Adams and Victor's

PRINCIPLES OF NEUROLOGY- 10th edition

2.exam HEADACHE
Series Editors
MICHAEL J. AMINOFF, FRANC¸ OIS BOLLER, AND
DICK F. SWAAB
Volume Editors
GIUSEPPE NAPPI AND MICHAEL A. MOSKOWITZ
VOLUME 97
3rd Series
EDINBURGH LONDON NEW YORK OXFORD
PHILADELPHIA
ST LOUIS

Bradley’s Neurology in
Clinical Practice
VOLUME I
SEVENTH EDITION

Exam ichd -3 beta –(cephalagia-2018)

19th Harrison’s
Principlesof
Internal
Medicine
Jefferson
Headache Manual
William B. Young, MD, FAHS, FAAN
Associate Professor of Neurology
Director, Inpatient Program
Stephen D. Silberstein, MD, FACP
Professor of Neurology
Director, Jefferson Headache Center
Stephanie J. Nahas, MD
Assistant Professor of Neurology
Michael J. Marmura, MD
Assistant Professor of Neurology

Cambridge Pocket Clinicians

Cambridge Pocket Clinicians headache
Todd J. Schwedt MD
Department of Neurology, Washington University School of
Medicine, St Louis, MO, USA
Jonathan P. Gladstone MD FRCPC
Division of Neurology, Gladstone Headache Clinic,
Sunnybrook
Health Sciences Centre, The Hospital for Sick Children,
Toronto
Rehabilitation Institute and Cleveland Clinic Canada,
Toronto,
Ontario, Canada
R. Allan Purdy MD FRCPC
Division of Neurology, Dalhousie University, Queen Elizabeth
Health Sciences Centre, Halifax, Nova Scotia, Canada
David W. Dodick MD
Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA
(page-168LU) Of all the painful states that afflict
humans, headache
is undoubtedly the most frequent and rivals
backache
as the most common reason for seeking medical
help.

Semantically, the term headache encompasses

all aches
and pains located in the head, but in practice, its
application
is restricted to discomfort in the region of the
cranial
vault. Facial, lingual, and pharyngeal pains are
put aside
as something different and are discussed
separately in the
latter part of this chapter and in Chap. 47, on the
cranial
nerves.

(Page-169RM)
Pa i n -Sensitive Cra n i a l Structu res
Our understanding of headache has been
augmented by
observations made during operations on the
brain (Ray
and Wolff). These observations have informed us
that
only certain cranial structures are sensitive to
noxious
stimuli: (1) skin, subcutaneous tissue, muscles,
extracranial
arteries, and external periosteum of the skull; (2)
the
delicate structures of the eye, ear, nasal cavities,
and paranasal
sinuses; (3) intracranial venous sinuses and their
large tributaries because they are intradural; (4)
parts of
the dura at the base of the brain and the arteries
within
the dura, particularly the proximal parts of the
anterior
and middle cerebral arteries and the intracranial
segment
of the internal carotid artery; (5) the middle
meningeal
and superficial temporal arteries; and (6) the first
three
cervical nerves and cranial nerves as they pass
through
the dura. Interestingly; pain is practically the only
sensation
produced by stimulation of these structures; the
pain
arises in the walls of blood vessels containing
pain fibers
(the nature of vascular pain is discussed further
on) .
Much of the pia-arachnoid, the parenchyma of
the brain,
and the ependyma and choroid plexuses lack
sensitivity.

(Page-170LM) To summarize, pain from

supratentorial structures
is referred to the anterior two-thirds of the head,
i.e., to
the territory of sensory supply of the first and
second
divisions of the trigeminal nerve; pain from
infratentorial
structures is referred to the vertex and back of
the head
and neck predominantly by the second cervical
roots.
Trigeminal and cervical sensory inputs converge
on the
second order neurons at the C2 level, permitting
pain
from the neck and occipital regions to be referred
to the
forehead, and vice versa. The seventh, ninth, and
tenth
cranial nerves refer pain to the nasoorbital
region, ear,
and throat. There may be local tenderness of the
scalp at
the site of the referred pain. Dental or
temporomandibular
joint pain impulses are carried by the second and
third
divisions of the trigeminal nerve. With the
exception of
the cervical portion of the internal carotid artery,
from
which pain is referred to the eyebrow and
supraorbital
region, and the upper cervical spine, from which
pain
may be referred to the occiput, pain because of
disease in
extracranial parts of the body is not referred to
the head.

GENERAL CONSIDERATIONS:
In the introductory chapter on pain, reference
was made
to the necessity, in dealing with any painful state,
of
determining its quality, severity, location,
duration, and
time course as well as the conditions that
produce, exacerbate,
or relieve it. In the case of headache, a detailed
history following these lines will determine the
diagnosis
more often than will the physical examination or
imaging.

(Page-168RU) Auscultation of the

skull may disclose a bruit (with large
arteriovenous
malformations), and palpation may disclose the
tender,
hardened or elevated arteries of temporal
arteritis, sensitive
areas overlying a cranial metastasis, an inflamed
paranasal sinus, or a tender occipital nerve,
examination
of neck flexion may reveal meningitis; however,
apart
from such special instances, examination of the
head
itself, although necessary, seldom discloses the
diagnosis.
As to the quality of cephalic pain, the patient's
description may or may not be helpful. When
asked to
compare the pain to some other sensory
experience, the
patient may allude to tightness, aching, pressure,
bursting,
sharpness, or stabbing. The most important
information
to be obtained is whether the headache is
pulsatile,
but one must keep in mind that patients
sometimes use
the word throbbing to refer to a waxing and
waning of the
headache without any relation to the pulse, or
simply use
the term to transmit the severity of pain,
whereas authentic
pulsatile throbbing, is characteristic of migraine.
Similarly, statements about the intensity of the
pain
must be accepted with caution, as they reflect as
much
the patient's temperament, attitudes and
customary ways
of experiencing and reacting to pain as its true
severity.
A better index of severity is the degree to which
the pain
has incapacitated the patient, especially if he is
not prone
to illness.

(Page-168RL)
Data regarding the location of a headache are
apt to
be more informative. Migraine headache is
unilateral in
two-thirds of attacks and is commonly associated
with
nausea, vomiting, and sensitivity to light, sound,
and
smells. Inflammation of an extracranial artery
causes pain
localized to the site of the vessel. Lesions of the
paranasal
sinuses, teeth, eyes, and upper cervical
vertebrae induce
a less sharply localized pain but still one that is
referred
to a certain region, usually the forehead or
maxilla or
around the eyes. Intracranial lesions in the
posterior

fossa generally cause pain in the occipitonuchal

region

(Page-169LU) and usually are homolateral if the

lesion is one-sided.
Supratentorial lesions induce frontotemporal
pain, or
approximate the site of the lesion. Localization,
however,
may also be deceiving. Pain in the frontal regions
may
be caused by such diverse lesions and
mechanisms as
glaucoma, sinusitis, thrombosis of the vertebral
or basilar
artery; pressure on the tentorium, and increased
intracranial
pressure. Similarly, ear pain may signify disease
of the ear itself, but as often, it is referred from
other
regions, such as the throat, cervical muscles,
spine, or
structures in the posterior fossa. Periorbital and
supraorbital
pain, while usually indicative of local disease,
may
reflect dissection of the cervical portion of the
internal
carotid artery. Headaches localized to the vertex
or biparietal
regions are infrequent and should raise the
suspicion
of sphenoid or ethmoid sinus disease or
thrombosis
of the superior sagittal venous sinus.

The mode of onset, the variation of the pain over

time,
and duration of the headache, with respect both
to a
single attack and to the profile of the headache
over a
period of years, are also useful data. At one
extreme, the
headache of subarachnoid hemorrhage (caused
by a ruptured
aneurysm) occurs as an abrupt attack that
attains
its maximal severity in a matter of seconds or
minutes,
or, in the case of meningitis, it may come on
more gradually,
over several hours or days. Simulating the rapid
onset, severe headache of subarachnoid
hemorrhage are
a group of "thunderclap headaches" of diverse
causes but
principally cerebral venous thrombosis and
vasospasm
syndromes. Brief sharp pain, lasting a few
seconds, in the
eyeball (ophthalmodynia) or cranium ("ice-pick"
pain)
and "ice-cream headache" caused by pharyngeal
cooling
is more common in migraineurs, with or without
the
characteristic headache, but otherwise cannot be
interpreted
and is significant only by reason of its benignity.
(Page-169LM) Migraine of the classic type usually
has its onset in the
early morning hours or in the daytime, reaches
its peak of
severity typically over several to 30 min, and
lasts, unless
treated, for 4 to 24 h, occasionally for as long as
72 h
or more. Often, it is terminated by sleep. A
migrainous
patient having several attacks per week usually
proves to
have a combination of migraine and tension
headaches,
an analgesic "rebound headache," or, rarely,
some unexpected
intracranial lesion. By contrast, the occurrence of
unbearably severe unilateral orbitotemporal pain
coming
on within an hour or two after falling asleep or at
predictable times during the day and recurring
nightly
or daily for a period of several weeks to months
is typical
of cluster headache; usually an individual attack
of
"cluster" dissipates in 30 to 45 min but some
blend into
more prolonged migraine. The headache of
intracranial
tumor may appear at any time of the day or
night; it will
interrupt sleep, vary in intensity, and last a few
minutes to
hours as the tumor raises intracranial pressure.
With posterior
fossa masses, the headache tends to be worse in
the
morning, on awakening. Tension headaches,
described
further on, may persist with varying intensity for
weeks
to months or even longer; when such headaches
are protracted,
there is usually an associated depressive illness.
In general, headaches that have recurred
regularly for
many years prove to be migraine or tension in
type.

(page-169RU) The more or less constant

relationship of headache to
certain biologic events and also to certain
precipitating or
aggravating (or relieving) factors can be of great
significance
in diagnosis. Headaches that occur regularly in
the
premenstrual period are usually generalized and
mild in
degree, but attacks of migraine may also occur
at this time
(catamenial migraine). Headaches that have their
origin
in cervical spine disease are most typically
intense after a
period of inactivity, such as a night's sleep, and
the first
movements of the neck are stiff and painful.
Headache, or
more often face ache, from infection of the nasal
sinuses
may appear, with clock-like regularity, upon
awakening
or in midmorning and is characteristically
worsened by
stooping and changes in atmospheric pressure;
there is
associated midfrontal or maxillary tenderness.
On the
other hand, the regular recurrence of migraine
headache
is often misdiagnosed as chronic sinusitis.
Eyestrain
headaches, of course, follow prolonged use of the
eyes,
as after long-sustained periods of reading, or
exposure
to the glare of video displays, but the pain is
transient.
In certain individuals, alcohol, intense exercise
(such as
weight lifting), stooping, straining, coughing, and
sexual
intercourse are known to initiate a special type of
bursting
headache, lasting a few seconds to minutes. If a
headache is made worse by sudden movement
or by
coughing or straining, an intracranial source is
tentatively
suggested.

Pain that is noticed when the scalp is stroked

in combing or fixing the hair (allodynia) is
common in
migraine but could be a symptom of
inflammation of the
temporal arteries (temporal arteritis).

Types of Headache

(page-4)The Primary Headaches

1. Migraine 18
2. Tension-type headache 35
3. Trigeminal autonomic cephalalgias 41
4. Other primary headache disorders 48

The Secondary Headaches

5. Headache attributed to trauma or injury to the
head and/or neck 64
6. Headache attributed to cranial and/or cervical
vascular disorder 73
7. Headache attributed to non-vascular
intracranial disorder 99
8. Headache attributed to a substance or its
withdrawal 115
9. Headache attributed to infection 129
10. Headache attributed to disorder of
homoeostasis 138
11. Headache or facial pain attributed to disorder
of the cranium, neck, eyes, ears, nose, sinuses,
teeth, mouth or other facial or cervical structure
149
12. Headache attributed to psychiatric disorder
160

Painful Cranial Neuropathies, Other Facial Pain

and Other Headaches
13. Painful lesions of the cranial nerves and other
facial pain 165
14. Other headache disorders

Epidemiology of headache

(Page-5RM) Prevalences related to sex, age,

region,
and socioeconomic status
In adults, female sex is related to a higher
prevalence
of headache in general (Figure 1.1) and TTH, but
this tendency is much more marked for migraine
(Figure 1.2).
Among children, the prevalences of headache
and migraine are similar in the two sexes
(Figures 1.1
and 1.2).
(Page-6LU)

Averaged data from three European studies

showed that the prevalence in both men and
women
dropped markedly after the age of 60 (Figure 1.1)
(Stovner
et al., 2006). The effect of age is much more
dramatic
among women with migraine, in whomthere is a
dramatic
increase in prevalence after puberty and a
similarly
dramatic decrease after menopause (Figure 1.2).

(Page-6RM) Epidemiology of migraine

Few studies have been published so far in the
medical
literature on migraine incidence. Of these, two
are retrospective
studies (Stewart et al., 1991; Rasmussen,
1995) and therefore carry all the limitations
inherent
in recall of age at migraine onset, such as
telescoping,
failing to report real symptoms, and incorrectly
reporting
symptoms not actually experienced. These
retrospective
studies and another study (Stang et al., 1992)
conducted through the linked medical record
system
show incidence rates that are not much different
(in
the under-30 age group, about 1.5–2 per 1000
personyears
for men, and about 3–6 per 1000 person-years
for women). The only two longitudinal studies
point
to higher rates. The study conducted on people
of the
same age group by Breslau et al. (1996) shows a
rate
of 6 per 1000 person-years for men, and 24 per
1000
person-years for women

(Page-10LM)In Asia, if we do not consider the two

values at the
extremes of the range, i.e., 0.5% reported in
China by
Kong et al. in 2001 and 11% found in India by
Shivpuri
et al. in 2003, the rates are fairly homogeneous
and
vary between 3.8% and 6.8% (Table 1.2).

Epidemiology of tension-type headache

Compared to migraine, relatively few studies
have
been performed on TTH; the majority of these
studies
are from Europe (9/17), but some are also from
the
Americas, and East and South Asia (Table 1.4).
There
is a large variation in prevalence, from 11.5%
lifetime
prevalence in Singapore to an almost eight times
higher
86.5% 1-year prevalence in Denmark.

(Page-1713RM)The prevalence of tension-type

headache ranges in the
general population from 30% to 78% (Headache
Classification
Committee, 2013). In the United States, an
epidemiological
study showed a higher prevalence in Caucasian
women
and in patients aged 30–39 (Schwartz et al.,
1998).
Tension-type headaches can begin at any age,
are generally
bilateral, and are often described as a sense of
pressure or
wearing a tight band around the head.

Epidemiology of cluster headache

Even if CH has very distinctive clinical features,
there
are very few data available on CH epidemiology,
in
particular in the general population. The reasons
that
may explain why epidemiological studies on CH
are
so few probably have to do with its low
frequency.

(Page-1708 LL)Compared with tension headache

and migraine, the syndrome
of cluster headaches is considerably less
common. In many
headache clinic populations, migraine is 10 to 50
times more
common than cluster headache. The prevalence
of cluster
headache is about 1 person per 500. It occurs
approximately
three times more often in men than in women
but is clinically
(Page-1709LU) identical in both genders.
Although not universally observed,
there is a tendency for cluster headache
symptoms to remit
with age (May, 2005). Unlike migraine, cluster
headache has
not been considered until recently to be an
inherited condition.
Several twin studies have demonstrated 100%
concordance
in monozygotic twins. Two genetic
epidemiological
surveys suggest that first-degree relatives may
have up to an
18-times higher risk, and second-degree relatives
a 1- to
3-times higher risk of cluster headache than the
general population.
The increased familial risk of cluster headaches
suggests
a genetic underpinning. Inheritance is likely to be
autosomal
dominant with variable penetrance; nonetheless,
in some
families it may be autosomal recessive or
multifactorial
(Russell, 2004).

New Daily onset persistent Headache

Lastly, for new daily persistent headache (coded
as
4.8 of ICHD-II), the only evidence available for
the
general population (Castillo et al., 1999) suggests
a prevalence
rate around 1% (2 cases out of 1883 subjects),
although this should be considered a
conservative estimate
given the small size of the sample studied.

(page-1714)
NDPH is a daily headache that is unremitting
from onset or
very soon after onset (within 24 hours at most)
(Headache
Classification Committee, 2013). The vast
majority of patients
can pinpoint the exact date their headache
started. Infection,
flu-like illness, surgery, and stressful life events
may precede
NDPH. How these may result in NDPH is unclear
and in
many, no precipitating factors are identified.
Clinically, NDPH
may have features suggestive of either migraine
or tension-type
headache.

Epidemiology of chronic daily headache

About a quarter-century ago, more or less
simultaneously
in different parts of the world, Mathew et al.
(1982), Nappi and Savoldi (1985) and Sjaastad
(1985)
became intrigued with the large number of
headache
clinic patients who had been reporting headache
attacks
every day or almost every day for many months
or even
many years on end. To describe these patients,
they
introduced the term “chronic daily headache.”
In spite of the fact that a long time has passed
from
that first description and a huge amount of
literature
has been published on this subject, there is no
consensus
yet on how to classify this form of headache and
whether to recognize it as an autonomous entity
hence,
the difficulties encountered in the systematic
organization
of the different CDH subtypes within the
framework of ICHD-II (Headache Classification
Subcommittee
of the International Headache Society,
2004).
Before dealing briefly with CDH prevalence, we
should first recapitulate the characteristics of this
disorder on which all investigators agree: (1) it is
a primary
headache; (2) often it represents an evolution
over time of migraine without aura, which
worsens to
the point that there are no longer any symptom-
free
intervals between attacks; and (3) it is often
associated
with symptomatic drug overuse. On the other
hand,
there is no agreement as yet on: (1) how many
days
per month the headache must be present in
order for
a CDH diagnosis to be made; (2) how many
months
the patient must have been suffering from it;
and, (3)
the number and type of clinical entities that
constitute
it. Certainly, chronic TTH is part of CDH.

(Page-16 RM) Oddly enough, despite the

methodological inconsistencies
of the various epidemiological studies conducted
so far, which are obviously the result of
different investigational approaches, prevalence
rates
are fairly comparable, suggesting that about 4%
of
the adult population suffers from CDH.
Scher et al. (1998) found a prevalence

(page-16RL)
Analgesic overuse was found in 25–34% of CDH
patients (Castillo et al. 1999; Lu et al., 2001
respectively).
CDH is also frequent in adolescents. Wang et al.
(2006) found a prevalence rate of 1.5% (three
times
as high in women as in men) among 7900
Taiwanese
students aged 12–14.
Prevalence rates in the elderly are fairly similar
to
those in middle-aged adults. Wang et al. (2000)
reported a 3.9% rate among 1533 Chinese over
65
(F/M ratio of 3.1), while Prencipe et al. (2001)
found
a rate of 4.4% in 833 65-plus Italians (F/M ratio of
2.4).

CONCLUSION
Primary headaches are among the most
prevalent disorders
of humanity, the 1-year prevalence of migraine
being around 10–14% and of tension headache
above
40%. Other primary headaches probably
contribute less
to the total headache burden due to their much
lower prevalence.
Little is known about the contribution of the
secondary headaches to the total headache
burden, both
because of difficulties with making these
diagnoses in
population-based epidemiological studies, and
because
it is very incompletely known how often the
underlying
conditions cause headache. There are still severe
limitations
in our knowledge about the headache prevalence
and burden in large and populous regions of the
world,headaches probably contribute less
to the total headache burden due to their much
lower prevalence.
Little is known about the contribution of the
secondary headaches to the total headache
burden, both
because of difficulties with making these
diagnoses in
population-based epidemiological studies, and
because
it is very incompletely known how often the
underlying
conditions cause headache. There are still severe
limitations
in our knowledge about the headache prevalence
and burden in large and populous regions of the
world,

(Page-202)
()
Migraine

Migraine: Classification and clinical features

(Page-18LU)
1. Migraine
1.1 Migraine without aura
1.2 Migraine with aura
1.2.1 Migraine with typical aura
1.2.1.1 Typical aura with headache
1.2.1.2 Typical aura without headache
1.2.2 Migraine with brainstem aura
1.2.3 Hemiplegic migraine
1.2.3.1 Familial hemiplegic migraine (FHM)
1.2.3.1.1 Familial hemiplegic migraine type 1
(FHM1)
1.2.3.1.2 Familial hemiplegic migraine type 2
(FHM2)
1.2.3.1.3 Familial hemiplegic migraine type 3
(FHM3)
1.2.3.1.4 Familial hemiplegic migraine, other loci
1.2.3.2 Sporadic hemiplegic migraine (SHM)
1.2.4 Retinal migraine
1.3 Chronic migraine
1.4 Complications of migraine
1.4.1 Status migrainosus
1.4.2 Persistent aura without infarction
1.4.3 Migrainous infarction
1.4.4 Migraine aura-triggered seizure
1.5 Probable migraine
1.5.1 Probable migraine without aura
1.5.2 Probable migraine with aura
1.6 Episodic syndromes that may be associated
with
migraine
1.6.1 Recurrent gastrointestinal disturbance
1.6.1.1 Cyclical vomiting syndrome
1.6.1.2 Abdominal migraine
1.6.2 Benign paroxysmal vertigo
1.6.3 Benign paroxysmal torticollis

(page-18RL) 1.1 Migraine without aura

Previously used terms: Common migraine;
hemicrania
simplex
Description: Recurrent headache disorder
manifesting in
attacks lasting 4–72 hours Typical characteristics
of the
headache are unilateral location, pulsating
quality,
moderate or severe intensity, aggravation by
routine
physical activity and association with nausea
and/or
photophobia and phonophobia.

(Page-19LU) Diagnostic criteria:

A. At least five attacks1 fulfilling criteria B–D
B. Headache attacks lasting 4–72 hours (when
untreated or unsuccessfully treated)2,3
C. Headache has at least two of the following four
characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation by or causing avoidance of routine
physical activity (e.g. walking or climbing
stairs)
D. During headache at least one of the following:
1. nausea and/or vomiting
2. photophobia and phonophobia
E. Not better accounted for by another ICHD-3
diagnosis.

(Page-19LM) Comments: Migraine headache in

children and adolescents
(aged under 18 years) is more often bilateral
than
is the case in adults; unilateral pain usually
emerges in
late adolescence or early adult life. Migraine
headache
is usually frontotemporal. Occipital headache in
children
is rare and calls for diagnostic caution. A subset
of otherwise typical patients have facial location
of
pain, which is called ‘facial migraine’ in the
literature;
there is no evidence that these patients form a
separate
subgroup of migraine patients.
Prodromal symptoms may begin hours or a day
or
two before the other symptoms of a migraine
attack without
aura. They include various combinations of
fatigue,
difficulty in concentrating, neck stiffness,
sensitivity to
light and/or sound, nausea, blurred vision,
yawning
and pallor. Postdromal symptoms, most
commonly
feeling tired or weary, difficulty with
concentration and
neck stiffness, may follow resolution of the
headache,
persisting for up to 48 hours; these are less well
studied.
Migraine attacks can be associated with cranial
autonomic
symptoms and symptoms of cutaneous allodynia.
In young children, photophobia and phonophobia
may be inferred from their behaviour.
A minority (<10%) of women have attacks of
migraine in association with the majority of their
menstrual
cycles; most such attacks are without aura.
Attacks during menstruation tend to be longer
and
accompanied by more severe nausea than
attacks outside
the menstrual cycle. ICHD-3 offers criteria for

(Page-20LM) 1.2 Migraine with aura

Previously used terms: Classic or classical
migraine;
ophthalmic, hemiparaesthetic, hemiplegic or
aphasic
migraine; migraine accompagne´e; complicated
migraine.
Description: Recurrent attacks, lasting minutes,
of unilateral
fully reversible visual, sensory or other central
nervous system symptoms that usually develop
gradually
and are usually followed by headache and
associated
migraine symptoms.
Diagnostic criteria:
A. At least two attacks fulfilling criteria B and C
B. One or more of the following fully reversible
aura
symptoms:
1. visual
2. sensory
3. speech and/or language
4. motor
5. brainstem
6. retinal
C. At least three of the following six
characteristics:
1. at least one aura symptom spreads gradually
over _5 minutes
2. two or more aura symptoms occur in
succession
3. each individual aura symptom lasts 5–60
minutes1
4. at least one aura symptom is unilateral2
5. at least one aura symptom is positive3
6. the aura is accompanied, or followed within
60 minutes, by headache
D. Not better accounted for by another ICHD-3
diagnosis.
Notes:
1. When, for example, three symptoms occur
during an
aura, the acceptable maximal duration is 3_60
minutes.
Motor symptoms may last up to 72 hours.
2. Aphasia is always regarded as a unilateral
symptom;
dysarthria may or may not be.
3. Scintillations and pins and needles are positive
symptoms of aura.

(Page-20RM) Visual aura is the most common

type of aura, occurring
in over 90% of patients with 1.2 Migraine with
aura, at least in some attacks. It often presents
as a
fortification spectrum: a zigzag figure near the
point
of fixation that may gradually spread right or left
and
assume a laterally convex shape with an
angulated scintillating
edge, leaving absolute or variable degrees of
relative scotoma in its wake. In other cases,
scotoma
without positive phenomena may occur; this is
often
perceived as being of acute onset but, on
scrutiny, usually
enlarges gradually. In children and adolescents,
less
typical bilateral visual symptoms occur that may
represent
an aura. A visual aura rating scale with high
specificity
and sensitivity has been developed and
validated.
Next in frequency are sensory disturbances, in
the
form of pins and needles moving slowly from the
point
of origin and affecting a greater or smaller part of
one side
of the body, face and/or tongue. Numbness may
occur in
its wake, but numbness may also be the only
symptom.
Less frequent are speech disturbances, usually
aphasic
but often hard to categorize.

(Page-21RU)
1.2.1 Migraine with typical aura
Description: Migraine with aura, in which aura
consists
of visual and/or sensory and/or speech/language
symptoms,
but no motor weakness, and is characterized by
gradual development, duration of each symptom
no
longer than one hour, a mix of positive and
negative
features and complete reversibility
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2 Migraine with
aura and criterion B below
B. Aura with both of the following:
1. fully reversible visual, sensory and/or speech/
language symptoms
2. no motor, brainstem or retinal symptoms.
1.2.1.1 Typical aura with headache
Description: Migraine with typical aura in which
aura is
accompanied or followed within 60 minutes by
headache
with or without migraine characteristics.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2.1 Migraine with
typical aura and criterion B below
B. Headache, with or without migraine
characteristics,
accompanies or follows the aura within 60
minutes.
1.2.1.2 Typical aura without headache
Description: Migraine with typical aura in which
aura is
neither accompanied nor followed by headache
of any sort.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2.1 Migraine with
typical aura and criterion B below
B. No headache accompanies or follows the aura
within 60 minutes.

(Page-22LM)
1.2.2 Migraine with brainstem aura
Previously used terms: Basilar artery migraine;
basilar
migraine; basilar-type migraine.
Description: Migraine with aura symptoms clearly
originating
from the brainstem, but no motor weakness.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2 Migraine with
aura and criterion B below
B. Aura with both of the following:
1. at least two of the following fully reversible
brainstem symptoms:
a. dysarthria1
b. vertigo2
c. tinnitus
d. hypacusis3
e. diplopia4
f. ataxia not attributable to sensory deficit
g. decreased level of consciousness (GCS
13)5
2. no motor6 or retinal symptoms.

(Page-22RU) Many of the symptoms listed under

criterion B1 may
occur with anxiety and hyperventilation, and are
therefore
subject to misinterpretation.
1.2.3 Hemiplegic1 migraine
Description: Migraine with aura including motor
weakness.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2 Migraine with
aura and criterion B below
B. Aura consisting of both of the following:
1. fully reversible motor weakness2
2. fully reversible visual, sensory and/or speech/
language symptoms.
Notes:
1. The term plegic means paralysis in most
languages,
but most attacks are characterized by motor
weakness.
2. Motor symptoms generally last less than 72
hours
but, in some patients, motor weakness may
persist
for weeks.
Comment: It may be difficult to distinguish
weakness
from sensory loss.
1.2.3.1 Familial hemiplegic migraine (FHM)
Description: Migraine with aura including motor
weakness,
and at least one first- or second-degree relative
has
migraine aura including motor weakness.
Diagnostic criteria:
A. Attacks fulfilling criteria for 1.2.3 Hemiplegic
migraine
B. At least one first- or second-degree relative
has
had attacks fulfilling criteria for 1.2.3 Hemiplegic
migraine.

(Page-22RL)comments:
In Familial hemiplegic migraine (FHM) Specific
genetic subforms have
been identified: in FHM1 there are mutations in
the
CACNA1A gene (coding for a calcium channel)
on chromosome 19; in FHM2 there are
mutations in the
ATP1A2 gene (coding for a K/Na-ATPase) on
chromosome
1; and in FHM3 there are mutations in the
SCN1A
gene (coding for a sodium channel) on
chromosome 2.
There may be other loci not yet identified.

(Page-23 RM) 1.2.4 Retinal migraine

Description: Repeated attacks of monocular
visual disturbance,
including scintillations, scotomata or blindness,
associated with migraine headache.

(Page-24LU) 1.3 Chronic migraine

Description: Headache occurring on 15 or more
days/
month for more than three months, which, on at
least
eight days/month, has the features of migraine
headache.
Diagnostic criteria:
A. Headache (migraine-like or tension-type-like1)
on
_15 days/month for >3 months, and fulfilling
criteria
B and C
B. Occurring in a patient who has had at least
five
attacks fulfilling criteria B–D for 1.1 Migraine
without
aura and/or criteria B and C for 1.2 Migraine
with aura
C. On _8 days/month for >3 months, fulfilling any
of the following2:
1. criteria C and D for 1.1 Migraine without aura
2. criteria B and C for 1.2 Migraine with aura
3. believed by the patient to be migraine at onset
and relieved by a triptan or ergot derivative
D. Not better accounted for by another ICHD-3
diagnosis.3–5
Notes:
1. The reason for singling out 1.3 Chronic
migraine from
types of episodic migraine is that it is impossible
to
distinguish the individual episodes of headache in
patients with such frequent or continuous
headaches.
In fact, the characteristics of the headache may
change not only from day to day but even within
the same day. Such patients are extremely
difficult
to keep medication-free in order to observe the
natural
history of the headache. In this situation, attacks
with and those without aura are both counted, as
are
both migraine-like and tension-type-like
headaches
(but not secondary headaches).
:

(Page-24RM)
3. Because tension-type-like headache is within
the
diagnostic criteria for 1.3 Chronic migraine, this
diagnosis excludes the diagnosis of 2. Tension-
type
headache or its types.
4. 4.10 New daily persistent headache may have
features
suggestive of 1.3 Chronic migraine. The latter
disorder
evolves over time from 1.1 Migraine without aura
and/
or 1.2 Migraine with aura; therefore, when these
criteria
A–C are fulfilled by headache that,
unambiguously,
is daily and unremitting from <24 hours after
its first onset, code as 4.10 New daily persistent
headache.
When the manner of onset is not remembered or
is otherwise uncertain, code as 1.3 Chronic
migraine.
5. The most common cause of symptoms
suggestive
of chronic migraine is medication overuse, as
defined
under 8.2 Medication-overuse headache. Around
50%
of patients apparently with 1.3 Chronic migraine
revert to an episodic migraine type after drug
withdrawal;
such patients are in a sense wrongly diagnosed
as 1.3 Chronic migraine. Equally, many
patients apparently overusing medication do not
improve after drug withdrawal; the diagnosis of
8.2
Medication-overuse headache may be
inappropriate
for these (assuming that chronicity induced by
drug
overuse is always reversible). For these reasons,
and
because of the general rule to apply all relevant
diagnoses,
patients meeting criteria for 1.3 Chronic
migraine and for 8.2 Medication-overuse
headache
should be coded for both. After drug withdrawal,
migraine will either revert to an episodic type or
remain chronic, and should be re-diagnosed
accordingly;
in the latter case, the diagnosis of 8.2
Medication-overuse headache may be rescinded.
1.4 Complications of migraine
Comment: Code separately for both the migraine
type,
subtype or subform and for the complication.
1.4.1 Status migrainosus
Description: A debilitating migraine attack lasting
for
more than 72 hours.
Diagnostic criteria:
A. A headache attack fulfilling criteria B and C
B. Occurring in a patient with 1.1 Migraine
without
aura and/or 1.2 Migraine with aura, and typical of
previous attacks except for its duration and
severity

(Page-25LU)
C. Both of the following characteristics:
1. unremitting for >72 hours1
2. pain and/or associated symptoms are
debilitating2
D. Not better accounted for by another ICHD-3
diagnosis.
Notes:
1. Remissions of up to 12 hours due to
medication or
sleep are accepted.
2. Milder cases, not meeting criterion C2, are
coded
1.5.1 Probable migraine without aura.
Comment: Headache with the features of 1.4.1
Status
migrainosus may often be caused by medication
overuse.
When headache in these circumstances meets
the criteria
for 8.2 Medication-overuse headache, code for
this disorder
and the relevant type or subtype of migraine but
not for 1.4.1 Status migrainosus. When overuse
of medication
is of shorter duration than three months, code for
the appropriate migraine type or subtype(s) only.

1.4.2 Persistent aura without infarction

Description: Aura symptoms persisting for one
week or
more without evidence of infarction on
neuroimaging.
Diagnostic criteria:
A. Aura fulfilling criterion B
B. Occurring in a patient with 1.2 Migraine with
aura
and typical of previous auras except that one or
more aura symptoms persists for _1 week
C. Neuroimaging shows no evidence of infarction
D. Not better accounted for by another ICHD-3
diagnosis.

(Page-25RU)Migrainous Infarction:

Diagnostic criteria:
A. A migraine attack fulfilling criteria B and C
B. Occurring in a patient with 1.2 Migraine with
aura
and typical of previous attacks except that one or
more aura symptoms persists for >60 minutes1
C. Neuroimaging demonstrates ischaemic
infarction
in a relevant area
D. Not better accounted for by another ICHD-3
diagnosis.
Note:
1. There may be additional symptoms
attributable to
the infarction.
Comments: Ischaemic stroke in a migraine
sufferer may
be categorized as cerebral infarction of other
cause
coexisting with 1. Migraine, cerebral infarction of
other cause presenting with symptoms
resembling 1.2
Migraine with aura, or cerebral infarction
occurring
during the course of a typical attack of 1.2
Migraine
with aura. Only the last fulfils criteria for 1.4.3
Migrainous infarction.
1.4.3 Migrainous infarction mostly occurs in the
posterior
circulation and in younger women.
A twofold increased risk of ischaemic stroke in
patients with 1.2 Migraine with aura has been
demonstrated
in several population-based studies. However, it
should be noted that these infarctions are not
migrainous
infarctions. The mechanisms of the increased risk
of ischaemic stroke in migraine sufferers remain
unclear;

1.4.4 Migraine aura-triggered seizure

Description: A seizure triggered by an attack of
migraine
with aura.

(Page-26RM)

1.6 Episodic syndromes that may be associated

with migraine
Previously used terms: Childhood periodic
syndromes;
periodic syndromes of childhood.
Comments: This group of disorders occurs in
patients
who also have 1.1 Migraine without aura or 1.2
Migraine with aura, or who have an increased
likelihood
to develop either of these disorders. Although
historically noted to occur in childhood, they may
also occur in adults.
Additional conditions that may also occur in
these
patients include episodes of motion sickness and
periodic
sleep disorders including sleep walking, sleep
talking,
night terrors and bruxism.
1.6.1 Recurrent gastrointestinal disturbance
Previously used terms: Chronic abdominal pain;
functional
abdominal pain; functional dyspepsia; irritable
bowel syndrome; functional abdominal pain
syndrome.
Description: Recurrent episodic attacks of
abdominal
pain and/or discomfort, nausea and/or vomiting,
occurring infrequently, chronically or at
predictable
intervals, that may be associated with migraine.

(Page-27LL) Abdominal migraine

Description: An idiopathic disorder seen mainly in
children
as recurrent attacks of moderate to severe
midline
abdominal pain, associated with vasomotor
symptoms,
nausea and vomiting, lasting 2–72 hours and with
normality
between episodes. Headache does not occur
during these episodes.
Diagnostic criteria:
A. At least five attacks of abdominal pain,
fulfilling
criteria B–D
B. Pain has at least two of the following three
characteristics:
1. midline location, periumbilical or poorly
localized
2. dull or ‘just sore’ quality
3. moderate or severe intensity
C. At least two of the following four associated
symptoms or signs:
1. anorexia
2. nausea
3. vomiting
4. pallor
D. Attacks last 2–72 hours when untreated or
unsuccessfully
treated
E. Complete freedom from symptoms between
attacks
F. Not attributed to another disorder.1
Note:
1. In particular, history and physical examination
do
not show signs of gastrointestinal or renal
disease,
or such disease has been ruled out by
appropriate
investigations.

(page-28RL)Most children with abdominal

migraine will develop
migraine headache later in life.
1.6.2 Benign paroxysmal vertigo
Description: A disorder characterized by
recurrent
brief attacks of vertigo, occurring without
warning
and resolving spontaneously, in otherwise
healthy
children.
(Page-29RU) A. At least five attacks fulfilling
criteria B and C
B. Vertigo1 occurring without warning, maximal
at
onset and resolving spontaneously after minutes
to hours without loss of consciousness
C. At least one of the following five associated
symptoms
or signs:
1. nystagmus
2. ataxia
3. vomiting
4. pallor
5. fearfulness
D. Normal neurological examination and
audiometric
and vestibular functions between attacks
E. Not attributed to another disorder.2

1.6.3 Benign paroxysmal torticollis

Description: Recurrent episodes of head tilt to
one side,
perhaps with slight rotation, which remit
spontaneously.
The condition occurs in infants and small
children,
with onset in the first year.

Pathogenesis of Migraine
(Page-1698LM) Migraine Genetics
Although prior familial migraine studies have
shown no clear
Mendelian inheritance patterns, recent genetic
epidemiological
surveys and large national registry-based twin
studies
strongly support the hypothesis of a genetic
contribution.
Perhaps the most striking evidence of a genetic
basis for
migraine has come to us over the past decade
from investigation
of familial hemiplegic migraine.
Familial hemiplegic migraine (FHM) is a rare
autosomal
dominant subtype of migraine with aura in which,
in the
context of otherwise typical migraine attacks,
patients experience
hemiplegia. Thus far, three genes for FHM have
been
identified: CACNA1A, ATP1A2, and SCNA1A. A
mutation in
CACNA1A, a gene located on chromosome 19p13
that codes
for the α1-subunit of a brain-specific voltage-
gated P/Q-type
calcium channel, is associated with FHM1 (Ophoff
et al.,
1996).

(Page-1698LM) Common forms of migraine (e.g.,

migraine without aura,
migraine with aura) have complex underlying
genetic profiles.
It is estimated that about half of the underlying
propensity
towards developing migraine is due to additive
gene effects,
while the other half is attributable to
environmental factors
(Gasparini et al., 2013; Silberstein and Dodick,
2013).

(Page-1698RL)
Pathophysiology
Vascular Versus Neuronal. Whereas the migraine
attack was
once considered attributable to vascular
dysfunction, the
migraine attack is now considered to be primarily
due to brain

(Page-1698LU) dysfunction, perhaps with

secondary vascular effects. During
most of recent history, the migraine aura was
thought to be
due to cerebral vasoconstriction while the
headache was
thought to be due to cerebral vasodilation.
However, recent
investigations question the role of the
intracranial vasculature
in generating the migraine attack. First, there is
solid evidence
from functional MRI studies that a phase of focal
hyperemia
precedes the phase of oligemia during the
migraine aura.
Second, headache may begin while cortical blood
flow remains
reduced, thereby rendering obsolete the theory
that vasodilatation
is the sole mechanism of the pain.

(Page-102LM)Astrocyte waves
Glial cells may also play a key role in the changes
in
cortical activity associated with migraine. Direct
evidence
for such a role comes from the discovery that
a mutation in an Na
þ
/K
þ
ATPase that is expressed primarily
in astrocytes is responsible for familial
hemiplegic
migraine type 2 (De Fusco et al., 2003;
Vanmolkot
et al., 2006). In vitro studies indicate that this
mutation
reduces the function of the enzyme (Segall et al.,
2005;
Vanmolkot et al., 2006), an effect that would be
expected to increase excitability by increasing
extracellular
K
þ
. Astrocytes are abundant cells in the central
nervous system that have been traditionally
viewed as
playing only a passive and supportive role in
nervous
system function. But recent studies demonstrate
that
astrocytes are capable of extensive intercellular
signaling
that can modulate both neuronal and vascular
activity.

(Page-102RU) Astrocytes are capable of

extensive intercellular
communication via increases in intracellular
calcium
concentration that are propagated from cell to
cell in
a wave-like pattern (Charles et al., 1991). The
primary
mechanism for these intercellular calcium waves
appears to be release of ATP into the
extracellular
space and activation of purinergic receptors on
adjacent
cells (Guthrie et al., 1999). These intercellular
calcium
waves in astrocytes can be triggered by
chemical,
electrical, or mechanical stimuli, and spread with
temporal
and spatial characteristics that are remarkably
similar to those of CSD (Charles, 1998). In fact,
recent
microscopic imaging studies have shown that
calcium
waves in astrocytes consistently occur in
association
with spreading depression, both in vitro and in
vivo
(Peters et al., 2003; Chuquet et al., 2007).

(Page-1698RM) A Migraine Generator. The

existence of a “migraine generator,”
a brain region that is responsible for triggering
the
migraine attack, is a matter of debate. Searches
for a migraine
generator typically center around pain
modulating regions of
the brainstem and on the hypothalamus.
Although brainstem
and hypothalamic generators have been
proposed, the brain
location initiating a migraine attack is still
unclear. In support
of a brainstem region serving as a migraine
generator, functional
magnetic resonance studies performed during
migraine
attacks have demonstrated activation of
brainstem regions
prior to activation of cortical regions and prior to
onset
of migraine symptoms (Stankewitz and May,
2011). The
hypothalamus has also been considered a
possible migraine
generator since many symptoms of the
premonitory phase
(e.g., mood changes, thirst, food cravings,
excessive yawning,
and drowsiness) are suggestive of hypothalamic
dysfunction.
A positron emission tomography (PET) study of
nitroglycerin triggered
migraine attacks found premonitory phase
activations
in posterolateral hypothalamus, several
brainstem regions
(e.g., midbrain tegmental area, periaqueductal
gray, dorsal
pons), and several cortical areas (Maniyar et al.,
2014). While
a single brain region might generate the
migraine attack or
functional alteration within a single brain region
might reduce
the threshold for the migraine attack to be
generated, it seems
probable that there is not a single ‘migraine
generator’ shared
by all people with migraine and that there is not
a single
‘migraine generator’ within individuals from
attack to attack.
Migraine symptoms are quite variable from
attack to attack
and from patient to patient. There is not a
specific symptom
that is reliably identified as the first symptom
from migraine
attack to migraine attack. In fact, during the
migraine attack
there is substantial co-occurrence of symptoms,
meaning that
multiple symptoms are present in an overlapping
pattern, as
opposed to there being a linear cascade of one
symptom
leading to the next.

(page1699LM) Cortical Spreading

Depression:
Cortical spreading depression
is considered the electrophysiological substrate
of the
migraine aura. Cortical spreading depression
tends to start in
the occipital pole and spreads forward over the
cerebral hemisphere
at a rate of about 2 to 4 mm/min. The cortical
spreading
depression wave causes disruption in ionic
gradients and
depolarization followed by a period of
hyperpolarization.
Secondary to this cortical spreading depression
wave, there is
a corresponding initial phase of hyperemia
followed by
oligemia. The period of brain activation followed
by the
period of brain deactivation might correspond
with the pattern
of “positive” symptoms (e.g., visual scintillations)
followed by
“negative” symptoms (e.g., visual scotoma)
typical of the
migraine aura.

(page-1699LL) The Trigeminocervical System and

Migraine Headache.
The trigeminocervical system is the basic
anatomic system that
underlies the migraine attack. The
trigeminocervical system
consists of the trigeminal nucleus caudalis, the
trigeminal ganglion,
the three branches of the trigeminal nerve (V1,
ophthalmic
branch; V2, maxillary branch; V3 mandibular
branch),
and ascending fibers from the trigeminal nucleus
caudalis to
higher order cortical regions. The trigeminal
nucleus caudalis
extends caudally to C2, and thus C2 nerve roots
(which give
rise to the occipital nerves) provide sensory input
to the
trigeminal nucleus caudalis. Nerve fibers of the
trigeminocervical
system innervate intracranial and extracranial
blood
vessels. The innervation of pain-sensitive
intracranial structures
including large cerebral blood vessels, pial
vessels, dura
mater, and large venous sinuses is by a plexus of
largely unmyelinated
fibers that arise from the ophthalmic branch of
the
trigeminal nerve.
Activation of the trigeminocervical system results
in tra
nsmission
of impulses centrally toward the first synapse
within

(Page-1699RU) laminae I and IIo of the trigeminal

nucleus caudalis. From this
point, nerve impulses travel rostrally to the
cortex via thalamic
relay centers. Activation of the trigeminocervical
system leads
to release of vasoactive neuropeptides from
sensory afferents
that innervate the major intracranial arteries, a
process
termed “neurogenic inflammation” (Akerman et
al., 2013).
Neuropeptides that are released include
calcitonin gene related
peptide (CGRP), substance P, vasoactive
intestinal polypeptide
(VIP), nitric oxide (NO), and pituitary adenylate
cyclaseactivating
peptide (PACAP) (Gasparini et al., 2013). Release
of
these vasoactive neuropeptides results in
vasodilation, plasma
protein extravasation, inflammation, and likely
contributes to
causing the headache of the migraine attack.
The Hyperexcitable Migraine Brain. The migraine
brain has
exuberant responses to sensory stimuli, a
hyperexcitability
likely linked to the allodynia, photosensitivity,
phonosensitivity,
and olfactory hypersensitivity of migraine.

(Page-105RU)
AN INTEGRATED MODEL
The following is a hypothesized model for the
sequence of events leading to migraine. In the
cortex,
a variety of different factors (genetic,
neurochemical,
ionic, and/or hormonal) lead to a dysregulation of
excitability. This altered excitability triggers
propagated
waves of neuronal and glial activation, including
astrocyte calcium waves, that are similar to, but
not
necessarily identical to, classical CSD. These
cortical
waves are associated with propagated changes
in vascular
caliber, and also breakdown of the blood–brain
barrier. Cortical waves are also associated with
release
of a wide variety of neurotransmitters and
neuromodulators,
as well as changes in the ionic composition of
the extracellular space that can activate
nociceptive signaling
pathways. These signaling pathways may also be
activated by vascular constriction associated with
cortical
waves, through the release of messengers such
as
CGRP and nitric oxide that also evoke
vasodilation,
as well as by changes in the extracellular
chemical
and ionic condition resulting from vascular-
metabolic
uncoupling. Events occurring primarily in the
cortex
are then transmitted via peripheral trigeminal
pathways
to the brainstem, where second-order neurons
are activated
and eventually become sensitized. Alternatively,
second-order neurons in the brainstem are
activated
in parallel to, or even in the absence of, cortical
phenomena
by changes in cellular excitability that may
be similar to those described in the cortex. Third-
order
neurons in the thalamus and cortex are then
activated
and sensitized.
Specific neuronal, glial, and vascular signaling
pathways
may represent distinct targets for acute and
preventive
migraine therapies (Figure 7.2). An increased
understanding of these pathways is now more
accessible
with advanced imaging and physiological
recording
techniques in combination with novel genetic
models
and molecular and pharmacological approaches.
It is
likely that there is extensive variation in the
specific
pathways that lead to migraine in different
individuals.
There may be opportunities to tailor new
treatments to
these specific molecular and cellular pathways in
order
to maximize efficacy and tolerability of therapy
for
this complex neurobiological disorder.
(Page-106U)

(Page-1696RM) Triggers of the Migraine Attack

At least three-quarters of migraineurs can
identify triggers of
their migraine attacks (Kelman, 2007). However,
it seems that
the susceptibility of the migraine brain to
potential migraine
attack triggers fluctuates from day-to-day. Thus,
many
migraineurs will find that exposure to a potential
trigger does
in fact trigger a migraine attack on some days
and does not
on other days. The most commonly identified
migraine attack
triggers include emotional stress, fluctuating
female hormones,
missed meals, weather factors, sleep
disturbance,
odors, certain visual stimuli, alcohol, muscle
tension, physical
exercise, and being overheated (Kelman, 2007).

(Page-163U)

(Page-165)
(Page-1696 RM)
The Migraine Attack
Migraine Prodrome. Many patients with migraine
report
that a prodromal phase precedes the headache,
typically starting
1–2 hours prior to onset of migraine headache
(Kelman,
2004). The most frequent prodromal symptoms
include
fatigue, mild cognitive dysfunction, irritability,
neck pain, light
and noise sensitivity, blurred vision, excessive
yawning and
excessive thirst. When premonitory symptoms
are observed by
the migraineur, a migraine develops within the
next several
days about three-quarters of the time.
Migraine Aura: Migraine auras occur in about
one-third of
migraine patients (Cutrer and Huerter, 2007).
Most patients
who have migraine attacks with aura also have
attacks without
aura, with only one-fifth of migraine with aura
patients having
aura with every migraine attack. Typical aura
symptoms
develop and progress gradually over several
minutes and then
resolve within 60 minutes. The resolution of aura
symptoms
often coincides with the onset of headache. Much
less commonly
aura symptoms can occur during the headache
phase
of the migraine attack, after the headache phase
or in the
absence of headache altogether (“acephalgic
migraine” or
“aura without headache”). Individual aura
symptoms may
occur in isolation during an individual migraine
attack or
more than one aura symptom may occur
sequentially.
Visual phenomena are the most common aura
symptom,
reported by over 80% of patients with migraine
aura (Eriksen
et al., 2004; Russell and Olesen, 1996). Like all
migraine
aura symptoms, visual symptoms progress
slowly, moving
across the visual field. Visual auras consist of
positive symptoms
such as seeing flashing lights and wavy lines
(“scintillating
scotoma”), often followed by negative scotomas
within the same distribution of the preceding
positive visual
phenomena.
Sensory aura, the second most common aura
type, is, like
the visual aura, characterized by positive
symptoms (paresthesias)
followed by negative symptoms (numbness),
which
slowly spread or migrate (Eriksen et al., 2004;
Russell and

(Page-1697LU) Olesen, 1996). Sensory aura is

usually unilateral and has a
predilection for the hand, arm, shoulder and face.
This may
be due to the large representation of these
structures in the
sensory cortex or thalamus. Commonly, sensory
symptoms
begin in the hand and then slowly spread up the
ipsilateral
arm to the shoulder and face with perioral and
tongue involvement.
The rate of spread of a sensory aura is important
to help
distinguish it from a sensory seizure and the
sensory disturbance
of a TIA. Just as a visual aura spreads across the
visual
field slowly, taking as long as 20 minutes to
reach maximum,
the paresthesias may take 10 to 20 minutes to
spread from the
point at which they are first felt to their maximal
distribution.
This is slower than the spread of a sensory
seizure and much
slower than the spread of sensory symptoms
associated with
TIA. A migrainous sensory aura generally
resolves over the
course of 20 to 60 minutes, most often within 30
minutes.
After sensory aura, the next most common type
is a language
aura (Eriksen et al., 2004; Russell and Olesen,
1996).
Expressive dysphasias, including paraphasic
errors, are the
most common language symptoms of migraine
aura, with
receptive dysphasias being less common.
Language symptoms
of migraine aura are typically of mild severity.
When unilateral motor weakness is present with
migraine
aura, the diagnosis is “hemiplegic migraine.”
Hemiplegic
migraine can be “familial” or “sporadic.” Motor
weakness of
hemiplegic migraine most often involves the
hand and arm.
Although the term “plegia” suggests paralysis,
the motor
symptom of hemiplegic migraine is usually
weakness as
opposed to true paralysis. In addition to the
hemiparesis, there
must be at least one other aura symptom
including a visual,
sensory, or language/speech symptom. Like with
all migraine
auras, the aura symptoms of hemiplegic migraine
have a slow
spreading onset over several minutes with each
symptom
resolving within 60 minutes. However, the motor
weakness of
hemiplegic migraine can endure for several days.
The genetics
of familial hemiplegic migraine are discussed
further under
Migraine Genetics.
When aura consists of at least two brainstem
symptoms but
no motor or retinal symptoms, the diagnosis is
“migraine with
brainstem aura” (previously called “basilar
migraine”).
Migraine with brainstem aura consists of a
combination of
fully reversible visual, sensory, and
language/speech symptoms
with at least two brainstem symptoms including
dysarthria, vertigo, tinnitus, hypacusis, diplopia,
ataxia, and
decreased level of consciousness. Each aura
symptom resolves
within 60 minutes.
When a migraine aura is not followed by a
headache, the
episode is termed migraine aura without
headache, a migraine
equivalent, or acephalgic migraine. Most
commonly encountered
in patients who have a past history of migraine
with
aura, the episodes can begin de novo, usually
after 40 years of
age, but they can occur at almost any age.
Migraine equivalents
are easily recognizable when the attacks occur
on a background
of migraine with aura. In the absence of such a
history,
the transitory disturbance may be difficult to
distinguish from
an episode of transient cerebral or brainstem
ischemia and
thus diagnostic tests might be required.

Headache Phase. The headache of migraine is

typically a
moderate to severe unilateral throbbing pain that
is exacerbated
by routine physical activities. In addition to the
headache,
patients are hypersensitive to visual, auditory,
olfactory
and somatosensory stimuli often resulting in the
migraine
patient desiring rest in a dark and quiet room.
Nausea, vomiting,
and neck pain are frequent accompaniments.
A migraine headache can be felt anywhere
throughout the
head, including retro- and peri-orbital locations,
frontal,
occipital, temporal, vertex, and parietal regions.
Pain is
(Page-1697RU)
unilateral in 60%–75% of patients and bilateral in
others
(Kelman, 2005; Russell et al., 1996; Wober-Bingol
et al.,
2004). Often, pain starts unilaterally and then
becomes bilateral
as the migraine attack endures. Pain is most
commonly
described as throbbing/pulsating, but other pain
qualities are
also common. Headache intensity increases over
approximately
90 minutes before reaching moderate to severe
intensity.
Pain is intensified by physical activity in the
majority of
patients.
During a migraine attack there is a
hypersensitivity to
visual, auditory, cutaneous, and olfactory stimuli.
Most
migraineurs have hypersensitivity to light and
visual patterns,
exposure to which results in generalized
discomfort, visual
discomfort and worsening headache. Similarly,
exposure to
normal and loud volume sound results in
discomfort and
worsening headache intensity in most
migraineurs. Increased
sensitivity to odors is present in a minority of
migraineurs.
Scents that more commonly result in olfactory
hypersensitivity
include perfumes, food smells, and cigarette
smoke. An
increased sensitivity to touch of the skin,
“cutaneous allodynia,”
develops in about two-thirds of migraineurs
during a
migraine attack (Ashkenazi et al., 2007; Bigal et
al., 2008a;
Lipton et al., 2008). The allodynic migraineur
experiences
pain or discomfort with normally non-noxious
stimulation of
the skin such as occurs with light touch of the
face or scalp,
wearing eyeglasses, shaving the face, and
wearing a tight collar
or necklace. Although allodynia symptoms are
most commonly
noted within the trigeminal nerve distribution,
about
one-fourth of migraineurs develop extracephalic
allodynia,
typically involving the upper extremity (Mathew
et al., 2004).
Nausea is present during the migraine attack in
the majority
of patients and vomiting occurs in about half.
Besides the
obvious discomfort of vomiting itself, vomiting
can complicate
the migraine attack by leading to dehydration
and preventing
the absorption of orally administered
medications.
Even when vomiting is absent, the absorption of
orally administered
migraine medications might be unpredictable
due to
the presence of gastric stasis (Aurora et al.,
2006).
Untreated, the migraine headache phase usually
lasts from
4 to 72 hours, with the majority subsiding within
a day or
after a night’s sleep. When the migraine attack
endures for
longer than 72 hours, “status migrainosus” is
diagnosed.
Migraine Postdrome. The majority of
migraineurs continue
to have migraine symptoms for up to 24 hours
following resolution
of the migraine headache (Kelman, 2006). The
constellation
of symptoms, commonly referred to by patients
as the
“migraine hangover,” is very similar to those
symptoms experienced
during the premonitory phase of the migraine
attack.
Symptoms often include fatigue, mild cognitive
dysfunction,
atypical mood, generalized weakness, feeling
dizzy, neck stiffness,
light and sound hypersensitivity, and excessive
thirst
(Kelman, 2006).

Treatment and Management

Avoidance of trigger factors is important in the

management
of migraine, but simply advising a patient to
avoid stress

(Page-1700LU) and relax more is usually

meaningless. Advice to reduce excessive
caffeine intake, stop smoking, and reduce alcohol
intake
may be more useful. Medication use should be
reviewed
and modified if necessary. The use of drugs
known to cause
headaches (e.g., reserpine, nifedipine,
theophylline derivatives,
caffeine, vasodilators [including long-acting
nitrates],
alcohol) should be discontinued, or substituted to
other
agents if possible. Use of estrogens and oral
contraceptives
should be discontinued if they are suspected of
contributing
to the headaches, although in some patients this
may not be
possible. Exercise programs to promote well-
being, correction
of dietary excesses, and avoidance of prolonged
fasts and
irregular sleeping habits can be helpful.

(Page-1700LM) Persons with migraine may note

that stress is a trigger for
attacks, but helping them deal with or avoid
stress is difficult.
Long-term stress management may require the
help of a psychologist
or other appropriately trained professional.
Useful
self-management techniques include
biofeedback, relaxation
training, hypnosis, and cognitive behavioral
training.

Pharmacotherapy. Medical therapy can be

administered
prophylactically to prevent attacks of migraine or
symptomatically
to relieve the pain, nausea, and vomiting of an
attack.
Prophylactic therapy is needed when the
frequency or duration
of attacks seriously interferes with the patient’s
lifestyle.
Other indications for prophylaxis include severe
or prolonged
neurological symptoms or lack of response to
symptomatic
treatment. In general, prophylaxis should be
considered if
attacks occur as often as 1 to 2 days a week.

Symptomatic Treatment
Start symptomatic treatment as early in the
development of
an attack as possible. If an aura is recognized,
patients should
take medications during it rather than waiting for
the pain
to begin. It must be recalled, though, that once
the attack is
fully developed, oral preparations are almost
always less effective
because of decreased gastrointestinal motility
and poor
absorption.

THE BASICS OF ACUTE MIGRAINE TREATMENT

Stratifi ed Care
Two basic strategies, step care and stratifi ed care, are
used to treat acute migraine.
In the step-care model, patients progress through a
sequence of medications—
usually starting with a simple analgesic, then perhaps an
antiemetic, and then a
specifi c medication if the initial treatments are
ineffective. This can mean escalating
treatment across or within attacks. With stratifi ed care,
attacks are treated based
on severity. In this model, patients use nonspecifi c
medications for minimally disabling
attacks and specifi c medications for severe attacks.
Stratifi ed care improves
treatment outcomes, improves quality of life, and
reduces costs (Table 5.2).

(Page-39L)Treat Early
Treating migraine with specific medication early in the
attack improves
outcomes. Patients who take triptans early, when the
pain is still mild, have
increased pain-free rates. When taken early, triptans may
prevent the development
of central sensitization, as manifested clinically by
cutaneous allodynia
(pain in response to normally nonpainful stimuli). Once
cutaneous allodynia has
developed, patients are less likely to respond to triptans
(Page-45LM)Nonspecifi c medications
Despite the emergence of triptans, nonspecifi c medications are still popular,
and triptans are still underutilized. Few direct comparisons of specifi c and
nonspecifi c medications exist, and some patients may fi nd combinations of
nonspecifi c medications to be superior. Because many patients have contraindications
to specifi c agents, and because they are not always effective or well
tolerated, clinicians should be comfortable prescribing multiple classes of
nonspecifi c medications for acute migraine.
Nonsteroidal anti-infl ammatory drugs
NSAIDs are effective for the acute treatment of migraine. They may work by
suppressing infl ammation and by preventing and treating central sensitization by
blocking glial production of prostaglandins. They may also treat other migraine
symptoms, such as neck pain and sinus pressure, that are commonly associated
with acute migraine attacks. NSAIDs are less likely to cause MOH than other
treatments, but their frequent use can lead to systemic AEs, such as peptic ulcers
or renal disease. NSAIDs that have proven effectiveness in migraine (Table 5.8)
can be combined with triptans and antiemetics for severe attacks.

For many patients, a simple oral analgesic such

as aspirin,
acetaminophen, naproxen, ibuprofen, or an
analgesic combination
with caffeine may be effective. Caffeine aids
absorption,
helps induce vasoconstriction, and may reduce
the firing
of serotonergic brainstem neurons. However, the
use of
caffeine-containing combination analgesics more
than 2 days
per week may lead to increased incidence of
headaches. The
patient may need rest in a dark, quiet room with
an ice pack
on the head. This provides the best situation for
the analgesic

(Page-1700RU) to relieve the pain. If sleep

occurs, the patient often awakens
headache free.

(Page-41L) Medications
Acute attack medications include those specifi c for migraine (and cluster) headache,
such as triptans, ergots and dihydroergotamine (DHE), and nonspecifi c
medications (those used for headache and other pain disorders) (Table 5.4).
Specifi c medications
Triptans
Triptans are selective serotonin receptor agonists with high affi nity for 5-HT 1B
and 5-HT1D receptors and variable activity at the 5-HT1F receptor. Although
initial research suggested that the effectiveness of triptans occurred because of
their vasoconstrictive properties, their ability to both block the transmission of
pain signals from the trigeminal nerve to the trigeminal nucleus caudalis and
(Page-42M) prevent release of infl ammatory neuropeptides is more important.

Triptan choice depends on the patient’s headache patterns, how medications

are metabolized, and what AEs are experienced (Table 5.6). SC sumatriptan
is the most effective and fastest-acting triptan, but it causes the most AEs.

For simplicity, we dose all triptans in the following manner: take one as
needed for migraine, may repeat in 2 hours, and limit to 2 per day, 2 days a
week. Exceptions include frovatriptan (which may be repeated in 4 hours),
rizatriptan (max 24-hour dose, 30 mg), and ½ dose tablets (could take more
tablets per 24 hours

(Page-44LM) Common triptan-related AEs include paresthesias, dizziness, weakness, nausea,

and fatigue. Transient throat and chest tightness may occur but are rarely
related to coronary artery disease. Because of their potential for vasoconstriction,
triptans are contraindicated for patients with ischemic heart disease, vasospasm,
uncontrolled hypertension, or transient ischemic attacks. There have
been reports of possible serotonin syndrome in patients taking both triptans
and selective serotonin reuptake inhibitors (SSRIs) or other antidepressants.
However, headache specialists are convinced that the FDA was unjustifi ed in
issuing a black box warning for serotonin syndrome when combining SSRIs
or serotonin-norepinephrine reuptake inhibitors (SNRI) and triptans. The cases
cited as serotonin syndrome because of this combination do not actually fulfi ll
the criteria for the phenomenon.

Triptans. The development of sumatriptan

heralded a new
class of antimigraine agents that are highly
selective at
certain 5-HT receptors. These agents, collectively
called triptans,
together with the less selective ergot
preparations, have strong
agonist activity at the 5-HT1B receptor, which
mediates cranial
vessel constriction, and at the 5-HT1D receptor,
which leads
to inhibition of the release of sensory
neuropeptides from
perivascular trigeminal afferents. Experiments
show that activation
of 5-HT1B/5-HT1D receptors can attenuate the
excitability
of cells in the TNC, which receives input from the
trigeminal
nerve. Accordingly, 5-HT1B/5-HT1D agonists may
act at central
as well as peripheral components of the
trigeminal vascular
system, and at least part of their clinical action
may be
centrally mediated.

Administration of sumatriptan can be oral,

intranasal, and
by subcutaneous injection (Tables 103.2, e103.3,
and e103.4).
Self-administered as a 6-mg subcutaneous
injection, either
using the manufacturer’s auto-injector device or
conventional
subcutaneous injection, sumatriptan results in
significant pain
relief at 1- and 2-hour time points after drug
administration
(see eTable 103.3). For patients who had no
significant pain
relief after 1 hour, administration of a second
dose of 6 mg
provided little further benefit. Zolmitriptan is
available as an
oral and intranasal preparation.
Seven triptans are now available in the United
States. All
seem to have a beneficial effect on migraine-
associated symptoms,
including nausea, photophobia, and
phonophobia,
which also improves the patient’s ability to return
to normal
functioning. Side effects of sumatriptan by
injection include
local reaction at the injection site, usually of mild
or moderate
severity, and a transient tingling or flushed
sensation that
may localize or generalize. A more unpleasant
sense of heaviness
or pressure in the neck or chest occurs in a small
percentage
of recipients. It rarely lasts more than a few
minutes and
is generally not associated with
electrocardiogram (ECG)
changes or other evidence of myocardial
ischemia. However,
because sumatriptan has been shown to produce
a minor
reduction in coronary artery diameter, it should
be used with
caution in patients who have significant risk
factors for coronary
artery disease and should not be given to
patients with
any history suggestive of coronary insufficiency.
It is also contraindicated
in patients with untreated hypertension, ischemic
or vaso-occlusive cerebrovascular disease,
peripheral vascular
disease and in those using ergot preparations. It
is contraindicated
in women during pregnancy and in patients with
hemiplegic
migraine or migraine with brainstem aura
(previously
“basilar-type migraine”). Per the American
Academy of Pediatrics,
at present, sumatriptan belongs to the group of
medications
usually compatible with breast feeding.
eTable 103.4 provides a comparison of the
currently available
oral triptans. The potential side effects are quite
similar:
tingling, flushing, and a feeling of fullness in the
head, neck,
or chest. In general, the indications and
contraindications for
all 5-HT1 agonists are similar. They are not safe
when administered
within 24 hours of ergot preparations or other
members
of the triptan class.
At this time, no evidence exists to allow accurate
prediction
of which of these agents will be most effective in
a given
patient.
 (Page-1701LM) For patients with benign but
intolerable side
effects from this group of medications, consider
naratriptan,
almotriptan, or frovatriptan, given their favorable
side-effect
profiles. Recurrence of headache after initial
relief may necessitate
a repeat dose. With future attacks, a higher dose
(if
available) may be used, or the triptan can be
combined with
an NSAID and/or an antiemetic. If one agent fails,
it seems
reasonable, barring major side effects, to try
another agent in
the class. Since there is evidence that some of
these agents have
a lower oral bioavailability when taken by
patients with
migraine, both during an attack and interictally
(Aurora et al.,
2006), it is logical to consider combining them
with metoclopramide
to improve gastric emptying.
Ergots. Although increasingly less available and
supplanted
in many cases by newer agents, ergot
preparations still have a
role in the symptomatic treatment of migraine.
The actions of
ergotamine tartrate and other ergot preparations
are complex.
They are both vasoconstrictors and vasodilators,
depending on
the dose and the resting tone of the target
vessels, and probably
exert their effects on migraine via agonist
activity at 5-HT
receptors. Oral preparations are far less effective
than those
given rectally or parenterally.
If selected for use, 2 mg of ergotamine tartrate
by mouth
should be taken as soon as the patient
recognizes the symptoms
of an acute migraine attack. This dose, combined
with
a simple oral analgesic-caffeine combination, can
be taken
again in 1 hour. Possibly a better regimen, but
inconvenient
and unpleasant to some patients, is ergotamine
tartrate by
rectal suppository. The patient should be
instructed to insert
a 1- or 2-mg rectal suppository of ergotamine
tartrate at the
onset of the aura or pain and take a simple
analgesic orally.
The ergot preparation can be repeated in 60
minutes if
needed. Experience over the course of several
attacks is useful
to determine the amount of ergotamine needed
to obtain
relief. With subsequent attacks, the entire dose
can be taken
at onset. If nausea is troublesome,
metoclopramide in doses
of 10 mg orally aids absorption of the ergotamine
tartrate
and may prevent vomiting. For patients who are
close to
vomiting or who are vomiting, an antiemetic
suppository
such as chlorpromazine (25–100 mg) or
prochlorperazine
(25 mg) can be helpful.
(page-1701RM) With frequent attacks of
migraine, care must be taken to
avoid the vicious cycle of medication overuse
headache (discussed
elsewhere in this chapter). If more than 6 mg of
ergotamine
is required per week, use an alternative
preparation.
Ergotamine must be used cautiously by patients
with
hypertension and those with peripheral vascular
disease. It is
contraindicated in patients with coronary artery
disease and
in women who are pregnant. It is unwise to
administer ergotamine
to patients in whom the aura is particularly
prolonged
or characterized by a major neurological deficit.
The fear of
potentiating the vasospasm to the point of
cerebral infarction
may be unjustified, but avoid the potential risk by
withholding
potent vasoconstrictors. As an alternative to
ergotamine in
the symptomatic treatment of migraine, the
sympathomimetic
agent, isometheptene mucate, is useful. It is
available in proprietary
preparations combined with acetaminophen and
dichloralphenazone and has the advantages of
not increasing
nausea and being well-tolerated, but it may fail
to give relief
for severe attacks.

(Page-44LM) Ergotamine and DHE

Ergotamine and DHE (an ergot derivative) are older medications for moderate to
severemigraine. Bothareserotoninagonistswithvasoconstrictiveand α-adrenergic
activity. Ergotamine has more arterial vasoconstriction than DHE, which is a more
potent α-adrenergic antagonist with less emetic effect. Ergotamine causes more
AEs, especially nausea and vomiting, than triptans, which limits its usefulness.
Ergotamine is available as suppositories or tablets with and without caffeine.

Dihydroergotamine (DHE) has been a

treatment for
migraine since the 1940s. Its poor oral
bioavailability limits
its administration to the parenteral and
intranasal routes (see
Tables 103.2 and e103.3). Patients can self-
administer this
drug by each of these routes. This medication
should be considered
when nausea and vomiting limit the use of oral
medications
or when other medications are ineffective.
Although
DHE’s effects are slower than sumatriptan (see
eTable 103.3),
efficacy after 2 hours is similar, and the drug is
associated with
a lower recurrence of headache in 24 hours.

(Page-1701LL) Symptomatic treatment of

migraine with typical aura is
essentially the same as that described
previously, although
some data suggests subcutaneous sumatriptan
may not be
effective if taken during the aura phase before
headache onset

(Page-1702LU) This, however, remains an

unsettled controversy. Modification
of the aura is rarely possible or needed.
Transcranial magnetic stimulation (TMS), a
noninvasive
technique utilizing a magnetic pulse
hypothesized to disrupt
cortical spreading depression, has now been
approved by
the FDA for the symptomatic treatment of
migraine with
aura.

(Page-1702LM) While
there are no concrete guidelines currently
available for status
migrainosus treatment, several strategies have
been used by
some in the past. One can use neuroleptic agents
acutely, with
or without DHE. DHE (0.5–1 mg) with
metoclopramide
(10 mg) by IV injection is an effective treatment
for acute
headache and provides an alternative to the use
of an opioid.
Similarly, prochlorperazine, 10 mg IV over 3 to 4
minutes,
alone or combined with DHE, can be effective.
Sumatriptan,
6 mg subcutaneously, may provide relief of both
the headache
and the associated symptoms. Evidence for the
efficacy of
magnesium sulfate as an acute treatment for
migraine generally
favors only individuals with aura, where infusion
of 1 g
of magnesium sulfate may result in relief.
Alternatively, chlorpromazine,
0.1 mg/kg IV at a rate of 1 mg/min, is also an
effective agent when used acutely. The dose may
be repeated
twice at 15-30 minute intervals but the maximum
dose should
not exceed 37.5 mg (Lane et al., 1989). The
latter agent often
produces hypotension, and patients should first
receive a
bolus of 250 to 500 mL of 5% dextrose in one-
half normal
saline. Dehydrated patients should always
receive appropriate
IV hydration. Some patients develop acute
extrapyramidal
symptoms after treatment with neuroleptic
agents. These are
treatable with parenteral diphenhydramine, 25 to
50 mg. The
neuroleptic agents do produce sedation, and
patients should
be advised not to operate a motor vehicle after
treatment.
Injectable ketorolac, 60 mg given
intramuscularly, is another
alternative to the narcotic or sedative agents.
The use of this
NSAID in elderly patients, those who are
dehydrated, or those
having any history of renal insufficiency should
be avoided. A
single dose of dexamethasone combined with
other parenteral
antimigraine agents is useful for the emergency
room treatment
of attacks of intractable migraine. Intravenous
infusion
of valproate sodium 500 mg in normal saline over
1 hour is
yet another potentially efficacious abortive
option. In a female
patient, obtaining a pregnancy test prior to
administering this
treatment must be considered due to the
potential for teratogenic
effects. Although not a first-line treatment,
combination
of an opioid and an agent for nausea, such as
chlorpromazine (25–50 mg), promethazine
hydrochloride
(12.5–25 mg), or prochlorperazine (5–10 mg) is
an effective
treatment if the physician is sure the patient
genuinely has a
headache of major proportions.
When status migrainosus occurs, dehydration,
tiredness
due to lack of sleep, and continued pain may
necessitate
admission to a hospital to terminate the attack.
Fluid replacement,
correction of electrolyte imbalance, and
suppression of
vomiting with metoclopramide, chlorpromazine,
or prochlorperazine
generally result in improvement. DHE combined
with an antiemetic, initially given IV, may abort
status migrainosus.
It is effective, but increased nausea and vomiting
may be
a reason to switch to an alternative regimen.
Corticosteroids
such as dexamethasone or prednisolone are
useful and are
thought to reduce risk of headache recurrence. A
dose of prednisolone
of 20 mg every 6 hours initially, followed by a
rapidly

(page-1702RU) tapering dose over 2 to 3 days

may help abort status migrainosus.
It is best to avoid narcotic and benzodiazepine
agents
when treating status migrainosus.
\
Other nonspecific medication for migraine

(Page 47M) Opioids

Opioids provide therapeutic benefi t but are associated with a high risk of abuse,
dependency, and MOH. Opioids are most useful for patients with infrequent

(Page-48U)but disabling migraine, especially if a patient has contraindications (such as

cardiovascular disease or pregnancy) to specifi c treatments. Although AEs may
include sedation or confusion, patients might use opioids as a rescue medication
to avoid a visit to the emergency room. Codeine with acetaminophen is
effective in migraine, and other opioids commonly used as rescue treatments
include fentanyl, hydromorphone, hydrocodone, methadone, morphine, oxycodone,
propoxyphene, and pentazocine
(Page-48M) Treating frequent migraine with opioids is problematic and should be
considered
only under certain circumstances. Do not use opioids when patients
have addictive tendencies, a history of substance abuse, severe psychiatric
disorders, or MO. Fewer than 20% of patients taking long-term daily opioids
for CDH have sustained improvement, and many patients are nonadherent.
When using opioids, prescribe with strict limits and monitor the patient closely
(Table 5.11).

(Page-50L) Barbiturates
Butalbital-containing analgesics include combinations of acetaminophen or
aspirin with caffeine and, sometimes, codeine. No clinical trial has demonstrated
that butalbital, a barbiturate, adds to the effectiveness of the constituent
components, and the risk of dependency and MOH is high.

(Page-51U) Antiemetics and neuroleptics

Neuroleptics are antidopaminergic medications that block dopamine at D2
receptors in the brain. They are usually effective both for treating pain and
improving the nausea or vomiting associated with migraine. Neuroleptics are
often effective even in severe migraine and many are available as PR, IM,
or IV treatments (Table 5.14). They are effective as rescue medications, and
studies suggest that neuroleptics are underutilized in the emergency room for
the treatment of acute migraine. Other antiemetics work by antagonizing serotonin
5-HT3 receptors.
Oral metoclopramide is effective as an adjuvant medication with NSAIDs
or triptans and decreases gastric stasis that can impair absorption of medications.
Chlorpromazine, droperidol, prochlorperazine, and haloperidol are all
useful for acute migraine, including refractory cases. Sedation and extrapyramidal
AEs are common. Promethazine and hydroxyzine are antiemetics
that are less likely to cause extrapyramidal AEs. Serotonin receptor (5-HT 3)
antagonists may help treat nausea but do not appear effective for migraine pain
(Table 5.14).
(Page-52M) Other analgesics
Acetaminophen is effective for migraine at a dose of 1000 mg and is useful
for patients with contraindications to NSAIDs. Caffeine enhances the
effect of other migraine medications and has analgesic properties of its own.

(Page -52L) Prodrome and aura

Treating migraine when premonitory symptoms, such as hunger, neck pain,
thirst, or drowsiness, are present, before the headache begins, is occasionally
effective. Domperidone 20 to 40 mg and metoclopramide may help prevent
headaches, and triptans also may be useful. No medication is proven to reverse
the neuronal dysfunction of prolonged migraine aura, but case reports suggest
IV magnesium 1000 mg, ketamine NS 25 mg, and carbon dioxide may be
effective. Transcranial magnetic stimulation is effective for some patients in
experimental studies.

Bridge therapy
Bridges are treatments given for an intermediate length of time, usually
3 to 7 days, for status migrainosus or exacerbations of chronic migraine
(Table 5.16). They are often useful when the goal is stopping overused medications
(triptans, combination drugs, or opioids) before preventive treatments
become effective. Steroids are often effective for this, as are combinations
of NSAIDs and an antiemetic. Our goal is to keep the patient functional and
avoid IV treatments or hospital admission; so advise a higher dose of antiemetics
before bedtime.
Peripheral procedures
Peripheral anesthetic procedures, such as nerve blocks, offer the potential for
rapid headache relief with minimal AEs. Greater occipital nerve blocks have been
used for migraine and reports are generally positive, especially for patients with
allodynia. We use local anesthetics such as lidocaine (1% or 2% solution), longeracting
bupivacaine (0.25%–0.5%) solution, or a combination of two agents, for
the blocks. Corticosteroids are sometimes added, but these drugs have no proven
additional benefi t, except in cluster headache (Figure 5.1, Table 5.17).

Prophylactic Treatment

(Page-58)

MIGRAINE PREVENTION: WHEN?

Prevention is necessary when migraine causes undue distress, dysfunction,
and spending of healthcare dollars (Table 6.2).
The recommendation to start preventive treatment when headaches occur
more than once weekly is supported by data from a large population of episodic
migraine patients (Figure 6.1).
(Page-59M)

MIGRAINE PREVENTION: HOW?

When deciding to start preventive therapy, there are many medications to
choose from. The ideal medication is highly effective across a broad population,
has few side effects (or advantageous ones), and does not interfere
with (or even better, enhances) the treatment of coexistent conditions. Once
the treatment is selected, set realistic expectations. Inform the patient of
common and uncommon side effects and how to manage them. Explain that
preventive treatment takes time to work (several weeks if not months) and
is unlikely to eliminate attacks entirely, but will make them far more manageable
in terms of reduced frequency, intensity, and duration, and should
improve responsiveness to acute treatment.

Start
with 10% to 30% of the target preventive medication dose and increase
incrementally and gradually (5–14 days between dose escalations). If the
fi rst preventive trial fails, try something from another therapeutic class, and
revisit any issue of medication overuse. If multiple single trials fail, consider
(Page-60U)
using two or more preventive medications in combination. When results
seem suboptimal, daily calendars can be useful in establishing whether any
type of gains are being made (frequency, intensity, responsiveness to acute
treatment) and can also reveal unrecognized medication overuse. For women
of childbearing potential, ensure contraception is adequate

Have patients keep track of their headaches to monitor for changes

in frequency, intensity, responsiveness to acute medications, and temporal
pattern. Sometimes these changes are not obvious and require a headache
calendar to document them. Many patients are mistaken about their baseline
headache frequency and patterns. Once adequate control has been attained
and maintained for 6 months, consider tapering preventive medication.
Patients can often taper medication without worsening and can maintain
control with lifestyle changes and nonprescription supplements (Table 6.3).
A recent placebo-controlled, double-blind study has shown that the effects
of 6 months of preventive treatment with topiramate (Topamax) can last for
at least 6 months after discontinuation.
How do preventive medications work? Many believe that preventive medications
reduce neuronal hyperexcitability. Evidence from an animal model
of migraine supports this: preventives raise the threshold for cortical spreading
depression. Endothelial stabilization may be another mechanism, because
angiotensin converting enzyme inhibitors, as well as angiotensin receptor
blockers, have demonstrated preventive benefi t.

(Page-60L)
(Page-61U)
MIGRAINE PREVENTION: WHAT?
Preventive medications generally come in four categories: anticonvulsants,
antidepressants, antihypertensives, and others.

(Page-61M)
(Page-61)
(Page-1702RU)A preventive program is
appropriate when attacks occur weekly
or several times a month, or when they occur
less often but
are very prolonged and debilitating. The most
effective prophylactic
agents available typically reduce headache
frequency
by at least 50% in approximately 50% of
patients.
Preventive medications are generally titrated
gradually to
the minimum effective or maximum tolerated
dosage. This
target dosage is maintained for at least 3
months, and if there
is a beneficial response, the medication is
continued until
there has been clinical stabilization for at least 6
to 12 months.
The full benefit of a preventive medication may
take up to 6
months to be realized.

β-Adrenergic Blockers. β-Adrenergic

antagonists are widely
used for prophylaxis of migraine headaches
(Silberstein et al.,
2012). Propranolol in doses of 80 to 240 mg/day,
if tolerated,
should be given a trial of 2 to 3 months.
Compliance increases
with the use of a long-acting form of propranolol
given once
daily. Side effects are not usually severe.
Lethargy or depression
may occur and may be a reason for
discontinuation of the
medication. Hypotension, bradycardia,
impotence, insomnia,
and nightmares can all occur. As with all β-
adrenergic blocking
agents, propranolol should be discontinued
slowly to avoid
cardiac complications. It is contraindicated in
persons with a
history of asthma or severe depression and
should be used
with caution in patients using insulin or oral
hypoglycemic
agents, because it may mask the adrenergic
symptoms of
hypoglycemia. Timolol, nadolol, atenolol, and
metoprolol
probably have approximately the same benefit in
migraine as
propranolol.

Calcium Channel Blockers. Although the

relevant mechanism
by which calcium channel antagonists affect
migraine is
not known, their use in migraine was originally
based on their
ability to prevent vasoconstriction and on their
other actions,
including prevention of platelet aggregation and
alterations in
release and reuptake of serotonin. Several
clinical trials have
indicated some benefit for verapamil and
flunarizine in preventing
recurrent migraine. Little evidence exists to
support
the use of nimodipine. Verapamil in doses of 80
to 160 mg
three times a day reduces the incidence of
migraine with aura,
but it is not as useful in migraine without aura

Antidepressants. Amitriptyline and other

tricyclic antidepressants
can be helpful in migraine prophylaxis
(Silberstein
et al., 2012). The benefit seems to be
independent of their
antidepressant action, which typically requires
doses higher
than that used for migraine. Used in doses of 10
to 150 mg at
night, amitriptyline, nortriptyline, imipramine, or
desipramine
may all provide some reduction in attacks of
migraine,
although evidence of efficacy in clinical trials is
available only
for amitriptyline.
(Page-1703LU) Selective serotonin reuptake
inhibitors have not consistently
proven to be effective for migraine prophylaxis
and in
some cases may elicit or aggravate headaches.
Given the
frequent comorbidity of generalized anxiety
disorder and
panic disorder, a serotonin-norepinephrine
reuptake inhibitor
such as venlafaxine may be considered if a single
agent is
desired. Venlafaxine is probably used less
commonly than the
tricyclic antidepressants discussed above.

(Page-1703LM) Anticonvulsants. Antiepileptic

medications are in general a
highly efficacious class of prophylactic treatment.
Their mechanisms
of action in migraine prophylaxis are unknown’

Valproic acid, given in the form of divalproex

sodium,
is generally effective (Silberstein et al., 2012) at
a range of 500
to 1750 mg/day taken in divided doses. Side
effects include
sedation, dizziness, increased appetite, increased
bleeding
time, increased fragility of hair, and an
asymptomatic increase
in liver function test values. Valproate is
contraindicated in
women who are at risk for becoming pregnant,
because it is
associated with an increased risk for neural tube
defects.
While only limited evidence is available to
support its use,
gabapentin does appear to be effective in the
reduction of
migraine frequency in clinical practice. It also has
beneficial
effects in somatic pain and may be a good choice
if a patient
has neck pain, back pain, or painful peripheral
neuropathy as
well as migraine. It appears relatively well
tolerated, although
dizziness and sedation may limit its use in some
patients. The
usual therapeutic dose range for gabapentin is
900 to
2400 mg/day. Topiramate’s efficacy for migraine
was demonstrated
in pivotal large randomized trials (Brandes et al.,
2004). Topiramate has effects not only on γ-
aminobutyric
acid (GABA) but also on non-NMDA glutamate
and carbonic
anhydrase activity. It may have prominent
sedating and cognitive
side effects, making a slow gradual titration of
the drug
(15–25 mg/wk initially) to the therapeutic range
of 75 to
200 mg/day the most successful strategy. Too
rapid a titration
schedule increases the risk of precipitating
depression, especially
if there is a personal or family history (Mula et al.,
2009). Other side effects include paresthesia and
weight loss,
the latter making topiramate a particularly
attractive choice
for many patients. It is also associated with a
mildly increased
risk for calcium phosphate kidney stones.
Zonisamide may be
a good alternative in topiramate-intolerant
patients who had
previously experienced a good response
(Mohammadianinejad
et al., 2011).

Other Prophylactic Agents. Cyproheptadine is

a peripheral
serotonin antagonist, typically utilized in
pediatric patients

(Page-1703RU) Riboflavin administered orally in a

dose of 400 mg/day has
been shown by Schoenen to be effective in
migraine prophylaxis

Aspirin, 325 mg, taken every other day for the

prevention
of cardiovascular disease may slightly reduce the
frequency of
migraine. NSAIDs are being increasingly
recognized as having
benefit in migraine prophylaxis, and may be
associated with
reduced risk of chronic migraine development in
individuals
with less than 10 headache days per month
based on epidemiologic
studies (Lipton et al., 2013).
OnabotulinumtoxinA injection in the treatment of
chronic
migraine is now supported by two large
multicenter placebocontrolled
randomized clinical trials, and is currently the
only
FDA-approved treatment specifically for chronic
migraine
(Dodick et al., 2010). Botulinum toxin blocks the
release of
glutamate from nociceptive terminals and
therefore may
reduce or inhibit the development of peripheral
and central
trigeminal sensitization. The mechanism of action
may be
referable to the observation that single
trigeminal afferents
may have both dural and extracranial projections
(Schueler
et al., 2013).

(Page-1704LU) ). Menstrual Migraine. Migraine

attacks are generally associated
with menses in one of two ways. The attacks may
occur
exclusively during menstruation and at no other
time during
the cycle. This association is referred to as pure
menstrual
migraine (PMM), and it has been proposed that
PMM be
defined as attacks that occur between days −2
and +3 of the
menstrual cycle. The prevalence of PMM
according to this
definition is about 7%. More commonly, migraine
attacks
occur throughout the cycle but increase in
frequency or
intensity at the time of menstruation
(menstrually-related
migraine). This association occurs in up to 60%
of female
migraineurs. Menstrual migraines have a
tendency to be more
severe, disabling, and treatment-refractory. Aura
is uncommon.
(Page-71) There is a link between migraine and the female sex hormones—estrogen
and progesterone. Migraine occurs more frequently in adult women (18%)
than in men (6%), although prevalence is equal in children. Migraine develops
most frequently in the second decade, with the peak incidence occurring
with adolescence. Many migrainous women experience menstrual migraine
(MM) mainly at the time of menses (menstrually related migraine [MRM])
and some experience it exclusively with menses (pure menstrual migraine
[PMM]). Migraine may worsen during the fi rst trimester of pregnancy
and although many women become headache-free during the last two trimesters,
25% have no change in their migraine. MM typically improves
with pregnancy, perhaps due to sustained high estrogen levels. Hormonal
replacement with estrogens can exacerbate migraine, and oral contraceptives
(OCs) can change its character and frequency. Migraine prevalence
decreases with advancing age (>50) but may regress or worsen at menopause.

(page-72)
TABLE 7.2 Types of Menstrual Migraine
MRM
Attacks occur days −2 to +3 of menses and at
other times
PMM
Attacks only occur days −2 to +3 of menses
Premenstrual migraine
Attacks occur days −7 to −2 before menses
Abbreviations: MRM, menstrually related
migraine; PMM, pure menstrual migraine

(Page-1704LM) Management of Menstrual

Migraine
To establish a direct link between menstruation
and headache
attacks, ask the patient to keep a diary of
migraine attacks and
menstrual periods for at least 3 consecutive
months. The
nature of this relationship determines
subsequent therapy. For
example, for patients who have both menstrual
and nonmenstrual
migraine, a standard prophylactic medication
might be
used throughout the cycle rather than the
perimenstrual use
of a prophylactic agent. Clearly outline the goals
of therapy in
addition to the dosages, benefits, and side-effect
profile of
each recommended medication.
(Page-73M)Women can also be treated perimenstrually with short-term prophylaxis
(Table 7.5). NSAIDs in adequate doses can be used preventively 1 to 2 days before
the expected onset of headache and continued for the duration of vulnerability.
(page-1705LM) For those with PMM, attacks are
also preventable by stabilizing
estrogen levels during the late luteal phase of
the cycle.
Estrogen levels can be stabilized by maintaining
high levels
with estrogen supplements:
• Transdermal estradiol (1 × 100 μg days
−3/−1/+2)
• Combined oral contraceptive or transdermal
patch
(3–4 mo)
• Percutaneous estradiol (1.5 mg daily days −3
to +6).
Estrogen levels can also be stabilized by
maintaining low
levels that result from natural menopause or
from antiestrogen
agents such as danazol, tamoxifen, and
goserelin.
Estradiol implants, percutaneous estradiol gel,
and estrogen
patches produce reasonably stable levels of
estrogen, and
their use can be an effective preventive strategy.
If periods are
less predictable, suppression of the ovulatory
cycle with high
static estrogen levels can be accomplished with
either a lowdose
combined estrogen-progestin oral contraceptive
pill
taken continuously for 3 to 4 months or with two
100-μg
patches replaced every 3 days in combination
with cyclic
progestogens. Treatments that suppress the
cycle by reducing
estrogen levels (danazol), inducing a medical
menopause
(goserelin), or modifying the effect of estrogen
(tamoxifen)
have also been anecdotally reported to be
successful in the
treatment of resistant menstrual migraine

(Page-1705RU) Oral Contraception in Female

Migraineurs

The International Headache Society Task Force

developed
evidence-based recommendations for the use of
oral contraceptives
and hormone replacement therapy in
migraineurs
(Bousser et al., 2000). When prescribing
combination oral
contraceptives (COCs) in women with migraine,
their recommendations
were as follows:
• Identify and evaluate risk factors.
• Diagnose migraine type, particularly the
presence of aura.
• Women with migraine should stop smoking
before starting
COCs.
• Treat other conditions such as hypertension
and
hyperlipidemia.
• Consider nonethinylestradiol methods in
women at
increased risk for ischemic stroke. Progestogen-
only hormonal
contraception may not increase ischemic stroke
risk.
• High-dose COCs (50 μg ethinylestradiol) are not
recommended
for routine use.
• Low-dose formulations (<50 μg
ethinylestradiol) containing
either second- or third-generation progestogens
should
be used when possible.
Migraine symptoms that may necessitate further
evaluation or
cessation of COC include: new persisting
headache, new onset
of migraine aura, increased headache frequency
or intensity,
and/or development of unusual aura symptoms,
particularly
prolonged aura.

(Page-1706RU) Migraine and Pregnancy.

Pregnancy has a variable effect on
migraine (see Chapter 112). Although
approximately 70% of
women experience improvement or remission of
migraine
symptoms during pregnancy, the attacks can
either remain
unchanged or worsen. Moreover, migraine may
begin for the
first time during pregnancy.

(Page-1706RM)The use of medication to treat

migraine during pregnancy
should be limited. For most mild to moderate
attacks, use
nonpharmacological treatment, including
biofeedback, rest,
and relaxation therapy.

(Page-81L)
Nonpharmacologic therapy is especially important in headache management
during pregnancy. Behavior modifi cation (e.g., avoiding migraine triggers)
can be highly effective, especially when combined with other therapies.

(Page-82U) Regular habits, such as regular sleep, exercise, meals, work habits, and time for
relaxation, can reduce headache frequency. Patients should avoid sleeping-in,
over-exercising, skipping meals, excess stress, becoming overtired, and overusing
stimulants such as caffeine. They should be warned about the dangers of
overusing acute treatments. This can result in increased headache frequency
and may pose an additional risk to the fetus.
The most commonly used nonpharmacologic techniques are biofeedback,
acupuncture, and physical therapy.

Acetaminophen may be combined

with codeine, but the indiscriminate use of
codeine may
present a risk to the fetus during the first or
second
trimester.

(Page-79M)
For patients with severe attacks or status
migrainosus, the
risk to the developing fetus may be greater than
the judicious
use of medications. The IV use of neuroleptics,
supplemented
with either IV opioids or corticosteroids, can be
an effective
strategy. Chlorpromazine or prochlorperazine (10
mg) delivered
in 4 mL of crystalloid or 50 mL of normal saline
as a
bolus over 10 to 15 minutes can be effective for
the headache
as well as the nausea and vomiting associated
with a severe
attack. Methylprednisolone (50–250 mg)
delivered IV can also
be an effective method to terminate a severe
acute migraine
attack or status migrainosus during pregnancy.
Intravenous
magnesium sulfate (1 g) may be an effective
alternative

(Page-1706LL)Migraine in Menopause. Just

as with pregnancy, the effect
of menopause on the course of migraine is
somewhat unpredictable.
In two-thirds of women with a previous history,
migraine decreases with a physiological
menopause, but it can
either regress or worsen at menopause; in a
minority of
women, migraine or its functional equivalents
may begin after
menopause.
Women with menopausal symptoms resulting
from erratic
or diminished estrogen secretion may benefit
from HRT, but
consider potential risks. Few published studies
have assessed
the effects of HRT on migraine in perimenopausal
women,
but the evidence available appears to highlight
the importance
of both route and method of administration. With
any preparation
of estrogen, use the lowest effective dose. In
general,
parenteral or transdermal preparations provide a
physiological
ratio of estradiol to estrone and a steady-state
concentration
of estrogen.

Cyclic progestins may worsen migraine. For

women who
require combined estrogen and progesterone
therapy after
hysterectomy, a transdermal progestin patch
usually circumvents
this problem.

(Page-76) Hormone Replacement Therapy and Headaches

Hormone replacement therapy (HRT) can be with estrogen alone (estrogen
replacement therapy [ERT]) or combined with a progestin. Oral, but not transdermal,
HRT is often associated with worsening of migraine. Headaches that
develop as a result of HRT may be diffi cult to manage. Several empirical
strategies are useful (Table 7.9).
(Psage-77M) Reducing the dose of estrogen or changing the estrogen type from
conjugated
estrogen to pure estradiol, ethinyl estradiol, or estrone may reduce headache.
Changing from interrupted to continuous administration may be very
effective if the headaches are associated with estrogen withdrawal. Techniques
may be combined. The estradiol cutaneous patch, which provides a physiologic
ratio of estradiol to estrone and a steady-state concentration of estrogen,
has been associated with fewer headache side effects. The new selective estrogen
receptor modulator (SERM), raloxifene, can be used if a woman requires,
but cannot tolerate, estrogen.
Progestins, used to prevent endometrial hyperplasia, can cause headache,
particularly if used cyclically. Giving a lower dose of a progestin continuously

(Page-78) can often control this effect. Another strategy is to change the type of progestin
used. One can use targeted drug delivery, like the progesterone-containing
vaginal gel. This maximizes progesterone’s effect on the uterus while
minimizing its potential adverse effects, including headaches. Progestogens,
particularly norethisterone and megestrol, can relieve or reduce hot fl ushes
independently of estrogen.

(Page-1707LM) Chronic Migraine

Chronic migraine, previously referred to as
transformed
migraine, is characterized by headaches
(tension-type and/or
migraine) on 15 or more days per month in a
patient with
prior migraine history, with at least 8 days per
month being
migraine for at least 3 months (Headache
Classification Committee,
2013).
Patients with CM usually have a history of
episodic migraine
that began in their second or third decade of life.
In the majority,
the evolution from episodic migraine to chronic
migraine
is gradual, but the transition can be abrupt in
about 30% of
patients. Population studies estimate that
patients with episodic
migraine will transition to CM at the rate of
approximately
2.5% per year (Lipton, 2009). For the patient with
CM, on some days the headaches and associated
symptoms
(nausea, photo/phonophobia) may retain
characteristics of
migraine, whereas on other days, symptoms may
be indistinguishable
from a tension-type headache. These patients do
not have “mixed” or “combined tension-vascular
headaches,”
antiquated terms that are still used (Dodick,
2006).
Treatment of CM requires preventive medications
and judicious
use of acute medications. Only topiramate and
onabotulinumtoxinA
have been studied specifically in chronic
migraine
via controlled studies. Two randomized double-
blind placebocontrolled
studies demonstrated that topiramate was
effective
and achieved significant reductions in migraine
frequency
(Diener et al., 2007; Silberstein et al., 2007). A
pooled analysis
of results from two large phase-III placebo-
controlled studies
(PREEMPT 1 and 2) demonstrated a mean
decrease from baseline
in frequency of headache days, with statistically
significant
between-group differences favoring
onabotulinumtoxinA
over placebo at Week 24 (−8.4 vs −6.6; P <
0.001) (Dodick
et al., 2010). While the therapeutic gain over
placebo for this
and many of the PREEMPT trials’ outcomes
appeared to be
modest, onabotulinumtoxinA has been found to
significantly
reduce chronic migraine impact and improve
quality of life
(Lipton et al., 2011). The excellent tolerability of
onabotulinumtoxinA
makes it an extremely attractive alternative for
patients who fail to tolerate oral prophylactics.
The injection
protocol used in the PREEMPT trials is currently
the most
widely accepted method of administration
(Blumenfeld
et al., 2010).
While not rigorously studied for the treatment of
CM,
gabapentin, divalproex sodium, amitriptyline,
and β-adrenergic
blockers among other preventives used for
episodic migraine
prophylaxis are also frequently used in CM
prevention, based
on evidence for their effectiveness in patients
with episodic
migraine and a long clinical experience with
these medications
for migraine prevention (for more details, see
Migraine
Prophylactic Treatment, earlier).
Similarly to episodic migraine management (see
previous
discussion), preventive medications are generally
titrated to
the minimum effective or maximum tolerated
dosage over the
course of 1 to 2 months. This target dosage is
maintained for
at least 3 months, and if there is a beneficial
response (>50%
reduction in headache days), the medication is
continued

until there has been clinical stabilization for at

least 6 to 12
months. It must be remembered that the full
benefit of a
preventive medication may take up to 6 months
to be realized.
An attempt to taper and discontinue the
preventive medication
is reasonable, but only after consultation with the
patient
and after a reasonable period of stability (>6–12
months).

Medication Overuse Headache

Overuse of acute medications by patients with
frequent headache
may lead to a daily headache syndrome, now
known as
medication overuse headache (MOH). Previously
referred to as
rebound or medication-induced headache, this
syndrome is
induced and maintained by the very medications
used to relieve
the pain. The risk for development of medication
overuse
headache varies with individual substances.
Opioids, butalbitalcontaining
compounds, and some combination analgesics
appear to have the highest risk; triptans carry
moderate risk, and
NSAIDs the lowest risk. The population
prevalence of CDH
associated with acute medication overuse has
been estimated
to be 1.4% (Colas et al., 2004). The proportion of
patients in
the population with CDH who overuse acute
medications
ranges from 18% to 33%, indicating that
medication overuse is
not necessary for the development of CDH, nor is
the overuse
of acute medication synonymous with MOH. In
other words,
tapering and discontinuing the overused
medication does not
always return the patient to an episodic pattern
of headache.
The most frequently overused acute medications
include
analgesics, opioids, butalbital-containing
products, ergotamine,
and triptans, alone or in combination. The delay
between the
frequent intake of these medications and the
development of
CDH appears to be shortest for triptans (1.7
years), longer for
ergots (2.7 years), and longest for analgesics (4.8
years). The
duration of withdrawal symptoms after
discontinuation and
the recidivism rate are also shortest/lowest for
triptans and
longest/highest for analgesics.
The pathogenesis of MOH is unclear. A leading
hypothesis
suggests facilitation of central trigeminal
sensitization caused
by a medication-induced impairment of
descending inhibition
of nociceptive trafficking. In rats, chronic
morphine
exposure increases the pain, facilitating “on” cell
activation in
the rostral ventromedial medulla (RVM) that may
alter the
balance between the descending inhibition from
the nucleus
reticularis dorsalis (NRD) and the facilitation from
the RVM
in favor of a pro-nociceptive increased
descending facilitation
from the RVM (Meng and Harasawa, 2007;
Okada-Ogawa
et al., 2009). Similar neural adaptations may
contribute to
opiate-induced MOH in humans by increasing the
responsiveness
of the nociceptive system, as well as increasing
the
transmission of pain signals at the medullary
dorsal horn (De
Felice and Porreca, 2009). Animal studies have
found that
sustained or repeated administration of triptans
can also
induce pro-nociceptive neural adaptations,
enhance responses
to established triggers of migraine headache and
lower cortical
spreading depression threshold, the latter of
which can
increase the activation of the trigeminal nucleus
caudalis
(De Felice et al., 2010; Green et al., 2013). Some
individuals
may possess a genetically determined liability to
medication
overuse. A fluorodeoxyglucose-PET study in
patients with
chronic analgesic overuse in migraine sufferers
demonstrated
persistent hypometabolism of the orbitofrontal
cortex (especially
in patients overusing combination analgesics)
even after
withdrawal of the overused medication.
Persistent orbitofrontal
hypofunction is known to occur in substance
abuse (Fumal
et al., 2006).
Treatment of MOH is challenging and requires
aggressive
nonpharmacological and appropriate acute and
preventive
headache treatment. Rigorous controlled data
are lacking, but
development of CM identified in population-based
and
clinic-based prospective studies include baseline
high attack
frequency, obesity, stressful life events, snoring,
cutaneous
allodynia, and overuse of certain classes of
medications, particularly
opioid and barbiturate combination products
(Lipton, 2009; Louter et al., 2013). These risk
factors may help
clinicians identify those who may be at highest
risk for the
development of CM. It is important to recognize
and address
coexistent sleep and mood disorders that can
lead to exacerbation
of the underlying headache condition.
Chronic Migraine
Chronic migraine, previously referred to as
transformed
migraine, is characterized by headaches
(tension-type and/or
migraine) on 15 or more days per month in a
patient with
prior migraine history, with at least 8 days per
month being
migraine for at least 3 months (Headache
Classification Committee,
2013).
Patients with CM usually have a history of
episodic migraine
that began in their second or third decade of life.
In the majority,
the evolution from episodic migraine to chronic
migraine
is gradual, but the transition can be abrupt in
about 30% of
patients. Population studies estimate that
patients with episodic
migraine will transition to CM at the rate of
approximately
2.5% per year (Lipton, 2009). For the patient with
CM, on some days the headaches and associated
symptoms
(nausea, photo/phonophobia) may retain
characteristics of
migraine, whereas on other days, symptoms may
be indistinguishable
from a tension-type headache. These patients do
not have “mixed” or “combined tension-vascular
headaches,”
antiquated terms that are still used (Dodick,
2006).
Treatment of CM requires preventive medications
and judicious
use of acute medications. Only topiramate and
onabotulinumtoxinA
have been studied specifically in chronic
migraine
via controlled studies. Two randomized double-
blind placebocontrolled
studies demonstrated that topiramate was
effective
and achieved significant reductions in migraine
frequency
(Diener et al., 2007; Silberstein et al., 2007). A
pooled analysis
of results from two large phase-III placebo-
controlled studies
(PREEMPT 1 and 2) demonstrated a mean
decrease from baseline
in frequency of headache days, with statistically
significant
between-group differences favoring
onabotulinumtoxinA
over placebo at Week 24 (−8.4 vs −6.6; P <
0.001) (Dodick
et al., 2010). While the therapeutic gain over
placebo for this
and many of the PREEMPT trials’ outcomes
appeared to be
modest, on a botulinumtoxinA has been found to
significantly
reduce chronic migraine impact and improve
quality of life
(Lipton et al., 2011). The excellent tolerability of
onabotulinumtoxinA
makes it an extremely attractive alternative for
patients who fail to tolerate oral prophylactics.
The injection
protocol used in the PREEMPT trials is currently
the most
widely accepted method of administration
(Blumenfeld
et al., 2010).
While not rigorously studied for the treatment of
CM,
gabapentin, divalproex sodium, amitriptyline,
and β-adrenergic
blockers among other preventives used for
episodic migraine
prophylaxis are also frequently used in CM
prevention, based
on evidence for their effectiveness in patients
with episodic
migraine and a long clinical experience with
these medications
for migraine prevention (for more details, see
Migraine
Prophylactic Treatment, earlier).
Similarly to episodic migraine management (see
previous
discussion), preventive medications are generally
titrated to
the minimum effective or maximum tolerated
dosage over the
course of 1 to 2 months. This target dosage is
maintained for
at least 3 months, and if there is a beneficial
response (>50%
reduction in headache days), the medication is
continued

(Page-1707RU) until there has been clinical

stabilization for at least 6 to 12
months. It must be remembered that the full
benefit of a
preventive medication may take up to 6 months
to be realized.
An attempt to taper and discontinue the
preventive medication
is reasonable, but only after consultation with the
patient
and after a reasonable period of stability (>6–12
months).
(Page-1707RU) Medication Overuse Headache
Overuse of acute medications by patients with
frequent headache
may lead to a daily headache syndrome, now
known as
medication overuse headache (MOH). Previously
referred to as
rebound or medication-induced headache, this
syndrome is
induced and maintained by the very medications
used to relieve
the pain. The risk for development of medication
overuse
headache varies with individual substances.
Opioids, butalbitalcontaining
compounds, and some combination analgesics
appear to have the highest risk; triptans carry
moderate risk, and
NSAIDs the lowest risk.

(Page-40M) Monitor Frequency of

Medication Use
Overuse of acute pain medication is a
complication of frequent headache
and can lead to increased headache
frequency and treatment refractoriness.
Medication overuse headache (MOH) is defi
ned as using simple analgesics
more than 15 days a month or using
triptans, ergots, opioids, or combination
medications more than 10 days a month for
more than 3 months. There is no
credit for using multiple abortive types if the
patient still uses any abortive
more than one-half of the days of the
month.
MOH affects migraine patients more than
patients with other headache
disorders and is one cause of chronic daily
headache (CDH). Treating MOH
by withdrawing the offending agent can
bring about improvement, but often
only after a period of increased headache
that lasts days to weeks to months.
Migraineurs should be aware of MOH and
keep a calendar or diary of their
headaches and acute medication use. MOH
can also cause adverse events
(AEs), such as ergotism, constipation,
gastrointestinal and renal disease, or
tardive dyskinesias, specifi c to the class of
medication (Table 5.3).
It is diffi cult for patients with frequent
headaches or CDH to avoid medication
overuse. To manage this risk and navigate
between undertreatment and medication
overuse, we use “the rule of 4s”: If
headache days are <4 per month, be
aggressive in treating every migraine. In
general, treat aggressively; however,
some restraint is indicated, and if headache
frequency is >8 per month, stress
the use of preventive treatment, coping,
nonsteroidal anti-infl ammatory drugs
(NSAIDs), and neuroleptics, and modify the
early treatment paradigm.

(Oage-1707RM) The most frequently overused

acute medications include
analgesics, opioids, butalbital-containing
products, ergotamine,
and triptans, alone or in combination. The delay
between the
frequent intake of these medications and the
development of
CDH appears to be shortest for triptans (1.7
years), longer for
ergots (2.7 years), and longest for analgesics (4.8
years). The
duration of withdrawal symptoms after
discontinuation and
the recidivism rate are also shortest/lowest for
triptans and
longest/highest for analgesics

(Page-41U)
Management-
(Page-1708LU) it is generally considered that
lifestyle modifications such as
limiting or eliminating caffeine consumption,
exercise, and
establishing regular mealtimes and sleep
schedules can be
beneficial for some patients. Depression, anxiety,
and sleep
disturbances occur in more than half of patients
and must be
addressed. Training in relaxation techniques and
biofeedback
may be helpful, especially if stress or anxiety is a
frequent
provocative trigger. Patients should always be
provided with
support and close follow-up, particularly during
the first 8
weeks after treatment is initiated.

Pharmacological treatment involves tapering or

discontinuing
the overused medication. Abrupt drug withdrawal
is
the treatment of choice except with barbiturates,
benzodiazepines
and opioids. Typical withdrawal symptoms last 2
to 10 days (mean 3.5 days) but may persist for 2
to 4 weeks.
In most patients, the withdrawal can be managed
on an
outpatient basis. Patients with coexistent medical
or psychiatric
illnesses and overuse of agents containing
opioids,
benzodiazepines, and barbiturates may need
hospitalization
or withdrawal in a controlled environment.
Prednisone
60 mg daily for 5 days as a transitional and short-
term treatment
during the withdrawal phase to reduce
withdrawal
symptoms can be considered and may decrease
the need
for acute treatment during this time (Evers and
Jensen,
2011; Rabe et al., 2013). Preventive medication
aimed at the
underlying primary headache disorder should be
started
from the outset while initiating the taper of the
overused
substance.
Studies have indicated a high rate of relapse
following
withdrawal of acute headache medications in
patients with
presumed MOH. One prospective study reported
a relapse rate
of 41% in the first year and 45% after 4 years
(Katsarava et al.,
2005).

To avoid MOH relapse, in general, it is best to

avoid the
use of opioids and/or butalbital for the regular
management
of primary headache disorders. To prevent
relapse, limit
NSAIDs, aspirin, or acetaminophen use to ≤14
days/month
and limit combination analgesics, triptans, ergot
derivatives or
opioids to ≤9 days/month. Although data are
limited, the
effectiveness of preventive medications may be
decreased by
overuse of acute medications (Mathew et al.,
1990).