modalities,including medications, medical devices and mind-
body therapies continues to expand.The field of headache will
continue to be an exciting one for the foreseeable future.
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