Primary Headache Disorders










P
rimary headaches are disorders unto themselves and are not
attributed to any other cause or condition. The criteria for diag-
nosis include the descriptors and clinical presentation as well
as the exclusion of other disorders. Primary headaches account for
approximately 90% of headache cases in patients presenting to pri-
mary care.
1
The International Classication of Headache Disorders,
third edition (beta version) (ICHD) classies primary headache disor-
ders into four categories
2
:
1. Migraine
2. Tension-type headache (TTH)
3. Trigeminal autonomic cephalalgias (TACs)
4. Other primary headache disorders
Key Points
Clinicians who treat oral and facial pains should become
well versed in primary headache disorders.
Clinicians should use the most current version of the In-
ternational Classication of Headache Disorders to accu-
rately diagnose primary headache disorders.
Clinicians need to be familiar with the most up-to-date,
evidence-based care of primary headache disorders.
If they are in doubt as to a denitive diagnosis and ap-
propriate therapy, clinicians should consider referral to a
health care practitioner who is knowledgeable in the diag-
nosis and management of headache disorders.
Primary
Headache
Disorders
5
75
Migraine
A complete listing of primary headache dis-
orders can be found at the ICHD website. This
chapter focuses on the most common primary
headache presentations: migraine, TTH, and
select TACs. Each discussed disorder includes
the ICHD codes established by the Headache
Classication Committee of the International
Headache Society as well as those described
in the International Classication of Diseases,
Tenth Edition (ICD-10).
Migraine (ICHD 1.x.x,
ICD-10 G43.xxx)
Clinical presentation and diagnosis
Migraine is reported by the World Health Orga-
nization to be the third most prevalent and the
seventh most disabling illness in the world.
3,4
It
is considered a familial neurobiologic disorder
of the central nervous system (CNS) character-
ized by increased brain sensitivity and mostly
episodic pain presentation.
5
Migraine typically
presents with recurrent throbbing and mostly
unilateral painful attacks of moderate to severe
intensity lasting 4 to 72 hours untreated or un-
dertreated. In children and adolescents (aged
under 18 years), the attacks may last 2 to 72
hours. The head pain is associated with certain
characteristic features such as nausea, phono-
phobia, and photophobia and is typically ag-
gravated by activity. One-third of migraineurs
will experience transient neurologic symptoms
such as visual disturbance or other sensory
phenomena prior to the onset of the headache
event. This is known as aura.
6
Some individuals
will experience premonitory symptoms such
as tiredness, yawning, sensory hypersensitiv-
ity, increased food cravings, thirst, and polyuria
that tend to be highly predictive of the attack.
These symptoms may occur anywhere from 2
to 24 hours prior to the attack and are highly
suggestive of CNS etiology.
2,7
The ICHD crite-
ria may be used to conrm the diagnosis of mi-
graine when the described criteria are met and
after organic disease is excluded. If a patient
meets the criteria for more than one subtype
of migraine, all subtypes should be diagnosed
and coded. The ICHD criteria for migraine are
as follows: (1) Patients need to have experi-
enced at least ve previous and similar attacks,
fullling the following criteria: (a) two of the
following pain characteristics must be pres-
ent: unilateral pain, pulsatile quality, moderate
to severe intensity, and/or aggravation by or
causing avoidance of routine physical activity;
and (b) the attack must be accompanied by
nausea (and/or vomiting) or photophobia and
phonophobia. (2) The headache may not be
better described by another ICHD diagnosis.
Migraine attacks may occur without aura
(ICHD 1.1, ICD-10 G43.0) or with aura (ICHD
1.2, ICD-10 G43.1). Aura is the presence of
fully reversible focal neurologic symptoms that
develop gradually over 5 to 20 minutes and last
no more than 1 hour. Aura may also occur in
the absence of a typical migraine headache
(ICHD 1.2.1.2, ICD-10 G43.104). Aura often
takes the form of positive visual phenomena
that move across the visual eld over minutes,
migrating paresthesias, or dysphasic speech.
The ICHD criteria for migraine with aura are
as follows
2
:
At least two attacks fullling the following
criteria: (1) One or more of the following fully
reversible aura symptoms: visual, sensory,
speech and/or language, motor, brainstem,
and/or retinal. (2) At least two of the following
four characteristics: at least one aura symptom
spreads gradually over ≥ 5 minutes, and/or two
or more symptoms occur in succession; each
individual aura symptom lasts 5 to 60 min-
utes; at least one aura symptom is unilateral;
the aura is accompanied, or followed within 60
minutes, by headache.
Individuals who meet criteria for migraine
without aura but have had fewer than ve at-
tacks should be coded as probable migraine
without aura (ICHD 1.5.1, ICD-10 G43.83), and
individuals who meet criteria for migraine with
aura that have had only one attack should be

76
Primary Headache Disorders
5
coded as probable migraine with aura (ICHD
1.5.2, ICD-10 G43.83).
If migraine occurs on more than 15 days per
month for at least 3 months and has the fea-
tures of migraine headache on at least 8 days
of the month, it is classied as chronic mi-
graine (ICHD 1.3, ICD-10 G43.3). A debilitating
migraine persisting for more than 72 hours in
succession is classied as status migrainosus
(ICHD 1.4.1, ICD-10 G43.2). Complications of
migraines are rare but may include persistent
aura without infarction (ICHD 1.4.2, ICD-10
G43.3), migrainous infarct (ICHD 1.4.3, ICD-10
G43.3), and migraine aura-triggered seizure
(ICHD 1.4.4, ICD-10 G43.3).
Epidemiology
Migraine is a common condition affecting ap-
proximately 12% of the population in Western
countries.
8
In the United States, the preva-
lence of migraine is 18% in females and 6%
in males.
8
It has been reported that greater
than 90% of patients presenting with a stable,
recurring, severe headache probably have mi-
graine.
9
According to a recent Global Burden
of Disease report, migraine is now the sixth
highest cause of disability worldwide.
10,11
Mi-
graine is considered to be the most disabling
of all headache disorders.
12
In boys, migraine
with aura will peak at age 5 years while mi-
graine without aura tends to peak at age 10
to 11 years.
13
Migraine peaks later in girls than
in boys, with migraine with aura occurring at
age 12 to 13 years and migraine without aura
at age 14 to 17 years.
13
New onset of migraine
is an uncommon nding in men in their third
decade. The highest prevalence of migraine oc-
curs in ages 30 to 39 years and is at its lowest
after the age of 60. The prevalence is higher for
both men and women in whites than in blacks.
Because migraine usually affects people
during their most productive years, it is a major
burden to the patient and society. Not only does
it affect the patient’s quality of life by impairing
his or her ability to participate in family, social,
and recreational activities, but it also affects
society in terms of direct costs (eg, medical
care) and indirect costs (eg, absenteeism and
reduced effectiveness at work). It is estimated
that 23 million US residents have severe mi-
graines.
14
Twenty-ve percent of women expe-
rience four or more severe attacks per month,
35% experience one to three severe attacks
per month, and 40% experience one or fewer
than one severe attack per month. The study
also found that more than 85% of women and
more than 82% of men with severe migraine
had some migraine-related disability.
Pathogenesis
Many mechanisms and theories explaining
the causes of migraine have been proposed,
though the full picture is still unknown. The
extensive variability in the clinical presenta-
tion of the disorder provides an even greater
challenge to the identication of pathoetiologic
mechanisms. Migraine appears dependent on
activation of the trigeminovascular system.
15
Activation of the receptors on the dura and
associated vessels, activation of the thalami-
cortical pathways, and an inhibition of the de-
scending cortical pain-controlling pathway all
apparently contribute to the migraine event.
The cyclical and lifetime uctuations in female
sex hormone concentrations might explain why
migraine is so much more prevalent in women
and why migraine activity may vary so substan-
tially throughout life. Migraine has traditionally
been believed to be a genetic disorder due to
the common occurrence among family mem-
bers. It has been reported that at least 50%
of migraine patients have a rst-degree relative
who also experiences this disorder.
16–21
Typical migraine is believed to be polygenic,
but several monogenic forms of migraine have
been identied. Familial hemiplegic migraine
(FHM) is a monogenic form with aura present-
ing as hemiparesis. To date, mutations in three
different ion channels or ion pumps have been
found as potential causes of FHM.
5
In recent
77
Migraine
genome-wide association studies, common
migraine risk appears to be associated with
38 genomic loci.
22
It appears that the inu-
ence on migraine is a result of the interaction
of the group as a whole along with lifestyle
and environmental factors, as opposed to the
effect of each locus individually. While there
does not appear to be much in the way of
overlap of mechanisms between the mono-
genic or polygenic migraine subtypes, com-
mon pathways involving the development and
function of neurons and synapses, vascular
system development, and glutamate trans-
port mechanisms appear to be signicant for
both.
23
These ndings could potentially point
to a more signicant role of vascular dysfunc-
tion in migraine pathophysiology than previ-
ously thought. This role is further supported
by the frequent occurrence of disorders that
are commonly comorbid with migraine such as
stroke and cardiovascular disease.
24,25
The mi-
graine aura correlates with the cerebral cortical
event of cortical spreading depression (CSD),
a slowly propagating wave of depolarization,
hyperpolarization, and vascular changes. In
animal models, CSD has been shown to lead
to trigeminovascular activation, resulting in
the release of neuropeptides, neurogenic in-
ammation, increased vascular permeability,
and dilation of blood vessels.
26
Whether these
vascular changes are necessary for the full
expression of migraine symptoms including
headache is still debated.
27,28
Recent evidence
seems to suggest that vascular events do
not appear to be a necessary component of
the migraine event, nor are they sufcient to
induce migraine on their own.
29
Borsook and
Burstein
30
suggest that activation in the nuclei
of the dorsolateral pons may be partly respon-
sible for multiple processes including facial
pain and altered pain modulation. Recent func-
tional magnetic resonance imaging (MRI) stud-
ies have shown the hypothalamus to not only
be an important modulator of the premonitory
aspect of the migraine event but also the mi-
graine attack itself.
31
More specically, the pos-
terior portion of the hypothalamus appears to
be important for the headache phase, whereas
the anterior region seems to play a critical role
in migraine chronication. However, given the
available evidence, identifying a specic area
of the brain as the migraine generator is not
presently feasible.
32
Multiple neurotransmit-
ters and modulators, including serotonin,
calcitonin gene-related peptide (CGRP), nitric
oxide, dopamine, and glutamate, have been
implicated in migraine pathophysiologic mech-
anisms.
33,34
Central sensitization producing al-
lodynia and hyperalgesia is thought to be an
important clinical manifestation of migraine.
35
Management
In addition to pharmacotherapy, migraine
management modalities should include edu-
cational interventions, lifestyle and behavioral
modications, and trigger-avoidance strate-
gies. Pharmacologic interventions may be
abortive/symptomatic or prophylactic. Patients
who experience frequent severe migraine at-
tacks often require both approaches. The de-
cision of the most appropriate management
approach should be based on type of presen-
tation of the migraines (episodic or chronic),
the level of impairment that they cause, previ-
ous management history and response, and
patient preferences. Consideration should also
be given to any comorbid conditions such as
depression or hypertension. Abortive medica-
tions only may be used for individuals with
fewer than 4 headache days per month and
no impairment or those with no more than 1
headache day per month regardless of impair-
ment.
8
Individuals with more frequent attacks,
such as those with 6 or more migraine days
per month with normal functioning, 4 or more
migraine days with some impairment, or 3 or
more migraine days with severe impairment,
should be considered for management with
prophylactic medications.
8
If there is a co-
morbid illness, a prophylactic agent that can
treat both conditions should be used when

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P rimary headaches are disorders unto themselves and are not attributed to any other cause or condition. The criteria for diag-nosis include the descriptors and clinical presentation as well as the exclusion of other disorders. Primary headaches account for approximately 90% of headache cases in patients presenting to pri-mary care.1 The International Classication of Headache Disorders, third edition (beta version) (ICHD) classies primary headache disor-ders into four categories2:1. Migraine2. Tension-type headache (TTH)3. Trigeminal autonomic cephalalgias (TACs)4. Other primary headache disordersKey Points◊ Clinicians who treat oral and facial pains should become well versed in primary headache disorders.◊ Clinicians should use the most current version of the In-ternational Classication of Headache Disorders to accu-rately diagnose primary headache disorders.◊ Clinicians need to be familiar with the most up-to-date, evidence-based care of primary headache disorders. ◊ If they are in doubt as to a denitive diagnosis and ap-propriate therapy, clinicians should consider referral to a health care practitioner who is knowledgeable in the diag-nosis and management of headache disorders.Primary Headache Disorders5 75MigraineA complete listing of primary headache dis-orders can be found at the ICHD website. This chapter focuses on the most common primary headache presentations: migraine, TTH, and select TACs. Each discussed disorder includes the ICHD codes established by the Headache Classication Committee of the International Headache Society as well as those described in the International Classication of Diseases, Tenth Edition (ICD-10).Migraine (ICHD 1.x.x, ICD-10 G43.xxx)Clinical presentation and diagnosisMigraine is reported by the World Health Orga-nization to be the third most prevalent and the seventh most disabling illness in the world.3,4 It is considered a familial neurobiologic disorder of the central nervous system (CNS) character-ized by increased brain sensitivity and mostly episodic pain presentation.5 Migraine typically presents with recurrent throbbing and mostly unilateral painful attacks of moderate to severe intensity lasting 4 to 72 hours untreated or un-dertreated. In children and adolescents (aged under 18 years), the attacks may last 2 to 72 hours. The head pain is associated with certain characteristic features such as nausea, phono-phobia, and photophobia and is typically ag-gravated by activity. One-third of migraineurs will experience transient neurologic symptoms such as visual disturbance or other sensory phenomena prior to the onset of the headache event. This is known as aura.6 Some individuals will experience premonitory symptoms such as tiredness, yawning, sensory hypersensitiv-ity, increased food cravings, thirst, and polyuria that tend to be highly predictive of the attack. These symptoms may occur anywhere from 2 to 24 hours prior to the attack and are highly suggestive of CNS etiology.2,7 The ICHD crite-ria may be used to conrm the diagnosis of mi-graine when the described criteria are met and after organic disease is excluded. If a patient meets the criteria for more than one subtype of migraine, all subtypes should be diagnosed and coded. The ICHD criteria for migraine are as follows: (1) Patients need to have experi-enced at least ve previous and similar attacks, fullling the following criteria: (a) two of the following pain characteristics must be pres-ent: unilateral pain, pulsatile quality, moderate to severe intensity, and/or aggravation by or causing avoidance of routine physical activity; and (b) the attack must be accompanied by nausea (and/or vomiting) or photophobia and phonophobia. (2) The headache may not be better described by another ICHD diagnosis. Migraine attacks may occur without aura (ICHD 1.1, ICD-10 G43.0) or with aura (ICHD 1.2, ICD-10 G43.1). Aura is the presence of fully reversible focal neurologic symptoms that develop gradually over 5 to 20 minutes and last no more than 1 hour. Aura may also occur in the absence of a typical migraine headache (ICHD 1.2.1.2, ICD-10 G43.104). Aura often takes the form of positive visual phenomena that move across the visual eld over minutes, migrating paresthesias, or dysphasic speech. The ICHD criteria for migraine with aura are as follows2: At least two attacks fullling the following criteria: (1) One or more of the following fully reversible aura symptoms: visual, sensory, speech and/or language, motor, brainstem, and/or retinal. (2) At least two of the following four characteristics: at least one aura symptom spreads gradually over ≥ 5 minutes, and/or two or more symptoms occur in succession; each individual aura symptom lasts 5 to 60 min-utes; at least one aura symptom is unilateral; the aura is accompanied, or followed within 60 minutes, by headache. Individuals who meet criteria for migraine without aura but have had fewer than ve at-tacks should be coded as probable migraine without aura (ICHD 1.5.1, ICD-10 G43.83), and individuals who meet criteria for migraine with aura that have had only one attack should be 76Primary Headache Disorders5coded as probable migraine with aura (ICHD 1.5.2, ICD-10 G43.83).If migraine occurs on more than 15 days per month for at least 3 months and has the fea-tures of migraine headache on at least 8 days of the month, it is classied as chronic mi-graine (ICHD 1.3, ICD-10 G43.3). A debilitating migraine persisting for more than 72 hours in succession is classied as status migrainosus (ICHD 1.4.1, ICD-10 G43.2). Complications of migraines are rare but may include persistent aura without infarction (ICHD 1.4.2, ICD-10 G43.3), migrainous infarct (ICHD 1.4.3, ICD-10 G43.3), and migraine aura-triggered seizure (ICHD 1.4.4, ICD-10 G43.3).EpidemiologyMigraine is a common condition affecting ap-proximately 12% of the population in Western countries.8 In the United States, the preva-lence of migraine is 18% in females and 6% in males.8 It has been reported that greater than 90% of patients presenting with a stable, recurring, severe headache probably have mi-graine.9 According to a recent Global Burden of Disease report, migraine is now the sixth highest cause of disability worldwide.10,11 Mi-graine is considered to be the most disabling of all headache disorders.12 In boys, migraine with aura will peak at age 5 years while mi-graine without aura tends to peak at age 10 to 11 years.13 Migraine peaks later in girls than in boys, with migraine with aura occurring at age 12 to 13 years and migraine without aura at age 14 to 17 years.13 New onset of migraine is an uncommon nding in men in their third decade. The highest prevalence of migraine oc-curs in ages 30 to 39 years and is at its lowest after the age of 60. The prevalence is higher for both men and women in whites than in blacks. Because migraine usually affects people during their most productive years, it is a major burden to the patient and society. Not only does it affect the patient’s quality of life by impairing his or her ability to participate in family, social, and recreational activities, but it also affects society in terms of direct costs (eg, medical care) and indirect costs (eg, absenteeism and reduced effectiveness at work). It is estimated that 23 million US residents have severe mi-graines.14 Twenty-ve percent of women expe-rience four or more severe attacks per month, 35% experience one to three severe attacks per month, and 40% experience one or fewer than one severe attack per month. The study also found that more than 85% of women and more than 82% of men with severe migraine had some migraine-related disability.PathogenesisMany mechanisms and theories explaining the causes of migraine have been proposed, though the full picture is still unknown. The extensive variability in the clinical presenta-tion of the disorder provides an even greater challenge to the identication of pathoetiologic mechanisms. Migraine appears dependent on activation of the trigeminovascular system.15 Activation of the receptors on the dura and associated vessels, activation of the thalami-cortical pathways, and an inhibition of the de-scending cortical pain-controlling pathway all apparently contribute to the migraine event. The cyclical and lifetime uctuations in female sex hormone concentrations might explain why migraine is so much more prevalent in women and why migraine activity may vary so substan-tially throughout life. Migraine has traditionally been believed to be a genetic disorder due to the common occurrence among family mem-bers. It has been reported that at least 50% of migraine patients have a rst-degree relative who also experiences this disorder.16–21Typical migraine is believed to be polygenic, but several monogenic forms of migraine have been identied. Familial hemiplegic migraine (FHM) is a monogenic form with aura present-ing as hemiparesis. To date, mutations in three different ion channels or ion pumps have been found as potential causes of FHM.5 In recent 77Migrainegenome-wide association studies, common migraine risk appears to be associated with 38 genomic loci.22 It appears that the inu-ence on migraine is a result of the interaction of the group as a whole along with lifestyle and environmental factors, as opposed to the effect of each locus individually. While there does not appear to be much in the way of overlap of mechanisms between the mono-genic or polygenic migraine subtypes, com-mon pathways involving the development and function of neurons and synapses, vascular system development, and glutamate trans-port mechanisms appear to be signicant for both.23 These ndings could potentially point to a more signicant role of vascular dysfunc-tion in migraine pathophysiology than previ-ously thought. This role is further supported by the frequent occurrence of disorders that are commonly comorbid with migraine such as stroke and cardiovascular disease.24,25 The mi-graine aura correlates with the cerebral cortical event of cortical spreading depression (CSD), a slowly propagating wave of depolarization, hyperpolarization, and vascular changes. In animal models, CSD has been shown to lead to trigeminovascular activation, resulting in the release of neuropeptides, neurogenic in-ammation, increased vascular permeability, and dilation of blood vessels.26 Whether these vascular changes are necessary for the full expression of migraine symptoms including headache is still debated.27,28 Recent evidence seems to suggest that vascular events do not appear to be a necessary component of the migraine event, nor are they sufcient to induce migraine on their own.29 Borsook and Burstein30 suggest that activation in the nuclei of the dorsolateral pons may be partly respon-sible for multiple processes including facial pain and altered pain modulation. Recent func-tional magnetic resonance imaging (MRI) stud-ies have shown the hypothalamus to not only be an important modulator of the premonitory aspect of the migraine event but also the mi-graine attack itself.31 More specically, the pos-terior portion of the hypothalamus appears to be important for the headache phase, whereas the anterior region seems to play a critical role in migraine chronication. However, given the available evidence, identifying a specic area of the brain as the migraine generator is not presently feasible.32 Multiple neurotransmit-ters and modulators, including serotonin, calcitonin gene-related peptide (CGRP), nitric oxide, dopamine, and glutamate, have been implicated in migraine pathophysiologic mech-anisms.33,34 Central sensitization producing al-lodynia and hyperalgesia is thought to be an important clinical manifestation of migraine.35ManagementIn addition to pharmacotherapy, migraine management modalities should include edu-cational interventions, lifestyle and behavioral modications, and trigger-avoidance strate-gies. Pharmacologic interventions may be abortive/symptomatic or prophylactic. Patients who experience frequent severe migraine at-tacks often require both approaches. The de-cision of the most appropriate management approach should be based on type of presen-tation of the migraines (episodic or chronic), the level of impairment that they cause, previ-ous management history and response, and patient preferences. Consideration should also be given to any comorbid conditions such as depression or hypertension. Abortive medica-tions only may be used for individuals with fewer than 4 headache days per month and no impairment or those with no more than 1 headache day per month regardless of impair-ment.8 Individuals with more frequent attacks, such as those with 6 or more migraine days per month with normal functioning, 4 or more migraine days with some impairment, or 3 or more migraine days with severe impairment, should be considered for management with prophylactic medications.8 If there is a co-morbid illness, a prophylactic agent that can treat both conditions should be used when 78Primary Headache Disorders5Box 5-1 Common medications used to abort migraine attacks38Selective • Selective serotonin receptor agonists (triptans) • Dihydroergotamine Nonselective• Acetaminophen, aspirin plus caffeine • Aspirin• Butorphanol• Ibuprofen• Naproxen sodium• Diclofenac potassiumBox 5-2 Medications used for the prevention of migraine attacks41,42Established as effective• Divalproex/sodium valproate*• Metoprolol• Onabotulinim toxin A†• Petasites (butterbur)• Propranolol*• Timolol*• Topiramate*Probably effective• Amitriptyline• Atenolol • Fenoprofen• Feverfew• Histamine• Ibuprofen• Ketoprofen• Magnesium• Nadolol• Naproxen/naproxen sodium• Riboflavin• VenlafaxinePossibly effective• Candesartan• Carbamazepine• Clonidine• Coenzyme Q-10• Cyproheptadine• Guanfacine• Flurbiprofen• Lisinopril• Nebivolol• Mefenamic acid• Pindolol*FDA-approved for episodic migraine.†FDA-approved for chronic migraine.possible, and agents that might aggravate a comorbid illness should be avoided. Nonphar-macologic methods such as biofeedback, re-laxation techniques, acupuncture, and other behavioral interventions can be used as ad-junctive therapy.36Medications typically used for acute mi-graine management include selective sero-tonin receptor (5-HT1B/D) agonists, analgesics, nonsteroidal anti-inammatory drugs (NSAIDs), dopamine-antagonistic antiemetics, ergot al-kaloids, and corticosteroids. Opioid analgesics play a limited role in management, partly due to the enhanced risks of medication-overuse headache and opioid-induced hyperalgesia.37 Pharmacologic agents with evidence-based support of statistical and clinical benet, ac-cording to the American Academy of Neurol-ogy, are listed in Box 5-1 and should be given as rst-line management.38 Prophylactic medi-cations include a broad range of agents.39,40 The recently published US Headache Consortium Guidelines recommended evidence-based pharmacologic management for migraine pre-vention in adults based on a structured review process of published studies from June 1999 to May 2009 (Box 5-2).41 Anticonvulsants (eg, di-valproex, topiramate) and β-blockers (eg, meto-prolol, propranolol, timolol) have the strongest evidence of benet for migraine prevention. These medications are started at low doses and gradually titrated to the desired effect to 79Tension-Type Headacheminimize side effects and arrive at the minimal dose necessary for therapeutic effect. In more refractory cases, polypharmacy may be neces-sary. While a number of NSAIDs are included in the practice guidelines as effective for the pre-vention of episodic migraine, caution must be exercised about daily use because analgesic overuse can induce chronic daily headache.42 Botulinum toxin type A has been approved by the US Food and Drug Administration (FDA) for the preventive management of chronic mi-graine, in which headaches occur at least 15 days per month and at least 4 hours per day.43 For the management of menstrual-related mi-graine, perimenstrual use of frovatriptan has been recommended.41 Naratriptan and zolmi-triptan have been classied as “probably effec-tive” for this type of migraine presentation.42 Emerging abortive and prophylactic manage-ments include selective 5-HT1F agonists, CGRP receptor antagonists, nitric oxide synthase in-hibitors, and glutamate receptor antagonists.44In many cases, patients are able to identify factors that seem to precipitate the onset of a migraine attack. Strategies to identify and cope with or avoid these triggers often proves help-ful for these individuals.45 Some common trig-gers are environmental factors, including light, noise, allergens, and barometric changes; behavioral factors, such as emotional stress, missing meals, or getting too much or too little sleep; and food/beverage items, such as caf-feine, aspartame, monosodium glutamate, ni-trites, and nitrates.46Tension-Type Headache (ICHD 2.x.x; ICD-10 G44.2xx)Clinical presentation and diagnosisTTH is described as a dull ache or a nonpul-sating pain of mild to moderate intensity often manifesting as tightness, pressure, or sore-ness in a bandlike distribution as if the patient were wearing a hat. The pain location is not specic, though it is often bilateral and may extend into the neck. Temporalis and masse-ter muscle involvement may be present, and mastication may be affected in some patients. TTH is not accompanied by nausea or vomit-ing, nor is it aggravated by routine physical ac-tivity, but it may be associated with sensitivity to either light or noise.2 The headaches may last from 30 minutes to 7 days. TTHs are clas-sied as infrequent episodic (ICHD 2.1, ICD-10 G44.2) if they occur on fewer than 1 day per month (fewer than 12 days per year) and frequent episodic (ICHD 2.2, ICD-10 G44.2) if they occur on more than 1 day per month but fewer than 15 days per month for at least 3 months. Chronic TTH (ICHD 2.3, ICD-10 G44.2) evolves from episodic TTH and is diag-nosed when headaches occur daily or more often than 15 days per month for at least 3 months. The classication categories are typi-cally subdivided and coded according to the presence or absence of pericranial tenderness as assessed by manual palpation. In contrast, if a new-onset daily or unremitting headache with tension-type characteristics develops, the headache is classied as new daily persistent headache (ICHD 4.10, ICD-10 G44.52). Sensi-tivity to light and/or noise and mild nausea may be present with these types of headaches. There may be difculty distinguishing between chronic migraine and chronic TTH, and these disorders may be present simultaneously.EpidemiologyTTH is the most common of all primary head-aches.47 In a cross-sectional population study of 740 adult subjects, 74% had experienced TTH within the previous year, while 31% of the same population had experienced TTH for more than 14 days during the previous year.48 In another report, the 1-year prevalence rate for TTH was 63% in men and 86% in women.49 The onset of TTH is usually between 25 and 30 years of age. In both men and women, the prevalence will peak between the ages of 30 80Primary Headache Disorders5and 39 years and then decline with increasing age.49–51 PathogenesisFor many years, it was thought that TTH was directly related to muscle tension and was therefore referred to as a muscle contraction or a muscle tension headache. Muscle ten-derness may be present in some individuals; however, increased levels of electromyographic activity are not often associated with TTH.52,53 Electromyography has revealed an increased activity in response to emotional stressors in patients as compared with controls.54,55 It has been suggested that this increase in electromyographic-detected activity may not be the cause of the pain but rather a response to it. Ultimately, it has been determined that the nd-ing of a slight increase in muscle activity noted in patients on their headache-free days would seem to contradict the hypothesis that TTH is directly related to an increase in muscle ten-sion.56 Emotional stress, anxiety, and depres-sion appear to play a signicant role in TTH.57–60 A very controversial boundary exists be-tween migraine and TTH. Some experts regard these disorders as distinct entities, while oth-ers see them at opposite ends of a continuum, varying in severity and features but sharing a common pathogenesis.61,62 Voxel-weighted morphometric MRI scans of patients with chronic TTH have demonstrated reduced gray matter density within structures previously im-plicated in pain processing (eg, pons and cin-gulate, insular, and orbitofrontal cortices) that correlates with disease duration in years.63 Such changes may in fact be the consequence of central sensitization.64 Several studies have provided evidence for spinal and supraspinal sensitization in TTH patients.65–67 Others have suggested impairment of pain-inhibitory and modulatory mechanisms in TTH subjects.68–70 To date, the specic pathophysiologic mechanisms involved in TTH are yet to be fully described. ManagementMost individuals with TTH tend to self- medicate with over-the-counter analgesics. In a community-based telephone survey of frequent headache sufferers, the majority re-ported using acetaminophen (56%) and aspirin (15%).71 Only 1% reported the use of prescrip-tion medications for their headaches. Combi-nation analgesic agents with caffeine have been shown to be effective in clinical trials.72,73 Practice guidelines based on very limited pub-lished controlled data recommend NSAIDs and acetaminophen for acute care, while drugs of choice for the prevention of TTH are amitrip-tyline (rst choice); mirtazapine or venlafaxine (second choice); and clomipramine, maproti-line, and mianserin (third choice).74 For acute as well as preventive use, the potential side effects associated with these drugs may limit their tolerability. No drugs are FDA-approved for preventive TTH management. Management may also include behavioral methods such as relaxation training, biofeedback techniques, and physical therapy.75 Of these nonpharma-cologic therapies, the most evidenced-based approach is the combination of biofeedback with cognitive behavioral counseling.76 Trigeminal Autonomic CephalalgiasCluster Headache (ICHD 3.1.x; ICD-10 G44.01x– G44.02x)Clinical presentation and diagnosisCluster headache is a primary headache dis-order that is classied along with similar pain-ful conditions known as TACs.2 According to the ICHD, “cluster headache is described as a severe, unilateral headache lasting 15 to 180 minutes.”2 The headache is accompanied by 81Cluster Headacheautonomic features, restlessness or agitation, or both. Autonomic features include ipsilateral conjunctival injection, lacrimation, nasal con-gestion, rhinorrhea, forehead and facial sweat-ing, forehead and facial ushing, sensation of fullness in the ear, miosis, ptosis, and/or eyelid edema.2 Cluster headache is considered to be one of the most severe pain conditions that humans can experience. The pain presentation is usually periorbital, supraorbital, temporal, or in any combination of these areas. The attacks may occur anywhere from once every other day up to eight times per day, often occurring during sleep. Bilateral pain presentation was found to occur in 3% of subjects. Side shifts occur in approximately 8% of subjects during an individual attack and in approximately 31% of patients between individual headaches or headache cycles.77 The “cluster period,” in which the attacks occur daily or near daily, tends to last from 2 weeks to a few months. Cluster periods will often recur on an annual or biannual basis during the same seasons. Despite the unique features of cluster head-ache, only 21% of patients receive the correct diagnosis at the time of their initial consulta-tion with a clinician.77 The diagnostic delay for cluster headache has been found to average from 3 to 5 years.77,78 Factors responsible for the diagnostic delay may include reports of ac-companying photophobia, nausea, vomiting, and alternating sides of the attack, all of which are also characteristic of migraine headache.78 However, photophobia and phonophobia asso-ciated with cluster headache attacks tend to be unilateral, ipsilateral to the side of the head-ache as opposed to the bilateral presentation seen in migraine. Because of the location, se-verity, and abrupt onset of pain, cluster head-ache is often mistaken for trigeminal neuralgia, sinus disorders, or dental pain.79 The latter is the reason why up to 45% of cluster headache patients are rst evaluated for their condition by a dentist.80 In one recent survey, 23% of cluster headache patients reported that they received an initial diagnosis of a tooth- or jaw-related issue.81 In a retrospective study of 14 patients presenting to a dentist with clus-ter headache symptoms, six patients were prescribed oral appliances, four had tooth ex-tractions, three had occlusal equilibration, and two underwent endodontic procedures with unfavorable outcomes.82 Cluster headache may be episodic with more than 1 month of headache-free days per year (ICHD 3.1.1, ICD-10 G44.01x) or chronic and occur for more than 1 year without remission or with remissions lasting less than 1 month (ICHD 3.1.2 ICD-10 G44.02x). Between 80% and 90% of cluster headache patients have episodic cluster head-aches, while 13% of them will progress to chronic.83 Approximately one-third of chronic cluster headache patients will spontaneously remit to an episodic form.EpidemiologyCluster headache has traditionally been thought to primarily affect men; however, more recent studies have determined the sex ratio (male divided by female) to range from 1.3 to 14.0.84 Fischera et al84 found the prevalence of cluster headache in all adults, both men and women, to be 0.12%. A population-based, 1-year prevalence study in Germany found a similar prevalence.85 The average age of onset of attacks is between 20 and 40 years old, but cluster headache has been reported in all age groups.86 Approximately 73% of cluster head-ache patients are smokers or former smokers, and half of patients note that alcohol can trig-ger an attack during a cluster period. Over half of cluster headache patients have recurrent thoughts of suicide.77PathogenesisThe obvious circadian and circannual period-icity of cluster headache presentation would suggest that the hypothalamus plays a signi-cant role in the pathophysiology of this head-ache disorder.87 In fact, functional MRI and 82Primary Headache Disorders5Box 5-3 Common medications used to treat cluster headache95,96Abortive • 100% oxygen inhalation • Selective serotonin receptor agonists (sumatriptan, zolmatriptan) • Cocaine/lidocaine• OctreotideProphylactic • Suboccipital steroid injections• Melatonin• Verapamil• Lithium voxel-weighted morphometric MRI studies have identied a region of the posterior hypo-thalamus that is metabolically activated during attacks.88,89 This region is ipsilateral to the clus-ter attack pain presentation.88,89 Reports have described a close relationship between cluster headaches and sleep-disordered breathing.90,91 Kudrow92 postulated that altered hypothalamic inuence on the brainstem centers controlling respiration and vasomotor function diminishes carotid chemoreceptor activity. This may ex-plain the positive response of cluster head-aches to oxygen as well as the relationship between cluster headaches and altitude and sleep-disordered breathing.93ManagementThe management of cluster headache is es-sentially pharmacologic, with the goal of short-ening and alleviating the cluster headache at-tacks and shortening the cycle of attacks.94 Similar to migraine therapy, management of cluster headache can be divided into symp-tomatic/abortive and prophylactic regimens (Box 5-3). Because of the short duration and severe pain experienced in cluster headaches, abortive agents must have a rapid onset to be useful. Recently, the Guidelines Committee of the American Headache Society published evidence-based recommendations for the management of cluster headache.95 The abor-tive agents demonstrating the best efcacy were found to be sumatriptan subcutaneous, zolmitriptan nasal spray, and high-ow oxygen. Sumatriptan and zolmitriptan are serotonin re-ceptor agonists that are FDA-approved for the abortive management of migraine headache. Sumatriptan is FDA-approved in its subcuta-neous injection formulation for the abortive management of cluster headache. High-ow oxygen is delivered via non-rebreathing mask at rates from 12 to 15 L per minute for approxi-mately 15 to 20 minutes. Other agents con-sidered “possibly effective” are sumatriptan nasal spray, oral zolmitriptan, cocaine/lidocaine nasal spray, and subcutaneous octreotide, a hormone-modulating agent.Prophylactic therapies should ideally be initiated as soon as the cluster period begins. However, there are currently no agents cleared by the FDA for this indication. The only therapy to be considered as “effective” is suboccipi-tal steroid injections. Civamide nasal spray, a synthetic capsaicin isomer that is supposedly less irritating and more effective than capsaicin but is not readily available in the United States, is considered as “probably effective.” All other agents are considered “possibly effective” or “ineffective,” or there is a lack of evidence to make any recommendations as to the efcacy of the agent.95 Recent evidence seems to sug-gest that botulinum toxin may prove benecial in some cases of cluster headache.97 There are also limited data supporting the effectiveness of melatonin as a prophylactic agent.98,99 Typi-cally, prophylactic therapy is continued for 1 month after the last cluster attack and then dis-continued until the next cluster period begins.Surgical interventions are considered for severe, intractable cases of cluster headache when pharmacologic therapy has failed to provide relief. Deep brain stimulation, occipi-tal nerve stimulation, and γ knife radiation of the hypothalamus in patients with intractable 83SUNCT and SUNAchronic cluster headaches have yielded prom-ising results.100–105 External and implantable stimulators are currently being investigated for prophylactic and abortive therapy. In early trials, a novel handheld external vagus nerve stimulator showed promising results as a preventive and abortive therapy.106 Likewise, early trials of an implantable sphenopalatine ganglion stimulator have been promising for abortive therapy.107,108Paroxysmal Hemicrania (ICHD 3.2.x; ICD-10 G44.03x–G44.04x)Paroxysmal hemicrania is a headache with clinical characteristics similar to those of clus-ter headache, but the attacks are shorter in duration (2 to 30 minutes), more frequent, and equally prevalent in men and women.2,109 The attacks are likewise strictly unilateral, pre-dominantly presenting in the periorbital region. Paroxysmal hemicrania is accompanied by one or more of the following unilateral signs or symptoms: lacrimation, conjunctival injection, rhinorrhea, nasal congestion, forehead and facial sweating and ushing, miosis, ptosis, and eyelid edema. Unlike cluster headache, restlessness and agitation are not part of the diagnostic criteria, and an additional diagnos-tic criterion is that the headache must be pre-vented “absolutely” by therapeutic dosages of indomethacin. Attacks occurring in periods lasting 7 days to 1 year separated by pain-free periods lasting 1 month or more are classied as episodic (ICHD 3.2.1, ICD-10 G44.03), and attacks occurring for more than 1 year without remission or with remissions lasting less than 1 month are classied as chronic (ICHD 3.2.2, ICD-10 G44.04).Very little is known about the pathophysio-logic mechanisms behind paroxysmal hemicra-nias. The similarity in clinical presentations and therapeutic outcomes has led to the sugges-tion that all TACs may share a common patho-physiology.110 However, that does not explain why some TACs are absolutely responsive to indomethacin and others are not, nor why some TACs seem to be associated with cir-cadian rhythms and others do not. A positron emission tomography (PET) imaging study in patients with paroxysmal hemicrania revealed activation of the contralateral posterior hypo-thalamus, ventral midbrain, red nucleus, and substantia nigra during the attack.111 It is not yet known whether these structures are the actual generators of TACs or simply activate during an attack in response to an initiating fac-tor located elsewhere in the brain. The ICHD diagnostic criteria require 100% responsive-ness to a therapeutic dose of indomethacin, but a few cases of paroxysmal hemicrania have been reported as indomethacin-resistant.2,112,113 In a review of 74 paroxysmal hemicrania pa-tients, Boes and Dodick114 found that as many as 25% did not respond to indomethacin. The response of paroxysmal hemicrania to sumat-riptan has also been conicting with some reports citing a good response while others found only a partial response or no response at all.115– 118 Recent work by Prakash and Patell107 found topiramate to be successful in some pa-tients with paroxysmal hemicrania and other indomethacin-responsive headache disorders. A previous study by Cohen and Goadsby119 re-vealed similar outcomes. SUNCT and SUNA (ICHD 3.3.x; ICD-10 G44.05x)Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tear-ing (SUNCT) (ICHD 3.3.1, ICD-10 G44.05x) is a primary headache disorder rst described by Sjaastad et al.120,121 This disorder has clini-cal diagnostic features that bear strong re-semblances to those of cluster headache and paroxysmal hemicranias.122 SUNCT attacks are very brief (5 seconds to 4 minutes) and present with moderate to severe pain. The pain is uni-lateral and often orbital, supraorbital, or tempo- 84Primary Headache Disorders5ral, though it may be experienced anywhere in the head. The pain is commonly described as burning, stabbing, or electric in character with 3 to 200 attacks occurring per day. Ipsilateral conjunctival injection and lacrimation must ac-company the pain. When conjunctival injection or tearing (but not both) is present, or when other autonomic symptoms such as those listed for paroxysmal hemicranias are pres-ent, the condition is known as short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) (ICHD 3.3.2, ICD-10 G44.05x). SUNA is reported to occur approximately ve times less frequently than SUNCT.122 The differential diagnosis for SUNCT/SUNA prominently includes trigeminal neuralgia. Compared with trigeminal neuralgia, SUNCT attacks are more likely to be located in the ophthalmic division of the trigeminal nerve (V1). While both trigeminal neuralgia and SUNCT/SUNA may be triggered by cuta-neous stimuli, SUNCT/SUNA is less likely to do so and is also less likely to demonstrate a refractory period after attacks that may be so triggered.123 Some reports based on open-label trials indicate that carbamazepine, lamotrigine, gabapentin, topiramate, and intravenous lido-caine may be effective in some patients with SUNCT/SUNA, but there are no available data from large-scale controlled trials.124–128 Unlike paroxysmal hemicrania and hemicrania conti-nua, SUNCT/SUNA is not responsive to indo-methacin.123 It is also unresponsive to high-ow oxygen and subcutaneous sumatriptan, which are effective for cluster headaches.123Hemicrania Continua (ICHD 3.4; ICD-10 G44.51)Hemicrania continua, rst described by Medina and Diamond,129 is a persistent one-sided head-ache that uctuates in intensity but never remits. Ipsilateral autonomic features and/or restlessness/agitation accompany this head-ache during periods of more intense pain, as they do in cluster headache. An absolute response to therapeutic dosages of indo-methacin is necessary for a denitive diagno-sis.2 Hemicrania continua is considered a rare disorder but is most likely underdiagnosed.130 Nausea, photophobia, and phonophobia may be present in approximately 50% of patients, similar to migraine.131 As with cluster head-ache, approximately two-thirds of patients with hemicrania continua will display restless-ness or agitation during their attacks.131 Man-agement typically consists of indomethacin, but gastrointestinal disturbances may make this agent unacceptable. Cardiovascular issues may also develop with long-term use of indo-methacin.132 Alternative therapies may include the use of topiramate, greater occipital nerve blocks, and in select cases, greater occipital nerve stimulation.131,133,134ConclusionCluster headache, paroxysmal hemicranias, SUNCT/SUNA, and hemicrania continua are disorders considered to be TACs (Table 5-1). All of these disorders, except hemicra-nia continua, are characterized by relatively short-lasting, moderate to severe headaches with autonomic features, and all have also been associated with hypothalamic changes on imaging studies.123,124,135,136 Obtaining brain imaging with a focus on the pituitary region as well as laboratory pituitary function testing is recommended because pathologies in this area have occasionally been associated with TACs.137 85ReferencesReferences1. Tepper SJ, Dahlöf CG, Dowson A, et al. 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