Vol 30.2 Headache 2024

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APRIL 2024
VOL. 30 NO. 2 Headache
Guest Editor: Amy Gelfand, MD
294 Editor’s Preface

Editor-in-Chief: Lyell K. Jones Jr, MD, FAAN
REVIEW ARTICLES
296 Approach to the Patient With Headache

Deborah I. Friedman, MD, MPH, FAAN
325 Pathophysiology of Migraine

Nazia Karsan, PhD, MRCP
344 Acute Treatment of Migraine

Rebecca Burch, MD, FAHS
364 Preventive Treatment of Migraine

Richard B. Lipton, MD, FAAN
379 Medication-Overuse Headache

Paul Rizzoli, MD, FAAN, FAHS
391 Cluster Headache, SUNCT, and SUNA

Mark Burish, MD, PhD
411 Posttraumatic Headache

Todd J. Schwedt, MD, FAAN
425 New Daily Persistent Headache

Matthew Robbins, MD, FAAN, FAHS
DENOTES CONTINUUM
AUDIO INTERVIEW
438 Headache in Children and Adolescents
DENOTES SUPPLEMENTAL Serena L. Orr, MD, MSc, FRCPC
DIGITAL CONTENT
473 Cranial Neuralgias
Stephanie J. Nahas, MD, MSEd, FAAN
488 Indomethacin-Responsive Headache Disorders

Peter J. Goadsby, MD, PhD, FRS
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

SELECTED TOPICS IN NEUROLOGY PRACTICE
498 Diversity, Equity, and Inclusion in Headache Care

and Research
Rashmi B. Halker Singh, MD, FAAN; Jessica Kiarashi, MD
SELF-ASSESSMENT AND CME
284 Learning Objectives and Core Competencies
513 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
515 Postreading Self-Assessment and CME Test
527 Postreading Self-Assessment and CME Test—Preferred Responses
537 Index
List of Abbreviations (Back Cover)

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives ◆ Describe the clinical features, etiology, mimics,

management, and prognosis of new daily persistent
Upon completion of this Continuum: Lifelong
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headache
Learning in Neurology Headache issue,
participants will be able to: ◆ Describe the latest epidemiology, assessment, and
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management principles pertaining to children and

◆ Apply the principles of evaluating patients with adolescents presenting with headache
headache in clinical practice
◆ Distinguish primary and secondary presentations
of cranial neuralgias and apply evidence-based
◆ Identify the extended phenotypic spectrum of
management strategies to clinical practice
migraine, the likely central basis for attack initiation,
the neuroanatomy of key structures involved in
migraine neurobiology and their likely symptomatic ◆ Recognize the existence and treatability of the
correlates, and the neurochemical systems that may indomethacin-responsive headache disorders
have a role in migraine therapeutics paroxysmal hemicrania and hemicrania continua
◆ Describe the approach to the acute treatment

of migraine, including goals of therapy; review Core Competencies
nonspecific and migraine-specific options for the
acute treatment of migraine; discuss how to choose This Continuum: Lifelong Learning in Neurology
among the various treatment options; review the Headache issue covers the following core
safety of acute-treatment options in pregnancy; and
consider rescue and inpatient treatment options competencies:
◆ Describe strategies for preventive treatment of ◆ Patient Care and Procedural Skills
migraine including the emerging role of calcitonin
gene-related peptide–targeted therapies and discuss ◆ Medical Knowledge
novel paradigms of preventive treatment
◆ Practice-Based Learning and Improvement
◆ Discuss best practices for the diagnosis and
management of medication-overuse headache ◆ Interpersonal and Communication Skills
◆ Diagnose and manage cluster headache, SUNCT, ◆ Professionalism

and SUNA
◆ Systems-Based Practice
◆ Describe the epidemiology, diagnosis, clinical
presentation, pathophysiology, prognosis, and
treatment of posttraumatic headache attributed to
mild traumatic brain injury
284 A P R I L 2 0 24

CONTRIBUTORS a
Amy Gelfand, MD, Rebecca Burch, MD, FAHS

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Guest Editor Assistant Professor,

Associate Professor, Benioff Department of Neurological
Children’s Hospitals, University Sciences, Larner College
of California San Francisco, of Medicine, University of
San Francisco, California Vermont, Burlington, Vermont
Relationship Disclosure: Dr Gelfand has Relationship Disclosure: Dr Burch has
received personal compensation in the received personal compensation in the
range of $500 to $4999 for serving as a range of $10,000 to $49,999 for serving
speaker with Headache Cooperative of the as an editor, associate editor, or editorial
Pacific. Dr Gelfand has received publishing advisory board member for Neurology. Dr
royalties from a publication relating to Burch has received publishing royalties from
health care. The institution of Dr Gelfand a publication relating to health care. An
has received compensation in the range immediate family member of Dr Burch has
of $50,000 to $99,999 for her service as received personal compensation for serving
an editor, associate editor, or editorial as an employee of WellSky and has stock in
advisory board member for the American WellSky.
Headache Society. The institution of Dr
Gelfand has received research support Unlabeled Use of Products/Investigational
from the Duke Clinical Research Institute Use Disclosure: Dr Burch discusses
and UCSF Resource Allocation Program. An the unlabeled use of metoclopramide,
immediate family member of Dr Gelfand prochlorperazine, and promethazine for the
has received personal compensation in the treatment of migraine pain.
range of $50,000 to $99,999 for serving as
an expert witness with the United States
Department of Health and Human Services,
Vaccine Injury Compensation Program. An
immediate family member of Dr Gelfand
has received publishing royalties from a
publication relating to health care. The
institution of an immediate family member
of Dr Gelfand has received research
support from Genentech, Inc., the National
Institutes of Health (NIH)/National Institute
of Neurological Disorders and Stroke, the
National MS Society, and Vigil Neuroscience,
Inc. An immediate family member of Dr
Gelfand has a noncompensated relationship
as a clinical trial steering committee member
with Roche/Genentech that is relevant to
American Academy of Neurology (AAN)
interests or activities.
Unlabeled Use of Products/Investigational

Use Disclosure: Dr Gelfand reports no
disclosure.
a
All relevant financial relationships have been mitigated.
286 A P R I L 2 0 24

Mark Burish, MD, PhD Deborah I. Friedman, MD,
Associate Professor, UT Health MPH, FAAN

Houston, Houston, Texas Neuro-Ophthalmologist
and Headache Specialist,
Relationship Disclosure: Dr Burish has
received personal compensation in Dallas, Texas
the range of $0 to $499 for serving as a
consultant for Doximity, Inc. The institution Relationship Disclosure: Dr Friedman
of Dr Burish has received personal has received personal compensation in
compensation in the range of $500 to $4999 the range of $0 to $499 for serving as a
for his service as a consultant for Beckley consultant for Satsuma Pharmaceuticals,
Psytech and Praxis Precision Medicines. The Inc.; in the range of $500 to $4999 for serving
institution of Dr Burish has received research as a consultant for Axsome Therapeutics,
support from Lundbeck. Inc., LinPharma, and Lundbeck, as an editor,
associate editor, or editorial advisory
Unlabeled Use of Products/Investigational board member for MedLink Neurology
Use Disclosure: Dr Burish discusses the use and Neurology Reviews, and on a scientific
of baclofen, dihydroergotamine, ergotamine, advisory or data safety monitoring board
gabapentin, lidocaine, lithium, octreotide, for Lundbeck; and in the range of $10,000 to
oxygen gas, prednisone, sodium valproate, $49,999 for serving as a consultant for Lilly
sumatriptan nasal spray, topiramate, and Pfizer Inc. and on a speakers bureau
verapamil, warfarin, and zolmitriptan for for AbbVie Inc. and Impel Pharmaceuticals.
the treatment of cluster headache and The institution of Dr Friedman has
carbamazepine, duloxetine, gabapentin, received research support from Spinal
IV lidocaine, lamotrigine, oxcarbazepine, CSF Leak Foundation. Dr Friedman has
pregabalin, topiramate, and verapamil for noncompensated relationships as a medical
the treatment of short-lasting unilateral advisor with the Spinal CSF Leak Foundation,
neuralgiform headache attacks with as a program co-chair for the Scottsdale
conjunctival injection and tearing (SUNCT) Headache Symposium with the American
and short-lasting unilateral neuralgiform Headache Society, and as a treasurer and a
headache attacks with cranial autonomic member of the board of directors with the
symptoms (SUNA), none of which are Southern Headache Society that are relevant
approved by the US Food and Drug to American Academy of Neurology (AAN)
Administration (FDA). interests or activities.

Use Disclosure: Dr Friedman reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 287

CONTRIBUTORS a (CONTINUED)
Peter J. Goadsby, MD, PhD, FRS Rashmi B. Halker Singh, MD,

Professor of Neurology, King’s FAAN

College London, London, Associate Professor of
United Kingdom; Professor Neurology; Director, Headache
Emeritus of Neurology, Medicine Fellowship Program,
University of California, Los Mayo Clinic, Scottsdale, Arizona
Angeles, Los Angeles, California
Relationship Disclosure: Dr Halker Singh
Relationship Disclosure: Dr Goadsby has has received personal compensation in
received personal compensation in the range the range of $0 to $499 for serving as an
of $500 to $4999 for serving as a consultant editor, associate editor, or editorial advisory
for AbbVie Inc., CoolTech LLC, Epalex Corp., board member for Current Neurology &
Pfizer Inc., Praxis Precision Medicines, Sanofi, Neuroscience Reports; in the range of $500
Satsuma Pharmaceuticals, Inc., ShiraTronics, to $4999 for serving as a continuing medical
and Teva Pharmaceutical Industries Ltd. education (CME) speaker with WebMD LLC;
And as an editor, associate editor, or in the range of $5000 to $9999 for serving as a
editorial advisory board member for the CME speaker with Pri-Med and on a scientific
Massachusetts Medical Society; in the range advisory or data safety monitoring board
of $5000 to $9999 for serving as a consultant for Pfizer Inc; and in the range of $10,000 to
for Lundbeck and Sanofi; and in the range of $49,999 for serving as an editor, associate
$10,000 to $49,999 for serving as a consultant editor, or editorial advisory board member
for Amgen Inc., Lilly, and Novartis AG and on a for Headache. Dr Halker Singh has received
scientific advisory or data safety monitoring publishing royalties from a publication relating
board for AEON Biopharma, Inc, and Man and to health care.
Science. Dr Goadsby has received publishing
royalties from a publication relating to health Unlabeled Use of Products/Investigational
care. Dr Goadsby has noncompensated Use Disclosure: Dr Halker Singh reports no
relationships in an executive role with the disclosure.
American Headache Society and as a trustee
with the Migraine Trust and the Organisation
for Understanding Cluster Headache (UK)
that are relevant to American Academy Nazia Karsan, PhD, MRCP
of Neurology (AAN) interests or activities. Postdoctoral Clinical Fellow,
The institution of Dr Goadsby has received
research support from Celgene, Kallyope,
King's College London, London,
and the National Institute for Health and Care United Kingdom
Research.
Relationship Disclosure: Dr Karsan reports no
Unlabeled Use of Products/Investigational disclosure.
Use Disclosure: Dr Goadsby discusses
multiple medications and therapies for the Unlabeled Use of Products/Investigational
treatment of indomethacin-responsive Use Disclosure: Dr Karsan reports no
headache disorders, none of which disclosure.
are approved by the US Food and Drug
Administration (FDA).
a
288 A P R I L 2 0 24

Jessica Kiarashi, MD Richard B. Lipton, MD, FAAN
Assistant Professor of
Professor, The Saul R. Korey

Neurology; Headache Medicine Department of Neurology,
Fellowship Director, University Department of Psychiatry
of Texas Southwestern Medical and Behavioral Sciences, and
Center, Dallas, Texas Department of Epidemiology
Relationship Disclosure: Dr Kiarashi has
& Population Health; Edwin
received personal compensation in the range S. Lowe Chair in Neurology;
of $500 to $4999 for serving as a consultant Vice Chair, The Saul R. Korey
for Cove.
Department of Neurology;
Unlabeled Use of Products/Investigational Director, Montefiore Headache
Use Disclosure: Dr Kiarashi reports no Center, Albert Einstein College of
disclosure.
Medicine, Bronx, New York
Relationship Disclosure: Dr Lipton has
received personal compensation in the
range of $500 to $4999 for serving as a
consultant for Collegium Pharmaceutical,
Cool Tech, Genentech, Inc., LinPharma,
Merck & Co., Inc., and Satsuma
Pharmaceuticals, Inc.; in the range of
$5000 to $9999 for serving as a consultant
for Axon Optics, GSK plc, and Satsuma
Pharmaceuticals, Inc. and on a scientific
advisory or data safety monitoring board
for AbbVie Inc.; in the range of $10,000
to $49,999 for serving as a consultant for
AbbVie Inc., Amgen Inc., Biohaven, Ltd.,
Grifols, S.A., Lundbeck, Pfizer Inc., Teva
Pharmaceutical Industries Ltd., Vedanta
Biosciences, Inc. and on a scientific
advisory or data safety monitoring board for
Biohaven, Ltd., Lilly, and Lundbeck; and in the
range of $50,000 to $99,999 for serving as a
consultant for Lilly. Dr Lipton has received
publishing royalties from a publication
relating to health care. Dr Lipton has stock in
Biohaven, Ltd. and Manistee Partners, LLC.
The institution of Dr Lipton has received
research support from AbbVie Inc., Amgen
Inc., Axsome Therapeutics, Inc., Charleston
Laboratories, Inc., Lilly, electroCore, Inc.,
the National Institute of Neurological
Disorders and Stroke, the National Institute
on Aging, the National Institutes of Health
(NIH), Satsuma Pharmaceuticals, Inc., Teva
Pharmaceutical Industries Ltd., and the US
Department of Veterans Affairs.

Use Disclosure: Dr Lipton discusses
the unlabeled use of amitriptyline,
candesartan, lisinopril, memantine,
metoprolol, and venlafaxine for the
preventive treatment of migraine and the
unlabeled use of calcitonin gene-related
peptide–targeted migraine therapies for
the preventive treatment of migraine in
adolescent patients.

Stephanie J. Nahas, MD, MSEd, Serena L. Orr, MD, MSc, FRCPC

FAAN Assistant Professor,

Associate Professor of Departments of Pediatrics,

Neurology, Thomas Jefferson Community Health Sciences,
University; Assistant Director, and Clinical Neurosciences,
Headache Medicine Fellowship Cumming School of Medicine,
Program, Jefferson Headache University of Calgary; Pediatric
Center, Philadelphia, Neurologist, Alberta Children's
Pennsylvania Hospital, Calgary, Alberta,
Canada
Relationship Disclosure: Dr Nahas has
received personal compensation in the
Relationship Disclosure: Dr Orr has
range of $500 to $4999 for serving as a
received publishing royalties from a
consultant for Theranica Bio-Electronics
publication relating to health care. Dr Orr
Ltd., as an editor, associate editor, or
has noncompensated relationships as
editorial advisory board member for
an associate editor with Headache: The
Springer, and as an expert/talent for a
Journal of Head and Face Pain and as an
CME event with WebMD LLC; in the range
editorial board member with Neurology
of $5000 to $9999 for serving as an editor,
that are relevant to American Academy of
associate editor, or editorial advisory
Neurology (AAN) interests or activities. The
board member for HMP Global; in the
institution of Dr Orr has received research
range of $10,000 to $49,999 for serving as
support from the Alberta Children's
a consultant for Lilly and Lundbeck; and in
Hospital Research Institute and Canadian
the range of $50,000 to $99,999 for serving
Institutes of Health Research.
as a consultant for AbbVie, Inc. Dr Nahas
has received publishing royalties from a
publication relating to health care.
Use Disclosure: Dr Orr discusses the
unlabeled/investigational use of the
following treatments for children and
Use Disclosure: Dr Nahas discusses
adolescents, none of which are approved by
multiple medications and therapies for
the US Food and Drug Administration (FDA):
the treatment of cranial neuralgias, none
acetaminophen, amitriptyline, bupivacaine,
of which are approved by the US Food
cinnarizine, coenzyme Q10, the combined
and Drug Administration (FDA) , except for
trigeminal and occipital nerve stimulator
carbamazepine which is approved for the
device, cyproheptadine, diclofenac,
treatment of trigeminal neuralgia.
divalproex, eletriptan, eptinezumab,
erenumab, the external trigeminal
nerve stimulator device, flunarizine,
fremanezumab, frovatriptan, galcanezumab,
ibuprofen, ketoprofen, levetiracetam,
lidocaine, magnesium, melatonin,
metoclopramide, naproxen, naratriptan,
nimodipine, onabotulinumtoxinA,
ondansetron, pregabalin, prochlorperazine,
propranolol, riboflavin, rimegepant,
sumatriptan nasal spray, and ubrogepant
for the treatment of migraine; verapamil
for the treatment of cluster headache; and
indomethacin for the treatment of primary
stabbing headache, paroxysmal hemicrania,
and hemicrania continua.
a
290 A P R I L 2 0 24

Paul Rizzoli, MD Matthew Robbins, MD, FAAN,
Chief, Division of Headache, FAHS

Department of Neurology, Associate Professor of
Brigham and Women's Hospital; Neurology; Director, Neurology
Associate Professor of Residency Program,
Neurology, Harvard Medical NewYork-Presbyterian/Weill
School, Boston, Massachusetts Cornell Medical Center, New
York, New York
Relationship Disclosure: Dr Rizzoli has
received personal compensation in Relationship Disclosure: Dr Robbins has
the range of $0 to $499 for serving as a received personal compensation in the
consultant for CVS; in the range of $500 to range of $500 to $4999 for serving as
$4999 for serving on a scientific advisory or an editor, associate editor, or editorial
data safety monitoring board for Theranica advisory board member for Springer
Bio-Electronics Ltd. and as an editor, Publishing Company. Dr Robbins has
associate editor, or editorial advisory board received publishing royalties from a
member for Harvard Health Publishing; and publication relating to health care.
in the range of $10,000 to $49,999 for serving Dr Robbins has noncompensated
as an officer or member of the board of relationships as a board of directors
directors for Headache Cooperative of the member and education program speaker
Northeast. Dr Rizzoli has received publishing with the American Headache Society and
royalties from a publication relating to the New York State Neurological Society
health care. The institution of Dr Rizzoli has and as an editorial board member with
received research support from AbbVie, Inc. Continuum that are relevant to American
Academy of Neurology (AAN) interests or
Unlabeled Use of Products/Investigational activities.
Use Disclosure: Dr Rizzoli discusses
the use of monoclonal antibodies to Unlabeled Use of Products/Investigational
calcitonin gene-related peptide (CGRP) Use Disclosure: Dr Robbins discusses the
or CGRP receptors, onabotulinumtoxinA, unlabeled/investigational use of various
and topiramate for the treatment of medications and therapies for the treatment
medication-overuse headache, none of of new daily persistent headache, none of
which are approved by the US Food and which are approved by the US Food and Drug
Drug Administration (FDA). Administration (FDA).

Todd J. Schwedt, MD, FAAN

Professor of Neurology, Mayo

Clinic, Phoenix, Arizona
Relationship Disclosure: Dr Schwedt has
received personal compensation in the range
of $0 to $499 for serving as a consultant for
Amgen Inc.; in the range of $500 to $4999
for serving as a consultant for Biohaven,
Ltd. Satsuma Pharmaceuticals, Inc., Axsome
Therapeutics, Inc., Collegium Pharmaceutical,
Theranica Bio-Electronics Ltd., Scilex Holding;
in the range of $5000 to $9999 for serving
as a consultant for AbbVie Inc., BioDelivery
Science, and LinPharma; and in the range of
$10,000 to $49,999 for serving as a consultant
for AbbVie Inc., Lilly, and Lundbeck. Dr
Schwedt has received intellectual property
interests from a discovery or technology
relating to health care. Dr Schwedt has
received publishing royalties from a
publication relating to health care. Dr Schwedt
has stock in Aural Analytics and Nocira LLC.
The institution of Dr Schwedt has received
research support from Amgen Inc., the Henry
Jackson Foundation, the National Institutes of
Health (NIH), the Patient Centered Outcomes
Research Institute, SPARK Neuro, and the
United States Department of Defense.

Use Disclosure: Dr Schwedt discusses
multiple medications and therapies for the
treatment of posttraumatic headache, none
of which are approved by the US Food and
Drug Administration (FDA).
a
292 A P R I L 2 0 24

Self-Assessment and CME Test Writers
Nuri Jacoby, MD, FAAN Adam Kelly, MD, FAAN

Associate Professor of Clinical Associate Professor,
Neurology, Co-Clerkship Department of Neurology,
Director, SUNY Downstate Health Stroke Division; Associate
Sciences University; Vice Chair of Professor, Department of
Neurology, Maimonides Medical Neurosurgery, University of
Center, Brooklyn, New York Rochester Medical Center,
Rochester, New York
Relationship Disclosure: Dr Jacoby has
received personal compensation in the Relationship Disclosure: Dr Kelly has
range of $500 to $4999 for serving on a received personal compensation in the
scientific advisory or data safety monitoring range of $500 to $4999 for serving as a
board for Argenx, and in the range of $5000 consultant for Grand Rounds and as a
to $9999 for serving as an expert witness. question writer for various educational
offerings with the American Academy of
Unlabeled Use of Products/Investigational Neurology (AAN), and in the range of $5000
Use Disclosure: Dr Jacoby reports no to $9999 for serving as an editor, associate
disclosure. editor, or editorial advisory board member
for the AAN.

Use Disclosure: Dr Kelly reports no
disclosure.

EDITOR’S PREFACE
Headache Neurology’s Call

to Action
xuuEz7eS8qG9jDyji+66jItqa21Lm0C8fO+TRdrPp0LK0PsDc2Uk4mWNvRW/NKVHByBFkVLt5QNTXXJjB on 04/06/2024
It’s no secret that patients with headache disorders are underserved

in our health care system. Headache disorders are among the most
common diagnoses in medicine, not just neurology. There are too
few neurologists, much less neurologists with subspecialty training
in headache, to serve the tens of millions of people in the United
States alone with chronic headache disorders. There are unacceptable disparities in
access and outcomes for patients with headache. Headache research is underfunded
when measured by prevalence of disease. Despite these circumstances, the field of
headache neurology is justifiably overflowing with optimism. Why? In large part,
improvements in headache care can be attributed to the sustained, dedicated efforts
of headache neurologists, including the contributors to this issue of Continuum. In
addition to previewing the issue, this editor’s preface is an ode to the headache
neurologist.
Plenty of physicians and neurologists are issue with a thorough discussion of the most
passionate about their work, but headache important diagnostic tool in headache, the patient’s
neurologists take it to a completely different level. history, and generously shares some of her own
They advocate for their patients. They advocate for patient questionnaires. Dr Nazia Karsan follows with
more research funding. They advocate for improved a complete review of our evolving understanding of
insurance coverage for evidence-supported migraine pathophysiology. Drs Rebecca Burch and
therapies. Some of them even dye their hair purple to Richard Lipton provide comprehensive updates on
raise awareness for invisible disease. Supported by the explosion of migraine therapeutic options in their
complementary efforts from patient organizations respective reviews on the acute and preventive
and national specialty societies, their work has led to treatment of migraine. Medication-overuse
increased research funding, better coverage, and, headache, another commonly encountered challenge
most importantly, better treatments for headache in neurology practice, gets a complete review from
disorders. Their successes are a case study for Dr Paul Rizzoli, including new data on the timing of
advocacy in health care. preventive therapies.
This issue of Continuum is loaded with new Many uncommon headache disorders require the
insights into mechanisms and novel treatments for expertise of a neurologist or headache specialist. Dr
patients with headache disorders, and no one is Mark Burish authors a thorough review of cluster
better suited to lead this issue than Dr Amy Gelfand. headache, SUNCT, and SUNA. Dr Todd Schwedt
Dr Gelfand, who also serves as editor-in-chief of the covers the increasingly recognized posttraumatic
journal Headache, has assembled an extraordinary headache, and new daily persistent headache
group of authors. Dr Deborah Friedman kicks off the receives a complete review from Continuum editorial
294 A P R I L 2 0 24

board member Dr Matthew Robbins. Pediatric written for the issue by Drs Nuri Jacoby and
headache disorders are themselves an underserved Adam Kelly.
area of headache neurology, and Dr Stephanie Orr Following our recent successful launch of
covers an extraordinary amount of territory in her Continuum Audio on open podcast platforms
thorough review of the topic. Dr Stephanie Nahas including Apple and Spotify, interviews with our
delivers an outstanding overview of the cranial guest editor and expert authors are now available to
neuralgias, including trigeminal neuralgia. Dr Peter all. CME for these interviews will be available to
Goadsby rounds out the clinical reviews with a stellar American Academy of Neurology (AAN) members
discussion of the indomethacin-responsive headache at continpub.com/AudioCME. Continuum subscribers
disorders, informed by his clinical experience and have access to exclusive interviews not found on the
unparalleled grasp of the evidence. podcast and CME accompanying those interviews.
The Selected Topics in Neurology Practice article Verbatim audio recordings of each article are available
in this issue, coauthored by Drs Rashmi Halker Singh to subscribers through our rebranded Continuum
and Jessica Kiarashi, delves into a topic relevant to all Aloud program, found at the article level at
facets of our field: diversity, equity, and inclusion as ContinuumJournal.com and in the AAN’s Online
it relates to headache clinical practice and research. Learning Center at continpub.com/Audio. We hope
After reading this issue, subscribers can obtain up you’ll enjoy the open and refreshed format of
to 20 AMA PRA Category 1 CreditsTM toward Continuum Audio; please follow the podcast and rate
self-assessment CME or, for Canadian participants, a us if you haven’t already.
maximum of 20 hours toward the Self-Assessment Neurologists are society’s essential headache
Program [Section 3] of the Maintenance of specialists, and those neurologists who have
Certification Program of the Royal College of dedicated their careers to the care of these patients
Physicians and Surgeons of Canada with our posttest, deserve special recognition. Headache is
unfortunately an invisible disease for millions of
patients: the burden of disease is often overlooked by
clinicians, policymakers, and the general public alike.
Thanks to the efforts of a growing number of
… the field of headache neurology is headache neurologists, these millions of patients now
justifiably overflowing with have access to a much improved portfolio of disease-
optimism. Why? In large part, specific and disease-modifying therapies. The rest of
us would do well to emulate their call to action.
improvements in headache care can
—LYELL K. JONES JR, MD, FAAN
be attributed to the sustained,
EDITOR-IN-CHIEF
dedicated efforts of headache
neurologists… © 2024 American Academy of Neurology.
CONTINUUMJOURNAL.COM 295

REVIEW ARTICLE

Approach to the Patient
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E With Headache
DfPb7+FD2OtVDlN5JueqpnPzM07ridmdO6AvkBXJJKlYRFSyNge3S+Gr9w3tzSF0wbX/RwNuvr5OBrvEDfbuizsORmcDPEW2ZIq2
ONLINE
By Deborah I. Friedman, MD, MPH, FAAN
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
S U P P L E M E N T AL D I G I T A L
CONTENT (SDC)
A VA I L A B L E O N L I N E ABSTRACT
OBJECTIVE: The evaluation of patients with headache relies heavily on the
history. This article reviews key questions for diagnosing primary and
secondary headache disorders with a rationale for each and phrasing to
CITE AS:
optimize the information obtained and the patient’s experience.
zpJGzRWDZDcIdHdkboDCxBjo= on 04/03/2024
CONTINUUM (MINNEAP MINN)

2024;30(2, HEADACHE):296–324.
LATEST DEVELOPMENTS: The availability of online resources for clinicians and

Address correspondence to
Dr Deborah I. Friedman, 12740
patients continues to increase, including sites that use artificial
Hillcrest Rd, Ste 269, Dallas, TX intelligence to generate a diagnosis and report based on patient responses
75230, deborahfriedman@tx.rr. online. Patient-friendly headache apps include calendars that help track
com.
treatment response, identify triggers, and provide educational
RELATIONSHIP DISCLOSURE: information.
Dr Friedman has received
personal compensation in the
range of $0 to $499 for serving as ESSENTIAL POINTS: A structured approach to taking the history, incorporating
a consultant for Satsuma online resources and other technologies when needed, facilitates making
Pharmaceuticals, Inc.; in the
an accurate diagnosis and often eliminates the need for unnecessary
range of $500 to $4999 for
serving as a consultant for testing. A detailed yet empathetic approach incorporating interpersonal
Axsome Therapeutics, Inc., skills enhances relationship building and trust, both of which are integral to
LinPharma, and Lundbeck, as an
editor, associate editor, or
successful treatment.
editorial advisory board member
for MedLink Neurology and
Neurology Reviews, and on a
scientific advisory or data safety
monitoring board for Lundbeck;
and in the range of $10,000 to INTRODUCTION
H
$49,999 for serving as a eadache medicine relies heavily on the patient’s history, perhaps
consultant for Lilly and Pfizer Inc.
and on a speakers bureau for
more than any other field in neurology. While laboratory tests and
AbbVie Inc. and Impel imaging studies assist in diagnosing a secondary headache disorder,
Pharmaceuticals. The institution all headache disorders are diagnosed largely by history. Unlike
of Dr Friedman has received
research support from the Spinal
other neurologic diseases, the diagnosis of some headache
CSF Leak Foundation. conditions requires no further testing beyond the history and confirming that the
Dr Friedman has neurologic examination demonstrates no concerning abnormalities.
noncompensated relationships
as a medical advisor with the The overwhelming majority of patients with headaches seen in the outpatient
Spinal CSF Leak Foundation, as a setting have a primary headache disorder, most often migraine. However, certain
program co-chair for the
aspects of the history and examination raise the possibility of a secondary cause.
Continued on page 324
Thus, a systematic approach is critical in evaluating patients with headache, with
UNLABELED USE OF vigilance for worrisome etiologies.1
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Headache specialists typically spend at least 30 to 40 minutes taking a history
Dr Friedman reports no during the initial outpatient visit. The concept of doing this is daunting,
disclosure. particularly in a busy office with time constraints. Moreover, the amount of
© 2024 American Academy information one needs to obtain for certain complex headache disorders can
of Neurology. seem overwhelming. Taking a headache history is as much an art as a skill; the
296 A P R I L 2 0 24

ability to relate to the patient and get the necessary information from a KEY POINT
conversation improves with practice and experience.2
● Primary headache
This article focuses on a logical and systematic approach to taking a headache disorders are the most
history in adults in the ambulatory setting, key questions to ask when suspecting frequent types encountered
particular diagnoses, and tools and techniques to incorporate before the visit to in the outpatient setting.
make the encounter more efficient and productive. For information on pediatric Basic knowledge of the
International Classification
headache treatment, refer to the article “Headache in Children and Adolescents”
of Headache Disorders,
by Serena L. Orr, MD, MSc, FRCPC,3 in this issue of Continuum. Third Edition (ICHD-3)
Having some background knowledge of the diagnostic criteria for common criteria for the most
headaches (eg, tension-type, migraine, cluster headache) helps direct the common headache types
helps to direct the line of
interview (CASE 1-1). The International Classification of Headache Disorders,
questioning during the
Third Edition (ICHD-3) details the diagnostic criteria for primary and secondary interview.
disorders, with a formulaic structure for both types.4 While the clinical
evaluation of the patient with headache sometimes requires “rule-out” testing to
exclude a secondary disorder, the diagnosis of primary headache disorders is

based primarily on the history:
u Number of lifetime episodes needed to diagnose the headache disorder

u Minimum required characteristics of the headache
u Minimum requirements for associated symptoms (eg, photophobia, nausea, trigeminal
autonomic features)
u Not attributable to another ICHD-3 disorder
Note that diagnosing the disorder is not the same as diagnosing the headache
phenotype. A single attack of migraine without aura (“You had a migraine.”)
does not satisfy the criteria for having the disorder, which requires at least five
lifetime attacks (“You have migraine.”).
Secondary headaches have a common diagnostic structure as well:
u The patient has a headache (which may be further elaborated)

u A secondary cause was diagnosed (eg, intracranial pressure disorder, subarachnoid
hemorrhage, tumor, infection, inflammatory condition)
u There is a temporal relationship between the onset of the headache and the
secondary diagnosis
u The headache improves or resolves when the underlying cause is treated
Keep in mind that the ICHD-3 is designed to diagnose the headache, not the
underlying condition. Many of the secondary headache criteria do not specify
particulars regarding the examination or diagnostic testing needed to make the
causative diagnosis.
There is no need to memorize the ICHD-3 (available online at
ichd-3.org), but it is important to become familiar with the most common
primary headache disorders (eg, tension-type headache, migraine with and
without aura, cluster headache) and be aware of red flags for suspecting a
secondary cause.
CONDUCTING THE INTERVIEW

The best results occur when the patient’s headaches are the sole topic covered
during the visit. If a patient happens to mention that they have headaches as they

APPROACH TO THE PATIENT WITH HEADACHE
CASE 1-1 A 51-year-old woman was seen in the clinic with a primary concern of
“eye migraines.” Her headaches had started in her mid-twenties and had
not changed over time. They were exclusively located in and around her
right eye. She described pressure, “like someone is pushing my eye out,”
that peaked to excruciating pain within 20 minutes of onset. There was

associated photophobia (more so in the right eye), nausea, vomiting,
ipsilateral conjunctival injection, and rhinorrhea. Lying down did not help
and she generally sat in a chair with her fist pressed into her eye socket.
Sumatriptan 100 mg orally had little effect. The headaches occurred two
to three times weekly and lasted 5 hours in total with no interictal pain.
They sometimes awakened her from sleep between 2:00 AM and 5:30 AM
but there was no consistent circadian pattern. Alcohol triggered them so
she stopped drinking.
She had well-controlled hypercholesterolemia and no other medical

problems. She never smoked cigarettes. Her son had similar headaches
with no other family history of headache. Her medications consisted of a
multivitamin, a vitamin D supplement, atorvastatin daily, and sumatriptan
100 mg orally as needed. Previous acute treatments consisted of
butalbital compound, eletriptan, ibuprofen, naproxen, and a combined
formulation of acetaminophen, aspirin, and caffeine, all of which were
ineffective. Previous preventive medications consisted of topiramate
200 mg daily (which produced cognitive dysfunction), nortriptyline 10 mg
(which was too sedating to increase further), sodium valproate (which
was ineffective and stopped due to weight gain), and
onabotulinumtoxinA, all of which were ineffective. Further questioning
revealed that the most severe pain lasted for 2.5 hours with lingering pain
for another 1.5 hours.
Verapamil 80 mg twice daily was initiated for prevention and gradually
increased to 160 mg twice daily with improvement, but it produced
intolerable constipation. Galcanezumab 300 mg subcutaneous self-
injection monthly was started with a marked reduction in her headache
frequency and severity, so verapamil was tapered and discontinued.
Zolmitriptan nasal spray 5 mg at the onset of headaches aborted them.
COMMENT This case exemplifies how obtaining detailed information about the
headache pain pattern (intensity and duration) can lead to an accurate
diagnosis in a patient whose headaches were previously misdiagnosed as
migraine and thus ineffectively treated. The patient’s headaches had
features of both migraine and cluster headache, and she met the
International Classification of Headache Disorders, Third Edition,
diagnostic criteria for cluster headache. Patients with cluster headache
may also have “migraine” features, such as nausea, vomiting, and
photophobia.
298 A P R I L 2 0 24

are walking out the door from a visit that addressed a different problem, schedule KEY POINTS
a separate visit to discuss their headaches. That way, the patient can prepare and
● Good communication and
organize their information, you will have enough time to address the problem, interpersonal skills, along
and it conveys the message that their headaches are taken seriously. with active listening and
awareness of nonverbal
Communication and Interpersonal Skills cues, contribute to an

empathetic and caring
Effective interviewing incorporates communication and interpersonal skills.5
conversation with patients

Communication skills can be operationalized, and hence computerized undergoing evaluation for
questionnaires and artificial intelligence applications can obtain a history, make a headache.
diagnosis, and recommend therapy with good reliability.6 Structured interviews
can help diagnose common chronic headache types and exclude secondary ● While closed-ended
questions are necessary to
causes.7 Interpersonal skills or “humanistic qualities,” on the other hand, are make a headache diagnosis,
more difficult to operationalize as they involve relationships. Constructs the American Migraine
important to effective interpersonal skills include demonstrating respect for the Communication Study found
patient, being fully present and paying attention through verbal and nonverbal that open-ended questions
were often more time
signs of interest, and showing empathy and genuine caring.8 efficient and provided
Active listening is a technique that focuses on the patient. It involves listening critical information
to and understanding the patient’s spoken content, interpreting nonverbal regarding impairment.
messages (eg, posture, facial expressions, tone, observable responses),
● When evaluating patients
incorporating socioeconomic factors (eg, cultural beliefs, access to support from
with headache, establishing
others), and listening with empathy.9 the primary concern sets the
Repeating what the patient conveyed helps to reflect empathy (eg, “Your stage and immediately
migraines really affect your life. They cause you to miss work, your job is in informs the interviewer of
the patient's goals.
jeopardy, and you cannot make plans.”).
Taking the History

The American Migraine Communication Study showed that open-ended
questions tend to yield the most information during the interview, particularly
regarding impairment.10 However, the patient’s approach to the narrative may
be structured completely differently than the interviewer’s thought processes.
The interviewer needs to know about specific aspects of the headaches to make a
diagnosis, while the patient often wants to convey the impact of the headaches on
their life and (surprisingly) may not have paid much attention to the details of
what they experience during a headache attack.
WHAT IS THE PRIMARY CONCERN THAT BRINGS YOU HERE? The primary concern is not
the referring diagnosis, but rather the patient’s own words. “Dr XYZ referred me
here” is not a primary concern.
As in a novel or play, the opening line is important. Ranging from analytical to
profound, mundane, or emotional, you know where the patient is coming from
in ten words or fewer. Some patients seek a diagnosis, while others are looking
for an etiology, a prognosis, a more effective treatment, or just someone who
listens and takes them seriously.
TELL ME ABOUT YOUR HEADACHES. Some patients are not sure where to start when
describing their headache history. As we are interested in the course of headaches
over time, ask them to start at the beginning. (This author also follows the
request with, “I will probably interrupt you at some point. Please don’t be
offended; I am not trying to be rude”.) Many adults seeking care started having
headaches in childhood. They may not remember the details but most can recall

the approximate frequency of headaches; whether they had any warning

symptoms, needed to lie down in a dark, quiet room, experienced nausea and
vomiting, missed school or events, or left school early or went to the nurse’s
office; the headaches’ duration; and how they treated their headaches. You may
be able to determine the location and quality of the pain (eg, aching, throbbing,
stabbing). Females can usually recall whether there was a relationship to

menarche, menses, or pregnancy. If the information is not spontaneously
forthcoming, just ask what you need to know.

The next step is finding out what happened over time. Did the headaches
change in character, duration, intensity, or frequency? Commonly, the patient
replies that “they got worse.” One way to discern whether the worsening was an
intensification of the initial headache is to ask, “Was it the same headache but
with the volume turned up, or a completely different headache?” At that
juncture, more pointed questions can determine exactly what changed.
Some people have more than one type of headache and each needs to be
described separately. They may name them (correctly diagnosed or not, eg,
migraine, stress headache, eye headache, dagger headache), and using the
patient’s own terminology or numbering them (eg, headache number one,
headache number two,) helps focus the interview (CASE 1-1). Ask the patient to
prioritize their most severe, disabling, concerning, or bothersome headache type
in those situations. When eliciting the history of a headache attack, I find it
helpful to ask the patient to “talk me through a typical headache from start to
finish; describe everything that you experience during an attack.” It may take
more than one visit to work through all of them.
This is the opportunity to get the details regarding the timing of various
aspects of the headache phenotype. Certain features of the headache help make
the diagnosis, including age at onset, warning signals (prodrome or aura),
location of the pain, character of the pain, tempo of pain progression and time to
peak intensity, circadian pattern (eg, awakening the patient from sleep at a
particular time, present upon awakening, occurring at specific times during the
day), associated symptoms, aggravating or relieving factors, how they feel after
the pain resolves, and how the headache affects their ability to function. Besides
knowing about the bad times, ask about the good times: “How often are you
completely headache free?” It may be surprising to learn that a patient always has
some type of headache but can continue functioning with it or perhaps even
ignore the milder ones.
DO YOU GET ANY WARNING THAT YOU ARE GETTING A HEADACHE BEFORE THE PAIN
STARTS? This question addresses prodrome and aura. Prodrome may occur up to
48 hours before the onset of migraine pain. Patients may not even realize that
they experience prodrome symptoms or that they are related to migraine;
prodromal symptoms are often misinterpreted as triggers.11 Ask specific
questions, querying about uncontrollable yawning, change in mood, tiredness,
cognitive dysfunction, food cravings, excessive thirst or urination, or neck
pain.12,13 When the associated symptoms of migraine (ie, nausea, photophobia,
and osmophobia) begin before the onset of aura or headache, they are
considered prodromal.
Aura is a transient symptom arising from the brain that typically precedes the
headache but may occur during the headache phase, after the headache, or as an
isolated event.14 Aura transpires in approximately 30% of patients with migraine
300 A P R I L 2 0 24

and occasionally occurs with cluster headache. Typical aura is visual, KEY POINTS
somatosensory, or affects speech and language, lasting 5 to 60 minutes.
● One of the most helpful
Manifestations of aura include flashing lights, shimmering zigzag lines with or questions to ask during a
without an enclosed area of scotoma, sparkles, dots, homonymous hemianopia, headache evaluation is,
tunnel vision, visual distortion (metamorphopsia), transient visual loss, other “How often do you feel
vision problems, aphasia (typically expressive), numbness, paresthesia, completely clear and
headache free?”
phantosmia, auditory hallucinations, weakness, imbalance, vertigo, diplopia,
altered levels of consciousness, Alice in Wonderland syndrome (ie, an alteration of ● Prodromal symptoms of
visual perception characterized by distorted body images, external environment, headache are often
or both), and other neurologic symptoms.15 Multiple aura symptoms generally misinterpreted as triggers.
occur in succession rather than a simultaneous onset, distinguishing them from
● When considering
transient ischemic attack or stroke. For more on aura, refer to the article “Migraine migraine, ask about specific
Pathophysiology” by Nazia Karsan, PhD, MRCP,16 in this issue of Continuum. “warning signs,” such as
prodrome and aura
LET’S TALK ABOUT HOW YOUR HEAD PAIN STARTS. WHERE IS IT LOCATED AT FIRST? DOES manifestations.
IT SPREAD OR TRAVEL? Migraine often starts in the neck and spreads anteriorly.
● Side-locked (strictly
Alternatively, it may start on one side of the head, around the eye or sinus area. unilateral) headaches may
Sometimes it begins on one side and later moves to the contralateral side of the occur in migraine and cluster
head or becomes bilateral. While the diagnostic criteria for migraine include headache but sometimes
unilaterality, about 40% of adults and most children have bilateral head pain. signal a more worrisome
secondary cause.
Unlike other types of headaches, the location may vary from attack to attack in
an individual.17
The trigeminal autonomic cephalalgias are almost always centered around one
eye. Cluster headache pain may be orbital or retro-orbital, involving the ipsilateral
temple, forehead, jaw, or face. Patients will often point to the specific area of pain.
Tension-type headache is nearly always bilateral, sometimes bandlike, but need
not involve the entire head. Patients with nummular headache outline a
well-circumscribed round or oval area on the head to localize the pain.
If the headache is unilateral, ask the patient, “Are your headaches always on
the same side of your head?” The head pain in individuals with unilateral
migraine pain commonly occurs on either side of the head unpredictably, but
some people have attacks that always occur on the same side of the head. During
a bout of cluster headache and with the other trigeminal autonomic cephalalgias,
the pain is side-locked, always occurring on the same side. Hemicrania continua
is side-locked by definition, although the pain may not encompass the entire side
of the head (CASE 1-2). A de novo side-locked headache may signal a secondary
headache disorder such as a structural intracranial process, giant cell arteritis, or
a CSF pressure disorder.
HOW WOULD YOU DESCRIBE THE PAIN? WHAT DOES IT FEEL LIKE? Prompting is
sometimes required for this question, such as throbbing, pounding, sharp,
stabbing, shooting, aching, pressurelike, or burning. Sometimes this question
backfires and the patient responds with adjectives describing the pain intensity
or a number on the pain scale, in which case you can either redirect them or
transition to the question about intensity.
Throbbing, pounding pain is characteristic of migraine. However, migraine
pain may be steady, aching, or stabbing.18 Tension-type headache is pressurelike,
aching, or squeezing, like wearing a hat or headband that is too tight.19 Cluster
headache is described as stabbing, boring, hot poker, knifelike, or drilling, “like
someone stuck an ice pick in my eye.”

HOW SEVERE IS THE PAIN WHEN IT STARTS AND HOW SEVERE DOES IT GET? HOW LONG
DOES IT TAKE FOR THE PAIN TO REACH PEAK INTENSITY? The intensity questions are
helpful for diagnosis and treatment. Migraine characteristically starts with mild
pain that gradually builds in intensity. The time to peak intensity is quite variable
and this aspect of pain development is extremely important when selecting an
acute treatment strategy. If the pain crescendos over hours, oral acute therapies
are the preferred option as there is enough time for systemic absorption if they
are taken early in the episode. Patients experiencing pain that peaks in intensity
within 30 minutes may require nonoral acute treatment if rapidly acting oral
treatment is ineffective. For more on acute treatments, refer to the article “Acute
Treatment of Migraine” by Rebecca Burch, MD, FAHS,20 in this issue
of Continuum.
Cluster headache and episodic and chronic paroxysmal hemicrania typically
peak in intensity within several minutes.21 Hence, there is not enough time for
oral agents to take effect, and other routes of administration are employed such
CASE 1-2 A 24-year-old woman presented to the clinic for evaluation of recurrent
headaches that had been previously diagnosed as chronic migraine
without response to initial treatments. Her headaches were always left
sided, occurring 16 days a month. There was no prodrome or aura. She
described moderate to severe pain associated with photophobia,
phonophobia, osmophobia, nausea, and worsening with activity. The pain
was throbbing in quality and peaked in intensity within 2 hours of onset.
Zolmitriptan reduced the pain intensity and the headaches resolved in 8
to 10 hours with residual fatigue the next day. Thus, each attack impaired
her for 2 days and she often missed work because of them. Previous
preventive treatments were all ineffective, including amitriptyline 75 mg
daily, nortriptyline 50 mg daily, topiramate 150 mg daily, propranolol
160 mg daily, and onabotulinumtoxinA. Her neurologic examination and
brain MRI were normal. Erenumab 140 mg monthly subcutaneous
self-injection was prescribed.
The patient returned for follow-up 6 weeks later and reported no
change in her headache. Having done some online research, she asked,
“Could I have hemicrania continua?” A review of her initial visit note
showed no mention of interictal pain. However, further questioning
revealed that she had constant left temporal pain which was typically
mild and she was able to function with it. All of her pain resolved after
beginning treatment with indomethacin 50 mg 3 times daily. After a few
months, the dose was tapered but her headaches returned at a dose of
25 mg 3 times daily. She remained on indomethacin 100 mg thereafter
with no headache recurrence or adverse effects.
COMMENT This case stresses the importance of asking about completely

headache-free days, particularly in an individual with side-locked
headaches. Although previously diagnosed with chronic migraine, the
patient had hemicrania continua which responded to indomethacin.
302 A P R I L 2 0 24

as inhalation (oxygen for cluster headache), subcutaneous injection, and KEY POINTS
intranasal delivery.
● Determining the time
The pain intensity of migraine varies but is generally moderate to severe, between pain onset and
compared with mild to moderate pain in tension-type headache. Severe to very peak intensity helps with
severe pain characterizes cluster headache and paroxysmal hemicrania; most both headache diagnosis
patients indicate that it is the worst pain they have ever experienced and some and treatment.
patients report suicidal ideation during an attack.22
● Nocturnal awakening
Pain that starts instantly at peak intensity is called thunderclap headache.23 from headache does not
While thunderclap headache may be a primary headache disorder, it raises always signal a brain tumor.
concern for a secondary headache, particularly as a new-onset headache. It occurs with acute
Conditions producing thunderclap headache include reversible cerebral medication overuse and in
primary headaches, sleep
vasoconstriction syndrome, subarachnoid hemorrhage, meningitis, and apnea, and other medical
spontaneous intracranial hypotension. Thus, primary thunderclap headache is a conditions.
diagnosis of exclusion, requiring brain and cerebrovascular imaging.
● Associated symptoms,
including trigeminal
DO YOUR HEADACHES OCCUR AT ANY PARTICULAR TIME OF THE DAY OR NIGHT? DO THEY
autonomic features, are
AWAKEN YOU FROM SLEEP? ARE THEY PRESENT UPON AWAKENING? Headaches that characteristic of cluster
awaken the patient from sleep need to be distinguished from waking up during headache and other
the night for other reasons and noticing that the headache is present. Some trigeminal autonomic
cephalalgias but may also
patients have a hard time discerning the difference. If the patient has nocturnal
occur in migraine, although
awakening or wakes up in the morning with a headache, it is helpful to note the usually less prominently.
severity of the pain, whether it has already peaked in intensity, and if other
symptoms (eg, nausea, vomiting, tearing, rhinorrhea) are present at the time. ● Ascertaining the patient's
These questions assist in both diagnosis and treatment. Recurrent episodes of behavior and actions during
a headache helps diagnose
nocturnal awakening can be a symptom of secondary headaches, particularly migraine and cluster
sleep disorders, acute medication overuse (when the medication wears off during headache.
sleep), chronic obstructive pulmonary disease, nocturnal hypertension, or brain
tumors.24,25 However, nocturnal awakening also occurs in primary headache
disorders including migraine, cluster headache, hypnic headache, and
paroxysmal hemicrania.26,27 Circadian periodicity is a feature of cluster
headache.27,28 Migraine may also display a circadian preference as the most
common time to experience migraine is upon waking up in the morning.29
ARE THERE OTHER SYMPTOMS OF A PRIMARY HEADACHE DISORDER? The associated

symptoms of various types of headache conditions sometimes lead to greater
impairment than the head pain (referred to as most bothersome symptoms).
Photophobia is the most common associated symptom in the United States. Others
include phonophobia, osmophobia, nausea, vomiting, diarrhea, aura symptoms
during the headache, and the following trigeminal autonomic features21:
u Ptosis
u Lacrimation
u Conjunctival injection
u Nasal congestion or rhinorrhea
u Miosis
u Aural fullness
u Facial pallor, flushing, diaphoresis
u Red ear (may occur separately from a headache)30

Suggested wording for asking questions about some of the associated symptoms
is listed in TABLE 1-1.
Ask the patient if they have photographed their appearance during an attack.
If not, request that they do so during a future episode.
Although trigeminal autonomic symptoms suggest a trigeminal autonomic
cephalalgia, they may also occur in migraine. Their presence in migraine is often
less pronounced (eg, slight watering of the eyes rather than tears streaming down
the face) than with the trigeminal autonomic cephalalgias and are most often
bilateral.31 Headaches accompanied by nasal congestion or rhinorrhea may be
incorrectly interpreted as sinus related; such headaches are usually either
migraine or cluster headache.32,33
The associated symptoms can be inferred in children or adults who cannot
communicate these details. For information on pediatric headache treatment,
refer to the article “Headache in Children and Adolescents” by Serena L. Orr,
MD, MSc, FRCPC,3 in this issue of Continuum.
WHAT DO YOU PREFER TO DO (PHYSICALLY) DURING AN ATTACK? Even if the patient

cannot lie down because of situational circumstances, do they prefer lying down,
sitting, pacing, or moving? If recumbent, can they lie motionless, or are they unable to
get comfortable due to thrashing, tossing, or turning.? If they sit, do they sit quietly or
rock back and forth in the chair? Is there a change in demeanor such as agitation?
One of the most diagnostically helpful characteristics of migraine is worsening
with activity, and the overwhelming majority of patients with migraine prefer to
lie down motionless in a dark, quiet environment. However, circumstances often
dictate or constrain a patient’s physical response to a headache attack. In
contrast, patients with cluster headache rarely prefer being motionless and
experience restlessness or agitation.21,27 They may pace, rock back and forth,
toss, turn, or thrash in bed (eg, “Are you able to lie still, or do you thrash in
bed?”), or inflict bodily injury on themselves for distraction, such as banging
their head or body parts against the wall or digging their fingernails into their
skin. Vocalization during a cluster attack may occur, including yelling
or screaming.
IS YOUR SKIN SENSITIVE TO TOUCH DURING THE HEADACHE? Cutaneous allodynia is the
experience of pain or discomfort with a stimulus that is not ordinarily painful,
such as touching the skin. About 60% of patients with migraine report that their
hair hurts, they cannot brush their hair or put it in a ponytail, they need to take
off jewelry or clothing, they are unable to tolerate taking a shower or the weight
of the sheets or blankets touching them, and they do not want anyone else to
touch them during a migraine.
Cutaneous allodynia is a feature of the central sensitization of second-order
(cephalic sensitization) and third-order (somatic sensitization) nociceptive
trigeminal nucleus caudalis neurons.34 During central sensitization, the threshold
for noxious stimuli to produce pain decreases and the nervous system is in a
heightened state of reactivity, causing a sensation of pain in response to stimuli
that are normally not pain provoking. Central sensitization is also associated with
the development and sustainment of chronic pain.35
HOW LONG DOES THE SEVERE PAIN LAST? The headache diagnosis is often defined by
its duration, particularly for the trigeminal autonomic cephalalgias. Cluster
304 A P R I L 2 0 24

Suggested Wording for Selected Headache Interview Questions TABLE 1-1
Phenomenon Question Comments

a
Migraine-associated symptoms
Photophobia Does light bother your eyes?

Would you prefer being in a dark Some people will keep working or continue other
environment? activities despite the associated symptoms
Are you able to use the computer or watch TV?
Do you keep your home dark? Interictal photophobia
Phonophobia Does noise bother you?
Do noises sound abnormally loud?

Do you need to turn off music or the TV?
Would you prefer being in a quiet environment?
Osmophobia Do smells or odors bother you? Odors can also be a trigger or perceived trigger
Nausea Are you nauseous? A common answer is “No, I don’t vomit.”
Are you queasy, sick to your stomach, or Many people confuse nausea for vomiting
feel like you will vomit?
Vomiting Do you vomit?
(If so) Does vomiting help? People may even induce vomiting if it provides relief
Worsening with Does moving around, such as walking or This is characteristic of migraine
routine physical going up stairs, affect your headaches?
activity
Do you prefer lying down during one?
Worsening with Does exercise, heavy lifting, or sexual

exertion activity affect your headaches?
March of symptoms When you experience (name the symptoms Spread of numbness or weakness is typical of
that the patient describes, typically migraine
numbness or weakness), does it start all at
once or does it travel or spread?
Progression of When you experience (name the symptoms Aura symptoms progress, as opposed to transient
symptoms that the patient relates), do they start all at ischemic attack or stroke
once or do they progress from one to another?
(If they progress) Is there a typical pattern

of progression?
Visual symptoms
Homonymous Do you lose vision from one eye only or is Homonymous visual field loss is often mistaken for
hemianopia one-half of the world missing? monocular vision loss; monocular visual loss does
not split the world in half because of the intact nasal
visual field in the contralateral eye
If you looked at a clock, what would you If only half of the clock is seen, the defect
see? is homonymous
Have you ever covered one eye, then the With true monocular visual loss, the vision looks
other, to see if your vision looks the same or different from the affected eye
different with either eye?
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CONTINUED FROM PAGE 305

Scintillating scotoma Is the image still present with your The classic scintillating scotoma persists when the
eyes closed? eyes are closed
Have you ever covered one eye, then the The classic scintillating scotoma originates from the
other, to see if your vision looks the same or cortex and is binocular; patients sometimes report
different with either eye? that it is seen in one eye only, rather than the
ipsilateral visual field
Blurred vision Do you mean blurred as in “out of focus,” or Distinguishing true blurred vision from a scotoma;
is part of your vision missing? blurred vision is not considered an aura symptom
Diplopia When you see double, are the images Demonstrate with your hands
separated horizontally or vertically?
If you cover one eye and then the other, Migraine with brainstem aura and hemiplegic migraine
does the double vision go away? can produce binocular diplopia; the diplopia is present
only with both eyes open, and each eye sees only
one image; other types of primary headaches cause
monocular diplopia, which may be bilateral and is likely
due to ocular surface dryness
Alice in Wonderland Do things ever look too large, too small, too
syndrome close, or too far away?
Do you ever feel like you are larger or

smaller than you really are?
Trigeminal autonomic symptoms and signsb
Ptosis Do your eyelids droop or close?
Lacrimation Do your eyes tear? If yes, ascertain if one or both eyes and whether the
tearing is ipsilateral to the pain
Do the tears stream down your face or is it Mild tearing may occur in migraine but profuse tearing
just a little bit of tearing? is typical of the trigeminal autonomic cephalalgias
Rhinorrhea Do you have a runny nose?
(If yes) Do you have the sniffles or fluid Mild rhinorrhea may occur in migraine, but profuse
dripping down your face? rhinorrhea is typical of the trigeminal autonomic
cephalalgias
Miosis Has anyone noticed that one pupil is smaller Pupils can become larger or smaller during a
(or larger than the other)? headache attack, affecting one or both eyes
(If yes) Which is the smaller pupil? Horner syndrome consists of a smaller pupil and
ipsilateral ptosis
Aural fullness Do you have a sensation of fullness or

stuffiness in your ear?
(If yes) Which ear?
306 A P R I L 2 0 24

Symptoms of various secondary headache conditions

Orthostatic headache How do you feel when you first wake up, When patients have orthostatic headaches that start
before you get out of bed? or worsen almost immediately after arising, asking
“How do you feel in the morning?” may provide a

misleading answer
How long does it take once you are upright

for the headache to start?
Does lying down, without going to Patients often confuse lying down with going to
sleep, help? sleep; you are trying to isolate the postural
component from relief with sleep
If so, how long does it take for your

headache to get better?
Does the headache completely go away

when you lie down?
How long can you be upright before you

need to lie down?
Worsening with Does coughing, sneezing, straining (such as

Valsalva maneuver during a bowel movement), laughing, or
singing affect your headaches?
Transient visual Does your vision ever completely “go out”

obscurations on you?
(If yes) Does that happen in one or both

eyes? If one, which eye?
Is there anything that brings it on? Bending over and eye movements are
common precipitators
How long does the visual loss last? When associated with increased intracranial
pressure, the episodes usually last seconds to a
few minutes
Jaw claudication Do you have pain or weakness in your jaw Very sensitive screen for giant cell arteritis
while chewing your food?
a
May be present in other headache types.
b
Trigeminal autonomic cephalgias and migraine.
headaches last 15 to 180 minutes when untreated or unsuccessfully treated, but

some patients experience milder pain in between the severe attacks; the duration
of the severe pain is the defining characteristic. While the severe pain of migraine
is the most disabling, patients often have lingering pain lasting up to a
day afterward.
Questions such as “How do you feel after the pain is over?” and “How long
does it take to feel ‘back to normal’?” allude to the postdrome, which is a common
feature of migraine, otherwise known as the migraine “hangover.” There may be

mild residual pain, fatigue, cognitive dysfunction (“brain fog”), hunger,

gastrointestinal symptoms, sensory sensitivity, or vertigo lasting up to 1 to
2 days.36 Note that this is part of the migraine attack and should be considered
when determining the number of migraine days in a given period. Effects or side
effects of acute medications may cause similar symptoms, making it difficult to
distinguish the etiology in some patients; however, postdrome symptoms are

most frequently incorrectly attributed to medications.36 For patients who are
rarely or never headache free, it is important to ask how long it takes to return to
their baseline state.
DO YOU HAVE SYMPTOMS BETWEEN ATTACKS (EG, PAIN, PHOTOPHOBIA, PHONOPHOBIA,

OSMOPHOBIA)? Although we tend to concentrate on headache attacks when taking
a history, symptoms can persist into the interictal phase, particularly in migraine,
tension-type headache, and cluster headache.37,38 Several lines of evidence
document that patients with episodic and chronic migraine have a poorer quality
of life in between episodes compared with those without migraine.37
Functional imaging studies corroborate changes in the brain during this
interictal phase.39 In addition to the aforementioned symptoms, the interictal
burden of migraine is associated with photophobia, anxiety (fear of the next
attack), depression (inability to make plans because of the possibility of having a
migraine episode), motion sickness, fear of upcoming events, stigma (reluctance
to tell others about their headaches), and worse interpersonal interactions with
others.37,40 Individuals experiencing interictal impact from migraine report
having to alter their lifestyle to avoid triggers or in response to an impending
attack.41 Furthermore, migraine affects work, career, daily activities,
relationships, and even the decision to have children. Preventive migraine
treatment benefits patients experiencing interictal burden.34,38 For more
information, refer to the article “Preventive Treatment of Migraine” by Richard
B. Lipton, MD, FAAN,42 in this issue of Continuum.
HOW MANY DAYS IN ONE MONTH ARE YOU COMPLETELY HEADACHE FREE AND “CLEAR
HEADED”? People tend to report their worst headaches but may have other, milder
headaches that they “live with” and can continue functioning through.
Neglecting to ask about pain freedom in addition to pain days may lead to an
incorrect diagnosis. An example is hemicrania continua, where chronic,
low-level pain on one side of the head is punctuated by more severe ipsilateral
attacks that resemble migraine.43 The diagnosis of hemicrania continua is
predicated on a therapeutic response to indomethacin, so missing the constant
unilateral headache delays the diagnosis. This point is demonstrated in CASE 1-2.
For more on hemicrania continua, refer to the article “Indomethacin-Responsive
Headache Disorders” by Peter J. Goadsby, MD, PhD, FRS,44 in this issue of
Continuum.
The ICHD-3 diagnosis of chronic migraine specifies having headaches on more
days than not (at least 15 days per month), of which at least 8 days are migraine.4
Capturing only the 8 migraine days puts the patient in a different diagnostic
category, which affects their preventive treatment options.
HAVE YOU IDENTIFIED ANYTHING THAT TRIGGERS YOUR HEADACHES? The concept of
migraine triggers is controversial, as some presumed triggers may actually be
premonitory symptoms (eg, food cravings, bright lights, loud noise, neck pain).
308 A P R I L 2 0 24

Classifying one exposure followed by a migraine episode as a trigger is KEY POINTS
insufficient, as a pattern of cause and effect must be established. That said, many
● Determining how long it
individuals with migraine relate that exposure to a trigger does not result in a takes to return to normal
migraine 100% of the time. One observational study using a smartphone app after headache pain
showed that, except for neck pain, even the most frequently reported triggers resolves provides insight
were present in fewer than one-third of individuals reporting them.45 Commonly into the attack’s true
duration and the patient’s
perceived triggers include odors (eg, volatile substances, fragrances, smoke),
ability to function.
stress (during or following a migraine attack), weather (eg, heat, sferics
[atmospheric electromagnetic impulses resulting from lightning]), missing meals ● Patients tend to
or hypoglycemia, changes in sleep pattern, dehydration, menses, alcohol, emphasize their most severe
caffeine, and various foods (eg, aged cheese and other aged foods, monosodium headaches, leading to an
underestimation of their
glutamate).46 Headache is a side effect of many medications, including headache burden.
medications used to treat headache, which also needs to be considered.
When patients identify a reproducible trigger, avoiding it is helpful. However, if ● The subject of headache
the suspected trigger is actually a premonitory symptom, the patient may be triggers is somewhat
controversial. Patients may
restricting their exposure unnecessarily. One example of this is chocolate, which mistakenly attribute an
may be consumed as a prodromal food craving when the headache occurs regardless exposure before a migraine
of what one eats. Thus, identifying true triggers helps mitigate exposure, but as a trigger when it is
incorrect trigger attribution leads to hypervigilance that affects quality of life. actually part of the
prodrome (eg, food
cravings, neck pain).
HOW DOES MIGRAINE (OR YOUR HEADACHES) IMPACT YOUR LIFE, EVEN WHEN YOU ARE
NOT HAVING ONE? The American Migraine Communication Study recorded office ● Some types of headaches
visits with 60 patients and clinicians (14 primary care physicians, 8 neurologists, run in families, such as
and 6 advanced practice providers) and subsequently interviewed the patient migraine, cluster headache,
familial hemiplegic migraine,
and clinician separately to determine their impressions of the visit.10 There was a and cerebral autosomal
marked discordance between the patients’ and clinicians’ perceptions. While dominant arteriopathy with
clinicians were generally satisfied with the flow, content, and outcome of the subcortical infarcts and
encounter, patients indicated that the personal impact of having migraine was leukoencephalopathy
(CADASIL).
not addressed. This study highlighted the importance of incorporating a question
about impairment or migraine-related disability into the interview. Assessing
this information adds to the overall understanding of the patient experience,
strengthens the relationship with the patient, and drives treatment decisions
regarding headache prevention.
DO ANY OF YOUR FAMILY MEMBERS HAVE HEADACHES (OR THE PATIENT’S SPECIFIC
TYPE)? Some patients have clear knowledge of their family history, while others
are less certain. Inaccuracies arise almost 50% of the time when taking the family
history from the patient’s report.47,48 When unable to interview the relative
personally, a diagnosis may be inferred, but not confirmed, if some basic details
are known. For example, if a patient relates that her mother had headaches
associated with vomiting (“sick headaches”) and spent 2 days lying down in her
dark, quiet bedroom, she likely had migraine. An uncle who had very severe
headaches associated with tearing and a runny nose may have had cluster
headache. Challenges to obtaining an accurate family history arise when some
family members never received a diagnosis, were incorrectly diagnosed, or did
not talk about their headaches.
Migraine tends to run in families, with up to 80% of children with migraine
having a positive family history of migraine.49 However, studies of family history
in migraine and cluster headache are limited by validation of the diagnosis in
family members and increased awareness of the condition over time. Certain

types of migraine have a higher genetic load, such as migraine with aura,
hemiplegic migraine, and cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL). The latter two
disorders are caused by known genetic variations with autosomal dominant
inheritance. As is true with most genetic diseases, early onset of migraine is
associated with migraine in first-degree relatives.50 A population study of 73

probands and 72 matched controls including interviews with 511 first-degree
relatives showed a 50% higher risk of migraine in probands versus controls.51 The
risk was higher for relatives of probands with disabling migraine. The authors
concluded that familial factors (genetic or family environment) accounted for
less than one-half of migraine cases. A family history of migraine in both parents
is associated with migraine frequency in adult males.52
A positive family history in cluster headache ranges from 2% to 22%, but is
likely 6% to 10% overall based on studies with a confirmed diagnosis of
relatives.53,54 Patients with chronic cluster headache are twice as likely to have a
positive family history compared with those with episodic cluster headache (23%
versus 13%), as well as a higher attack frequency.55 When one parent has cluster
headache, about one-third of their relatives also have cluster headache.56 An
autosomal dominant pattern is common but not universal, and the penetrance
rate is higher in males who typically inherit it from their fathers.53 Among both
men and women with cluster headache, almost 50% have a parent with migraine,
typically a father. About one-half of patients with cluster headache also have
migraine and a similar percentage report a family history of migraine.56
Learning of a family history is useful in several respects. It helps to explain to a
patient that a genetic component contributes to the reason that they have a
particular type of headache; it is estimated that up to 64% of cases can be
primarily attributed to genetics.57 If a relative exhibited a particular pattern of
headache (eg, the mother of a female patient had migraine that remitted after
menopause) the patient may follow a similar pattern. Treatments that were
effective for one family member may also work well for their relatives. Genetic
testing may be offered to patients with suspected familial hemiplegic migraine or
CADASIL, or to unaffected relatives of known probands. Confirming a headache
diagnosis in the patient, and sometimes in their relatives, provides families with
additional information about their potential susceptibility to headaches.
MEDICAL HISTORY. The medical history yields clues for diagnosing migraine if the
patient experienced infantile colic, torticollis, unexplained abdominal pain,
vomiting or vertigo, or motion sickness in childhood. Suggest a parental
consultation if the patient is unsure. Changes in headache patterns related to
menses, pregnancy, perimenopause, and menopause frequently occur in people
with migraine. A history of cancer or human immunodeficiency virus (HIV)
raises the possibility of a secondary headache.
The general medical history helps guide treatment, as some medications are
either contraindicated or ill-advised in patients with certain medical problems.
Examples include triptans in patients with coronary artery disease, tricyclic
antidepressants in patients who are prone to constipation, and topiramate in
patients with a history of calcium phosphate kidney stones. Certain conditions
are associated with primary or secondary headaches, including thyroid disease,
systemic lupus erythematosus, polycystic ovarian syndrome, and joint
hypermobility disorders.58-61
310 A P R I L 2 0 24

SOCIAL HISTORY. A standard social history reveals information about smoking, KEY POINTS
alcohol consumption, drug use, employment type and status, physical activity,
● The general medical
and the home environment. It is particularly important to ask about current or history may reveal
previous physical, emotional, and sexual abuse. Migraine and tension-type conditions that are
headache are more prevalent in individuals with recalled childhood maltreatment, associated with headaches
particularly in sexual and gender minority adults, often associated with coexisting as well as those posing
contraindications to certain
anxiety, depression, and posttraumatic stress disorder.62,63 This author includes a
headache treatments.
question on the new patient intake form regarding a history of physical, emotional,
or sexual abuse and addresses it during the patient interview after confirming that ● Familiarization with
the patient feels comfortable discussing it. If the patient does not seem amenable to headache red flags reduces
direct questioning, an indirect approach, such as asking “What was the worst thing the likelihood of missing a
potentially serious
that ever happened to you (as a child)?” and following up with more specific secondary headache
questions about being hurt, battered, assaulted, or having something sexual done disorder.
to them against their will, may yield more information.64 Adverse childhood
experiences are risk factors for migraine and other headaches in adults, as well as ● When the phenotype
suggests a primary
the progression from episodic to chronic migraine.65 headache disorder but
Alcohol often triggers headaches, specifically migraine and cluster headache. treatments are ineffective,
Patients with cluster headache are more likely to smoke or have been exposed to consider the possibility of a
secondhand smoke than the general population, although there is no evidence secondary headache
disorder or acute
that smoking cessation improves the headaches.66,67 Certain stressors at home or
medication overuse.
work may be identified that contribute to the headache burden.
CURRENT AND PREVIOUS MEDICATIONS. While the electronic health record is

frequently used as a source of medication and allergy information, clinicians
should avoid relying on it exclusively because inaccuracies related to entry
errors and omissions can occur. This is particularly true for over-the-counter
medications, specifically those used for pain relief. It is important to know
exactly what medication the patient is taking and how often they take it.
The timing of acute medication use during an attack is critical to assess
effectiveness.68
In addition to current medications, obtain a list of drugs that the patient has
tried in the past for headache treatment, including the strength, frequency,
duration of action, effect, and side effects. The patient may need to check at
home, with their pharmacy, or a pharmacy app and send the list at a later time.
The medication list can provide very useful information, such as a
subtherapeutic dose of a preventive medication, overuse of acute pain
medications that contribute to refractory headache, the potential for drug
interactions with medications and potential headache treatments, or a
medication that frequently produces headache (or another relevant
symptom) as an adverse effect.
Knowing previous medications helps to formulate a treatment plan by either
avoiding a past medication, trying it at a different dosage or trial duration, or
combining it with another medication.
Assessing For Secondary Headache Disorders

The differential diagnosis of secondary headache disorders is vast. The
mnemonic SNOOP (to snoop for red flags) provides a framework for
thinking about secondary headache disorders, noting “red flags” in the
history or examination that prompt further investigation. Initially described
as SNOOP4 with four items beginning with a P, the list gradually expanded

over the years to SNNOOP10, which is detailed in TABLE 1-2.69 Additionally,

the possibility of a secondary headache disorder should be revisited when
headaches with the phenotype of a primary headache disorder do not respond
to treatment.
Keeping the possibility of a secondary headache in mind while taking the
history, this section further expands on two secondary headache disorders.

PSEUDOTUMOR CEREBRI SYNDROME AND IDIOPATHIC INTRACRANIAL HYPERTENSION.

Pseudotumor cerebri syndrome encompasses all cases of intracranial
hypertension without ventriculomegaly or a mass lesion. Idiopathic intracranial
hypertension (IIH) is diagnosed when no secondary cause is identified. The
TABLE 1-2 SNNOOP10 List of Headache Red Flagsa
Sign or symptom Related secondary headaches (most relevant ICHD-3 categories)

b
1 Systemic symptoms including fever Headache attributed to infection or nonvascular intracranial disorders,
carcinoid or pheochromocytoma
2 Neoplasm in history Neoplasms of the brain; metastasis
3 Neurologic deficit or dysfunction (including Headaches attributed to vascular, nonvascular intracranial disorders;
decreased consciousness) brain abscess and other infections
4 Onset of headache is sudden or abrupt Subarachnoid hemorrhage and other headaches attributed to cranial or
cervical vascular disorders
5 Older age (>50 years) Giant cell arteritis and other headache attributed to cranial or cervical
vascular disorders
6 Pattern change or recent onset of headache Neoplasms, headaches attributed to vascular, nonvascular intracranial
disorders
7 Positional headache Intracranial hypertension or hypotension
8 Precipitated by sneezing, coughing, or exercise Posterior fossa malformations; Chiari malformation
9 Papilledema Neoplasms and other nonvascular intracranial disorders; intracranial

hypertension
10 Progressive headache and atypical presentations Neoplasms and other nonvascular intracranial disorders
11 Pregnancy or puerperium Headaches attributed to cranial or cervical vascular disorders; postdural

puncture headache; hypertension-related disorders (eg, preeclampsia);
cerebral venous sinus thrombosis; hypothyroidism; anemia; diabetes
12 Painful eye with autonomic features Pathology in posterior fossa, pituitary region, or cavernous sinus;
Tolosa-Hunt syndrome; ophthalmic causes
13 Posttraumatic onset of headache Acute and chronic posttraumatic headache; subdural hematoma and
other headache attributed to vascular disorders
14 Pathology of the immune system such as HIV Opportunistic infections
15 Painkiller overuse or new drug at onset of Medication-overuse headache; drug incompatibility

headache
HIV = human immunodeficiency virus; ICHD-3 = International Classification of Headache Disorders, Third Edition.
a
Reprinted with permission from Do TP, et al, Neurology.69 © 2019 American Academy of Neurology.
b
Orange flag for isolated fever.
312 A P R I L 2 0 24

red flags for IIH and pseudotumor cerebri syndrome are a pattern change or KEY POINT
recent onset of headache, progressive headache, atypical presentations, and
● The symptoms of
papilledema. intracranial hypertension are
The headache phenotype of increased intracranial pressure does not myriad. Orthostatic
distinguish it from primary headaches; most individuals with IIH experience headache is the most
headaches that fit the description of either migraine without aura or tension-type common initial symptom but
the postural component may
headache. Headaches arising from IIH often respond to analgesics early in their
resolve over time. Careful

course. The Idiopathic Intracranial Hypertension Treatment Trial found that questioning about other
more than 40% of participants, of whom 161 of 165 were women, had a prior symptoms is needed,
history of migraine, more than twice the estimated prevalence in the general particularly if the headache
onset pattern is a new daily
population of women.70 However, patients with IIH can generally distinguish persistent headache.
their IIH-related headaches from their previous migraine attacks.
Transient obscurations of vision and pulsatile tinnitus are common symptoms
of IIH. Transient obscurations of vision generally last seconds to a minute with
either complete or partial loss of vision in one or both eyes. They are often
provoked by arising after bending over. The new onset of pulsatile or
nonpulsatile tinnitus coinciding with the onset of headache also suggests
intracranial hypertension.71 Patients frequently do not volunteer the auditory
symptoms, so direct questioning is imperative.
Although positional headache is mentioned in TABLE 1-2 as a red flag, patients
with IIH rarely report rapid changes in headache severity with positional changes.
The headache may be worse in the morning, as intracranial pressure increases after
prolonged recumbence.72
IIH affects people of childbearing age with obesity, but pseudotumor cerebri
syndrome does not share the same predilection due to the various causative
etiologies. Thus, suspected patients should also be queried regarding the use of
tetracycline and its derivatives (eg, doxycycline, minocycline), vitamin A and
retinoids (eg, all-trans retinoid acid, isotretinoin), and lithium.71
INTRACRANIAL HYPOTENSION FROM A SPINAL CSF LEAK. The red flags for suspecting a
spinal CSF leak include the following69:
u Sudden or abrupt onset of headache

u Pattern changes or recent onset of headache
u Orthostatic headache
u Headache precipitated by sneezing, coughing, or exercise
u Progressive headache and atypical presentations
u Posttraumatic onset of headache
Spontaneous intracranial hypotension includes spinal CSF leaks arising

without an apparent precipitating factor or following relatively trivial trauma
(CASE 1-3).73 Dural puncture from procedures or surgery produces similar
symptoms. The hallmark symptom, present in more than 90% of cases, is
orthostatic headache.74 The headache is often posteriorly located, involving the
occipital region, neck, and shoulders (“coat hanger headache”), and is classically
worse in the upright position and relieved in recumbency. The clinical
presentation is quite variable among affected individuals, most of whom have
other symptoms, such as neck pain and stiffness, vestibulocochlear symptoms
(eg, tinnitus, hearing changes, imbalance, vertigo), cognitive changes (ranging

from “brain fog” to dementia), facial pain, movement disorders, nausea, and
photophobia (CASE 1-3).74
There are no particular defining features of headaches due to a spinal CSF
leak, although spontaneous intracranial hypotension is a cause of new daily
persistent headache that begins abruptly. It may also masquerade as chronic
migraine without aura. The headache typically worsens with Valsalva maneuvers
(TABLE 1-1) and worsens as the day progresses. Subsequent limitations in
upright time lead to marked disability, with some patients being incapable of
performing basic activities of daily living.
In addition to asking about symptoms, one should inquire about potential
precipitating causes and factors. Relatively minor trauma such as whiplash
CASE 1-3 A 39-year-old woman was referred for evaluation of severe photophobia
which had previously been attributed to migraine. She had a history of

migraine with visual aura since age 30 years that occurred with menses
and one other time per month, and was easily relieved with rizatriptan.
Her current headache began 3 years before her initial visit when she
developed a “migraine” lasting 6 weeks. Rizatriptan was ineffective and a
course of prednisone helped for 1 day. The fluorescent lights at her
workplace bothered her. Several months later she could drive and
tolerated sunlight and fluorescent lights. A year after symptom onset she
only tolerated incandescent light. By the following year, she could only
eat dinner by candlelight. At the time of her visit, she was no longer
working, ate in darkness, and all light exposure triggered a migraine.
Her head pain felt like a knife stabbing her in the head, a skewer in her
head, or acid burning. The pain was occasionally bilateral with neck pain,
associated with photophobia, phonophobia, osmophobia, and motion
sickness. Once vomiting ensued, she had to go to the emergency
department because her antiemetic medication did not work. She could
not concentrate during a severe headache and she felt off balance, as
though she would fall.
Her mental status and affect were normal. She wore dark sunglasses
and covered her head with a towel during the visit when possible. She also
covered the computer monitor with a towel when not in use. She brought a
floor lamp to the examination with a 38-watt incandescent bulb. Her
neuro-ophthalmic examination was normal. MRI of the brain with contrast,
performed when her symptoms began, was reviewed and was normal.
Further questioning revealed that she had lifted heavy equipment before
the start of her first migraine episode. She had a history of joint
hypermobility. Her symptoms were typically milder in the morning and
worsened as the day progressed. Suspecting a spinal CSF leak, a
nontargeted blood patch was performed.
COMMENT This case demonstrates the importance of considering red flags for
secondary headaches. The patient had a history of migraine but experienced
a change in the pattern of her preexisting headache as well as profound
photophobia, with features suggestive of intracranial hypotension.
314 A P R I L 2 0 24

injury, roller coaster rides, chiropractic manipulation, fly fishing, yoga, heavy
lifting, protracted coughing, or vomiting may precede the headache onset.71
Females are more commonly affected, many of whom have joint hypermobility,
connective tissue disorders, or postural orthostatic tachycardia syndrome.73-75
PHYSICAL EXAMINATION IN THE HEADACHE EVALUATION

The physical examination in patients with headache should include:
u Vital signs (blood pressure, temperature, height, weight, heart rate)

u General neurologic examination including a fundoscopic examination
u Palpation of cranial peripheral sensory nerves for tenderness or pain reproduction
including the greater and lesser occipital nerves, auriculotemporal nerves,
supraorbital and supratrochlear nerves, zygomaticotemporal nerves, and the
trochleae. FIGURE 1-176 shows the distribution of peripheral nerves supplying the head.
u Nuchal range of motion and palpation for tenderness
u Neck circumference and Mallampati grade
Additional examination maneuvers that are directed by specific clinical

features include:
u Assessment of jaw opening distance, crepitus, tenderness

u Palpation of the temporal arteries
u Otoscopic examination
u Trendelenburg test (This is useful for evaluating patients with a suspected spinal CSF
leak. Place the patient in 5 to 10 degrees of Trendelenburg for 5 to 10 minutes.
Improvement of headache or other symptoms in the Trendelenburg position is highly
suggestive of this diagnosis.77)
QUESTIONNAIRES
Taking a headache history should be a comprehensive process with many different
facets. Headache specialists routinely incorporate various questionnaires, filled
FIGURE 1-1
Cranial and upper cervical nerve branch injection sites for peripheral nerve blocks for
headache disorders. Common peripheral nerve block injection site locations include the
greater and lesser occipital nerves (A), the supraorbital and supratrochlear nerves (B, C),
and the auriculotemporal nerves (B, C).
Reprinted with permission from Blumenfeld A, et al, Headache.76 © 2013 American Headache Society.

out before the appointment, to glean as much information as possible during the
office visit. Paper questionnaires may be used, although programming the
questionnaires into the electronic medical record and distributing them before the
visit eliminates the cost of staff time and postage for mailing paper forms.
New Patient Questionnaire TABLE 1-3 lists commonly employed validated questionnaires.
Recommended questionnaires cover headache disability (the Migraine

Disability Assessment is often used in practice for all headache types but was
developed specifically for migraine), anxiety, depression, sleep apnea, and

posttraumatic stress disorder.
A questionnaire specifically targeting important aspects of the history is
extremely useful. It serves as a guide to the interview, directs the flow of the
interview, and gives the patient an idea of what types of questions will be asked
Follow-up Questionnaire before they enter the examination room. This author’s new-patient and
follow-up questionnaires are available as Supplemental Digital Content for this
article (links.lww.com/CONT/A403, links.lww.com/CONT/A404), and both can

be accessed through the QR codes in the margin.
Online questionnaires incorporating machine learning use data entered by
the patient to develop a diagnosis (or differential diagnosis) and treatment
suggestions that patients can take to their clinician or provider.6,78,79
Although questionnaires and online tools are helpful for data gathering and
classification, a face-to-face encounter is often more accurate and still has
considerable value for observing facial expressions, body language, tone of
communication, and other cues.80,81
TABLE 1-3 Commonly Used Validated Questionnaires in Headache Medicine
Number of License
Questionnaire Abbreviation Purpose questions needed?
Allodynia Symptom Checklist ASC-12 Cutaneous allodynia 12 No
Berlin Questionnaire Sleep apnea in adults 6 No
General Anxiety Disorder-7 GAD-7 Anxiety 7 No
Headache Impact Test-6 HIT-6 Headache impact on functioning 6 Yes
Migraine Disability Assessment MIDAS Migraine disability 5+2 No
Migraine Functional Impact MFIQ Impact of migraine on physical, 26 Yes, for

Questionnaire emotional, and social functioning research
(adults)
Migraine Treatment Optimization MTOQ Response to acute migraine treatment 5 No
Neck circumference, NoSAS Sleep apnea 5

Obesity, Snoring, Age, Sex
Patient Global Impression of PGIC Change in condition in response to 7 No

Change treatment
Patient Health Questionnaire PHQ-9 Depression 9 No
PTSD Checklist for DSM-5 PCL-C Posttraumatic stress disorder (civilian) 17
STOP-BANG Questionnaire STOP-BANG Sleep apnea 8
316 A P R I L 2 0 24

WRAPPING IT UP KEY POINTS
First and foremost, straightforwardly convey the diagnosis. The American
● The history often yields
Migraine Prevalence and Prevention study, performed in the early 2000s, the headache diagnosis but
reported survey results of 162,576 individuals from almost 80,000 households certain aspects of the
regarding migraine diagnosis and treatment.82 Participants’ responses to physical examination should
migraine features based on the International Classification of Headache be included, especially

fundoscopy.
Disorders, Second Edition identified them as having migraine or other severe
headaches. Surprisingly, only 56.2% of those with an International Classification ● Both intake
of Headache Disorders, Second Edition diagnosis of migraine had ever received a questionnaires and
medical diagnosis of migraine. Self-reported headache types from the validated questionnaires for
undiagnosed group included sinus headache (39%), tension-type headache common headache
comorbidities provide
(31%), and stress headache (29%). Diagnoses are now coded in electronic useful insight and help make
medical records and patients can easily access them, although this is not an ideal history taking more
communication strategy. If the diagnosis is uncertain, explain why and outline efficient. The most
the next steps to confirming one. successful results arise from

having the patient complete
The “ask-tell-ask” strategy incorporates building on, and correcting when questionnaires before the
needed, the patient’s existing knowledge83: appointment.
● The “ask-tell-ask”
u ASK the patient to describe their understanding of the issue.
strategy reinforces the
u TELL the patient the facts at an understandable level, correct misconceptions, and patient’s understanding of
validate their correct responses. This should not be overwhelming in length or detail. their headache diagnosis
and plan. Make sure to
u ASK the patient if they understood what you said, and to explain or rephrase it.
communicate realistic goals
and expectations and invite
Convey realistic expectations. Patients often want their headaches “cured,” the patient to ask questions.
which is an unrealistic goal for most primary headache disorders. Most patients
will achieve marked improvement with headache management but it may take
some time to find an optimal individualized treatment strategy. A reasonable
goal is to have fewer and less severe headaches with effective acute treatment
when needed. This is a good time to repeat back what the patient conveyed in
the interview (eg, “Our goal is to improve your headaches so you can go to work
or school, be present at your children’s activities, make plans, or go
on vacation.”).
Some patients are too intimidated to ask questions. A nonthreatening way to
frame the request for questions is, “Is there anything else I can help you with
today?”
Discuss prescriptions, common side effects, and dosing schedules (nursing
staff can help with this, if available). Schedule a follow-up appointment and
instructions for between-office communication.
TAKE-HOME INFORMATION, LATEST DEVELOPMENTS,

AND RESOURCES
Patients have various degrees of health literacy and abilities to retain what is
conveyed in an outpatient encounter. Numerous studies show that patients recall
and understand as little as 50% of information conveyed during an office visit.84
Differences also exist among both patients and physicians when using the patient
portal for secure electronic messaging.85 These factors affect adherence to
treatment plans.
The electronic medical record allows us to easily put our instructions in
writing and provide information about a patient’s condition using “smart

phrases” in the after-visit summary. Links to various reputable websites vetted

by the practitioner can also be included. Several studies performed in the primary
care setting show that the after-visit summary reduces the number of telephone
calls for medications and test results between visits, and patients perceive them
as useful.86-88
After-visit summaries have the potential to be a powerful educational tool but

they are often poorly organized, too long, contain unnecessary information with
pages of general health information, and are confusing for patients to navigate.
Redesigning them to be patient centered, with enhanced readability and
understandability, is frustratingly difficult and sometimes impossible depending
on the platform.89 Despite our good intentions to convey clear information to
TABLE 1-4 Resources for the Office Visit and Beyond
Name Website Description
Clinician resources
International Classification ichd-3.org Official classification system and diagnostic

of Headache Disorders, criteria for primary and secondary headache
Third Edition disorders
American Headache americanheadachesociety.org Professional organization, meeting information,

Society find a headache specialist, education on
demand for clinicians and residents
Beighton Score ehlers-danlos.com/assessing-joint- Scoring for joint hypermobility

hypermobility
New Patient Intake Available as Supplemental Digital Content Dr Friedman’s questionnaire that can be printed
Questionnaire for this article or programmed for online use; add validated
questionnaires (eg, MIDAS, GAD-7, PHQ-9,
STOP-BANG, ASQ-12, PTSD) as desired from
TABLE 1-3
Follow-up Visit Available as Supplemental Digital Content Dr Friedman’s questionnaire that can be printed
Questionnaire for this article or programmed for online use; suggest also
including a headache disability/impact
questionnaire
Resources for clinicians and patients
BonTriage bontriage.com Patients answer questions online about their

headaches; software generates a diagnosis and
suggested treatments to discuss with their
clinician with electronic medical record–
compatible reports
Resources for patients and families
American Migraine americanmigrainefoundation.org Educational resources and advocacy tools for

Foundation people with migraine
National Headache headaches.org Educational resource for patients, find a

Foundation (NHF) provider, training for primary care professionals,
resources for military personnel, tracking app
318 A P R I L 2 0 24

patients, including manually highlighting important educational information,
the paper after-visit summary often ends up in the trash.87 Studies also show that
prepopulated information in the after-visit summary, such as medication and
allergy lists, is often inaccurate and that the highest recall is for medications and
physician instructions.87,90
As written information is not always effective, one might consider video

recordings of the visit. Many medical centers prohibit the unauthorized use of
video and many physicians are reluctant to be recorded. However, a study

surveying 2800 patients seeing eight different neurosurgeons generated
responses from about one-third of survey recipients.91 More than one-half
watched their video more than once, and more than two-thirds shared it with a
Name Website Description
Office of Women’s Health womenshealth.gov Answers to commonly asked questions about

migraine
WebMD webmd.com Migraine information for patients
Miles for Migraine milesformigraine.org Walk/run/relax fundraisers, educational events

for patients and family programs, support
groups, social events
Migraine Canada migrainecanada.org Patient education, advocacy, library, headache

clinics, Canadian health care coverage issues
Clusterbusters clusterbusters.org Supports research for cluster headache,

advocacy, patient resources
Cluster Headache Warriors clusterheadachewarriors.org Patient support, education, education,

advocacy, research support for cluster
headache and other trigeminal autonomic
cephalalgias
Diary apps
Migraine Buddy migrainebuddy.com Migraine tracking app
Manage My Pain Pro managemypainapp.com Tracks headaches and other chronic pain
Migraine Mentor bontriage-headache-tracker-ios.soft112. Uses artificial intelligence to provide patient

com feedback
iHeadache iheadache.com Detailed headache tracking
Migraine Insight migraineinsight.com Migraine tracking app
Paper diaries
Paper Headache Diary Available as Supplemental Digital Content Dr Friedman’s downloadable paper diary
for this article
NHF Headache Diary headaches.org/wp-content/uploads/ Downloadable paper diary

2021/05/HEADACHE-DIARY.pdf

family member, friend, or other physician. Three-quarters of those surveyed

reported that they could remember more from their visit, and one-half indicated
that the video made them feel more at ease with their medical problem. Almost
90% felt that the video was helpful and 98.5% recommended that future visits be
Headache Diary
recorded. No one felt that it was intrusive and no one used the video in a
medical-legal action.
Headache diaries are invaluable for assessing a patient’s progress. Options
include a paper calendar, a calendar on the patient’s smartphone or computer,

and apps specifically designed for headache or migraine tracking. TABLE 1-4
provides resources for use in the office visit, patient education, and diary apps.
This author’s paper headache diary is available as Supplemental Digital Content
for this article (links.lww.com/CONT/A407), accessible through the QR code in
the margin.
CONCLUSION
Each patient with headaches is different, and each initial visit is different. The
process of getting to know your patient and arriving at the correct diagnosis and
optimal treatment is largely comprised of conversations; new information
emerges with every visit as you and the patient think more deeply over time.
Familiarity with common headache disorders helps to focus the line of
questioning. Similar to doing a neurologic examination, an organized approach is
helpful. Previsit questionnaires help the patient know what types of information
are needed and prevent the clinician from leaving out essential aspects of the
history. The detective work of history taking, patient relationships, advances in
science and therapeutics, and the ability to help individuals with headaches
substantially improve their quality of life are what make headache medicine fun
and rewarding.
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DISCLOSURE
Continued from page 296

Scottsdale Headache Symposium with the Southern Headache Society that are relevant to
American Headache Society, and as a treasurer and American Academy of Neurology (AAN) interests or
a member of the board of directors with the activities.
324 A P R I L 2 0 24

Pathophysiology of REVIEW ARTICLE
Migraine

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Nazia Karsan, PhD, MRCP
ABSTRACT
OBJECTIVE: This article provides an overview of the current understanding of
migraine pathophysiology through insights gained from the extended
symptom spectrum of migraine, neuroanatomy, migraine neurochemistry,
and therapeutics.
zpIyX172RtLjRB/c0oGHr6Ys= on 04/03/2024
LATEST DEVELOPMENTS: Recent advances in human migraine research,

including human experimental migraine models and functional
neuroimaging, have provided novel insights into migraine attack initiation,
neurochemistry, neuroanatomy, and therapeutic substrates. It has become
clear that migraine is a neural disorder, in which a wide range of brain areas
and neurochemical systems are implicated, producing a heterogeneous
clinical phenotype. Many of these neural pathways are monoaminergic and
peptidergic, such as those involving calcitonin gene-related peptide and
pituitary adenylate cyclase-activating polypeptide. We are currently
witnessing an exciting era in which specific drugs targeting these pathways
have shown promise in treating migraine, including some studies
suggesting efficacy before headache has even started.
Migraine is a brain disorder involving both headache and

ESSENTIAL POINTS:
altered sensory, limbic, and homeostatic processing. A complex interplay
between neurotransmitter systems, physiologic systems, and pain
processing likely occurs. Targeting various therapeutic substrates within
these networks provides an exciting avenue for future migraine
therapeutics.
CITE AS:
2024;30(2, HEADACHE):325–343.
INTRODUCTION Address correspondence to
M
igraine is the most common primary headache disorder seen Dr Nazia Karsan, Wellcome
in emergency departments, acute medical services, and Foundation Building, King’s
College Hospital, Denmark Hill,
outpatient neurology clinics.1 While defined and classified London, SE5 9PJ, United
as a condition of headache,2 migraine is a complex and Kingdom, nazia.karsan@kcl.ac.uk.
symptomatically heterogeneous brain disorder that
RELATIONSHIP DISCLOSURE:
predisposes to recurrent attacks of disabling headache, as well as sensory, limbic, Dr Karsan reports no disclosure.
and homeostatic symptoms in genetically susceptible individuals.3 In some
UNLABELED USE OF PRODUCTS/
patients, nonheadache features of migraine can be equally, if not more, disabling INVESTIGATIONAL USE
than the headache, and clinical trial design in migraine therapeutics is evolving to DISCLOSURE:
incorporate nonheadache primary endpoints as outcome measures based on such Dr Karsan reports no disclosure.
observations. When trying to understand migraine pathophysiology, it is easiest © 2024 American Academy
to consider the migraine attack in someone who has distinct attacks of headache of Neurology.

PATHOPHYSIOLOGY OF MIGRAINE
and associated symptoms in the absence of daily or continuous headache. This is

perhaps simplistic and not representative of every patient who has migraine
since some patients experience continuous symptoms with high headache
frequency and others may have interictal symptoms in between more discrete
attacks of headache; however, it forms a suitable model to understand the
entirety of the migraine symptomatic spectrum.

While the presence of symptoms other than headache (such as light or sound
sensitivity) is needed to make a migraine diagnosis according to the International

Classification of Headache Disorders, Third Edition (ICHD-3),2 several
migraine-associated symptoms do not form part of the canonical symptoms in
the diagnostic criteria yet still contribute to the extended migraine phenotype.
These symptoms include those that occur before a headache and warn of an
impending headache, so-called premonitory symptoms, which can be broadly
divided into groups, such as limbic symptoms (eg, arousal, cognitive, mood
changes), migraine-associated symptoms (eg, photophobia, phonophobia,

movement sensitivity, neck discomfort), and homeostatic symptoms (eg, thirst,
CASE 2-1 A 9-year-old boy experienced migraine with brainstem aura for the past
2 years. Over time, his parents noticed that they could predict that a
headache attack was coming as he behaved differently in the 48 hours
leading up to an attack. They reported that he started behaving in a
disinhibited way, was hyperactive, and could laugh or cry without reason.
He admitted that he could irritate his brother during this time and that he
tended to giggle randomly. His parents were generally able to predict
that he would need to be home from school for a migraine attack 2 days
later. Consistently, 2 days after these symptoms would start, he
subsequently had headache for 1 day accompanied by 1 hour of brainstem
aura symptoms at onset. These included diplopia and unsteady gait. After
the headache resolved, his parents noticed that he looked pale, had red
puffy eyes, lost his appetite, wanted to sleep, and could be moody and
irritable. He would often tell his brother to go away and did not want to
play with him. This would last around 12 hours and he would be unable to
go to school that day; afterward, he would be back to normal. In between
attacks, his parents reported that he was a very mild-mannered and
happy boy and that they had no behavioral concerns.
COMMENT This child has typical premonitory symptoms preceding headache by

48 hours. He and his parents reported behavioral changes and emotional
lability. After the headache resolved, he also experienced a symptomatic
postdrome with associated cranial autonomic symptoms, with conjunctival
injection and periorbital edema. The associated symptoms of migraine
such as premonitory symptoms, cranial autonomic symptoms, and
postdrome symptoms can present in both young children and adults and
contribute to the extended migraine phenotype. Premonitory symptoms
provide an opportunity to predict impending headache and, in some cases,
to preempt changes in routine in advance of headache.
326 A P R I L 2 0 24

hunger, yawning, cravings, frequency of micturition). It has been proposed that KEY POINTS
the premonitory phase should be defined as the 48 hours leading up to headache,
● The migraine attack is
based on imaging changes being observed during this window, and some studies typically divided into
have used this definition to study this phase with functional neuroimaging, phases. The premonitory
regardless of clinical phenotype.4-6 Other sensitivities like osmophobia (an phase starts hours to days
aversion to smells), vertigo, and allodynia are also reported in migraine, as are before headache onset and
aura may follow in those
cranial autonomic symptoms such as lacrimation, conjunctival injection, and
with aura. The migraine itself

rhinorrhea. Although cranial autonomic symptoms are canonical of the rarer occurs next and is followed
trigeminal autonomic cephalalgia headaches, they can be present in migraine, by a postdrome in many
can lateralize to the side of headache, and should not deter from a migraine individuals, typically lasting
up to 24 hours.
diagnosis.7
Postdrome symptoms following headache resolution are present in many ● Migraine is a
patients with migraine and can include ongoing tiredness, cognitive changes, and symptomatically
hunger,8 which may delay the return to normal function. A proportion of heterogeneous brain
disorder that can manifest
patients with migraine will also experience aura, a phenomenon of transient

with several symptoms apart
positive or negative neurologic symptoms typically occurring before or with from headache, some of
migraine and usually visual in nature.9 These migraine-associated symptoms can which can start before
present in both children and adults (CASE 2-1). FIGURE 2-1 demonstrates the headache and in its absence.
“phases” of a migraine attack, although these do not need to occur in defined
● While migraine involves
phases and symptoms can represent a continuum,8 some of which can be present
vasodilatation, and
interictally. It is useful to use such a model of an attack to understand migraine vasoconstrictive agents
pathophysiology. have proven efficacy in
treating migraine, the
discovery that these drugs
MIGRAINE NEUROANATOMY
also have neural effects and
The identification that the pulsating nature of migraine is not in sync with the that vasoconstriction is not
cardiac pulse10 and that meningeal vessels do not significantly dilate on magnetic needed for a migraine
resonance angiography (MRA) during spontaneous migraine attacks11,12 abortive effect have
provided evidence against an initial vascular theory of migraine. It has since been changed the landscape of
acute therapeutics
demonstrated that vasoconstriction is not required for pain abortion,13 and that research.
the triptans, serotonin 5-HT1B/1D receptor agonists, and ergot alkaloids, which
cause vasoconstriction and have therapeutic effects in migraine, have both neural
and vascular effects.14 A dural inflammatory theory poses that the vasoactive
neurotransmitters released by dural stimulation cause neurogenic inflammation
and secondary vasodilatation,15 but this mechanism is not supported by the fact
that nonvasoconstricting inhibitors of neurogenic inflammation have not been
effective in the treatment of migraine16 and that longitudinal structural imaging
has never detected the consequences of repeated dural inflammation.17
In recent years, a primarily neural theory has been supported by functional
imaging studies during migraine, which have consistently demonstrated
activation of central brain areas, including the brainstem in both spontaneous
and triggered migraine,18 as well as early functional imaging changes before pain
onset, suggesting that attack initiation must occur centrally.6 An intact
blood-brain barrier has been suggested on imaging during migraine attacks,19 so
dural changes that could be the source of headache are unlikely to be the first
process in the migraine attack.
Many extracranial structures of the head, such as the skin, muscles, arteries,
and periosteum, can generate pain. Peripheral sensory afferents (unmyelinated C
fibers and myelinated Aδ fibers) from structures of the head and neck (via the
trigeminal nerve, largely V1 and V2 and to a lesser extent V3, and C1 and C2)
converge with nociceptive fibers from intracranial vascular structures and the

FIGURE 2-1
Typical timeline of an attack of migraine without aura. Premonitory symptoms start hours to
days before pain onset and are followed by headache in most cases. A symptomatic
postdrome can be troublesome in some patients after headache improvement.
Figure created with BioRender.
meninges, both of which are pain sensitive and trigeminally innervated. These
afferents project from the trigeminal ganglion to the trigeminocervical complex
within the brainstem. Ascending projections between the trigeminocervical
complex and various cortical processing areas pass through the thalamus.
Cortical projections from the trigeminocervical complex via the hypothalamus,
midbrain, pontine, and medullary nuclei are also present, including the locus
coeruleus, rostral ventromedial medulla, and nucleus raphe magnus. A reflex
connection from the trigeminocervical complex to the superior salivatory
nucleus in the pons via the sphenopalatine ganglion to the extracranial and
intracranial vasculature also exists and mediates parasympathetic cranial
autonomic symptoms associated with the primary headache disorders. Fibers
innervating the dura release various neuropeptides on activation including
neurokinin A, calcitonin gene-related peptide (CGRP), and pituitary adenylate
cyclase-activating polypeptide (PACAP), and these cause vasodilation of dural
and pial blood vessels which is thought to cause and maintain headache.20
Thalamocortical projections to the somatosensory, limbic, and prefrontal cortices
are likely important in migraine, as well as in the modulation of the sensory,
limbic, and cognitive components of pain.21 Other limbic areas such as the
amygdala, hippocampus, and insula have demonstrated involvement, likely in
mediating these responses and the altered emotional and cognitive states that
patients with migraine experience with attacks.22 There is therefore a
328 A P R I L 2 0 24

combination of subcortical and cortical brain dysfunction, and the pathways KEY POINTS
between these nuclei and cortical areas are responsible for mediating the broad
● Migraine neuroanatomy
clinical phenotype via complex networks. Descending brainstem modulation of involves extracranial
nociceptive and sensory processing via various nuclei and structures has also structures of the face, head,
been implicated.20 Experimental studies show that electrical or mechanical neck, dura, intracranial large
stimulation of large vessels within the meninges causes headache similar to vessels, and brain areas
such as the thalamus,
migraine and can also cause associated migraine symptoms, yet stimulation away
hypothalamus, brainstem,
from vessel regions is not painful.23 How these meningeal perivascular and cerebral cortex.
nociceptive fibers become activated is unknown.
It seems unlikely that dural activation is the first process involved in migraine ● The premonitory phase
pathophysiology. Central brain structures that provide feasible neural correlates provides a unique
opportunity to study
for premonitory symptoms are activated before headache onset on imaging migraine attack initiation and
studies.24 Whether these regions are the origin of the attack or the cause of brain function in the
trigeminovascular activation, which happens first (in the absence of headache) absence of pain and offers
remains an unanswered question. FIGURE 2-2 shows some of the anatomic areas the ability to study
headache prevention in
involved in migraine, particularly via monoaminergic neurotransmission, and those who can use the
the clinical manifestations that they may cause. TABLE 2-1 shows the parts of these symptoms to reliably
brain regions that may be implicated and via which connections. Early central predict headache.
modulation of pain processing during premonitory symptoms poses a novel and
● The interaction between
exciting therapeutic approach.
migraine and other
physiologic processes, such
A PHASE-BY-PHASE APPROACH TO MIGRAINE PATHOPHYSIOLOGY as those controlling feeding
For ease of understanding, the migraine attack can be separated into different and sleep, and the early
involvement of these
phases, although each phase does not have to occur in every patient; even if they
systems in the premonitory
do, they may not occur sequentially, and some patients experience more of a phase may explain how
symptom continuum throughout the attack.8 This section discusses each phase in some patient-perceived
more detail as an approach to understanding migraine pathophysiology. migraine triggers may
actually be misattributions
of early premonitory
Premonitory Symptoms of Migraine symptoms.
Premonitory symptoms have been an evolving area of interest in headache
research because of their early onset and occurrence in the absence of headache
and the valuable opportunity they provide to study attack initiation and explore
early therapeutic intervention. In some patients, the phenotype of premonitory
symptoms is consistent across different attacks25,26 and a high proportion can
predict impending headache within a few hours of premonitory-symptom
onset.25 Certain symptoms, such as yawning and mood and cognitive changes,
have been shown to be the most reliable and consistent predictors of headache.25,26
The ability to potentially treat a migraine attack before headache onset by patients
reliably predicting their attacks using premonitory symptoms is a unique
therapeutic option that is currently producing exciting outcomes in early studies of
novel targeted migraine therapies.27 There is also emerging evidence that some of
these therapies can actually reduce the occurrence of premonitory symptoms.27,28
Historically, domperidone,29,30 dihydroergotamine,31,32 and naratriptan33 had been
tested in small studies during the premonitory phase, and results were
encouraging but difficult to generalize to a wider population. For both patients and
physicians, attack prediction with effective early treatment and pain prevention is
a very attractive therapeutic strategy.
Over time, prevalence studies have shown a generally increasing prevalence of
premonitory symptoms in both adults and children, likely owing to increased
recognition and understanding of these symptoms by patients and their

FIGURE 2-2
Summary of monoaminergic neurotransmission centrally via areas of interest in migraine
biology and the symptom correlates for each area. The dural vasculature, trigeminal ganglion,
and sphenopalatine ganglion are not included here.
CAS = cranial autonomic symptoms; DA = dopamine; 5HT = serotonin; LC = locus coeruleus;
NA = noradrenaline; NRM = nucleus raphe magnus; PAG = periaqueductal gray; RVM = rostral ventromedial
medulla; SSN = superior salivatory nucleus; TCC = trigeminocervical complex; VTA = ventral tegmental area.
Figure created with BioRender.
physicians.3 Prospective recording of premonitory symptoms is useful for

patients to recognize impending headache, therefore allowing possible lifestyle
modifications in case headache does occur and early treatment, if this is effective
(CASE 2-1). It is also important for patients and those treating migraine to
understand the entirety of attack-related disability. The premonitory-symptom
phenotype is varied and includes a range of symptoms across the different
symptom groups discussed above. There is an association between the likely
anatomical substrates mediating these symptoms on functional imaging studies
and the clinical phenotype. It is feasible that alterations in homeostatic
mechanisms (such as those affecting feeding and arousal) arise from the
hypothalamus and its connections, such as those to the locus coeruleus, and the
hypothalamus has been an area of interest in migraine attack generation for some
time. Limbic symptoms such as mood and cognitive changes could arise from
changes in the insula, amygdala, and cingulate cortex,34,35 as well as changes in
limbic connectivity with brainstem structures.36 Sensory sensitivities could arise
330 A P R I L 2 0 24

from altered thalamocortical connections.36 Neck stiffness could arise from the
convergence of trigeminal and cervical sensory afferents in the trigeminocervical
complex in the brainstem and activation of this area ahead of headache.37
There is also electrophysiologic evidence for alterations in cortical sensory
thresholding and pain sensitivity during the premonitory phase, supporting early
central brain dysfunction mediating sensory sensitivities during this time.38-40 It

has been suggested that augmentation of auditory evoked potentials interictally
in migraine (and therefore a lack of the normal sensory habituation) normalizes
Summary of Subnuclei or Regions of Interest in Migraine Pathophysiology TABLE 2-1
Brain area
implicated Links with migraine

in migraine Specific nuclei and other
pathophysiology or brain region Connections Role in migraine physiologic systems
Hypothalamus A11, anterior, posterior, Trigeminocervical Autonomic regulation, Autonomic,

ventromedial, supraoptic, complex, rostroventral pain modulation, arousal, feeding
suprachiasmatic medulla, periaqueductal feeding, arousal, sleep
gray, locus coeruleus, regulation
nucleus raphe magnus,
superior salivatory
nucleus, parabrachial
nucleus, thalamus, spinal
cord
Thalamus Venteroposteromedial, Retinal ganglion cells; Pain and sensory Limbic, sensory
posterior, lateral posterior/ trigeminocervical modulation, allodynia, processing
dorsal thalamic, pulvinar complex; somatosensory, photophobia
visual, and associative
cortices; limbic cortex
Striatum Caudate, putamen, Prefrontal, sensorimotor, Cognitive and limbic Limbic, cognition,
nucleus accumbens and limbic cortices; processing behavioral change
substantia nigra;
thalamus; amygdala;
hippocampus; ventral
tegmental area
Cerebral cortex Anterior cingulate, insula, Thalamus, hypothalamus Sensitization, pain Limbic, sensory
primary somatosensory, processing, affective processing,
visual, auditory and cognitive aspects cognition
of pain processing
Pons Parabrachial nucleus, Hypothalamus, thalamus, Nausea, feeding Arousal and

locus coeruleus, superior cerebral cortex regulation, cranial feeding
salivatory nucleus autonomic symptoms
Midbrain Periaqueductal gray, Hypothalamus, superior Pain, sensitization, Sensitization,

ventral tegmental area salivatory nucleus, homeostatic processes, feeding, mood
rostroventral medulla food cravings, mood
disturbance
Medulla Rostral ventromedial medulla, Periaqueductal gray, Headache, nausea, neck Nausea, neck
spinal trigeminal nuclei, locus coeruleus, discomfort stiffness
nucleus tractus solitarius, hypothalamus, thalamus
nucleus raphe magnus,
trigeminocervical complex

in the lead-up to and during a migraine attack.41 At-home EEG technology has
been used to show alterations in physiology before migraine symptoms,
supporting early or preheadache treatment of a migraine attack.42 Tablet-based
vision testing at home during the premonitory phase has shown altered
visual processing.43
The similarities between premonitory symptoms and some patient-perceived

migraine triggers (such as bright light being a trigger and premonitory
photophobia, or chocolate being a trigger and premonitory sweet cravings), as

well as the neuroimaging findings of early central alterations in areas controlling
sensory processing, feeding, and fluid regulation,44 have led to the suggestion
that perhaps these are not trigger factors at all and are actually misattributed
early premonitory symptoms. This concept may be supported by the fact that
migraine interacts with several physiologic processes, such as those controlling
feeding and sleep,45 and there is a suggestion of the poor reliability of
patient-perceived triggers actually triggering an attack in prospective diary

recording.44 For at least some patient-perceived triggers, research has indicated
that there is an association in the same individual with premonitory symptoms,
and so there may be a case that lifestyle modification and trigger avoidance in
some patients is futile as what they perceive as a trigger is actually a
manifestation of early brain changes during the premonitory phase.46,47 This
relationship is important to recognize when counseling patients on how to
manage their migraine.
Migraine Aura
The most common subtype of migraine is migraine without aura (Section 1.1 in
the ICHD-3).2 Migraine with aura (Section 1.2) can pose more diagnostic
challenges. While typically defined as occurring before headache, aura can occur
at the same time as headache48 or without headache and can be persistent.2 The
headache and associated symptom phenotypes are similar in both migraine
subtypes, raising the possibility that the aura and pain mechanisms may be
biologically distinct. Given the scope of this article, the mechanisms of aura itself
will not be discussed further here.
Migraine without aura attacks are more common than those with
accompanying aura, even in individuals with migraine with aura (CASE 2-2).
It is unclear if and how aura and migraine mechanisms are related in
migraine pathophysiology.
Migraine Headache
While the anatomical pathways implicated in migraine pathophysiology are well
described, the links between the central activation of neural structures during
premonitory symptoms and the generation of headache are less well understood.
Imaging studies since 1995 have demonstrated brainstem and midbrain activation
during spontaneous migraine, as well as activation of other brain areas, which
are feasibly related with the clinical symptoms of a migraine attack.49 Other
studies have since also demonstrated a likely occipital cortex substrate for
photophobia in migraine.50,51 The brainstem findings in the first imaging study
of migraine persisted after headache resolution following sumatriptan
administration.49 Similar findings have since been found with imaging changes
in the hypothalamus during spontaneous migraine persisting after headache
treatment.52 These identified studies suggested that these imaging findings
332 A P R I L 2 0 24

represent more than central pain processing. These identified subcortical brain
regions of the pons, midbrain, and hypothalamus also have effects on
trigeminovascular processing in animal models of migraine20 and are distinct
from those shown on imaging in other noxious head pain states.53 It is possible
that peripheral nociceptor activation is necessary for headache and that a central-
to-peripheral mechanism of perivascular sensory terminal sensitization occurs

between premonitory symptoms and headache.
There is evidence that, at least at a macroscopic level, the blood-brain barrier is

not disrupted during migraine attacks,19 but it is clear that some migraine drugs
that are felt to be peripherally acting (such as sumatriptan54) or of too large a
molecular size to cross the blood-brain barrier in large amounts (such as a
monoclonal antibody targeting CGRP55) are still found in CSF following
administration. It seems unlikely that dural changes would be able to directly
affect central brain areas. However, it is perhaps altered central sensory
regulation that leads to the perception of normally innocuous or painless stimuli

being painful during the headache phase of migraine, given the brain findings
during premonitory symptoms and headache. Some investigators believe that the
proposed cortical mechanism behind migraine aura, cortical spreading
depression, causes the activation of peripheral nociceptors via neurotransmitter
release and therefore headache; however, migraine without aura is more
common than migraine with aura and there is no real evidence for asymptomatic
cortical spreading depression mechanisms in those with migraine without clinical
aura symptoms. Functional neuroimaging evidence suggests that attack initiation
across migraine with and without aura attacks, at least in the same individual, is
shared and involves the hypothalamus 48 hours preceding headache, suggesting
that aura is likely unrelated to the other parts of the attack and may be an
epiphenomenon in some patients with migraine and in some attacks.5
Functional imaging studies have suggested dynamic and oscillating brainstem
findings during different phases of the migraine attack,56,57 and
A 26-year-old woman experienced migraine since menarche at age CASE 2-2

12 years. She had twice-weekly attacks of right-sided headache
associated with cognitive changes, light and sound sensitivity, vertigo,
and nausea. Each headache attack lasted 6 hours. Around 20% of her
attacks were associated with an enlarging bilateral area of visual loss in
the center of her vision. She would sometimes see colored flashing lights
within this area. The area started small and grew over 30 minutes as the
headache escalated and would last another 30 minutes, obscuring her
vision. It would then gradually decrease in size and her vision would
return to normal despite ongoing headache. Very occasionally, she
experienced the visual symptoms without headache.
This patient has migraine with visual aura. However, the majority of her COMMENT
attacks are not associated with aura. Migraine-without-aura attacks are
more common than those with aura even in patients with migraine with
aura. Aura can occur without headache.

neurophysiological changes in the visual cortex ictally and interictally suggest

oscillations in the excitatory-inhibitory equilibrium in migraine,58 as well as in
cyclical sensory thresholds.38-40 These observations support the theory that
perhaps attack initiation and attack maintenance and sensitization are all
centrally mediated and that these fluctuations cause interictal symptoms in some
patients with migraine. Whether this is the only process and whether there are
contributory peripheral processes remain areas of debate.
Postdrome Symptoms of Migraine

The migraine postdrome is very common in the 24 hours following headache
resolution and is typically dominated by symptoms of tiredness and cognitive
changes,8 which can often be disabling and delay return to work or school.
However, other symptoms similar to premonitory symptoms can also occur,
including homeostatic symptoms and afferent sensitivities. There has been a lack
of systematic imaging studies during the migraine postdrome, and there are clear
challenges with capturing this phase in individuals who have not been treated
with acute medications. While in some cases postdrome symptoms may be an
effect of abortive medications used to treat the migraine attack, there is
suggestion both clinically59 and with functional neuroimaging60 that some of
these changes are independent of medication and occur spontaneously in the
absence of attack treatment.
Electrophysiologic studies suggest fluctuating cortical neurophysiology during
the migraine cycle and interictally, so ongoing sensory dysregulation is likely
present during this time, but further studies are warranted. The similarities in
phenotypes between the migraine postdrome and premonitory symptoms have
led to a theory that perhaps these symptoms represent a continuum from the
early phases of the migraine attack through to the postdrome, and that some
of these symptoms may be present though less noticeable in the headache phase.
It has been suggested that symptoms such as cognitive changes are actually
at their most severe during the headache phase,61 yet are commonly reported in
the premonitory and postdrome phases. Some symptoms have been reported
throughout both the premonitory phase and the postdrome,8 so it is possible
that this theory may hold true. The interaction between perceived triggers
and premonitory symptoms and the similarities between premonitory symptoms
and postdrome symptoms provide evidence for the fluctuating sensory, limbic,
and homeostatic dysregulation via hypothalamic, thalamic, brainstem, and
cortical mechanisms interacting with nociceptive pathways during the
migraine attack.
The Interictal Period

Many migraine imaging studies have been performed in the interictal state (ie,
between attacks). Some patients are symptom-free during this period, whereas
others may experience migraine-related symptoms such as photophobia and
cognitive changes. Various task-evoked and resting-state functional imaging
methodologies have been used, but outcomes have been somewhat inconsistent.
There is a suggestion of widespread brain dysfunction affecting areas that have
demonstrated roles in migraine pathophysiology and their connections,
including the insula,62 amygdala,63 hypothalamus and locus coeruleus,64 and
brainstem.65 These findings, along with cyclical neurophysiological changes
demonstrated in migraine interictally, including those affecting thalamocortical
334 A P R I L 2 0 24

pathways,66 suggest that there may be inherent sensory dysregulation with a lack KEY POINTS
of sensory habituation in the brain of the patient with migraine causing interictal
● Multiple interacting
sensitization as well as other symptoms. pathways are likely
responsible for mediating
MIGRAINE NEUROCHEMISTRY the relationship between
The symptoms of migraine are mediated via a range of neuroanatomic structures patient-perceived triggers
and migraine-associated
and neurotransmitter transmission within pathways from cortical and
symptoms, as well as the

diencephalic brain areas, involving monoamines and neuropeptides. Some of the interactions between
main neurotransmitters of interest will be discussed here, although this is by no migraine and other
means an exhaustive list. physiologic processes
mediating stress, behavior,
feeding, and sleep.
Monoamines
Monoamines include serotonin, dopamine, and norepinephrine. All of these have ● Migraine aura does not
implicated roles in migraine. need to precede headache.
Migraine-without-aura
attacks are more common

SEROTONIN. Serotonin has been implicated in migraine pathophysiology for than those with aura, even in
decades and this led to the development of the triptans in the 1990s.67 Seven individuals with migraine
drugs are available in this class. These drugs likely have both vascular and neural with aura.
effects and may act within the trigeminocervical complex, superior salivatory
● Migraine is a clinically
nucleus, and nucleus raphe magnus.45 Despite good therapeutic efficacy for some
heterogeneous cyclical and
of these drugs, they are vasoconstrictive and hence contraindicated in those with fluctuating disorder,
vascular risk factors and are not suitable or effective for all. More recently, involving widespread
targeting the 5-HT1F receptor specifically with a class of drugs called the ditans sensory, limbic, and
homeostatic brain
(with lasmiditan being the only one tested in human clinical trials) has been
dysfunction ictally and
shown to have an antimigraine effect without significant vasoconstriction,13,68,69 interictally.
despite the 5-HT1F receptor being expressed on cerebral vasculature.70,71
Lasmiditan is now US Food and Drug Administration (FDA) and European ● The generation of the
Medicines Agency approved as an acute migraine therapy. migraine attack likely occurs
centrally, but it is unclear
how the subsequent
DOPAMINE. The evidence for the role of dopamine in migraine comes from the initiation and maintenance
induction of many migraine symptoms with dopaminergic stimulation, such as of pain via sensitization of
vomiting, nausea, and yawning (a purely dopaminergic symptom), and a trigeminocervical neurons
occurs, and if this is purely
suggestion of dopamine hypersensitivity in patients with migraine.72 The central or both central and
existence of many dopaminergic premonitory symptoms supports the early role peripheral in mechanism.
of dopaminergic dysfunction in migraine, with premonitory activation of the
hypothalamus, substantia nigra, and ventral tegmental areas being demonstrated ● Monoaminergic and
peptidergic pathways via
in imaging studies.34,35 Migraine commonly coexists with other dopaminergic
key cortical and subcortical
disorders such as Parkinson disease and restless legs syndrome,73,74 as well as brain regions and their
with disorders of mood and fatigue in which dopamine plays a role.22 There is structural and functional
experimental evidence for hypothalamic A11 dopaminergic neurons being connections are likely
involved in trigeminovascular nociception75 and some evidence for the use of important in the
pathophysiology of
domperidone, a dopamine receptor antagonist, in migraine when taken during migraine, from early
premonitory symptoms,29,30 as well as for other dopamine antagonists in the premonitory symptoms
acute management of migraine.76 through to the postdrome.
NOREPINEPHRINE. The locus coeruleus has been implicated in migraine because of

its key roles in arousal, cognition, and pain,64,77,78 and this pontine nucleus is one
of the major norepinephrine sources to the dorsal spinal cord and cortex.79 In
preclinical models, locus coeruleus disruption changes migraine phenotypes by
reducing nociceptive responses, but it increases the threshold for cortical

spreading depression.80 Therefore, there is a feasible association between early

locus coeruleus and hypothalamic dysfunction mediating premonitory
symptoms, and also modulating pain during the headache phase of migraine via
norepinephrinergic pathways. A functional imaging study has suggested altered
hypothalamic–locus coeruleus functional connectivity in migraine as a substrate
for autonomic symptoms associated with migraine.64 While targeting

norepinephrine from a therapeutic perspective with serotonin-norepinephrine
reuptake inhibitors (SNRIs) has shown only some effect in migraine,81 this may
be an area that warrants further work.
Peptides
There is evidence for the role of vasoactive neuropeptides in migraine biology
and targeted therapies in this area have reached clinical practice. Some of the
important peptides in migraine biology are discussed here.
CALCITONIN GENE-RELATED PEPTIDE. CGRP was the second neuropeptide to be

discovered within the trigeminovascular system (substance P being the first) and
now has a well-established role in migraine biology. Electrical trigeminal
ganglion stimulation in an animal model was found to lead to plasma CGRP
release within the superior sagittal sinus, effectively reversed by sumatriptan and
dihydroergotamine, both agents that are now known to have efficacy in migraine
via neural and vascular mechanisms.82 CGRP is a more potent vasodilator than
substance P and is expressed in several areas of interest in migraine, such as
perivascular trigeminal sensory afferents, vascular walls of the cerebral
circulation, and the trigeminal ganglion.83 It has been shown that IV infusion of
CGRP triggers migrainelike attacks without aura (although not so much
premonitory symptoms84) in a high proportion of patients.85 It is thought to
mediate its actions in migraine through vasodilation and activation of peripheral
meningeal nociceptors, among other mechanisms, and may also have a role in
nonheadache symptoms of migraine such as photophobia.86,87
Novel treatments targeting this pathway have become available to patients in
many countries over the last few years and are changing the landscape of
migraine treatment. These treatments include the small-molecule CGRP
antagonists (gepants) and the receptor-targeted or peptide-targeted monoclonal
antibodies. Emerging results suggest the efficacy of treatment with ubrogepant
when taken during the premonitory phase,27 and a previous study suggested a
positive effect of fremanezumab on nonheadache symptoms (such as cognition)
and function on nonheadache days.88 Galcanezumab has recently been shown to
reduce premonitory symptom occurrence in migraine.28
PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE. PACAP is another

peptide found in perivascular trigeminal nerve fibers. It is also widely expressed
in the sphenopalatine ganglion and trigeminal ganglia and has been implicated,
along with its associated peptide vasoactive intestinal peptide, in both migraine
and cluster headache. Vasoactive intestinal peptide has been shown to be
involved in parasympathetic cranial autonomic symptoms89 and prolonged
infusion may provoke migrainelike attacks.90 Like CGRP, PACAP has been
shown to experimentally provoke migrainelike attacks when infused into
patients with migraine,91 and it can also trigger premonitory symptoms in
some.84 PACAP levels are centrally increased in blood during migraine and
336 A P R I L 2 0 24

cluster headache, and the levels decrease with effective headache treatment with KEY POINT
sumatriptan.92 PACAP binds to several receptors, some of which, like the PAC1
● Targeted therapies
receptor, mediate mast cell degranulation and vasodilatation, leading to dural against monoaminergic and
C-fiber activation. Neuronal PAC1 receptors have a role in trigeminovascular peptidergic receptors may
nociception in an animal model,93 and an anti-PACAP antibody showed have therapeutic use in
therapeutic promise in a rodent migraine model.94 This work culminated in a migraine.

phase 2 clinical trial of an anti-PACAP antibody in humans, which has shown
promising results.95 It is hoped that phase 3 trials will follow and that this could be
a novel targeted therapeutic approach in migraine.
Other Therapeutic Targets

The experimental administration of amylin, a neuropeptide in the CGRP family,
via its analog pramlintide,96 and adrenomedullin, another CGRP-related
peptide,97 can provoke migrainelike headache in patients with migraine.
Targeting these mechanisms may hold future potential for migraine treatment.
In addition, glutaminergic transmission is likely involved in mediating cortical
hyperexcitability in migraine (particularly in migraine with aura).98 Opioid
systems may also have a modulatory role via the trigeminocervical complex in
migraine,99 so these may also be viable targets in the future treatment of
migraine. Endocannabinoids have been shown to influence trigeminovascular
processing in the periaqueductal gray, which is reversed by triptans,100 and this
system may also warrant further therapeutics research.
Experimental provocation of migraine has been pivotal to understanding the
molecular mechanisms of the disorder, and it has been shown that various
compounds can trigger migrainelike attacks in patients with migraine with
varying affinities.101 The oldest model is the nitroglycerin model, which triggers
an attack via nitric oxide mechanisms and can also provoke premonitory
symptoms in patients with migraine.102 Unfortunately, selective nitric oxide
synthase inhibition via inducible nitric oxide synthase was not a useful strategy
for migraine treatment,103,104 despite nonselective nitric oxide synthase
inhibition showing initial promise in a small study.105 Interestingly, experimental
attacks triggered by nitric oxide, CGRP, and PACAP tend to be
triptan-responsive,106-108 whereas those triggered by phosphodiesterase
inhibition with cilostazol and sildenafil tend not to be.109 This triggering and
treatment-related heterogeneity is poorly understood but may provide an
opportunity to study individualized migraine pathways and treatment prediction
in the future. Monoaminergic and peptidergic pathways via key cortical and
subcortical brain regions and their structural and functional connections are
likely important in the pathophysiology of migraine, from early premonitory
symptoms through to the postdrome. Targeting any of these, as well as other
molecular pathways, has therapeutic potential in migraine and to some extent
has already led to exciting advances in migraine treatment.
CONCLUSION
The interplay between triggers and premonitory symptoms, the presence of
premonitory symptoms in the absence of headache with corresponding neural
substrates on functional imaging, the potential continuum of symptoms
throughout a migraine attack and the interictal symptoms, and imaging and
neurophysiological findings all point toward migraine being a primarily neurally

driven brain disorder. Migraine involves both ictal and interictal sensory
thresholding via a complex network of cortical and subcortical brain regions and
modulatory centers including the brainstem and diencephalic nuclei. This
thresholding culminates in dysfunction in homeostatic, sensory, and limbic
processing in those who are genetically susceptible either during attacks only,
during both attacks and the interictal state, or in a continuous manner in those
most severely affected. There are anatomical and biochemical interactions
between these pathways and pain-processing pathways, providing a link

between migraine and disordered sleep, the overlap between migraine and mood
states, and the cognitive dysfunction that is commonly experienced with the
condition. This dysregulation likely occurs partly via monoaminergic and
peptidergic pathways among others, and further exploration of therapeutics
targeting different receptors within these pathways has led to approved
treatments and promises to hold future potential in migraine
therapeutics research.
Central neuronal changes in those genetically predisposed to migraine lead to
an inherent sensitivity to attacks of migraine in the interictal state and the
initiation of attacks ictally in a cyclical and oscillating trait-and-state fashion. The
involved nociceptive pathways interact with several others modulating sensory,
homeostatic, and limbic regulation, causing complex and diverse migraine
phenotypes. These systems also share neurotransmitter and neuropeptide
signaling such as those involving CGRP, PACAP, dopamine, and noradrenaline,
and early attack intervention through targeted therapeutics during premonitory
symptoms holds much promise. The activation of early brain regions during
premonitory symptoms may alter descending control of trigeminovascular
nociception via brainstem and diencephalic structures, leading to the
development and maintenance of headache, but it is unclear if headache
mechanisms are purely central. While migraine is classified as one condition with
various subtypes, the clinical and treatment-related heterogeneity suggests that
perhaps this is too broad an umbrella term for a widespread brain disorder, in
which some neurochemical systems may be more dominant in some individuals
than others. Further characterization of its true pathophysiology using disease
biomarkers and prediction is necessary to advance future treatments.
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018-0841-7

REVIEW ARTICLE

Acute Treatment of
I NT E R V I E W A V AI L A B L E Migraine
ONLINE
By Rebecca Burch, MD, FAHS
ABSTRACT
OBJECTIVE: Most patients with migraine require acute treatment for at least
some attacks. This article reviews the approach to the acute treatment of
migraine, migraine-specific and nonspecific treatment options, rescue
treatment and options for management in the emergency department and
inpatient settings, and treatment during pregnancy and lactation.
LATEST DEVELOPMENTS: Triptans, ergot derivatives, and nonsteroidal anti-

inflammatory drugs have historically been the main acute treatments for
migraine. The development of new classes of acute treatment, including
the small-molecule calcitonin gene-related peptide receptor antagonists
CITE AS: (gepants) and a 5-HT1F receptor agonist (lasmiditan), expands available
2024;30(2, HEADACHE):344–363.
options. These new treatments have not been associated with vasospasm
or increased cardiovascular risk, therefore allowing migraine-specific
Address correspondence to acute treatment for the more than 20% of adults with migraine who are at
Dr Rebecca Burch, 1 South
increased risk of cardiovascular events. Neuromodulation offers a
Prospect St, Burlington,
VT 05451, Rebecca.Burch@ nonpharmacologic option for acute treatment, with the strongest evidence
uvmhealth.org. for remote electrical neuromodulation.
Dr Burch has received personal ESSENTIAL POINTS: The number of available migraine treatments continues to
compensation in the range of expand, although triptans are still the mainstay of migraine-specific acute
$10,000 to $49,999 for serving
as an editor, associate editor, treatment. There is no one-size-fits-all acute treatment and multiple
or editorial advisory board treatment trials are sometimes necessary to determine the optimal
member for Neurology. regimen for patients. Switching within and between classes, using the
Dr Burch has received
publishing royalties from a maximum allowed dose, using combination therapy, and counseling
publication relating to health patients to treat early are all strategies that may improve patient response
care. An immediate family
member of Dr Burch has
to acute treatment.
received personal
compensation for serving as
an employee of WellSky and
has stock in WellSky.
UNLABELED USE OF INTRODUCTION
A
PRODUCTS/INVESTIGATIONAL cute treatment for migraine, also called symptomatic or abortive
USE DISCLOSURE:
treatment, is a medication or other therapy used to relieve pain and
Dr Burch discusses the
unlabeled use of other symptoms of migraine at the time of an attack. Migraine
metoclopramide, attacks are associated with significant disability due to pain severity
prochlorperazine, and
promethazine for the
and associated photophobia, phonophobia, and nausea. Nearly
treatment of migraine pain. every person with migraine will benefit from acute treatment for at least some
attacks. The number of available migraine treatments continues to expand, with
© 2024 American Academy multiple new classes of migraine-specific medication and neuromodulation
of Neurology. devices adding to existing options. This article reviews the treatment options in
344 A P R I L 2 0 24

detail, discusses how to choose among these options, and explores situations KEY POINTS
where acute treatment decision making may be more complex.
● Nearly every person with
migraine will benefit from
APPROACH TO ACUTE TREATMENT acute treatment for at least
The characteristics of an ideal acute migraine treatment include the following: some attacks as migraine
attacks are usually severe

and accompanied by
u Rapid and complete relief of pain and any associated symptoms that cause greater bothersome nausea and
impairment than the head pain (referred to as most bothersome symptoms) sensory symptoms.
u Prompt return to function and reduction in attack-related disability ● Complete pain relief at
u Effectiveness at first dose with no recurrence of headache and limited need for repeat 2 hours after treatment
treatment should be the goal in acute
migraine therapy rather than
u Minimal side effect burden improvement without
u Cost effective and easily available1 complete relief.
● Acute treatment is more

Complete pain relief at 2 hours after treatment should be the goal rather than effective when used early
improvement without complete relief. A partial response to acute treatment is on in a migraine attack.
associated with lower patient satisfaction with treatment, a higher risk of Patients should keep acute
headache recurrence, a higher burden of migraine-related disability, and an migraine medications with
them and treat at the first
increased risk of migraine chronification.2,3 Relief from other migraine-
sign of an attack.
associated symptoms is also desirable and, with pain freedom, is a coprimary
endpoint in modern clinical trials of acute migraine treatments. ● Treatment should be
Treatment effectiveness should be specifically evaluated at each follow-up matched to the severity of
visit. The Migraine Treatment Optimization Questionnaire describes elements the headache. Mild-to-
moderate attacks may
that should be discussed with patients when evaluating the effectiveness of an respond to nonspecific
acute treatment.2 Topics include pain freedom, headache recurrence, reliability therapies. Migraine-specific
of treatment, and reduction in disability (TABLE 3-1). An optimal score requires therapy should be chosen
each element to be true for more than one-half of treated episodes. first if the attack is expected
to be moderate to severe.
The availability of a specific treatment is essential for effectiveness.
Insurance coverage limitations and out-of-pocket costs are major barriers to ● Other acute migraine
treatment for many patients, particularly for newer treatments. These potential treatment strategies to
barriers should be considered at the time of treatment and assessed at follow-up improve response include
increasing the dose,
visits with a question such as, “Did you have any difficulty getting the
switching to a formulation
medication?” with a faster onset,
switching treatment within
Optimizing Acute Treatment or between classes, and
using combinations of
Regardless of which acute treatment is initiated, these universal principles can
migraine-specific and
increase the chances of a positive response: nonspecific treatments.
u Treat early, when pain tends to still be mild ● The assessment of nausea
and vomiting should be a
u Match medication type to attack severity routine part of migraine care
u Use the maximum dose4 and any patient with nausea
or vomiting should be
u Consider nonoral formulations offered an antiemetic.
u Use combination treatments
u Treat nausea
Acute treatment is more effective when used early on in a migraine attack

when pain tends to be mild.5,6 Early treatment is especially important in patients
who have attacks accompanied by cutaneous allodynia, characterized by normal

ACUTE TREATMENT OF MIGRAINE
stimuli being perceived as painful, as acute treatment is less effective after

cutaneous allodynia develops.6 Unless medication overuse is a major concern,
patients should be counseled to keep acute migraine medications with them and
treat at the first sign of a migraine attack.
A common clinical question among patients with migraine with aura is
whether to treat at the onset of aura. Older studies comparing the timing of
triptan use during the aura phase versus the early pain phase of a migraine did
not show benefit for treating during aura; however, a small 2009 study found the
opposite.7 Anecdotal clinical experience suggests that some patients do find that
treatment during the aura may reduce the likelihood of subsequent headache.
Some patients experience symptoms such as photophobia, fatigue, or neck pain
prior to the onset of headache. A randomized controlled trial including
participants who could reliably identify these prodromal symptoms found that
treatment with ubrogepant 100 mg during the prodromal phase reduced the
occurrence of subsequent headache from 71% (placebo) to 64% (treatment).8

Patients can try treating at different times to see what works best for them.
The class of treatment should be matched to the severity of the headache.
Patients who have mild to moderate attacks may be able to be treated
successfully with nonspecific therapies. More severe attacks almost always
require migraine-specific pharmacotherapy. The use of a nonspecific treatment
followed by a migraine-specific treatment is less effective than matching the
initial treatment to the anticipated attack severity.9 Patients should be counseled
to use a migraine-specific therapy as first-line treatment if the attack is expected
to be moderate to severe.
Response to acute treatment is typically correlated with the dose of
medication.10 Patients may initially be prescribed lower doses of acute treatment
out of concern for tolerability and the medical principle of using the lowest
effective dose. This can lead to inadequate treatment response and the patient’s
perception that the treatment is not effective. In particular, in the case of
migraine-specific medications, it can be helpful to start with the highest available
dose and counsel patients to try one-half of this dose with the first use to ensure
tolerability.
Other strategies to address suboptimal acute treatment responses include
switching to a formulation with faster onset, such as a nasal spray; trying
TABLE 3-1 Migraine Treatment Optimization Questionnaire-4a,b
1 After taking your migraine medication, are you pain free within 2 hours for most attacks?
2 Does one dose of your migraine medication usually relieve your headache and keep it away
for at least 24 hours?
3 Are you comfortable enough with your migraine medication to be able to plan your daily
activities?
4 After taking your migraine medication, do you feel in control of your migraines enough so that
you feel there will be no disruption to your daily activities?
a
Modified with permission from Lipton RB et al, Neurology.2 © 2015 American Academy of Neurology.
b
Each item is scored 0 for an answer of “never” or “rarely,” 1 for “less than half the time,” and 2 for “half the
time or more.” A score of 0 indicates very poor treatment efficacy, 1 to 5 indicates poor treatment efficacy, 6 to
7 indicates moderate treatment efficacy, and 8 indicates maximum treatment efficacy.
346 A P R I L 2 0 24

different medications within the same class; trying a different class; and using
combinations of migraine-specific and nonspecific treatments. Combinations of
treatments are often effective in patients who do not respond completely to one
treatment alone. Common combinations include 5-HT1B and 5-HT1D receptor
agonists (triptans) or small-molecule calcitonin gene-related peptide (CGRP)
antagonists (gepants) with a nonsteroidal anti-inflammatory drug (NSAID), an

antiemetic, or both. CASE 3-1 illustrates a situation where several elements needed
optimization for acute treatment to be effective.
Treatment of Nausea
Nausea accompanies migraine headache in more than 70% of patients and is
associated with increased migraine-related disability.11,12 Persistent frequent
nausea is associated with an increased risk of chronic migraine and may be a
marker for more severe disease.13 Vomiting also prevents the absorption of oral
medications. The assessment of nausea and vomiting should therefore be a

routine part of migraine care and any patient with nausea or vomiting should be
offered an antiemetic. Nonoral antiemetics, such as promethazine or
prochlorperazine suppositories, should be considered in any patient with
vomiting. Metoclopramide and prochlorperazine reduce migraine pain and
A 34-year-old man presented to the neurology clinic to discuss options to CASE 3-1
improve acute treatment of migraine occurring about 4 times a month.
Only mild nausea was associated with the migraine attacks and severe
pain was the most debilitating aspect of an attack. Sumatriptan 50 mg
orally prescribed by his primary care physician was not effective, nor
were the over-the-counter analgesics. At the first neurology visit,
sumatriptan was increased to 100 mg and ibuprofen 400 mg was added.
This was effective but caused intolerable adverse effects of nausea and
fatigue. Rizatriptan 10 mg was suboptimally effective and he had only a
minimal response to ubrogepant 100 mg. Eletriptan 40 mg alone did not
cause adverse effects but only produced pain freedom some of the time.
The combination of eletriptan 40 mg and naproxen sodium 550 mg was
well tolerated and reliably effective.
This case illustrates a typical treatment optimization pathway. Many COMMENT

patients respond well and without adverse effects to the first one or two
acute treatments tried, but some require a longer trial-and-error process to
determine the best treatment strategy. A response to sumatriptan only at
the 100 mg dose is sometimes seen in clinical practice and is supported by
clinical trial data. If patients are concerned about tolerability when starting
triptans for the first time, they can be counseled to take one-half of a dose
the first time and then the whole dose with the next attack. This case also
illustrates the finding that some patients respond better to certain triptans
than others and that it can be difficult to predict which triptan will be most
effective in a given patient. Combination therapy with a nonsteroidal
anti-inflammatory drug proved to be most effective in this patient.

nausea.14 Promethazine is another commonly used phenothiazine antiemetic.

Ondansetron is a common choice due to the lower risk of bothersome side effects
including sedation.
ACUTE TREATMENT OPTIONS FOR MIGRAINE

14,15
TABLE 3-2 lists acute treatment options with evidence for efficacy in migraine.
A 2015 evidence review was updated with new clinical trial evidence in a 2021
American Headache Society (AHS) Consensus Statement.15 In 2021, a systematic

review and evidence synthesis from the Agency for Healthcare Research and
Quality was also published, providing strength-of-evidence context to the AHS
Consensus Statement.14
Nonspecific treatments include simple analgesics such as acetaminophen,
NSAIDs, and combination analgesics. Migraine-specific acute treatments include
triptans, the ergot derivative dihydroergotamine (DHE), gepants, and the 5-HT1F
receptor agonist lasmiditan. For more on the role of CGRP and therapies
TABLE 3-2 Evidence-based Options for Acute Treatment of Migraine
AHRQ strength of
Treatment evidence14,a
Established as effective15
Triptans (all doses, all formulations) Moderate to high
Dihydroergotamine nasal spray Moderate to high
Calcitonin gene-related peptide receptor antagonists (gepants) Low to high
Lasmiditan High
Over-the-counter nonsteroidal anti-inflammatory drugs Moderate

(NSAIDs): aspirin, ibuprofen, naproxen
Prescription NSAIDs: celecoxib oral solution, diclofenac Moderate

15
Probably effective
NSAIDs: ketoprofen, IV and IM ketorolac NA
IV magnesium (for migraine with aura) Insufficient to low
Opioid-containing combinations: codeine/acetaminophen, Low

tramadol/acetaminophen
Ergotamine/caffeine Moderate
Antiemetics: prochlorperazine, promethazine, droperidol, Low

chlorpromazine, metoclopramide
Acetaminophen Moderate
AHRQ = Agency for Healthcare Research and Quality.

a
High: confidence that the estimate of effect lies close to the true effect (the body of evidence has few or
no deficiencies and is judged to be stable); Moderate: moderate confidence that the estimate of effect lies
close to the true effect (the body of evidence has some deficiencies and is judged to be likely stable); Low:
limited confidence that the estimate of effect lies close to the true effect (the body of evidence has major
or numerous deficiencies and is likely unstable); Insufficient: no evidence, unable to estimate an effect, or
no confidence in the estimate of effect.
348 A P R I L 2 0 24

targeting CGRP in migraine, refer to the article “Preventive Treatment of KEY POINTS
Migraine” by Richard B. Lipton, MD, FAAN,16 in this issue of Continuum.
● Nonspecific acute
migraine treatments include
Nonspecific Treatments simple analgesics,
Many patients benefit from nonspecific treatments for migraine, many of which nonsteroidal
are available without a prescription. Most patients will have tried at least one anti-inflammatory drugs,
and combination analgesics,
nonspecific acute treatment prior to initial evaluation for migraine.
while migraine-specific
treatments include triptans,
SIMPLE ANALGESICS. For nonincapacitating attacks, acetaminophen 1000 mg was dihydroergotamine,
associated with higher rates of pain relief and pain freedom at 2 and 6 hours and gepants, and lasmiditan.
greater reduction in disability and most bothersome associated symptoms
● Aspirin, ibuprofen,
compared with placebo.17 Acetaminophen is associated with hepatotoxicity at naproxen, diclofenac, and
higher doses. Many combination analgesics contain acetaminophen and patients celecoxib all have Level A
should be educated to consider the total daily dose across medication types. evidence for efficacy in
Acetaminophen is generally well tolerated. acute migraine treatment,

while ketoprofen and
ketorolac have Level B
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. Over-the-counter NSAIDs have evidence.
demonstrated benefit for migraine in multiple clinical trials. Aspirin 500 mg to
1000 mg orally, ibuprofen 400 mg orally, and naproxen 500 mg to 550 mg orally ● The combined
formulation of
all have at least two positive randomized controlled trials showing improved pain
acetaminophen, aspirin, and
reduction or relief at 2 hours compared with placebo (Level A evidence).18 Level caffeine is effective for the
A evidence also supports diclofenac 50 mg to 100 mg orally and celecoxib 25 mg/mL acute treatment of migraine
oral solution.18 The new formulation of celecoxib, a 25 mg/mL oral solution, but should be used
infrequently due to
was US Food and Drug Administration (FDA) approved specifically for acute
concerns about caffeine
migraine treatment in 2020 with a recommended dose of 120 mg.19 NSAIDs with withdrawal headache.
Level B evidence include ketoprofen 100 mg orally and ketorolac 30 mg to 60 mg
IM or IV.18 ● All seven triptans are
NSAIDs may be effective monotherapy for less severe migraine attacks. Some more effective than placebo
for acute migraine
people with migraine have a combination of more and less severe attacks and can treatment, with the most
accurately predict attack severity. In this situation, the use of NSAIDs to treat less effective triptans producing
severe attacks may decrease the likelihood of developing medication-overuse pain freedom in up to
headache. In a longitudinal study from the American Migraine Prevalence and one-half of attacks. Triptans
primarily differ in
Prevention Study, participants who had fewer than 10 headache days a month pharmacokinetics and route
and used NSAIDs had a lower risk of progression to chronic migraine in of administration.
subsequent years compared with those who used triptans.20 For more
information, refer to the article “Medication-Overuse Headache” by Paul Rizzoli, ● Recent evidence suggests
that serotonin syndrome is
MD,21 in this issue of Continuum. NSAIDs can also be used as adjunctive therapy
very rare with the
along with a triptan or gepant. The combination of sumatriptan 85 mg and coprescription of triptans
naproxen 500 mg has been specifically studied and is available as a single and selective serotonin
prescription.22 reuptake inhibitors (SSRIs)
Adverse effects of NSAIDs include gastric irritation and increased risk of or serotonin-norepinephrine
reuptake inhibitors (SNRIs).
gastric bleeding, which are more common with frequent use. Patients who take It may be safe to prescribe
NSAIDs frequently for migraine should be monitored for the development of triptans in patients taking
gastrointestinal symptoms. NSAIDs should not be taken by people with renal SSRIs or SNRIs, and
dysfunction. As a class, NSAIDs increase the risk of cardiovascular events education about serotonin
syndrome should be
including myocardial infarction, so cardiac risk factors should be considered in provided.
patients who may use NSAIDs frequently.23
COMBINATION ANALGESICS. The over-the-counter combination of aspirin 500 mg,

acetaminophen 500 mg, and caffeine 130 mg is established as effective (Level A

evidence) for acute migraine treatment per the AHS acute treatment evidence
review.18 Combinations of butalbital and caffeine with either aspirin or
acetaminophen, available by prescription, received Level C evidence (possibly
effective).18 Frequent but inconsistent use of caffeine may cause a withdrawal
phenomenon. A combined formulation of acetaminophen, aspirin, and caffeine
is best for patients with milder infrequent attacks and using this combination
more than 8 times monthly should be discouraged. Butalbital combination
medications should not be used as acute migraine treatment under most

circumstances given poor evidence for efficacy and risk of worsening headache
burden. Patients who use this combination should be monitored carefully for
increases in attack frequency.
Migraine-Specific Treatments
TABLE 3-3describes migraine-specific treatment formulations, dosing
recommendations, and relevant medication interactions.
TABLE 3-3 Migraine-specific Acute Treatments
Maximum daily
Medication Dose and route of administration dose Important interactions
a
Triptans
Almotriptan 12.5 mg orally; may repeat after 2 hours 25 mg MAO-A inhibitors; CYP3A4
inhibitors such as ketoconazole
Eletriptan 20 mg, 40 mg orally; may repeat after 80 mg CYP3A4 inhibitors such as

2 hours ketoconazole, erythromycin, and
verapamil
Frovatriptan 2.5 mg orally; may repeat after 4 hours 7.5 mg
Naratriptan 1 mg, 2.5 mg orally; may repeat after 5 mg

4 hours
Rizatriptan 5 mg, 10 mg orally and orally disintegrating 30 mg; 15 mg if MAO-A inhibitors

tablets; may repeat after 2 hours taking propranolol
Sumatriptan oral 25 mg, 50 mg, 100 mg orally; may repeat 200 mg orally MAO-A inhibitors
after 2 hours
Sumatriptan/ 85 mg sumatriptan/500 mg naproxen; may 2 tablets per MAO-A inhibitors

naproxen oral repeat once after 2 hours 24 hours
Sumatriptan nasal 5 mg, 10 mg, 20 mg nasal spray, 22 mg 40 mg nasal spray MAO-A inhibitors
nasally inhaled powder; may repeat after
44 mg nasal
2 hours
powder
Sumatriptan 3 mg, 4 mg, 6 mg subcutaneous injection; 12 mg SQ injection MAO-A inhibitors

subcutaneous may repeat after 1 hour
injection
Zolmitriptan 2.5, 5 mg orally, orally disintegrating tablet, 10 mg MAO-A Inhibitors, cimetidine

nasal spray, may repeat after 2 hours
350 A P R I L 2 0 24

TRIPTANS. Triptans are the mainstay of migraine-specific acute treatment and
are usually the first prescription acute treatment offered. All seven triptans
are available as oral tablets. Rizatriptan and zolmitriptan are available as
orally dissolving tablets, sumatriptan and zolmitriptan as nasal sprays, and
sumatriptan as a subcutaneous injection. A 2015 network meta-analysis of
triptan studies found that the most effective triptans produced pain freedom
37% to 50% of the time, compared with 11% in the placebo group.24 This study
also found that subcutaneous sumatriptan, rizatriptan and zolmitriptan orally

disintegrating tablets, and eletriptan tablets were the most effective
formulations.
Triptans differ primarily in pharmacokinetics.25 The long half-lives of
naratriptan and frovatriptan may reduce recurrence, making these good options
for patients with long-duration attacks or who have recurrence after initially
successful treatment. They may also be given twice daily for the management of
migraine associated with menses. Patients who require fast-acting acute
Maximum daily
Medication Dose and route of administration dose Important interactions
Dihydroergotamine
nasal spray
4 mg/ml formulation 0.5 mg spray, 1 spray to each nostril, repeat 3 mg/24 hours CYP3A4 inhibitors such as
after 15 minutes; limit 6 sprays/24 hours; ketoconazole; triptans; SSRIs
and SNRIs
0.725 mg per device 0.725 mg, 1 spray to each nostril; may 3 mg/24 hours CYP3A4 inhibitors such as
actuation repeat after 1 hour if needed; limit 4 ketoconazole; triptans; SSRIs
sprays/24 hours. and SNRIs
Gepants
Rimegepant 75 mg orally dissolving tablet; repeat dose 75 mg Strong CYP3A4 inhibitors (avoid
is not recommended use); moderate CYP3A4
inhibitors including verapamil
Ubrogepant 50 mg, 100 mg orally; may repeat after 200 mg Strong CYP3A4 inhibitors (avoid
2 hours use); moderate CYP3A4
inhibitors including verapamil
(limit dose to 50 mg per 24 hours)
Lasmiditan 50 mg, 100 mg, 200 mg orally; repeat dose One dose SSRIs, SNRIs and other
is not recommended serotonergic medications;
P-glycoprotein or breast cancer
resistance protein substrates
MAO-A = monoamine oxidase A; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor.
a
Important interactions for all triptans: ergots, SSRIs, and SNRIs (see text).

treatment may do best with sumatriptan nasal spray or subcutaneous injection,

zolmitriptan nasal spray, or rizatriptan orally disintegrating tablets.
Triptans are generally well tolerated but a small percentage of patients may
experience triptan sensations (ie, facial flushing, heat, or pressure).25 Patients
should be counseled at the time of prescription about the possibility of triptan
sensations and reassured that such sensations do not indicate an allergic

reaction. Triptans are contraindicated in patients with a history of coronary
heart disease or coronary vasospasm. Current practice is to exercise caution in

patients with multiple risk factors for coronary artery disease. Other
contraindications include a history of ischemic stroke and poorly controlled
hypertension. Triptans have historically been avoided in patients with
hemiplegic migraine or migraine with brainstem aura due to concern for
increased stroke risk. Although observational studies have called this
prohibition into question, treatment options without potential vascular effects
are still preferred when possible.26

Concurrent use of triptans and selective serotonin reuptake inhibitors (SSRIs)
or serotonin-norepinephrine reuptake inhibitors (SNRIs) has historically been
contraindicated due to concern for serotonin syndrome. FDA labels for all
triptans include a boxed warning regarding concurrent use with SSRIs or SNRIs;
however, subsequent studies have questioned the likelihood of serotonin
syndrome with a triptan and SSRI or SNRI coprescription. One literature review
found that none of the published cases met modern criteria for serotonin
syndrome.27 A large database review study found that out of roughly 19,000
patients coprescribed triptans and an SSRI or SNRI, only two were diagnosed
with serotonin syndrome and in both cases other serotonergic medications were
also involved.28 Based on the available evidence, it may be appropriate to
prescribe triptans in patients taking SSRIs or SNRIs and to provide education
about serotonin syndrome at the time of prescription.
DIHYDROERGOTAMINE. In the outpatient setting, DHE is primarily available as a

nasal spray.29 Two formulations are available: one with a 4 mg/ml solution
administering 0.5 mg per spray and another with 0.725 mg per spray. The dosing
regimen is different depending on the formulation (TABLE 3-3). DHE can cause
significant nausea, which often limits tolerability. Frequent or long-term use of
ergot derivatives has been associated with retroperitoneal and pleural fibrosis.
Due to these limitations, DHE is more often used as a rescue treatment rather
than initial therapy for migraine attacks. It may be considered in patients who
have not responded to first-line or second-line acute treatments. It is also
particularly helpful as a rescue treatment and in the inpatient setting (see the
Management of Refractory Attacks section).
DHE is contraindicated in patients with coronary artery disease, vascular risk
factors, peripheral vascular disease, poorly controlled hypertension, or who are
taking other vasoconstrictors. DHE should not be used in the same 24-hour
period as a triptan.
GEPANTS. Rimegepant and ubrogepant are small-molecule CGRP receptor

antagonists, also known as gepants. Both are FDA approved for acute treatment
of migraine, with efficacy supported by multiple randomized controlled trials. In
phase 3 clinical trials of ubrogepant 100 mg or rimegepant 75 mg, 19% to 21% of
participants in the active arm experienced pain freedom at 2 hours compared
352 A P R I L 2 0 24

with 9% to 10% in the placebo group, and 35% to 37% showed relief of the most KEY POINTS
bothersome symptom in the active group compared with 9% to 10% in the
● Gepants are effective for
placebo group. Ubrogepant may be repeated once after 2 hours, while acute treatment, well
rimegepant should not be repeated.30 tolerated in clinical trials,
Ubrogepant and rimegepant were very well tolerated in clinical trials. The and not associated with
most commonly reported adverse events were dry mouth, nausea, and vasoconstriction. Gepants
may also be less likely to
somnolence, all occurring in less than 4% of the trial population.30 Ubrogepant
cause medication-overuse
should be avoided in patients taking strong CYP3A4 inhibitors and the dose headache.
should be limited to 50 mg in patients taking verapamil.
Evidence to date suggests that gepants do not cause vasoconstriction or ● Lasmiditan may be a good
increase the risk of cardiac events and are therefore good alternatives for patients alternative to triptans in
patients who responded to
with cardiac disease or vascular risk factors. Gepants are also thought not to triptans previously but
contribute to medication-overuse headache. Rimegepant is approved for cannot take them due to
preventive treatment of migraine with every-other-day dosing. Gepants may be cardiovascular disease or
particularly helpful in patients with medication-overuse headache. risk factors. Patients should
not drive after taking
lasmiditan.
LASMIDITAN. Like triptans, lasmiditan is a serotonin receptor agonist. Lasmiditan
has a high affinity for the 5-HT1F receptor, which provides similar ● Metoclopramide and
antinociceptive effects as triptans but without the vasoconstrictive potential. In prochlorperazine reduce
migraine pain and treat
phase 3 trials of lasmiditan 100 mg, 28% to 31% of participants reported pain
nausea, but frequent use
freedom at 2 hours, and 42% to 44% reported freedom from their most may cause extrapyramidal
bothersome symptom at 2 hours, versus 10% to 13% for both endpoints in the symptoms. They cause more
placebo groups.31 sedation than ondansetron,
which treats nausea but
The side-effect burden of lasmiditan is higher than that for triptans and
does not have anti–migraine
gepants, with 13% to 18% of participants in the lasmiditan 100 mg arm pain properties.
experiencing dizziness compared with 2% to 3% in the placebo arm. Somnolence,
fatigue, nausea, and paresthesia were also experienced by 3% to 6% of patients in
the active arm versus 1% to 2% in the placebo arm. Safety evaluations showed
that driving was impaired after lasmiditan use at all doses, and patients reported
more sedation at 8 hours after lasmiditan use compared with placebo.32,33 Patients
should therefore be counseled to avoid any activity requiring alertness, including
driving, for at least 8 hours after taking lasmiditan.
Lasmiditan is a good alternative to triptans in patients with vascular disease or
vascular risk factors, especially if they have responded to triptans previously. It
may be better tolerated at night due to the side effects of somnolence and the
restrictions on activity after taking it.
Antiemetics
Several dopamine receptor antagonist antiemetics, including metoclopramide
10 mg orally and prochlorperazine 10 mg orally, are effective for the reduction of
migraine pain and freedom from migraine pain at 2 hours.14,18 They may be good
choices for patients who need a combination of acute treatments, especially
when nausea is a prominent symptom. Promethazine and prochlorperazine can
be sedating and may be especially helpful in patients who benefit from deep rest
as part of their acute treatment plan. Antiemetics have not been associated with
an increased risk of medication-overuse headache and metoclopramide
monotherapy is sometimes used in this setting. Frequent use of metoclopramide
and the phenothiazine antiemetics may cause extrapyramidal symptoms.
Although ondansetron is an effective treatment for nausea and is not sedating, it
does not have intrinsic antimigraine pain properties.

Neuromodulation
Five noninvasive neuromodulation devices have been FDA cleared for acute
treatment of migraine: supraorbital trigeminal nerve stimulation, noninvasive
vagus nerve stimulation, remote electrical neuromodulation, single-pulse
transcranial magnetic stimulation, and external combined occipital and
trigeminal neurostimulation.34-40 Neuromodulation devices for migraine deliver

electric or magnetic stimulation through the skin with the goal of altering pain
perception and processing. Recommended use, efficacy data, and potential

adverse effects are listed in TABLE 3-4.
The devices are used at the time of a migraine attack, similar to pharmacologic
treatments, and the goals of treatment are the same as for medications.
Neuromodulation devices are largely well tolerated. Among the available
devices, the remote electrical neuromodulation and external combined occipital
and trigeminal neurostimulation devices have the strongest evidence for
efficacy. In the largest randomized controlled trial evaluating remote electrical

neuromodulation versus sham, 37.4% of the active group were pain free at
2 hours versus 18.4% of the sham group.38 Two clinical trials have shown benefit
from external combined occipital and trigeminal neurostimulation, with 2-hour
pain freedom in 46% of the active group versus 12% of the sham group in the
larger trial.40
Device use in clinical practice is currently limited despite the clear need for
more nonpharmacologic treatment options. Cost and lack of insurance coverage
are major barriers to access. Devices are currently cleared by the FDA based on
safety data, rather than approved based on efficacy as is the case for medications.
Many payors exclude coverage of treatments that have not been approved by the
TABLE 3-4 Neuromodulation Devices for Acute Treatment of Migraine
Device Frequency and duration of use Effectiveness Adverse effects
Supraorbital trigeminal 60 minute stimulation as Mean change in pain intensity Paresthesia

nerve stimulation35 needed after 1 hour on 0-10 visual analogue
scale −3.46 versus −1.78 with sham
Noninvasive vagus nerve Bilateral 120-second Pain freedom at 2 hours not Discomfort at site of
stimulation37 stimulations to the right and left statistically different from contact with skin
sides of the neck within placebo, but pain relief at 2 hours
20 minutes of migraine onset; and pain freedom at 30 and
allowed to repeat once after 60 minutes were better than
15 minutes if pain not improved placebo
Remote electrical Stimulation of upper arm for Pain freedom at 2 hours in 37.4% of Paresthesia; redness,
neuromodulation38 45 minutes, starting within the active group versus 18.4% in warmth in area of
1 hour of attack onset the sham group device contact with skin
Single-pulse transcranial Two pulses at aura onset Pain freedom at 2 hours 39% with Headache, migraine,
magnetic stimulation36 active treatment versus 22% with sinusitis
sham
External combined 30-60 minute stimulation within Pain freedom at 2 hours 46% with Migraine, pain,
occipital and trigeminal 30 minutes of headache onset active treatment versus 12% with unpleasant sensation
neurostimulation40 sham during treatment,
numbness or tingling
354 A P R I L 2 0 24

FDA, including neuromodulation devices for migraine. The supraorbital KEY POINTS
trigeminal nerve stimulation device is available over the counter.
● Five neuromodulation
Neuromodulation can be considered for any patient who wants to avoid devices are available for
pharmacologic therapy, who has contraindications to pharmacologic acute acute migraine treatment
treatment, who needs to treat frequently and is at risk for medication-overuse and are well tolerated.
headache, or in whom a combination of treatment approaches may be beneficial. Consider neuromodulation

in patients who want to
The AHS Consensus Statement recommends considering neuromodulation
avoid or are unable to take

devices in the same circumstances under which a gepant or ditan would be medications, or who need a
appropriate.15 combination of treatment
approaches.
CHOOSING ACUTE TREATMENTS
● Triptans are the mainstay
The choice of initial acute treatment should take into consideration attack of migraine-specific
severity, the time course of attacks, whether pronounced nausea or vomiting is treatment based on the
present, and contraindications related to comorbidities or polypharmacy. Many strongest evidence for
patients with migraine experience attacks with a range of severity. In this setting, effectiveness, wide
availability, and long history
the use of a nonspecific treatment such as an NSAID for milder attacks and of use.
saving migraine-specific treatment for more severe attacks may reduce the
likelihood of medication-overuse headache. ● An American Headache
The first-line treatments for mild-to-moderate attacks are acetaminophen and Society Consensus
Statement recommends that
NSAIDs, either prescription or over the counter.15 Migraine-specific treatments
gepants, ditans, or
should be considered for moderate-to-severe attacks, or for milder attacks that neuromodulation devices be
do not typically respond to nonspecific analgesics. Triptans should be considered considered in patients with
as first-line migraine-specific therapy for eligible patients based on the strongest migraine who have not
responded to two or more
evidence for efficacy, wide availability, and long history of use. The choice of
oral triptans, or who have
triptan is often dictated by insurance or other economic factors. Sumatriptan, the contraindications or
oldest triptan, is almost universally covered by insurance and is often prescribed intolerable side effects to
first. The next choice of triptan may be dictated by the need for a faster onset or a triptans.
longer duration of response. Several studies showed that participants who did not
● Acute migraine
respond to one triptan may respond well to another.41 treatments with the best
A US population-based study found that 38.9% of women and 41.6% of men evidence for safety in
with migraine had at least two cardiac risk factors, while 18.6% of women and pregnancy are
19.1% of men had at least three.42 Nontriptan treatments, such as gepants or metoclopramide (for
migraine pain as well as
lasmiditan, should be considered for these patients at higher risk for cardiac nausea), cyclobenzaprine,
events. The AHS Consensus Statement recommends that gepants, ditans, or diphenhydramine (adjunct
neuromodulation devices be considered in patients who have not responded to therapy), triptans, and
two or more oral triptans, or who have contraindications or intolerable side ondansetron (for nausea).
effects to triptans.15 Gepants are generally well tolerated and are therefore the
typical next step after triptans. Patients who respond well to triptans but have
vascular contraindications may be good candidates for lasmiditan due to their
similar mechanisms of action.
ACUTE TREATMENT DURING PREGNANCY AND LACTATION

The prospective, ambulatory headache center–based American Registry for
Migraine Research study found that 20% of respondents changed pregnancy
plans due to migraine.43 Respondents reported concerns about worsening
migraine and migraine-associated disability and the effect of migraine
medications on the health of the child. Clinicians also frequently express
discomfort with treating more severe migraine during pregnancy.44 Despite the
challenges associated with incomplete information about medication safety in
pregnancy, the treatment of pain during pregnancy is important. In addition to

the obvious quality-of-life benefit of treatment, antenatal pain is associated with

an increased risk of mental health conditions in the antenatal and postnatal
periods.45
The safety profiles of acute treatments for migraine in pregnancy are
summarized in TABLE 3-546,47. Both pain and nausea should be addressed.
Migraine-associated nausea and pregnancy-associated nausea may both be

present, which can lead to dehydration and electrolyte abnormalities if vomiting
is frequent. Treatments with the best evidence for safety are metoclopramide
(for migraine pain as well as nausea), cyclobenzaprine, diphenhydramine
(adjunct therapy), triptans, and ondansetron (for nausea).46,48 Butalbital
combination medications have historically been preferred over triptans, but a
large body of high-quality evidence now supports the safety of triptan use in
pregnancy. Triptans are also typically more effective than butalbital combination
TABLE 3-5 Acute Migraine Treatment Options in Pregnancy and Lactation, Based on
Safety and Efficacya
Treatment Use in pregnancy Use in lactation

Acetaminophen First line First line
Cyclobenzaprine First line Likely safe; monitor infant for drowsiness
Diphenhydramine First line May decrease milk supply
Metoclopramide First line Infant exposure likely; may increase milk

supply
Lidocaine Likely safe; first line for rescue if available Infant exposure unlikely
(subcutaneous)
Triptans First line for rescue; next best option if other Minimal infant exposure expected; eletriptan
first-line treatments are not reliably effective may have lowest exposure risk
Aspirin Low-dose aspirin likely safe Avoid
Ibuprofen Second line; use only in second trimester First line
Ondansetron (nausea) Second line First line
Prednisone Second line for rescue Minimal infant exposure expected
Prochlorperazine Second line Minimal infant exposure expected
Oxycodone Third line; not recommended for treatment of Avoid; monitor for sedation, poor feeding and
migraine weight gain, breathing difficulties
Butalbital Third line; not recommended for treatment of Avoid; monitor for sedation, poor feeding and
migraine weight gain
Lasmiditan Avoid No data available
Gepants Avoid; rimegepant preferred over ubrogepant Minimal infant exposure of rimegepant is
expected; no data available for ubrogepant
Ergots and Always avoid Avoid

dihydroergotamine
a
Data from Rayhill M, Continuum (Minneap Minn)46 and the National Institute of Child Health and Human Development.47
356 A P R I L 2 0 24

treatments, resulting in more effective treatment with less medication exposure.
Observational studies have shown an association between acetaminophen use
and autism, attention deficit hyperactivity disorder, and language delay in girls.49
These associations are stronger with longer duration of use and higher doses, and
the strength of the findings is limited by confounding by indication.
Acetaminophen is still commonly used as a first-line treatment for migraine in

pregnancy.46,50 Low-dose aspirin may be safe.48 Ergots, DHE, lasmiditan, and
gepants should be avoided. CASE 3-2 describes a common scenario where acute
treatment needed to be changed due to pregnancy.
Acute treatment in lactation is generally less restrictive than in pregnancy.
Breastfeeding should not be considered a contraindication to the use of acute
migraine treatment. If needed, breast milk can be expressed and discarded once
after using an acute treatment. Acute treatments with the best evidence for safe
use in lactation are acetaminophen and ibuprofen. Second-line treatments
include other NSAIDs and triptans (with eletriptan being preferred if effective
due to its likely lower excretion in breast milk).51 The safety of gepants and
lasmiditan in the setting of lactation is currently unknown, although the
excretion of rimegepant into breastmilk is low.52 These treatments should be
avoided until more information is available. Aspirin and ergots should be
avoided. The comprehensive Drugs and Lactation Database (LactMed) is easily
accessible online and is an excellent resource regarding medication safety
in lactation.47
MANAGEMENT OF REFRACTORY ATTACKS

Although a reliably effective acute treatment plan can be developed for most
patients with migraine, a minority experience attacks that do not respond to
A 29-year-old woman who experienced migraine 2 to 3 times a month CASE 3-2

planned to become pregnant in the near future and wanted to discuss
treatment options. She was concerned about the possibility of not being
able to treat the severe attacks and being disabled by pain. Rimegepant
was currently effective, and she had only partial benefit from three
different triptans previously. She had never taken an antiemetic. The
patient was educated that migraine often improves after the first
trimester of pregnancy and that acute treatment options compatible with
pregnancy were available. She was prescribed metoclopramide to try
with acetaminophen as a first-line treatment, and the most effective of
the previously tried triptans was prescribed as a rescue treatment. Five
months later, she sent a message through the patient portal to say that
she was 10 weeks pregnant and had only required the triptan twice.
Although she sometimes had mild residual pain, this combination was
sufficient to allow her to function well.
Reassurance and education can be the most powerful initial interventions COMMENT
in the setting of pregnancy. While the most effective treatment for this
patient, rimegepant, should not be continued after conception, she had at
least a partial response to treatments that can be used during pregnancy.

first-line treatment at least some of the time. These patients require a plan for
rescue therapy. Attacks that do not respond to home treatments may require more
intensive therapy in an urgent care, emergency department, or inpatient setting.
Rescue Treatment
Rescue therapy should be considered in any patient who has a rapid escalation of
pain or attacks accompanied by severe nausea or vomiting, who sometimes have
attacks that do not respond to typical treatment, or who have a history of

emergency department visits for migraine for any reason. CASE 3-3 describes one
approach to managing migraine associated with significant nausea. Nonoral
treatments are necessary for patients with significant vomiting and typically
have a faster onset than oral treatments.53-55
The most effective nonoral migraine-specific treatment is subcutaneous
sumatriptan. Subcutaneous sumatriptan can be used as a rescue 2 hours after
shorter-acting triptans and 4 hours after longer-acting triptans if needed. The

total triptan exposure should be limited to 2 doses per 24-hour period. The side
effects of parenteral sumatriptan are similar to those of the oral formulation but
are typically stronger and have a faster onset. Triptans and DHE nasal sprays are
another alternative. DHE nasal spray can be used 24 hours after a triptan dose,
making it more useful for situations where the headache lingers into the
following day and backup treatment is needed, or if a nontriptan medication is
used as a first-line treatment. Pretreatment with an antiemetic is necessary.53 The
NSAID indomethacin is also available as a 50 mg suppository and can be useful if
triptans and DHE are contraindicated or not tolerated. For more information on
this medication, refer to the article “Indomethacin-Responsive Headache
Disorders” by Peter J. Goadsby, MD, PhD, FRS,56 in this issue of Continuum.
CASE 3-3 A 51-year-old woman with a lifelong history of episodic migraine

presented to the neurology clinic after a recent emergency department
visit for severe migraine with vomiting. The attack had escalated quickly
and was associated with early vomiting. She had tried rizatriptan melts
and oral metoclopramide but vomited shortly after taking the
medications.
The neurologist prescribed ondansetron 8 mg orally dissolving tablets,
sumatriptan 6 mg subcutaneous injection, and prochlorperazine 25 mg as
a rectal suppository. She was instructed to use the sumatriptan injections
and prochlorperazine suppositories if migraine symptoms escalated
quickly from onset again, or 2 hours after trying the orally dissolving
rizatriptan and ondansetron if that was ineffective. At the next visit, she
reported that she was able to manage all five subsequent attacks at
home. The prochlorperazine suppositories caused sedation but were
beneficial for the severe attacks.
COMMENT Patients who have prominent nausea or vomiting with their attacks may
need nonoral treatment as a backup. Any patient who has been to the
emergency department should also have a rescue plan in place.
358 A P R I L 2 0 24

Many people with migraine find sleep therapeutic and sedating medications
are helpful in this circumstance. The phenothiazine antiemetics promethazine
and prochlorperazine typically cause sedation and are available as suppositories
and may treat migraine pain as well. Other sedating medications, such as
antihistamines, are sometimes used for similar reasons.54
In-office treatments may include IM injections of ketorolac or occipital nerve

blocks with lidocaine. Clinical trials support the use of IM injections of ketorolac
as an acute treatment. Several positive trials have evaluated occipital nerve block
as an acute treatment for migraine as well. The availability of urgent
appointments is the major barrier to this strategy.
Acute Treatment in the Emergency Department and Inpatient Settings

Patients who have severe migraine attacks with inconsistent or incomplete
response to home acute treatment, or who have early or severe vomiting that
prevents the absorption of oral treatments, are at risk for presenting to the
emergency department for urgent management of migraine symptoms.57 The
management of vomiting and rehydration are important first steps. Evidence-
based pharmacologic treatments of migraine in the emergency department or
inpatient settings are summarized in TABLE 3-657,58. For the management of
migraine pain, evidence supports IV metoclopramide and prochlorperazine,
as well as subcutaneous sumatriptan.58 Corticosteroids, specifically
Evidence-based Options for Emergency Department and Inpatient TABLE 3-6

Migraine Treatmenta
Medication Dose
Dopamine receptor antagonists
Metoclopramide 10 mg IV
Prochlorperazine 10 mg IV
Migraine specific
Sumatriptan 6 mg subcutaneously
Dihydroergotamine 1 mg IV
Nonsteroidal anti-inflammatory drugs
Ketorolac 15 mg to 30 mg IV or IM
Other
Dexamethasone 10 mg IV
Magnesium (for migraine with aura) 1 g to 2 g IV
Sodium valproate 400 mg to 500 mg IV
Procedures
Occipital nerve blocks with lidocaine
IM = intramuscular; IV = intravenous.
a
Data from Friedman et al, Neurol Clin57 and Orr et al, Headache.58

KEY POINTS dexamethasone, were shown in a meta-analysis to reduce the likelihood of

headache recurrence in the days following an emergency department visit but
● Migraine rescue therapy
should be considered in any
did not reduce acute pain better than placebo.58 Although sodium valproate is
patient who has rapid effective compared with placebo and is sometimes used as a rescue treatment,
escalation of pain or attacks studies consistently show that it is no more effective than dopamine receptor
accompanied by severe antagonists such as metoclopramide and prochlorperazine.59 Two small clinical
nausea or vomiting, who
trials have also shown benefit from the older antipsychotic medications
occasionally has attacks

that do not respond to haloperidol and chlorpromazine.60,61 These drugs are associated with a higher
typical treatment, or who risk of adverse effects, including hypotension and prolonged QT interval, and
has a history of emergency should be considered third-line treatments. Available evidence suggests that
department visits for
occipital nerve blocks are not as effective as metoclopramide but may be helpful
migraine for any reason.
if metoclopramide is not effective.62 Nerve blocks are generally safe and well
● IV formulations of tolerated, however, and may be an option for patients in whom other
metoclopramide and treatments are contraindicated.62
prochlorperazine and Opioid use should be avoided in the emergency department as opioids have
subcutaneous sumatriptan
all have good evidence for
lower evidence for effectiveness, are associated with medication-overuse
the treatment of migraine in headache and decreased subsequent responsiveness to acute treatment, and may
the emergency department. reinforce emergency department use in patients seeking opioids. Opioid use for
Dexamethasone may the acute treatment of migraine in the emergency department has decreased over
prevent headache
recurrence.
time, but more than one-fourth of patients in the United States were still given
opioids for migraine in the emergency department as recently as 2018.63
● Although sodium Inpatient admission for the management of severe migraine may be necessary
valproate is effective if adequate pain control is not achieved in the emergency department.
compared with placebo and
Dihydroergotamine with metoclopramide IV every 8 hours is an effective but
is sometimes used as a
rescue treatment, studies side effect–prone inpatient treatment approach. An observational study
consistently show that it is suggested that a longer duration of repetitive DHE was more effective than the
no more effective than originally studied 2-day period.64 In addition to nausea, DHE IV can cause leg
dopamine receptor pain or cramping, chest discomfort, sedation, flushing, diarrhea, abdominal
antagonists such as
metoclopramide and cramping, vasoconstriction, and hypertension.53,64
prochlorperazine.
● Dihydroergotamine 1 mg CONCLUSION
IV given every 8 hours is an
effective strategy for
There are many choices for the acute treatment of migraine, representing
treating refractory migraine multiple classes of treatment with different mechanisms of action and
pain in the inpatient setting. pharmacokinetics. Neuromodulation and new drug classes provide options for
Pretreatment with an patients who need alternatives to triptans. There is no one-size-fits-all acute
antiemetic is necessary.
treatment and multiple treatment trials are sometimes necessary to determine
the optimal regimen for patients. Switching within and between classes, using
the maximum allowed dose, using combination therapy, and counseling patients
to treat early are all strategies that may improve patient response to acute
treatment.
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WNL.0b013e3182377dbb

REVIEW ARTICLE

Preventive Treatment of
I NT E R V I E W A V AI L A B L E Migraine
ONLINE
By Richard B. Lipton, MD, FAAN
ABSTRACT
CITE AS:
OBJECTIVE: This article describes strategies for the preventive treatment of
2024;30(2, HEADACHE):364–378. migraine including the emerging role of calcitonin gene-related peptide
(CGRP)-targeted therapies and introduces novel paradigms for the
Address correspondence to preventive treatment of migraine.
Dr Richard B. Lipton, 1165 Morris

Park Ave, Rousso Building, Room
332, Bronx, NY 10461, richard. LATEST DEVELOPMENTS: Multiple migraine medications targeting CGRP have
lipton@einsteinmed.edu.
been introduced since 2018, including injectable monoclonal antibodies
RELATIONSHIP DISCLOSURE: (ie, eptinezumab, erenumab, fremanezumab, and galcanezumab) and oral
Dr Lipton has received personal small-molecule CGRP receptor antagonists (ie, ubrogepant, rimegepant,
compensation in the range of
$500 to $4999 for serving as a
atogepant, and zavegepant). With the exceptions of ubrogepant and
consultant for Collegium zavegepant, which are approved only as acute treatments, all of these
Pharmaceutical, CoolTech, agents have demonstrated efficacy in the preventive treatment of migraine;
Genentech, Inc., LinPharma,
Merck & Co., Inc., and Satsuma the monoclonal antibodies and atogepant have evidence of effectiveness in
Pharmaceuticals, Inc.; in the adults with either episodic or chronic migraine. The safety and tolerability
profiles of CGRP-targeted therapies in migraine are favorable.
serving as a consultant for Axon
Optics, GSK plc, and Satsuma
Pharmaceuticals, Inc. and on a ESSENTIAL POINTS: The
goals of preventive migraine therapy include reducing
scientific advisory or data safety
monitoring board for AbbVie
the frequency, severity, duration, and disability associated with attacks,
Inc.; in the range of $10,000 to reducing the need for acute treatment and the risk of medication overuse,
$49,999 for serving as a enhancing self-efficacy and health-related quality of life, and reducing
consultant for AbbVie Inc.,
Amgen Inc., Biohaven, Ltd., headache-related distress and interictal burden. Six drugs targeting CGRP
Grifols, S.A., Lundbeck, Pfizer (four monoclonal antibodies and two gepants) are now available for the
Inc., Teva Pharmaceutical preventive treatment of episodic migraine in adults. The efficacy of
Industries Ltd., and Vedanta
Biosciences, Inc. and on a CGRP-targeted medications in the acute and preventive treatment of
scientific advisory or data safety migraine, together with good safety and tolerability, has led to the
emergence of new approaches to preventive treatment.
INVESTIGATIONAL USE
DISCLOSURE:
Dr Lipton discusses the INTRODUCTION
unlabeled use of amitriptyline,
P
candesartan, lisinopril, reventive treatments for migraine are intended to decrease the
memantine, metoprolol, and frequency and severity of attacks, render acute treatment more
venlafaxine for the preventive
effective, reduce headache-related disability, and improve
treatment of migraine and the
unlabeled use of calcitonin headache-related quality of life. There are multiple classes of effective
gene-related peptide–targeted preventive treatments, including antihypertensive medications,
migraine therapies for the
preventive treatment of
antidepressants, and antiseizure medications. The names of these classes of
migraine in adolescent patients. medications reflect their development and initial approval for indications other
than migraine with the subsequent discovery of efficacy in migraine.1 Herein,
© 2024 American Academy they are referred to as migraine-nonspecific preventive medications and they remain
of Neurology. a mainstay of preventive treatment.
364 A P R I L 2 0 24

Mounting evidence has suggested that the vasoactive neuropeptide calcitonin KEY POINTS
gene-related peptide (CGRP) plays a crucial role in migraine pathophysiology.2
● The goals of preventive
The success of CGRP-targeted therapies confirmed the mechanistic hypothesis migraine therapy include
and led to the approval of a new generation of treatments developed specifically reducing the frequency,
for migraine. For prevention, there are two classes of CGRP-based therapies: severity, duration, and
monoclonal antibodies, which target the ligand or its receptor, and small- disability associated with
attacks, reducing the need
molecule receptor antagonists (gepants). There are four marketed CGRP
for acute treatment and the

monoclonal antibodies and four marketed gepants. All four monoclonal risk of medication overuse,
antibodies are indicated for the preventive treatment of episodic migraine and enhancing self-efficacy and
chronic migraine. Of the gepants, ubrogepant and zavegepant are exclusively health-related quality of
life, and reducing
available as acute treatments, atogepant is approved for the prevention of
headache-related distress
episodic and chronic migraine, and rimegepant is approved for the acute and and interictal burden.
preventive treatment of episodic migraine. There is now a large body of evidence
from randomized trials, long-term safety studies, real-world evidence, and ● The initial preventive
treatment of migraine is
clinical practice experience using CGRP-targeted therapies for migraine

often a conventional oral
prevention. Several treatment guidelines and consensus statements,3,4 systematic medication or, sometimes, a
reviews, and meta-analyses inform this area.5-9 This article takes a practical natural product. Among the
approach to applying the science to the preventive management of migraine and evidence-based options,
presents two illustrative patient cases. the choice is often based on
the patient’s comorbidities
and potential adverse
GENERAL CONSIDERATIONS events.
Migraine treatments have long been divided into preventive treatments, taken
even in the absence of attacks, and acute treatments, taken at the time of an attack ● For migraine-nonspecific
oral preventive medications,
to relieve pain and associated symptoms while restoring function. Short-term
the best practice is to start
prevention and treatment during the prodrome represent emerging strategies at a low dose and gradually
with features of both acute and preventive treatment. Although most preventive increase the dose based on
and acute treatments are pharmaceuticals or biologics, devices, behavioral tolerability and response.
therapies, and lifestyle approaches are widely used.10 Broadly speaking, the goals
● The calcitonin
of preventive treatment include reducing the frequency, severity, duration, and gene-related peptide
disability associated with attacks, reducing the need for acute treatment and risk (CGRP)-targeted migraine
of medication overuse, enhancing self-efficacy and health-related quality of life, therapies are offered to
and reducing headache-related distress and interictal burden.4,11 Not everyone patients who are at least
18 years old if they cannot
with migraine needs preventive treatment. As attack frequency and disability tolerate or have failed to
increase, the need for preventive treatment increases. According to the American respond to at least two
Headache Society Consensus Statement, prevention should be considered if traditional migraine
attacks interfere with daily activities despite optimized acute treatment and if preventive medications with
established or probable
attack frequency and disability exceed specified thresholds (TABLE 4-112), in the
efficacy.
setting of medication-overuse headache, or based on patient preference. For
people with less than 6 monthly headache days, the choice to initiate treatment ● For CGRP-targeted
may be determined, in part, by the presence and extent of migraine-related therapies, treatment begins
disability. Disability can be defined by scores indicating moderate or severe at an optimal dose and
treatment benefits often
disability on the Migraine Disability Assessment questionnaire (11 or greater)13 develop more rapidly than
or Headache Impact Test questionnaire (scores of 50 or greater).14 For people with migraine-nonspecific
with 6 or more monthly migraine days, disability is usually not required for a oral preventive medications.
recommendation to offer prevention and is not required for the recommendation
to consider prevention for people with 4 or 5 monthly headache days.
MIGRAINE-NONSPECIFIC PREVENTIVE MEDICATIONS

Preventive treatment should always be part of a comprehensive approach to migraine
management for people with a sufficient combination of monthly headache-day

PREVENTIVE TREATMENT OF MIGRAINE
frequency and disability. A complete plan also includes recommendations for

acute treatment and guidance on lifestyle and behavioral approaches. This
section outlines principles for choosing and modifying a preventive treatment.
Whenever possible, it is best to use evidence-based treatments. TABLE 4-24,15,16
shows traditional and CGRP-targeted preventive pharmacologic treatments that
are effective or probably effective based on findings from clinical trials.

In patients who have not previously received preventive treatment, the initial
treatment is often a nonspecific oral medication or, sometimes, a natural

product. Among the evidence-based options, the choice is often based on the
patient’s comorbidities and potential adverse events. For patients with
hypertension, a beta-blocker or candesartan are frequent choices. For patients
with obesity, topiramate may promote weight loss and is a reasonable option. For
patients with comorbid depression and insomnia, amitriptyline may be a
preferred choice. For most migraine-nonspecific oral preventive medications,
the best practice is to start at a low dose and gradually increase the dose based on
tolerability and response. Preventive treatment is most likely to be effective if it
is individualized. A major limitation of many nonspecific oral medications is that
they are poorly tolerated. Of all patients who start on an oral migraine preventive
medication for chronic migraine, only 25% remain on their initial therapy after
6 months, and 14% remain on the medication at 1 year.17 The most frequently
cited reasons for discontinuing nonspecific oral preventive medications are
insufficient efficacy, poor tolerability, or both.
An adequate trial of a nonspecific medication requires a period of dose
optimization followed by observation to assess its effectiveness as the onset of
treatment benefits is gradual. This process may take weeks to several months.
Tolerability problems can be identified much more quickly. If the initial
nonspecific medication fails completely, it is tapered and a medication from a
different pharmacologic class is initiated. If the initial medication brings partial
benefits, a second medication is often added to the first. If the desired therapeutic
effects are achieved, then the initial medication can be tapered to see if
monotherapy with the second agent is sufficient.
TABLE 4-1 Criteria for Identifying Candidates for Preventive Treatments for Migrainea
Headache days/month Degree of disabilityb

Prevention offered 6 or more None
4 or more Some
3 or more Severe
Prevention considered 4 or 5 None
3 Some
2 Severe
a
Data from Ailani J, et al, Headache4 and Lipton RB, et al, Neurology.12
b
As measured using the Migraine Disability Assessment, Migraine Physical Function Impact Diary, or
Headache Impact Test.
366 A P R I L 2 0 24

After the failure of two classes of migraine-nonspecific preventive
medication, consideration should be given to trying either onabotulinumtoxinA
or a CGRP-targeted therapy.
Medication Options for Migraine Preventiona,b TABLE 4-2

Antidepressant
◆ Amitriptyline (tricyclic)
◆ Venlafaxine (SNRI)
Antihypertensive
◆ Atenolol
◆ Candesartan
◆ Lisinopril
◆ Metoprolol
◆ Nadolol
◆ Propranolol
◆ Timolol
Antiseizure
◆ Divalproex sodium
◆ Sodium valproate
◆ Topiramate
CGRP pathway targeted treatments
◆ Atogepant (small-molecule CGRP-receptor antagonist)
◆ Eptinezumab (monoclonal antibody to CGRP)
◆ Erenumab (monoclonal antibody to the canonical CGRP receptor)
◆ Fremanezumab (monoclonal antibody to CGRP)
◆ Galcanezumab (monoclonal antibody to CGRP)
◆ Rimegepant (small-molecule CGRP-receptor antagonist)
NMDA antagonist
◆ Memantine
OnabotulinumtoxinAc
Triptans used for short-term prevention of menstrually related migraine:
◆ Frovatriptan
◆ Naratriptan
◆ Zolmitriptan
CGRP = calcitonin gene-related peptide; NMDA = N-methyl-D-aspartate; SNRI = serotonin-norepinephrine

reuptake inhibitor.
a
Data from Ailani J, et al, Headache,4 Gronseth GS, et al, American Academy of Neurology (AAN),15 and
Simpson DM, et al, Neurology.16
b
All medications are administered orally, except for the monoclonal antibodies targeting the CGRP pathway
and onabotulinumtoxinA which are administered parenterally.
c
For the prevention of chronic migraine.

In addition to pharmacotherapy, several neuromodulatory devices have been

approved for the preventive treatment of migraine. Options include supraorbital
transcutaneous nerve stimulation, noninvasive vagus nerve stimulation, single-
pulse transcranial magnetic stimulation, transcutaneous direct and alternating
current stimulation, and remote electrical neuromodulation, among others.
These devices have favorable safety profiles and are widely used in people who
cannot take or prefer to avoid preventive medications. They are often used in
pregnancy. Insurance coverage is often difficult to obtain.
The Role of OnabotulinumtoxinA

OnabotulinumtoxinA is currently approved for the treatment of chronic migraine
(ie, not episodic migraine). This treatment is given using the PREEMPT protocol
through a series of 31 intramuscular injections of 5 units each (155 units in total) to
seven muscle groups associated with the trigeminal, occipital, and cervical sensory
nerves.18,19 OnabotulinumtoxinA has been a valuable tool in the preventive
treatment of migraine and is currently being studied in episodic migraine.13
CGRP-TARGETED MIGRAINE PREVENTIVE MEDICATIONS

The CGRP-targeted migraine therapies may be offered to adult patients and are
often given off-label to adolescents. These agents are generally used in people
who cannot tolerate or do not respond to at least two migraine-nonspecific
preventive medications with established or probable efficacy.4 Guidelines
published by the European Headache Federation reviewed 15 studies in episodic
migraine and ten studies in adults with chronic migraine; on that basis, they
recommend the use of eptinezumab, erenumab, fremanezumab, and
galcanezumab as preventive treatments for adults with episodic or chronic
migraine.3 Of the CGRP monoclonal antibodies, eptinezumab, fremanezumab,
and galcanezumab target the ligand, while erenumab acts at the receptor.
Erenumab, fremanezumab, and galcanezumab are administered as subcutaneous
injections, while eptinezumab is administered by IV infusion.
Treatment with the CGRP monoclonal antibodies, gepants,
onabotulinumtoxinA, neuromodulation devices, and most natural supplements
with evidence for efficacy in migraine can be started at the optimal dose. This
eliminates the need for gradual dose escalation that characterizes nonspecific
preventive medication and the associated delay in the onset of benefit and the
assessment of efficacy. Eptinezumab is given by IV infusion in doses of 100 mg or
300 mg every 3 months. Erenumab can be started as a 70-mg or 140-mg subcutaneous
dose once monthly. Fremanezumab can be started as a 225-mg subcutaneous dose
once monthly or 675 mg (3 225-mg injections) every 3 months. Galcanezumab is
administered subcutaneously in a loading dose of 240 mg (2 120-mg injections)
and then dosed at 120 mg once monthly. The three subcutaneous agents are
prescribed with autoinjectors. Eptinezumab is most commonly given at an
infusion center and is also available as a 30-minute in-office IV infusion.
The gepants atogepant and rimegepant have the advantage of oral dosing. For
rimegepant, the preventive dose is 75 mg every other day, not to exceed 18 orally
disintegrating tablets per month. Rimegepant has regulatory approval and
evidence for efficacy for episodic migraine; it has not received regulatory
approval for the prevention of chronic migraine. Atogepant is dosed at 10 mg,
30 mg, or 60 mg for episodic migraine and at 60 mg once daily for chronic
migraine; it is the only orally administered CGRP-targeted drug with established
368 A P R I L 2 0 24

efficacy and regulatory approval for the preventive treatment of adults with
either episodic or chronic migraine. In most patients, treatment is usually
initiated at the 60-mg dose. The exception is in patients who are prone to
constipation, who may be started at the 30-mg dose. For nonspecific oral
preventive treatments, the principle is to start at a low dose and slowly escalate
the dose based on tolerability. For CGRP-targeted therapies, treatment begins at

an optimal dose and treatment benefits often develop more rapidly than with
nonspecific oral medications.20,21
Efficacy of CGRP-Targeted Treatments

The efficacy of CGRP monoclonal antibodies for the preventive treatment of
migraine has been evaluated in at least 25 randomized clinical trials: 15 trials in
patients with episodic migraine and ten trials in patients with chronic migraine.3
In adults with episodic or chronic migraine, the CGRP monoclonal antibodies
(eptinezumab, erenumab, galcanezumab, and fremanezumab) were more

effective than placebo, as measured by reduced monthly migraine days,
improved response rate, and less use of medications for acute treatment
(TABLE 4-3). In general, the efficacy benefits of the subcutaneous monoclonal
antibodies become statistically significant within the first week following
administration. Incremental benefits often accumulate with repeated doses. Two
medications in the gepant class have evidence of efficacy as preventive
treatments. Atogepant was assessed in a phase 3, double-blind trial of adults with
Evidence-based Recommendations For the CGRP-targeted Monoclonal TABLE 4-3

Antibodies in the Preventive Treatment of Migrainea
Recommendation Agent Dosing Evidence of efficacyb

The CGRP monoclonal antibodies are Eptinezumab 100 mg or 300 mg every 12 weeks. High
effective for preventive treatment of
episodic migraine Erenumab 70 mg or 140 mg every 4 weeks. High
Fremanezumab 225 mg every 4 weeks High
Galcanezumab 240 mg loading High

120 mg every 4 weeks
The CGRP monoclonal antibodies are Eptinezumab 100 mg or 300 mg every 12 weeks High
effective for preventive treatment of
chronic migraine Erenumab 70 mg every 4 weeks High
Erenumab 140 mg every 4 weeks Moderate
Fremanezumab 225 mg every 4 weeks Moderate
Galcanezumab 240 mg loading High

120 mg every 4 weeks
CGRP = calcitonin gene-related peptide.

a
Reprinted from Sacco S, et al, J Headache Pain.3
b
Measured by reduced monthly migraine days, improved response rate, and less use of medications for acute treatment.

episodic migraine who were administered a once-daily dose of oral atogepant

(10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The changes from baseline in
mean monthly migraine days across 12 weeks were −3.7 with 10 mg atogepant,
−3.9 with 30 mg atogepant, −4.2 with 60 mg atogepant, and −2.5 with placebo.22
Atogepant was also assessed in the preventive treatment of chronic migraine. In
patients with chronic migraine, over 12 weeks of treatment, the mean change
from baseline in monthly migraine days was −6.9 (standard error: 0.4) with
atogepant 60 mg once a day and −5.1 (standard error: 0.4) with placebo. The
least squares mean difference from placebo was −1.8 with atogepant 60 mg once a
day (−2.9 to −0.8; adjusted P = .0009).23 As a preventive medication, rimegepant
75-mg orally disintegrating tablets dosed every other day was assessed in a phase
2/3 randomized, double-blind, placebo-controlled trial.24 It was found to be more
effective than placebo on the primary endpoint: the change in mean monthly
migraine days during weeks 9 through 12 (−4.3 versus −3.5; P = .0099).24
There are limited data comparing CGRP-targeted treatments with oral generic
medications. One trial compared erenumab 70 mg to 140 mg monthly with
topiramate 50 mg to 100 mg daily over 6 months.25 The reduction in monthly
migraine days was greater with erenumab than with topiramate (−5.86 versus
−4.02; P < .001) and patients were more likely to have a greater than 50%
reduction in monthly migraine days with erenumab than with topiramate (55.4%
versus 31.2%; P < .001). Discontinuing treatment due to adverse events was
almost 4 times more common with topiramate than with erenumab (38.9%
versus 10.6%; P < .001).24 In these studies, poor tolerability limited treatment
and may have influenced efficacy.
Tolerability of CGRP-Targeted Treatments

The CGRP monoclonal antibodies and the gepants are generally well tolerated.
In clinical trials, the most commonly reported adverse events with the CGRP
monoclonal antibodies are constipation and injection site reactions.26 With respect
to relative tolerability, in a meta-analysis of 19 clinical trials of CGRP monoclonal
antibodies and gepants,8 atogepant 60 mg 2 times a day (this dose does not have
regulatory approval; odds ratio [OR]: 2.22; 95% confidence interval [CI]: 1.26 to 3.
91) and galcanezumab 240 mg (OR: 1.63; 95% CI: 1.33 to 2.00) were most likely to
be associated with treatment-emergent adverse events. Although this review
found that eptinezumab 30 mg was most likely to cause adverse events that lead
patients to discontinue treatment (OR: 2.62; 95% CI: 1.03 to 6.66), the result was
based on the only clinical trial with eptinezumab 30 mg, which had an outsized
influence on the outcome. Eptinezumab had the lowest odds of treatment-
emergent adverse events and serious adverse events, erenumab had the lowest
odds of any adverse events, and quarterly fremanezumab had the lowest odds of
treatment discontinuation due to adverse events.8 The European Headache
Federation guideline found no major concerns in 25 trials reviewed for safety.
Nonetheless, the safety of CGRP monoclonal antibodies in pregnancy and
lactation has not been demonstrated and these drugs should likely be avoided in
these settings. The European Headache Federation recommends caution in
patients who have vascular disease or risk factors and Raynaud phenomenon.3
The guideline also recommended that erenumab be used with caution in patients
with a history of severe constipation.3 These recommendations are in line with
prescribing information for the CGRP monoclonal antibodies. The gepants for
prevention, atogepant and rimegepant, are both well tolerated. With atogepant
370 A P R I L 2 0 24

10 mg, 30 mg, or 60 mg once per day, the most common adverse events were
constipation (6.9% to 7.7%) and nausea (4.4% to 6.1%); some adverse events (eg,
fatigue, anxiety) were dose dependent. The serious adverse events identified in the
trials included asthma in one patient and optic neuritis in another, neither of which
were judged to be drug attributable.23 In the rimegepant trial, adverse events
occurred at similar rates in the active and placebo groups, and the only adverse
events that affected at least 2% of those who received rimegepant were
nasopharyngitis, nausea, urinary tract infection, and upper respiratory tract

infection.24 No treatment-related serious adverse events were reported with
rimegepant. Rimegepant has a slightly lower rate of adverse events than
atogepant, but that may be related to differences in relative dose; head-to-head
clinical trials are needed to determine if these differences are significant.3
Selection of CGRP-Targeted Migraine Preventives

Generally, CGRP-targeted treatments are offered to patients who have had an

insufficient response to one to four nonspecific oral preventives, depending on
the setting.4 Multiple studies show that CGRP-targeted treatments are effective
in patients who have not responded to two to four nonspecific oral preventive
medications.4,27-30 It is unknown how the number of previous preventive
treatment nonresponses to nonspecific oral preventives predicts the conditional
probability of response to the next nonspecific oral preventive or the first
CGRP-targeted therapy. These data would help optimize the requisite number
of ineffective treatment trials before CGRP-targeted therapies are used.
The decision to prescribe a specific CGRP monoclonal antibody or a gepant is
multifactorial, and the selection between them should be individualized based on
drug attributes (TABLE 4-4), patient characteristics (eg, migraine features,
comorbidity profile), and patient preference. Routes of administration differ
Comparing CGRP Monoclonal Antibodies With Gepants For the Preventive TABLE 4-4
Treatment of Migraine: Chemistry, Indications, Formulation, and Pharmacology
Time to
maximum
Indicated for the Routes of plasma Elimination
preventive treatment of administration concentration half-life
Monoclonal antibodies
Eptinezumab Episodic migraine/chronic migraine IV 4.8 hours 27 days
Erenumab Episodic migraine/chronic migraine Subcutaneous 6 days 28 days
Fremanezumab Episodic migraine/chronic migraine Subcutaneous 5-7 days 30 days
Galcanezumab Episodic migraine/chronic migraine Subcutaneous 5 days 27 days
Gepants
Atogepant Episodic migraine/chronic migraine Oral 1-2 hours 11 hours
Rimegepant orally disintegrating tablet Episodic migraine Oral 1.5 hours 11 hours
CGRP = calcitonin gene-related peptide; IV = intravenous.

among the monoclonal antibodies and gepants. The monoclonal antibodies are
given subcutaneously with an autoinjector, except for eptinezumab which is
given intravenously every 3 months. The gepants are oral agents. In the author’s
experience, most patients prefer the oral option, but some prefer monthly
injections or IV infusions every 3 months. Another issue is the side effect profile,
which is generally favorable. Of the monoclonal antibodies, erenumab is

associated with constipation, perhaps because it binds the CGRP receptor rather
than the ligand. In constipation-prone patients, monoclonal antibodies that

target the ligand are preferred. An association between increased blood pressure
and erenumab has been reported,31 but an analysis of pooled data from four long-
term clinical trials found no differences between placebo and erenumab 70 mg or
140 mg in the clinical worsening of blood pressure category over the first 3
months of therapy (14% placebo versus 13% erenumab 70 mg and 14% erenumab
140 mg) regardless of baseline blood pressure category.32 As evidence
accumulates, patients with migraine taking erenumab should be monitored for

the development of hypertension and worsening of preexisting hypertension.
Another factor to consider is pregnancy planning, as safety during pregnancy
is not known. Because monoclonal antibodies have a 1-month half-life on
CASE 4-1 A 39-year-old woman presented to her neurologist with a 25-year history of
typical migraine without aura occurring in about nine discrete attacks per
month. She was on topiramate 50 mg 2 times a day (prior preventive agents
were metoprolol and natural products) and rizatriptan 10 mg (previous
nonresponse to sumatriptan and eletriptan). On topiramate, her monthly
headache day frequency had fallen from 14 to 9. With a single daily dose of
topiramate 100 mg, she had some cognitive side effects that improved but
did not resolve after the regimen was changed to 50 mg 2 times a day. She
delayed taking her rizatriptan because of “triptan” adverse events
(diaphoresis and flushing). Rizatriptan relieved her headaches in about
2 hours, but she rarely achieved pain freedom and often needed to take a
second dose of medication when the headache returned. Redosing with
rizatriptan was effective, but she ran out of medication most months.
Calcitonin gene-related peptide (CGRP)-targeted therapies were discussed
as an additional preventive agent, and she preferred an oral preventive
medication to an injectable every 4 weeks. She was started on atogepant
60 mg daily, and she experienced a rapid decline from 9 to 2 monthly
headache days. For breakthrough headaches, she continued to use
rizatriptan and tried to take it early in the attack when the pain was mild. She
experienced pain freedom at 2 hours for most attacks, rarely had
headaches return, and no longer ran out of rizatriptan. After a few months,
she was able to taper topiramate down to 50 mg daily but no further. Her
cognitive side effects cleared on the reduced dose.
COMMENT This patient had an insufficient response to two standard oral preventive
medications and several natural products. Atogepant was chosen as an
additional agent because she preferred a daily oral CGRP-targeted treatment.
372 A P R I L 2 0 24

average, 95% washout is achieved after 5 months, requiring a long washout KEY POINTS
period if a patient decides to become pregnant. Atogepant and rimegepant have
● The choice between
11-hour half-lives and are 95% eliminated in 55 hours, greatly reducing the CGRP-targeted migraine
washout period. Similarly, if a monoclonal antibody produces an adverse event, treatment with monoclonal
washout will be prolonged. Having decided to give a CGRP-targeted preventive antibodies or oral
medication, choosing between a monoclonal antibody and a gepant medication is medication is often
determined by patient
often determined by patient preference. Some patients prefer frequent oral
preference. Some patients

dosing while others prefer an injection every 4 or 12 weeks. prefer frequent oral dosing,
Although the European Headache Federation guideline neither endorses nor while others prefer an
rejects combining nonspecific with anti-CGRP preventive agents, leaving the injection every 4 or
12 weeks.
decision to be individualized,3 experience and small studies suggest there may be
benefits to this approach. A retrospective, real-world observational study of 166 ● Combining migraine-
adults found that patients who were taking tricyclic antidepressants, antiseizure nonspecific oral preventive
medications, beta-blockers, or calcium-channel blockers had fewer monthly agents with CGRP-targeted
preventive medications is
headache days and used less acute medication when they were given erenumab as
common in clinical practice.
add-on therapy.33 In a real-world observational study (N = 69), 11 patients taking a CGRP-targeted therapies
nonspecific oral preventive medication (eg, topiramate, metoprolol, flunarizine, may be added as a second
pizotifen [flunarizine and pizotifen are not available in the United States]) who agent, and if the patient
were given erenumab as add-on therapy had monthly migraine-day reductions of responds well, the first oral
preventive medication can
5 to 7 days.34 In practice, many patients who benefit from CGRP-targeted drugs subsequently be tapered.
have a partial response to nonspecific oral medications. After adding a CGRP-
targeted treatment to an existing oral regimen, there may be an opportunity to ● The available evidence
taper the nonspecific oral preventive over several months, as illustrated in suggests that gepants can
be given to patients with
CASE 4-1. Combining nonspecific oral preventive agents with CGRP-targeted
migraine who are also
preventive medications is common in clinical practice. CGRP-targeted therapies receiving CGRP-targeted
may be added to partially effective nonspecific oral medications. monoclonal antibodies with
few safety and tolerability
Duration of CGRP-Targeted Treatments problems.
No studies have been done to determine when to stop treatment in patients ● A second emerging
who have a good long-term response to preventive treatment with a CGRP- migraine treatment
targeted medication. It is also unknown if extended treatment with a CGRP- paradigm is known as
targeted drug has disease-modifying effects, which raises the question of situational prevention,
where patients treat in
whether they should be stopped, especially given their favorable safety profiles.3 periods of high headache
The question becomes more complicated in patients who do not improve after a risk on a short-term basis
therapeutic trial of reasonable duration. Despite evidence of treatment effects while completely
within the first week after starting treatment, and sometimes on the next day,35-37 asymptomatic.
studies with erenumab and galcanezumab have shown that patients who do
not have a meaningful response within 1 month of starting treatment may
substantially improve after 3 or more months of treatment.38,39 To ensure an
adequate trial, CGRP-targeted preventive medications should be given for at
least 6 months. When treatment is successful, a pause may be possible after 12 to
18 months of continuous therapy.3 Randomized withdrawal studies would
facilitate the formulation of evidence-based guidance for discontinuing
these medications.
For CGRP monoclonal antibodies, switching between antibody classes (ligand
versus receptor) can be beneficial in some patients. A retrospective cohort study
of outpatients treated consecutively with two CGRP monoclonal antibodies
evaluated response to a CGRP monoclonal antibody in patients who switched
between a drug targeting the CGRP receptor (erenumab) and a drug targeting
the ligand and vice versa.40 By month 3 after the switch, patients had fewer

monthly headache days, used less medication for acute treatment, and had lower
disability scores. The direction of the switch (ligand to receptor versus receptor
to ligand) had no effect on outcomes.40 A retrospective headache diary review of
patients with migraine (n = 78) who were switched from erenumab to
galcanezumab or fremanezumab because of a poor response to erenumab
(ineffective or intolerable) found a significant reduction in monthly headache

days at month 3 (20.8 versus 17.8; P = .009).41 A follow-up study of patients
switching from galcanezumab or fremanezumab to erenumab found similar

monthly headache-day reductions at month 3 (18.6 versus 14.5; P < .001).42 In
deciding to switch between CGRP monoclonal antibodies, the site of action
(ligand or receptor), dosing frequency (monthly versus quarterly), and
formulation (subcutaneous versus IV) can be factors.3 Patients who do not
respond to a CGRP monoclonal antibody may also benefit from a switch to one of
the gepant drugs (rimegepant or atogepant).
Combining CGRP-Targeted Therapies

Several small studies with rimegepant and ubrogepant support the concomitant
use of CGRP monoclonal antibodies and gepants. A case series of two patients
CASE 4-2 A 60-year-old woman who experienced migraine with aura for 40 years
presented to her neurologist with new occasional attacks, usually
triggered by stress and travel. She treated acutely with rimegepant 75 mg
after an inadequate response to several nonsteroidal anti-inflammatory
drugs and triptans. She was anxious about possibly having an attack
during her daughter’s wedding and wanted a strategy to prevent
headaches during the wedding weekend. Rimegepant 75 mg was started
2 days before the wedding and continued through the end of the wedding
weekend (ie, 4 consecutive days). She successfully attended all the
festivities without migraine attacks that weekend. She subsequently used
rimegepant in the situational prevention of migraine in times of stress and
travel on several occasions.
COMMENT Situational prevention is a treatment strategy entailing short-term

preventive treatment in a period of increased risk for headache.48 In this
case, the patient’s short-term need for preventive treatment was
precipitated by the anticipation of travel and a stressful life event. A 4-day
course of rimegepant 75 mg per day was successful in preventing migraine
and associated disability during a period of increased risk. This approach has
many names, including mini-prophylaxis and short-term prevention.
Situational prevention is an approach that is now being used by headache
neurologists with some success. Gepants are appealing drugs for this
approach because the mechanism is effective for both acute and
preventive treatment given their favorable tolerability profiles and because
they have not been associated with medication-overuse headache. Support
for this approach is entirely anecdotal at the time of this writing.45
374 A P R I L 2 0 24

being treated with rimegepant and erenumab was the first to describe patients
taking a gepant for acute treatment and a CGRP monoclonal antibody for
preventive treatment.43 This was followed by data from an open-label, long-term
safety study of rimegepant,44 during which 13 patients were simultaneously
being treated with erenumab (n = 7), fremanezumab (n = 4), or galcanezumab
(n = 2). Of the five (38%) patients who reported at least one adverse event, two
(15%) had mild or moderate nasopharyngitis; no other adverse events occurred
in two or more patients. None of the patients who received rimegepant while
taking a CGRP monoclonal antibody had a serious adverse event or dropped out
of the study due to adverse events, and there were no hepatic complications (ie,
aminotransferases greater than 3 times the upper limit of normal).44 In the
prospective, multiple-attack, observational study COURAGE, which used a
headache diary and tracking application, 245 patients used ubrogepant (50 mg or
100 mg) for acute treatment and used the application for 30 days while also
taking a CGRP monoclonal antibody for preventive treatment (mostly erenumab

[44.5%] and galcanezumab [35.1%]). Over 30 days and up to ten ubrogepant-
treated attacks, 51.3% of patients experienced 2-hour pain relief, 34.7% had
2-hour restoration of function,45 and 73% of patients who took the ubrogepant-
CGRP monoclonal antibody combination were satisfied with treatment.46
The available evidence suggests that gepants can be given to patients also
receiving CGRP-targeted monoclonal antibodies with few safety and tolerability
problems.
Novel Treatment Paradigms in the Era of CGRP-Targeted Therapies

The line between acute and preventive treatments for migraine has been
increasingly blurred by CGRP-targeted treatments which have strong effects in
both roles. Longitudinal epidemiologic studies have shown that within
individuals, migraine frequency can vary over time in a pattern referred to as the
migraine roller coaster.47 Patients using rimegepant as an acute treatment
sometimes transition to using rimegepant as a preventive treatment as headache
frequency rises. Conversely, as headache frequency declines, they may transition
back to acute treatment. This approach, facilitated by the approval of rimegepant
as both an acute treatment and a preventive treatment, is used in practice but not
supported by rigorous studies. Other available gepants have been studied
exclusively as acute or preventive treatments.
A second emerging paradigm is known as situational prevention, where
patients treat during short-term periods of increased risk for migraine while
completely asymptomatic (CASE 4-2).48 Situational prevention has been
applied to the short-term prevention of menstrual migraine, Saturday
morning headaches, and headaches associated with stress or travel. Although
the short-term prevention of menstrual migraine has been explored for longer
half-life triptans and nonsteroidal anti-inflammatory drugs, there are no
studies using gepants.49 The author has had success using longer–half-life
gepants for menstrual migraine, Saturday morning headaches, and headaches
associated with stress or travel.
A third novel paradigm involves treating patients during the prodrome, before
headache begins, to prevent the onset of headache. This approach has been
shown to be effective in a large randomized trial, the Prodrome Study.50 If the
prodrome is considered the first part of the migraine attack, this could be
considered a form of acute treatment.50

CONCLUSION
There are many choices for migraine prevention, including several evidence-
based traditional oral medications. Over the past several years, two new classes
of migraine medications targeting CGRP have been introduced. The injectable
monoclonal antibodies eptinezumab, erenumab, fremanezumab, and
galcanezumab and the oral small-molecule CGRP receptor antagonist atogepant

have established preventive efficacy in episodic and chronic migraine, while
rimegepant has established preventive efficacy only for episodic migraine. The
CGRP-targeted therapies are generally safe and no liver safety issues or
association with medication-overuse headache has been reported. Their
distinctive characteristics permit flexibility in dosing that has enabled clinicians
to develop treatment approaches designed to meet changing patient needs. These
emerging approaches require additional study.
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a phase 2/3, randomised, double-blind, placebo- episodic and chronic migraine. J Headache Pain
controlled trial. Lancet Lond Engl 2021;397(10268): 2018;19(1):92. doi:10.1186/s10194-018-0923-6
51-60. doi:10.1016/S0140-6736(20)32544-7
36 Detke HC, Millen BA, Zhang Q, et al. Rapid onset
25 Reuter U, Ehrlich M, Gendolla A, et al. Erenumab of effect of galcanezumab for the prevention of
versus topiramate for the prevention of migraine episodic migraine: analysis of the EVOLVE
- a randomised, double-blind, active-controlled studies. Headache 2020;60(2):348-359. doi:
phase 4 trial. Cephalalgia Int J Headache 2022; 10.1111/head.13691
42(2):108-118. doi:10.1177/03331024211053571

37 Winner PK, Spierings ELH, Yeung PP, et al. Early 45 Adams AM, Lama JCD, Serrano D, et al. Real-
onset of efficacy with fremanezumab for the world effectiveness of ubrogepant for the acute
preventive treatment of chronic migraine. treatment of migraine when used in combination
Headache 2019;59(10):1743-1752. doi:10.1111/ with an anti-calcitonin gene–related peptide
head.13654 monoclonal antibody preventive: results from
the courage study (p10-2.003). Neurology 2022;
38 Goadsby PJ, Dodick DW, Martinez JM, et al.
98(18 Supplement). Accessed October 3, 2023.
Onset of efficacy and duration of response of

https://n.neurology.org/content/98/18_
galcanezumab for the prevention of episodic
Supplement/3177
migraine: a post-hoc analysis. J Neurol Neurosurg
Psychiatry 2019;90(8):939-944. doi:10.1136/jnnp- 46 Lama JCD, Adams AM, Serrano D, et al.

2018-320242 Treatment satisfaction and optimization with
real-world use of ubrogepant for the acute
39 McAllister PJ, Turner I, Reuter U, et al. Timing and
treatment of migraine in combination with an
durability of response to erenumab in patients
anti-calcitonin gene–related peptide
with episodic migraine. Headache 2021;61(10):
monoclonal antibody preventive: results from
1553-1561. doi:10.1111/head.14233
the COURAGE study (p10-2.001). Neurology 2022;
40 Iannone LF, Burgalassi A, Vigani G, et al. Switching 98(18 Supplement). Accessed October 3, 2023.
anti-CGRP(R) monoclonal antibodies in https://n.neurology.org/content/98/18_
multi-assessed non-responder patients and Supplement/3129
implications for ineffectiveness criteria: a

47 Serrano D, Lipton RB, Scher AI, et al. Fluctuations
retrospective cohort study. Cephalalgia Int J
in episodic and chronic migraine status over the
Headache 2023;43(4):3331024231160519. doi:10.
course of 1 year: implications for diagnosis,
1177/03331024231160519
treatment and clinical trial design. J Headache
41 Overeem LH, Peikert A, Hofacker MD, et al. Pain 2017;18(1):101. doi:10.1186/s10194-017-0787-1
Effect of antibody switch in non-responders to a
48 Graf M, Kim E, Brewer I, et al. Expert consensus
CGRP receptor antibody treatment in migraine: a
established around flexible, individualized
multi-center retrospective cohort study.
migraine treatment utilizing a modified Delphi
Cephalalgia Int J Headache 2022;42(4-5):291-301.
panel. Headache 2023;63(4):506-516. doi:10.1111/
doi:10.1177/03331024211048765
head.14479
42 Overeem LH, Lange KS, Fitzek MP, et al. Effect of
49 Zhang H, Qi JZ, Zhang ZH, et al. Comparative
switching to erenumab in non-responders to a
efficacy of different treatments for menstrual
CGRP ligand antibody treatment in migraine: a
migraine: a systematic review and network
real-world cohort study. Front Neurol 2023;14:
meta-analysis. J Headache Pain 2023;24(1):81.
1154420. doi:10.3389/fneur.2023.1154420
doi:10.1186/s10194-023-01625-x
43 Mullin K, Kudrow D, Croop R, et al. Potential for
50 Dodick DW, Goadsby PJ, Schwedt TJ, et al.
treatment benefit of small molecule CGRP
Ubrogepant for the acute treatment of migraine
receptor antagonist plus monoclonal antibody in
when administered during the prodrome
migraine therapy. Neurology 2020;94(20):
(premonitory phase): results from a phase 3,
e2121-e2125. doi:10.1212/
randomized, double-blind, placebo-controlled,
WNL.0000000000008944
crossover study (s47.001). Neurology 2023;
44 Berman G, Croop R, Kudrow D, et al. Safety of 100(17 Supplement 2). doi:10.1212/WNL.
rimegepant, an oral CGRP receptor antagonist, 0000000000202043
plus CGRP monoclonal antibodies for migraine.
Headache 2020;60(8):1734-1742. doi:10.1111/
head.13930
DISCLOSURE
monitoring board for Biohaven, Ltd., Lilly, and
Lundbeck; and in the range of $50,000 to $99,999
for serving as a consultant for Lilly. Dr Lipton has
received publishing royalties from a publication
relating to health care. Dr Lipton has stock in
Biohaven, Ltd. and Manistee Partners, LLC. The
institution of Dr Lipton has received research
support from AbbVie Inc., Amgen Inc., Axsome
Therapeutics, Inc., Charleston Laboratories, Inc.,
electroCore, Inc., Lilly, the National Institute of
Neurological Disorders and Stroke, the National
Institute on Aging, the National Institutes of Health
(NIH), Satsuma Pharmaceuticals, Inc., Teva
Pharmaceutical Industries Ltd., and the US
Department of Veterans Affairs.
378 A P R I L 2 0 24

Medication-Overuse REVIEW ARTICLE

Headache C O N T I N U UM A U D I O
ONLINE
By Paul Rizzoli, MD, FAAN, FAHS
ABSTRACT
OBJECTIVE: Medication-overuse headache (MOH) has been described for
almost 100 years and is characterized as a daily or near-daily headache that CITE AS:
usually presents in patients with preexisting primary headache disorders CONTINUUM (MINNEAP MINN)
2024;30(2, HEADACHE):379–390.
who are overusing one or more acute or symptomatic headache
medications. This article reviews the diagnosis and management of Address correspondence to
patients with MOH. Dr Paul Rizzoli, Department of
Neurology, Suite 4H, 1153
Centre St, Boston, MA 02130,
LATEST DEVELOPMENTS: The International Classification of Headache Disorders prizzoli@bwh.harvard.edu.
criteria for MOH have changed over time. The worldwide prevalence
appears to be between 1% and 2%. Together, headache disorders, including Dr Rizzoli has received personal
MOH, are currently ranked as the second leading cause of years lived with compensation in the range of $0
disability in the Global Burden of Disease world health survey. Significant to $499 for serving as a
consultant for CVS; in the range
neurophysiologic changes are seen in the brains of patients with MOH, of $500 to $4999 for serving on a
including functional alterations in central pain processing and modulating scientific advisory or data safety
monitoring board for Theranica
systems and central sensitization. Research supports updates to the
Bio-Electronics Ltd. and as an
principles of management, including weaning off the overused medication, editor, associate editor, or
preventive therapy, biobehavioral therapy, and patient education. editorial advisory board
member for Harvard Health
Publishing; and in the range of
ESSENTIAL POINTS: MOH is a fairly common and treatable secondary headache $10,000 to $49,999 for serving as
disorder that produces significant disability and a substantial reduction in an officer or member of the
board of directors for
quality of life. The costs related to lost income and disability are Headache Cooperative of the
substantial. MOH is intimately related to chronic migraine, which continues Northeast. Dr Rizzoli has
to be underrecognized and undertreated. Treatment focuses on both the received publishing royalties
from a publication relating to
institution of effective preventive migraine therapy and the reduction or health care. The institution of
removal of the overused medications. Educational efforts directed toward Dr Rizzoli has received research
support from AbbVie, Inc.
both providers and patients have been shown to be effective in reducing
the effect of MOH. UNLABELED USE OF
USE DISCLOSURE:
Dr Rizzoli discusses the use of
monoclonal antibodies to
INTRODUCTION calcitonin gene-related
Medication-overuse headache (MOH) is viewed as a secondary headache peptide (CGRP) or CGRP
receptors,
disorder. It is described in Section 8.2 of the International Classification of
onabotulinumtoxinA, and
Headache Disorders, Third Edition (ICHD-3) as “[h]eadache occurring on 15 or topiramate for the treatment
more days/month in a patient with a pre-existing primary headache and of medication-overuse
headache, none of which are
developing as a consequence of regular overuse of acute or symptomatic approved by the US Food and
headache medication (on 10 or more or 15 or more days/month, depending on the Drug Administration (FDA).
medication) for more than three months” (TABLE 5-1).1 MOH usually resolves
once the overused medication is withdrawn. It is felt to be a common cause of the © 2024 American Academy
development of chronic migraine. of Neurology.

MEDICATION-OVERUSE HEADACHE
Chronic headache related to the overuse of combination analgesics was

initially described in the German literature in the early 1900s resulting from the
widespread use by Swiss factory watchmakers of combination analgesic
medications containing phenacetin. As many as 30% of these workers developed
chronic headache as a result.2 US headache specialists did not seem aware of this
at the time, possibly because the reports were not published in English.
In the United States in the 1930s, the use of ergot-containing abortive
medications to treat migraine was recognized as a trigger for chronic headache.

Headache specialists at the time were familiar with diagnosing and treating this
complication. Multiple authors, including Lennox, O’Sullivan, Graham,
Friedman, and, later, Peters and Horton discussed the complications of
ergotamine use in the treatment of migraine.2 Slowly, other analgesics, initially
used in combination with ergotamine, became recognized as separate possible
causes of MOH.3 In the 1980s, further detailed descriptions emerged from
Rapoport,4 Saper,5 and others of what was at the time termed analgesic rebound
headache.6,7 Guidelines for management followed, and in the ensuing 20 years,

there has been a sharp increase in the number of publications on the topic.
In the initial classification in 1988, daily use of the acute abortive medication
was required for the diagnosis and MOH, then called headache induced by chronic
substance use or exposure, was differentiated from withdrawal headache (Section
8.4 of the ICHD). At that time, both ergotamine-containing medications and
opioids were recognized to produce either withdrawal headache or MOH.
Additional descriptive features were added in 2004 and there was an attempt to
characterize the nature of the headache in MOH. In 2005, the headache
characteristics of MOH were removed and a subform was added to account for
MOH from the overuse of individual abortive medications taken in combination.
2005 appendix criteria removed the diagnostic requirement for headache to
improve postdiscontinuation, which had limited providers to making a
retrospective diagnosis only. Ergotamine-containing medications were removed
from the list of medications causing withdrawal, leaving caffeine and opioids,
and estrogen was added. Changes in 2018 emphasized the need for a preexisting
primary headache disorder in those with MOH.
DEFINITION AND TERMINOLOGY

MOH and chronic migraine are interrelated concepts and any discussion of MOH
is complicated by the varying criteria for both conditions that have been used
TABLE 5-1 ICHD-3 Diagnostic Criteria for Medication-overuse Headachea
A Headache occurring on ≥15 or more days/month in a patient with a pre-existing headache

disorder
B Regular overuse for >3 months of one or more drugs that can be taken for acute and/or
symptomatic treatment of headache
C Not better accounted for by another ICHD-3 diagnosis
ICHD-3 = International Classification of Headache Disorders, Third Edition.

a
Reprinted with permission from the Headache Classification Committee of the International Headache
Society, Cephalalgia.1 © 2018 SAGE Publications.
380 A P R I L 2 0 24

over the years.8 In the initial ICHD classification, the only possible category KEY POINTS
available for the description of a daily headache pattern was chronic tension-type
● Medication-overuse
headache, and this failed to capture the majority of patients with daily headache headache (MOH) involves
seen in the clinic. Later, the 1994 Silberstein-Lipton criteria detailed four types of the overuse of acute
daily headache, each with or without medication overuse: transformed migraine, abortive headache
chronic tension-type headache, hemicrania continua, and new daily persistent medications in patients with
a primary headache disorder
headache.9,10 The term transformed migraine was ultimately rejected and in 2004
presenting with daily or

the ICHD introduced the term chronic migraine as a complication of migraine; near-daily headache.
however, the restrictive criterion requiring 15 days of migraine symptomatology
per month continued to prevent the appropriate categorization of most patients ● MOH has been
with daily headache.11 Subsequent changes have improved the utility of the considered an important
driving risk factor for the
ICHD in the diagnosis of chronic migraine. development of chronic
Meanwhile, as previously mentioned, the classification of MOH, which migraine.
contains within it the concept of daily headache, changed as well (TABLE 5-1). Per
● MOH was previously
the ICHD, MOH (Section 8.2) has always been distinguished from withdrawal
known as analgesic rebound
headache (Section 8.3), presumably based on the timing of headache onset. headache, withdrawal
Withdrawal headache occurs within hours of stopping the causative medication headache, or drug-induced
and clears with a repeat dose, and MOH is a longer-lasting headache that occurs headache.
because of the continuation of the overused agent. Ergotamine was initially listed
● The concepts of MOH and
as a cause of each; it has since been dropped from the withdrawal section but has
chronic migraine are
remained as a cause of MOH. intimately interrelated.
Besides analgesic rebound headache, other previously used terms included
withdrawal headache or drug-induced headache. The current term, medication- ● The International
overuse headache, as used in the ICHD-3, is intended to be descriptive without Classification of Headache
Disorders criteria for the
implying a specific mechanism of action.1 Criteria are based on the frequency of diagnosis of MOH have
abortive medication use, not dosage. changed over the years as
Medications implicated in the development of MOH include ergotamine, our understanding of the
triptans, simple and combination analgesics including nonsteroidal anti- condition has improved.
inflammatory drugs and butalbital, and opioids (TABLE 5-2). It is the frequency of
● It is the frequency of the
use of the abortive medication that creates the risk. The use of combination use of the overused
analgesic medication for more than 15 days a month for more than 3 months is medication, rather than the
thought to put the patient at risk for MOH. For all other medication categories, dose, that is critical to the
development of MOH.
patients are clinically restricted to a use of less than 10 days per month to avoid
the risk of MOH. In addition, the use of any combination of these medications ● The International
(ie, multiple drug classes not individually overused) totaling 10 or more days per Classification of Headache
month could cause MOH. Disorders noted that the
The ICHD identifies the frequent and regular use of these medications as a most common cause of
migrainelike headache
crucial factor in the development of MOH. In addition, the use of these occurring on 15 or more days
medications in the treatment of other pain conditions in a susceptible individual per month is medication
may also induce MOH. The phenomenology of the resulting headache may be overuse.
variable and shift from a migraine to a tension-type pattern over time. Two
months after cessation of the overused medication, the headache of MOH is
expected to resolve, although perhaps with a resumption of the prior underlying
primary headache pattern. The importance of MOH, according to the Internation
Classification of Headache Disorders, Second Edition, is that it is “by far the
most common cause of migraine-like headache occurring on ≥ 15 days per
month”.11
Regarding the underlying primary headache type, tension-type headache is
less likely associated with medication overuse than migraine, but MOH can occur
in either condition.

EPIDEMIOLOGY AND RISK FACTORS

In 2016, almost 3 billion people worldwide had a headache disorder, either
migraine or tension-type headache, and headaches were the second leading cause
of disability years.12 Estimates are that 1.4% to 3% of patients with migraine have
chronic migraine, and approximately one-half of chronic migraine cases are
thought to be caused by MOH.13,14 One Swedish prevalence study showed that

56% of those with chronic daily headache demonstrated medication overuse,
giving a prevalence of 1.8% for MOH itself.15

However, prevalence estimates are complicated by several methodologic
issues including study design, changing diagnostic criteria, sample size estimates,
and positive predictive value.12 We do not know how many individuals who meet
the criteria for MOH (headache + medication overuse) have the true condition
(headache caused by medication overuse).16 A prevalence estimate of 57.8% for
MOH was used in the 2015 Global Burden of Disease analysis of neurologic
disorders,17 which could well be an overestimate, leading to an unrealistically
high prevalence.
Since 2016, the Global Burden of Disease study group has viewed MOH
as a complication of migraine or tension-type headache and thus combined
reported data on these conditions, resulting in an upward recalculation of years
lived with disability from headache disorders from seventh place in earlier
surveys to second place as of 2016.17 Additionally, for women aged 15 to 50 years,
headache is now the leading cause of years lived with disability based on
combined data.18
Besides the presence of a preexisting primary headache disorder, general risk
factors predisposing to medication overuse and MOH include female sex, low
socioeconomic status, smoking, and comorbid psychiatric disorders. The most
encountered psychiatric comorbidities are depression, anxiety, and, in at least
one study, obsessive-compulsive disorder.18
TABLE 5-2 ICHD-3 Medication-overuse Headache Subformsa
Ergotamine-overuse headache
Triptan-overuse headache
Nonopioid analgesic–overuse headache
◆ Paracetamol (acetaminophen)-overuse headache
◆ Nonsteroidal anti-inflammatory drug–overuse headache
◇ Acetylsalicylic acid–overuse headache
◆ Other nonopioid analgesic–overuse headache
Opioid-overuse headache
Combination analgesic–overuse headache
Medication-overuse headache attributed to multiple drug classes not individually overused
Medication-overuse headache attributed to unspecified or unverified overuse of multiple
drug classes
Medication-overuse headache attributed to other medication
a
382 A P R I L 2 0 24

A 2022 study provides perhaps more insight by suggesting that patients with KEY POINTS
MOH, compared with patients with episodic migraine and healthy controls,
● Headache disorders
exhibited higher levels of alexithymia, a reduced capacity for introspection including MOH are currently
leading to an inability to recognize and express feelings and emotions.19 This is ranked as the second
described as causing confusion in distinguishing between emotions and bodily leading cause of years lived
sensations and, in the setting of headache, could contribute to poor coping skills with disability.
and facilitate medication overuse. Early recognition of such difficulties by the
● Prevalence estimates
provider could aid management, for example by leading to the alteration of indicate that, at any one
treatment recommendations (eg, earlier use of calcitonin gene-related peptide time, 1.8% of all headache
[CGRP] medications that are not as associated with MOH), enhanced patient patients may have MOH.
education of the risks of MOH, stricter monitoring of medication use and earlier
● It remains unclear in
follow-up, and heightened provider awareness. patients with MOH whether
The most frequently overused individual medications implicated in the the increased abortive
development of MOH appear to be triptans, opioids, and barbiturates. However, medication use drives the
worsening headache or
a 2022 study of a patient population not exposed to barbiturates suggested that,

whether worsening
overall, the most common profile was a patient overusing multiple individual headache drives the
abortive medications, such as triptans along with nonopioid analgesics.20 This medication overuse.
finding supports the ICHD’s 2005 addition of the category 8.2.6 Medication-
overuse headache attributed to multiple drug classes not individually overused as a
subform of MOH.
CLINICAL FEATURES, EVALUATION, AND DIAGNOSIS

As illustrated in CASE 5-1, MOH is a daily or near-daily headache that typically
develops in a patient with a preexisting primary headache disorder. The process
is usually gradual, and although it is often recognized as a change from the prior
pattern of headache, there is no characteristic or pathognomonic pattern to the
headache.6 There may be a predilection to headache onset with waking and
headache is often associated with neck pain, but otherwise headache quality,
intensity, and location vary. It may also be that the headache characteristics vary
in relation to the type and dosing frequency of the overused medication.21
Irritability, anxiety, and concentration difficulty are often reported in association
with headache. The headache is often described as easily triggered by any mental
or physical exertion. Other reported symptoms may reflect the adverse effects of
the overused medication. Transient improvement in the headache may be
described after a dose of the overused abortive medication, but otherwise, the
headache is relatively refractory.
Patients with MOH may exhibit certain psychological characteristics in
addition to alexithymia. Anticipatory anxiety and fear of headache may play a
role in the overuse behavior. Obsessional and drug-dependence behaviors may
be present. Patients with MOH may more frequently exhibit features of a
personality disorder that may manifest in early requests for medication, defiance
of medication limits, and exaggerated pain behaviors.22 Actual addiction and
medication dependence, while present in some patients with MOH, do not
appear to be frequent.
PATHOPHYSIOLOGY
The pathophysiology of MOH is unexplained, in part complicated by the fact that
it remains unclear whether the increased abortive medication use drives the
increased headache or whether increased headache drives the medication
overuse. It is hypothesized that chronic medication exposure in the brain can

result in neuronal hyperexcitability in both the cerebral cortex and the trigeminal
system, ultimately leading to increased peripheral and central sensitization.23
Preclinical studies of chronic central nervous system exposure to opioids and
triptans show that these medications can facilitate the nociceptive process in the
trigeminal system and increase the frequency of cortical spreading depression,
which is thought to be a marker of migraine activity, in the cortex.23 Chronic

administration of acetaminophen can change the expression of 5-HT receptors in
the cortex.23 Clinical electrophysiologic studies24 also support disruption in the

central pain-modulating system as the basis for the daily headache of MOH. Most
of the functional, structural, and metabolic changes seen in studies localize to the
pain network of the brain. MRI studies have shown a volume reduction in the
orbitofrontal cortex and the left middle occipital gyrus in patients with MOH
compared with controls.25 Another study found reduced cortical thickness in the
left orbitofrontal cortex and, alternatively, greater volume was observed in the
periaqueductal gray, thalamus, and ventral striatum.26 Again, these data suggest
dysfunction of pain processing and modulating systems.27

Functional MRI studies show reduced activity in the pain matrix and a
reduced functional continuity of the orbitofrontal cortex and cerebellum.28 Apart
from changes in the orbitofrontal cortex, substantia nigra, and ventral
tegmentum, many of the physiologic changes in MOH are thought to be
reversible, clearing with discontinuation of the overused medication.29 Areas that
return to normal include the ventromedial prefrontal cortex, thalamus, insula,
cingulate cortex, and parietal cortex. Neuronal hyperexcitability with increased
responses to external stimuli and deficits in habituation also appears to reverse
CASE 5-1 A 59-year-old woman with prior diagnoses of episodic migraine, anxiety,
depression, and cervical spine degenerative disease reported a daily
bifrontal throbbing headache for the past 6 months. For management,
she used ibuprofen 600 mg to 800 mg daily as needed or acetaminophen
1000 mg daily as needed, with an average use of each medication on
4 days per week. She also used oral sumatriptan 50 mg 9 days per month.
She did not overuse caffeine and reported no dietary restrictions;
however, she did report fragmented and nonrestorative sleep.
Examination showed a body mass index of 27 and bitemporal and
bilateral occipital tenderness. She was diagnosed with episodic migraine,
medication-overuse headache, and possible cervicogenic headache.
She was advised to stop the overused medications, increase the dose of
sumatriptan to 100 mg, and begin preventive management with
topiramate. At her 2-month follow-up, she reported a reduction to 5
headache days per month along with reduced headache severity,
increased exercise activity, and some weight loss.
COMMENT This case shows that medication-overuse headache can result from the
overuse of medications in combination and thus may not be immediately
recognizable, but, when recognized, it may be fairly easily managed
through patient education and adjustment of medications.
384 A P R I L 2 0 24

after medication withdrawal. Genetic predispositions have also been shown in KEY POINTS
MOH; a systematic literature search found 17 candidate gene variations
● Functional, structural,
associated with MOH, most of which were associated with proteins expressed in and metabolic changes seen
the dopaminergic system.30 in imaging studies localize
Studies have also shown important associations between MOH and MOH to the pain network of
dependency in some patients.31 As noted above, patients with MOH may display the brain.
many of the psychological and physical characteristics of dependency, especially
● With the goal of improved
those overusing opioids and barbiturates. headache control, the focus

of treatment in MOH is on
MANAGEMENT both the removal of the
The goal of clinical management is improved overall headache control. To overused abortive
medication and the
achieve this, efforts focus on both the removal of the overused abortive institution of a more
medication and the institution of a more effective preventive and abortive effective preventive and
regime. However, there is a dispute over exactly how and in what order to abortive regime.
proceed. Should the overused medication be removed suddenly or tapered

● The first step in the
slowly? Should prevention be started immediately or only after withdrawal of the management of MOH is to
overused medication? What are the appropriate educational approaches to best explain to the patient the
inform patients and caregivers about the issue of MOH? And lastly, what is the nature of the condition and
best way to prevent relapse? the need to reduce or stop
the overused medication.
The first step may simply be explaining to the patient with MOH the nature of
the condition and the need to reduce or stop the overused medication. ● Studies have not shown a
Educational efforts have been shown to be helpful when provided in a general significant difference in
medical setting, in a neurology office, or through a specialty headache medicine benefit between abrupt and
setting. Simply explaining the condition to the patient may result in a slow discontinuation of the
overused medication in
self-modification of behavior on the part of the patient; if this does not occur, a MOH.
more structured recommendation to pause or stop the medication may be
necessary. Some centers recommend abrupt discontinuation as long as the dose ● Both chronic migraine and
and type of medication do not require a slow withdrawal for safety.32 Patients are MOH are underrecognized
and undertreated.
advised that, with abrupt discontinuation, they will likely experience withdrawal
symptoms, including nausea, dizziness, and disordered sleep, for up to 10 days.
However, treatment studies have not shown a significant difference in benefit
between abrupt and slow discontinuation, and many patients resist the
recommendation to go without treatment for a period of time before
improvement is anticipated.33 Further, countering this resistance and
encouraging the patient to go through the process is challenging for the provider
since calculations based on the data suggest that for every patient ultimately
helped by withdrawal alone, three will go through the process without benefit,
and that is assuming that it is the medication overuse that causes the headache.34
A major concern raised by one review is that all of the observational studies
purporting to demonstrate the cause of MOH are hopelessly confounded by
indication; it cannot be determined whether the increased symptomatic
medication use led to the headache or if a refractory headache pattern
precipitated the symptomatic medication overuse.34
But does the patient with MOH even need to stop the overused medication?
The Medication Overuse Treatment Strategy (MOTS) trial attempted to address
this question.33 The MOTS trial was a multicenter, pragmatic, open-label trial
evaluating two MOH management strategies: optimizing preventive treatment
with or without removal of the overused medication, with the endpoint of
measurement of moderate-to-severe headache days during weeks 9 to 12 of the
study. Not switching or limiting the overused medication was judged to be not

inferior to switching and limiting the symptomatic medication. As a result, many

centers, especially those in the United States, default to recommending a
reduction of the overused medication followed by or along with optimization
of prevention.
With either approach, management during withdrawal may require
supplemental or supportive therapy in some cases to help the patient through the
process. This bridge therapy can include hydration, corticosteroids, neuroleptic
agents, tranquilizers, or antiemetics.35,36 Short-term use of daily nonsteroidal

anti-inflammatory medications (eg, naproxen 550 mg twice a day for 2 to
4 weeks) with or without a muscle relaxant, corticosteroids (eg, a short
prednisone taper starting at 60 mg), IV dihydroergotamine, IV sodium
valproate, or IV prochlorperazine may be helpful.35,37,38 IV medications would
require a hospital or infusion center setting, and more dangerous withdrawals
such as from high-dose opioids may require hospitalization. Otherwise, most of
the time, treatment can usually be completed on an outpatient basis.

The selection of a preventive therapy in the setting of MOH can be based on
the typical management for the suspected underlying primary headache
disorder. However, there is evidence that several agents may be helpful in the
specific setting of MOH. These include topiramate, onabotulinumtoxinA, and
monoclonal antibodies against CGRP or the CGRP receptor. Studies of
topiramate in chronic migraine have suggested benefit in the subgroup with
MOH.39 A post-hoc analysis of onobotulinumtoxinA study data suggested that it
was better than placebo in those with MOH,40 although another study did not
show benefit over withdrawal alone.41 Lastly, MOH subgroup analyses have been
carried out for all of the anti-CGRP monoclonal antibodies and all have shown
benefit in patients with MOH.
Biobehavioral management is important as well, especially in patients with
comorbid psychiatric conditions like anxiety, depression, and obsessive-
compulsive disorder. Techniques such as relaxation training, mindfulness
training, biofeedback, cognitive behavioral therapy, acceptance and
commitment therapy, and motivational interviewing may show efficacy alone
but can also support medical management.42,43 Access to providers with
expertise in these therapies can be limited and treatment can take time to
implement. Also, depending on the health care system involved, there may be
financial barriers to accessing these treatments.
Rates of relapse after successful treatment of MOH can be as high as 50% and
most patients relapse within the first year.38 Multiple risk factors for relapse have
been identified, including the presence of a prior tension-type primary headache,
longer acute medication overuse prior to withdrawal, a higher number of
overused medications, and prior opioid use.36 Those with a concomitant
substance use disorder may present a higher risk of relapse.
Based on evidence and pragmatic considerations, a treatment algorithm
(FIGURE 5-1)44 has been constructed for patients with both medication overuse
and MOH that accommodates variations in management seen in clinics around
the world. However, for uncomplicated cases, management using prevention
along with medication withdrawal is considered the more pragmatic
approach.38,45 Patients with an additional diagnosis of a substance use disorder or
a comorbid psychiatric condition and those who are overusing larger amounts of
more dangerous medications may be considered complicated cases and may
require more intensive management according to the algorithm.46
386 A P R I L 2 0 24

FIGURE 5-1
Proposed medication-overuse headache treatment algorithm.
CGRP = calcitonin gene-related peptide; MO = medication overuse; MOH = medication-overuse headache.
a
Monoclonal antibodies to CGRP or the CGRP receptor are indicated for prevention of episodic and chronic
migraine.
b
OnabotulinumtoxinA should be used only for prevention in a patient with chronic migraine.
Reprinted with permission from Ashina S, et al, Nat Rev Dis Primer.44 © 2023, Springer Nature Limited.
Clinical trials assessing the efficacy of antibodies to CGRP or its receptor

showed a treatment benefit for patients with MOH.47 Subsequently, the oral
small-molecule CGRP antagonists (gepants) rimegepant and atogepant were also
shown to be efficacious in patients with chronic migraine and medication
overuse.48 Ubrogepant may confer a similar benefit, but the efficacy of
lasmiditan in patients with MOH is as yet unclear.49
As a whole, the newer migraine medications may eventually provide a
pathway out of medication overuse since, as they become more available, they
may provide abortive management options with a reduced risk MOH. Currently,
switching to one of these agents in a patient in the midst of medication overuse
may obviate the need for long periods of withdrawal or discontinuation and the
symptoms associated with the current treatment pathways.
CONCLUSION
MOH, a fairly common and treatable secondary headache disorder attributed to
the overuse of acute headache medications, is underrecognized and produces
significant disability and substantial reduction in quality of life. MOH is
intimately related to chronic migraine which itself continues to be
underrecognized and undertreated.50 The pathophysiology of MOH involves

functional alteration in central pain processing and modulating systems and

central sensitization along with psychological and biobehavioral factors.
Treatment focuses on both the institution of effective preventive migraine
therapy and the reduction or removal of the overused medications. Educational
efforts directed toward both providers and patients have been shown to be
effective in reducing the impact of MOH.

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390 A P R I L 2 0 24

Cluster Headache, REVIEW ARTICLE
SUNCT, and SUNA


ONLINE
By Mark Burish, MD, PhD
CITE AS:
ABSTRACT 2024;30(2, HEADACHE):391–410.
OBJECTIVE: This article reviews the epidemiology, clinical features,

differential diagnosis, pathophysiology, and management of three types of Dr Mark Burish, 6400 Fannin St,
trigeminal autonomic cephalalgias: cluster headache (the most common), Ste 2010, Houston, TX 77030,
short-lasting unilateral neuralgiform headache attacks with conjunctival mark.burish@gmail.com.
zpJGzRWDZDcId2d2jIGxGxxU= on 04/03/2024
injection and tearing (SUNCT), and short-lasting unilateral neuralgiform RELATIONSHIP DISCLOSURE:
headache attacks with cranial autonomic symptoms (SUNA). Dr Burish has received personal
compensation in the range of $0
to $499 for serving as a
LATEST DEVELOPMENTS: Thefirst-line treatments for trigeminal autonomic consultant for Doximity, Inc. The
cephalalgias have not changed in recent years: cluster headache is institution of Dr Burish has
received compensation in the
managed with oxygen, triptans, and verapamil, and SUNCT and SUNA are range of $500 to $4999 for his
managed with lamotrigine. However, new successful clinical trials of service as a consultant for
high-dose prednisone, high-dose galcanezumab, and occipital nerve Beckley Psytech and Praxis
Precision Medicines. The
stimulation provide additional options for patients with cluster headache. institution of Dr Burish has
Furthermore, new genetic and imaging tests in patients with cluster received research support from
Lundbeck.
headache hold promise for a better understanding of its pathophysiology.
UNLABELED USE OF
ESSENTIAL POINTS: The
trigeminal autonomic cephalalgias are a group of PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
diseases that appear similar to each other and other headache disorders Dr Burish discusses the use of
but have important differences. Proper diagnosis is crucial for proper baclofen, dihydroergotamine,
treatment. ergotamine, gabapentin,
lidocaine nasal spray, lithium,
melatonin, octreotide, oxygen
gas, prednisone, sodium
valproate, sumatriptan nasal
INTRODUCTION spray, topiramate, verapamil,
T
warfarin, zolmitriptan, and
he trigeminal autonomic cephalalgias are a group of four primary zucapsaicin nasal spray for the
headache disorders that share clinical features but differ in triggers, treatment of cluster headache
duration, frequency, and treatment (TABLE 6-11-6). These disorders are and carbamazepine, duloxetine,
gabapentin, IV lidocaine,
cluster headache, paroxysmal hemicrania, hemicrania continua, and lamotrigine, oxcarbazepine,
short-lasting unilateral neuralgiform headache attacks which come in pregabalin, topiramate, and
two subtypes: short-lasting unilateral neuralgiform headache attacks with verapamil for the treatment of
short-lasting unilateral
conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks
neuralgiform headache attacks with cranial autonomic symptoms (SUNA). with conjunctival injection and
tearing (SUNCT) and short-lasting
Correct diagnosis can be difficult as the diseases can overlap in their duration and
unilateral neuralgiform headache
frequency (FIGURE 6-1), but diagnostic accuracy is crucial because the two attacks with cranial autonomic
hemicrania disorders are exquisitely responsive to indomethacin while cluster symptoms (SUNA), none of
which are approved by the US
headache, SUNCT, and SUNA are not. This article discusses the non– Food and Drug Administration
indomethacin-responsive trigeminal autonomic cephalalgias (cluster headache, (FDA).
SUNCT, and SUNA). For more information on paroxysmal hemicrania and
hemicrania continua, refer to the article “Indomethacin-Response Headache © 2024 American Academy
Disorders” by Peter J. Goadsby, MD, PhD, FRS,7 in this issue of Continuum. of Neurology.

CLUSTER HEADACHE, SUNCT, AND SUNA
Cluster headache is the most common and most researched of the trigeminal
autonomic cephalalgias and will be the major focus of this article; SUNCT and
SUNA will be presented together as some authors consider them to be a single
disease.8 In the last 3 years, several cluster headache discoveries have occurred,
including successful clinical trials (prednisone and occipital nerve stimulation),
unsuccessful trials (continuous positive airway pressure),9 and promising

early-stage trials (psilocybin). Moreover, there have been recent discoveries in
TABLE 6-1 Comparison of the Trigeminal Autonomic Cephalalgiasa
Cluster Paroxysmal
headache2 hemicrania3 SUNCT/SUNA4 Hemicrania continua5
Ratio of female to male 1:3 Slightly more 1:1.5 2:1

female
Pain
Quality Sharp, stabbing, Sharp, stabbing, Sharp, stabbing, Baseline: aching; exacerbations:
throbbing throbbing throbbing sharp, stabbing, throbbing
Severity Very severe Very severe Moderate or Baseline: mild to moderate;

severe exacerbations: moderate to severe
Attacks
Frequency (per day) 1-8b 5-50 1 to hundreds Constant
Duration 15-180 minutes 2-30 minutes 1 second to Baseline: 3 months or more;

10 minutes exacerbations: 30 minutes to 3 days
Ratio of episodic to chronic 90:10 20:80 10:90 20:80c
Associated features
Restlessness 90% 80% 65% 70%
Circadian periodicity 71%6 Rare Rare Rare
Triggers
Alcohol Yes Occasional No Occasional
Nitroglycerin Yes Yes No Rare
Neck movements No Yes Yes No
Cutaneous No No Yes No
Treatment response
Oxygen 70% No effect No effect No effect
Sumatriptan 6 mg subcutaneous 90% 20% Rare effect No effect
Indomethacin Rare effect 100% No effect 100%
SUNA = short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT = short-lasting unilateral neuralgiform
headache attacks with conjunctival injection and tearing.
a
Modified with permission from Burish M, Continuum (Minneap Minn).1 © 2018 American Academy of Neurology.
b
Cluster headache frequency is officially one headache every other day up to eight per day.
c
For hemicrania continua, the ratio of episodic to chronic refers to the ratio of remitting to unremitting attacks.
392 A P R I L 2 0 24

FIGURE 6-1
The trigeminal autonomic cephalalgias and their overlapping features. All five disorders
share unilateral pain and ipsilateral autonomic features but overlap in duration and frequency.
For example, having six 20-minute attacks per day meets criteria for both paroxysmal
hemicrania and cluster headache; furthermore, hemicrania continua can have short-lasting or
long-lasting flares, while all of the other disorders can have continuous interictal pain. When
the diagnosis is unclear, an indomethacin test will either treat it or distinguish it.
SUNA = short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms;
SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.
a
The frequency of cluster headache is between one attack every other day and eight attacks per day.
pathophysiology: three genomewide association studies identifying several

susceptibility genes, and functional imaging studies aimed at discovering a
biosignature for cluster headache.
CLUSTER HEADACHE
Cluster headache is an exquisitely painful unilateral headache disorder with
ipsilateral autonomic features, most commonly of the eye (lacrimation,
conjunctival injection, edema, and ptosis) and nose (congestion and rhinorrhea).
Cluster headache is associated with a notable restlessness, a circadian pattern of
attacks, and sensitivity to oxygen that sets it apart from many other
headache disorders.
Epidemiology
Cluster headache is more common than generally thought, with a prevalence of
0.1%10 which is on par with the 0.3% rate of multiple sclerosis in the United
States.11 Cluster headache has a male predominance of 2:1 to 4:110,12,13 and a peak
age of onset in the twenties for both sexes.14 Six percent to eight percent of
patients have a family history of cluster headache; both autosomal dominant and
autosomal recessive patterns of inheritance have been found.15,16

Cluster headache has two subtypes: episodic, which has headache-free

remission periods of 3 months or longer per year, and chronic, which has shorter
or absent remission periods. Episodic cluster headache is 6 to 25 times more
common than chronic cluster headache; interestingly, chronic cluster headache is
more prevalent in women compared with men and in Europe and North America
compared with Asia.10,17-21 Up to 15% of patients can transition from one subtype
to another,22 and there have been cases where patients transition multiple times.
Cluster headache is associated with an increased risk of sleep apnea,

depression, and anxiety, and is linked to smoking.7 Unfortunately, stopping
smoking does not seem to stop the headaches.23 However, the most concerning
comorbidity is the high rate of suicidality. In American and South Korean studies,
the rate of suicidal ideation was 55% to 64% and the rate of suicidal planning was
6%; for patients with episodic cluster headache, the risk was highest during
headache bouts and the rates dropped significantly during remission periods.13,24
Clinical Features
There are currently no diagnostic tests for cluster headache, and thus the
diagnosis is made clinically (TABLE 6-225). The typical pattern is one to two
attacks a day lasting 1 to 2 hours each with both autonomic features and
restlessness,2,13,17,26 although restlessness is less common in Asian countries.14
The cranial autonomic features involve either parasympathetic activation (most
features) or sympathetic inactivation (miosis and ptosis); more than 70% of
patients have all five features of conjunctival injection, lacrimation, nasal
congestion, rhinorrhea, and ptosis.2 For patients with episodic cluster headache,
the headache cycles usually last 6 to 12 weeks2 and occur once per year. Thus,
patients with episodic cluster headache are arguably considered urgent neurology
referrals because of the high rate of suicide and the short periods of headaches.
Patients can have headache cycles as short as 1 week, and thus it is easy to see
how patients can go untreated for an entire headache cycle while waiting for an
appointment with a busy neurologist, only to cancel their appointment when
their headaches remit and repeat the process the following year.
There are a few notable features of the International Classification of
Headache Disorders, Third Edition criteria. First, the pain of cluster headache is
remarkable: in a retrospective study of 1604 patients, cluster headache ranked 9.7
on the 0 to 10 numerical rating scale, while the next highest was childbirth at 7.2;
kidney stones were technically considered moderate pain at 6.9.27 The headache
intensity can be highly variable even within individuals; there is often a
“volcano” pattern to headache cycles, with milder, less-frequent headaches in the
first days of the cycle that gradually build, peak in the middle, and then taper off.
This is most prominent in those with episodic cluster headache, but patients with
chronic cluster headache also have cycles of increasing and decreasing headache
frequency. Second, the pain is side-locked in most patients, where it will only
appear on one side (left or right) their entire life.28 Finally, patients are quite
restless during an attack and may describe pacing, rocking, hitting their head, or
exercising. This restlessness distinguishes cluster headache from migraine in
which patients often prefer to lie still because movement worsens the headache.
Some features of cluster headache, while not part of the official criteria, aid in
the diagnosis. First, the headache intensity escalates quickly, usually becoming
maximal in less than 20 minutes; the end of the attack is similarly abrupt.29
Second, there are common headache triggers including alcohol, nitroglycerin, and
394 A P R I L 2 0 24

increased body temperature (from heat or exercise). These triggers take effect
quickly; for nitroglycerin, it is less than 1 hour.29 While these triggers can also be
seen in patients with migraine, there is a clear distinction in episodic cluster
headache: the triggers have no effect when the headaches are in remission. In this
author’s experience, patients with episodic cluster headache often refrain from
alcohol during a headache cycle and then resume when the cycle is over, while
patients with migraine always avoid alcohol if it is perceived to be a strong trigger.
However, the most peculiar feature of cluster headache may be its circadian
rhythmicity. More than 70% of patients state that the attacks start at the same
time each day like clockwork; the most common hour across 8856 patients was
2:00 AM.6 Additionally, there is a circannual rhythmicity for episodic cluster
headache, with the headache cycles typically starting in the northern hemisphere
ICHD-3 Diagnostic Criteria for Cluster Headache, Episodic Cluster TABLE 6-2
Headache, and Chronic Cluster Headachea
Cluster headache
A At least five attacks fulfilling criteria B-D
B Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180
minutes (when untreated)b
C Either or both of the following
1 At least one of the following symptoms or signs, ipsilateral to the headache
a Conjunctival injection and/or lacrimation
b Nasal congestion and/or rhinorrhea
c Eyelid edema
d Forehead and facial sweating
e Miosis and/or ptosis
2 A sense of restlessness or agitation
D Occurring with a frequency between one every other day and eight per dayc
E Not better accounted for by another ICHD-3 diagnosis
Episodic cluster headache
A Attacks fulfilling criteria for cluster headache and occurring in bouts (cluster periods)
B At least two cluster periods lasting from seven days to one year (when untreated) and
separated by pain-free remission periods of ≥3 months
Chronic cluster headache
A Attacks fulfilling criteria for cluster headache and criterion B below
B Occurring without a remission period, or with remissions lasting <3 months, for at least
one year

a
b
During part, but less than half, of the active time-course of cluster headache, attacks may be less severe
and/or of shorter or longer duration.
c
During part, but less than half, of the active time-course of cluster headache, attacks may be less frequent.

spring (March and April) or fall (September, October, and November).6 These
circadian and circannual patterns are common in cluster headache but atypical
for the other trigeminal autonomic cephalalgias.
Differential Diagnosis and Workup

Unfortunately, many people with cluster headache do not receive a timely

diagnosis; the average diagnostic delay is 4 to 9 years across many countries.17,30
In a meta-analysis of more than 4000 patients, the most common misdiagnoses

were migraine, trigeminal neuralgia, dental disease, and sinusitis.30 The
differential diagnosis for cluster headache includes three categories: primary
headache and facial pain disorders with cluster headache features, secondary
headaches with cluster headache features, and symptomatic cluster headache.
PRIMARY HEADACHE AND FACIAL PAIN DISORDERS WITH CLUSTER HEADACHE FEATURES.
The other trigeminal autonomic cephalalgias can be confused with cluster

headache; all of these disorders present with unilateral pain and ipsilateral
autonomic symptoms. Some patients with cluster headache have mild interictal
pain (overlapping with hemicrania continua) and other patients with cluster
headache have six headache attacks per day lasting 20 minutes (which fulfills
criteria for both cluster headache and paroxysmal hemicrania). Thus, an
indomethacin trial is warranted in some patients to differentiate these disorders.
Trigeminal neuralgia, SUNCT, and SUNA have intense side-locked pain;
CASE 6-1 A 24-year-old otherwise healthy man presented for evaluation of a new
headache type that started 2 years ago. He reported severe, throbbing,
left-sided orbital pain that was associated with bilateral lacrimation,
nasal congestion, photophobia, phonophobia, and nausea. The
headaches typically started in the late morning and occurred twice a
week with no remission periods. He had never timed the headaches but
says that they lasted about 3 to 5 hours. There was no restlessness; in
fact, movement seemed to make the headaches worse so he tried to lie
still. He had tried oxygen, verapamil, and lithium without relief but
sumatriptan injections were very effective.
COMMENT This is a presentation of a patient with migraine who has many cluster
headache–like features. Both patients with migraine and patients with
cluster headache can have unilateral severe pain with autonomic features,
phonophobia, photophobia, nausea, and a circadian rhythmicity. The
autonomic features, however, tend to be ipsilateral (not bilateral) in cluster
headache, and the circadian rhythmicity is more common in cluster
headache. The features that indicate migraine include the frequency of
twice a week (cluster headache frequency is between one every other day
and eight per day), the lack of restlessness, and headaches that last longer
than 3 hours. Sumatriptan injections are effective treatments for both
migraine and cluster headache, while oxygen, verapamil, and lithium are
typically more effective for cluster headache.
396 A P R I L 2 0 24

however, trigeminal neuralgia (2 minutes or less) and SUNCT/SUNA KEY POINTS
(10 minutes or less) attacks are much shorter than cluster headache attacks.
● The typical patient with
Moreover, only trigeminal neuralgia, SUNCT, and SUNA have cutaneous cluster headache has the
triggers such as touching the face. Hypnic headaches have a circadian pattern, episodic subtype with the
usually occur in the early morning, and last 15 to 240 minutes (overlapping with following features: one to
the 15 to 180 minutes for cluster headache). However, hypnic headaches have no two attacks a day, lasting 1
to 2 hours each, occurring
autonomic features or restlessness and never occur when awake. Finally,
every day for 6 to 12 weeks.

migraine overlaps significantly with cluster headache. Migraine and cluster These headache cycles
headache share potential triggers (such as alcohol and nitroglycerin) and usually occur once per
unilateral pain. Moreover, patients with migraine often have cranial autonomic year.
features, while patients with cluster headache often have prototypical migraine
● Common cluster
features (photophobia, phonophobia, nausea, and premonitory features such as headache triggers include
yawning, thirst, and concentration problems).29,31 Approximately one-half of alcohol and nitroglycerin.
patients with migraine also have a circadian pattern of attacks.6 Migraine can For patients with episodic
best be distinguished from cluster headache by its longer duration (4 hours or cluster headache, these
triggers have no effect
longer in migraine versus 3 hours or shorter in cluster headache) and the activity when the headaches are in
pattern; patients with migraine typically refrain from movement, while patients remission.
with cluster headache are restless (CASE 6-1).
● Cluster headache
attacks usually occur at the
SECONDARY HEADACHES WITH CLUSTER HEADACHE FEATURES. Several secondary
same time of day like
disorders display unilateral pain and ipsilateral cranial autonomic features: clockwork. The time of
acute angle-closure glaucoma can present with conjunctival injection, maxillary onset may differ between
sinusitis with nasal congestion, Tolosa-Hunt syndrome with ptosis, and carotid patients, but it is consistent
for each patient and is most
dissection with miosis and ptosis. Temporal arteritis and impacted molars can
commonly around 2 AM.
have a similar location of pain as cluster headache. However, cluster headache is
an intermittent disorder lasting 15 to 180 minutes and recurring on a daily or ● Symptomatic causes of
every-other-day basis, while most of these secondary headaches present with cluster headache include
more constant symptoms. pituitary adenomas and
meningiomas. A brain MRI
with and without contrast is
SYMPTOMATIC CLUSTER HEADACHE. Symptomatic cluster headache mimics cluster recommended for all
headache but has a secondary cause that, when treated, leads to the resolution of patients with cluster
the headaches. Several symptomatic causes of headaches with a cluster-headache headache.
phenotype have been found including pituitary tumors (most commonly
prolactinomas), meningiomas located in the cranium or upper cervical spine, and
vascular causes such as strokes, venous sinus thromboses, and
arteriovenous malformations.33,34
Given this extensive differential diagnosis, the recommended workup from the
European Headache Federation in all patients with cluster headache is a brain
MRI with dedicated views of the pituitary and cavernous sinus.35 For patients who
have not responded to three or more preventive medications, additional
recommended workup includes vascular imaging of the head and neck (such as
magnetic resonance angiography [MRA] of the head and carotid ultrasound),
pituitary function testing, polysomnography (as continuous positive airway
pressure [CPAP] has been helpful as a preventive treatment in patients with
cluster headache and sleep apnea36), and, if Horner syndrome is present,
imaging of the apex of the lung (with concern for apical lung tumors given the
high rate of smoking in this group).35 Other considerations include an
indomethacin trial for hemicrania continua or paroxysmal hemicrania, an
erythrocyte sedimentation rate for temporal arteritis, or referral to an
ophthalmologist, dentist, or otolaryngologist.

Pathophysiology
The cause of cluster headache is
unclear but at least three brain
systems are involved: the
hypothalamus, the
trigeminovascular system,
and the autonomic system
(FIGURE 6-2). The clearest

evidence that these systems are
involved is that
neuromodulation of any one of
them can treat cluster headache,
including posterior
hypothalamic stimulation,
occipital nerve stimulation

(trigeminovascular system),
vagus nerve stimulation
(trigeminovascular system), and
sphenopalatine ganglion FIGURE 6-2
Pathogenesis of trigeminal autonomic
stimulation (autonomic system). cephalalgias. At least three systems are involved
including the pain system (the trigeminal nerve,
HYPOTHALAMUS. The trigeminovascular complex, and general pain
hypothalamus may be involved system called the pain neuromatrix), the cranial
autonomic system (the superior salivatory nucleus
in the initiation of attacks; the and sphenopalatine ganglion), and the
posterior hypothalamus is one of hypothalamus. Human studies have shown
only a few areas activated when a alterations in several molecules, and animal
cluster headache starts.37 The research has suggested that cluster headache
medications work on different systems as shown.
circadian and circannual features CGRP = calcitonin gene-related peptide; VIP = vasoactive
of cluster headache also point to intestinal peptide.
the hypothalamus, as the central Modified with permission from Burish M, Continuum
(Minneap Minn).1 © 2018 American Academy of Neurology.
clock is the suprachiasmatic
nucleus located in the anterior
hypothalamus. Other suspected
hypothalamic components include restlessness and agitation (in the ventromesial
hypothalamus) and control of the autonomic system (the paraventricular
nucleus). Melatonin therapy is suspected to work via the hypothalamus.
TRIGEMINOVASCULAR SYSTEM. The trigeminovascular system involves two

peripheral pathways that converge on the trigeminocervical complex and
continue to higher-order brain areas. The first peripheral pathway extends from
the pain receptors in the face, sinuses, dura, and large intracranial blood vessels
to the trigeminal ganglion, and then connects centrally to the trigeminal nucleus
(the superior part of the trigeminocervical complex). The nucleus tractus
solitarius (the nucleus for the vagus nerve) also connects to the trigeminal
nucleus38 and this may be the pathway underlying therapeutic noninvasive vagus
nerve stimulation. Interestingly, many of the structures implicated in
symptomatic cluster headache, such as meningiomas, carotid dissections, and
venous sinus thromboses, are innervated by the trigeminal nerve.33,34 The second
peripheral pathway is from pain receptors in the occiput and neck to the upper
cervical dorsal root ganglia, which then connect centrally to the upper cervical
398 A P R I L 2 0 24

dorsal horn (the inferior part of the trigeminocervical complex). Involvement of KEY POINTS
the upper cervical dorsal horn may explain why occipital nerve blocks and
● Research suggests that
occipital nerve stimulation are effective for cluster headache. The cluster headache starts in
trigeminocervical complex then connects to the brainstem, thalamus, cortex, and the hypothalamus and
subcortical structures in the widely distributed pain neuromatrix. connects to the pain and
One prominent neuropeptide used by the trigeminovascular system is autonomic systems.

calcitonin gene-related peptide (CGRP). CGRP is elevated in external jugular
● At the beginning of a
venous blood during a cluster headache attack, and infusion of CGRP can cluster headache cycle,
provoke an attack in patients with cluster headache.39,40 Triptans and patients are often started
galcanezumab (a CGRP blocker) are suspected to work in patients with cluster on multiple concurrent
headache via the trigeminovascular system. therapies: two acute
medications (subcutaneous
sumatriptan and high-flow
AUTONOMIC SYSTEM. Many of the parasympathetic features of cluster headache oxygen), one bridge
are mediated through the autonomic connection from the superior salivatory treatment (greater occipital
nucleus to the sphenopalatine ganglion and then to peripheral structures such as nerve block with
corticosteroids or oral
the lacrimal glands.41 This system forms a reflex with the trigeminovascular prednisone), and one or
system (the trigeminoautonomic reflex) via a connection between the trigeminal more preventive
nucleus and superior salivatory nucleus.41 The autonomic system uses the medications.
neuropeptide vasoactive intestinal polypeptide. Similar to CGRP in the
● The first-line acute
trigeminovascular system, vasoactive intestinal polypeptide is elevated in
treatments for cluster
external jugular venous blood during a cluster headache attack and a vasoactive headache are subcutaneous
intestinal polypeptide infusion can provoke an attack.39,42 In animal studies, sumatriptan and high-flow
oxygen has been shown to block signals from the autonomic system to the oxygen gas; typically, both
treatments are prescribed.
trigeminovascular system.43
RECENT DEVELOPMENTS IN CLUSTER-HEADACHE PATHOPHYSIOLOGY. New findings in

genetics and imaging are noteworthy as they may eventually inform a deeper
understanding of this disorder. Given the familial pattern in 6% to 8% of patients
with cluster headache including both autosomal dominant and recessive
patterns,15,16 multiple susceptibility genes were suspected and indeed have been
found. Three large-scale genomewide association studies have been performed
since 2021 encompassing 3161 patients with cluster headache across five
countries.44-46 When combined with previous smaller studies, a meta-analysis
found 20 potentially causal genes for cluster headache.47 In imaging research,
two recent studies have noted imaging changes that separate cluster headache
from migraine and healthy control patients,48,49 raising the promise of a distinct
biosignature for cluster headache.
Management
Treatments can be divided into three groups: acute or as-needed medications;
bridge or short-term preventive treatments, which work quickly but cannot be
taken for extended periods of time; and preventive treatments. The goal of acute
therapies is to abort individual cluster attacks, while the goal of bridge and
preventive therapies is to suppress attacks during the weeks or months of the
cluster episode. A full list of recommended treatments is shown in TABLE 6-350,51.
ACUTE TREATMENTS. Subcutaneous sumatriptan and high-flow oxygen are

considered the first-line acute treatments for cluster headache, a
recommendation recently reinforced by a network meta-analysis (a technique
that allows the comparison of medications across clinical trials as long as they

TABLE 6-3 Treatment of Cluster Headache Based on Guidelines from the American
Headache Society and the European Federation of Neurological Societiesa
American European Federation

Dose used in Headache Society of Neurological

clinical trials recommendationb Societies recommendationc
Acute
Oxygen (high flow) 6 L/min to 12 L/min A A
Sumatriptan subcutaneous 6 mg A A
Zolmitriptan nasal 5 mg to 10 mg A A
Sumatriptan nasal 20 mg B A
Zolmitriptan oral 5 mg to 10 mg B B
Octreotide subcutaneous 100 μg C B
Lidocaine nasal 10% C B

d
Noninvasive vagus nerve stimulation 3 2-min stimulations New Newd
(episodic only)
Bridge
Prednisone 17-day taper starting at Newd A

100 mg daily
Ipsilateral greater occipital Multiple; all use steroids A Not rated

nerve injection
Preventive
Verapamil 360 mg divided 3 times a day C A
Lithium 900 mg divided 3 times a day C B
Melatonin 10 mg at bedtime C C
Warfarin Titrated to an international C Not rated

normalized ratio of 1.5 to 1.9
Galcanezumab (episodic only) 300 mg monthly Newd Newd
Valproic acid 600 mg to 2000 mg divided Unfavorablee C

2 times a day
Refractory
Occipital nerve stimulation See clinical trials Newd Newd
Sphenopalatine ganglion stimulation See clinical trials B Not rated

e
Hypothalamic deep brain stimulation See clinical trials Unfavorable Not rated
a
Data from Evans S, et al, European Handbook of Neurological Management50 and Robbins MS, et al, Headache J Head Face Pain.51
b
A: Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the
specified population. (Level A rating requires at least two consistent Class I studies.) B: Probably effective, ineffective, or harmful (or probably
useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study
or at least two consistent Class II studies.) C: Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive)
for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)
c
A denotes effective, B denotes probably effective, and C denotes possibly effective.
d
For several treatments, clinical trial data was published after the guidelines that may lead to updated recommendations in the future.
e
American Headache Society guidelines rated both sodium valproate and deep brain stimulation as “probably ineffective.”
400 A P R I L 2 0 24

have one intervention in common).52 Many patients are prescribed both KEY POINTS
sumatriptan and oxygen because each has advantages and disadvantages.
● As a general rule, in the
Sumatriptan is portable, but daily use for weeks or months is not recommended. acute treatment of cluster
Oxygen is less portable, although portable tanks exist and portability is usually headache faster modes of
not an issue for patients with 2 AM headaches, and oxygen is safe for regular use. delivery (subcutaneous,
For sumatriptan, the route of administration is crucial; subcutaneous is more nasal, inhalational, and
neuromodulatory) are
effective than nasal, which is more effective than oral. For oxygen, the effective
preferred over slower ones

flow rate is typically 6 L/min to 15 L/min, but 15 L/min seems to be more effective (tablets and capsules).
than 6 L/min to 7 L/min.52 Oxygen for patients with cluster headache requires
two parts: a mask (a nonrebreather mask is highly preferred) and a delivery ● A new successful clinical
system (an oxygen tank plus an accessory called a regulator can achieve higher trial of prednisone as bridge
therapy for cluster
flow rates than an oxygen concentrator); oxygen is often ordered through a headache established a
durable medical equipment company which then works with the patient for higher-than-previously-
home delivery.53 Other effective treatments include noninvasive vagus nerve used dose: prednisone
stimulation (for episodic cluster headache only), zolmitriptan (nasal and oral), 100 mg daily for 5 days, with
a taper schedule decreasing
nasal lidocaine, and octreotide. Of all these treatments, sumatriptan and by 20 mg every 3 days until
octreotide have the highest risk of adverse events.52 off.
BRIDGE TREATMENTS. Corticosteroids are the first-line bridge treatment for cluster
headache, administered either orally or as a greater occipital nerve injection
ipsilateral to the pain. The American and European guidelines have differed on
the effectiveness of oral steroids, but a recent successful clinical trial has given
more guidance by using a higher dose than typically used: prednisone 100 mg
daily for 5 days, with a taper schedule decreasing by 20 mg every 3 days until
off.14 Greater occipital nerve injections have used a variety of steroids, and all
seem to be effective.54 Several immediate side effects of steroids are notable
including insomnia, agitation (including mania in patients with bipolar
disorder), and hyperglycemia (especially in those with diabetes). Delayed side
effects include gastrointestinal ulcers, adrenal suppression, and avascular
necrosis of the hip, and for these reasons, short courses of oral steroids (21 days or
less) are recommended.
Unblinded studies have suggested ergot derivatives (such as ergotamine or
dihydroergotamine) as second-line bridge medications.14,50 However, if ergot
derivatives are used then triptans should be stopped; therefore, patients taking
ergot derivates should have another effective acute treatment such as oxygen or
noninvasive vagus nerve stimulation. Zucapsaicin nasal spray (an isomer of
capsaicin) has also been shown to be effective for 7 days, although it is currently
not available in the United States.
PREVENTIVES. For patients with episodic cluster headache with 2-week to 3-week
headache cycles, bridge treatments without preventive treatments may be
sufficient; for all other patients, a preventive treatment is recommended.
However, preventive treatments take effect more slowly than the bridge
treatments; thus, patients are often started on both bridge medications and
preventive medications to provide continuous relief. For patients with episodic
cluster headache, preventive medications can be stopped approximately 2 weeks
after the last headache unless there are other reasons to continue it (eg, taking
verapamil for antihypertensive effects or if the headache cycles occur every few
months). There is no clear evidence that any medication can avert the next
headache cycle.

The first-line preventive medication is verapamil, and there is limited

evidence that suggests that immediate-release tablets are more effective than
extended-release tablets.55 High doses are often needed; while clinical trials
investigated 120 mg 3 times daily (360 mg total daily dose), doses more than
twice that have been used.56 Because of these high doses, side-effect
monitoring is recommended. The most concerning is heart block, and a

proposed ECG monitoring schedule57 is to obtain ECGs (primarily for the PR
interval) before starting verapamil, 10 to 14 days after each dose increase and
every 6 months while on the medication as some delayed cases of heart block
have been seen.56
The newest available preventive medication is galcanezumab. Galcanezumab
is the only CGRP blocker or CGRP-receptor blocker currently approved for
cluster headache, although others are currently in clinical trials. Galcanezumab
was found to be effective for episodic cluster headache, although the dose is
higher (300 mg once monthly) than the standard migraine dose (240 mg once,
then 120 mg every 28 days thereafter). Galcanezumab was not effective for
chronic cluster headache, although the clinical trials focused on the 3-week time
point and patients with chronic cluster headache may improve on galcanezumab
when taken for a longer period of time.58,59 Other preventive medications
include lithium, melatonin, warfarin, and sodium valproate.
Unblinded studies have suggested effectiveness of topiramate, gabapentin,
baclofen, and noninvasive vagus nerve stimulation.7 Noninvasive vagus nerve
stimulation prevented attacks in both episodic and chronic cluster headache, and
thus noninvasive vagus nerve stimulation can be used as either an abortive
treatment (for patients with episodic cluster headache) or a preventive
treatment (for both patients with episodic cluster headache and patients with
chronic cluster headache).
Special Groups
In several populations, the standard cluster headache medications are either
ineffective, unsafe, or not approved. These include refractory chronic cluster
headache, pediatric cluster headache, and cluster headache during pregnancy
and lactation.
REFRACTORY CHRONIC CLUSTER HEADACHE. Unfortunately, many medications

are not effective in some patients with chronic cluster headache, including
not only galcanezumab and noninvasive vagus nerve stimulation but also
oxygen and verapamil.17 In these treatment-refractory patients, invasive
neuromodulation can be considered. Proposed guidelines for surgical
treatment include near-daily attacks for 2 years, the failure or intolerance
of most if not all available preventive treatments, and a negative workup
including imaging.60,61 A 2021 trial showed that an implanted occipital
nerve stimulator was effective in patients with chronic cluster headache who
did not respond to or could not tolerate verapamil, lithium, and one other
preventive treatment.62 Both the experimental group (100% stimulation)
and the control group (30% stimulation) responded to treatment and thus
a placebo effect is possible; however, 41% of patients in the placebo group
experienced decreased weekly average attack frequency in weeks 21 to
24 compared with the baseline, and a placebo effect of this magnitude in a
medically refractory group is arguably unusual. Other implantable
402 A P R I L 2 0 24

neuromodulatory devices include a sphenopalatine ganglion stimulator KEY POINTS
(currently not available due to financial and industry issues) and a
● Galcanezumab is the
hypothalamic deep brain stimulator (which the American Headache Society newest preventive
considers “probably ineffective”). medication for episodic
cluster headache (it was not
PEDIATRICS. Pediatric cluster headache cases, once thought rare, have been well approved for chronic cluster
headache). The dose
documented in the literature.32 Up to one-quarter of patients have a pediatric age
(300 mg monthly) is higher

of onset,17,63 but only about 15% of these patients are diagnosed with cluster than the migraine dose
headache before age 18 years.17 In pediatric patients, indomethacin may (240 mg once, then 120 mg
interestingly be effective for cluster headache32 (or, conversely, paroxysmal every 28 days thereafter).
hemicrania may present differently in pediatric patients).9 Other effective
● Short-lasting unilateral
treatments in this group include oxygen, sumatriptan, zolmitriptan, gabapentin, neuralgiform headache
topiramate, and verapamil.64 attacks with conjunctival
injection and tearing
PREGNANCY AND LACTATION. For both pregnancy and lactation, oxygen and (SUNCT) and short-lasting
unilateral neuralgiform
intranasal lidocaine are typically considered safe. Sumatriptan is probably safe headache attacks with
for both pregnancy and lactation, but these data come from patients with cranial autonomic symptoms
migraine who use sumatriptan less often.14,64 The effects of preventive (SUNA) differ only in the
treatments are generally unclear. autonomic features they
have; their management is
identical.
Emerging Treatments
Several new treatments are currently being studied and, in this author’s ● SUNCT and SUNA are
experience, patients tend to ask about two in particular. First, patients have often mistaken for
trigeminal neuralgia. Other
found intranasal ketamine effective as an acute treatment according to
differential diagnoses are
retrospective surveys,12 and an initial open-label study showed promise primary stabbing headache
in relieving headaches at 30 minutes.65 The dose was 15 mg every 6 minutes and paroxysmal hemicrania.
as needed for up to five doses, performed in a hospital setting, and the
authors suggested that additional larger trials should be performed. Notable
exclusion criteria included severe depression, psychosis, or a history of
substance abuse.
Second, patients have found psilocybin effective as both an acute treatment
and a preventive treatment according to a retrospective survey.66 While
psilocybin is not available for medicinal use in most places, it is accessible in
several parts of the world including several parts of the United States.
An exploratory trial has begun to study it.67 The treatment protocol was
0.143 mg/kg given 3 times, with each dose separated by 3 to 7 days. Notable
exclusion criteria included a history of psychosis, recent substance abuse, the
cessation of serotonergic antidepressants for 6 weeks, and the cessation for
2 weeks of serotonergic antiemetics (such as ondansetron), steroids, and
immunosuppressants. Triptans and other vasoconstrictors could be used with a
caveat; they had to be stopped for 5 of their elimination half-lives before
beginning psilocybin treatment, and they could be resumed after 5 psilocybin
half-lives (equivalent to 15 hours). The authors noted that the study dose of
psilocybin is very low compared with recent psychiatric trials of psilocybin and
stated that this exploratory study provided useful information for future
trial design.
SUNCT AND SUNA

SUNCT and SUNA are distinguished not by treatment, headache duration, or
frequency, but solely by which cranial autonomic features they have; SUNCT has

both conjunctival injection and lacrimation, while SUNA has one or neither.
SUNCT and SUNA are the only two disorders within the category of short-lasting
unilateral neuralgiform headache attack (SUNHA), and several authors have
proposed that these two disorders should be combined as SUNHA.8,68 In this
review, SUNCT and SUNA will be discussed together.
Data for SUNCT and SUNA are more sparse than for cluster headache; no
well-powered clinical trials have been conducted. However, ample epidemiologic
and pathophysiologic data exist, as described below.
TABLE 6-4 ICHD-3 Diagnostic Criteria for Short-lasting Unilateral Neuralgiform

Headache Attacks, SUNCT, and SUNAa
Short-lasting unilateral neuralgiform headache attacks

A At least 20 attacks fulfilling criteria B-D
B Moderate to severe unilateral head pain, with orbital, supraorbital, temporal and/or other
trigeminal distribution, lasting for 1-600 seconds and occurring as single stabs, series of
stabs or in a saw-tooth pattern
C At least one of the following five cranial autonomic symptoms or signs, ipsilateral to the pain
1 Conjunctival injection and/or lacrimation
2 Nasal congestion and/or rhinorrhea
3 Eyelid oedema
4 Forehead and facial sweating
5 Miosis and/or ptosis
D Occurring with a frequency of at least one a dayb
SUNCT
A Attacks fulfilling criteria for short-lasting unilateral neuralgiform headache attacks, and
criterion B below
B Both of the following, ipsilateral to the pain
1 Conjunctival injection
2 Lacrimation (tearing)
SUNA
A Attacks fulfilling criteria for short-lasting unilateral neuralgiform headache attacks, and
criterion B below
B Not more than one of the following, ipsilateral to the pain
1 Conjunctival injection
2 Lacrimation (tearing)
ICHD-3 = International Classification of Headache Disorders, Third Edition; SUNA = short-lasting unilateral
neuralgiform headache attacks with cranial autonomic symptoms; SUNCT = short-lasting unilateral
neuralgiform headache attacks with conjunctival injection and tearing.
a
b
During part, but less than half, of the active time-course of short-lasting unilateral neuralgiform headache
attacks, attacks may be less frequent.
404 A P R I L 2 0 24

Epidemiology
SUNCT and SUNA have a prevalence of 6.6 per 100,000 individuals.69 They
have a slight male predominance (1.5:1)68 and a peak onset between ages 35 and
65 years, older than other trigeminal autonomic cephalalgias.70,71 SUNCT
and SUNA have the same episodic and chronic subtypes as cluster headache;
patients with episodic SUNCT and SUNA have remission periods of at least
3 months per year, while patients with chronic cluster headache have shorter or
no remission periods. Unlike cluster headache, most patients with SUNCT and
SUNA have the chronic subtype.4,72 Little is known about the natural history of
these disorders, although patients can transition from one subtype to another.4
Clinical Features
There are no diagnostic tests for SUNCT or SUNA, and thus the diagnostic
criteria are based on clinical features (TABLE 6-425). The average attack duration is
61 seconds and the frequency is 28 attacks per day, with high variability between
patients.20,73 Patients are equally divided in presenting with one of three attack
types—single stabs, groups of stabs, or a sawtooth pattern—and many patients
have more than one attack type.8,74 The pain quality is typically similar to
neuralgia and is sharp, stabbing, electric, or shooting.4,71 One notable unofficial
feature is cutaneous triggers. Common triggers for an extra SUNCT or SUNA
attack include touching the affected area, wind, brushing the teeth, and
chewing.8,71,74 In trigeminal neuralgia, the cutaneous triggers typically have a
refractory period, a brief moment when the pain cannot be triggered again. In
SUNCT and SUNA there is typically no refractory period.
Differential Diagnosis of SUNCT and SUNAa TABLE 6-5
Trigeminal Paroxysmal
SUNCT/SUNA neuralgia Primary stabbing headache hemicrania
Location V1 > V2 > V3b V2 and V3 > V1 Trigeminal and nontrigeminal V1 onlyb
parts of head
Intensity Moderate or Severe Not defined Severe

severe
Duration 1-600 seconds 1-120 seconds 1-120 seconds 120 seconds to

30 minutes
Frequency At least 1 per day Not defined At least 1 per day At least 6 per day
Cranial autonomic symptoms Pronounced Mild or Absent Absent Pronounced
Cutaneous Triggers Present Present Absent Absent
Refractory period Absent Present Not applicable Not applicable
First line treatment Lamotrigine Carbamazepine Indomethacin Indomethacin
SUNA = short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT = short-lasting unilateral neuralgiform
headache attacks with conjunctival injection and tearing.
a
Data from the Headache Classification Committee of the International Headache Society, Cephalalgia,25 Levy A and Matharu MS, Ann Indian
Acad Neurol,70 and Benoliel R, et al, Headache J Head Face Pain.75
b
SUNCT, SUNA, and paroxysmal hemicrania extend into the temporal area which is nontrigeminal, but the most common locations are in the
trigeminal territory.

Differential Diagnosis and Workup

The differential for these disorders includes trigeminal neuralgia, primary
stabbing headache, and paroxysmal hemicrania (TABLE 6-525,70,75). Trigeminal
neuralgia is quite similar in many respects including its susceptibility to sodium-
channel blockers. For more information on trigeminal neuralgia, refer to the
article “Cranial Neuralgias” by Stephanie J. Nahas, MD, MSEd, FAAN,76 in this

issue of Continuum. Emerging evidence also suggests that vascular compression
of the trigeminal nerve may be a cause of SUNCT and SUNA as it is in trigeminal

neuralgia.68,77 Other symptomatic causes of SUNCT and SUNA typically involve
pituitary adenomas (especially prolactinomas) and posterior fossa lesions. For
these reasons, it is recommended for all patients to have an MRI of the brain with
detailed views of the pituitary, cavernous sinus, and brainstem (including
sequencing to evaluate for neurovascular compression); in refractory cases,
vessel imaging of the head and neck and pituitary function testing should be
considered, as well as imaging of the apex of the lung if Horner syndrome is

present (CASE 6-2).35
Pathophysiology
Less is known about SUNCT and SUNA than cluster headache, although they are
thought to involve the same systems (hypothalamic, autonomic, and
trigeminovascular). Similar to cluster headache, imaging studies during an attack
have shown activation of the posterior hypothalamus.78 Given the findings of
neurovascular compression, it is possible that SUNCT and SUNA share
physiologic features with both trigeminal autonomic cephalalgias and
trigeminal neuralgia.79
CASE 6-2 A 55-year-old man with hypertension presented for evaluation of a new
headache type that started 6 months ago. He stated that he had severe,
stabbing right eye pain lasting 2 minutes and occurring ten times per day.
During the attacks, he had ipsilateral conjunctival injection, lacrimation,
and ptosis. He could trigger attacks by touching his face. A brain MRI with
and without contrast was negative, including detailed views of the
pituitary, posterior fossa, and cavernous sinus.
COMMENT This patient likely has short-lasting unilateral neuralgiform headache

attacks with conjunctival injection and tearing (SUNCT). He has many
features of paroxysmal hemicrania including location, duration, frequency,
and autonomic features. However, the cutaneous trigger (touching his
face) is typical of SUNCT. He also has many features of trigeminal neuralgia;
however, the pronounced autonomic features are again typical of SUNCT.
This patient should be treated with lamotrigine or other SUNCT
medications. If multiple medications fail, additional workup should be
considered including pituitary hormone testing for microadenomas and
vessel imaging of the head and neck; additionally, a trial of indomethacin
could be considered.
406 A P R I L 2 0 24

Management KEY POINT
SUNCT and SUNA attacks are too short for acute treatment, and thus
● SUNCT and SUNA are
management consists of bridge treatments and preventive treatments. Bridge responsive to
treatments are not as commonly used in SUNCT and SUNA as they are in cluster sodium-channel blockers
headache, but include steroids (dose unclear) and IV lidocaine (1 mg/kg/hr to such as lamotrigine,
3.5 mg/kg/hr).79 IV lidocaine may be the single most effective treatment, and carbamazepine, and
oxcarbazepine.
typical protocols include a 1-week inpatient admission by experienced providers
with continuous telemetry. The use of IV lidocaine is contraindicated in patients

with cardiac conduction abnormalities. While IV lidocaine can be temporary,
some patients have received relief lasting several months.
The first-line preventive treatment for SUNCT and SUNA is lamotrigine,
supported by several cohort studies that found lamotrigine to be the most
effective treatment other than IV lidocaine.68,72,74 Other effective treatments
included carbamazepine, duloxetine, gabapentin, oxcarbazepine, pregabalin,
topiramate, and verapamil.68,72,74
CONCLUSION
Cluster headache, SUNCT, and SUNA have somewhat similar clinical features
and potentially a similar pathophysiology but differ in timing and treatment.
Familiarity with the diagnostic criteria is key, as patients may experience a delay
of years before the correct diagnosis is made. New treatment trials and scientific
discoveries in cluster headache will hopefully continue to yield new treatment
options for patients.
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410 A P R I L 2 0 24

Posttraumatic Headache REVIEW ARTICLE

By Todd J. Schwedt, MD, FAAN C O N T I N U UM A U D I O
ONLINE
ABSTRACT
OBJECTIVE: This article provides an overview of the epidemiology, diagnosis,
clinical presentation, pathophysiology, prognosis, and treatment of
posttraumatic headache attributed to mild traumatic brain injury (mTBI).
LATEST DEVELOPMENTS: The International Classification of Headache

Disorders, Third Edition requires that posttraumatic headache begin within CITE AS:

7 days of the inciting trauma. Although posttraumatic headache 2024;30(2, HEADACHE):411–424.
characteristics and associated symptoms vary, most commonly there is
substantial overlap with symptoms of migraine or tension-type headache. Address correspondence to
Dr Todd J. Schwedt, 5777 East
New insights into posttraumatic headache pathophysiology suggest roles
Mayo Blvd, Phoenix, AZ 85054,
for neuroinflammation, altered pain processing and modulation, and schwedt.todd@mayo.edu.
changes in brain structure and function. Although the majority of
posttraumatic headache resolves during the acute phase, about one-third Dr Schwedt has received
of individuals have posttraumatic headache that persists for at least personal compensation in the
several months. Additional work is needed to identify predictors and early range of $0 to $499 for serving
as a consultant for Amgen Inc.;
markers of posttraumatic headache persistence, but several potential in the range of $500 to $4999 for
predictors have been identified such as having migraine prior to the mTBI, serving as a consultant for
the total number of TBIs ever experienced, and the severity of initial Biohaven, Ltd. Satsuma
Pharmaceuticals, Inc., Axsome
symptoms following the mTBI. Few data are available regarding Therapeutics, Inc., Collegium
posttraumatic headache treatment; studies investigating different Pharmaceutical, Theranica
Bio-Electronics Ltd., Scilex
treatments and the optimal timing for initiating posttraumatic headache Holding; in the range of $5000
treatment are needed. to $9999 for serving as a
consultant for AbbVie Inc.,
BioDelivery Science, and
ESSENTIAL POINTS:Posttraumatic headache begins within 7 days of the LinPharma; and in the range of
causative injury. The characteristics of posttraumatic headache most $10,000 to $49,999 for serving as
commonly resemble those of migraine or tension-type headache. a consultant for AbbVie Inc.,
Lilly, and Lundbeck. Dr Schwedt
Posttraumatic headache persists for 3 months or longer in about one-third has received intellectual
of individuals. Additional studies investigating posttraumatic headache property interests from a
discovery or technology relating
treatment are needed.
to health care. Dr Schwedt has
received publishing royalties
from a publication relating to
INTRODUCTION UNLABELED USE OF
P
osttraumatic headache is a secondary headache that is due to an PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
underlying injury of the head or neck. According to the International
Dr Schwedt discusses multiple
Classification of Headache Disorders, Third Edition (ICHD-3), medications and therapies for
posttraumatic headache can be attributed to mild traumatic brain the treatment of posttraumatic
headache, none of which are
injury (mTBI), moderate or severe TBI, whiplash, or craniotomy.1 approved by the US Food and
Headache is the most common acute and persistent symptom following mTBI.2 Drug Administration (FDA).
This article focuses on the epidemiology, diagnosis, clinical presentation,
pathophysiology, prognosis, treatment, and future research directions of © 2024 American Academy
posttraumatic headache attributed to mTBI. of Neurology.

POSTTRAUMATIC HEADACHE
TABLE 7-1 ICHD-3 Diagnostic Criteria for Acute Headache Attributed To Traumatic
Injury and Mild Traumatic Injury To The Heada
Acute headache attributed to traumatic injury to the head

A Any headache fulfilling criteria C and D

B Traumatic injury to the head has occurredb
C Headache is reported to have developed within 7 days after one of the following
1 The injury to the head
2 Regaining of consciousness following the injury to the head
3 Discontinuation of medication(s) impairing ability to sense or report headache following
the injury to the head
D Either of the following
1 Headache has resolved within 3 months after its onset

2 Headache has not resolved but 3 months have not yet passed since its onset
Acute headache attributed to mild traumatic injury to the head
A Headache fulfilling criteria for acute headache attributed to traumatic injury to the head
B Injury to the head fulfilling both of the following
1 Associated with none of the following
a Loss of consciousness for >30 minutes
b Glasgow Coma Scale (GCS) score <13
c Posttraumatic amnesia lasting >24 hoursc
d Altered level of awareness for >24 hours
e Imaging evidence of a traumatic injury such as a skull fracture, intracranial hemorrhage
and/or brain contusion
2 Associated with one or more of the following symptoms and/or signs
a Transient confusion, disorientation or impaired consciousness
b Loss of memory for events immediately before or after the injury
c Two or more of the following symptoms suggestive of mild traumatic brain injury
i Nausea
ii Vomiting
iii Visual disturbances
iv Dizziness and/or vertigo
v Gait and/or postural imbalance
vi Impaired memory and/or concentration

a
Society, Cephalalgia.1 © 2018, SAGE Publications.
b
Traumatic injury to the head is defined as a structural or functional injury resulting from the action of
external forces upon the head. These include impact between the head and an object, penetration of the
head by a foreign body, forces generated from blasts or explosions, and other forces yet to be defined.
c
The duration of posttraumatic amnesia is defined as the time between head injury and resumption of
normal continuous recall of events.
412 A P R I L 2 0 24

EPIDEMIOLOGY KEY POINTS
Among adults and children in the United States, approximately 2.8 million
● Headache is the most
TBI-related emergency department visits, hospitalizations, and deaths occur common acute and
each year, and more than 2 million individuals are diagnosed with mTBI.3,4 Acute persistent symptom
posttraumatic headache is experienced by one-half to two-thirds of individuals following mild traumatic
who have an mTBI.5-7 A study of 1594 patients who presented to the emergency brain injury (mTBI).
department with an mTBI found that 60% had posttraumatic headache at
● Acute posttraumatic
2 weeks postinjury.5 Risk factors associated with developing posttraumatic headache is experienced by
headache after an mTBI include younger age, female sex, fewer years of one-half to two-thirds of
education, abnormalities on head CT, TBI-related altered consciousness, having individuals who have an
migraine prior to the mTBI, and having pre-TBI psychiatric disease.5 About mTBI.
one-third of those with acute posttraumatic headache have posttraumatic ● Risk factors for acute
headache persistence, a topic discussed further below. posttraumatic headache
include younger age, female
DIAGNOSIS sex, fewer years of

education, abnormalities on
The diagnostic criteria for posttraumatic headache require that the headache head CT, TBI-related altered
begin within 7 days of one of the following: (1) the causative mTBI, (2) regaining consciousness, having
consciousness following the causative mTBI, or (3) discontinuing medications migraine prior to the mTBI,
that might have initially impaired the person’s ability to sense or report the and having pre-TBI
psychiatric disease.
presence of posttraumatic headache.1 New or worsening headache following
mTBI is the only evidence required that the post-TBI headache was caused by the ● About one-third of those
mTBI. No specific headache characteristics, accompanying symptoms, or with acute posttraumatic
diagnostic tests are currently included in the diagnostic criteria for posttraumatic headache have
headache. Posttraumatic headache is considered acute when it has been present posttraumatic headache
persistence at 3 months
for less than 3 months and persistent when it has been present for at least following onset.
3 months.
The extent to which posttraumatic headache begins beyond the first 7 days ● Diagnostic criteria for
following an mTBI is a matter of debate. The majority of posttraumatic headache posttraumatic headache
require that posttraumatic
begins within the first 7 days of the mTBI, most commonly within the first day.8 headache begin within
Since there is no evidence for causation other than the timing of posttraumatic 7 days of the causative
headache onset included in the ICHD-3 diagnostic criteria, the posttraumatic injury.
headache working group of the ICHD-3 chose to keep the interval between injury
● When pre-TBI headaches
and posttraumatic headache onset relatively short (7 days), favoring specificity
substantially worsen in
of the diagnostic criteria over sensitivity. However, a minority of the time frequency or severity
posttraumatic headache might begin more than 7 days after the injury; it is left to following TBI, patients
the clinician’s discretion to determine when this is the case. should receive their pre-TBI
There are several diagnostic criteria for assigning TBI severity; a review of headache diagnosis (eg,
migraine) and a diagnosis of
these different criteria is beyond the scope of this article. The ICHD-3 diagnostic posttraumatic headache.
criteria include a definition for mTBI used when assigning a posttraumatic
headache diagnosis (TABLE 7-1). ● Posttraumatic headache
Assigning a diagnosis of posttraumatic headache is typically straightforward symptoms most commonly
resemble those of migraine
when a person did not have headaches prior to a TBI and then develops or tension-type headache.
headaches within 7 days of the TBI. However, since headaches are frequent in the
general population and having headaches prior to a TBI is a risk factor for
developing posttraumatic headache, it is common for individuals with
posttraumatic headache to have a history of pre-TBI headaches such as migraine
or tension-type headache. According to the ICHD-3, when pre-TBI headaches
worsen substantially in frequency or severity following TBI, individuals are to
receive their pre-TBI headache diagnosis (eg, migraine) and a diagnosis of
posttraumatic headache.

No diagnostic tests are required to make a diagnosis of posttraumatic headache

attributed to mTBI. Of course, diagnostic testing might be necessary to evaluate
the underlying TBI. Several published guidelines and decision rules are helpful
for determining when brain or head imaging is indicated for the assessment of
TBI.9-12 Diagnostic testing for those with posttraumatic headache might also be
needed to determine if the TBI caused other problems that explain the post-TBI
headaches and evaluate symptoms other than posttraumatic headache. For
example, in those with posttraumatic headache, brain and vascular imaging

might be needed to investigate for evidence of more severe TBI (eg, intracranial
hemorrhage, skull fractures) and for head or neck injury–related conditions in
addition to TBI that could cause headaches (eg, headaches due to CSF leak,
headaches due to cervical artery dissection). Diagnostic investigations might be
needed to assess for post-TBI vestibular and balance problems, sleep issues,
cognitive dysfunction, autonomic dysfunction, and musculoskeletal injuries that
might have occurred along with the posttraumatic headache. When post-mTBI
symptoms are significant and do not quickly resolve, input from a
multidisciplinary team of providers in addition to the clinician with mTBI
expertise might be needed, such as experts in neuropsychology, sleep, balance
and vestibular disorders, sports medicine, autonomic neurology, and physical
medicine and rehabilitation.
CLINICAL PRESENTATION
It is common practice to describe posttraumatic headache according to the
primary headache type or other secondary headache type that it most resembles
when considering its characteristics and associated symptoms. This is done
because there are no specific treatments for posttraumatic headache, leading to
the recommendation that posttraumatic headache be treated with therapies that
are used for the headache types that it most resembles (eg, migraine,
tension-type headache).13 Posttraumatic headache attributed to mTBI most often
resembles migraine or tension-type headache.2,14 Less often, posttraumatic
headache resembles other primary and secondary headaches such as trigeminal
autonomic cephalalgias (eg, cluster headache) and cervicogenic headache.15 For
more on the treatment of cluster headache, refer to the article “Cluster Headache,
SUNCT, and SUNA” by Mark Burish, MD, PhD,16 in this issue of Continuum.
Posttraumatic headache can be mild to moderate in intensity and featureless,
like tension-type headache, or moderate to severe in intensity and associated
with migrainelike symptoms such as unilateral location, throbbing quality,
worsening with physical activity, and nausea.14,17 Photophobia and phonophobia
are present in one-half to two-thirds of individuals with posttraumatic
headache.14,17 Cutaneous allodynia, the perception of normally nonpainful
stimuli of the skin as painful, is present in about one-third of those with
posttraumatic headache and is a symptom that suggests the presence of
peripheral or central sensitization.14,17 The severity of allodynia, photosensitivity,
and phonosensitivity symptoms among those with posttraumatic headache is
similar to the severity among people with migraine.18 Exposure to lights and
sounds can result in visual and auditory discomfort and can exacerbate the
intensity of the posttraumatic headache and associated symptoms.19
Posttraumatic headache and persistent posttraumatic headache often exist
among other post-mTBI symptoms, including changes in mood, sleep problems,
mild cognitive deficits, balance and vestibular issues, symptoms associated with
414 A P R I L 2 0 24

autonomic dysfunction, and abnormal ocular motor control.20 Posttraumatic KEY POINTS
headache might be part of postconcussion syndrome which manifests as a
● Posttraumatic headache
combination of physical, cognitive, emotional, and sleep symptoms.21 For the is often accompanied by
optimal treatment of posttraumatic headache and the patient’s overall health, it is other post-mTBI symptoms
essential to recognize these other post-mTBI symptoms and treat them including changes in mood,
as appropriate. sleep problems, mild

cognitive deficits, balance
and vestibular issues,

PATHOPHYSIOLOGY symptoms associated with
The complex pathophysiologic mechanisms leading to acute and persistent autonomic dysfunction, and
posttraumatic headache need further investigation. However, preclinical and abnormal ocular motor
control.
human research provide evidence for contributions from neuroinflammation,
altered pain processing and modulation, and aberrations in brain structure ● Mechanisms underlying
and function.22 posttraumatic headache
The post-mTBI neuroinflammatory response, perhaps via activation of mast likely include
cells and microglial cells, increases brain excitability, the propensity for cortical neuroinflammation, altered
pain processing and
spreading depolarization, and activation of trigeminal nociceptors, mechanisms modulation, and changes in
that could contribute to initiating and sustaining posttraumatic headache.23-25 brain structure and function.
Calcitonin gene-related peptide (CGRP), a vasoactive neuropeptide strongly
implicated in migraine pathophysiology, and nitric oxide synthase might also
play roles in posttraumatic headache pathophysiology by activating and
sensitizing meningeal and trigeminal system nociceptors.26 Preclinical
experiments suggest that CGRP is essential for the development of acute
posttraumatic headache and that it contributes to the development of central
sensitization, which might lead to posttraumatic headache persistence.27 A study
of 60 people with persistent posttraumatic headache due to mTBI demonstrated
that CGRP infusion can trigger headache episodes.28 Although none of the
individuals had migraine prior to their mTBI, 72% developed migrainelike
headaches within 12 hours of experimental CGRP infusion, suggesting its role in
the generation of posttraumatic headache attacks.28
Enhanced facilitation and reduced inhibition of pain might play important
roles in the development and persistence of posttraumatic headache. Studies
have demonstrated evidence for thermal and mechanical sensitization among
those with posttraumatic headache.29 For example, there is greater pericranial
tenderness and reduced pressure pain thresholds in the head and neck regions
among those with persistent posttraumatic headache.30 This sensitized state can
be exacerbated by exposing individuals to bright light, which may be evidence
for atypical multisensory integration in those with posttraumatic headache.19
There is also evidence for loss of normal pain inhibition in preclinical animal
models of mTBI (ie, loss of diffuse noxious inhibitory controls) and in humans
with posttraumatic headache (ie, loss of conditioned pain modulation).31,32 This
loss of normal pain inhibition could lead to more severe pain experiences and
contribute to posttraumatic headache persistence.33
Alterations in brain structure and function have been demonstrated in
research imaging studies of those with acute and persistent posttraumatic
headache.34 These studies compared those with posttraumatic headache to
(1) healthy controls, (2) those with mTBI but without posttraumatic headache
(differentiating imaging findings associated with posttraumatic headache from
those attributable to the underlying mTBI), and (3) people with migraine. These
cross-sectional and longitudinal studies demonstrate that posttraumatic
headache attributed to mTBI is associated with alterations in white matter tract

integrity, gray matter structure, brain metabolism, iron deposition, and static
and dynamic resting-state functional connectivity.35-38 Several studies found
correlations between the extent of the imaging abnormalities with headache
frequency, headache intensity, and duration since the onset of posttraumatic
headache.35-37 Imaging studies also demonstrate that despite significant
phenotypic overlap between posttraumatic headache and migraine, differences

in brain structure and function can be used to accurately differentiate between
the two headache types.36,37,39,40 Longitudinal studies show that imaging findings
CASE 7-1 A 26-year-old woman presented to the neurology clinic for evaluation
and management of headaches. She had never experienced headaches
prior to a ground-level fall that occurred 22 months earlier. The fall led to
a direct impact of her head on the ground. She immediately felt dizzy and
had blurred vision, cognitive fog, and head pain. There was no loss of
consciousness and no amnesia. She presented to the local emergency
department, had a normal neurologic examination and head CT, and was
diagnosed with a concussion. The dizziness, blurred vision, and cognitive
fog resolved within a couple of hours of the mild traumatic brain injury
(mTBI), but the headaches continued. She reported having continuous
holocephalic headache that was mild to moderate in severity, with
superimposed more severe headaches a couple of days per week. She
had mild continuous sensitivity to light and sound that worsened with
increasing headache intensity. Severe headaches were exacerbated by
physical and mental activities, and she developed nausea during these
headaches. The headache intensity did not substantially change when
moving from lying down to standing, coughing, bending, or lifting. On
most days she treated the headaches with over-the-counter ibuprofen, a
combined formulation of acetaminophen, aspirin, and caffeine, or both.
Her general physical and neurologic examinations were normal.
She was diagnosed with persistent posttraumatic headache attributed
to mTBI and medication-overuse headache. Since the patient had
continuous posttraumatic headache for 22 months and her symptoms
were “migrainelike,” the following off-label treatments were
recommended: (1) headache prevention with topiramate, (2) referral for
biobehavioral therapy, (3) reduction in the frequency of taking as-needed
medications to no more than an average of 8 days per month, and (4) a
triptan for treating severe headaches.
COMMENT This case exemplifies a common clinical scenario in which persistent

posttraumatic headache of a “migrainelike phenotype” develops in an
individual who did not have pre-TBI headaches. Her clinical course was
complicated by the overuse of as-needed medications, possibly causing
medication-overuse headache. Since there is no strong evidence for which
treatments are safe and effective for posttraumatic headache and the
patient’s symptoms resemble those of migraine, pharmacologic and
nonpharmacologic migraine treatments were recommended.
416 A P R I L 2 0 24

might predict future posttraumatic headache outcomes and that imaging
findings change along with changing posttraumatic headache clinical
patterns.41-43 Overall, research imaging studies demonstrate structural and
functional brain changes associated with posttraumatic headache that are not
solely attributable to the underlying mTBI, some imaging findings that might be
specific for posttraumatic headache and not shared by other headache types, that
imaging findings can predict future posttraumatic headache outcomes, and that
imaging abnormalities are not necessarily permanent but rather change along
with posttraumatic headache clinical patterns.
PROGNOSIS
About one-third of individuals who develop acute posttraumatic headache have
posttraumatic headache persistence (CASE 7-1).2,5,44,45 In a study of 1594
individuals who presented to the emergency department with mTBI, 27.5% had
posttraumatic headache at 3 months post-mTBI, representing 52% of individuals

who had posttraumatic headache at 2 weeks post-mTBI.5 The ability to predict
who will have early resolution of acute posttraumatic headache versus who will
have posttraumatic headache persistence would help determine which patients
might benefit from early posttraumatic headache treatment. Preclinical research
models of posttraumatic headache suggest that early treatment might be more
effective than late treatment, but knowing who to treat early (ie, identifying
patients who are likely to have posttraumatic headache persistence) would be
key for when effective therapies are available.31
Characteristics Possibly Associated With Posttraumatic Headache TABLE 7-2

Persistence For At Least 3 Months Following Onset
◆ Abnormal posttraumatic brain injury brain imaging

◆ Dizziness or unsteadiness
◆ Duration of posttraumatic amnesia
◆ Female sex
◆ Greater number of post–mild traumatic brain injury (TBI) symptoms
◆ Having pre-TBI headaches
◆ History of neurologic disease
◆ History of psychiatric disease
◆ Lower recovery expectations by the patient
◆ More severe headache intensity
◆ Neck stiffness
◆ Not employed at the time of injury
◆ Presence of extracranial injuries
◆ Substance use
◆ Symptoms of anxiety and depression
◆ TBI mechanism (eg, vehicular crashes)
◆ Total number of lifetime TBIs

Several characteristics might be associated with a higher likelihood of

posttraumatic headache persistence (TABLE 7-2), including female sex, being
unemployed at the time of the injury, substance use, a history of neurologic
disease, a history of psychiatric disease, pre-TBI headaches, the number of TBIs,
abnormal brain imaging, the TBI mechanism, more severe headache intensity, a
greater number of post-mTBI symptoms, the presence of extracranial injuries,

the duration of posttraumatic amnesia, symptoms of anxiety and depression, and
lower recovery expectations by the patient.5,46-48 Although further validation is

required, a 2020 study using data collected at a median of 10 days after a motor
vehicle accident found that a prediction model based on age, employment status,
headache pain intensity, the presence of symptoms in the arms or hands,
dizziness or unsteadiness, neck stiffness, pre-TBI headaches, and lower recovery
expectations by the patient had a specificity of 95.5% (sensitivity of 27.2%) for
predicting the existence of posttraumatic headache with at least a moderate pain
intensity at 6 months.47 These features should be considered along with close
CASE 7-2 A 42-year-old woman presented to the clinic with 1 month of headaches
that began following a head injury. Prior to the head injury, she would
experience headaches on 3 days per month that were moderate in
intensity, throbbing, and associated with light and sound sensitivity and
nausea. She would treat with sumatriptan and rest in a dark and quiet
room during these headaches. One month ago, she slipped and fell,
hitting the back of her head. She immediately felt mild dizziness, had
blurred vision and cognitive disconnection, and a headache. There was
no loss of consciousness and no memory loss. She did not go to the
emergency department and did not seek evaluation prior to presenting to
the clinic. Her post–head injury symptoms had resolved except for the
mild dizziness and headaches that she had experienced every day since
the injury. She reported that the headaches were quite like those she had
prior to the head injury, except that the frequency and severity had
increased since her head injury. Her physical and neurologic examinations
were normal other than pain with palpation over the bilateral occipital
head regions, in the expected locations of the greater occipital nerves.
Since she had been experiencing daily headaches and dizziness for one
month and had not been evaluated acutely following her injury, a head CT
was completed and was normal. She was diagnosed with acute
posttraumatic headache attributed to mild traumatic brain injury (mTBI)
and migraine. Since her headaches were severe and daily, her neurologist
recommended off-label treatment with bilateral greater occipital nerve
blocks, 10 days of a long-acting nonsteroidal anti-inflammatory drug, and
continued use of sumatriptan up to an average of 8 days per month for her
most severe headaches. A 2-week follow-up was scheduled to assess
her headache improvement and begin preventive medication, if
necessary.
418 A P R I L 2 0 24

monitoring of posttraumatic headache frequency and severity during the early
acute phase, to differentiate those patients who are improving from those who
are not improving or worsening. Further work is needed prior to integrating
existing prediction models into the clinic. Thus, the clinician must use their
judgment to assess the risk of posttraumatic headache persistence and determine
if and when treatment should be initiated.

TREATMENT
Posttraumatic headache treatment might include simple observation, as-needed
abortive treatment for individual headaches, and posttraumatic headache
preventive treatment. There is little available evidence to inform treatment
recommendations specific to this disorder. Thus, suggestions are based on
low-quality evidence, clinical experience, and expert recommendations. It is
often suggested to treat posttraumatic headache according to the primary
headache or other secondary headache phenotype that the posttraumatic
This case demonstrates a situation frequently encountered in clinical COMMENT

practice in which an individual experiences migraine prior to an mTBI but
with substantial worsening of headaches following the injury. When there is
a substantial worsening of pre-TBI headaches following a TBI, the patient
maintains their pre-TBI diagnosis (migraine, in this case) and also receives a
diagnosis of posttraumatic headache. Since this patient was having daily
severe headaches for 1 month and she had not previously been imaged, a
head CT was completed. Of note, although there are guidelines and
decision rules for when to recommend brain imaging in the acute setting
following a mild head injury (see the Diagnosis section), guidelines are
lacking for when to recommend brain imaging for the evaluation of
posttraumatic headache, especially during the subacute and persistent
posttraumatic headache periods. Thus, clinical judgment is required. The
clinician should consider features included in guidelines for recommending
imaging in the acute post-TBI setting (eg, coagulopathy, focal neurological
deficits, vomiting), headache characteristics (eg, orthostatic headaches,
headaches triggered by Valsalva maneuver), associated signs and
symptoms (eg, papilledema, diplopia), and the patient’s longitudinal
symptom pattern (eg, worsening headaches over time, onset of new
post-TBI symptoms after the acute post-TBI phase).
Acute treatments for headache were clearly indicated to reduce the
patient’s pain. However, the timing of potentially recommending
preventive treatments for acute posttraumatic headache is left to the
discretion of the clinician who should try to balance the risk of unnecessary
exposure to preventive treatments (if the posttraumatic headache is going
to resolve during the acute phase without treatment) with the risk of
missing an opportunity to provide symptom relief. Additional studies are
needed to determine if the use of preventive treatments during the acute
phase of posttraumatic headache reduces the risk of posttraumatic
headache persistence.

headache most closely resembles.13 For example, if the posttraumatic headache

has a migrainelike phenotype then it should be treated like migraine. This advice
might be especially applicable when a person with posttraumatic headache had
migraine prior to their inciting injury and their posttraumatic headache has
similar symptoms. When there is not a preinjury primary headache type, this
recommendation presumes that the pathophysiology of posttraumatic headache

with a migrainelike phenotype overlaps with that of migraine and thus should
respond similarly to the migraine treatment. However, the extent to which

posttraumatic headache and migraine share pathophysiology is still being
defined, and this author’s clinical experience suggests that migraine
treatments provide more benefits when treating migraine than posttraumatic
headache.
Clinicians must use their clinical judgment to determine if and when to initiate
posttraumatic headache treatment (CASE 7-2). As discussed previously, the
majority of posttraumatic headache resolves within several days to a few weeks

of its onset. In such a situation, it might be optimal to simply use as-needed
treatments such as over-the-counter or prescription nonsteroidal
anti-inflammatory drugs for treating or lessening headache severity until its
resolution. However, if the clinician believes that the patient is unlikely to have
natural headache resolution within days to a few weeks it could be helpful to
initiate therapy aimed at reducing the risk of posttraumatic headache
persistence. Although there is no evidence for which treatments might be
effective in this regard, it can be theorized that scheduled long-acting
nonsteroidal anti-inflammatory drugs for 1 week to 10 days, early
nonpharmacologic treatment, or early initiation of preventive headache
medication could reduce the risk of posttraumatic headache
persistence.
Neurologists and other clinicians should provide education about
medication-overuse headache to patients with posttraumatic headache.
Medication-overuse headache is a secondary headache disorder that can develop
when as-needed headache medications are used too frequently, a condition
termed medication overuse. For more information, refer to the article
“Medication-Overuse Headache” by Paul Rizzoli, MD, FAAN, FAHS,49 in this
issue of Continuum. Unless absolutely required for the treatment of other
injuries, opioids should be avoided when treating posttraumatic headache due
to their high risk of leading to medication-overuse headache and the possibility
that they could increase the risk of posttraumatic headache persistence.
Education is essential for the primary prevention of medication-overuse
headache in those with posttraumatic headache, as is early identification of
individuals who are frequently using as-needed medications to intervene with
preventive headache therapies and avoid the development of
medication-overuse headache.
When headaches are frequent, severe in intensity, and cause disability
or functional impairment, preventive treatments should be considered.
Preventive treatments that are used for migraine and tension-type headache
can be used.13,50-54 However, it is important to carefully select among these
medication options, since the side effects from some of them could exacerbate
post-mTBI issues such as cognitive dysfunction, orthostatic intolerance, and
sleep problems. Nonmedication treatments should also be considered and
might include physical therapy, nerve blocks, trigger-point injections,
420 A P R I L 2 0 24

noninvasive neuromodulation devices, vitamins, supplements, and biobehavioral KEY POINTS
therapies.55,56
● There is a lack of
Posttraumatic headache is often accompanied by other post-mTBI symptoms high-quality evidence for
that can impact overall health and success with treating posttraumatic headache. determining which
For example, sleep problems, dizziness, anxiety, depression, and autonomic treatments are safe,
nervous system dysfunction can all exacerbate the symptoms of posttraumatic effective, and tolerable for
posttraumatic headache.
headache. Therefore, the successful treatment of posttraumatic headache can
Thus, it is generally
depend upon the recognition and management of these accompanying recommended to treat
post-mTBI symptoms. posttraumatic headache like
the other headache type (eg,
migraine, tension-type
POSTTRAUMATIC HEADACHE RESEARCH AND FUTURE DIRECTIONS
headache) that it most
Substantial work is needed to fully understand the pathophysiology of acute resembles.
posttraumatic headache and the mechanisms that lead to posttraumatic headache
persistence in certain individuals. The identification of features and biomarkers ● To avoid the development
to differentiate posttraumatic headache from other headache types would assist of medication-overuse
headache as a complication
the clinician in determining if headaches after mTBI are a new secondary of posttraumatic headache,
headache (ie, posttraumatic headache) or if they are exacerbations of headaches clinicians should educate
that existed prior to the mTBI. Prognostic models that can be employed early patients about avoiding the
after posttraumatic headache onset that accurately predict posttraumatic overuse of as-needed
headache medications.
headache persistence would be useful for clinical prognoses, determining the
need for close patient follow-up, and deciding whether preventive posttraumatic ● When preventive
headache treatment should be started. Finally, preclinical research and clinical treatments are indicated for
trials of therapeutics for acute and persistent posttraumatic headache are posttraumatic headache,
nonpharmacologic and
required, including studies that investigate the optimal timing for initiating such
pharmacologic treatments
treatments after mTBI or posttraumatic headache onset. could be considered.
CONCLUSION
Acute and persistent posttraumatic headache are common sequelae of mTBI. The
availability of standardized clinical diagnostic criteria, investigations into
posttraumatic headache pathophysiology, and the identification of predictors
for posttraumatic headache persistence represent meaningful advances in the
posttraumatic headache field. However, substantially more high-quality research
is needed to identify safe, effective, and tolerable acute and preventive
treatments for posttraumatic headache and the timing by which such treatments
should be initiated.
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27 Navratilova E, Rau J, Oyarzo J, et al. CGRP-

dependent and independent mechanisms of 38 Nikolova S, Schwedt TJ, Li J, et al. T2* reduction in
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39 Dumkrieger G, Chong CD, Ross K, Berisha V,
28 Ashina H, Iljazi A, Al-Khazali HM, et al. CGRP- Schwedt TJ. The value of brain MRI functional
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fpain.2022.1012831
29 Defrin R, Gruener H, Schreiber S, Pick CG.
Quantitative somatosensory testing of subjects 40 Chong CD, Berisha V, Ross K, et al. Distinguishing
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30 Ashina H, Al-Khazali HM, Iljazi A, et al. Total
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in persistent post-traumatic headache attributed Thalamic subfield iron accumulation after acute
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31 Kopruszinski CM, Turnes JM, Swiokla J, et al.
CGRP monoclonal antibody prevents the loss of 42 Niu X, Bai L, Sun Y, et al. Disruption of
diffuse noxious inhibitory controls (DNIC) in a periaqueductal grey-default mode network
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326-332. doi:10.1136/jnnp-2018-318886
32 Defrin R, Riabinin M, Feingold Y, Schreiber S, Pick
CG. Deficient pain modulatory systems in 43 Obermann M, Nebel K, Schumann C, et al. Gray
patients with mild traumatic brain and chronic matter changes related to chronic posttraumatic
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doi:10.1089/neu.2014.3359
44 Ingebrigtsen T, Waterloo K, Marup-Jensen S,
33 Naugle KM, Carey C, Evans E, et al. The role of Attner E, Romner B. Quantification of
deficient pain modulatory systems in the post-concussion symptoms 3 months after minor
development of persistent post-traumatic head injury in 100 consecutive patients. J Neurol
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an exploratory longitudinal study. J Headache
45 Voormolen DC, Haagsma JA, Polinder S, et al.
Pain 2020;21(1):138. doi:10.1186/s10194-020-01207-1
Post-concussion symptoms in complicated vs.
34 Schwedt TJ. Structural and functional brain uncomplicated mild traumatic brain injury
alterations in post-traumatic headache patients at three and six months post-injury:
attributed to mild traumatic brain injury: a results from the CENTER-TBI study. J Clin Med
narrative review. Front Neurol 2019;10:615. 2019;8(11):1921. doi:10.3390/jcm8111921
doi:10.3389/fneur.2019.00615
46 Andersen AM, Ashina H, Iljazi A, et al. Risk factors
35 Chong CD, Berisha V, Chiang CC, Ross K, for the development of post-traumatic
Schwedt TJ. Less cortical thickness in patients headache attributed to traumatic brain injury: a
with persistent post-traumatic headache systematic review. Headache 2020;60(6):
compared with healthy controls: an MRI study. 1066-1075. doi:10.1111/head.13812
Headache 2018;58(1):53-61. doi:10.1111/head.13223
47 Cancelliere C, Boyle E, Côté P, et al.
36 Chong CD, Peplinski J, Berisha V, Ross K, Schwedt Development and validation of a model
TJ. Differences in fibertract profiles between predicting post-traumatic headache six months
patients with migraine and those with persistent after a motor vehicle collision in adults. Accid
post-traumatic headache. Cephalalgia Int J Anal Prev 2020;142:105580. doi:10.1016/
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48 Mao L, Dumkrieger G, Ku D, et al. Developing 53 Lew HL, Lin PH, Fuh JL, et al. Characteristics and
multivariable models for predicting headache treatment of headache after traumatic brain
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traumatic brain injury: a preliminary study. 01.phm.0000223235.09931.c0
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54 Zirovich MD, Pangarkar SS, Manh C, et al.
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49 Rizzoli PB. Medication-overuse headache. post-traumatic headache: a randomized,
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30(2, Headache):379-390. 2021;186(5-6):493-499. doi:10.1093/

milmed/usaa391
50 Ashina H, Iljazi A, Al-Khazali HM, et al. Efficacy,
tolerability, and safety of erenumab for the 55 McGeary DD, Resick PA, Penzien DB, et al.
preventive treatment of persistent Cognitive behavioral therapy for veterans with
post-traumatic headache attributed to mild comorbid posttraumatic headache and
traumatic brain injury: an open-label study. posttraumatic stress disorder symptoms: a
J Headache Pain 2020;21(1):62. doi:10.1186/ randomized clinical trial. JAMA Neurol 2022;
s10194-020-01136-z 79(8):746-757. doi:10.1001/jamaneurol.2022.1567
51 Erickson JC. Treatment outcomes of chronic 56 Mollica A, Greben R, Oriuwa C, Siddiqi SH, Burke
post-traumatic headaches after mild head MJ. Neuromodulation treatments for mild
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52 Larsen EL, Ashina H, Iljazi A, et al. Acute and
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s10194-019-1051-7
DISCLOSURE
health care. Dr Schwedt has stock in Aural Analytics Health (NIH), the Patient Centered Outcomes
and Nocira LLC. The institution of Dr Schwedt has Research Institute, SPARK Neuro, and the United
received research support from Amgen Inc., the States Department of Defense.
Henry Jackson Foundation, the National Institutes of
424 A P R I L 2 0 24

New Daily Persistent REVIEW ARTICLE
Headache

ONLINE
By Matthew Robbins, MD, FAAN, FAHS
ABSTRACT
OBJECTIVE: This article describes the clinical features, etiology, differential
diagnosis, management, and prognosis of new daily persistent headache.
LATEST DEVELOPMENTS: New daily persistent headache has attracted renewed

attention as it may arise in the setting of a COVID-19 infection. Spontaneous CITE AS:
intracranial hypotension, particularly from CSF-venous fistulas, remains an
2024;30(2, HEADACHE):425–437.
important secondary headache disorder to consider before diagnosing
new daily persistent headache. Symptomatic treatment for new daily Address correspondence to
persistent headache may include acute and preventive therapies used for Matthew Robbins, 525 East 68th
St, F 603, New York, NY 10065,
migraine and tension-type headache, such as triptans, oral preventive mar9391@med.cornell.edu.
agents, onabotulinumtoxinA, and agents that target calcitonin gene-
related peptide. RELATIONSHIP DISCLOSURE:
Dr Robbins has received
New daily persistent headache is a daily headache
ESSENTIAL POINTS: range of $500 to $4999 for
serving as an editor, associate
syndrome that starts acutely and can only be diagnosed after 3 months
editor, or editorial advisory
have elapsed and other secondary and primary headache diagnoses have board member for Springer
been excluded. The clinical manifestations largely resemble either chronic Publishing Company. Dr Robbins
has received publishing
migraine or chronic tension-type headache. The underlying cause is royalties from a publication
unknown, but it is plausible that multiple etiologies exist and that it is not a relating to health care. Dr
single disease entity. The prognosis is variable but often poor, and the Robbins has noncompensated
relationships as a board of
treatment approach is largely extrapolated from the management of directors member and
chronic migraine and chronic tension-type headache. education program speaker with
the American Headache Society
and the New York State
Neurological Society and as an
editorial board member with
INTRODUCTION Continuum that are relevant to
N
ew daily persistent headache is a syndrome characterized by the American Academy of
Neurology (AAN) interests or
acute onset of a continuous headache for at least 3 months in the activities.
absence of any alternative cause.1 New daily persistent headache
was first described by Walter Vanast in the 1980s as distinct from UNLABELED USE OF
other primary headache disorders with its abrupt and continuous USE DISCLOSURE:
nature, and without a history of preexisting migraine or tension-type headache.2 Dr Robbins discusses the
unlabeled/investigational use of
Triggers are commonly reported by patients at headache onset, including an
various medications and
infection or stressful life event. New daily persistent headache has since been therapies for the treatment of
studied in more detail, mainly in clinical series from international headache new daily persistent headache,
none of which are approved by
clinics. the US Food and Drug
Two studies assessed the prevalence of new daily persistent headache in the Administration (FDA).
general adult population. Investigators in Spain assessed the prevalence of daily
headaches overall and new daily persistent headache in particular using similar © 2024 American Academy
criteria to the latest version of the International Classification of Headache of Neurology.

NEW DAILY PERSISTENT HEADACHE
Disorders, Third Edition (ICHD-3)1 and estimated the prevalence to be 0.1%.3

Another population-based study undertaken in Norway used more restrictive
criteria excluding those who had migrainous symptoms, in line with a previous
iteration of the ICHD, and reported a prevalence of 0.03%.4 Therefore, new daily
persistent headache seems to occur on a population level in 1 in 1000 to 3000
individuals, although it may be more frequent since children and adolescents

were excluded from these studies.
In clinical practice, new daily persistent headache is seen much more

commonly, with reported rates of up to 2% to 11% in adult headache practices
and 13% to 36% in pediatric headache practices.5-8 In one large comparative study
of 638 patients from the same practice setting, new daily persistent headache was
diagnosed in 21.1% of adolescents and 10.8% of adults.9
The age of onset typically ranges from teens to 50 years, mirroring the
incidence and prevalence of migraine and tension-type headache. Most series
show that new daily persistent headache is twice as common in women relative
to men, and the syndrome has been reported in practices globally.
CLINICAL FEATURES
The onset of new daily persistent headache is distinctly remembered, a requisite
for the diagnosis per the ICHD-3 (TABLE 8-1). In one study, 42% of patients
recalled the exact day of onset, and 79% could at least recall the month of onset.10
Aside from the tempo of onset and its continuous nature for at least 3 months,
new daily persistent headache is defined by neither specific pain characteristics
nor any associated symptoms. More broadly, its symptoms can directly resemble
other primary headache disorders of long duration, namely, chronic migraine
TABLE 8-1 ICHD-3 Diagnostic Criteria for New Daily Persistent Headachea
A Persistent headache fulfilling criteria B and C

B Distinct and clearly remembered onset, with pain becoming continuous and unremitting
within 24 hours
C Present for >3 months
D Not better accounted for by another ICHD-3 diagnosisb–e

a
b
New daily persistent headache is unique in that headache is daily from onset, and very soon unremitting,
typically occurring in individuals without a prior headache history. Patients with this disorder invariably recall
and can accurately describe such an onset; if they cannot do so, another diagnosis should be made.
Nevertheless, patients with prior headache (migraine or tension-type headache) are not excluded from this
diagnosis, but they should not describe increasing headache frequency prior to its onset. Similarly, patients
with prior headache should not describe exacerbation associated with or followed by medication overuse.
c
New daily persistent headache may have features suggestive of either migraine or tension-type headache.
Even though criteria for chronic migraine and/or chronic tension-type headache may also be fulfilled, the
default diagnosis is new daily persistent headache whenever the criteria for this disorder are met. In
contrast, when the criteria for both new daily persistent headache and hemicrania continua are met, then
the latter is the default diagnosis.
d
Abortive drug use may exceed the limits defined as causative of medication-overuse headache. In such
cases, the diagnosis of new daily persistent headache cannot be made unless the onset of daily headache
clearly predates the medication overuse. When this is so, both diagnoses, new daily persistent headache
and medication-overuse headache, should be given.
e
In all cases, other secondary headaches such as acute headache attributed to traumatic injury to the head,
headache attributed to increased cerebrospinal fluid pressure and headache attributed to low
cerebrospinal fluid pressure should be ruled out by appropriate investigations.
426 A P R I L 2 0 24

and chronic tension-type headache. Patients can have typical migraine- KEY POINTS
associated symptoms such as aura, nausea, photophobia, phonophobia,
● New daily persistent
allodynia, and bilateral autonomic symptoms, although unilateral head pain headache is a syndrome
regardless of phenotype is rare.10 A high rate of migraine features is also typical characterized by the acute
for adolescents with new daily persistent headache.5 Several large clinical series onset of a continuous
have assessed new daily persistent headache symptomatology, including a headache for at least
3 months in the absence of
breakdown of phenotypic resemblance to chronic migraine versus chronic
any alternative cause.

tension-type headache. New daily persistent headache with migraine features
seems to be more commonly encountered in clinical practice, and patients with ● New daily persistent
migraine features are more likely to be younger, women, and have coexisting headache seems to occur on
depression, which could suggest an etiological link to migraine biology in these a population level in 1 in 1000
to 3000 individuals and is
patients.10,11 Generalized anxiety and panic disorder can accompany or follow the even more commonly
onset of new daily persistent headache.12,13 encountered in neurology
If new daily persistent headache has been present for less than 3 months but practices, with rates varying
from 2% to 36% of patients.
other causes have been excluded, the ICHD-3 permits the diagnosis of probable
new daily persistent headache. In field testing of these criteria and in other ● Aside from the tempo of
observations, the majority of such patients had continued headache for at least onset and its continuous
3 months after onset,14,15 and this knowledge can help with setting patient nature for at least 3 months,
expectations. new daily persistent
headache is defined by
neither specific pain
ETIOLOGY characteristics nor any
Although not a diagnostic requirement, many patients with new daily persistent associated symptoms.
headache report an inciting factor associated with headache onset. Since new
daily persistent headache is a diagnosis only made in retrospect, there may be ● The most frequently
described inciting factor of
strong recall bias with such events, and attributing causality should be cautiously new daily persistent
considered. However, frequent distinctive patterns have emerged that could headache is an infection,
have etiological implications in some patients. typically a viral illness,
The most frequently described inciting factor is an infection, typically a which occurs in 10% to 30%
of patients. A typical pattern
viral illness, which occurs in 10% to 30% of patients.10,11,16,17 A typical pattern is is where headache emerges
where headache emerges as a continuous symptom in the setting of an upper as a continuous symptom in
respiratory infection after rhinorrhea, sinus congestion, cough, or systemic the setting of an upper
symptoms such as fever subside. The original description by Walter Vanast in a respiratory infection even
after rhinorrhea, sinus
series of 32 patients found serologic signs of active infection with Epstein-Barr congestion, cough, or
virus in 84% of patients with new daily persistent headache versus 25% of systemic symptoms such as
controls.18 A serologic study of 18 consecutive patients with new daily persistent fever subside.
headache revealed recent infection with herpes simplex virus in 42% and
cytomegalovirus in 11%.19
Continuous headache has been observed to take place after COVID-19
infection (CASE 8-1). In one large study of 905 patients who experienced
headache with COVID-19 infection between March to April 2020 in Spain, the
median duration of headache was 14 days, but at 3 months postinfection, 19% of
patients still had continuous headache.15 Although 52.7% had a history of primary
headache, which makes a diagnosis of new daily persistent headache less certain
for one-half of these patients, the total number of patients with continuous
headache postinfection demonstrates the broad scope of this phenomenon. In
another study assessing de novo pain after a hospitalization caused by COVID-19
infection, 13% of patients with COVID-19 developed a chronic daily headache
versus 0% of non–COVID-19 controls.20
Long COVID, or postacute sequelae of SARS-CoV-2 infection, has a consensus
definition by the World Health Organization.21 Patients must have a history of

probable or confirmed COVID-19 infection with at least 2 months of symptoms,

starting within 3 months of infection. Such symptoms commonly include fatigue,
shortness of breath, and cognitive dysfunction and have an impact on daily
functioning. The symptoms can start after initial recovery from a COVID-19
infection or persist from the initial illness, can fluctuate or relapse over time, and
cannot be explained by an alternative diagnosis.

Patients with new daily persistent headache arising from a COVID-19 infection
would therefore qualify as having long COVID. In a systematic review, the

prevalence of headache as a part of long COVID was 21.3% (95% confidence
interval: 3.3% to 48.9%).22 In descending order, fatigue, dyscognition,
paresthesia, sleep disorders, musculoskeletal pain, and dizziness are more
common in long COVID. However, the number of patients impacted by long
COVID including headache may depend on the COVID-19 strain, as the risk may
be 25% to 50% lower with omicron variants versus delta variants, as well as the
overall number of infections.23
There are many potential mechanisms by which headache may potentially be

triggered by COVID-19 or other viral illnesses, leading to new daily persistent
headache.24,25 Direct neuronal entry of COVID-19 via the olfactory bulb has been
observed and on a cellular level could occur via angiotensin-converting enzyme 2
host receptors, leading to trigeminovascular activation. Direct viral invasion
remains plausible, and systemic inflammation with cytokine release may also
contribute. Finally, in the setting of any infection, those with migraine may have
headache mechanisms that are disproportionately engaged as an evolutionary
protective response for them to seek help earlier, a hypothesis suggested by an
observation that patients with preexisting migraine have significantly lower
mortality from COVID-19.26
In long COVID, little has been confirmed about the risks of headache such as
new daily persistent headache, but direct pathogenic viral invasion, upregulation
of microglial activity, microvascular injury, autoimmunity, aggravation of
CASE 8-1 A 27-year-old man with very infrequent tension-type headache attacks
developed a holocephalic headache with fever, sore throat, and nasal
congestion. A home rapid antigen test was positive for COVID-19. After
4 days his symptoms resolved except for the headache, which persisted
continuously, was throbbing in character, and featured nausea, photophobia,
and aggravation by routine physical activity 4 out of 7 days per week
when his head pain escalated. This pattern continued for 4 months. His
neurologic examination was normal aside from cranial allodynia, and an
MRI of the brain with and without gadolinium was unremarkable.
COMMENT This patient experienced a continuous headache disorder that arose from a
COVID-19 infection. Other secondary causes were excluded. Although the
headache phenotype resembled that of chronic migraine, the abrupt onset
of continuous headache was consistent with a diagnosis of new daily
persistent headache. An infection is the most commonly identified
circumstance associated with the onset of this headache type.
428 A P R I L 2 0 24

cervical hypermobility, and genetic risks have all been proposed as potential KEY POINTS
mechanisms.27 However, studying headache post–COVID-19 infection is
● A stressful life event may
exceptionally difficult as infection is so prevalent and pandemic waves may be the second most
increase the risks of headache disorders due to psychosocial factors in the frequently reported inciting
population. In a large study that analyzed a sample of the general population who factor in new daily
had regular symptom inventories, no increase of headache post–COVID-19 persistent headache,

ranging from 10% to 20% in
relative to pre–COVID-19 versus controls was seen prospectively at 90 to
many series.
150 days after infection.28
Vaccinations are a very rare cause of new daily persistent headache,10 although ● A presentation of a
headache is a common symptom after vaccinations overall. In a systematic continuous headache from
review of 84 studies including 1.57 million participants for mRNA COVID-19 onset is a red flag warranting
diagnostic testing which
vaccine trials, headache was experienced after the first dose in 22% (95% should include
confidence interval: 18% to 27%) and after the second dose in 29% (95% neuroimaging, typically
confidence interval: 23% to 35%), but also after placebo in 10% to 12%.29 Among brain MRI with and without
gadolinium contrast to
non–COVID-19 vaccines, headache occurs most commonly after vaccination

assess for spontaneous
for varicella-zoster virus, followed by influenza and human papillomavirus.30 intracranial hypotension.
However, it is important to note that in an analysis of the Vaccine Adverse Event
Reporting System, the risk of experiencing headache is 500 times higher with ● Chronic, long-term
COVID-19 infection relative to vaccination.31 Purported mechanisms of headache primary headache disorders
such as chronic migraine,
and new daily persistent headache developing after vaccination include systemic
chronic tension-type
reactogenicity with the release of prostaglandins (such as those in the E family), headache, and hemicrania
interleukin-6, and C-reactive protein, increased blood-brain barrier continua should all be
permeability, and the activation of trigeminal nociceptors.30,32 strongly considered in the
differential diagnosis of new
A stressful life event may be the second most frequently reported inciting
daily persistent headache.
factor in new daily persistent headache, ranging from 10% to 20% in many
series.10,11,17 As stress or stress let down (moving from high-stress to low-stress ● Once secure in the
environments) can be a strong migraine trigger, and a major stressful life event diagnosis of new daily
can incite migraine to progress to chronic migraine, this observation for new persistent headache,
management is symptomatic
daily persistent headache could suggest underlying migraine biology. In one and akin to how other
analysis, patients with new daily persistent headache who had a stressful life chronic primary headache
event as an inciting factor had a very high rate of a history of infrequent episodic disorders such as chronic
migraine at 67%.16 In one prospective study of adolescent campers who survived migraine and chronic
tension-type headache
a terrorist attack in Norway, 12% of girls (versus 2% of controls) and 5% of boys are treated.
(versus 1% of controls) still had daily headache 4 to 5 months later.33 As
adolescents with migraine often have a more abrupt transition to chronic ● A variety of small,
migraine, this also reinforces a link of new daily persistent headache to migraine uncontrolled studies or
retrospective reviews show
biology.6 The timing of onset of new daily persistent headache may also be
treatment benefits for some
seasonal10,34,35 with the fall being the most common time of onset, although it is patients who have new daily
not clear if this is related to the prevalence of viral infections or societal events persistent headache with
such as the start of school. therapies used for migraine,
Other etiologies for subsets of patients with new daily persistent headache including triptans, tricyclic
antidepressants,
have been proposed in studies and case series. In one case-control study, much beta-blockers, topiramate,
higher rates of hypothyroidism were found in comparison with patients with valproic acid, monoclonal
migraine (odds ratio 16.0; 95% confidence interval: 3.6 to 72.0).8 Other case series antibodies targeting
found associations in some patients with cervical spine joint hypermobility36 as calcitonin gene-related
peptide or its receptor,
well as patients who experience new daily persistent headache arising from an onabotulinumtoxinA, and
extracranial, non-neurologic surgery, which may also suggest a cervicogenic nerve blocks.
etiology associated with neck and head positioning related to anesthesia. Patients
with new daily persistent headache who have defective internal jugular venous
drainage37 and a more crowded posterior fossa in the setting of headache

provoked by Valsalva maneuver without fulfilling criteria for Chiari

malformation38 have also been reported. A small minority of patients with new
daily persistent headache feature a thunderclap onset,39 including up to 4% in a
large 2021 series.11 These patients had normal vascular neuroimaging, but it could
be that their headache still fell within the spectrum of reversible cerebral
vasoconstriction syndrome; a large 2021 study reported that 3% of patients can

experience persistent headache akin to new daily persistent headache long after
the thunderclap pattern subsides.40

Finally, a 2022 functional imaging study detected perfusion variations
between patients who have new daily persistent headache and those who have
chronic migraine that could suggest biological differences. Those with new daily
persistent headache had decreased cerebral blood flow or arterial cerebral blood
volume in multiple right hemisphere cortical regions as opposed to those with
chronic migraine who had increases in these parameters in the bilateral thalami.41
Another study examined adolescents with new daily persistent headache versus
headache-free control subjects, revealing reduced thickness in multiple cortical
areas (bilateral superior temporal gyrus, left superior frontal gyrus, and middle
frontal gyrus) and altered functional connectivity in the amygdala, insula, frontal
regions, and cerebellum, regions involved in the emotional and cognitive
regulation of pain.42
DIAGNOSTIC TESTING
It is very important to diagnose new daily persistent headache carefully and to
systematically consider alternative diagnoses that can present with daily
headache.43 These diagnoses may encompass both secondary and primary
headache disorders (TABLE 8-2). A presentation of a continuous headache from
onset is a red flag warranting diagnostic testing which should include
neuroimaging,44 typically brain MRI with and without gadolinium contrast to
assess for spontaneous intracranial hypotension. Although most patients with
spontaneous intracranial hypotension will have orthostatic headache, 8% may
only have a daily headache that is nonpositional.45 A normal brain MRI with and
without contrast is present in 19% of patients with spontaneous intracranial
hypotension,45 and if there is any clinical suspicion, further diagnostic testing
such as different forms of myelography may still be needed. CSF-venous fistulas
in the spine are the most elusive cause of spontaneous intracranial hypotension
and may require even more specialized testing such as decubitus CT
myelography, MR myelography, or digital subtraction myelography.46
Conversely, idiopathic intracranial hypertension is also a diagnosis that can be
challenging, although often there are stigmata of chronic intracranial
hypertension present on brain MRI and head magnetic resonance venography
(MRV). Regardless of the presence of such MRI findings, lumbar puncture for
opening pressure and a neuro-ophthalmologic assessment may be needed for the
diagnosis. Giant cell arteritis should also be considered in adults 50 years old or
older as its headache phenotype can be nonspecific, and all patients at such an age
should have their erythrocyte sedimentation rate and C-reactive protein level
measured. Thyroid function tests should be performed since hypothyroidism
may be found at much greater rates in patients with new daily persistent
headache.8 In select patients, human immunodeficiency virus (HIV) testing and
assessing for tick-borne illnesses such as Lyme disease may be necessary if there
are systemic symptoms that suggest an infectious cause of continuous headache.
430 A P R I L 2 0 24

Chronic, long-term primary headache disorders such as chronic migraine,
chronic tension-type headache, and hemicrania continua should all be strongly
considered in the differential diagnosis of new daily persistent headache. Chronic
migraine and chronic tension-type headache should feature a more evolutive
pattern from their episodic counterparts, episodic migraine and episodic
tension-type headache, typically in the setting of risk factors for headache

progression such as medication overuse, excessive caffeine intake, depression,
sleep disturbance, a comorbid pain disorder, allodynia, ineffective acute

treatment, and persistent frequent nausea (FIGURE 8-147).48 Hemicrania continua
is characterized by continuous unilateral pain with ipsilateral cranial autonomic
symptoms that are also often constant from onset. Autonomic symptoms may
not always be appreciated as they typically become prominent only with pain
exacerbations. This diagnosis is particularly important to consider as new daily
persistent headache uncommonly features unilateral pain, so all such patients
Differential Diagnosis of New Daily Persistent Headachea TABLE 8-2
Secondary or
Diagnosis primary headache Comments
Spontaneous intracranial Secondary This disorder features abrupt-onset, continuous headache that
hypotension often manifests with an orthostatic pattern
A sizable proportion of patients can have normal brain and spine MRI
Idiopathic intracranial Secondary Continuous headache is the most common symptom; visual
hypertension symptoms may be absent; signs of optic disc edema may be subtle
Giant cell arteritis Secondary Giant cell arteritis can feature headache with any type of pain
location and character
Reversible cerebral Secondary A continuous, daily headache can emerge after an initial pattern of
vasoconstriction syndrome single or multiple thunderclap headaches
Cerebral venous thrombosis Secondary Isolated daily continuous headache is the most common
presentation
Explicitly querying for known risk factors (eg, estrogen-containing

hormone therapy) is needed as they are often omitted from
medication lists
Cervicogenic headache Secondary Pain referred anteriorly and away from the cervical and occipital
regions may distract from the diagnosis
Chronic migraine Primary Lack of ascertainment of previous headache frequency or false

attribution of situational headache attacks such as menstrual-related
migraine may lead to underdiagnosis of preexisting migraine
Chronic tension-type Primary Lack of ascertainment of previous headache frequency may lead to
headache underdiagnosis of preexisting tension-type headache
Hemicrania continua Primary Autonomic symptoms may not always be queried or prominent, such
as eyelid edema, ear fullness, or an ocular foreign body sensation,
and may only manifest during painful exacerbations
a
The disorders described mimic new daily persistent headache because of a continuous-from-onset, headache-predominant presentation that
can last for at least 3 months.

FIGURE 8-1
Contrasting the abrupt onset of new daily persistent headache with chronic migraine or
chronic tension-type headache. Chronic migraine or chronic tension-type headache
typically develops gradually in the presence of one or more risk factors for headache
progression (gray box).
Modified with permission from Robbins MS, Grosberg BM, Lipton RB, eds. Headache, 2013.47 © 2013 by
John Wiley & Sons, Ltd.
with continuous unilateral headache without any other clear cause should receive
a trial of indomethacin. For more on indomethacin treatment, refer to the article
“Indomethacin-Responsive Headache Disorders” by Peter J. Goadsby, MD, PhD,
FRS,49 in this issue of Continuum.
MANAGEMENT
Once secure in the diagnosis of new daily persistent headache, management is
symptomatic and akin to how other chronic primary headache disorders such as
chronic migraine and chronic tension-type headache are treated, given the
absence of any clinical trial data (CASE 8-2). A variety of small, uncontrolled
studies or retrospective reviews show treatment benefits for some patients who
have new daily persistent headache with therapies used for migraine, including
triptans, tricyclic antidepressants, beta-blockers, topiramate, valproic acid,
monoclonal antibodies targeting calcitonin gene-related peptide or its receptor,
onabotulinumtoxinA, and nerve blocks.10,50,51 Although no evidence is available,
neuromodulation devices that are US Food and Drug Administration (FDA)
approved for migraine may also be used to treat new daily persistent headache.
Some authors have advocated for early IV and oral corticosteroids to treat new
daily persistent headache, particularly if there is an infectious trigger.52 An
elective hospitalization for repetitive IV dihydroergotamine with other
parenteral medications including lidocaine or ketamine may help some patients
432 A P R I L 2 0 24

with new daily persistent headache.53-56 An anecdotal report of just four patients
treated with doxycycline57 led to hundreds if not thousands of patients being
treated with this antibiotic course as it has been postulated to have anti-
inflammatory properties, but given the lack of evidence for any headache
disorder and the potential for serious adverse effects, this treatment is not
recommended.
Acute medication overuse frequently accompanies new daily persistent
headache, ranging from 13% to 45%.10,58,59 In a study of adolescents, the

proportion of patients with new daily persistent headache who reported acute
medication overuse was lower than that of patients with chronic migraine with
continuous pain (21.9% versus 34.4%).60 Cognitive behavioral therapy and other
nonpharmacologic treatments should play an important role for patients with
new daily persistent headache given their evidence in the treatment of
adolescents and adults with primary chronic headache disorders and the inherent
difficulty in coping with a highly disabling disorder featuring sudden onset of

continuous pain.
PROGNOSIS
In the initial description by Walter Vanast,2 headache resolution was the most
common outcome, with rates of 68% at 6 months, 80% at 12 months, and 86% at
24 months. However, subsequent studies have shown a far more unfavorable rate
A 42-year-old woman with no headache history spontaneously CASE 8-2

developed the continuous onset of a severe daily headache with nausea,
photophobia, phonophobia, and a worsening of all symptoms by
movement. Her baseline level of pain was 7/10, and on most days there
were several hours of pain at a 9/10 to 10/10 level. She also experienced
severe insomnia and depression. Neurologic examination and an MRI of
the brain with and without gadolinium were normal. Nortriptyline titrated
to 30 mg nightly provided only very mild relief; topiramate and
propranolol were not well tolerated. OnabotulinumtoxinA injections
every 3 months reduced the number of days of severe painful
exacerbations by one-third, and fremanezumab was added which led to a
reduction of her baseline pain to 5/10. Ultimately, she was weaned off
nortriptyline and transitioned to venlafaxine extended release 75 mg
daily, which helped with her mood and further reduced the baseline pain
level to 4/10 2 years after headache onset. After trials of multiple acute
therapies, naratriptan was the most well-tolerated acute treatment to
reduce pain exacerbations. Cognitive behavioral therapy was helpful as a
coping strategy in the management of pain and depression.
This patient had new daily persistent headache with chronic migraine COMMENT
features in a persisting subform. After 2 years of multiple treatments in
combination, she still had a daily headache of moderate intensity with
exacerbations but experienced modest improvements using treatments
known to be successful for migraine.

KEY POINTS of headache resolution, at months to years later of 7% to 30%, which has led to
new daily persistent headache having a distinctive reputation of having a poor
● Cognitive behavioral
therapy and other
prognosis.10,11,17 However, one study assessed new daily persistent headache
nonpharmacological outcomes at an average of 2 years with a more typical outcome targeted in clinical
treatments should play an trials for headache disorders (50% or greater reduction of headache frequency),
important role for patients and 66% of patients experienced such an outcome.59
with new daily persistent
A prognostic classification was proposed to categorize patients with new daily
headache given their

evidence in the treatment of persistent headache into groups with headache persistence, headache remission,
adolescents and adults with and a relapsing-remitting pattern where periods of symptom persistence are
primary chronic headache interspersed with periods of remission.10 In this study, 76.1% of patients had the
disorders and the inherent
persisting subform, 15.5% had the remitting subform, and 8.5% had a
difficulty coping with a
highly disabling disorder relapsing-remitting pattern. Time to first remission can range from months to
featuring sudden onset of several years. In clinical practice, patients with new daily persistent headache
continuous pain. may also devolve into a pattern with a low baseline daily headache intensity and
superimposed attacks that are more typical for migraine. There is no clear
● A prognostic
classification has been
consistency of prognosis across studies stratifying patients with new daily
proposed to categorize persistent headache who have a chronic migraine versus chronic tension-type
patients with new daily headache phenotype, or with regard to the potential inciting factor at onset.10,11,59
persistent headache into In an analysis of patients with daily headache after COVID-19 infection, the
groups with headache
persistence, headache
persistence of daily headache was observed to be 19.0% at 3 months and 16.0% at
remission, and a 9 months, suggesting a low rate of remission.15 In this particular study, migraine
relapsing-remitting pattern features were positively correlated with persistence.
where periods of symptom
persistence are
interspersed with periods of TRENDS
remissions. Little is known about new daily persistent headache, given that it may have
● There remains diagnostic
multiple different etiologies. Strong diagnostic uncertainty remains since there is
uncertainty since there is no no clear consensus61 or guidance in the ICHD-31 for what attack frequency of a
clear consensus or guidance preexisting episodic headache disorder such as migraine would preclude the
in the International diagnosis of new daily persistent headache. For those who have a remote or
Classification of Headache
infrequent history of migraine, it is not clear if migraine biology is simply
Disorders, Third Edition for
what attack frequency of a “switched on” or if these patients should be considered as having status
preexisting episodic migrainosus that does not stop.62,63 The intense attention on COVID-19 should
headache disorder such as help to elucidate mechanisms for new daily persistent headache with viral
migraine would preclude the
infections in the setting of long COVID, which hopefully will include the
diagnosis of new daily
persistent headache. discovery of a biomarker. Clinical trials for new daily persistent headache are
entirely lacking. Measuring outcomes has been challenging since assessing
● Measuring outcomes for headache days per month may not be realistic to show meaningful and
patients with new daily incremental improvements. Akin to those with chronic migraine and continuous
persistent headache is
challenging, and lowering
pain, lowering the baseline intensity of pain may be the most meaningful
the baseline intensity of pain outcome, although patient-centered outcomes with input from patients
may be the most meaningful themselves are clearly needed or else those with new daily persistent headache
outcome. will continue to be excluded from clinical trials.64
CONCLUSION
New daily persistent headache is a daily headache syndrome that starts acutely
and can only be diagnosed after 3 months have elapsed and other secondary and
primary headache diagnoses have been thoroughly excluded. The clinical
manifestations largely resemble either chronic migraine or chronic tension-type
434 A P R I L 2 0 24

headache with bilateral and continuous pain. It is plausible that there are multiple
etiologies, and it is not a single disease entity. The prognosis is variable but often
poor, and the treatment approach is largely extrapolated from the management
of chronic migraine and chronic tension-type headache.
USEFUL WEBSITES
NEW DAILY PERSISTENT HEADACHE | AMERICAN UNDERSTANDING NEW DAILY PERSISTENT HEADACHE
HEADACHE SOCIETY A podcast from the Association of Migraine
A short summary of new daily persistent headache Disorders covering new daily persistent headache
for patients, published in the American Headache from both the clinician and patient perspectives.
Society journal Headache. migrainedisorders.org/podcast/s4ep16-
americanheadachesociety.org/wp-content/ understanding-new-daily-persistent-headache
uploads/2018/05/Tepper-2016-Headache_
NDPH.pdf
NEW DAILY PERSISTENT HEADACHE | AMERICAN

MIGRAINE FOUNDATION
A guide to new daily persistent headache for

patients, developed by the American Migraine
Foundation.
americanmigrainefoundation.org/resource-library/
new-daily-persistent-headache
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REVIEW ARTICLE
Headache in Children and
Adolescents

I NT E R V I E W A V AI L A B L E
ONLINE
By Serena L. Orr, MD, MSc, FRCPC
CITE AS:
2024;30(2, HEADACHE):438–472. ABSTRACT
OBJECTIVE: This article reviews the assessment of children and adolescents
Dr Serena Orr, 28 Oki Dr NW, presenting with headache, provides an overview of primary headache
Calgary, Alberta T3B 6A8, disorders, and reviews evidence-based management of headache in this
Canada, serena.orr@ucalgary.ca. age group.
Dr Orr has received publishing LATEST DEVELOPMENTS: In the last few years, new epidemiological data have
royalties from a publication
relating to health care.
shed light on less common pediatric headache disorders (eg, pediatric
Continued on page 472 trigeminal autonomic cephalalgias) and psychosocial risk factors
associated with primary headache disorders in children and adolescents.
INVESTIGATIONAL USE
There has also recently been a substantial increase in interventions that
DISCLOSURE: target the calcitonin gene-related peptide pathway and that treat primary
Dr Orr discusses the unlabeled/ headache disorders using noninvasive neuromodulation. Although these
investigational use of the
following treatments for children interventions have primarily been studied in adults, there is emerging
and adolescents, none of which evidence of their use in the pediatric population.
are approved by the US Food
and Drug Administration (FDA):
acetaminophen, amitriptyline, ESSENTIAL POINTS: Primary headache disorders are very common in youth, and
bupivacaine, cinnarizine, the most commonly encountered headache diagnosis in neurology
coenzyme Q10, the combined
trigeminal and occipital
practice is migraine, which affects approximately 10% of children and
nerve stimulator device, adolescents. Diagnosing and effectively treating primary headache
cyproheptadine, diclofenac, disorders before adulthood may have a sustained impact on the patient by
divalproex, eletriptan,
eptinezumab, erenumab, the improving long-term headache and mental health outcomes, thereby
external trigeminal nerve significantly reducing the burden of disability over time. There are several
stimulator device, flunarizine, available and emerging acute and preventive interventions for youth with
fremanezumab, frovatriptan,
galcanezumab, ibuprofen, primary headache disorders, and treatment decisions should be made in
ketoprofen, levetiracetam, the context of available evidence using a shared decision-making
lidocaine, magnesium, melatonin,
metoclopramide, naproxen,
approach.
naratriptan, nimodipine,
onabotulinumtoxinA,
ondansetron, pregabalin,
prochlorperazine, propranolol, INTRODUCTION
riboflavin, rimegepant,
T
sumatriptan nasal spray, and he majority of children and adolescents experience headache, with
ubrogepant for the treatment of pooled estimates suggesting that approximately 60% of youth are
migraine; verapamil for the
affected.1 Frequent recurrent headaches, defined as experiencing 1 or
treatment of cluster headache;
and indomethacin for the more days per week with headache, occur in approximately 8% to
treatment of primary stabbing 30% of children and adolescents.2-4 Headaches can have a debilitating
headache, paroxysmal
hemicrania, and hemicrania
impact on youth: primary headache disorders, such as migraine and tension-type
continua. headache, are the leading cause of neurologic disability among children and
adolescents 10 years old and older.5 The impact of headache disorders is
© 2024 American Academy pervasive and encompasses academic performance,6,7 school attendance,8,9
of Neurology. home life,8,9 social life,10 and extracurricular endeavors.8,9 Despite the massive
438 A P R I L 2 0 24

prevalence and burden of pediatric headache disorders, they remain the most KEY POINTS
underfunded pediatric disease category when considering allocated public
● The early diagnosis and
research dollars,11 which has impeded progress in understanding their etiology, treatment of children and
prognosis, and optimal treatment. adolescents with headache
Unsurprisingly, given the prevalence and disability associated with headache disorders may lead to better
disorders, they consistently rank among the top three reasons for consultation to long-term outcomes.
pediatric neurology.12,13 In treating this population, providers have a unique
● Appropriate headache
opportunity to change the lives of children and adolescents with headache treatment not only appears
disorders by addressing current treatment needs and mitigating long-term risks to lead to short-term
associated with the persistence of headache disorders into adulthood. The improvements in
majority of youth with headache disorders will continue to experience attacks of headache-related outcomes
but has also been shown to
headache throughout adulthood.14 In addition, children and adolescents with improve long-term
headache disorders are at risk of developing mental health disorders in outcomes and have a
adulthood.15,16 Early diagnosis and treatment may impact the long-term sustained impact even after
prognosis of children and adolescents with headache disorders, as data suggest a initial preventive headache
treatment is discontinued.
better long-term outcome for youth with a shorter lag between headache onset
and access to care.17 Appropriate headache treatment not only leads to ● The clinician’s first task in
short-term improvements in headache-related outcomes but has also been shown assessing a child or
to improve long-term outcomes18 and have a sustained impact even after initial adolescent with headache is
to determine whether the
preventive headache treatment is discontinued.18 In considering the critical
patient has a primary or
importance of accessing a diagnosis and care, the role that disparities in access to secondary headache
care play in perpetuating sex, gender, socioeconomic, race, and ethnicity-based disorder.
differences in outcomes cannot be ignored. For example, while Black people19
and men20 are less likely to get a diagnosis for their headaches, White children ● While unilateral cranial
autonomic symptoms may
and adolescents are more likely to be prescribed acute medications for primary suggest a trigeminal
headache disorders than children of other races.21 In addition, higher autonomic cephalalgia, 55%
socioeconomic status is associated with higher prevalence of triptan use to 70% of children and
(reflecting access to treatment)22 and higher likelihood of accessing medical adolescents with migraine
experience cranial
consultation and a migraine diagnosis in adults,20 as well as a higher likelihood of autonomic symptoms.
admission to the hospital for migraine in children and adolescents.23 Improving
access to care for all children and adolescents with headache disorders, with a ● Prodromal symptoms
focus on ensuring equity in access to care, should be a top priority for the field. occur in approximately 67%
to 85% of children and
This article provides an overview of how to evaluate, diagnose, and treat
adolescents with migraine
children and adolescents with headache, with a focus on evidence-based and may be more apparent
strategies. to the patient’s parents than
to the patient themself (eg,
the parent may note an
TAKING A FOCUSED HISTORY
appearance of sunken eyes
This section provides an overview of how to take a focused history from the child or a mood change before the
or adolescent presenting with headache, with a description of both what to elicit onset of headache).
and how to elicit relevant history.
● Traditionally, occipital
headache was thought to be
Content of the History a red flag for secondary
The most critical aspect of a provider’s illness script for children and adolescents etiologies in children and
with headache is to recognize that the first decision point hinges on whether adolescents, although
the patient has a primary headache or a secondary headache. A comprehensive recent data suggest that the
yield of neuroimaging in this
list of primary and secondary headache etiologies is available in the setting is low.
International Classification of Headache Disorders, Third Edition (ICHD-3).24
The likelihood of encountering a primary versus a secondary headache disorder
will vary by setting; secondary headaches such as headache attributed to
systemic viral infection account for the largest proportion (approximately 30% to

HEADACHE IN CHILDREN AND ADOLESCENTS
60%) of headache presentations to the pediatric emergency department,25

whereas migraine is the most common diagnosis in adult and pediatric
outpatient neurology practice (approximately 50% to 88% of patients in this
setting).13,26,27
In approaching the initial decision point of primary versus secondary headache,
clinicians should strive to take a history that aims to elicit all facets of the pain. To
elicit details about the headache itself, the mnemonic OPQRST (onset,
provocation, quality, radiation, severity, and time) may be useful. In addition,

clinicians will want to inquire about associated symptoms, with particular
attention to symptoms that may help differentiate among the primary headache
disorders, including photosensitivity, phonosensitivity, nausea, vomiting, and
cranial autonomic symptoms such as lacrimation, conjunctival injection, nasal
congestion, rhinorrhea, ptosis, miosis, facial flushing and sweating, sense of aural
fullness, and eyelid edema.24 Of note, although unilateral cranial autonomic
symptoms should alert clinicians to the possibility of a trigeminal autonomic

cephalalgia, the majority (approximately 55% to 70%) of children and adolescents
with migraine also experience cranial autonomic symptoms, and approximately
15% to 23% of them report unilateral cranial autonomic symptoms.27,28
Asking about symptoms that occur before the onset of the headache may elicit
symptoms related to the migraine prodrome, such as fatigue, irritability, sunken
eyes, pallor, and mood changes. Prodromal symptoms occur in approximately
67% to 85% of children and adolescents with migraine29,30 and may be more
apparent to the patient’s parents than to the patient themself (eg, the parent may
note an appearance of sunken eyes or a mood change before the onset of
headache). Symptoms of aura may also present before headache onset and occur
in approximately one-fourth of children and adolescents with migraine.31,32
Aura comprises fully reversible neurologic symptoms that are often unilateral,
spread gradually, occur in succession, and last between 5 and 60 minutes.24 Of
note, visual aura is the most common type of aura among children and
adolescents,32,33 and youth commonly have atypical visual aura features, such as
bilateral symptoms.34 Visual blurring may occur before headache onset and is
considered a prodromal symptom29 as opposed to a symptom of visual aura.
Clinicians must inquire about potential red flags in this population which
may indicate a secondary mechanism for headache. The SNNOOP10 mnemonic35
provides a high-yield framework for covering headache red flags in both adult
and pediatric patients. For the SNNOOP10 list of headache red flags, refer to
the article “Approach to the Patient with Headache” by Deborah I. Friedman,
MD, MPH, FAAN,36 in this issue of Continuum. While overall the level of
evidence for headache red flags is low,35 this list remains the cornerstone for
guiding clinicians in selecting which patients require further investigations to
exclude secondary headache etiologies. Red flags can pertain to features of the
headache as well as associated symptoms. Headaches that reach their maximal
severity within less than a minute (ie, thunderclap headache) signal underlying
secondary pathology such as subarachnoid hemorrhage or reversible cerebral
vasoconstriction syndrome.25 The headache pattern is important to elicit, since
acute or subacute onset headaches,37 as well as headaches with a progressively
worsening pattern over a subacute time frame, may be more likely to be caused
by underlying secondary pathology.38 Pain location is not included in the
SNNOOP10 list, but traditionally occipital-only headaches have been considered
a red flag in children and adolescents with headache. However, recent data
440 A P R I L 2 0 24

suggest that the yield of neuroimaging for occipital headache as an isolated red
flag in youth with headache is low,39,40 calling into question the use of occipital
location as a red flag.
Headaches with a positional trigger that begin or substantially worsen
when the patient lies down or stands up should compel clinicians to consider
the possibility of intracranial hypertension (onset with lying down) and

intracranial hypotension or postural orthostatic tachycardia syndrome (onset with
standing). When the headaches consistently begin in the context of exercise, sex,
cough, or sneezing, vascular pathology or space-occupying lesions (eg, Chiari I
malformation) need to be considered,35 although when headaches simply worsen
temporarily with these activities, it is possible that the patient may have a primary
headache disorder such as migraine, which can be aggravated by physical
activity24 or cough.41 The child or adolescent who presents with side-locked
unilateral eye pain associated with cranial autonomic symptoms should be
investigated for potential structural headache etiologies, with a focus on ruling out
lesions in the pituitary or cavernous sinus.35 With regards to associated symptoms,
any neurologic deficit identified should be considered a red flag, with the
exception of recurrent auras.24 In addition, a history of morning-onset headaches
with vomiting should raise concerns for increased intracranial pressure, while
isolated morning headache (ie, without vomiting) could also be indicative of
obstructive sleep apnea. On review of systems and medication history, trauma,
fever, or the initiation of a new medication occurring around the time of headache
onset may indicate secondary pathology and excessive use of analgesics may signal
medication-overuse headache.24 On medical history, children and adolescents
presenting with undiagnosed headache who are pregnant or postpartum, who
have a history of immune deficiency, or who have a history of cancer should be
considered for investigations to rule out secondary headache etiologies.35
In addition to eliciting history aimed at determining the diagnosis, clinicians
must also identify the impact of headaches on the patient’s life and seek to
determine if comorbidities of primary headache disorders are complicating the
clinical picture. The Pediatric Migraine Disability Assessment Tool is a
validated8,9 and widely used patient-reported tool aimed at understanding
disability experienced by children and adolescents with headache disorders. It is
useful for quantifying disability and tracking a patient-reported outcome in
clinical practice, particularly since disability may improve before other outcome
metrics such as headache frequency in children and adolescents with primary
headache disorders.42 Regarding comorbidities, recent pooled data and
guidelines43,44 recommend that every child with migraine be screened for
anxiety and depressive symptoms and disorders, as these are substantially more
common in this population.
Data also suggest that children and adolescents with primary headache
disorders are more likely to experience other medical comorbidities compared
with their peers (TABLE 9-1).14 In particular, clinicians should address the
association between certain comorbidities and the risk of progression to
chronic migraine (15 or more headache days/month, of which more than 8 meet
migraine criteria).24 A substantial amount of data shows that obesity and
depression are associated with a higher risk of progression to chronic migraine
among adults,45 and preliminary data show that these factors may also be
associated with a higher risk of having high-frequency attacks among children
and adolescents with migraine.43,46

How To Elicit the History

Many pediatric headache practices use standardized questionnaires to elicit the
history from children and adolescents with headache disorders, and these may
serve as a guidepost for semistructured headache interviews. Evidence shows
that standardized headache questionnaires can improve diagnostic specificity,47
although, when used in isolation, they have lower sensitivity than clinical
diagnoses48 and thus must be supported with semistructured interviews to
maximize diagnostic accuracy.

When taking a headache history in younger children or children and
adolescents with learning disabilities, autism spectrum disorder, attention deficit
hyperactivity disorder, or who otherwise process information in different ways,
clinicians may need to use different strategies than those used with older
adolescents and adults. For patients with expressive language limitations,
clinicians can obtain information by speaking to parents about how the patient
behaves and appears before and during their headache attacks. As an example,
during the prodromal phase of migraine, parents may notice that their child is
“off” and may describe that their facial appearance changes (eg, sunken eyes,
pale or flushed face) or that their behavior changes. A consistent pattern of
attacks occurring after specific triggers may also help determine the likelihood of
a primary headache disorder (ie, migraine). Although recent data from
prospective electronic diary studies suggest that migraine triggers are less
consistent and less common than previously thought,48-51 when families have
observed relatively consistent trigger patterns, this may constitute a clue to the
diagnosis. For example, in Western Canada the seasonal, warm wind patterns
known as Chinook winds may act as a migraine trigger; Chinook-wind days and
TABLE 9-1 Common Comorbidities of Primary Headache Disorders in Children and

Adolescents
Medical
◆ Anemia
◆ Asthma
◆ Atopic dermatitis
◆ Obesity
◆ Sleep disorders
Neurologic
◆ Epilepsy
◆ Restless legs syndrome
◆ Tourette syndrome
Psychiatric
◆ Anxiety
◆ Attention deficit hyperactivity disorder
◆ Depression
◆ Suicidality
442 A P R I L 2 0 24

pre-Chinook days have been shown to increase the probability of migraine KEY POINTS
attacks,52 and families will often report relatively consistent associations between
● An assessment of
Chinook winds and attacks in their child. headache-related disability
The patient’s behavior during attacks can also be very informative to the helps the clinician
clinician. Side-locked headaches can be inferred when the patient consistently understand the impact of
holds one side of their head during attacks. Photosensitivity and phonosensitivity headaches on the patient’s
life and track an important
may be inferred by asking if the patient prefers to go to a dark and quiet location
patient-reported outcome.
during attacks.24 Pacing or hypermotor behavior may indicate that the patient is
agitated or restless during the attack, which may suggest the possibility of cluster ● All children and
headache.24 Anorexia during attacks may indicate associated nausea. Observed adolescents with primary
changes to the patient’s facial appearance during the attacks such as ptosis, headache disorders should
be screened for anxiety and
conjunctival injection, and lacrimation suggest a primary headache disorder, depressive symptoms and
either migraine or a trigeminal autonomic cephalalgia if the cranial autonomic disorders.
symptoms are unilateral and associated with side-locked orbital, supraorbital, or
temporal headache.24 For nonverbal children and adolescents, asking the parents ● Asking children to draw a
picture of what their
to obtain a brief video of typical behavior during headaches can help with headache feels like can be
history taking. informative for the clinician,
If the patient has sufficient fine motor skills, asking them to draw a picture and data suggest that
of what it feels like when they have a headache can yield helpful clues to a certain depicted elements
have a high positive
possible diagnosis and can help them express themselves to the clinician. Existing
predictive value for a
data suggest that these drawings can be used to support a diagnosis of migraine, diagnosis of migraine.
with a positive predictive value of 87.1%53; elements with the highest positive
predictive values for ● Given the prevalence of
migraine include adverse childhood
experiences and trauma
features depicting among children and
periorbital pain (eg, adolescents with headache
sharp object to the disorders, clinicians should
eye), sleep or screen for these
experiences and engage in
recumbency, visual trauma-informed care with
symptoms (eg, patients.
scotoma, visual
field deficit), ● In the setting of
posttraumatic headache,
photophobia,
guidelines recommend that
nausea and vestibular and ocular motor
vomiting, and screening maneuvers be
severe, pounding, or performed to identify
abnormalities or symptom
throbbing pain,
provocation from the
often portrayed maneuvers, which may be
with a hammer associated with a higher risk
(FIGURE 9-1).53,54 of prolonged
A final but critical post-concussive symptoms.
consideration for
clinicians taking a
history of any child
or adolescent with
recurrent headaches FIGURE 9-1
is that many Drawing of migraine features by a 16-year-old girl.
The sunglasses and the sun indicate photosensitivity, and the
patients are living
hammer indicates pounding pain quality.
with a history of Reprinted with permission from Lee E, et al, Pediatr Neurol.54
adverse childhood © 2018 Elsevier Science & Technology Journals.

experiences, trauma, or both (be it at the personal, collective, or interpersonal

level).55,56 Existing data have established a temporal relationship between
adverse childhood experiences in early childhood and migraine incidence in
adolescence55 and a dose-response relationship between adverse childhood
experiences and headache disorders,55 which suggest a potentially causal
relationship. Some patients may have experienced stigmatizing or traumatizing

encounters within the health care system in relation to pain presentations, and
these experiences are more common among groups facing collective trauma,
such as Indigenous, Black, Latino, multiracial, and lesbian, gay, bisexual,
transgender, and queer people who frequently face structural racism or bias.56
Stigmatizing, racist, or traumatic health care experiences can discourage care
seeking in the future as the risk of having another negative experience within the
health care system may outweigh the perceived benefit of accessing care. In the
context of our growing knowledge of the relationship between adverse childhood
experiences, trauma, and headache disorders in children and adolescents,

clinicians must become informed about and strive to practice trauma-informed
care. The basis of trauma-informed care is taking a biopsychosocial, holistic
approach to caring for the patient, as opposed to a strict disease-focused
approach.57 Screening patients for adverse childhood experiences and other types
of trauma and supporting families to explore the role that trauma and personal
life experiences play in their pain experience can help support this holistic care
approach.57 Clinicians also need to focus on their communication skills to provide
appropriate trauma-informed care, by engaging in empathetic and active
listening, asking open-ended questions, and building a trusting and empowering
environment for patients.57 In particular, building trust, mutual respect, and
respectful communication practices (eg, asking the patient if you can touch
them during applicable parts of the physical examination) can prevent
retraumatization during the clinical encounter.56
THE PHYSICAL EXAMINATION

The physical examination should start with vital signs and growth parameters,
which may identify contributors to headache etiology including hypertension,
constitutional signs that may be red flags (eg, significant weight loss, fever),35
and obesity (eg, via its association with migraine and idiopathic intracranial
hypertension). If patients endorse orthostatic headaches, vertigo or
lightheadedness preceding or triggering the headaches, and new-onset motion
sickness,58,59 clinicians should consider the possibility of postural orthostatic
tachycardia syndrome and perform orthostatic vitals.
A thorough neurologic examination should be carried out for every new
patient. On cranial nerve examination, fundoscopy is mandatory given that
papilledema is a red flag that should prompt further workup, and any focal
cranial nerve deficits should prompt further evaluation.35 Vestibular and ocular
motor screening should be carried out in the setting of posttraumatic headache;
provocation of symptoms by or abnormalities in saccades or smooth pursuit,
near point of convergence (abnormal when 6 cm or more), accommodation, and
the vestibulo-ocular reflex can be seen after a concussion and have been
associated with prolonged postconcussion symptoms in children and
adolescents.60,61 Standard motor, sensory, coordination, and gait examinations
should be pursued, again to elicit focal deficits that should compel further
workup. In the setting of concussion, in addition to the maneuvers described
444 A P R I L 2 0 24

above, after the gait assessment, more detailed testing of postural stability and KEY POINTS
balance should be completed with tests such as the standing balance test where
● A detailed headache
balance is assessed with eyes open, eyes closed, with the feet in tandem, and with examination can help
a single-leg stance. Further guidelines on how to assess patients after a establish the diagnosis and
concussion are available in the Living Guideline for Pediatric Concussion Care.62 identify conditions that may
For more information, refer to the article “Posttraumatic Headache” by Todd J. overlap with and contribute
to primary headache (eg,
Schwedt, MD, FAAN,63 in this issue of Continuum.
temporomandibular joint
A detailed headache examination should also be performed. Palpation over the disorder).
supratrochlear, supraorbital, greater occipital, and lesser occipital nerves can
elicit the Tinel sign (ie, tingling with palpation) or excessive tenderness to ● Most children and
palpation over the nerve, which may be accompanied by pain radiation along the adolescents presenting with
headache and no red flags
distribution of the nerve in the setting of neuralgia.24 The temporomandibular will not require any
joint should be palpated for tenderness to palpation and during jaw opening to investigations outside of a
assess for joint range of motion, instability, or locking, given that headache thorough history and
attributed to temporomandibular joint disorder can be comorbid with primary physical examination.
headache disorders in children and adolescents64,65 and requires distinct ● The majority of headache
management. In the setting of acute headache, screening for sinusitis by consultations seen in
palpating over the sinuses can alert the clinician to the possibility of sinus disease, pediatric neurology
keeping in mind that migraine is commonly misdiagnosed as sinusitis in the outpatient clinics are for
migraine.
context of chronic recurrent headaches.66 Clinicians may also auscultate the
neck, orbits, and temples for bruits that may signal underlying turbulent flow ● Some children and
through craniocervical vasculature, which in turn may be associated with adolescents with migraine
underlying vascular disease.67 An examination of the neck aimed at assessing will have a history of
range of motion and pain with movement or provocation of headache with episodic syndromes that
may be associated with
movement can be useful in identifying signs consistent with cervicogenic migraine, and abdominal
headache.24 Palpation of the cervical musculature may be useful in identifying migraine confers the
trigger points, which commonly occur in the trapezius in children and strongest risk of subsequent
adolescents with migraine.68 Finally, the Beighton score is a screening technique incident migraine.
for detecting joint hypermobility using simple maneuvers; a Beighton score of ● Migraine is a highly
6 or more can alert the clinician to the possibility of an underlying connective heritable disease and
tissue disorder, which can increase the risk of certain secondary headache approximately two-thirds of
disorders such as cervicogenic headache and spontaneous intracranial children and adolescents
with migraine will have a
hypotension,69 or to joint hypermobility syndrome, which may have an
family history of migraine.
association with migraine in children and adolescents.70
● Approximately 25% of
INVESTIGATIONS children and adolescents
The majority of children and adolescents presenting with headache and no red with “chronic daily
headache” will have new
flags will not require any investigations outside of a thorough history and daily persistent headache,
physical examination. This is supported by the Choosing Wisely campaign, whereby there is a
which recommends (1) to not perform neuroimaging on patients with continuous unrelenting
uncomplicated headache,71 (2) to not perform neuroimaging on patients headache with a distinct
recalled onset that has
presenting with stable attacks that meet migraine criteria,71 and (3) to not persisted for at least
perform EEGs for headache.71,72 These recommendations are also supported by 3 months.
data reviewed in American Academy of Neurology (AAN) evidence-based
guidelines showing that the rate of nonincidental imaging abnormalities (ie,
abnormalities requiring medical or surgical intervention) in children and
adolescents presenting with headache is approximately 2% and that all of these
cases had abnormalities on neurologic examination.73 Studies published since the
initial publication of these 2002 AAN practice recommendations have found
similarly low rates of nonincidental imaging abnormalities in children and

adolescents presenting with headache without red flags.73-78 Although children

and adolescents with primary headache disorders may have nonspecific EEG
abnormalities, particularly during attacks,79 it has long been recognized that there
is no role for EEG in the evaluation of suspected primary headache disorders.70-72
In select cases, laboratory investigations, lumbar puncture, or both may be
indicated, although these are not part of the routine evaluation of children and
adolescents with suspected primary headache disorders.73 As an example, a child
with papilledema, headache, and no mass lesion on neuroimaging should have a

lumbar puncture to measure opening pressure and assess routine chemistries and
cell counts as part of the workup for possible idiopathic intracranial
hypertension. In the setting of headache, altered mental status, and fever, a
lumbar puncture is indicated to rule out meningoencephalitis. Laboratory
investigations may be indicated in select cases where a medical cause of the
headaches is suspected, such as in celiac disease given its established association
with headache in this age group.80
MAKING A PRIMARY HEADACHE DIAGNOSIS

To set the patient up for effective treatment and lifelong disease self-management
strategies, clinicians must first establish a diagnosis and educate the patient about
their diagnosis. Primary headache disorders account for most headache diagnoses
in outpatient pediatric neurology practice and are reviewed below.
Migraine
Migraine is the most common primary headache disorder encountered in
pediatric neurology practice, and this section provides a detailed overview of its
epidemiology, approach to diagnosis and differential diagnosis, and
management.
EPIDEMIOLOGY. In pediatric neurology practice, migraine is ubiquitous and is

diagnosed in 50% to 88% of headache encounters.13,26,27 This is unsurprising, given
that migraine is highly disabling and very common,5 with a global prevalence of
approximately 8% in children and adolescents.1 Children and adolescents with
migraine may experience significant migraine-related disability, with increased
rates of school absenteeism,8,9 lower academic performance,6,7 and fewer
friendships compared with their peers,10 as well as substantial impacts on
functioning at home8,9 and in extracurricular activities.8,9 While the sex ratio for
migraine is approximately 1:1 before puberty, after puberty the incidence curves
diverge and the sex ratio transitions to 2:1 to 3:1 for females relative to males.81 At
least one-third of incident migraine cases occur in childhood or adolescence82 and
the majority of children and adolescents with migraine will continue to experience
headache attacks throughout their life; while about 50% will persist with migraine,
25% will transition to a tension-type headache phenotype over time.14 It is difficult
to predict which patients will constitute the 25% who will outgrow migraine in
adulthood, although data suggest that males82-85 and those who receive an early
diagnosis are more likely to remit.17
DIAGNOSIS. The diagnosis of migraine remains a clinical diagnosis, as no reliable

biomarkers exist. The ICHD-324 outlines the diagnostic criteria for migraine, and
these are listed and compared with the diagnostic criteria for tension-type
headache in TABLE 9-2. Differences to note, as compared with the standard
446 A P R I L 2 0 24

ICHD-3 Diagnostic Criteria for Migraine Without Aura and Infrequent TABLE 9-2
Episodic Tension-type Headachea
Migraine without aura

A At least five attacksb fulfilling criteria B-D

B Headache attacks lasting 4-72 hours (when untreated or unsuccessfully treated)c,d
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 (eg, walking or climbing
stairs)
D During headache at least one of the following

1 Nausea and/or vomiting
2 Photophobia and phonophobia
Infrequent episodic tension-type headache
A At least 10 episodes of headache occurring on <1 day/month on average (<12 days/year) and
fulfilling criteria B-D
B Lasting from 30 minutes to 7 days
C At least two of the following four characteristics
1 Bilateral location
2 Pressing or tightening (nonpulsating) quality
3 Mild or moderate intensity
4 Not aggravated by routine physical activity such as walking or climbing stairs
D Both of the following
1 No nausea or vomiting
2 No more than one of photophobia or phonophobia
E Not better accounted for by another ICHD-3 diagnosise

a
Society, Cephalalgia.24 © 2018, SAGE Publications.
b
One or a few migraine attacks may be difficult to distinguish from symptomatic migraine-like attacks.
Furthermore, the nature of a single or a few attacks may be difficult to understand. Therefore, at least five
attacks are required. Individuals who otherwise meet criteria for migraine without aura but have had fewer
than five attacks should be coded probable migraine without aura.
c
When the patient falls asleep during a migraine attack and wakes up without it, duration of the attack is
reckoned until the time of awakening.
d
In children and adolescents (aged under 18 years), attacks may last 2-72 hours (the evidence for untreated
durations of less than two hours in children has not been substantiated).
e
When headache fulfils criteria for both probable migraine and infrequent episodic tension-type headache,
code as infrequent episodic tension-type headache (or as either subtype of it for which the criteria are
fulfilled) under the general rule that definite diagnoses always trump probable diagnoses.

diagnostic criteria for migraine in adults, are that (1) the location of the pain is
often bilateral and in the frontotemporal regions in younger patients and (2) the
duration of attacks is often shorter compared with adults (2-hour lower threshold
versus 4-hour lower threshold).
These differences in the diagnostic criteria for migraine in children and
adolescents reflect some of the differences in the semiology of migraine across

development. In addition, many younger patients will present with episodic
syndromes that may be associated with migraine later in childhood, adolescence,

or adulthood, whereby headache is not yet a feature (TABLE 9-3) (CASE 9-1). The
ICHD-3 describes four such syndromes: benign paroxysmal torticollis, benign
paroxysmal vertigo, abdominal migraine, and cyclic vomiting syndrome.24 The
prevalence of episodic syndromes that may be associated with migraine has been
estimated at approximately 5% in children.86 The risk of developing migraine
may depend on which syndrome the child presents with, with estimates varying
from approximately 3% to 70%.86-88 Abdominal migraine may confer the highest

risk, with a probability of approximately 70% of developing migraine later in
TABLE 9-3 Periodic Syndromes That May Be Associated With Migrainea,b
Abdominal migraine
◆ At least five recurrent attacks of abdominal pain, lasting 2-72 hours, that have at least two of
the following: midline/periumbilical/poorly localized location, dull or “just sore” quality,
moderate to severe intensity
◆ At least two of: pallor, vomiting, nausea, anorexia
◆ No symptoms between attacks
Benign paroxysmal torticollis
◆ Recurrent attacks of head tilt remitting after minutes to days
◆ Associated with at least one of: pallor, vomiting, ataxia, irritability, or malaise
Benign paroxysmal vertigo
◆ At least five attacks of vertigo that occurs suddenly, is maximal at onset, and resolves
spontaneously in minutes to hours
◆ No loss of consciousness
◆ Associated with at least one of: pallor, vomiting, ataxia, nystagmus, or fearfulness
Cyclical vomiting syndrome
◆ At least five attacks of intense nausea and vomiting (at least four times/hour), that are
stereotypical and recurring with predictable periodicity, lasting from 1 hour to 10 days, and
occurring at least 1 week apart
◆ No symptoms between attacks
Recurrent gastrointestinal disturbance
◆ At least five recurrent attacks of abdominal pain/discomfort with nausea and/or vomiting
◆ Normal gastrointestinal examination and evaluation
a
Data from the Headache Classification Committee of the International Headache Society, Cephalalgia.24
b
Each of these International Classification of Headache Disorders, Third Edition diagnoses requires a normal
neurologic examination (at least in between attacks) and the ruling out of other disorders.
448 A P R I L 2 0 24

life.86 Although many patients will outgrow their episodic syndrome and later
present with migraine, it is also not uncommon that the episodic syndrome may
persist in tandem with the onset of migraine.89 In addition to these syndromes,
the earliest manifestation of migraine risk is infant colic, which occurs in
approximately 20% of infants24 and has been shown to confer an approximately
threefold to fivefold increase in the odds of developing migraine later in life.90

The association between migraine, colic, and the episodic syndromes is likely due
to overlapping predisposing genetic factors.89 As a highly heritable disease, with

heritability estimates of approximately 35% to 60%,91 migraine and the episodic
syndromes often run in families. Inquiring about family history can support a
diagnosis of migraine, as at least two-thirds of children and adolescents with
migraine will report a family history.92
Tension-Type Headache
Tension-type headaches are characterized by lower-severity attacks that are

most often pancranial, with a pressing or tightening quality, and without
An 8-year-old girl presented to a pediatric neurologist for evaluation of CASE 9-1

recurrent headaches over the past year. She had a history of infantile
colic and a long-standing history of intermittent episodes of diffuse
moderate-intensity abdominal pain associated with nausea and pallor
with no diagnosed cause. Over the past year, she had experienced 1 to
2 days per month of bilateral frontotemporal headaches characterized by
throbbing pain of severe intensity, associated with sensitivity to light and
nausea. These attacks were unresponsive to acetaminophen and typically
lasted 6 to 10 hours even when treated. There was a strong family history
of migraine. There were no red flags in her history. She weighed 30 kg and
had a normal neurologic examination. She was diagnosed with migraine
without aura by her neurologist and advised to use ibuprofen 300 mg at
the onset of attacks. At follow-up, the family reported that ibuprofen had
been ineffective. Her neurologist advised adding rizatriptan 5 mg orally
disintegrating tablets to the ibuprofen 300 mg for acute treatment, and
with this combination, her attacks were consistently aborted within 1 to
2 hours.
This case demonstrates how migraine is strongly heritable and how the COMMENT
genetic tendency for migraine can be expressed differentially throughout
development, starting with infant colic, progressing to abdominal migraine,
and finally to a typical migraine without aura presentation in this patient.
The case also illustrates that migraine without any red flags is a clinical
diagnosis that does not require further investigation. Finally, the case
illustrates an evidence-based approach to acute migraine treatment,
whereby ibuprofen 10 mg/kg was tried as a first-line preventive, and a
triptan was added next to try and achieve better efficacy where
monotherapy was ineffective.

significant associated symptoms, in contrast with migraine attacks (TABLE 9-2).

The epidemiology of tension-type headache is less well delineated than that
of migraine, but the majority of existing studies suggest a prevalence of
approximately 30%, with reported ranges from approximately 15% to 60%.6,93,94
Because tension-type headache is substantially less disabling and severe
compared with migraine, it is encountered in neurology practice much

less commonly.
Trigeminal Autonomic Cephalalgias

The trigeminal autonomic cephalalgias are a category of primary headache
disorders that share features of severe, unilateral pain and ipsilateral unilateral
cranial autonomic symptoms.24 These disorders vary in terms of attack length,
chronicity, and response to indomethacin, with paroxysmal hemicrania and
hemicrania continua being indomethacin responsive, and cluster headache,
short-lasting unilateral neuralgiform headache attacks with conjunctival

injection and tearing (SUNCT), and short-lasting unilateral neuralgiform
headache attacks with cranial autonomic symptoms (SUNA) being
nonresponsive to indomethacin. Reliable estimates of the prevalence of
trigeminal autonomic cephalalgias among children and adolescents are
unavailable as no large population-based studies have been carried out to
estimate the frequency of their occurrence in the general pediatric population.
Generally, trigeminal autonomic cephalalgias are considered to be rarer in
children and adolescents compared with adults, although this may be due to
the under-recognition of these disorders in the pediatric setting (CASE 9-2).
As an example, cluster headache onset before age 20 years is diagnosed on
average 13 years after onset,95 which represents a substantially longer average
diagnostic delay than what is reported in adult-onset cases.95 As it stands, there
are very few published cases of trigeminal autonomic cephalalgias in this age
group. Cluster headache is the most commonly reported pediatric trigeminal
autonomic cephalalgia, with approximately 125 published cases reported
to date.96
Existing summative data suggest that the trigeminal autonomic cephalalgias
may present differently in children and adolescents compared with adults, with
more associated migraine features and different attack frequencies as well as pain
locations that may deviate from the ICHD-3 criteria.96,97 To make an accurate
diagnosis and avoid prolonged delays in diagnosis, clinicians must maintain a
high index of suspicion for trigeminal autonomic cephalalgias. One key
consideration when seeing a child or adolescent with headache is whether they
may have an indomethacin-responsive headache disorder. Although rare, it is
important not to miss these cases, as these patients may be absolutely responsive
to indomethacin and establishing the correct diagnosis and treatment can be
curative. Recent data from the largest reported case series of pediatric-onset
indomethacin-responsive headache disorders provide some guidance to
clinicians regarding when to consider an indomethacin trial97:
u Clinical presentation of a known indomethacin-responsive headache disorder (eg,

paroxysmal hemicrania, hemicrania continua, primary stabbing headache)
u Side-locked unilateral headache that has not improved with other interventions
u Primary headache disorder refractory to multiple interventions, associated with
significantly reduced quality of life or function
450 A P R I L 2 0 24

Other Primary Headaches
Several other primary headache disorders may be considered in children and
adolescents, although they are generally rare and not very well defined in the
pediatric population. Primary stabbing headache, characterized by attacks of
brief (lasting seconds) stabs or series of stabs of pain without associated
symptoms, may occur in 3% to 10% of children and adolescents presenting to

neurology clinics with headache.98,99 Although the frequency of primary
stabbing headache is variable, in most cases, attacks are infrequent enough that
treatment is not required. When attacks are frequent and disabling,
indomethacin may be trialed first-line as many (but not all) cases are
indomethacin responsive.99
New daily persistent headache is another primary headache disorder that can
occur in children and adolescents. While new daily persistent headache, like
A 16-year-old boy with a history of chronic migraine was seen in follow-up CASE 9-2
by his pediatric neurologist. He was diagnosed with migraine 2 years
earlier after presenting with status migrainosus and having an admission
to the hospital whereby dihydroergotamine was unsuccessful in aborting
his attack. He had a head CT at the time, which was normal. Since his
presentation, he had experienced daily attacks lasting on average 2 hours
whereby he had unilateral severe temporal pain. The pain was so severe
that he paced during the attacks. Although he had not previously brought
this concern to medical attention, recently one of his family members had
taken a picture of him during an attack and noticed that he had ipsilateral
conjunctival injection and ptosis, which he had consistently noted during
attacks since then. He had tried multiple acute and preventive migraine
interventions without success and given this and the newly reported
unilateral cranial autonomic symptoms, his neurologist revisited the
diagnosis and considered the possibility of chronic cluster headache. A
brain MRI with thin cuts through the pituitary was done to rule out a
structural lesion and was normal. He was tried on inhaled high-flow 100%
oxygen (12 L/minute) for acute therapy, and he was started on verapamil
for prevention. At his 2-month follow-up, he reported that high-flow
oxygen was consistently effective in aborting his attacks within an hour
and that he was now experiencing only 9 days/month of attacks.
This case illustrates the concept of revisiting the patient’s diagnosis when COMMENT
they are not responding to treatment and the fact that cluster headache is
underdiagnosed, with typically long diagnostic delays in the pediatric
population. In this case, the clinician appropriately questioned the chronic
migraine diagnosis when the patient did not respond to several acute and
preventive migraine interventions, and when unilateral cranial autonomic
symptoms were reported. As the patient had only had a head CT, an MRI
was done to rule out pituitary lesions that may be associated with cluster
headache.

other causes of chronic daily headache, leads to persistent headache, it is distinct

from other causes in that (1) the headache is unrelenting (ie, no breaks from the
pain), (2) there is a distinct onset of the headache that is clearly remembered by
the patient and that is followed by continuous pain, and (3) the headache must
have a continuous duration of 3 months or longer to meet ICHD-3 diagnostic
criteria.24 Although on a population basis new daily persistent headache is rare, it

comprises approximately 25% of cases of chronic daily headache in children and
adolescents.100,101 New daily persistent headache is one of the most difficult-to-

treat primary headache disorders, with no high-level evidence to guide treatment
decisions. Although there are minimal data available on the prognosis of
pediatric-onset new daily persistent headache, continuous headache has been
reported to last an average of 8 months in this age group, and improvement is
seen in 80% to 90% of patients by approximately 2 years.101,102 For more
information, refer to the article “New Daily Persistent Headache” by Matthew
Robbins, MD, FAAN, FAHS,103 in this issue of Continuum. Several other primary
headache disorders that rarely occur in children and adolescents are listed in
Section 4 of the ICHD-3.24
TREATMENT
Given that the majority of children and adolescents who are seen in neurology
clinics present with migraine,13,26,27 this section focuses on migraine
management in the pediatric population.
Acute Treatment
The prescription of acute migraine treatment is considered a key metric for
headache care as detailed in the 2021 AAN headache quality measures.104 Thus, it
is crucial that every child with migraine receives a written, step-by-step acute
treatment plan and that this plan be reviewed frequently until there is evidence
of consistent efficacy (eg, 8 to 10 times out of 10 the attack is aborted within
2 hours when the acute treatment is taken appropriately, that is, within 1 hour of
attack onset as per the written action plan). The Pediatric Migraine Action
Plan105 provides a template for stepped acute treatment, similar to the Asthma
Action Plan, and is a useful tool for producing written plans. Aside from
producing written treatment plans, the latest AAN guidelines on the acute
treatment of migraine in children and adolescents outline several evidence-based
recommendations for acute treatment (TABLE 9-4).44
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. Based on pediatric-specific available

evidence, ibuprofen 10 mg/kg is the recommended first-line acute treatment for
children and adolescents with migraine (CASE 9-1).44 It has been shown to be
superior to both placebo106 and acetaminophen107 for the acute treatment of
migraine in children and adolescents. Although pediatric-specific evidence for
other noncombination nonsteroidal anti-inflammatory drugs is not available,
sumatriptan and naproxen combination tablets have been shown to be effective
in treating acute attacks of migraine in adolescents,108,109 and naproxen is
therefore commonly used in pediatric headache practice and recommended in
the AAN guidelines as a possible add-on to triptan therapy for adolescents who
have not responded to a triptan alone.44 Other nonsteroidal anti-inflammatory
drugs are sometimes used off-label in practice based on extrapolated data from
the adult literature (eg, diclofenac, ketoprofen).
452 A P R I L 2 0 24

TRIPTANS. Four triptans are US Food and Drug Administration (FDA) approved KEY POINTS
for use in pediatric patients (TABLE 9-5) and are recommended for use in
● Prescribing an effective
adolescents in the AAN guidelines44: rizatriptan orally disintegrating tablets (FDA acute treatment plan for
labeled for patients 6 years old and older), zolmitriptan nasal spray, almotriptan children and adolescents
tablets, and sumatriptan and naproxen combination tablets. Although these four with migraine is a consensus
triptans have the highest level of evidence for use in pediatric patients, pooled best practice and may
mitigate the risk of disease
evidence does suggest that triptans as a class are superior to placebo for acute
progression.
migraine treatment in adolescents.110 In practice, the other triptans are used
off-label in children and adolescents, based on available safety data from existing ● Ibuprofen 10 mg/kg is the
trials and pharmacokinetic studies. In the author’s experience and practice, recommended first-line
dosing of the triptans, which all come in at least two different dosage strengths, acute migraine intervention
for children and adolescents
can be guided by the child’s weight, and most clinicians administer the according to the latest
lower-dose strength for patients who weigh less than 30 kg to 40 kg (66.1 lbs to American Academy of
88.2 lbs), and the higher-dose strength for patients who weigh more than 30 kg to Neurology (AAN) guidelines.
40 kg (66.1 lbs to 88.2 lbs). A substantial benefit of the triptans is their availability
● Patients who have a rapid
in various formulations. Both sumatriptan and zolmitriptan are available as nasal peak in severity or nausea
sprays, sumatriptan is available in an injectable form, and rizatriptan and and vomiting with their
zolmitriptan are available as orally disintegrating tablets. Patients with rapid attacks of migraine should
peaks in attack severity, significant nausea or vomiting, or both can benefit from be offered acute
interventions with alternate
intranasal formulations, injectable routes, or orally disintegrating tablet
routes of administration
formulations. such as nasal sprays, oral
dissolving tablets, or
ANTINAUSEANTS. Although not specifically studied for acute migraine subcutaneous injections.
management in children and adolescents outside of the emergency department
setting, antinausea medication has an important role to play in acute migraine ● Three noninvasive
neuromodulation devices
management for certain patients. As outlined in the recent AAN guidelines, none
are US Food and Drug
of the nonsteroidal anti-inflammatory drugs or triptans appear to produce Administration (FDA)
significant relief in nausea or vomiting based on the available evidence.44 In this cleared for use in
context, there is a recommendation that clinicians offer additional antinausea adolescents 12 years old and
older with migraine: remote
treatment to children and adolescents with migraine and prominent nausea or
electrical neuromodulation,
vomiting.44 The most commonly used antinauseants in this setting are single-pulse transcranial
ondansetron and neuroleptics like prochlorperazine and metoclopramide. While magnetic stimulation, and
these medications are available as swallowed tablets, ondansetron also comes in noninvasive vagus nerve
an orally dissolving tablet formulation, and prochlorperazine is available in rectal stimulation.
suppository form for cases where swallowing a tablet is precluded by the severity ● Preventive treatment
of the vomiting. should be offered to
children and adolescents
GEPANTS. The gepants comprise a new class of migraine-specific medications with migraine who are
that act as antagonists at the calcitonin gene-related peptide (CGRP) receptor. experiencing attacks at a
Three of the gepants have phase 3 clinical trial data to support their efficacy for frequency or severity that is
leading to significant
acute treatment of migraine in adults and have been FDA approved for this disability.
indication: ubrogepant tablets, rimegepant orally dissolving tablets, and
zavegepant nasal spray. At present, there are no published data on gepant use in
children and adolescents. There are ongoing phase 3 trials that are recruiting
children and adolescents with migraine to assess the efficacy and safety of
ubrogepant111 and rimegepant112 for acute migraine treatment. In the absence of
any pediatric-specific data, the use of gepants is off-label and poses challenges
with respect to insurance coverage.
NONINVASIVE NEUROMODULATION. Given the relatively recent FDA clearance of

three neuromodulation devices for the treatment of migraine in adolescents

TABLE 9-4 Summary of Recommendations From the American Academy of Neurology

(AAN) Guidelines on the Acute Treatment of Migraine in Children and
Adolescentsa
Level of
Summary of recommendation rationale Summary of recommendation statements obligationb
1 Appropriate care requires a specific headache 1a Clinicians should diagnose a specific headache B
diagnosis type
1b Clinicians should ask about premonitory and aura B

symptoms, headache semiology, associated
symptoms, and pain-related disability to improve
diagnostic accuracy and appropriately counsel the
patient
2 Acute migraine treatment – need for fast and 2a Clinicians should counsel that acute migraine B
complete pain relief treatments are more likely to be effective when
used early in the attack, when the pain is still mild
2b Clinicians should prescribe ibuprofen 10 mg/kg B

as the initial acute treatment option
2c Clinicians should prescribe sumatriptan/ B

naproxen (10 mg/60 mg, 30 mg/180 mg, 85 mg/
500 mg), zolmitriptan nasal spray (5 mg/actuation),
sumatriptan nasal spray (20 mg/actuation),
rizatriptan orally disintegrating tablets (5 mg, 10 mg),
or almotriptan (6.25 mg, 12.5 mg) to reduce
headache pain in adolescents with migraine
3 Acute migraine treatment – need to treat 3a Clinicians should counsel patients and families B
individual headache characteristics that a series of medications may be needed prior
to finding the most beneficial treatment
3b Clinicians should instruct patients and families B

to use the medication that best treats the
characteristics of each attack to balance efficacy,
side effects, and patient preference
3c Clinicians should offer an alternative triptan if a B

triptan is ineffective
3d Clinicians may prescribe a nonoral route when C

the attack peaks in severity rapidly, is associated
with nausea or vomiting, or oral formulations are
ineffective
3e Clinicians should counsel patients to take a B

second dose of acute medication if their headache
recurs within 24 hours of successful treatment
4 Adding a nonsteroidal anti-inflammatory drug 4 Clinicians should offer ibuprofen or naproxen in B

to a triptan may increase effectiveness addition to a triptan in adolescents with migraine
who are incompletely responsive to a triptan alone
5 Acute migraine medications may not treat 5 Clinicians should offer additional antiemetic B
nausea and vomiting treatments to children and adolescents with
prominent nausea and vomiting
454 A P R I L 2 0 24

Level of
6 Patient education around behavioral aspects of 6a Clinicians should counsel patients and families B
self-care can improve outcomes about lifestyle modifications, identification/
disproof/resolution of migraine triggers and
alleviating factors, and avoidance of medication
overuse
6b Clinicians should collaborate with patients and B

families on treatment goals that are individualized
to the patient
6c Clinicians may counsel patients and families to C

maintain a headache diary
6d Clinicians should counsel patients to use no B

more than:
14 Days of ibuprofen or acetaminophen/month
9 Days of triptans/month
9 Days of any combination of triptans, analgesics,

or opioids
There is no evidence to support the use of opioids

in children and adolescents with migraine
7 Triptans have cardiac contraindications 7 Clinicians must not prescribe triptans to patients A
with a history of ischemic vascular disease or
accessory conduction pathway disorders
8 Triptans are not as effective during the aura 8a Clinicians should counsel adolescent patients B
phase and are contraindicated in brainstem and that triptans, while safe to take during the aura, are
hemiplegic aura more effective if taken at onset of head pain
8b Clinicians may refer patients with hemiplegic C

migraine or migraine with brainstem aura who do
not respond to other treatments to a headache
specialist
a
Data from Oskoui M, et al, Neurology.44
b
Each level of obligation corresponds to a helping verb that denotes the strength of the recommendation: Level A is denoted by the use of the
word must, Level B is denoted by the use of the word should, and Level C is denoted by the use of the word may.

(TABLE 9-5), neuromodulation is playing a more prominent role in treating

migraine in the pediatric population. Neuromodulation has the advantage of
being an option for patients with contraindications to pharmacologic migraine
interventions. Three neuromodulation devices can be used to treat acute attacks
of migraine that have FDA clearance for use in adolescents: the remote electrical
neuromodulation device, the single pulse transcranial magnetic stimulation

device, and the noninvasive vagus nerve stimulator device. The data that led to
the FDA clearance of these devices for use in adolescents are derived from
observational, uncontrolled, open-label studies. Two of the devices have data to
support their efficacy and safety for treating acute attacks of migraine in
adolescents: the noninvasive vagus nerve stimulator that was studied in a study
with nine adolescent participants,113 and the remote electrical neuromodulation
device that was studied in an open-label study with 60 adolescent participants.114
The approval of the single-pulse transcranial magnetic stimulation device
was based on an open-label study that collected data on the efficacy of the device
for preventive migraine treatment in 21 adolescents,115 although the device can
also be used to treat attacks acutely. Although not FDA cleared for use in
adolescents, there is also an external trigeminal nerve stimulator device and a
device that concurrently stimulates the trigeminal and occipital nerves, both of
which can be used off-label to treat acute attacks of migraine in this population.
Neuromodulation was not covered in the scope of the 2019 AAN guidelines,44
and some of the pertinent data and FDA decisions have emerged since their
publication. Despite the absence of recommendations around neuromodulation,
in the author’s opinion, given published favorable safety profiles and some
preliminary efficacy data, clinicians should discuss neuromodulation options
with patients and families, especially when there are contraindications to
pharmacologic interventions or when the family is interested in these
treatment modalities.
TABLE 9-5 US Food and Drug Administration Approved or Cleared Interventions for
Acute Migraine in Children and Adolescents
US Food and Drug

Administration Applicable
Intervention (FDA) status ages
Rizatriptan 5 mg orally disintegrating tablets FDA approved ≥6 years
Zolmitriptan 2.5 mg/actuation nasal spray FDA approved ≥12 years
Almotriptan 6.25 mg and 12.5 mg tablets FDA approved ≥12 years
Sumatriptan/naproxen 10 mg/60 mg to 85 mg/ FDA approved ≥12 years

500 mg range
Remote electrical neuromodulation device FDA cleared ≥12 years
Noninvasive vagus nerve stimulation device FDA cleared ≥12 years
Single-pulse transcranial magnetic stimulation FDA cleared ≥12 years

device
456 A P R I L 2 0 24

Preventive Treatment KEY POINTS
Children and adolescents with migraine who experience attacks at a frequency
● Clinical trial data suggest
or severity that causes significant migraine-related disability should be that approximately
offered preventive treatment.44 Preventive treatment exists in multiple two-thirds of children and
different modalities with varying levels of evidence: pill-based treatment adolescents with migraine
(pharmacologic or nutraceutical), psychological treatment, neuromodulation will achieve treatment goals

(ie, 50% or greater reduction
devices, injection-based treatments (eg, onabotulinumtoxinA injections,
in headache frequency)
nerve blocks), and alternative interventions (eg, acupuncture, massage). The using pill-based preventive
scope of the 2019 AAN guidelines on preventive treatment for children and interventions.
adolescents with migraine focused on pharmacologic pill-based interventions
with or without cognitive behavioral therapy (TABLE 9-6).116 At present, to the ● Psychological
interventions have a
author’s knowledge, there are no guidelines on how to integrate other significant body of evidence
preventive treatment modalities into the care of children and adolescents to support their use in
with migraine. children and adolescents
with migraine and should be

considered as potential
PILL-BASED PREVENTIVES. Pill-based preventive interventions for children and first-line interventions (in
adolescents with migraine have traditionally been borrowed from adult practice combination with pill-based
and “downsized” for use in younger patients. The Childhood and Adolescent interventions).
Migraine Prevention trial, which randomized 361 children and adolescents
● Other treatment
with migraine to amitriptyline, topiramate, or placebo for a 24-week treatment
modalities (eg,
period, put into question whether available pill-based preventives have interventional,
benefit over placebo in pediatric practice. In this trial, there was no statistically neuromodulation) should be
significant difference between the trial interventions with regards to the considered when children
and adolescents with
primary outcome (ie, the proportion of participants achieving a 50% or greater
migraine have not improved
reduction in headache frequency); regardless of the intervention, approximately with two or more pill-based
two-thirds of participants achieved the primary outcome117 and the vast preventive interventions.
majority of participants sustained this improvement over a 3-year follow-up
period, even though almost all participants discontinued the intervention ● While pediatric clinical
trials are underway, there
soon after trial completion.18 A recent network meta-analysis that examined are expert consensus
multiple pill-based preventive interventions corroborated this finding and guidelines to guide clinicians
supported the conclusion that it is unclear if current pill-based preventive in when to consider
interventions are superior to placebo among clinical trial participants, who off-label use of anti–
calcitonin gene-related
tend to be different from real-world clinical populations (eg, patients with peptide monoclonal
medication overuse, psychiatric comorbidity, and continuous headache are antibodies in children and
excluded).118 adolescents with migraine.
In 2019, the AAN published evidence-based guidelines on the use of
● Although evidence in this
preventive pharmacologic interventions for children and adolescents
area is limited, children and
with migraine, alone or in combination with cognitive behavioral therapy adolescents with headache
(TABLE 9-6).44 In practice, a critical consideration for prescribing pill-based disorders should be
interventions for prevention is that providers must engage families in shared counseled on the
decision making and educate families about the state of the evidence for relationship between
headaches and poor sleep,
preventive interventions for children and adolescents with migraine. Because the obesity, meal skipping
placebo response is likely driving most, if not all, of the improvements seen when (particularly breakfast), and
patients take pill-based preventives, in the author’s opinion, clinicians should low physical activity.
focus on shared decision making, choose interventions that minimize side effects
as first-line treatments, and use honest strategies that promote treatment
expectancy for patients (eg, being cautiously optimistic about treatment
potential given high reported placebo response rates).117 A list of preventive
interventions that are used in practice in children and adolescents with migraine
is provided in TABLE 9-7.119-131

TABLE 9-6 Summary of Recommendations from the American Academy of Neurology

(AAN) Guidelines on Preventive Treatment of Migraine in Children and
Adolescentsa
Level of
1 Lifestyle and behavioral factors play a role in 1a Clinicians should counsel patients and families B
disease management that lifestyle and behavioral factors can impact headache
frequency
1b Clinicians should educate patients and families about B

identifying and modifying modifiable contributors to
disease severity
2 Patients with frequent and/or severe attacks 2a Clinicians should discuss the potential role of B
should be offered preventive treatment preventive treatment in patients with frequent headache,
migraine-related disability, or both
2b Clinicians should discuss the potential role of B

preventive treatment in patients with medication overuse
3 There is some evidence for pharmacologic 3a Clinicians should inform patients and families that B
interventions and cognitive behavioral therapy clinical trials show that many children and adolescents
in the preventive treatment of children and with migraine improve with placebo and the majority of
adolescents with migraine and placebo preventive medications are not superior to placebo in the
response rates are high in this context existing trials
3b Clinicians should acknowledge the limitations of the B

available evidence and engage in shared decision making
with families regarding the use of short-term treatment
trials (minimum 2 months) in patients who could benefit
from preventive treatment
3c Clinicians should discuss the evidence for amitriptyline B

combined with cognitive behavioral therapy for migraine
prevention, inform patients of potential amitriptyline side
effects (including risk of suicide), and work with families to
find providers who offer this type of treatment
3d Clinicians should discuss the evidence for topiramate in B

migraine prevention in children and adolescents and
discuss its side effects
3e Clinicians should discuss the evidence for propranolol B

in migraine prevention in children and adolescents and
discuss its side effects
4 Available medications have teratogenic 4a Clinicians must consider the teratogenic effect of A
potential topiramate and valproate in their choice of migraine
preventive therapy for patients of childbearing potential
4b Clinicians who offer topiramate or valproate for A

migraine prevention to patients of childbearing potential
must counsel these patients about effects on fetal/
childhood development
458 A P R I L 2 0 24

Level of
4c Clinicians who prescribe topiramate for migraine A

prevention to patients of childbearing potential must
counsel these patients about the potential of topiramate
to decrease the efficacy of oral contraceptives,
particularly in doses ≥200 mg/day
4d Clinicians who prescribe topiramate or valproate to B

patients of childbearing potential should counsel patients
to discuss contraception methods with their health care
provider
4e Clinicians must recommend daily folic acid A

supplementation to patients of childbearing potential who
take topiramate or valproate
5 Migraine is a chronic disease with a fluctuating 5a Clinicians must periodically monitor medication A
course and evidence on stopping medications is effectiveness and adverse events when prescribing
limited preventive treatments
5b Clinicians should counsel patients and families about B

the risks and benefits of stopping preventive medication
once treatment goals are reached
6 Comorbid negative emotional states, 6a Clinicians should screen patients for mood and anxiety B
including anxiety, depression, and mental disorders
distress may be associated with higher risk of
6b Clinicians should discuss management options for B
headache persistence
anxiety and depressive disorders in patients with these
comorbid conditions
a
Data from Oskoui M, et al, Neurology.116
b
Each level of obligation corresponds to a helping verb that denotes the strength of the recommendation: Level A is denoted by the use of the
word must, Level B is denoted by the use of the word should, and Level C is denoted by the use of the word may.

TABLE 9-7 Preventive Interventions for Children and Adolescents With Migraine
Highest level of
evidence (American
Academy of Neurology Primary 2019 AAN
Intervention [AAN] classes)a recommendation Dosing Side effects

116
Pill-based pharmaceuticals addressed in 2019 AAN Guidelines
Topiramate Class I Moderate 2 mg/kg/day to Word-finding

confidence that it is 3 mg/kg/day given in difficulties, weight loss,
more likely than two divided doses; paresthesia, decreased
placebo to decrease maximum 200 mg/day sweating, decreased
the frequency of efficacy of oral
headache days contraceptive pills at
doses ≥200 mg/day
Serious: teratogenic (eg,

cleft lip, cleft palate),
nephrolithiasis, glaucoma
Cinnarizineb Class II Moderate confidence 1.5 mg/kg/day if Sedation, weight gain

that it is more likely than <30 kg (66.1 lbs) and
placebo to decrease 30 mg/day if ≥30 kg
the frequency of (66.1 lbs)
headache days
Propranolol Class III Low confidence that 0.5 mg/kg/day to May worsen asthma
it is more likely than 4 mg/kg/day divided in and depression,
placebo to decrease three doses; maximum hypotension,
the frequency of 120 mg/day bradycardia, weight
headache days by gain
≥50%
Amitriptylinec Class I Insufficient evidence 1 mg/kg/day given once Constipation, dry eyes,
in the evening; dry mouth, sedation,
maximum 100 mg/day QT prolongation
Serious: increased risk
of suicidality if patient is
depressed, increased
risk of serotonin
syndrome when
combined with other
medications that
increase serotonin
Divalproex Class II Insufficient evidence 15 mg/kg/day to Sedation, weight gain,

sodium 30 mg/kg/day; hair loss, hair curling,
maximum 1000 mg/day dizziness, ataxia,
nystagmus, tremor
Serious: monitor for
thrombocytopenia and
other bone marrow
suppression,
pancreatitis,
hyperammonemic
encephalopathy,
hepatotoxicity,
teratogenic (eg,
congenital heart
defects, developmental
disorders), carnitine
deficiency, polycystic
ovary syndrome
460 A P R I L 2 0 24

Highest level of
evidence (American

b
Flunarizine Class III Insufficient evidence 5 mg/day to 10 mg/day Sedation, weight gain
given once in the
evening
Nimodipine Class III Insufficient evidence 30 mg/day to Hypotension,

60 mg/day divided in bradycardia, nausea and
three doses gastrointestinal side
effects
Select pill-based pharmaceuticals not covered in 2019 AAN Guidelines

Levetiracetam Class I119 N/A 20 mg/kg/day to Psychiatric and

40 mg/kg/day divided behavioral side effects
in two doses, maximum (irritability, mood
3000 mg/day lability), fatigue
Cyproheptadine Class IV120 N/A 0.25 mg/kg/day to Sedation, weight gain

0.5 mg/kg/day divided
in two doses, maximum
16 mg/day
Pregabalin Class II121 N/A 50 mg/day to Sedation, dizziness

75 mg/day
Serious: angioedema
Nutraceuticals
Coenzyme Q10 Class II122 N/A 100 mg 1 time a day if Increased eructations
<30 kg (66.1 lbs) and
100 mg 2 times a day if
≥30 kg (66.1 lbs)
Magnesium Class I123 N/A 9 mg/kg/day of Soft stools/diarrhea,

elemental magnesium gastrointestinal
symptoms
Riboflavin Class I N/A 200 mg/day to Orange discoloration of

(vitamin B2) (negative 400 mg/day urine
trial)124
Melatonin Class II125,126 N/A 0.3 mg/kg/day given Sedation

once at bedtime
(maximum 10 mg/day)
Injection-based treatments
OnabotulinumtoxinA Class I Insufficient evidence 74 U IM to 155 U IM Injection-site pain,

injections (negative every 12 weeks worsened headache,
trial)127 ptosis, neck weakness

CONTINUED
CONTINUED FROM FROM PAGE 461
PAGE 461
Highest level of
evidence (American
Occipital nerve Class IV128 N/A 1 cc to 2 cc129 of 0.25% Injection-site pain,

blocks to 0.5% bupivacaine or worsened headache,

1% to 2% lidocaine per transient dizziness,
injection site, can be alopecia when steroids
repeated every 2 to used
4 weeks or less
frequently if response Serious: local
more prolonged anesthetic systemic
(sometimes steroids toxicity
are added to injectate
and frequency of
injections would be
every 3 months in this
case)
Neuromodulation devices
Single pulse Class IV115 N/A Two magnetic pulses Lightheadedness,

transcranial are given over tingling, tinnitus,
magnetic 2 minutes and in dizziness, headache,
stimulation 15 minutes the two discomfort (scalp, from
device pulses over 2 minutes noise)
are repeated (for a total
of four pulses);
stimulation in this
protocol is given twice
a day
Noninvasive Class IV113 N/A 2 2-minute treatments Pain or discomfort at

vagus nerve given 3 times a day application site,
stimulator erythema, rash,
dizziness
External Class IV130 N/A Used 1 time a day for Discomfort from the
trigeminal nerve 20 minutes of tingling sensations,
stimulator preventive stimulation sleepiness, headache,
rash after application
of electrode glue
Remote electrical Class IV131 N/A Used once daily every Pain, discomfort,
neuromodulation second day pruritis, paresthesia, or
device for 45 minutes warm sensation at the
of preventive application site; pain in
stimulation the arm, shoulders, or
neck; transient arm/
hand numbness;
muscle spasm
a
AAN levels of evidence denote the risk of bias: Class I = low risk of bias; Class II = moderate risk of bias; Class III = moderately high risk of bias;
Class IV = very high risk of bias.
b
Not available in the United States.
c
Amitriptyline in combination with cognitive behavioral therapy has Class I evidence to support its efficacy, with the 2019 AAN recommendations
stating high confidence that this combination is superior to amitriptyline plus headache education to achieve a reduction in headache frequency.
462 A P R I L 2 0 24

PSYCHOLOGICAL PREVENTIVE INTERVENTIONS. There is Class I level evidence to
support using the combination of a pill-based preventive intervention (ie,
amitriptyline) and cognitive behavioral therapy for the treatment of chronic
migraine in children and adolescents.116 In general, psychological interventions,
including cognitive behavioral therapy, biofeedback, and relaxation-based
strategies, have a solid foundation of meta-analysis–level evidence to support

their use in children and adolescents with migraine132 and should be considered
as first-line preventive interventions (in combination with a pill-based

approach), particularly in children and adolescents with chronic migraine.
INTERVENTIONAL PREVENTIVE THERAPIES. When two or more pill-based preventive

interventions have been ineffective (alone or in combination with psychological
interventions), in the author’s opinion, clinicians should consider offering
another type of treatment modality (CASE 9-3). Interventional approaches, while
generally having lower levels of supportive evidence compared with pill-based

and psychological interventions, are used commonly in pediatric headache
practice (TABLE 9-7). OnabotulinumtoxinA injections, given every 12 weeks in the
Phase III Research Evaluating Migraine Prophylaxis Therapy protocol pattern,133
are used in older children and adolescents with chronic migraine who have tried
two or more other preventive treatments without efficacy or tolerability.
Peripheral nerve blocks are also used as preventive treatments both in the
context of comorbid occipital neuralgia24 and for isolated migraine in patients
where less invasive interventions have not been effective. While many different
peripheral nerves may be blocked for migraine prevention, the majority of both
pediatric clinical experience134 and data128 pertains to the blockade of the greater
and lesser occipital nerves.
NONINVASIVE NEUROMODULATION PREVENTIVE INTERVENTIONS. Noninvasive

neuromodulation is another important part of both the acute and preventive
treatment landscape for migraine in children and adolescents. The evidence for
neuromodulation in children and adolescents with migraine is reviewed in the
Acute Treatment section. Although three devices with preventive treatment
modes have been FDA cleared for use in adolescents with migraine (TABLE 9-7),
only two of these devices have pediatric data on preventive use: the remote
electrical neuromodulation device131 and the single-pulse transcranial magnetic
stimulation device.115
GEPANTS. In addition to the gepants that have FDA-approved indications for

acute migraine treatment, two gepants are FDA approved for preventive use in
adults based on clinical trial data: rimegepant and atogepant. Although there
are presently no published data on preventive gepant use in children and
adolescents, there are ongoing clinical trials that aim to study the efficacy and
safety of rimegepant135 and atogepant136 for preventive use in children and
adolescents.
ANTI–CALCITONIN GENE-RELATED PEPTIDE MONOCLONAL ANTIBODIES. Four

monoclonal antibodies that target CGRP (fremanezumab, galcanezumab, and
eptinezumab) or its receptor (erenumab) have been FDA approved for
preventive use in adults with migraine based on multiple clinical trials. There are
two observational studies on the use of the anti-CGRP antibodies in children and

adolescents. A Class IV uncontrolled observational study reported on the use of

various anti-CGRP antibodies (predominantly erenumab) in adolescents with
chronic headache disorders (the majority of whom had chronic migraine). The
study population differed from the adult trials in that approximately two-thirds
of the adolescents had continuous headache and participants had on average 9.5
prior preventive treatment trials. On average, patients had a decrease of 2

headache days/month and approximately one-third of patients had adverse
events, with the most common being injection-site reactions, constipation,

fatigue, dizziness, nausea, and worsening headache.137 There is also a small
uncontrolled observational study on the use of intravenous eptinezumab among
CASE 9-3 A 14-year-old boy was referred to a pediatric neurologist by his

pediatrician for treatment-resistant migraine. He was diagnosed with

migraine 3 years earlier and with the help of his pediatrician had found
effective acute treatment with a combination of naproxen 600 mg and
zolmitriptan nasal spray 5 mg, which consistently aborted his attacks
within 1 to 2 hours. However, despite adequate trials of coenzyme Q10,
amitriptyline, topiramate, and propranolol, whereby therapeutic doses
were obtained and tried for a minimum of 6 to 8 weeks, he continued to
experience 20 headache days/month, of which 10 met criteria for
migraine. He was missing an average of 2 days/week of school and had
stopped extracurricular activities in this context. His neurologist
discussed other treatment modality options with him, strongly
recommending pain-focused cognitive behavioral therapy, in
combination with a trial of either onabotulinumtoxinA injections, an anti–
calcitonin gene-related peptide monoclonal antibody, or a
neuromodulation device. Preferring a less invasive approach, he pursued
ten sessions of pain-focused cognitive behavioral therapy with a
psychologist and purchased a remote electrical neuromodulation device.
At 3-month follow-up, his headache frequency was reduced to 8 days/
month of headache, of which 3 met migraine criteria. He continued to use
the device for 12 months, after which he was successfully weaned off and
maintained treatment goals.
COMMENT This case illustrates the management of resistant migraine in an

adolescent. When this patient first presented to care, migraine-focused
cognitive behavioral therapy should ideally have been offered as a first-line
preventive intervention along with pill-based treatment, although
accessing psychological interventions is often challenging outside of the
tertiary care setting. Given several ineffective trials of pill-based
interventions, the neurologist appropriately offered the patient several
other treatment modality options in combination with cognitive behavioral
therapy and engaged in shared decision making to select the best
treatment. The patient improved with combined cognitive behavioral
therapy and neuromodulation, and he was able to come off interventions
after 12 months of clinical stability.
464 A P R I L 2 0 24

nine adolescents and young adults with chronic headache disorders (seven
had chronic migraine) that showed preliminary but promising efficacy and
safety data.138 After the initial FDA approvals in adults, expert consensus
recommendations were published to guide clinicians regarding when to consider
prescribing the off-label use of anti-CGRP antibodies in children and
adolescents139:
u Eight or more headache days per month

u Failure of two or more preventive therapies (eg, pharmacologic, nutraceutical,
nonpharmacologic)
u Pediatric Migraine Disability Assessment score of 30 or greater
u Postpubertal adolescent, or prepubertal child in selected cases
The recommendations and published observational data can be used to

navigate insurance issues related to off-label pediatric anti-CGRP antibody use.
Self-Management Counseling
Although there is minimal evidence available to support the use of
self-management recommendations about lifestyle interventions for children
and adolescents with headache disorders, educating patients about healthy day-
to-day choices is a routine part of clinical practice. The data in this area come
from observational studies, and to date, no clinical trials have been published to
strengthen the level of evidence behind these recommendations. In this context,
it is important for clinicians to explain the level of evidence to patients and
families and avoid approaching the conversation in a manner whereby the
patient and family may interpret the headaches as their “fault” because of
lifestyle choices. It is also important to acknowledge external factors such as early
school start times that may impact sleep duration and financial factors that may
affect the availability of healthy food choices when having these discussions
with patients.
Generally, recommendations should focus on areas where there is some
evidence to support a link between headaches and the lifestyle factor. Poor
sleep140 and early wake times141 have been associated with headaches in children
and adolescents, and education around sleep hygiene is likely helpful in this
population. Where there is comorbid insomnia, there is preliminary evidence to
support the use of cognitive behavioral therapy for insomnia in adolescents with
chronic migraine.142 Given the association between obesity and migraine,143 and
given some observational data to show that weight loss is associated with a
reduction of headache frequency in children and adolescents,46 counseling
around the possible benefits of weight loss in overweight patients may be
beneficial. Skipping meals, particularly breakfast,144 may also be associated with
frequent headaches in adolescents, and generally consistency in meal timing and
eating regularly is recommended to patients and families. Low physical activity
has also been correlated with frequent headaches in adolescents,144,145 and
increasing physical activity levels may benefit patients.
Comorbidity Screening and Management

While pediatric migraine has been shown to be comorbid with a variety of
physical and medical disorders (TABLE 9-1), the strongest level of evidence

pertains to the association between migraine (as well as other primary headache
disorders) and anxiety and depressive symptoms and disorders.43 Given this
well-established association, all children and adolescents with migraine or
another primary headache disorder should be screened for anxiety and
depressive symptoms and disorders.
CONCLUSION
Headache disorders are very common in children and adolescents, with migraine
being the most frequently encountered pediatric headache disorder in practice.
The population burden associated with pediatric headache disorders is massive,5
and access to evidence-based care is limited, particularly for minoritized patient
populations.19-21 To date, advances in care for pediatric headache disorders have
been limited by a severely underfunded research landscape.11 Currently,
treatment decisions are based on limited evidence, although existing data do

suggest that most children and adolescents with migraine will improve with
multimodal care that includes pill-based interventions and education.18 Working
toward broader and more equitable access to a diagnosis and evidence-based care
for children and adolescents with headache disorders not only will likely reduce
the burden of headache disorders in childhood and adolescence, but also has
significant potential to contribute to a reduced burden of disease in adulthood.
USEFUL WEBSITES
AMERICAN MIGRAINE FOUNDATION MIGRAINE CANADA
The American Migraine Foundation has many useful Migraine Canada is a registered charity that aims to
educational resources for patients and families improve the lives of people living with migraine. The
about migraine in children and adolescents. website has educational resources for both
americanmigrainefoundation.org/ patients and families and for health care providers
treating children and adolescents with migraine.
migrainecanada.org/
MIGRAINE AT SCHOOL
Migraine at School is an advocacy organization
developed by the Coalition for Migraine and PEDIATRIC MIGRAINE ACTION PLAN
Headache Disorders and the Daniele Byron Henry This is a link to the Pediatric Migraine Action Plan
Migraine Foundation that provides resources to that provides clinicians with a framework for
patients, their families, and educators about how to developing written acute treatment plans for
advocate for youth with migraine in school. children and adolescents with migraine.
www.migraineatschool.org/ headachejournal.onlinelibrary.wiley.com/doi/10.
1111/head.13681
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DISCLOSURE
Dr Orr has noncompensated relationships as an
associate editor with Headache: The Journal of
Head and Face Pain and as an editorial board
member with Neurology that are relevant to
American Academy of Neurology (AAN) interests or
activities. The institution of Dr Orr has received
research support from the Alberta Children's
Hospital Research Institute and the Canadian
Institutes of Health Research.
472 A P R I L 2 0 24

Cranial Neuralgias REVIEW ARTICLE

By Stephanie J. Nahas, MD, MSEd, FAAN C O N T I N U UM A U D I O
ONLINE
ABSTRACT
OBJECTIVE: The cranial neuralgias are relatively rare, but recognizing
these syndromes and distinguishing among them is critical to reducing
unnecessary pain and disability for affected patients. Despite their CITE AS:
distinctive features, cranial neuralgias may go undiagnosed or 2024;30(2, HEADACHE):473–487.
misdiagnosed for several years. A notable proportion of cranial
neuralgia presentations are due to secondary causes and require Address correspondence to
zpIyX172RtLjRfXyq2HnHWTE= on 04/03/2024
targeted treatment. The purpose of this article is to review the Dr Stephanie Nahas, 900
Walnut St, Suite 200
diagnosis and management of cranial neuralgias encountered in clinical Philadelphia, PA 19107,
practice. stephanie.nahas@
jefferson.edu.
LATEST DEVELOPMENTS: In 2020, the International Classification of Orofacial RELATIONSHIP DISCLOSURE:

Pain was released for the first time. Modeled after the International Dr Nahas has received
Classification of Headache Disorders, it includes updated terminology for range of $500 to $4999 for
cranial neuralgias. The underlying pathophysiology of the cranial neuralgias serving as a consultant for
is currently believed to be rooted in both peripheral and central Theranica Bio-Electronics Ltd.,
as an editor, associate editor,
nociceptive systems. In addition, a growing number of familial cases are or editorial advisory board
being identified. Recent therapeutic advancements include a better member for Springer, and as
understanding of how to utilize older therapies and procedures more an expert/talent for a CME
event with WebMD LLC; in the
effectively as well as the development of newer approaches. range of $5000 to $9999 for
serving as an editor, associate
editor, or editorial advisory
Cranial neuralgia syndromes are rare but important
ESSENTIAL POINTS:
board member for HMP
to recognize due to their debilitating nature and greater likelihood of Global; in the range of $10,000
having potentially treatable underlying causes. While management to $49,999 for serving as a
consultant for Lilly and
options have remained somewhat limited, scientific inquiry is continually Lundbeck; and in the range of
advancing the understanding of these syndromes and how best to $50,000 to $99,999 for serving
address them. as a consultant for AbbVie, Inc.
Dr Nahas has received
publishing royalties from a
publication relating to health
care.
UNLABELED USE OF
INTRODUCTION PRODUCTS/INVESTIGATIONAL
T
he cranial neuralgias comprise a distinct set of disorders typified by USE DISCLOSURE:
Dr Nahas discusses multiple
short-lasting attacks of intense pain in the distribution of a particular medications and therapies for
nerve in the cranium.1,2 While considered very rare, the overall the treatment of cranial
prevalence may be as high as 0.3%.3 The characteristic feature in this neuralgias, none of which are
approved by the US Food and
spectrum of disease is the brief, lancinating, shocklike neuropathic Drug Administration (FDA),
pain in a localizable distribution. Despite the distinctive phenotype, diagnostic except for carbamazepine
which is approved for the
delays of up to several months or even years are common.4 Diagnosis is just the treatment of trigeminal
first step, after which an informed and appropriate management plan must be set neuralgia.
into motion. Some cranial neuralgia cases are due to potentially treatable
secondary causes, underscoring the need for early identification and proper © 2024 American Academy
diagnosis to steer therapy.5,6 of Neurology.

CRANIAL NEURALGIAS
The most common of the cranial neuralgias is trigeminal neuralgia, which

has a broad range of classical, secondary, and idiopathic presentations. Other
cranial neuralgias include glossopharyngeal neuralgia and nervus intermedius
neuralgia, also delineated as classical, secondary, or idiopathic. Separate from
these neuralgias, distinct syndromes of neuropathic pain referable to these
nerves, both idiopathic and secondary, are also described. The International
Classification of Orofacial Pain (ICOP) terms these entities neuropathic pain
syndromes, as opposed to neuropathies as in the International Classification of

Headache Disorders, Third Edition (ICHD-3), but otherwise the criteria for
the disorders referable to the trigeminal and glossopharyngeal nerves are
essentially identical in both classifications.1,2 Another important cranial
neuralgia is occipital neuralgia (not covered in the ICOP). Other entities
classified in the same section of the ICHD-3 (also not covered in the ICOP),
which may or may not include neuralgiform pain, include neck-tongue
syndrome, painful optic neuritis, headache attributed to ischemic ocular

motor nerve palsy, Tolosa-Hunt syndrome, Raeder paratrigeminal
syndrome, recurrent painful ophthalmoplegic neuropathy, and burning
mouth syndrome.1
The available evidence suggests that the underlying pathophysiology of most
cranial neuralgia syndromes is due to not only injury, disease, or dysfunction of a
peripheral nerve itself but also central mechanisms involving dysfunctional
nociceptive processing, which may evolve after nerve injury or irritation.
Secondary causes of the neuralgias and neuropathic pain syndromes (also
referred to as neuropathies) include multiple sclerosis (MS), compressive lesions,
trauma, infection, and inflammation.1,2
The management of these syndromes is different from that of primary
headaches.5,6 Important distinctions in the approach to cranial neuralgia
TABLE 10-1 ICHD-3 Diagnostic Criteria for Trigeminal Neuralgiaa
A Recurrent paroxysms of unilateral facial pain in the distribution(s) of one or more divisions
of the trigeminal nerve, with no radiation beyond,b and fulfilling criteria B and C
B Pain has all of the following characteristics
1 Lasting from a fraction of a second to 2 minutesc
2 Severe intensityd
3 Electric shocklike, shooting, stabbing, or sharp in quality
C Precipitated by innocuous stimuli within the affected trigeminal distributione
D Not better accounted for by another ICHD-3 diagnosis

a
Reprinted from the Headache Classification Committee of the International Headache Society,
Cephalalgia.1 © 2018 SAGE Publications.
b
In a few patients, pain may radiate to another division, but it remains within the trigeminal dermatomes.
c
Duration can change over time, with paroxysms becoming more prolonged. A minority of patients will
report attacks predominantly lasting for >2 minutes.
d
Pain may become more severe over time.
e
Some attacks may be, or appear to be, spontaneous, but there must be a history or finding of pain
provoked by innocuous stimuli to meet this criterion. Ideally, the examining clinician should attempt to
confirm the history by replicating the triggering phenomenon. However, this may not always be possible
because of the patient’s refusal, awkward anatomical location of the trigger, and/or other factors.
474 A P R I L 2 0 24

syndromes include greater focus on the possibility of a secondary cause, KEY POINTS
pharmacologic options drawn predominantly from antiseizure medications, and
● The cranial neuralgias are
a range of procedural approaches, some of which may be definitive. distinct from most other
As the name would imply, cranial neuralgias are syndromes typically classified headache
involving intense neuralgiform pain in the distribution of a nerve in the disorders in that attacks are
cranium. Migrainous and autonomic features are rarely present. In most cases, stereotyped with very
short-lasting, neuralgiform
the pain is unilateral and brief in nature, but subtypes may involve bilateral or
pain in the distribution of a

continuous pain. The syndromes are distinguished mainly by their location, but particular peripheral nerve
the history and phenotype are also important aspects of diagnosis to guide an located in the head or face.
appropriate management plan, as options may differ depending on the etiology.
In most cases, the pain appears referable to the nerve itself (ie, based on ● Distinguishing primary
from secondary etiologies is
distribution, cutaneous or other triggers, or a lesion disclosed on neuroimaging), critical in crafting an
but central mechanisms have also been implicated in the perception and appropriate approach to
maintenance of pain. This article focuses on the named neuralgias (trigeminal, patients with cranial
glossopharyngeal, nervus intermedius, and occipital), with a brief commentary neuralgia.

on the neuropathic pain syndromes (also referred to as neuropathies) and ● The pathophysiology of
neck-tongue syndrome. cranial neuralgias is likely
linked to dysfunction in both
TRIGEMINAL NEURALGIA peripheral and central
pathways responsible for
Trigeminal neuralgia is classified in both the ICHD-3 and the ICOP under Pain
nociception.
attributed to a lesion or disease of the trigeminal nerve. It has also been called tic
douloureux. By description, it is “a disorder characterized by recurrent unilateral ● Trigeminal neuralgia
brief electric shock-like pains, abrupt in onset and termination, limited to the predominantly affects
distribution of one or more divisions of the trigeminal nerve and triggered by adults of middle age and is
usually sporadic, but familial
innocuous stimuli.”1,2 The diagnostic criteria are listed in TABLE 10-1. cases are also described.
The exact prevalence of trigeminal neuralgia is unknown, owing to the likely
underdiagnosis of the disorder, but lifetime prevalence is estimated to be 0.16% ● Trigeminal neuralgia
to 0.3% with an annual incidence of 4 to 29 per 100,000 person-years. It is carries an increased risk for
the development of
slightly more common in women, and the average age of onset is in the sixth depression, anxiety, and
decade. It is rare in young adults and children.7 In addition to sporadic cases, an dementia, and is associated
increasing number of familial cases are being described. In these cases, there may with functional and
be a genetic susceptibility to peripheral nerve demyelination, such as in Charcot- structural changes in the
brain.
Marie-Tooth disease.8 Several different associated channelopathies are also
described.9 ● Distinguishing primary
The pathophysiology of trigeminal neuralgia is not so straightforward as to be from secondary cases of
related solely to trigeminal nerve injury or dysfunction, although this can be trigeminal neuralgia is
apparent and demonstrable with neuroimaging (which can disclose vascular difficult to achieve on a
purely clinical basis, so
compression of the nerve, root, or both) and neurophysiologic testing (which can further investigation is
reveal abnormal trigeminal reflexes). Visualization is best achieved with MRI, warranted.
with specific sequences to include thin and heavily T2-weighted cuts through the
brainstem. This helps to distinguish neural tissue from vascular flow voids and ● Treatments for trigeminal
neuralgia range from
cerebrospinal fluid. The dysfunction of the trigeminal nerve can be related to pharmacologic options to
demyelination, resulting in ephaptic transmission of amplified pain signals procedures and
activated by light touch as well as pain generated through pathologic interventions, although only
spontaneous firing within the trigeminal ganglia.10-12 Based on animal models one treatment
(carbamazepine) is
and functional neuroimaging, theories suggest that central mechanisms, or at
specifically approved by the
least central consequences of neuropathic pain, are also likely to be at play.13 US Drug and Food
Functional neuroimaging studies have demonstrated a wide array of Administration (FDA) for this
abnormalities in function and connectivity within the brain, including both deep indication.
nuclei and cortical regions, and networks such as the visual, sensorimotor,

CRANIAL NEURALGIAS
salience, default mode, and basal ganglia networks.14,15 Furthermore, a potential

consequence of trigeminal neuralgia is central neurodegeneration, which can
manifest with cognitive dysfunction. Persons with chronic neuropathic pain,
including trigeminal neuralgia, are at greater risk of developing Alzheimer
disease,16 and also may display atrophy of the frontal cortex17 and hippocampal
gray matter volume reduction.18 This risk may be related to increased

neuroinflammation with resultant neuronal apoptosis. In one rodent model of
trigeminal neuralgia neuropathic pain, rats were observed to have significant

cognitive impairment and coincident alterations in brain fatty acid content.
Specifically, levels of docosahexaenoic acid, which plays roles in both cognition
and regulating central neuroinflammation at the microglial level, are reduced in
the central nervous system in this rodent model. Continuous supplementation
with docosahexaenoic acid improved both brain levels of docosahexaenoic acid
and cognitive function in these rats.19 It is also reported that patients with
trigeminal neuralgia have a higher risk of depression and anxiety than the general
population.20 This association may also be linked to neuroinflammation in the
hippocampus.21
The characterization of trigeminal neuralgia is further delineated in the
ICHD-3 and ICOP as classical, meaning due to neurovascular conflict, or
idiopathic, meaning no identifiable cause. In both instances, there is
subclassification into “purely paroxysmal” versus “with concomitant continuous
pain.”1,2 Finally, there is a subsection describing “secondary” trigeminal
neuralgia, due to MS, space-occupying lesions, or other causes (eg, skull-base
TABLE 10-2 Pharmacologic Options for Trigeminal Neuralgiaa
Drug Typical target dose rangeb
Carbamazepine 300-800 mg/day
Oxcarbazepine 600-1200 mg/day
Gabapentin 300-1800 mg/day
Pregabalin 150-600 mg/day
Levetiracetam 1000-4000 mg/day
Topiramate 100-400 mg/day
Lamotrigine 100-400 mg/day
Baclofen 60-80 mg/day
Pimozide 2-12 mg/day
OnabotulinumtoxinA 5-75 unitsc
a
Data from Al-Quliti KW, Neurosciences.23
b
The initial doses are typically 10% to 25% of the target dose, with incremental titration as tolerated. The total
daily dose is usually divided for administration 2 to 4 times per day. With medications that may cause
sedation, daytime doses may need to be reduced, with higher doses reserved for later in the day.
c
For onabotulinumtoxinA, the initial dose is 5 units to 15 units, depending on the size of the affected area.
The dose may be increased with subsequent treatments to maximal effect. Treatment is repeated every 12
weeks to maintain therapeutic benefit.
476 A P R I L 2 0 24

bone deformity, connective tissue disease, arteriovenous malformation, dural KEY POINTS
arteriovenous fistula, genetic causes of neuropathy, nerve hyperexcitability).
● Acute exacerbations of
Usually, pain is localized to V2 or V3, but can involve any branch or multiple trigeminal neuralgia may
branches. When the pain is restricted to the V1 distribution, mild autonomic require additional
features are sometimes present,1 but if they are prominent, an alternative intervention, which should
diagnosis of short-lasting neuralgiform headache attacks should be considered. not include the use of
opioids.
For more information on short-lasting neuralgiform headache attacks, refer to
the article “Cluster Headache, SUNCT, and SUNA” by Mark Burish, MD, PhD,22 ● Lacosamide and
in this issue of Continuum. onabotulinumtoxinA are
Do clinical features or physiologic testing results help identify secondary emerging as newer
cases? According to the American Academy of Neurology (AAN) and European therapeutic options with
relatively high effectiveness
Federation of Neurological Societies' evidence-based guidelines, the presence for trigeminal neuralgia, but
of trigeminal sensory deficits or bilateral involvement increases the risk of the role of treatments
an underlying secondary cause, but their absence does not rule it out. MRI targeting the calcitonin
is usually the best modality to identify secondary causes. Gadolinium gene-related peptide
system remains uncertain.
administration, while not always required, can reveal if there is inflammation
of the nerve or root and may be necessary to adequately delineate mass lesions. ● It is important to
CT is of limited utility, except in cases associated with acute traumatic injury recognize other trigeminal
or hemorrhage. Abnormal trigeminal reflexes detected via investigation in a neuropathic pain disorders
as distinct from trigeminal
qualified neurophysiologic laboratory also may point to secondary etiologies.5
neuralgia in terms of clinical
The European Academy of Neurology guidelines also note that younger patients presentation and underlying
may be more likely to have secondary etiologies, but caution that the sensitivity is etiology, although treatment
low and evidence is weak.6 may be similar to trigeminal
neuralgia.
Trigeminal neuralgia treatment can involve pharmacologic, procedural, and
interventional approaches. Carbamazepine is the only medication specifically ● Glossopharyngeal
approved by the US Food and Drug Administration (FDA) for this indication. neuralgia shares many
No devices or procedures have been cleared by the FDA for trigeminal neuralgia. similarities with trigeminal
Pharmacologic options are drawn chiefly from a range of oral antiseizure neuralgia, but the pain often
involves areas outside the
medications.5,6 Procedural approaches can include peripheral nerve blockade distribution of the nerve,
for temporary relief and injections of onabotulinumtoxinA for more lasting and other nonpain
(but still temporary) relief. Interventional approaches, which in some cases symptoms may be present.
are curative, depend on the etiology. When there is identifiable nerve compression
● Nervus intermedius
(vascular or otherwise), decompression procedures are often tried after an initial
neuralgia presents variably,
failure of medical therapy. Regardless of etiology or subtype, a range of ablative more often has an
procedures (eg, radiosurgery, thermal ablation, chemical ablation, mechanical underlying secondary cause,
ablation) may also be considered after failure of medical therapy.7 and more often requires
interventions beyond
First-line medications for trigeminal neuralgia include carbamazepine and
pharmacologic approaches.
oxcarbazepine, which are closely related in chemical structure and mechanism
of action. Other agents to consider are gabapentin, baclofen, lamotrigine, and ● Occipital neuralgia most
onabotulinumtoxinA, among others (TABLE 10-223). Once an agent is selected, it often co-occurs with
is initiated at a lower dose and titrated relatively rapidly as tolerated to effect, another headache or facial
pain disorder and is likely
along with any recommended laboratory monitoring (such as complete blood more common than
count and serum sodium). When practical, drug levels may help guide therapy in epidemiologic studies
cases when the medication is poorly tolerated (to guide assessment for clinical suggest.
toxicity) or ineffective (to ensure it is within the typical therapeutic range). If it is
not beneficial or is poorly tolerated, either a different medication or a procedure
would be entertained next. There is no clear guidance on how long medical
therapy should be tried or how many treatment failures should occur before
considering a procedural intervention, but it is advisable to inform patients of a
range of options, including those of an invasive nature, from the outset.7 In

CRANIAL NEURALGIAS
refractory cases, multiple simultaneous medications and serial procedures may

be necessary to achieve relief (CASE 10-1).
Acute exacerbations may require additional treatment. If trigeminal neuralgia
pain results in poor oral intake and dehydration, IV fluid resuscitation may be
necessary. In addition, infusions of fosphenytoin and lidocaine are also reported
to be useful.24 Opioids should be avoided.24

More information on the utility of other medical approaches has come to
light in recent years. For example, a retrospective chart review of patients

with refractory trigeminal neuralgia treated with oral lacosamide showed that
among 86 patients (16 with secondary trigeminal neuralgia and 29 with
concomitant continuous pain), 57 (66%) experienced pain relief, and 28 (33%)
experienced mild adverse events.25 Another retrospective analysis revealed
that IV lacosamide was as effective as, and better tolerated than, IV
fosphenytoin.26 In a retrospective study of onabotulinumtoxinA for both
primary trigeminal neuralgia and trigeminal neuralgia due to MS, outcomes

were favorable and similar for both types (effective for 45% of patients with
primary trigeminal neuralgia and 52% of those with trigeminal neuralgia due
to MS) and, regardless of etiology, those with concomitant continuous pain
and no prior interventional procedures had a greater chance of improvement.27
Finally, there is conflicting evidence regarding erenumab. A retrospective
CASE 10-1 A 79-year-old woman presented with a history of episodes of right-sided

jaw pain since she was approximately 72 years old. She described the
attacks as sharp and lancinating over the right cheek, jaw, and side of the
tongue, and rarely involving the right upper face. These attacks happened
numerous times per day and could be triggered with light touch or cold
wind to the right side of the face. She consulted her dentist who believed
she had trigeminal neuralgia and referred her to a neurologist. The
neurologist prescribed carbamazepine and later added gabapentin with
some improvement. She described a pattern of typically feeling the
worst in the winter months, but with her current regimen, she could be
pain free for several months during warmer weather. Her maintenance
doses of medication were carbamazepine extended release 200 mg 4
times a day and gabapentin 400 mg 4 times a day. During periods with
increased attacks (eg, in colder months, after requiring dental work on
her right lower teeth), she would increase her carbamazepine dose to
1000 mg to 1600 mg per day total with partial benefit. Her physical
examination was notable only for a reluctance to have sensory testing
performed on her face due to the triggering of neuralgiform pain. Brain
MRI with routine and vascular loop sequences was normal.
Over time, despite continued treatment with carbamazepine and
gabapentin, her attacks became year round, requiring dose escalations of
each medication to carbamazepine 1200 mg per day and gabapentin
2400 mg per day. Her brain MRI was unchanged. Since she wished to
avoid exploring additional oral medications and did not want to consider
any kind of ablative procedure, she agreed to be treated with
onabotulinumtoxinA for the off-label indication of trigeminal neuralgia.
478 A P R I L 2 0 24

analysis of 10 patients revealed a response in 90% after 6 months,28 but a
randomized double-blind placebo-controlled proof-of-concept trial failed to
show a difference between erenumab and placebo after 4 weeks.29
Entities distinct from trigeminal neuralgia but also classified in the same section
include painful trigeminal neuropathies (the term used in the ICHD-3), also
known as “other trigeminal neuropathic pain disorders” in the ICOP.

The latter terminology is gaining favor over the former and is also utilized by
the International Classification of Diseases and the International Association

for the Study of Pain. What distinguishes these is mainly the presence of
continuous or nearly continuous pain, typically described as burning, squeezing,
aching, or “pins and needles,” and the variable presence of superimposed
neuralgiform attacks (which are not required by criteria). Sensory deficits,
allodynia, or both are also present. Etiologies include acute herpes zoster,
postherpetic pain, trauma, and others such as MS and space-occupying lesions.
Treatment approaches are similar to that of primary trigeminal neuralgia.30
GLOSSOPHARYNGEAL NEURALGIA
Glossopharyngeal neuralgia is very similar to trigeminal neuralgia in many
respects, except for the nerve involved and the presence of some unique
symptoms. Overlap with trigeminal neuralgia symptomatology can exist and the
Her initial treatment was with a total of 20 units spread in a grid pattern
over the areas of greatest pain. This helped significantly but
incompletely. With subsequent treatments, the dose and pattern were
optimized for maximal pain relief, with careful consideration for doses
close to the mouth and muscles of facial expression, to preserve function
and achieve as much facial symmetry as possible (40 units on the right
and 10 units on the left to compensate for facial asymmetry). Ultimately,
she became pain free year round (except when the onabotulinumtoxinA
started wearing off about 3 months after every treatment) and was able
to reduce her doses of antiseizure medications to carbamazepine 400 mg
per day and gabapentin 800 mg per day.
This patient’s history is consistent with idiopathic trigeminal neuralgia, with COMMENT
neuralgiform pain in a unilateral trigeminal distribution with cutaneous
triggers, lack of interictal pain, a normal examination, and normal imaging.
Her partial improvement with antiseizure medications is quite typical. Her
disease progressed without explanation, warranting repeat imaging, but this
was unchanged. With no compressive lesion to target, her surgical options
were limited to ablative procedures, which she wished to avoid due to the
uncertainty of benefit and risk of developing anesthesia dolorosa (a
deafferentation pain that can occur after traumatic or surgical injury to the
trigeminal nerve, wherein pain is felt in this distribution even though
cutaneous sensation has been lost). Treatment with onabotulinumtoxinA
rendered her essentially pain-free for the duration of the treatment effect,
although she still needed to take lower doses of antiseizure medications.

CRANIAL NEURALGIAS
two can occur simultaneously in the same individual. Pain is not necessarily
restricted to the distribution of the nerve and may be perceived in the eye, nose,
chin, larynx, or shoulder. Due to proximity and interconnectedness with other
structures, particularly the vagus nerve, symptoms such as cough, hoarseness,
bradycardia, and syncope can be present. As with trigeminal neuralgia,
glossopharyngeal neuralgia is divided into classical, secondary, or idiopathic

etiologies, and may similarly present with purely paroxysmal or continuous pain,
or as a neuropathic pain syndrome.1,2 Treatment overlaps substantially with

trigeminal neuralgia.31 Like trigeminal neuralgia, glossopharyngeal neuralgia is
rare, but the incidence and prevalence are uncertain. The diagnostic criteria are
listed in TABLE 10-3.1
NERVUS INTERMEDIUS NEURALGIA

This entity is only covered in the ICHD-3. It is similar to trigeminal neuralgia
and glossopharyngeal neuralgia, except for location, and is even rarer. Pain is
felt deeply and primarily in the auditory canal. The pain sometimes radiates to
other regions (eg, auricle, mastoid process, angle of mandible, soft palate,
temporal region, parieto-occipital region). It can be provoked by cutaneous
stimulation of the posterior wall of the auditory canal or the periauricular
region. Vascular compression is eventually discovered in the vast majority of
cases and therefore procedural intervention may be definitive.1,32 As with
trigeminal neuralgia, visualization is best achieved with MRI and compression
is typically at or near the entry zone in the brainstem.33 However, at least one
attempt at conservative medical management (similar to therapies used in
trigeminal neuralgia and glossopharyngeal neuralgia) is recommended.
Secondary causes may underlie the problem; the most common is herpes zoster.
Very rarely, MS or a tumor may be identified as the culprit. Disorders of
lacrimation, salivation, or taste may accompany this disorder.1 The diagnostic
criteria are listed in TABLE 10-4.
Because the innervation of the ear is complex and derived from multiple
cranial nerves besides the nervus intermedius branch of the facial nerve
TABLE 10-3 ICHD-3 Diagnostic Criteria for Glossopharyngeal Neuralgiaa
A Recurrent paroxysmal attacks of unilateral pain in the distribution of the glossopharyngeal

nerveb and fulfilling criterion B
1 Lasting from a few seconds to 2 minutes
2 Severe intensity
3 Electric shocklike, shooting, stabbing, or sharp in quality
4 Precipitated by swallowing, coughing, talking, or yawning

a
b
Within the posterior part of the tongue, tonsillar fossa, pharynx or angle of the lower jaw and/or in the ear.
480 A P R I L 2 0 24

(including the auriculotemporal branch of the trigeminal nerve, the
glossopharyngeal nerve, and the vagus nerve), it may be difficult to attribute the
entity to a singular point of pathophysiology in cases where neurovascular
conflict is not apparent. Medical management largely mirrors that of trigeminal
neuralgia and glossopharyngeal neuralgia, but interventional approaches are
often necessary.32
OCCIPITAL NEURALGIA
Occipital neuralgia has been considered by some as quite rare and
underdiagnosed and by others as overdiagnosed, leading to some confusion as to
its true prevalence. According to one source, it is estimated that only around
250,000 people worldwide have occipital neuralgia,34 but this is likely an
underestimate as this study relied heavily on data available in medical charts of a
population of about 800,000 individuals in the Netherlands. Furthermore,
occipital neuralgia most commonly co-occurs with another headache diagnosis

(isolated cases are relatively uncommon). This notion is supported by a study of
the prevalence of occipital neuralgia in a specialized headache clinic setting,
wherein it was determined that out of 35 consecutive patients diagnosed with
occipital neuralgia, 20 also had migraine.35 In addition, a larger study in a
community hospital–based headache specialty clinic setting found that occipital
neuralgia was present in nearly 25% of patients presenting to that clinic, but it
was isolated in only 15% of those patients. About 60% had concomitant episodic
or chronic migraine with or without aura, and multiple other headache disorders
also co-occurred, such as chronic and episodic tension-type headache, trigeminal
autonomic cephalalgias, new daily persistent headache, posttraumatic headache,
and various secondary headaches, among others.36
The pain of occipital neuralgia is paroxysmal, shooting or stabbing in quality,
felt primarily in the occipital region (although extension to the fronto-orbital
ICHD-3 Diagnostic Criteria for Nervus Intermedius Neuralgiaa TABLE 10-4
A Paroxysmal attacks of unilateral pain in the distribution of nervus intermediusb and fulfilling
criterion B
1 Lasting from a few seconds to minutes
2 Severe in intensity
3 Shooting, stabbing, or sharp in quality
4 Precipitated by stimulation of a trigger area in the posterior wall of the auditory canal and/
or periauricular region

a
b
Pain is located in the auditory canal, auricle, in the region of the mastoid process and occasionally the soft
palate, and may sometimes radiate to the temporal region or the angle of the mandible.
c
In view of the complex and overlapping innervation of the external ear, deriving from trigeminal
(auriculotemporal), facial (nervus intermedius), glossopharyngeal, vagus and second cervical nerves,
attribution of neuralgias to a single nerve may not be easy in this body region when a specific neurovascular
contact cannot be visualized.

CRANIAL NEURALGIAS
area is possible due to trigeminocervical interneuronal connections in the

trigeminal spinal nuclei), and is accompanied by dysesthesia or allodynia. Pain
can be elicited by palpation of the point of emergence of the greater occipital
nerve or along the distribution of C2. It is usually unilateral but may be bilateral.
It is one of few disorders also classified by its response to a particular treatment,
in this case, anesthetic blockade of the affected nerves. The diagnostic criteria are
In making the diagnosis, it is important to distinguish occipital pain due to

occipital neuralgia from occipital pain that is referred from the atlantoaxial or
upper zygapophyseal joints or from tender trigger points in neck muscles or their
insertions.1 Since the co-occurrence of two or more headache syndromes may
require distinct approaches for each, and knowing that improper treatment can
lead to refractory states, it is critical for clinicians to identify occipital neuralgia
correctly within the complete clinical picture. Aids to the diagnosis include
expanding the history to assess explicitly for lancinating pain in the occipital
region triggered by mechanical pressure upon the occiput or by certain head and
neck movements.36 On physical examination, occipital neuralgia may be
suggested by a positive Tinel sign, elicited by percussing across the skull from
one mastoid to the other.36 Another helpful technique is to assess for pain or
paresthesia within a particular nerve distribution elicited by passive range of
motion of the neck.36
The pathophysiology in most cases is believed to be irritation or
compression of one or more branches of the occipital nerve or its origins.
The occipital nerve is divided into the greater occipital nerve arising from the
C2 dorsal ramus, the lesser occipital nerve arising from the C2 ventral ramus,
TABLE 10-5 ICHD-3 Diagnostic Criteria for Occipital Neuralgiaa
A Unilateral or bilateral pain in the distribution(s) of the greater, lesser and/or third occipital
nerves and fulfilling criteria B–D
B Pain has at least two of the following three characteristics
1 Recurring in paroxysmal attacks lasting from a few seconds to minutes
2 Severe in intensity
3 Shooting, stabbing, or sharp in quality
C Pain is associated with both of the following
1 Dysesthesia and/or allodynia apparent during innocuous stimulation of the scalp
and/or hair
2 Either or both of the following
a Tenderness over the affected nerve branches
b Trigger points at the emergence of the greater occipital nerve or in the distribution of C2
D Pain is eased temporarily by local anesthetic block of the affected nerve(s)

a
482 A P R I L 2 0 24

and the third (also termed least) occipital nerve derived from the C3 dorsal
ramus. Therefore, it is important to evaluate both the nerves themselves
and elements of the cervical spine, which may lead to the discovery of a
causative lesion.37 Additionally, a 2021 report detailed occipital neuralgia
secondary to MS. Two cases were identified wherein the solitary (and, in one
case, the initial) manifestation of acute MS symptomatology was an occipital

neuralgia phenotype referable to demyelinating lesions in the upper cervical
spinal cord. In both cases, treatment with IV methylprednisolone led to

improvement.38
There is very little high-quality evidence available to guide treatment options,
and treatment selection remains largely empiric at this time. Besides nerve
blockade, medications typically used for neuralgiform or neuropathic pain are
utilized, along with physical therapy to reduce muscular tension, and in
A 32-year-old woman presented with a 5-year history of refractory CASE 10-2

chronic migraine accompanied by superimposed episodes of sharp,
stabbing, burning, and lancinating pain arising from the right occipital
region and traversing superiorly toward the vertex of the skull. Her
migraine was described as daily right hemicranial pain with fluctuations in
the intensity of pain, nausea, photophobia, and phonophobia. She
reported partial response to her current treatment with topiramate
and prior treatment failures of amitriptyline and propranolol. Her
examination was notable for muscle spasm and tenderness in the cervical
paraspinal muscles (right greater than left), reduced range of motion
in the neck, scalp allodynia on the right, and a positive Tinel sign at the
right greater occipital notch. A greater occipital nerve block was
performed which rendered the patient pain free for several weeks.
Repeat occipital nerve blockade was again successful but temporary.
Gabapentin was added to topiramate, serial greater occipital nerve
blocks were arranged, and she was sent for a course of physical therapy,
which resulted in much better control of both her migraine and her
occipital neuralgia. With the combination of daily medication, occipital
nerve blocks every 3 to 4 months, and maintenance of a home physical
therapy regimen, her migraine attacks diminished to one to two
per month, and her occipital neuralgia attacks became almost
nonexistent.
This case illustrates how two primary headache diagnoses can be present COMMENT
in the same individual, and when both are adequately treated, substantial
improvement may occur. This underscores the importance of recognizing
an occipital neuralgia syndrome as distinct from but intertwined with a
chronic migraine syndrome. Once occipital neuralgia was addressed more
directly with occipital nerve blockade and gabapentin, and once the
cervicalgia component was addressed with gabapentin and physical
therapy, her neuralgiform symptoms went from daily to almost negligible.

CRANIAL NEURALGIAS
appropriate cases, decompression or ablative procedures are warranted

(CASE 10-2).37 One reported case of occipital neuralgia was 100% responsive to
therapy with memantine.39
NECK-TONGUE SYNDROME
While not formally termed a “neuralgia,” the characteristics of neck-tongue

syndrome fit well within the spectrum of cranial neuralgias. This entity is
typified by immediate-onset, unilateral, sharp or stabbing, and usually severe

pain in the occiput, upper neck, or both, brought on by sudden head turning.
In addition, there are ipsilateral tongue symptoms, which may include
abnormal sensations and posture. The pain itself lasts seconds to minutes.1
Neck-tongue syndrome was first described clinically in 1962 and anatomically
in 1980. It was formally classified in the first iteration of the ICHD and
remained there in the Second Edition, but was relegated to the appendix in
the beta version of the ICHD-3. In the current classification scheme, it is once
again categorized with the cranial neuralgias.40 The diagnostic criteria are
There have been two recent systematic reviews on neck-tongue
syndrome.40,41 The first cemented neck-tongue syndrome’s place back in
the main section of ICHD-3.40 This review also detailed epidemiologic
characteristics, such as the predominance of onset in childhood or adolescence
(in some cases after mild head or neck trauma), a slight female preponderance,
and the existence of a few familial cases. It is theorized that the pathophysiology
lies mainly in ligamentous laxity during growth and development, which may
facilitate transient subluxation of the lateral atlantoaxial joint with sudden head
turning. This can cause the C2 ventral ramus to become impinged against bone,
leading to pain. Afferent proprioceptive fibers from the lingual nerve
anastomose with the hypoglossal nerve in the tongue, then course through the
ansa cervicalis, continuing on via the ventral ramus of the C2 spinal nerve,
explaining symptoms in the tongue. Treatments lie chiefly in the realm of
physical therapy, although other approaches, such as amitriptyline, gabapentin,
anti-inflammatory drugs, and peripheral nerve blockade may also be useful.40
The latter review included only published manuscripts (the former utilized data
TABLE 10-6 ICHD-3 Diagnostic Criteria for Neck-Tongue Syndromea
A At least two episodes fulfilling criteria B–D

B Sharp or stabbing unilateral painb in the upper neck and/or occipital region with concurrent
abnormal sensation and/or posture of the ipsilateral tongue
C Precipitated by sudden turning of the neck
D Lasting from seconds to several minutes

a
b
There may or may not be simultaneous dysaesthesia.
484 A P R I L 2 0 24

from many congress abstracts) and confirmed the critical elements of the KEY POINTS
diagnosis and treatment of neck-tongue syndrome (CASE 10-3).41
● The diagnosis of occipital
neuralgia relies on a careful
and thorough history and
CONCLUSION examination to distinguish it
The cranial neuralgias are relatively rare in the spectrum of disorders of headache from a concomitant disorder
and to evaluate for
and facial pain, but recognition, accurate diagnosis, and evaluation for secondary
underlying secondary
causes are crucial to best manage these disorders. A careful and thorough history causes.
and examination may yield early clues to certain secondary causes, but even in
the absence of red flags or other signs and symptoms suggesting that this is the ● Neck-tongue syndrome is
increasingly recognized as
case, investigation with neuroimaging is usually warranted and may need to be an important entity among
repeated with dedicated techniques before an underlying problem is discovered. the cranial neuralgias, with
It should be remembered that pain may be referred to the distribution of a nerve distinct pathophysiology
in the cranium by secondary etiologies of the soft tissues and bony structures in and treatment options.
the head and neck. Medical therapy is pursued from the outset, even in cases
when clear neurovascular conflict is apparent or a secondary cause is identified.
An array of interventional procedures may be considered to address secondary
A 16-year-old boy presented with episodes of brief but intense sharp pain CASE 10-3
in the left neck, head, and tongue triggered by head turning. He also
described that sometimes his tongue felt strange on the left side and that
it seemed “to have a mind of its own,” protruding involuntarily to the right
during these painful episodes. Stretching and massaging the neck and
avoiding turning his head too quickly were the only approaches that he
had found helpful. Another clinician prescribed nortriptyline, which he
stopped after a brief trial due to drowsiness and constipation. He had
also been referred to physical therapy and was given a series of
neck-stretching exercises, which did not help. His examination was
notable for diffuse joint laxity and hypermobility, most notable in the
knees, elbows, and neck. He was given a presumptive diagnosis of
neck-tongue syndrome and sent back to physical therapy with explicit
instructions to address hypermobility and joint laxity with strengthening
exercises, particularly of the neck. After several weeks, the frequency of
attacks with head turning diminished substantially. He maintained a home
physical therapy regimen and continued to do well for several years.
Ultimately, in his twenties, he no longer needed to be as consistent with
his exercises and was rarely bothered by attacks.
This case is typical of neck-tongue syndrome, which usually starts in COMMENT

childhood and adolescence and usually abates by early adulthood. Clues
to the diagnosis are the syndromic features, the presence of joint laxity,
and the improvement upon addressing musculoskeletal factors. It is
important to note that joint hypermobility must be treated primarily with
strengthening exercises to compensate for joint laxity; stretching exercises
are only likely to help pain from resultant muscle spasms temporarily and
may even aggravate pain from joint laxity by increasing instability.

CRANIAL NEURALGIAS
etiologies directly or after the failure of medical therapy. Antiseizure medications

targeting sodium channels are the mainstay, but other options exist, including
other medications used in neuropathic pain syndromes and injections of local
anesthetic or onabotulinumtoxinA, before advancing to microvascular
decompression or an ablative procedure.
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doi:10.1080/14656566.2022.2087507 medicina57101097

REVIEW ARTICLE

Indomethacin-
I NT E R V I E W A V AI L A B L E Responsive Headache
ONLINE
Disorders
By Peter J. Goadsby, MD, PhD, FRS
ABSTRACT
CITE AS: OBJECTIVE: This article describes the clinical features and treatment of the
CONTINUUM (MINNEAP MINN) indomethacin-responsive headache disorders paroxysmal hemicrania and

2024;30(2, HEADACHE):488–497.
hemicrania continua.
Professor Peter J. Goadsby, LATEST DEVELOPMENTS: Both paroxysmal hemicrania and hemicrania continua
Wellcome Foundation Building, are treated with indomethacin at the lowest clinically useful dose. It has
King’s College Hospital, London
SE5 9PJ, United Kingdom, recently become clear that some patients with either condition may
peter.goadsby@kcl.ac.uk. respond to treatment with noninvasive vagus nerve stimulation, which can
be both indomethacin sparing and, in some cases, headache controlling.
Dr Goadsby has received Given the lifelong nature of both paroxysmal hemicrania and hemicrania
personal compensation in the continua, brain imaging with MRI is recommended when the conditions are
serving as a consultant for
identified, specifically including pituitary views.
AbbVie Inc., CoolTech LLC,
Epalex Corp., Pfizer Inc., Praxis Paroxysmal hemicrania and hemicrania continua are
ESSENTIAL POINTS:
Precision Medicines, Sanofi,
Satsuma Pharmaceuticals, Inc.,
indomethacin-responsive headache disorders that offer a rewarding and
ShiraTronics, and Teva unique opportunity to provide marked clinical improvement when
Pharmaceutical Industries Ltd. recognized and treated appropriately. These disorders share the final
and as an editor, associate
editor, or editorial advisory common pathway of the trigeminal-autonomic reflex, with head pain and
board member for the cranial autonomic features, and are differentiated pathophysiologically by
Massachusetts Medical
the pattern of brain involvement, which can be seen using functional
Society; in the range of $5000 to
$9999 for serving as a imaging. They have distinct differential diagnoses to which the clinician
consultant for Lundbeck and needs to remain alert.
Sanofi; and in the range of
$10,000 to $49,999 for serving as
a consultant for Amgen Inc.,
Lilly, and Novartis AG and on a
INTRODUCTION
Indomethacin-responsive headache disorders are rare conditions whose hallmark
UNLABELED USE OF is an absolute response to the medicine. The exemplar conditions are paroxysmal
USE DISCLOSURE: hemicrania and hemicrania continua; these are defined by the International
Dr Goadsby discusses multiple Classification of Headache Disorders, Third Edition,1 and are broadly grouped as
medications and therapies for
trigeminal autonomic cephalalgias.2 While other headache disorders may
the treatment of
indomethacin-responsive respond to indomethacin in some patients, such as its use as a preemptive
headache disorders, none of treatment in primary headache associated with sexual activity, the remarkable
which are approved by the
US Food and Drug
feature of paroxysmal hemicrania and hemicrania continua is that they are, in
Administration (FDA). part, defined by a necessary response to indomethacin. While rare, patients
whose headaches are completely controlled by the medicine certainly reward the
© 2024 American Academy aware clinician by their excellent response.3 It should be noted that these
of Neurology. conditions occur in children and adolescents,4 which necessitates particular
488 A P R I L 2 0 24

diagnostic vigilance. This article outlines some of the basics of indomethacin and
discusses these two conditions in more detail.
INDOMETHACIN
Indomethacin (1-[p-chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid;
indometacin [international nonproprietary name]) is a nonsteroidal anti-

inflammatory drug of the acetic acid class, in contrast to naproxen or ibuprofen,
which are propionic acids. Indomethacin is available as a capsule, an

extended-release capsule, and by formulation as a suppository. In some countries
outside of the United States, an adult dose (50 mg to 200 mg) can be
administered by injection. The main formulations in practice are the ordinary
and extended-release capsules. The highest blood concentration of the
extended-release formulation is 55% lower than that of the immediate-release
formulation and thus is sometimes better tolerated. It is the author’s clinical
experience that in these indomethacin-responsive headache disorders the

ordinary-release formulation is, on average, more useful.
Pharmacokinetics
Indomethacin pharmacokinetics are broadly linear and dose-dependent.
Indomethacin is highly lipid soluble and readily enters the brain with drug
detectable 30 minutes after administration. Indomethacin is 60% renally
excreted. Indomethacin lowers CSF pressure5,6 and thus can provide a
false-positive response when first used if the underlying issue is increased CSF
pressure. This is remarkable when one considers its use in primary cough
(Valsalva maneuver) or primary headache associated with sexual activity. The
key pharmacologic properties are summarized in TABLE 11-1.7,8
Adverse Events
The major adverse effects of indomethacin are dyspepsia, nausea, and abdominal
pain. The use of H2 blockers or proton pump inhibitors may be useful in these
Properties of Indomethacin Formulationsa TABLE 11-1
Capsule, ordinary release Capsule, slow release Suppository

Dose 25 mg to 75 mg 3 times daily 25 mg to 75 mg 2 times daily 50 mg to 100 mg 2 times daily
Bioavailability 100% 100% 80%
Plasma half-life 7 hours 7 hours 7 hours
Plasma protein binding ~90% ~90% ~90%
Excretion Renal: 60%, glucuronidated Renal: 60%, glucuronidated Renal: 60%, glucuronidated
Biliary: 40% Biliary: 40% Biliary: 40%
Distribution Blood-brain barrier: permeable Blood-brain barrier: permeable Blood-brain barrier: permeable
Placenta: permeable Placenta: permeable Placenta: permeable
8 8
Breast milk: small amount Breast milk: small amount Breast milk: small amount8
a
Data from Villar-Martinez MD, et al, Headache.7

INDOMETHACIN-RESPONSIVE HEADACHE DISORDERS
settings. At high doses, some patients describe a lightheadedness almost like the
sensation after a mild concussion, consistent with some degree of central nervous
system penetration.9 Interestingly, indomethacin may produce headache in a
limited number of susceptible individuals.10 The author has recognized this
adverse effect in patients who have a personal or family history of migraine.
Indomethacin when coadministered with lithium can raise lithium levels,

potentially leading to toxicity.11 This interaction needs to be kept in mind when a
patient with a diagnosis of chronic cluster headache is considered for

indomethacin exposure to exclude chronic paroxysmal hemicrania. For more
information, see the article “Cluster Headache, SUNCT, and SUNA” by Mark
Burish, MD, PhD,12 in this issue of Continuum.
Mechanism of Action
The mechanism of action of indomethacin in indomethacin-responsive headache
disorders is unclear. Classically, indomethacin blocks the synthesis of

prostaglandins from arachidonic acid by inhibiting cyclo-oxygenase (COX).
There are two COX isoforms, COX-1 and COX-2, with indomethacin having
predominantly COX-1 selectivity compared with other commonly used
nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen.13 The
relative ineffectiveness of other nonsteroidal anti-inflammatory drugs on
indomethacin-responsive headaches has long suggested an alternative
mechanism for these disorders. In a preclinical model of trigeminovascular
TABLE 11-2 ICHD-3 Diagnostic Criteria for Paroxysmal Hemicraniaa
A At least 20 attacks fulfilling criteria B-E

B Severe unilateral orbital, supraorbital and/or temporal pain lasting 2 to 30 minutes
b Nasal congestion and/or rhinorrhoea
c Eyelid oedema
2 A sense of restlessness or agitation
D Occurring with a frequency of >5 per dayb
E Prevented absolutely by therapeutic doses of indomethacinc
F Not better accounted for by another ICHD-3 diagnosis

a
b
During part, but less than half, of the active timecourse of paroxysmal hemicrania, attacks may be less
frequent.
c
In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if
necessary up to 225 mg daily. The dose by injection is 100 mg to 200 mg. Smaller maintenance doses are
often employed.
490 A P R I L 2 0 24

nociception, indomethacin inhibited dural vasodilation elicited by electrical KEY POINTS
stimulation or administration of nitric oxide donors, but not calcitonin
● Certain rare headache
gene-related peptide (CGRP).14 Recordings from second-order nociceptive disorders have an absolute
trigeminocervical neurons in an experimental animal model show that response to indomethacin.
indomethacin can reduce firing triggered by a nitric oxide donor, while naproxen
does not.15 Given their structural similarities, another possibility is a ● Indomethacin lowers
intracranial pressure, which
melatonin-related mechanism, which is supported by the sometimes-useful
may produce a false-

effect of melatonin in these headache types.16 positive, nonsustained
clinical effect in patients
PATHOPHYSIOLOGY OF PAROXYSMAL HEMICRANIA AND with increased intracranial
HEMICRANIA CONTINUA pressure.
The trigeminal autonomic cephalalgias share much in terms of fundamental ● Indomethacin can elevate
pathophysiology, and this is especially true for paroxysmal hemicrania and lithium levels when the
hemicrania continua. Much of their phenotypes can be explained by the medicines are
activation of the trigeminal-autonomic reflex.17 This involves the activation, or coadministered.

the perception of activation, of trigeminal, largely ophthalmic, first-division
● Paroxysmal hemicrania
afferents. There is a reflex connection through the superior salivatory nucleus in and hemicrania continua
the pontine tegmentum whose transmission involves glutamate. The efferent involve activation of the
fibers course through the geniculate ganglion without synapsing and are joined trigeminal-autonomic reflex
with distinct brain networks
by the deep petrosal nerve, with its postsynaptic sympathetic fibers from the
of activations seen on
internal carotid plexus, before the parasympathetic fibers synapse in the functional imaging.
sphenopalatine ganglion that lies in the pterygopalatine fossa. The
sphenopalatine ganglion has a classic nicotinic hexamethonium-sensitive
synapse, with transmitters including CGRP,18 pituitary adenylate cyclase
activating polypeptide,19 vasoactive intestinal polypeptide,19 nitric oxide
synthase,20 and the serotonin 5-HT1B, 5-HT1D, and 5-HT1F receptors.21
The clinical differences between trigeminal autonomic cephalalgias, and
indeed paroxysmal hemicrania and hemicrania continua, can be reasonably
explained by the brain networks that have been identified on functional
imaging, specifically using positron emission tomography (PET). Untreated
paroxysmal hemicrania is marked by activations in the contralateral posterior
hypothalamic region and contralateral ventral midbrain, with the latter
including the red nucleus and substantia nigra.22 Untreated hemicrania
continua is characterized by activations in the contralateral posterior
hypothalamic region, ipsilateral dorsal rostral pons, and ipsilateral
ventrolateral midbrain, with the latter again extending over the red nucleus
and substantia nigra.23 It is remarkable that posterior hypothalamic region
activations are also seen in cluster headache, albeit ipsilaterally,24 given the
phenotypic similarities with paroxysmal hemicrania, and that dorsolateral
pontine activation is seen in migraine,25 given the phenotypic similarities with
hemicrania continua. Moreover, the ventrolateral midbrain may hold some
key to understanding the shared indomethacin effect between paroxysmal
hemicrania and hemicrania continua.
PAROXYSMAL HEMICRANIA
Paroxysmal hemicrania is a primary headache disorder first described by
Sjaastad and Dale.26 The syndrome is rare, with a prevalence of approximately
1 in 2000.27 Paroxysmal hemicrania is characterized by severe, strictly unilateral
attacks of pain, which may be in any cranial distribution and typically last 2
to 30 minutes. The attacks occur many times a day, with a median of nine in a

series of 31 cases.28 The attacks are associated with cranial autonomic symptoms
ipsilateral to the pain, including lacrimation, conjunctival injection, nasal
congestion, rhinorrhea, aural discomfort, eyelid edema, ptosis, or miosis
(TABLE 11-2, CASE 11-1). The disorder is defined as episodic if attack periods last
from 7 days to 1 year and are separated by a 3-month attack-free period while not
on treatment. It is considered chronic when the remission period is less than

3 months. About one-third of patients also report primary stabbing headache.
Paroxysmal hemicrania has a clear and usually absolute response to

indomethacin. The chronic form is dominant, comprising 80% of cases,
compared with the episodic form; this ratio is completely the reverse of
cluster headache.
Clinical Features
Given the definition, the phenotype of paroxysmal hemicrania is relatively clear.
However, as in all things in medicine, the clinical presentation can have some
aspects that complicate making a diagnosis. While the majority of patients
have short (approximately 20 minutes) attacks many times a day, some will
have longer attacks (often seen in adolescents) or fewer attacks. The sex ratio
is close to 1:1 in larger series.28 The author has often been rewarded for an
indomethacin trial (see the Management section) by the absolute effect that it
affords. Interattack pain can be seen in paroxysmal hemicrania and is generally
present when the patient has a personal or family history of migraine. Similarly,
one may see indomethacin control the short-lasting attacks yet produce a
persistent bothersome pain, again when there is a personal or family history
of migraine. The author has seen the latter respond to CGRP monoclonal
antibodies.
CASE 11-1 A 23-year-old woman presented with a 3-year history of attacks of

right-sided, very severe, nonthrobbing head pain located in the inner
canthus. The attacks were associated with right-sided lacrimation,
conjunctival injection, aural discomfort, and voice change. She tended to
sit, not move, and rocked back and forth. The attacks lasted 20 to
30 minutes and occurred between 10 and 15 times a day without any
particular circadian pattern. There was no relation to alcohol use or
menses. She had tried acetaminophen, ibuprofen, and naproxen, as well
as an opioid and sumatriptan orally and by nasal spray, none of which
were useful. She had also tried propranolol, amitriptyline, and verapamil,
none of which were helpful. Neurologic and general examinations
including blood pressure were normal. After 4 days on indomethacin
25 mg 3 times daily she was completely headache free. Attacks returned
if she skipped a dose and remained controlled for 7 years. She also took a
proton pump inhibitor daily.
COMMENT This case illustrates the rapid and complete response in paroxysmal
hemicrania to treatment with indomethacin.
492 A P R I L 2 0 24

Differential Diagnosis KEY POINTS
Cluster headache is the main differential diagnosis for paroxysmal hemicrania. It
● About one-third of
can effectively be clarified by the indomethacin test. While there is some patients with paroxysmal
controversy in the literature about “indomethacin-responsive cluster headache,” hemicrania also report
the question offers an addlepated understanding of the utility of the primary stabbing headache.
indomethacin response. Suffice it to say, until the mechanism is resolved the

● Paroxysmal hemicrania is
distinction that absolute indomethacin responders be diagnosed with paroxysmal
marked by short-lasting,
hemicrania seems appropriate. Compared with cluster headache, paroxysmal multiple attacks of strictly
hemicrania generally has shorter, more frequent attacks that have less of a unilateral head pain with
predilection for sleeping hours. The attacks do not tend to be triggered by alcohol marked cranial autonomic
(as in cluster headache) and are not triggered by cutaneous sensory stimulation, symptoms, and an absolute
response to indomethacin.
although some patients report sensitivity to neck position as may be seen in
patients with short-lasting unilateral neuralgiform headache attacks with ● Hemicrania continua is
conjunctival injection and tearing (SUNCT).29 Paroxysmal hemicrania can be characterized by a strictly
seen in the presence of pituitary pathology,30 which should be kept in mind at lateralized, persistent,
continuous headache often
first presentation. associated with cranial
autonomic features and an
Management absolute response to
After a careful history and examination, assuming it would be tolerated, the first indomethacin.
step is an indomethacin trial. This may be done as 25 mg orally 3 times daily
● Patients with paroxysmal
for 5 to 7 days, followed by 50 mg 3 times daily for 5 to 7 days, followed by 75 mg hemicrania or hemicrania
3 times daily for 2 weeks. Dose escalation is not necessary if at any point continua should undergo
there is a complete response. The author usually provides gastrointestinal contrasted brain MRI to
protection with a proton pump inhibitor. Alternatively, a single-blind placebo- exclude a pituitary
adenoma.
controlled indomethacin test done as 50 mg, 100 mg, or 200 mg IM, depending
on weight, and placebo on alternate days, with careful recording of attack
numbers and a suitable untreated baseline of 5 to 7 days, will make the diagnosis
clear.28 Once established, it can be recommended for the patient to test what their
minimum dose requirement may be. Neuromodulation with noninvasive vagus
nerve stimulation is a viable option to control some patients with paroxysmal
hemicrania and reduce indomethacin usage.31 COX-2 inhibitors such as celecoxib
may be useful in paroxysmal hemicrania, as may topiramate and melatonin.16
Topiramate can be used at doses from 50 mg twice daily to 200 mg twice daily,
although higher doses are usually poorly tolerated. Melatonin may require
anywhere from 5 mg to 20 mg daily, usually taken at night. In the author's
experience, verapamil is useless in paroxysmal hemicrania.
Given the essentially lifelong nature of the problem, except in children where
the author has followed prepubescent children into their twenties to see the
disorder settle, it is the author’s practice to image all new presentations of
paroxysmal hemicrania with MRI including pituitary views to exclude a pituitary
adenoma, with accompanying testing for prolactin, insulinlike growth factor
1/growth hormone, and thyroid function.30
HEMICRANIA CONTINUA
Hemicrania continua is a rare primary headache disorder first recognized by
Sjaastad and Spierings.32 Hemicrania continua is characterized by a persistent,
strictly unilateral headache that most often waxes and wanes over a day and has
been present for more than 3 months. Worsenings are associated with cranial
autonomic symptoms, such as lacrimation, conjunctival injection, nasal
congestion, rhinorrhea, aural discomfort, eyelid edema, ptosis, or miosis. There

may be either a sense of agitation or restlessness, or aggravation of pain with

movement (TABLE 11-3) (CASE 11-2). Hemicrania continua has a clear and usually
absolute response to indomethacin. As with paroxysmal hemicrania, the chronic
or unremitting form of hemicrania continua comprises 80% of cases and the
episodic (remitting) form makes up 20% of cases, which contrasts with cluster
headache where the episodic form dominates.

Clinical Features
Hemicrania continua should be considered when a patient presents with a strictly
unilateral headache. Typically, migraine preventives are not helpful although
migrainous sensory sensitivity, such as photophobia and phonophobia, can be
seen in three-quarters of patients33 and is often lateralized to the pain.34 In a
cohort of 39 patients, almost all had at least one cranial autonomic symptom.33
One seldom regrets a trial of indomethacin in this setting.
Differential Diagnosis
Although hemicrania continua is rare,33 unilateral chronic migraine is perhaps
less so. As with paroxysmal hemicrania, a discussion around the merits of the
label hemicrania continua for strictly unilateral non–indomethacin-responsive
headache is available in the literature.33 It seems unhelpful until we have
identified the mechanism of action of indomethacin in these patients and can use
that to differentiate their biology. Hemicrania continua is marked by worsenings
that usually persist for 4 to 6 hours, with an undulating pattern during the day,
which contrasts with paroxysmal hemicrania where attacks are shorter and
migraine where attacks are longer and responsive to triptan. Triptan response in
TABLE 11-3 ICHD-3 Diagnostic Criteria for Hemicrania Continuaa
A Unilateral headache fulfilling criteria B-D

B Present for >3 months, with exacerbations of moderate or greater intensity
b Nasal congestion and/or rhinorrhoea
c Eyelid oedema
2 A sense of restlessness or agitation, or aggravation of the pain by movement
D Responds absolutely to therapeutic doses of indomethacinb

a
b
In an adult, oral indomethacin should be used initially in a dose of at least 150 mg daily and increased if
necessary up to 225 mg daily. The dose by injections is 100 mg to 200 mg. Smaller maintenance doses are
often employed.
494 A P R I L 2 0 24

hemicrania continua is unconvincing. As with paroxysmal hemicrania,
consideration of a pituitary disorder is reasonable and an MRI with pituitary
views looking for a pituitary adenoma and tests for pituitary dysfunction (see the
Management section for paroxysmal hemicrania) may be useful.
Management
After a careful history and examination, one may proceed as for paroxysmal
hemicrania. The same regimen for testing indomethacin is recommended either

orally or by injection, again with a proton pump inhibitor. Remarkably,
hemicrania continua also responds to noninvasive vagus nerve stimulation.31 One
wonders if this is a particular utility of noninvasive vagus nerve stimulation in
indomethacin-responsive headache since it has also been reported for cough
headache,35 or a matter of the utility of the persistent use of noninvasive vagus
nerve stimulation for primary headache in more general terms, given what we
know of the antitrigeminal nociceptive effects36 mediated, in part, through the

delta opioid receptor.37
CONCLUSION
Indomethacin-responsive headache disorders, specifically paroxysmal
hemicrania and hemicrania continua, offer a rewarding and unique opportunity
to provide marked clinical improvement when recognized and treated with
indomethacin. These disorders share the final common pathway of the
trigeminal-autonomic pathway, with head pain and cranial autonomic features.
They have distinct differential diagnoses to which the clinician needs to
remain alert.
A 31-year-old man presented with an 8-year history of strictly left-sided CASE 11-2
pain that was continuous. The pain would wax and wane with worsenings
lasting 3 hours, three or four times a day with no circadian pattern. The
pain was throbbing and associated with left-sided photophobia, which
was a mixture of sensitivity and allodynia, with a sense of restlessness
and a worsening of pain with movement. Simple analgesics, such as
acetaminophen and ibuprofen, had not been useful, nor had opioids.
Sumatriptan, zolmitriptan, and rizatriptan, each used orally, were not
useful. The patient had been trialed on propranolol, amitriptyline,
topiramate, and onabotulinumtoxinA, all without useful effect.
Neurologic and general examinations including blood pressure were
normal. After 3 days on indomethacin 50 mg 3 times daily he was
completely headache free. The pain returned if he skipped a dose. He
also took a proton pump inhibitor daily. He was able to halve the
indomethacin dose by adding two 120-second noninvasive vagus nerve
stimulation treatments 3 times a day.
This case illustrates the importance of considering hemicrania continua in COMMENT

strictly lateralized headache presentations.

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trigeminal autonomic cephalalgias. Cephalalgia
27 Sjaastad O, Bakketeig LS. The rare, unilateral
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doi:10.1007/s10194-006-0292-4 35 Moreno-Ajona D, Villar-Martínez MD, Goadsby
PJ, Hoffmann J. Primary cough headache treated
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lasting unilateral neuralgiform headache attacks
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Goadsby PJ. The clinical characteristics of
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doi:10.1093/brain/awh525 indomethacin in human milk and estimation of its
milk to plasma ratio in vitro. Br J Clin Pharmacol
31 Tso AR, Marin J, Goadsby PJ. Noninvasive vagus
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nerve stimulation for treatment of
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jamaneurol.2017.2122 Goadsby PJ. Indomethacin-responsive
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another headache absolutely responsive to
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4(1):65-70. doi:10.1046/j.1468-
2982.1984.0401065.x
DISCLOSURE
scientific advisory or data safety monitoring board for Understanding Cluster Headache (UK) that are
for AEON Biopharma, Inc, and Man and Science. Dr relevant to American Academy of Neurology (AAN)
Goadsby has received publishing royalties from a interests or activities. The institution of Dr Goadsby
publication relating to health care. Dr Goadsby has has received research support from Celgene,
noncompensated relationships in an executive role Kallyope, and the National Institute for Health and
with the American Headache Society and as a Care Research.
trustee with the Migraine Trust and the Organisation

SELECTED TOPICS IN
NEUROLOGY PRACTICE Diversity, Equity, and
Inclusion in Headache
Care and Research
By Rashmi B. Halker Singh, MD, FAAN; Jessica Kiarashi, MD
ABSTRACT
This article reviews the disparities faced by individuals who experience
headache disorders and discusses potential solutions to deliver equitable
care. Disparities exist in the diagnosis and treatment of headache disorders
CITE AS: with regard to race, ethnicity, sex, gender, sexual orientation, geography,
CONTINUUM (MINNEAP MINN) and socioeconomic status. Furthermore, research in the realm of headache
2024;30(2, HEADACHE):498–511.
disparities is inadequate, and the clinical trial representation of patients
Address correspondence to from underserved communities is poor. Many barriers exist to optimizing
Dr Jessica Kiarashi, 5303 Harry care for underserved communities and this article addresses these barriers
Hines Blvd, Dallas, TX 75390, and presents ways to combat them.
jkiarashi@gmail.com.
Dr Halker Singh has received
INTRODUCTION
D
range of $0 to $499 for serving isparities in the diagnosis and treatment of headache disorders
as an editor, associate editor, or are prevalent and disproportionately impact members of
editorial advisory board
member for Current Neurology
underserved communities.1 Disparities are seen across racial and
& Neuroscience Reports; in the ethnic groups, across gender identity and expression, across sexual
range of $500 to $4999 for orientation, and among those from lower socioeconomic
serving as a continuing medical
education (CME) speaker with backgrounds. Additionally, there is a shortage of headache specialists across the
WebMD LLC; in the range of country, which further exacerbates the disparate care and creates geographic
$5000 to $9999 for serving as a
limitations. With 55 million people in the United States living with migraine,
CME speaker with Pri-Med and
on a scientific advisory or data there are less than 700 United Council for Neurologic Subspecialties (UCNS)-
safety monitoring board for certified headache specialists, and in many parts of the country, patients have no
Pfizer Inc; and in the range of
$10,000 to $49,999 for serving as
access to a headache specialist.2-4 With regard to the field of neurology as a
an editor, associate editor, or whole, a study looking at supply and demand in 2013 projected that by 2025 the
editorial advisory board demand for neurologists will fall 19% short of what is needed by the population.5
member for Headache. Dr
Halker Singh has received While more attention has been paid recently to investigating disparities in
publishing royalties from a headache medicine, research in the field is still sparse. In an article on diversity,
publication relating to health equity, and inclusion (DEI), Charleston and Halker Singh6 note the ongoing need
care. Dr Kiarashi has received
personal compensation in the for research that addresses DEI and point out that, over a 2-year period starting
range of $500 to $4999 for in 2019, few articles were published that highlight these topics. In this article, the
serving as a consultant for Cove.
authors share some of the disparities impacting clinical care and research in
UNLABELED USE OF PRODUCTS/ headache medicine, and outline some recommendations to implement change.
INVESTIGATIONAL USE
DISCLOSURE:
Dr Halker Singh and Dr Kiarashi DISPARITIES IN HEADACHE CARE FACED BY UNDERSERVED
report no disclosure. POPULATIONS
© 2024 American Academy Patients presenting with headache often face many barriers to appropriate care.
of Neurology. Disparities in headache care are initially seen in the treatment of patients in the
498 A P R I L 2 0 24

emergency department and extend to diagnosis in the ambulatory care setting, KEY POINTS
the selection of preventive and acute medications, and overall outcomes.
● Underserved
communities are heavily
Disparities in Emergency Department Care impacted by disparities in
Headache is the fourth or fifth most common reason for presenting to the the diagnosis and treatment
emergency department7 and migraine alone accounts for 1.5 million emergency of headache disorders.
department visits a year,8 so the emergency department is the first contact
● Headache disparities are
setting for many patients with headache disorders. Studies suggest that racial seen with regard to race,
differences exist in the management of patients with headache disorders in the ethnicity, gender, sex,
emergency department. In one study, African American patients who presented sexual orientation,
to the emergency department with headache were much less likely to receive a insurance status,
socioeconomic status, and
head CT than White or Hispanic patients (odds ratio: 0.21; 95% confidence geographic location.
interval: 0.09 to 0.52).9 This disparity is also seen in pediatrics where White
children presenting to the emergency department for headache were 3 times
more likely than children of other races to receive a head CT.10
In a retrospective study of children and adolescents, less than one in six
presenting with headache received evidence-based treatment for a primary
headache disorder or migraine.11 Almost one-half of the children and adolescents
received no treatment at all. Of the different treatment settings analyzed,
emergency department doctors and advanced practice providers were least likely
to prescribe any medication. If they did prescribe medication, they were twice as
likely to prescribe opioids compared with primary care providers, and 15.8% of
the patients who received medication were given an opioid or barbiturate. White
children were more likely than children of other races to receive medication.
Patients who received a diagnosis of migraine were also more likely to be
prescribed evidence-based medication. Comparing insurance status, a disparity
was also seen in that those with government insurance or no insurance were
more likely to be prescribed an opioid or barbiturate than those with
private insurance.
Disparities in the Diagnosis and Treatment of Migraine

Establishing a diagnosis of migraine improves one’s odds of being treated with
evidence-based treatments. One study showed that only 26.3% of patients with
episodic migraine and less than 5% of those with chronic migraine are able to see
a health care provider and receive an accurate diagnosis and appropriate
treatment.12 Achieving steps to the appropriate management of migraine is even
more difficult for patients from underserved communities. African American
patients were 67% less likely than White patients to present for care.13 Although
African American patients report more headache days per month,14 higher pain
intensity, more allodynia,15 and a lower quality of life,14 one study showed only
47% of them receive a primary headache diagnosis compared with 70% of White
patients.13 With migraine specifically, African American patients are 25% less
likely to receive a diagnosis of migraine and Hispanic patients are 50% less likely
to receive the diagnosis compared with White patients.7
Regarding treatment in the ambulatory care setting, similar disparities may be
seen across racial and ethnic groups. Latino patients are less likely to receive
prophylactic headache medications compared with White patients.16,17 While
there are limited data on headache disparities in the Latino population, Latino
ethnicity has been associated with lower access to the treatment of chronic pain.18
One study showed that African American patients were also less likely than White

DIVERSITY, EQUITY, AND INCLUSION IN HEADACHE CARE AND RESEARCH
patients to receive prescribed acute migraine medication (14% versus 37%).19 The
overuse of rescue treatments is a major risk factor for the development of chronic
migraine20 and is a predictor of poor prognosis.21 Medication overuse is associated
with an increase in headache days,22 lower quality of life,23 and the presence of
chronic headache at follow-up.24 Undertreatment or inappropriate treatment of
migraine increases the risk for medication-overuse headache, and thus patients
from underserved communities and of lower socioeconomic status are placed at
higher risk of increased disease burden. Patients from underserved communities
are more likely to be prescribed opioids and butalbital-containing medications,
with both contributing to the risk of medication-overuse headache.15
While Native and Indigenous people including American Indian and Alaskan
Native people have the highest prevalence of migraine compared to other racial
and ethnic groups at 19.2%,7 data are limited in this group regarding headache
outcomes; however, it is reported that this group is more likely to experience
allodynia, which is a risk factor for poor prognosis.21,25 Similarly, the data on
headache management and outcomes in Asian American patients are sparse.
While prevalence estimates for severe headache are 10.1% among Asian
American patients and 13.2% among Native Hawaiian or Pacific Islander
patients,7 the estimates may not be reliable given the small sample sizes in the
subgroups. Additionally, Asian subgroups (eg, Laotian, Bangladeshi, Pacific
Islander origin) are generally not studied on their own, but rather often
generalized as “Asian.”
Data on disparities in the lesbian, gay, bisexual, transgender, and queer
(LGBTQ+) population are also lacking, but a few recent reports have illuminated
potential headache disparities. In one study, sexual minority groups defined as
lesbian, gay, bisexual, and other nonheterosexual individuals across the United
States were found to have higher odds of experiencing migraine compared with
those who identified as exclusively heterosexual (prevalence 30.7% versus 19.4%,
respectively).26 A previous study showed higher prevalence of migraine in sexual
minority groups in a cohort in California.27 Compared to heterosexual men, gay
and bisexual men were found to have 50% higher odds of migraine.28
Additionally, individuals of sexual minority groups often have more physical and
mental health issues and face more barriers to health care, which can exacerbate
their migraine experience. In another article on the experience of transgender
patients with migraine, it is also suggested that stigma and discrimination
endured by transgender patients may worsen headache outcomes.29 High rates of
anxiety, depression, posttraumatic stress disorder, and other psychiatric
comorbidities are experienced by transgender patients, which impact quality of
life and migraine frequency and severity.29 Furthermore, the effects of
gender-affirming hormonal therapy should be considered.30 It is also necessary
to consider potential drug-drug interactions in transgender and gender-diverse
patients who are receiving gender-affirming hormonal therapy, although these
data are largely extrapolated from cisgender populations, in which the
formulations and indications for hormone therapy are distinct.31
In addition to racial and ethnic disparities and disparities faced by the
LGBTQ+ population, socioeconomic and insurance-related factors also contribute
to headache disparities. Household income is associated with the prevalence of
migraine as those who make less than $10,000 a year are at the highest risk of
migraine in comparison to households making more than $30,000 a year.32
Another study showed that individuals with annual family incomes of less than
500 A P R I L 2 0 24

$35,000 and less than $11,600 for someone in a single-income household have the KEY POINTS
highest prevalence of migraine and severe headache disorders.7 Additionally,
● The scarcity of headache
those with full-time employment have the lowest prevalence of migraine or providers in the United
severe headache at 13.2% compared with those who are employed part time at States contributes to
15.6%. The prevalence in patients who had never worked was 16.5%, and in those insufficient headache care.
who were presently unemployed but had previously worked it was 21.4%. This
● Disparities are also seen
study suggests that those who are unemployed have less access to headache care
in the conduct of headache
and experience more triggers that can exacerbate headache disorders. Patients research and there is a lack
with Medicaid who were under 65 years old had the highest migraine prevalence of representation of many
at 26%, whereas those with private insurance had a prevalence of 15.1%. Those patient populations in
without any insurance had a prevalence of 17.1%. In the above 65-year-old group, research studies.
the prevalence was also highest in those with Medicare and Medicaid at 16.4%.
One study that looked at school performance in preadolescents (5 to 12 years old)
in Brazil found that the prevalence of chronic migraine was significantly higher
in children from lower-middle-class families and those from poor families
compared to high-income families33 In the pediatric population, while children
from low-income backgrounds have a higher prevalence of migraine,32 their
odds of hospital admission for migraine are lower.34
Access to headache specialty care is impacted by both the geographic
distribution of those who treat headache disorders and the lack of specialists in
the field. While general neurologists also treat headache disorders, the supply of
neurologists across the United States does not meet the demand.5 With regard to
fellowship training for headache, most US programs are located in urban areas,
mainly in the mid-Atlantic and Northeast regions of the country, and graduating
fellows tend to practice where they train.35 There are currently 49 accredited
headache medicine fellowship programs3 in the United States and many states do
not have a UCNS certified graduate.4 As of 2022, the states with the highest
number of headache specialists are New York, California, Texas, Florida, and
Ohio.4 Many states have zero headache specialists including Delaware, Alaska,
Montana, North Dakota, and South Carolina.4 Additionally, there is a shortage of
general neurologists across the United States, which further exacerbates the
disparities in care. As a whole, given the number of patients with headache
disorders including migraine, there is a scarcity of headache specialists
nationwide to accommodate the population’s needs, and some regions of the
country are better equipped than others to care for patients with headache
disorders. In the United States, 55 million people are living with migraine, but
there are less than 700 UCNS-certified headache providers.2
Overall, as a result of the physician-shortage problem in the United States,
where twice as many physicians per capita work in metropolitan areas as in rural
areas,35 and the tendency of headache specialists to also favor working in urban
settings, rural Americans face more obstacles to receiving care.35 A study
conducted in Norway showed that patients in rural areas had to travel longer
distances and take more time off work, contributing to a greater loss of income
than patients in urban areas.36 Patients from rural areas also visit the emergency
department more frequently for headache than those in urban areas.37 They are
also usually older and have lower health literacy, lower median household
income, and lower education levels compared with patients from
urban communities.38
In addition to the racial, ethnic, socioeconomic, and geographic disparities
faced by patients with headache disorders from a clinical perspective, there is

also a lack of representation and diversity of patient populations in research. For

example, in a review of 16 migraine research publications in Neurology published
in 2019, only six mentioned participant race.1 Only one of these six studies looked
at categories of race other than White/non-White and 74.7% to 97% of these
patient samples were designated as White. Given that the prevalences of
migraine and severe headache are similar in White (15.5%), African American
(15.0%), and Hispanic (14.9%) populations,7 this lack of representation in
research is most likely related to challenges in recruiting study participants who
adequately represent the entire population with migraine.1 Additionally, in
another review, this time of clinical trials of patients with migraine published
between 2011 and 2016, only 25 of 36 trials reported race. All but one of the
studies had a majority White patient population and none of the studies observed
safety and efficacy broken down by race or gender.39 A lack of representation in
research trials can lead to worse outcomes as the safety and efficacy of newer
treatments are not evaluated across samples that represent the patient
population. Furthermore, there is the possibility that this lack of inclusion in
research could contribute to additional barriers to understanding headache
outcomes in people of color as race and ethnicity can be surrogate measures for
other social determinants that impact migraine. The first step to rectifying this is
to ensure trials include diverse groups of participants.
FACTORS THAT MAY CONTRIBUTE TO HEADACHE DISPARITIES

Many factors may contribute to headache disparities including implicit bias,
systemic racism, health care literacy, access to care, and barriers to the
patient-physician relationship. Identifying gaps in care and ways to rectify them
are integral to addressing disparities.
Racism, Systemic Racism, and Implicit Bias

While the headache medicine literature that focuses on the impact of racism is
sparse, numerous studies have demonstrated that pain is often undertreated in
Black and Hispanic patients compared with White patients across adult and
pediatric populations.40-43 Studies have also demonstrated that implicit bias
and discrimination from health care professionals impact the care received by
patients from underserved communities.40-45 Implicit bias is defined as
“subconscious associations between two disparate attributes that can result in
inequitable decisions.”46 A study assessing the views of medical students and
residents found that about one-half of them held at least one erroneous belief
about African Americans, for example, that Black people’s skin is thicker than
White people’s skin.44 A review of 15 studies revealed that health care
professionals displayed low-to-moderate levels of implicit bias against people
of color in 14 of the studies.45 In 13 of the studies reviewed, health care
professionals were more likely to associate a negative word with Black patients
versus White patients. Prevalence rates of anti-Black bias ranged from 42% to
100% in four of the studies. Four studies also found that Black patients are
viewed as less compliant, less responsible, and less cooperative by health care
professionals. The literature also reflects that underserved communities face
more discrimination in clinical encounters. In one study, 20% of Latino patients
reported discrimination when going to the doctor versus 5% of White patients,
and 17% of Latino patients avoided going to the doctor because they felt they
would be treated poorly versus 3% of White patients.47 The same study also
502 A P R I L 2 0 24

showed that being a US citizen, having a higher socioeconomic status, or being KEY POINT
a college graduate was not protective against this discrimination. Hispanic
● Issues with access to
patients also reported that they do not think health care professionals believe care, health and headache
them when they say they are in pain48 and are more likely not to seek care for literacy, systemic racism,
acute pain.49 More than one-third of African American patients reported and implicit bias all
discrimination in clinical settings and 22% of them do not seek care for contribute to the
perpetuation of headache
themselves or family members as a result.50 More than one in five American
disparities.
Indian and Alaskan Native individuals experienced discrimination and 15% of
them would not pursue care for themselves or their families because of
potential discrimination.51
Coupled with reported discrimination during clinical encounters, many
underserved populations may be less inclined to participate in research given the
history of medical atrocities committed in the name of research. The trauma and
damage endured by the African American community as a result of the
experiment known as the Tuskegee syphilis study along with other studies such
as gynecological studies on African American women have likely influenced
perceptions of both research and clinical care.52
Discrimination in the Treatment of LGBTQ+ Patients

It is reported that in the LGBTQ+ population, 8% of patients said a health care
provider refused to see them and 6% of them reported a health care provider
would not treat them based on their sexual orientation.53 Twenty-nine percent of
transgender patients surveyed reported experiencing unwanted physical contact
by a health care provider and 21% reported harsh or abusive language when being
treated. Those who tried to switch health care providers had difficulty finding a
new one.53
Barriers to the Patient-Clinician Relationship

The mistrust toward the medical system in both the clinical and research realms
greatly impacts the patient-clinician relationship. Minoritized racial and ethnic
groups in the United States exhibit more distrust of the health care system, with
African Americans exhibiting the lowest trust in the medical community.54 They
also report more negative views on communication between patients and
physicians. Effective communication between patients and providers is
especially important in headache medicine where the continuity of care is central
to treatment success. Treatment compliance, outcomes, and patient satisfaction
are dependent on effective communication.55
Access to Care
As noted earlier, geography contributes to the lack of access to headache care, as
do insurance status, immigration status, language barriers, and costs of health
care. This is especially true in the Hispanic community. Hispanic Americans in
the United States make up the largest proportion of people living in poverty and
have the lowest rates of health insurance coverage compared with White, Black,
and American Indian and Alaskan Native individuals.56 Hispanic ethnicity and
speaking Spanish as a first language were associated with decreased access to
management of chronic pain.47 Spanish-speaking Hispanic Americans are also
less inclined to see a health care professional for pain-related issues than
English-speaking Hispanic Americans. More than 50% of Hispanic Americans
cite the cost of medical care as a major problem and compared with White

patients, Hispanic patients often have a harder time filling their prescriptions due
to financial barriers and end up delaying care.57 Immigration status also impacts
care in the Hispanic American population as many patients are worried that
seeking care will disclose their immigration status or put an undocumented
family member at risk.58
Health and Headache Literacy

Approximately 36% of Americans have basic or below basic health literacy.59
Minoritized racial and ethnic groups as well as those with lower incomes have
higher rates of low health literacy.60 Having a thorough understanding of
headache and the treatments available allows patients to improve their headache
literacy and their quality of life. Headache literacy is defined as “the personal
characteristics and social resources for individuals and communities to be
empowered to access, understand, and use information and services to make
informed decisions regarding headaches.”61 In a randomized study, patients
who received headache education over 6 months had a significant decrease
in mean headache days per month and disabling headache days per month,
less medication overuse, and a reduction in disability as measured by the
Migraine Disability Assessment score and were more adherent with preventive
medications. They also made fewer calls to clinics for headache-related
issues.62
How Do We Address These Disparities?

As we look to address these disparities in health care, we can find ways to make
improvements at the bedside. The patient-clinician relationship can be
influenced by an understanding of culture and how a person’s culture shapes
their life and decision making. A clinician who is cognizant of these effects and
incorporates cultural awareness into their patient interactions can improve their
relationships with patients from backgrounds both similar to and different from
their own. In one article, Charleston63 explains culture as a shared set of values,
beliefs, knowledge, and practices, and that framing ourselves to strive for greater
“cultural sensitivity” is more appropriate than “cultural competence,” as culture
is complex and diverse, with many variables playing a role, such as age,
education, primary language, socioeconomic status, employment, gender, and
immigration status, among others.
While the headache medicine literature is sparse on the topic of cultural
sensitivity, we can make inferences from related disciplines that might also be
beneficial to the field. A recent review by Otte64 explored the topic of
patient-provider concordance, and whether better concordance improved
patient outcomes. Concordance was defined as a shared identity between the
patient and clinician, whether it be gender, race, ethnicity, or a multifactorial
circumstance with components including these and others (eg, age, language,
education). Twenty-three studies met inclusion criteria, and with these limited
data the analysis was unable to conclusively determine if the presence of
concordance improved patient outcomes. While some included articles noted
that race concordance, combined with patient-centric communication, led to
better patient satisfaction and decision making with Black patients, several
studies found no correlation between race concordance and different outcomes
including quality of surgical care, hospitalist performance, patient trust, or
quality of trust. These studies found that patient-centered communication, and
504 A P R I L 2 0 24

perhaps even clinician self-disclosure of their own similar health information to KEY POINTS
patients, were of greater importance than race concordance. Similar inconclusive
● Other potential ways to
and conflicting data were seen with gender concordance. Importantly, Otte64 mitigate disparities include
also noted that studies did not take into consideration individuals who might incorporating cultural
identify with more than one race or those who are nonbinary as examples of sensitivity training,
study limitations when examining concordance. improving patient-physician
communication, and
Highlighting the importance of communication, language concordance was
diversifying the physician
specifically studied by Diamond and colleagues65 in a systematic review. workforce and leadership.
Approximately 20% of people (58 million) in the United States speak a
language other than English, most commonly Spanish, Chinese, French, ● Efforts are being made to
Tagalog, or Vietnamese, with almost one-half of these individuals (25 million) increase the number of
headache specialists and
attesting to a limited proficiency in English. From the 33 primary manuscripts fellowship positions to
that were included in their analysis, the authors determined that language improve the issue of access.
concordance between the health care provider and patient with limited
English proficiency had several positive effects, including qualitative
outcomes such as patient satisfaction, self-reported understanding of
diagnosis, and utilization of and access to care. There was also a relationship
between language concordance and improved blood pressure, low-density
lipoprotein levels, and blood sugar control over time in studies that measured
those outcomes, suggesting that language concordance contributes to
improved long-term relationships with clinicians, which can lead to better
control of these chronic health concerns. These studies support efforts to
diversify the health care workforce in this way and serve as a reminder to
utilize interpreters to improve communication and optimize care when a
clinician lacks sufficient proficiency in the patient’s preferred language.
In their two-part series, Charleston and colleagues66,67 not only describe
the racial disparities impacting African American men who are headache
medicine specialists in the United States but also share a call to action with
several concrete steps that can be taken to educate the field. While their
perspective pieces focus on African American male physicians, many of
the themes offered as solutions could be generalized to the needs of other
marginalized groups in medicine. For instance, they highlight that training in
implicit bias is vital to understanding our personal barriers to advancing
equity.67
Furthermore, as it relates to caring for those who live with chronic pain,
formal bias training can help address conscious and unconscious prejudices that
underlie known racial disparities in pain evaluation and treatment.68-71 Multiple
studies have demonstrated that racial and ethnic differences exist when it comes
to patient care and managing pain, with the most vulnerable patients being at the
greatest risk of having pain undertreated.72,73 Implicit bias training often consists
of online modules, with a pretest and posttest using the Harvard Implicit
Association Test to measure change.67,71,74
Additionally, diversifying the health care workforce, particularly at positions
of leadership, with a deliberate effort to include those who are underrepresented
in medicine brings fresh perspectives and can have important downstream
impacts. Charleston and colleagues67 explain that this can be a powerful part of
the action plan. For example, one study demonstrated that hospitals with more
racially and ethnically diverse executives and board members had a greater
number of diversity initiatives.75 Another study uncovered that, all things being
equal, Black applicants are less likely to receive National Institutes of Health

(NIH) funding; with a more diverse review board, this racial difference with
funded projects possibly could be improved.76
In addition to broadening the diversity of funded researchers, there is also an
emphasis on improving racial and ethnic diversity in research participants.77
Including diverse groups in research allows for a deeper understanding of how
disease processes impact different populations and can increase the relevancy of
treatment recommendations. de Dhaem and colleagues77 provide several
recommendations to address this critical research need, with the context that
many marginalized groups have experienced systemic racism at the hands of
medicine; this must be addressed in a sensitive way to move forward.77 The
authors point to several strategies concerning study design, the recruitment
and retention of participants, data collection, and data analysis that could
improve representation in research studies. Some of these ideas include
creating headache research guidelines that encourage participant samples
to be representative of the patient population, involving community members in
each step of the research process and creating community advisory boards
to ensure safety standards are met, partnering with local businesses and
community organizations to build outreach programs, expanding access to
care in underserved communities, ensuring the availability of language
interpreter services, and advocating for telehealth capabilities. In an editorial
by Lipton and colleagues,78 the importance of utilizing screening instruments
and validating them across different languages and countries is emphasized,
as this would not only benefit patient outcomes but will likely impact the
ability to conduct research studies across diverse populations.
With their updated demographics data, capturing the decade of growth of
headache medicine subspecialists in the United States, Kanegi and Rosen79
found that in 2021 there was an increase in headache medicine clinicians
compared to 2012, with 692 UCNS board-certified headache medicine
subspecialists in 2021 as compared with 416 in 2012. However, the authors
found disparities in access, with areas of higher poverty lacking headache
medicine specialists. Improving access to headache medicine care remains an
important consideration and a high priority as education programs are created
to draw new individuals into the field. Charleston and colleagues67 have
shared that individuals who are underrepresented in medicine have been more
likely to return to their communities to practice, which could help meet this
critical gap.
Language is a powerful tool for identifying and addressing disparities in
headache medicine. In their editorial on sex and gender, Ackley and Halker
Singh80 draw attention to the need for researchers to be inclusive of all sexes and
genders in studies, as data are currently generally lacking on gender minorities
and intersex people. Additionally, authors should be specific when reporting on
sex and gender, including how those data were obtained, with the understanding
that the two are not the same. The careful use of language can help reduce biases,
and Flanagin and colleagues81 provide several suggestions in their editorial on
this topic. For example, from a race and ethnicity standpoint, they recommend
that researchers identify how race and ethnicity data are collected in the methods
section of an article (eg, is this self-identified by the participant, collected from a
database, observed by a researcher). Specific categories are preferred over
generalized terms and should be listed in alphabetical order; if a category of
“other” is listed, what that means should be explained. These are just some of the
506 A P R I L 2 0 24

recommendations made to ensure that research is more inclusive and
representative and uses improved language to reduce bias.
CONCLUSION
This review of the headache medicine literature reveals many gaps in research
and clinical care from a DEI perspective. Areas for improvement include care of
individuals belonging to underserved populations, understanding systemic
racism within medicine, addressing implicit biases, and improving access to
health care and health care literacy. Additionally, without a robust original
research literature base in headache medicine that focuses on DEI topics,
other areas where improvement is needed are likely, and those gaps remain
obscured. At the same time, this is an era of hope, with more recent articles
published on this topic that allow for improved understanding and abilities as
clinicians, educators, and researchers. Professional medical societies are also
aligned in this effort for change and have implemented several formal initiatives
including DEI task forces, social justice programs, and leadership development
opportunities.82-85 The authors are optimistic that the momentum to reduce
disparities in the care of underserved populations and diversify our medical
communities will remain strong and the creation and sustainment of long-lasting
change is possible.
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4610.2006.00428.x
75 Herrin J, Harris KG, Spatz E, et al. Hospital
63 Charleston L. Cross-cultural headache care
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76 Ginther DK, Schaffer WT, Schnell J, et al. Race,
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Gany F. A systematic review of the impact of
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82 American Headache Society. Diversity, equity 84 American Academy of Neurology. IDEAS
and inclusion task force. Accessed September programming & resources. Accessed September
21, 2023. https://americanheadachesociety.org/ 21, 2023. https://www.aan.com/membership/
about/board-committees/dei-taskforce/ ideas-programming-and-resources
83 American Academy of Neurology. Anti-racism 85 American Academy of Neurology. Diversity
education program. Accessed September 21, leadership. Accessed September 21, 2023.
2023. https://www.aan.com/membership/anti- https://www.aan.com/education/diversity-
racism-education-program leadership

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SELF-ASSESSMENT
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Self-Assessment and
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By Nuri Jacoby, MD; Adam Kelly, MD, FAAN

CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/08/2024
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POSTREADING TEST
ARTICLE 1: APPROACH TO THE PATIENT WITH HEADACHE
1 Which of the following factors, if present, is most suggestive of

neurologic symptoms being related to migraine aura as opposed to
stroke or transient ischemic attack?
A multiple symptoms occurring in succession as opposed to

simultaneously
B onset of neurologic symptoms unrelated to development of

headache
C single neurologic symptom as opposed to multiple symptoms
D symptom duration longer than 60 minutes
E symptoms being exclusively related to loss of function
2 A 33-year-old man is seen in clinic for symptoms of intermittent

headaches. When asked if his symptoms always involve one side of his
head, he answers that his symptoms can affect either side of his head.
This characteristic would be most consistent with which of the
following headache disorders?
A cluster headache
B hemicrania continua
C migraine
D paroxysmal hemicrania
E right hemispheric neoplasm
3 Cutaneous allodynia and other manifestations of central sensitization in

patients with migraine are associated with the development of which of
the following?
A chronic pain
B hyperemesis
C migrainous infarction
D nonvisual auras
E poor response to transcutaneous treatment modalities
4 A 24-year-old woman is seen in clinic for management of migraine.

She reports that for 1 to 2 days after her attacks she still feels somewhat
abnormal, even on occasions when she does not take any acute
medications. Which of the following symptoms would be a typical
feature of a migraine postdrome?
A cognitive dysfunction
B expressive language dysfunction
C hearing loss
D impaired consciousness
E visual scintillations
516 A P R I L 2 0 24

ARTICLE 2: PATHOPHYSIOLOGY OF MIGRAINE
5 Which of the following neurotransmitters is implicated in many

premonitory symptoms seen in migraine?
A acetylcholine
B dopamine
C epinephrine
D glutamate
E glycine
6 Infusion of which of the following peptides can provoke migrainelike

attacks?
A endocannabinoid
B enkephalin
C neurokinin A
D oxytocin
E pituitary adenylate cyclase-activating polypeptide
ARTICLE 3: ACUTE TREATMENT OF MIGRAINE
7 A 29-year-old woman is seen in the emergency department for

unrelenting migraine symptoms for the past 2 days, including severe
headache and nausea, that have not responded to her usual approaches
of sumatriptan and prochlorperazine. The use of IV dexamethasone in
this setting is associated with which of the following outcomes?
A decrease in acute pain

B decrease in need for antiemetic medications
C decrease in rate of headache recurrence in subsequent days
D increase in need for opioid medications
E increase in rate of hospitalization for migraine symptoms
8 A 57-year-old woman with a history of hypertension, diabetes, and

stroke is seen for the management of headache. She has questions about
using ubrogepant as an acute approach, since she has been told to avoid
nonsteroidal anti-inflammatory drugs due to her daily use of aspirin and
to avoid triptans in the setting of her prior stroke. She would be
recommended to limit her ubrogepant dose to 50 mg if she is also taking
which of the following antihypertensive medications?
A amlodipine
B lisinopril
C losartan
D propranolol
E verapamil

POSTREADING TEST
9 Patients taking lasmiditan as an acute migraine treatment should be

counseled specifically about which of the following concerning side
effects?
A acute angle closure glaucoma

B coronary vasospasm
C impaired driving performance

D intracranial hypertension
E toxic skin reaction
ARTICLE 4: PREVENTIVE TREATMENT OF MIGRAINE
10 Which of the following medications used for migraine prevention is

administered as an intravenous infusion?
A atogepant
B eptinezumab
C erenumab
D fremanezumab
E galcanezumab
11 A 55-year-old woman with a history of borderline hypertension presents

to establish care for migraine. She has had occasional migraine for
20 years that has recently become more frequent. She now gets seven
headaches per month with minimal benefit from acute medications. She
has never tried a preventive medication before. She is not on any
medications. Her neurologic examination is normal. Which of the
following is the best management option for her?
A amitriptyline
B candesartan
C galcanezumab
D rimegepant
E topiramate
12 According to the 2021 American Headache Society Consensus

Statement regarding preventive treatment for migraine, in which of the
following situations should a preventive medication be offered?
A the American Headache Society does not recommend preventive

medications based on headache frequency
B 2 headache days per month with severe disability
C 3 headache days per month with some disability
D 4 headache days per month with some disability
E 5 headache days per month with no disability
518 A P R I L 2 0 24

ARTICLE 5: MEDICATION-OVERUSE HEADACHE
13 According to the International Classification of Headache Disorders,

Third Edition, which of the following is a key diagnostic criterion for
the diagnosis of medication-overuse headache?
A age 50 years or younger

B headache occurrence on 15 or more days per month
C headache responsiveness to corticosteroid treatment

D preceding diagnosis of episodic migraine
E regular overuse of analgesic medications for at least 1 year
14 A 31-year-old woman is seen in clinic for the management of headache.

She has a diagnosis of migraine with aura dating back to adolescence,
though as of late has been experiencing nearly daily headaches. She uses
acetaminophen and sumatriptan as acute medications on a nearly daily
basis, so medication-overuse headache (MOH) is considered. Which of the
following factors would confer the highest risk of MOH in this patient?
A diagnosis of primary headache disorder during adolescence

B frequency of analgesic use
C preexisting diagnosis of migraine with aura
D sumatriptan dosage
E use of varying types of analgesic medication
15 Which of the following best describes the risk of relapse in patients

with previously treated medication-overuse headache (MOH)?
A prior opioid use is not a risk factor for relapse of MOH

B relapse rates can be as high as 50% in some settings
C relapses are uncommon within the first year but can be seen 3 to
5 years after diagnosis
D tension-type headache is associated with a lower risk of MOH
recurrence
E younger patient age is a strong predictor of MOH relapse
ARTICLE 6: CLUSTER HEADACHE, SUNCT, AND SUNA
16 Which of the following is the most common time that cluster headache
occurs?
A 2:00 AM
B 7:00 AM
C 12:00 PM
D 5:00 PM
E 10:00 PM

POSTREADING TEST
17 Which of the following headache features best differentiates migraine

from cluster headache?
A autonomic features
B duration
C premonitory features
D response to treatment with sumatriptan

E triggers
18 A 53-year-old man presents with 1 year of daily, right-sided, severe

periorbital headaches that are sharp in character, last for 60 to
90 minutes, and are associated with lacrimation and rhinorrhea. His
brain MRI is normal. Verapamil, lithium, and galcanezumab have not
led to any improvement. Which of the following is the most
appropriate next step?
A lumbar puncture
B prednisone
C prolactin level
D repeat trial of lithium at a higher dose
E sphenopalatine ganglion stimulation
19 What initial prednisone dose was found to be effective in a 2022 clinical

trial as a bridge treatment for cluster headaches?
A 20 mg
B 40 mg
C 60 mg
D 80 mg
E 100 mg
20 A 48-year-old man with no significant medical history presents with

4 months of episodes of severe, stabbing, left eye pain that are
associated with ipsilateral conjunctival injection, lacrimation, and
ptosis. The attacks last for 12 minutes and occur ten times per day.
Touching his face does not trigger the episodes. His brain MRI is
normal. Which of the following medications is most appropriate for
this patient?
A amitriptyline
B carbamazepine
C indomethacin
D lamotrigine
E topiramate
520 A P R I L 2 0 24

ARTICLE 7: POSTTRAUMATIC HEADACHE
21 A 56-year-old man is seen in the emergency department following a fall

with mild head injury. He was briefly dazed after his fall but is now back
to baseline. His medical history is notable for diabetes and migraine with
aura. His head imaging is normal. Which of the following represents a

potential risk factor for posttraumatic headache in this patient?
A age older than 50 years

B higher educational status
C history of diabetes
D history of migraine
E male sex
22 The phenotype of posttraumatic headache most commonly resembles

the symptoms seen in which of the following headache disorders?
A cervicogenic headache
B migraine
C posttraumatic headache has a distinct phenotype that does not
resemble other headache disorders
D primary stabbing headache
E trigeminal autonomic cephalgia
23 Which of the following patient-specific factors is associated with a

higher rate of persistence of posttraumatic headache at 3 months post–
brain injury?
A absence of extracranial injuries

B age younger than 30 years
C higher patient expectations for recovery
D history of psychiatric disease
E male sex

POSTREADING TEST
24 A 31-year-old man is seen in the emergency department for ongoing

headaches after a recent mild head injury. One week ago he was kneed
in the head during a soccer game; he experienced some brief amnesia
but quickly returned to baseline. Since then, he has been experiencing
continuous holocephalic headaches and some sensitivity to light and
sound, resulting in his primary care provider sending him in for
evaluation. His examination and brain and vascular imaging are

normal. Which of the following medications should be avoided in the
treatment of his posttraumatic headache?
A acetaminophen
B aspirin
C hydrocodone
D ibuprofen
E ketorolac
ARTICLE 8: NEW DAILY PERSISTENT HEADACHE
25 Which of the following is the most frequently described inciting factor

in patients who develop new daily persistent headache?
A head injury
B infection
C stressful life event
D surgery
E vaccination
26 Which of the following features best differentiates new daily

persistent headache from chronic migraine?
A at least 3 months duration

B autonomic symptoms
C clearly remembered onset of headache
D nausea and vomiting
E photophobia and phonophobia
522 A P R I L 2 0 24

27 A 65-year-old woman with a medical history of congestive heart failure
with a pacemaker that is MR unsafe presents with 25 years of daily
headaches that began abruptly. The headaches are holocephalic,
pulsating, and a 6/10 in pain severity. They are associated with
photophobia and phonophobia, neck stiffness, hypoacusis, and
tinnitus. The headaches do not change with position, but the patient
recalls that when the headaches started they were precipitated by

standing. Her neurologic exam including fundoscopy is normal. Head
CT with and without contrast is normal. Which of the following is the
most appropriate next step in this patient?
A CT myelography
B erythrocyte sedimentation rate
C occipital nerve block
D onabotulinumtoxinA
E topiramate
28 Approximately what percentage of patients with new daily persistent

headache eventually get complete headache resolution?
A 0%
B 20%
C 40%
D 60%
E 80%
ARTICLE 9: HEADACHE IN CHILDREN AND ADOLESCENTS
29 Guidelines from national organizations recommend that all children

and adolescents with migraine be screened for which of the following
comorbid conditions?
A depression
B eating disorders
C epilepsy
D intracranial aneurysm
E sleep apnea

POSTREADING TEST
30 A 15-year-old girl is seen in the neurology clinic for evaluation of

headache. She reports episodes of throbbing-quality headache
associated with nausea and photophobia, occurring at a rate of nearly
once per month and lasting an average of 4 hours. Her events usually
respond to ibuprofen or naproxen. Her mother and older brother have
similar events. Her neurologic examination, including fundoscopy, is
normal. Which of the following is needed prior to making a diagnosis

of migraine without aura in this patient?
A EEG
B lumbar puncture
C MR venogram of the head
D no additional diagnostic testing needed
E therapeutic trial of sumatriptan
31 Which of the following is a component of the diagnostic criteria for

migraine in younger patients that represents a major difference from
the criteria used in adults?
A attacks must include photophobia, phonophobia, and nausea

B brain imaging with MRI is required
C duration of attacks must be greater than 4 hours
D location of pain can be bilateral or unilateral
E pain must be posterior in location
32 Which of the following is one of the criteria of expert

recommendations regarding the off-label use of anti–calcitonin gene-
related peptide (CGRP) monoclonal antibody therapy in the treatment
of children and adolescents with migraine?
A 4 or more migraine days per month

B diagnosis of migraine without aura, as opposed to migraine with
aura
C failure of two or more preventive therapies
D initiation of anti-CGRP therapy prior to reaching puberty
E negative screening for symptoms of anxiety and depression
ARTICLE 10: CRANIAL NEURALGIAS
33 Patients with classical trigeminal neuralgia have a higher risk of

developing which of the following disorders?
A Alzheimer disease
B amyotrophic lateral sclerosis
C glioblastoma
D Parkinson disease
E restless legs syndrome
524 A P R I L 2 0 24

34 A 73-year-old man presents with a 3-month history of paroxysmal
severe shooting pain in the back of his mouth that radiates up to the
angle of the jaw and ear. The pain lasts for a few seconds and is
triggered by swallowing and yawning. Which of the following clinical
features may occur in this patient’s disorder?
A diplopia
B dysarthria
C dysphagia
D hearing loss
E syncope
35 A 63-year-old woman presents with severe stabbing pain that is located

deep in the internal auditory canal. It lasts for 30 seconds at a time and
is triggered by touching the skin around the ear. Which of the
following is the most common secondary cause for this patient’s
condition?
A arteriovenous fistula
B herpes zoster
C meningioma
D multiple sclerosis
E vestibular schwannoma
36 Occipital neuralgia most commonly co-occurs with which of the

following headache disorders?
A migraine
B new daily persistent headache
C posttraumatic headache
D tension headache
E trigeminal autonomic cephalgia
ARTICLE 11: INDOMETHACIN-RESPONSIVE HEADACHE DISORDERS
37 A 34-year-old man is diagnosed with paroxysmal hemicrania and is

started on a trial of oral indomethacin. The use of indomethacin in the
setting of concomitant use of which of the following medications could
result in toxicity in this patient?
A carbamazepine
B fluoxetine
C lithium
D pregabalin
E venlafaxine

POSTREADING TEST
38 Untreated paroxysmal hemicrania and hemicrania continua are both

associated with activations in which of the following brain regions on
positron emission tomography (PET) imaging?
A bilateral orbitofrontal cortex

B contralateral pontine tegmentum
C contralateral posterior hypothalamus

D ipsilateral thalamus
E periaqueductal gray
39 A 25-year-old woman is seen in clinic for recurrent episodes of severe

right-sided head pain. Her attacks last roughly 10 minutes and can
occur up to 10 to 15 times per day. Her events are associated with mild
right-sided tearing and rhinorrhea. The frequency of attacks has not
changed with trials of amitriptyline and topiramate as preventive
approaches. Her examination and brain imaging are normal. Which of
the following is the most likely diagnosis?
A cluster headache
B hemicrania continua
C migraine without aura
D paroxysmal hemicrania
E trigeminal neuralgia
40 A 37-year-old man is seen for evaluation of recurrent episodes of

severe unilateral pain, primarily around his left eye, which are
associated with significant conjunctival tearing and rhinorrhea. His
differential diagnosis includes cluster headache and paroxysmal
hemicrania. Distinguishing between these diagnoses could be done
based on a therapeutic response to which of the following
medications?
A erenumab
B indomethacin
C propranolol
D topiramate
E verapamil
526 A P R I L 2 0 24

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 04/09/2024
By Nuri Jacoby, MD; Adam Kelly, MD, FAAN
HEADACHE
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon
completion of the Postreading Self-Assessment and
CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Refer to the CME tab on
ContinuumJournal.com for dates of accreditation. Canadian participants
should visit MAINPORT (mainport.royalcollege.ca) to record learning and
outcomes. Canadian participants can claim a maximum of 20 hours per

POSTREADING TEST—PREFERRED RESPONSES
ARTICLE 1: APPROACH TO THE PATIENT WITH HEADACHE
1 The preferred response is A (multiple symptoms occurring in succession

as opposed to simultaneously). Aura is seen in roughly 30% of patients
with migraine and can manifest in a variety of different manners. The
focal nature of migraine aura in many patients can make distinguishing

this from a cerebrovascular process (eg, stroke, transient ischemic
attack) challenging in some circumstances. A single aura symptom may
be present in migraine or a transient ischemic attack, but in patients with

multiple symptoms as part of their aura, these will generally evolve and
develop in succession; this can differ from stroke or transient ischemic
attack, where it would be more common to see multiple symptoms occur
suddenly and simultaneously. Migraine aura symptoms can also cross the
midline (eg, bilateral sensory or motor symptoms). For more information,
refer to page 301 of the Continuum article “Approach to the Patient With
Headache.”
2 The preferred response is C (migraine). During an individual attack of

migraine, symptoms tend to be unilateral and affect only one side of the
head. However, over time, most patients with migraine have involvement
of either side of their head as opposed to being “side-locked.” This
contrasts with the other options listed here, including cluster headache
and other trigeminal autonomic cephalgias, which generally involve one
side of the head consistently. For more information, refer to page 301 of
the Continuum article “Approach to the Patient With Headache.”
3 The preferred response is A (chronic pain). Cutaneous allodynia and

other forms of central sensitization involve a hypersensitivity to noxious
stimulation or a perception of nonpainful stimulation as being painful in
nature. The prevention of central sensitization is critical as the
development of this symptom can be associated with a progression to a
chronic pain syndrome. For more information, refer to page 304 of the
Continuum article “Approach to the Patient With Headache.”
4 The preferred response is A (cognitive dysfunction). Many patients with

migraine report a “hangoverlike” state following migraine attacks, even
once their head pain resolves. This postdrome can involve a number of
typical symptoms, including mild cognitive dysfunction, vertigo, and
fatigue. The occurrence of these symptoms should be elicited in
patients with migraine, and their presence should be counted toward
migraine monthly days. For more information, refer to page 307 of the
Continuum article “Approach to the Patient With Headache.”
528 A P R I L 2 0 24

ARTICLE 2: PATHOPHYSIOLOGY OF MIGRAINE
5 The preferred response is B (dopamine). Dopamine plays a significant

role in migraine pathophysiology. Many of the premonitory symptoms,
including cognitive symptoms and yawning, are thought to be related to
dopamine’s impact on the hypothalamus, substantia nigra, and ventral

tegmental areas. For more information, refer to page 335 of the
Continuum article “Pathophysiology of Migraine.”
6 The preferred response is E (pituitary adenylate cyclase-activating

polypeptide). Pituitary adenylate cyclase-activating polypeptide, along
with calcitonin gene-related peptide and nitroglycerin (a nitric oxide
donor), can provoke migrainelike attacks when experimentally infused.
For more information, refer to page 336 of the Continuum article
“Pathophysiology of Migraine.”
ARTICLE 3: ACUTE TREATMENT OF MIGRAINE
7 The preferred response is C (decrease in rate of headache recurrence

in subsequent days). Patients who do not respond to typical migraine
abortive approaches may require treatment in an emergency
department or inpatient setting. Various intravenous options can be
considered in this setting, including dexamethasone or other
corticosteroids. Meta-analyses have shown that corticosteroid therapy
may lower the risk of recurrence of headache in the days following an
emergency department visit, but do not reduce acute pain better than
placebo. For more information, refer to page 359 of the Continuum
article “Acute Treatment of Migraine.”
8 The preferred response is E (verapamil). Ubrogepant and rimegepant

are both options for acute migraine treatment in patients where first-line
therapies, such as nonsteroidal anti-inflammatory drugs and triptans, are
either ineffective or contraindicated. Both medications should be
avoided in patients taking other medications with strong CYP3A4
inhibitory effects, and a dose reduction of ubrogepant is recommended
in patients taking verapamil. For more information, refer to page 353 of
the Continuum article “Acute Treatment of Migraine.”

9 The preferred response is C (impaired driving performance). Lasmiditan

is a serotonin receptor agonist that has been shown to improve rates of
headache freedom and freedom from other bothersome side effects in
patients with migraine. The rate of side effects with lasmiditan is felt to
be higher than that seen with triptans or gepants; in addition, patients
should be cautioned about the possibility of sedation to the point of
interfering with driving following use of lasmiditan. For more information,

refer to page 353 of the Continuum article “Acute Treatment of
Migraine.”
ARTICLE 4: PREVENTIVE TREATMENT OF MIGRAINE
10 The preferred response is B (eptinezumab). Eptinezumab is the only

calcitonin gene-related peptide–targeted drug that is administered as
an intravenous infusion. For more information, refer to page 371 of the
Continuum article “Preventive Treatment of Migraine.”
11 The preferred response is B (candesartan). Given the patient’s history of

borderline hypertension, candesartan, an antihypertensive with good
evidence for migraine prevention, would be a good option for her. For
more information, refer to page 367 of the Continuum article “Preventive
Treatment of Migraine.”
12 The preferred response is D (4 headache days per month with some

disability). As per the American Headache Society Consensus
Statement, a preventive medication should be offered to patients with
4 headache days per month with some disability. For more information,
refer to page 366 of the Continuum article “Preventive Treatment of
Migraine.”
ARTICLE 5: MEDICATION-OVERUSE HEADACHE
13 The preferred response is B (headache occurrence on 15 or more days

per month). Medication-overuse headache (MOH) is a frequent
comorbid condition in the setting of other headache diagnoses. Criteria
established by the International Classification of Headache Disorders,
Third Edition include a provision that headaches related to MOH should
occur on at least 15 days per month. For more information, refer to
page 379 of the Continuum article “Medication-Overuse Headache.”
530 A P R I L 2 0 24

14 The preferred response is B (frequency of analgesic use). Several
different factors are considered to increase the risk of
medication-overuse headache (MOH) in a patient with a primary
headache disorder. Among these, the frequency with which acute
analgesic medications are being utilized is considered to confer the
greatest risk for the development of MOH. For more information, refer
to page 381 of the Continuum article “Medication-Overuse Headache.”

15 The preferred response is B (relapse rates can be as high as 50% in

some settings). Medication-overuse headache can be successfully
managed but the risk of relapse is quite high, requiring significant
vigilance on the part of patients and providers. Rates of relapse are
quoted as high as 50% and are typically seen in the first year following
diagnosis. For more information, refer to page 386 of the Continuum
article “Medication-Overuse Headache.”
ARTICLE 6: CLUSTER HEADACHE, SUNCT, AND SUNA
16 The preferred response is A (2:00 AM). Cluster headache has a

circadian rhythmicity, with more than 70% of patients stating that their
headaches start at the same time each day. Multiple studies and one
meta-analysis found that the most common hour was 2:00 AM. For more
information, refer to page 395 of the Continuum article “Cluster
Headache, SUNCT, and SUNA.”
17 The preferred response is B (duration). Migraine and cluster headache

have many overlapping features that occasionally cause a diagnostic
dilemma. Autonomic features, premonitory features, and similar triggers
can occur with both primary headache disorders, and both may respond
to sumatriptan. However, the duration of the attack is helpful to distinguish
the two, as migraine lasts for 4 hours or longer and cluster headache
lasts from 15 minutes to 3 hours. For more information, refer to page 397 of
the Continuum article “Cluster Headache, SUNCT, and SUNA.”
18 The preferred response is C (prolactin level). Patients with a cluster

headache phenotype who have not responded to more than three
preventive medications should have an additional workup to look for a
secondary cause of symptomatic cluster headache. Pituitary function
tests, including a prolactin level, would be part of the workup. Of note,
this patient may have a pituitary microadenoma that may have been
seen if the original brain MRI was done with thin cuts through the
pituitary gland, as should be done for all patients who present with a
cluster headache phenotype. For more information, refer to page 397
of the Continuum article “Cluster Headache, SUNCT, and SUNA.”

19 The preferred response is E (100 mg). A 2022 clinical trial showed that an
initial dose of 100 mg prednisone for 5 days, with a taper schedule
decreased by 20 mg every 3 days until off, was effective as a bridge
treatment for cluster headache. For more information, refer to
page 401 of the Continuum article “Cluster Headache, SUNCT,
and SUNA.”
20 The preferred response is C (indomethacin). This patient’s clinical

features are most consistent with paroxysmal hemicrania, for which

indomethacin is the first-line treatment. Short-lasting unilateral
neuralgiform headache attacks with conjunctival injection and tearing
is in the differential, although the duration of attacks is too long. For
more information, refer to page 405 of the Continuum article “Cluster
Headache, SUNCT, and SUNA.”
21 The preferred response is D (history of migraine). Posttraumatic

headache is a relatively common occurrence in adults and children who
have sustained a mild traumatic brain injury. There are a number of
potential risk factors for the development of posttraumatic headache,
but in this patient, a preceding history of migraine would be most
relevant. For more information, refer to page 413 of the Continuum
article “Posttraumatic Headache.”
22 The preferred response is B (migraine). Posttraumatic headache does

not follow a distinctive symptom pattern and can resemble a number
of more readily classifiable headache disorders, most commonly
migraine and tension-type headache. Treatment recommendations
suggest management targeted toward the headache diagnosis that the
posttraumatic headache most closely resembles. For more
information, refer to page 414 of the Continuum article “Posttraumatic
Headache.”
23 The preferred response is D (history of psychiatric disease). The

persistence of posttraumatic headache is a common occurrence and
is more likely in the setting of certain patient-specific characteristics
and features of the inciting brain injury. Among the options listed, a
preceding history of psychiatric disease has been associated with a risk
of posttraumatic headache persistence. For more information, refer to
page 418 of the Continuum article “Posttraumatic Headache.”
532 A P R I L 2 0 24

24 The preferred response is C (hydrocodone). This patient is presenting
with a typical syndrome of posttraumatic headache 1 week following
head injury. Given his reassuring examination as well as brain imaging
ruling out concerning causes for continuous headache (eg, contusion,
cervical artery dissection), symptomatic treatment would be
considered the mainstay of therapy. Of the options listed, any are
reasonable options with the exception of hydrocodone; opioids should

be avoided in this setting due to a higher risk of posttraumatic
headache persistence and medication-overuse headache. For more
information, refer to page 420 of the Continuum article “Posttraumatic

Headache.”
ARTICLE 8: NEW DAILY PERSISTENT HEADACHE
25 The preferred response is B (infection). Infection, typically a viral

illness, is the most frequently described inciting factor in studies of
patients who have new daily persistent headache, seen in 10% to 30% of
patients. A stressful life event is the second most common inciting
factor, seen in 10% to 20% of patients. For more information, refer to
page 427 of the Continuum article “New Daily Persistent Headache.”
26 The preferred response is C (clearly remembered onset of headache).

A distinct and clearly remembered onset of headache is a requisite for
the diagnosis of new daily persistent headache and is an integral
component of the International Classification of Headache Disorders,
Third Edition diagnostic criteria. The features of new daily persistent
headache can otherwise resemble other primary headache disorders,
particularly chronic migraine and chronic tension-type headache. For
more information, refer to page 426 of the Continuum article “New
Daily Persistent Headache.”
27 The preferred response is A (CT myelography). This patient’s clinical

presentation has features consistent with spontaneous intracranial
hypotension, specifically the presence of neck stiffness, hypoacusis,
and tinnitus. The nonpositional aspect of the headaches is not classic,
although 8% of patients with spontaneous intracranial hypotension may
have a daily headache that is nonpositional, and it is possible that this
patient’s headaches were originally orthostatic when the headaches
first began 25 years ago but has since lost that distinctive quality. Head
CT is often nondiagnostic in patients with spontaneous intracranial
hypotension. As the patient cannot get an MRI due to her pacemaker,
CT myelography would be the next best step out of the options listed.
For more information, refer to page 430 of the Continuum article “New
Daily Persistent Headache.”

28 The preferred response is B (20%). Studies have shown that the

percentage of patients with headache resolution months to years after
the onset of new daily persistent headache is between 7% and 30%.
Despite this, studies have shown that a higher percentage of patients
can have improvement of the severity of symptoms despite not having
a complete resolution. For more information, refer to page 433 of the
Continuum article “New Daily Persistent Headache.”

ARTICLE 9: HEADACHE IN CHILDREN AND ADOLESCENTS
29 The preferred response is A (depression). Pediatric patients with

migraine have been shown to experience anxiety and depression
symptoms at high rates. The co-occurrence of these diagnoses may
have treatment implications for providers; as a result, national
organizations recommend screening children and adolescents with
migraine for symptoms of depression and anxiety. For more
information, refer to page 441 of the Continuum article “Headache in
Children and Adolescents.”
30 The preferred response is D (no additional diagnostic testing needed).

This patient is presenting with a history that is highly consistent with
migraine without aura, and this diagnosis is further supported by her
strong family history and reassuring neurologic examination. In this
setting, no additional diagnostic testing is warranted. The Choosing
Wisely campaign specifically recommends not performing
neuroimaging in patients with stable attacks that meet migraine criteria.
For more information, refer to page 445 of the Continuum article
“Headache in Children and Adolescents.”
31 The preferred response is D (location of pain can be bilateral or

unilateral). In general, considerable overlap occurs between the
diagnostic criteria for migraine in adults and in children or adolescents,
as outlined in the International Classification of Headache Disorders,
Third Edition. Of the options provided, the presence of bilateral as
opposed to unilateral headache pain represents a major difference
between pediatric and adult criteria, respectively. For more
information, refer to page 446 of the Continuum article “Headache in
Children and Adolescents.”
534 A P R I L 2 0 24

32 The preferred response is C (failure of two or more preventive
therapies). Anti–calcitonin gene-related peptide (CGRP) monoclonal
antibody therapies have been approved for migraine prevention in
adults, although there are only observational data regarding their use in
pediatric and adolescent populations. Expert recommendations have
been developed to guide the use of anti-CGRP therapies in patients
younger than 18 years old; these include a statement that potential

patients should have had an inadequate response to at least two
preventive approaches (pharmacologic or nonpharmacologic). For
more information, refer to page 464 of the Continuum article

“Headache in Children and Adolescents.”
33 The preferred response is A (Alzheimer disease). Patients with

trigeminal neuralgia have an increased risk of developing dementia,
including Alzheimer disease. This may be related to increased
neuroinflammation with resultant neuronal apoptosis. For more
information, refer to page 476 of the Continuum article “Cranial
Neuralgias.”
34 The preferred response is E (syncope). This patient’s symptoms are

consistent with glossopharyngeal neuralgia. As the glossopharyngeal
nerve connects anatomically with the vagus nerve, patients with
glossopharyngeal neuralgia can have vagal manifestations, including
syncope and bradycardia. For more information, refer to page 480 of
the Continuum article “Cranial Neuralgias.”
35 The preferred answer choice is B (herpes zoster). This patient’s clinical

features are consistent with nervus intermedius neuralgia. While the
most common cause is vascular compression, the most common
secondary cause is herpes zoster. For more information, refer to
page 480 of the Continuum article “Cranial Neuralgias.”
36 The preferred answer choice is A (migraine). Occipital neuralgia often

co-occurs with other headache disorders, the most common being
migraine. For more information, refer to page 481 of the Continuum
article “Cranial Neuralgias.”

ARTICLE 11: INDOMETHACIN-RESPONSIVE HEADACHE DISORDERS
37 The preferred response is C (lithium). Indomethacin, when used in

indomethacin-responsive headache syndromes, is generally well
tolerated and has limited interactions with other medications. One
exception to this is lithium; patients taking lithium who are then started
on indomethacin are at risk for developing lithium toxicity. For more
information, refer to page 490 of the Continuum article “Indomethacin-
Responsive Headache Disorders.”
38 The preferred response is C (contralateral posterior hypothalamus).

Functional imaging, specifically positron emission tomography (PET)
imaging, has identified brain regions with increased activity in
paroxysmal hemicrania and hemicrania continua. Some are unique to
these individual disorders, though one common area of activation is the
contralateral posterior hypothalamus. For more information, refer to
page 490 of the Continuum article “Indomethacin-Responsive
Headache Disorders.”
39 The preferred response is D (paroxysmal hemicrania). This patient is

presenting with intermittent episodes of severe unilateral pain
associated with ipsilateral autonomic features. The description of her
events, along with their duration and frequency, are most suggestive of
a diagnosis of paroxysmal hemicrania. For more information, refer to
page 491 of the Continuum article “Indomethacin-Responsive
Headache Disorders.”
40 The preferred response is B (indomethacin). Significant overlap can

occur between the clinical features of cluster headache and
paroxysmal hemicrania. While certain characteristics may help discern
one from the other (eg, cluster attacks tend to be longer and more
likely to occur at night), a therapeutic trial of indomethacin can be
highly effective in the diagnostic process. Patients with paroxysmal
hemicrania would be expected to respond exquisitely to
indomethacin, while minimal to no response would be expected in
cluster headache. For more information, refer to page 493 of the
Continuum article “Indomethacin-Responsive Headache Disorders.”
536 A P R I L 2 0 24

LIST OF ABBREVIATIONS
Headache LGBTQ+ Lesbian, gay, bisexual, transgender, and queer

MOH Medication-overuse headache
MOTS Medication Overuse Treatment Strategy

MRA Magnetic resonance angiography
AAN American Academy of Neurology MRI Magnetic resonance imaging
AHRQ Agency for Healthcare Research and Quality mRNA Messenger ribonucleic acid
AHS American Headache Society MRV Magnetic resonance venography
CADASIL Cerebral autosomal dominant arteriopathy with MS Multiple sclerosis
subcortical infarcts and leukoencephalopathy mTBI Mild traumatic brain injury
CGRP Calcitonin gene-related peptide NIH National Institutes of Health
CI Confidence interval NMDA N-methyl-
-methyl-D-aspartate
COVID-19 Coronavirus 2019 NSAID Nonsteroidal anti-inflammatory drug
COX Cyclo-oxygenase OR Odds ratio
CPAP Continuous positive airway pressure OTC Over the counter
CSF Cerebrospinal fluid PACAP Pituitary adenylate cyclase-activating polypeptide
CT Computed tomography PET Positron emission tomography
DHE Dihydroergotamine SNRI Serotonin-norepinephrine reuptake inhibitor
ECG Electrocardiogram SQ Subcutaneous
EEG Electroencephalogram SSRI Selective serotonin reuptake inhibitor
FDA US Food and Drug Administration SUNA Short-lasting unilateral neuralgiform headache attacks
HIV Human immunodeficiency virus with cranial autonomic symptoms
ICHD-3 International Classification of Headache Disorders, SUNCT Short-lasting unilateral neuralgiform headache attacks
Third Edition with conjunctival injection and tearing
ICOP International Classification of Orofacial Pain SUNHA Short-lasting unilateral neuralgiform headache attack
IIH Idiopathic intracranial hypertension TN Trigeminal neuralgia
IM Intramuscular UCNS United Council for Neurologic Subspecialties
IV Intravenous
© 2024 American Academy of Neurology.

xuuEz7eS8qG9jDyji+66jItqa21Lm0C8fO+TRdrPp0LK0PsDc2Uk4mWNvRW/NKVHByBFkVO+avhX8aGX5 on 04/06/2024
HEADACHE
ARTICLE 1: APPROACH TO THE PATIENT
WITH HEADACHE
Deborah I. Friedman, MD, MPH, FAAN. Continuum (Minneap Minn). April 2024;
30 (2 Headache):296–324.
ABSTRACT
OBJECTIVE:
The evaluation of patients with headache relies heavily on the history. This article reviews key
questions for diagnosing primary and secondary headache disorders with a rationale for each
and phrasing to optimize the information obtained and the patient’s experience.
LATEST DEVELOPMENTS:
The availability of online resources for clinicians and patients continues to increase, including
sites that use artificial intelligence to generate a diagnosis and report based on patient
responses online. Patient-friendly headache apps include calendars that help track treatment
response, identify triggers, and provide educational information.
ESSENTIAL POINTS:
A structured approach to taking the history, incorporating online resources and other
technologies when needed, facilitates making an accurate diagnosis and often eliminates the
need for unnecessary testing. A detailed yet empathetic approach incorporating interpersonal
skills enhances relationship building and trust, both of which are integral to successful
treatment.
KEY POINTS
• Primary headache disorders are the most frequent types encountered in the outpatient setting. Basic
knowledge of the International Classification of Headache Disorders, Third Edition (ICHD-3) criteria for the
most common headache types helps to direct the line of questioning during the interview.
• Good communication and interpersonal skills, along with active listening and awareness of nonverbal cues,
contribute to an empathetic and caring conversation with patients undergoing evaluation for headache.
• While closed-ended questions are necessary to make a headache diagnosis, the American Migraine
Communication Study found that open-ended questions were often more time efficient and provided critical
information regarding impairment.
• When evaluating patients with headache, establishing the primary concern sets the stage and immediately
informs the interviewer of the patient's goals.
• One of the most helpful questions to ask during a headache evaluation is, “How often do you feel completely
clear and headache free?”
• Prodromal symptoms of headache are often misinterpreted as triggers.
• When considering migraine, ask about specific “warning signs,” such as prodrome and aura manifestations.
• Side-locked (strictly unilateral) headaches may occur in migraine and cluster headache but sometimes signal
a more worrisome secondary cause.

• Determining the time between pain onset and peak intensity helps with both headache diagnosis and
treatment.
• Nocturnal awakening from headache does not always signal a brain tumor. It occurs with acute medication
overuse and in primary headaches, sleep apnea, and other medical conditions.
• Associated symptoms, including trigeminal autonomic features, are characteristic of cluster headache and
other trigeminal autonomic cephalalgias but may also occur in migraine, although usually less prominently.
• Ascertaining the patient's behavior and actions during a headache helps diagnose migraine and cluster
headache.
• Determining how long it takes to return to normal after headache pain resolves provides insight into the
attack’s true duration and the patient’s ability to function.
• Patients tend to emphasize their most severe headaches, leading to an underestimation of their headache
burden.
• The subject of headache triggers is somewhat controversial. Patients may mistakenly attribute an exposure
before a migraine as a trigger when it is actually part of the prodrome (eg, food cravings, neck pain).
• Some types of headaches run in families, such as migraine, cluster headache, familial hemiplegic migraine,
and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL).
• The general medical history may reveal conditions that are associated with headaches as well as those posing
contraindications to certain headache treatments.
• Familiarization with headache red flags reduces the likelihood of missing a potentially serious secondary
headache disorder.
• When the phenotype suggests a primary headache disorder but treatments are ineffective, consider the
possibility of a secondary headache disorder or acute medication overuse.
• The symptoms of intracranial hypertension are myriad. Orthostatic headache is the most common initial
symptom but the postural component may resolve over time. Careful questioning about other symptoms is
needed, particularly if the headache onset pattern is a new daily persistent headache.
• The history often yields the headache diagnosis but certain aspects of the physical examination should be
included, especially fundoscopy.
• Both intake questionnaires and validated questionnaires for common headache comorbidities provide useful
insight and help make history taking more efficient. The most successful results arise from having the patient
complete questionnaires before the appointment.
• The “ask-tell-ask” strategy reinforces the patient’s understanding of their headache diagnosis and plan.
Make sure to communicate realistic goals and expectations and invite the patient to ask questions.
ARTICLE 2: PATHOPHYSIOLOGY OF
MIGRAINE
Nazia Karsan, PhD, MRCP. Continuum (Minneap Minn). April 2024;

30 (2 Headache):325–343.
ABSTRACT
OBJECTIVE:
This article provides an overview of the current understanding of migraine pathophysiology
through insights gained from the extended symptom spectrum of migraine, neuroanatomy,
migraine neurochemistry, and therapeutics.
Recent advancezs in human migraine research, including human experimental migraine models
and functional neuroimaging, have provided novel insights into migraine attack initiation,
neurochemistry, neuroanatomy, and therapeutic substrates. It has become clear that migraine is
a neural disorder, in which a wide range of brain areas and neurochemical systems are
implicated, producing a heterogeneous clinical phenotype. Many of these neural pathways are
monoaminergic and peptidergic, such as those involving calcitonin gene-related peptide and
pituitary adenylate cyclase-activating polypeptide. We are currently witnessing an exciting era
in which specific drugs targeting these pathways have shown promise in treating migraine,
including some studies suggesting efficacy before headache has even started.
ESSENTIAL POINTS:
Migraine is a brain disorder involving both headache and altered sensory, limbic, and
homeostatic processing. A complex interplay between neurotransmitter systems, physiologic
systems, and pain processing likely occurs. Targeting various therapeutic substrates within these
networks provides an exciting avenue for future migraine therapeutics.
KEY POINTS
• The migraine attack is typically divided into phases. The premonitory phase starts hours to days before
headache onset and aura may follow in those with aura. The migraine itself occurs next and is followed by a
postdrome in many individuals, typically lasting up to 24 hours.
• Migraine is a symptomatically heterogeneous brain disorder that can manifest with several symptoms apart
from headache, some of which can start before headache and in its absence.
• While migraine involves vasodilatation, and vasoconstrictive agents have proven efficacy in treating migraine,
the discovery that these drugs also have neural effects and that vasoconstriction is not needed for a migraine
abortive effect have changed the landscape of acute therapeutics research.
• Migraine neuroanatomy involves extracranial structures of the face, head, neck, dura, intracranial large
vessels, and brain areas such as the thalamus, hypothalamus, brainstem, and cerebral cortex.
• The premonitory phase provides a unique opportunity to study migraine attack initiation and brain function in
the absence of pain and offers the ability to study headache prevention in those who can use the symptoms
to reliably predict headache.
• The interaction between migraine and other physiologic processes, such as those controlling feeding and
sleep, and the early involvement of these systems in the premonitory phase may explain how some patient-
perceived migraine triggers may actually be misattributions of early premonitory symptoms.
• Multiple interacting pathways are likely responsible for mediating the relationship between patient-
perceived triggers and migraine-associated symptoms, as well as the interactions between migraine and
other physiologic processes mediating stress, behavior, feeding, and sleep.
• Migraine aura does not need to precede headache. Migraine-without-aura attacks are more common than
those with aura, even in individuals with migraine with aura.

• Migraine is a clinically heterogeneous cyclical and fluctuating disorder, involving widespread sensory, limbic,
and homeostatic brain dysfunction ictally and interictally.
• The generation of the migraine attack likely occurs centrally, but it is unclear how the subsequent initiation
and maintenance of pain via sensitization of trigeminocervical neurons occurs, and if this is purely central or
both central and peripheral in mechanism.
• Monoaminergic and peptidergic pathways via key cortical and subcortical brain regions and their structural
and functional connections are likely important in the pathophysiology of migraine, from early premonitory
symptoms through to the postdrome.
• Targeted therapies against monoaminergic and peptidergic receptors may have therapeutic use in
migraine.
ARTICLE 3: ACUTE TREATMENT OF

MIGRAINE
Rebecca Burch, MD, FAHS. Continuum (Minneap Minn). April 2024;
30 (2 Headache):344–363.
ABSTRACT
OBJECTIVE:
Most patients with migraine require acute treatment for at least some attacks. This article
reviews the approach to the acute treatment of migraine, migraine-specific and nonspecific
treatment options, rescue treatment and options for management in the emergency department
and inpatient settings, and treatment during pregnancy and lactation.
Triptans, ergot derivatives, and nonsteroidal anti-inflammatory drugs have historically been the
main acute treatments for migraine. The development of new classes of acute treatment,
including the small-molecule calcitonin gene-related peptide receptor antagonists
(gepants) and a 5-HT1F receptor agonist (lasmiditan), expands available options. These new
treatments have not been associated with vasospasm or increased cardiovascular risk,
therefore allowing migraine-specific acute treatment for the more than 20% of adults with
migraine who are at increased risk of cardiovascular events. Neuromodulation offers a
nonpharmacologic option for acute treatment, with the strongest evidence for remote electrical
neuromodulation.
ESSENTIAL POINTS:
The number of available migraine treatments continues to expand, although triptans are still the
mainstay of migraine-specific acute treatment. There is no one-size-fits-all acute treatment and
multiple treatment trials are sometimes necessary to determine the optimal regimen for
patients. Switching within and between classes, using the maximum allowed dose, using
combination therapy, and counseling patients to treat early are all strategies that may improve
patient response to acute treatment.
KEY POINTS
• Nearly every person with migraine will benefit from acute treatment for at least some attacks as migraine
attacks are usually severe and accompanied by bothersome nausea and sensory symptoms.
• Complete pain relief at 2 hours after treatment should be the goal in acute migraine therapy rather than
improvement without complete relief.
• Acute treatment is more effective when used early on in a migraine attack. Patients should keep acute
migraine medications with them and treat at the first sign of an attack.
• Treatment should be matched to the severity of the headache. Mild-to-moderate attacks may respond to
nonspecific therapies. Migraine-specific therapy should be chosen first if the attack is expected to be
moderate to severe.
• Other acute migraine treatment strategies to improve response include increasing the dose, switching to a
formulation with a faster onset, switching treatment within or between classes, and using combinations of
migraine-specific and nonspecific treatments.
• The assessment of nausea and vomiting should be a routine part of migraine care and any patient with nausea
or vomiting should be offered an antiemetic.
• Nonspecific acute migraine treatments include simple analgesics, nonsteroidal anti-inflammatory drugs, and
combination analgesics, while migraine-specific treatments include triptans, dihydroergotamine, gepants,
and lasmiditan.
• Aspirin, ibuprofen, naproxen, diclofenac, and celecoxib all have Level A evidence for efficacy in acute
migraine treatment, while ketoprofen and ketorolac have Level B evidence.
• The combined formulation of acetaminophen, aspirin, and caffeine is effective for the acute treatment of
migraine but should be used infrequently due to concerns about caffeine withdrawal headache.
• All seven triptans are more effective than placebo for acute migraine treatment, with the most effective
triptans producing pain freedom in up to one-half of attacks. Triptans primarily differ in pharmacokinetics
and route of administration.
• Recent evidence suggests that serotonin syndrome is very rare with the coprescription of triptans and
selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). It
may be safe to prescribe triptans in patients taking SSRIs or SNRIs, and education about serotonin syndrome
should be provided.
• Gepants are effective for acute treatment, well tolerated in clinical trials, and not associated with
vasoconstriction. Gepants may also be less likely to cause medication-overuse headache.
• Lasmiditan may be a good alternative to triptans in patients who responded to triptans previously but cannot
take them due to cardiovascular disease or risk factors. Patients should not drive after taking lasmiditan.
• Metoclopramide and prochlorperazine reduce migraine pain and treat nausea, but frequent use may cause
extrapyramidal symptoms. They cause more sedation than ondansetron, which treats nausea but does not
have anti–migraine pain properties.
• Five neuromodulation devices are available for acute migraine treatment and are well tolerated. Consider
neuromodulation in patients who want to avoid or are unable to take medications, or who need a combination
of treatment approaches.
• Triptans are the mainstay of migraine-specific treatment based on the strongest evidence for effectiveness,
wide availability, and long history of use.
• An American Headache Society Consensus Statement recommends that gepants, ditans, or neuromodulation
devices be considered in patients with migraine who have not responded to two or more oral triptans, or who
have contraindications or intolerable side effects to triptans.
• Acute migraine treatments with the best evidence for safety in pregnancy are metoclopramide (for migraine
pain as well as nausea), cyclobenzaprine, diphenhydramine (adjunct therapy), triptans, and ondansetron (for
nausea).
• Migraine rescue therapy should be considered in any patient who has rapid escalation of pain or attacks
accompanied by severe nausea or vomiting, who occasionally has attacks that do not respond to typical
treatment, or who has a history of emergency department visits for migraine for any reason.
• IV formulations of metoclopramide and prochlorperazine and subcutaneous sumatriptan all have good
evidence for the treatment of migraine in the emergency department. Dexamethasone may prevent
headache recurrence.
• Although sodium valproate is effective compared with placebo and is sometimes used as a rescue treatment,
studies consistently show that it is no more effective than dopamine receptor antagonists such as
metoclopramide and prochlorperazine.

• Dihydroergotamine 1 mg IV given every 8 hours is an effective strategy for treating refractory migraine pain in
the inpatient setting. Pretreatment with an antiemetic is necessary.
ARTICLE 4: PREVENTIVE TREATMENT OF

MIGRAINE
Richard B. Lipton, MD, FAAN. Continuum (Minneap Minn). April 2024;
30 (2 Headache):364–378.
ABSTRACT
OBJECTIVE:
This article describes strategies for the preventive treatment of migraine including the emerging
role of calcitonin gene-related peptide (CGRP)-targeted therapies and introduces novel
paradigms for the preventive treatment of migraine.
Multiple migraine medications targeting CGRP have been introduced since 2018, including
injectable monoclonal antibodies (ie, eptinezumab, erenumab, fremanezumab, and
galcanezumab) and oral small-molecule CGRP receptor antagonists (ie, ubrogepant,
rimegepant, atogepant, and zavegepant). With the exceptions of ubrogepant and zavegepant,
which are approved only as acute treatments, all of these agents have demonstrated efficacy in
the preventive treatment of migraine; the monoclonal antibodies and atogepant have evidence
of effectiveness in adults with either episodic or chronic migraine. The safety and tolerability
profiles of CGRP-targeted therapies in migraine are favorable.
ESSENTIAL POINTS:
The goals of preventive migraine therapy include reducing the frequency, severity, duration, and
disability associated with attacks, reducing the need for acute treatment and the risk of
medication overuse, enhancing self-efficacy and health-related quality of life, and reducing
headache-related distress and interictal burden. Six drugs targeting CGRP (four monoclonal
antibodies and two gepants) are now available for the preventive treatment of episodic migraine
in adults. The efficacy of CGRP-targeted medications in the acute and preventive treatment of
migraine, together with good safety and tolerability, has led to the emergence of new
approaches to preventive treatment.
KEY POINTS
• The goals of preventive migraine therapy include reducing the frequency, severity, duration, and disability
associated with attacks, reducing the need for acute treatment and the risk of medication overuse,
enhancing self-efficacy and health-related quality of life, and reducing headache-related distress and
interictal burden.
• The initial preventive treatment of migraine is often a conventional oral medication or, sometimes, a natural
product. Among the evidence-based options, the choice is often based on the patient’s comorbidities and
potential adverse events.
• For migraine-nonspecific oral preventive medications, the best practice is to start at a low dose and
gradually increase the dose based on tolerability and response.

• The calcitonin gene-related peptide (CGRP)-targeted migraine therapies are offered to patients who are at
least 18 years old if they cannot tolerate or have failed to respond to at least two traditional migraine
preventive medications with established or probable efficacy.
• For CGRP-targeted therapies, treatment begins at an optimal dose and treatment benefits often develop
more rapidly than with migraine-nonspecific oral preventive medications.
• The choice between CGRP-targeted migraine treatment with monoclonal antibodies or oral medication is
often determined by patient preference. Some patients prefer frequent oral dosing, while others prefer an
injection every 4 or 12 weeks.
• Combining migraine-nonspecific oral preventive agents with CGRP-targeted preventive medications is
common in clinical practice. CGRP-targeted therapies may be added as a second agent, and if the patient
responds well, the first oral preventive medication can subsequently be tapered.
• The available evidence suggests that gepants can be given to patients with migraine who are also receiving
CGRP-targeted monoclonal antibodies with few safety and tolerability problems.
• A second emerging migraine treatment paradigm is known as situational prevention, where patients treat in
periods of high headache risk on a short-term basis while completely asymptomatic.
ARTICLE 5: MEDICATION-OVERUSE
HEADACHE
Paul Rizzoli, MD, FAAN, FAHS. Continuum (Minneap Minn). April 2024;
30 (2 Headache):379–390.
ABSTRACT
OBJECTIVE:
Medication-overuse headache (MOH) has been described for almost 100 years and is
characterized as a daily or near-daily headache that usually presents in patients with preexisting
primary headache disorders who are overusing one or more acute or symptomatic headache
medications. This article reviews the diagnosis and management of patients with MOH.
The International Classification of Headache Disorders criteria for MOH have changed over time.
The worldwide prevalence appears to be between 1% and 2%. Together, headache disorders,
including MOH, are currently ranked as the second leading cause of years lived with disability in
the Global Burden of Disease world health survey. Significant neurophysiologic changes are seen
in the brains of patients with MOH, including functional alterations in central pain processing and
modulating systems and central sensitization. Research supports updates to the principles of
management, including weaning off the overused medication, preventive therapy, biobehavioral
therapy, and patient education.
ESSENTIAL POINTS:
MOH is a fairly common and treatable secondary headache disorder that produces significant
disability and a substantial reduction in quality of life. The costs related to lost income and
disability are substantial. MOH is intimately related to chronic migraine, which continues to be
underrecognized and undertreated. Treatment focuses on both the institution of effective
preventive migraine therapy and the reduction or removal of the overused medications.
Educational efforts directed toward both providers and patients have been shown to be
effective in reducing the effect of MOH.
KEY POINTS
• Medication-overuse headache (MOH) involves the overuse of acute abortive headache medications in
patients with a primary headache disorder presenting with daily or near-daily headache.
• MOH has been considered an important driving risk factor for the development of chronic migraine.
• MOH was previously known as analgesic rebound headache, withdrawal headache, or drug-induced
headache.
• The concepts of MOH and chronic migraine are intimately interrelated.
• The International Classification of Headache Disorders criteria for the diagnosis of MOH have changed over
the years as our understanding of the condition has improved.
• It is the frequency of the use of the overused medication, rather than the dose, that is critical to the
development of MOH.
• The International Classification of Headache Disorders noted that the most common cause of migrainelike
headache occurring on 15 or more days per month is medication overuse.
• Headache disorders including MOH are currently ranked as the second leading cause of years lived with
disability.
• Prevalence estimates indicate that, at any one time, 1.8% of all headache patients may have MOH.
• It remains unclear in patients with MOH whether the increased abortive medication use drives the worsening
headache or whether worsening headache drives the medication overuse.
• Functional, structural, and metabolic changes seen in imaging studies localize MOH to the pain network of
the brain.
• With the goal of improved headache control, the focus of treatment in MOH is on both the removal of the
overused abortive medication and the institution of a more effective preventive and abortive regime.
• The first step in the management of MOH is to explain to the patient the nature of the condition and the need
to reduce or stop the overused medication.
• Studies have not shown a significant difference in benefit between abrupt and slow discontinuation of the
overused medication in MOH.
• Both chronic migraine and MOH are underrecognized and undertreated.
ARTICLE 6: CLUSTER HEADACHE,

SUNCT, AND SUNA
Mark Burish, MD, PhD. Continuum (Minneap Minn). April 2024;
30 (2 Headache):391–410.
ABSTRACT
OBJECTIVE:
This article reviews the epidemiology, clinical features, differential diagnosis, pathophysiology,
and management of three types of trigeminal autonomic cephalalgias: cluster headache (the
most common), short-lasting unilateral neuralgiform headache attacks with conjunctival
injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks with
cranial autonomic symptoms (SUNA).
The first-line treatments for trigeminal autonomic cephalalgias have not changed in recent years:
cluster headache is managed with oxygen, triptans, and verapamil, and SUNCT and SUNA are
managed with lamotrigine. However, new successful clinical trials of high-dose prednisone,
high-dose galcanezumab, and occipital nerve stimulation provide additional options for patients
with cluster headache. Furthermore, new genetic and imaging tests in patients with cluster
headache hold promise for a better understanding of its pathophysiology.
ESSENTIAL POINTS:
The trigeminal autonomic cephalalgias are a group of diseases that appear similar to each other
and other headache disorders but have important differences. Proper diagnosis is crucial for
proper treatment.
KEY POINTS
• The typical patient with cluster headache has the episodic subtype with the following features: one to two
attacks a day, lasting 1 to 2 hours each, occurring every day for 6 to 12 weeks. These headache cycles usually
occur once per year.
• Common cluster headache triggers include alcohol and nitroglycerin. For patients with episodic cluster
headache, these triggers have no effect when the headaches are in remission.
• Cluster headache attacks usually occur at the same time of day like clockwork. The time of onset may differ
between patients, but it is consistent for each patient and is most commonly around 2 AM.
• Symptomatic causes of cluster headache include pituitary adenomas and meningiomas. A brain MRI with and
without contrast is recommended for all patients with cluster headache.
• Research suggests that cluster headache starts in the hypothalamus and connects to the pain and autonomic
systems.
• At the beginning of a cluster headache cycle, patients are often started on multiple concurrent therapies:
two acute medications (subcutaneous sumatriptan and high-flow oxygen), one bridge treatment (greater
occipital nerve block with corticosteroids or oral prednisone), and one or more preventive medications.
• The first-line acute treatments for cluster headache are subcutaneous sumatriptan and high-flow oxygen
gas; typically, both treatments are prescribed.
• As a general rule, in the acute treatment of cluster headache faster modes of delivery (subcutaneous, nasal,
inhalational, and neuromodulatory) are preferred over slower ones (tablets and capsules).
• A new successful clinical trial of prednisone as bridge therapy for cluster headache established a higher-
than-previously-used dose: prednisone 100 mg daily for 5 days, with a taper schedule decreasing by 20 mg
every 3 days until off.
• Galcanezumab is the newest preventive medication for episodic cluster headache (it was not approved for
chronic cluster headache). The dose (300 mg monthly) is higher than the migraine dose (240 mg once, then
120 mg every 28 days thereafter).
• Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and
short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) differ only in
the autonomic features they have; their management is identical.
• SUNCT and SUNA are often mistaken for trigeminal neuralgia. Other differential diagnoses are primary
stabbing headache and paroxysmal hemicrania.
• SUNCT and SUNA are responsive to sodium-channel blockers such as lamotrigine, carbamazepine, and
oxcarbazepine.
Todd J. Schwedt, MD, FAAN. Continuum (Minneap Minn). April 2024;
30 (2 Headache):411–424.
ABSTRACT
OBJECTIVE:
This article provides an overview of the epidemiology, diagnosis, clinical presentation,
pathophysiology, prognosis, and treatment of posttraumatic headache attributed to mild
traumatic brain injury (mTBI).
The International Classification of Headache Disorders, Third Edition requires that posttraumatic
headache begin within 7 days of the inciting trauma. Although posttraumatic headache
characteristics and associated symptoms vary, most commonly there is substantial overlap with
symptoms of migraine or tension-type headache. New insights into posttraumatic headache
pathophysiology suggest roles for neuroinflammation, altered pain processing and modulation,
and changes in brain structure and function. Although the majority of posttraumatic headache
resolves during the acute phase, about one-third of individuals have posttraumatic headache
that persists for at least several months. Additional work is needed to identify predictors and
early markers of posttraumatic headache persistence, but several potential predictors have
been identified such as having migraine prior to the mTBI, the total number of TBIs ever
experienced, and the severity of initial symptoms following the mTBI. Few data are available
regarding posttraumatic headache treatment; studies investigating different treatments and the
optimal timing for initiating posttraumatic headache treatment are needed.
ESSENTIAL POINTS:
Posttraumatic headache begins within 7 days of the causative injury. The characteristics of
posttraumatic headache most commonly resemble those of migraine or tension-type headache.
Posttraumatic headache persists for 3 months or longer in about one-third of individuals.
Additional studies investigating posttraumatic headache treatment are needed.
KEY POINTS
• Headache is the most common acute and persistent symptom following mild traumatic brain injury (mTBI).
• Acute posttraumatic headache is experienced by one-half to two-thirds of individuals who have an mTBI.
• Risk factors for acute posttraumatic headache include younger age, female sex, fewer years of education,
abnormalities on head CT, TBI-related altered consciousness, having migraine prior to the mTBI, and having
pre-TBI psychiatric disease.
• About one-third of those with acute posttraumatic headache have posttraumatic headache persistence at 3
months following onset.
• Diagnostic criteria for posttraumatic headache require that posttraumatic headache begin within 7 days of
the causative injury.
• When pre-TBI headaches substantially worsen in frequency or severity following TBI, patients should receive
their pre-TBI headache diagnosis (eg, migraine) and a diagnosis of posttraumatic headache.
• Posttraumatic headache symptoms most commonly resemble those of migraine or tension-type headache.
• Posttraumatic headache is often accompanied by other post-mTBI symptoms including changes in mood,
sleep problems, mild cognitive deficits, balance and vestibular issues, symptoms associated with autonomic
dysfunction, and abnormal ocular motor control.
• Mechanisms underlying posttraumatic headache likely include neuroinflammation, altered pain processing
and modulation, and changes in brain structure and function.
• There is a lack of high-quality evidence for determining which treatments are safe, effective, and tolerable
for posttraumatic headache. Thus, it is generally recommended to treat posttraumatic headache like the
other headache type (eg, migraine, tension-type headache) that it most resembles.
• To avoid the development of medication-overuse headache as a complication of posttraumatic headache,

clinicians should educate patients about avoiding the overuse of as-needed headache medications.
• When preventive treatments are indicated for posttraumatic headache, nonpharmacologic and
pharmacologic treatments could be considered.
ARTICLE 8: NEW DAILY PERSISTENT

HEADACHE
Matthew Robbins, MD, FAAN, FAHS. Continuum (Minneap Minn). April 2024;
30 (2 Headache):425–437.
ABSTRACT
OBJECTIVE:
This article describes the clinical features, etiology, differential diagnosis, management, and
prognosis of new daily persistent headache.
New daily persistent headache has attracted renewed attention as it may arise in the setting of a
COVID-19 infection. Spontaneous intracranial hypotension, particularly from CSF-venous
fistulas, remains an important secondary headache disorder to consider before diagnosing new
daily persistent headache. Symptomatic treatment for new daily persistent headache may
include acute and preventive therapies used for migraine and tension-type headache, such as
triptans, oral preventive agents, onabotulinumtoxinA, and agents that target calcitonin gene-
related peptide.
ESSENTIAL POINTS:
New daily persistent headache is a daily headache syndrome that starts acutely and can only be
diagnosed after 3 months have elapsed and other secondary and primary headache diagnoses
have been excluded. The clinical manifestations largely resemble either chronic migraine or
chronic tension-type headache. The underlying cause is unknown, but it is plausible that
multiple etiologies exist and that it is not a single disease entity. The prognosis is variable but
often poor, and the treatment approach is largely extrapolated from the management of chronic
migraine and chronic tension-type headache.
KEY POINTS
• New daily persistent headache is a syndrome characterized by the acute onset of a continuous headache for
at least 3 months in the absence of any alternative cause.
• New daily persistent headache seems to occur on a population level in 1 in 1000 to 3000 individuals and is
even more commonly encountered in neurology practices, with rates varying from 2% to 36% of patients.
• Aside from the tempo of onset and its continuous nature for at least 3 months, new daily persistent headache
is defined by neither specific pain characteristics nor any associated symptoms.
• The most frequently described inciting factor of new daily persistent headache is an infection, typically a
viral illness, which occurs in 10% to 30% of patients. A typical pattern is where headache emerges as a
continuous symptom in the setting of an upper respiratory infection even after rhinorrhea, sinus congestion,
cough, or systemic symptoms such as fever subside.
• A stressful life event may be the second most frequently reported inciting factor in new daily persistent
headache, ranging from 10% to 20% in many series.

• A presentation of a continuous headache from onset is a red flag warranting diagnostic testing which should
include neuroimaging, typically brain MRI with and without gadolinium contrast to assess for spontaneous
intracranial hypotension.
• Chronic, long-term primary headache disorders such as chronic migraine, chronic tension-type headache,
and hemicrania continua should all be strongly considered in the differential diagnosis of new daily persistent
headache.
• Once secure in the diagnosis of new daily persistent headache, management is symptomatic and akin to how
other chronic primary headache disorders such as chronic migraine and chronic tension-type headache are
treated.
• A variety of small, uncontrolled studies or retrospective reviews show treatment benefits for some patients
who have new daily persistent headache with therapies used for migraine, including triptans, tricyclic
antidepressants, beta-blockers, topiramate, valproic acid, monoclonal antibodies targeting calcitonin gene-
related peptide or its receptor, onabotulinumtoxinA, and nerve blocks.
• Cognitive behavioral therapy and other nonpharmacological treatments should play an important role for
patients with new daily persistent headache given their evidence in the treatment of adolescents and adults
with primary chronic headache disorders and the inherent difficulty coping with a highly disabling disorder
featuring sudden onset of continuous pain.
• A prognostic classification has been proposed to categorize patients with new daily persistent headache into
groups with headache persistence, headache remission, and a relapsing-remitting pattern where periods of
symptom persistence are interspersed with periods of remissions.
• There remains diagnostic uncertainty since there is no clear consensus or guidance in the International
Classification of Headache Disorders, Third Edition for what attack frequency of a preexisting episodic
headache disorder such as migraine would preclude the diagnosis of new daily persistent headache.
• Measuring outcomes for patients with new daily persistent headache is challenging, and lowering the
baseline intensity of pain may be the most meaningful outcome.
ARTICLE 9: HEADACHE IN CHILDREN

AND ADOLESCENTS
Serena L. Orr, MD, MSc, FRCPC. Continuum (Minneap Minn). April 2024;
30 (2 Headache):438–472.
ABSTRACT
OBJECTIVE:
This article reviews the assessment of children and adolescents presenting with headache,
provides an overview of primary headache disorders, and reviews evidence-based management
of headache in this age group.
In the last few years, new epidemiological data have shed light on less common pediatric
headache disorders (eg, pediatric trigeminal autonomic cephalalgias) and psychosocial risk
factors associated with primary headache disorders in children and adolescents. There has also
recently been a substantial increase in interventions that target the calcitonin gene-related
peptide pathway and that treat primary headache disorders using noninvasive neuromodulation.
Although these interventions have primarily been studied in adults, there is emerging evidence of
their use in the pediatric population.
ESSENTIAL POINTS:
Primary headache disorders are very common in youth, and the most commonly encountered
headache diagnosis in neurology practice is migraine, which affects approximately 10% of
children and adolescents. Diagnosing and effectively treating primary headache disorders
before adulthood may have a sustained impact on the patient by improving long-term headache
and mental health outcomes, thereby significantly reducing the burden of disability over time.
There are several available and emerging acute and preventive interventions for youth with
primary headache disorders, and treatment decisions should be made in the context of available
evidence using a shared decision-making approach.
KEY POINTS
• The early diagnosis and treatment of children and adolescents with headache disorders may lead to better
long-term outcomes.
• Appropriate headache treatment not only appears to lead to short-term improvements in headache-related
outcomes but has also been shown to improve long-term outcomes and have a sustained impact even after
initial preventive headache treatment is discontinued.
• The clinician’s first task in assessing a child or adolescent with headache is to determine whether the patient
has a primary or secondary headache disorder.
• While unilateral cranial autonomic symptoms may suggest a trigeminal autonomic cephalalgia, 55% to 70% of
children and adolescents with migraine experience cranial autonomic symptoms.
• Prodromal symptoms occur in approximately 67% to 85% of children and adolescents with migraine and may
be more apparent to the patient’s parents than to the patient themself (eg, the parent may note an
appearance of sunken eyes or a mood change before the onset of headache).
• Traditionally, occipital headache was thought to be a red flag for secondary etiologies in children and
adolescents, although recent data suggest that the yield of neuroimaging in this setting is low.
• An assessment of headache-related disability helps the clinician understand the impact of headaches on the
patient’s life and track an important patient-reported outcome.
• All children and adolescents with primary headache disorders should be screened for anxiety and depressive
symptoms and disorders.
• Asking children to draw a picture of what their headache feels like can be informative for the clinician, and
data suggest that certain depicted elements have a high positive predictive value for a diagnosis of migraine.
• Given the prevalence of adverse childhood experiences and trauma among children and adolescents with
headache disorders, clinicians should screen for these experiences and engage in trauma-informed care with
patients.
• In the setting of posttraumatic headache, guidelines recommend that vestibular and ocular motor screening
maneuvers be performed to identify abnormalities or symptom provocation from the maneuvers, which may
be associated with a higher risk of prolonged post-concussive symptoms.
• A detailed headache examination can help establish the diagnosis and identify conditions that may overlap
with and contribute to primary headache (eg, temporomandibular joint disorder).
• Most children and adolescents presenting with headache and no red flags will not require any investigations
outside of a thorough history and physical examination.
• The majority of headache consultations seen in pediatric neurology outpatient clinics are for migraine.
• Some children and adolescents with migraine will have a history of episodic syndromes that may be
associated with migraine, and abdominal migraine confers the strongest risk of subsequent incident migraine.
• Migraine is a highly heritable disease and approximately two-thirds of children and adolescents with
migraine will have a family history of migraine.
• Approximately 25% of children and adolescents with “chronic daily headache” will have new daily persistent
headache, whereby there is a continuous unrelenting headache with a distinct recalled onset that has
persisted for at least 3 months.

• Prescribing an effective acute treatment plan for children and adolescents with migraine is a consensus best
practice and may mitigate the risk of disease progression.
• Ibuprofen 10 mg/kg is the recommended first-line acute migraine intervention for children and adolescents
according to the latest American Academy of Neurology (AAN) guidelines.
• Patients who have a rapid peak in severity or nausea and vomiting with their attacks of migraine should be
offered acute interventions with alternate routes of administration such as nasal sprays, oral dissolving
tablets, or subcutaneous injections.
• Three noninvasive neuromodulation devices are US Food and Drug Administration (FDA) cleared for use in
adolescents 12 years old and older with migraine: remote electrical neuromodulation, single-pulse
transcranial magnetic stimulation, and noninvasive vagus nerve stimulation.
• Preventive treatment should be offered to children and adolescents with migraine who are experiencing
attacks at a frequency or severity that is leading to significant disability.
• Clinical trial data suggest that approximately two-thirds of children and adolescents with migraine will
achieve treatment goals (ie, 50% or greater reduction in headache frequency) using pill-based preventive
interventions.
• Psychological interventions have a significant body of evidence to support their use in children and
adolescents with migraine and should be considered as potential first-line interventions (in combination with
pill-based interventions).
• Other treatment modalities (eg, interventional, neuromodulation) should be considered when children and
adolescents with migraine have not improved with two or more pill-based preventive interventions.
• While pediatric clinical trials are underway, there are expert consensus guidelines to guide clinicians in when
to consider off-label use of anti–calcitonin gene-related peptide monoclonal antibodies in children and
adolescents with migraine.
• Although evidence in this area is limited, children and adolescents with headache disorders should be
counseled on the relationship between headaches and poor sleep, obesity, meal skipping (particularly
breakfast), and low physical activity.

Stephanie J. Nahas, MD, MSEd, FAAN. Continuum (Minneap Minn). April 2024;
30 (2 Headache):473–487.
ABSTRACT
OBJECTIVE:
The cranial neuralgias are relatively rare, but recognizing these syndromes and distinguishing
among them is critical to reducing unnecessary pain and disability for affected patients. Despite
their distinctive features, cranial neuralgias may go undiagnosed or misdiagnosed for several
years. A notable proportion of cranial neuralgia presentations are due to secondary causes and
require targeted treatment. The purpose of this article is to review the diagnosis and
management of cranial neuralgias encountered in clinical practice.
In 2020, the International Classification of Orofacial Pain was released for the first time.
Modeled after the International Classification of Headache Disorders, it includes updated
terminology for cranial neuralgias. The underlying pathophysiology of the cranial neuralgias is
currently believed to be rooted in both peripheral and central nociceptive systems. In addition, a
growing number of familial cases are being identified. Recent therapeutic advancements include
a better understanding of how to utilize older therapies and procedures more effectively as well
as the development of newer approaches.
ESSENTIAL POINTS:
Cranial neuralgia syndromes are rare but important to recognize due to their debilitating nature
and greater likelihood of having potentially treatable underlying causes. While management
options have remained somewhat limited, scientific inquiry is continually advancing the
understanding of these syndromes and how best to address them.
KEY POINTS
• The cranial neuralgias are distinct from most other classified headache disorders in that attacks are
stereotyped with very short-lasting, neuralgiform pain in the distribution of a particular peripheral nerve
located in the head or face.
• Distinguishing primary from secondary etiologies is critical in crafting an appropriate approach to patients
with cranial neuralgia.
• The pathophysiology of cranial neuralgias is likely linked to dysfunction in both peripheral and central
pathways responsible for nociception.
• Trigeminal neuralgia predominantly affects adults of middle age and is usually sporadic, but familial cases are
also described.
• Trigeminal neuralgia carries an increased risk for the development of depression, anxiety, and dementia, and
is associated with functional and structural changes in the brain.
• Distinguishing primary from secondary cases of trigeminal neuralgia is difficult to achieve on a purely clinical
basis, so further investigation is warranted.
• Treatments for trigeminal neuralgia range from pharmacologic options to procedures and interventions,
although only one treatment (carbamazepine) is specifically approved by the US Drug and Food
Administration (FDA) for this indication.
• Acute exacerbations of trigeminal neuralgia may require additional intervention, which should not include the
use of opioids.
• Lacosamide and onabotulinumtoxinA are emerging as newer therapeutic options with relatively high
effectiveness for trigeminal neuralgia, but the role of treatments targeting the calcitonin gene-related
peptide system remains uncertain.
• It is important to recognize other trigeminal neuropathic pain disorders as distinct from trigeminal neuralgia in
terms of clinical presentation and underlying etiology, although treatment may be similar to trigeminal
neuralgia.
• Glossopharyngeal neuralgia shares many similarities with trigeminal neuralgia, but the pain often involves
areas outside the distribution of the nerve, and other nonpain symptoms may be present.
• Nervus intermedius neuralgia presents variably, more often has an underlying secondary cause, and more
often requires interventions beyond pharmacologic approaches.
• Occipital neuralgia most often co-occurs with another headache or facial pain disorder and is likely more
common than epidemiologic studies suggest.
• The diagnosis of occipital neuralgia relies on a careful and thorough history and examination to distinguish it
from a concomitant disorder and to evaluate for underlying secondary causes.
• Neck-tongue syndrome is increasingly recognized as an important entity among the cranial neuralgias, with
distinct pathophysiology and treatment options.
ARTICLE 11: INDOMETHACIN-
RESPONSIVE HEADACHE DISORDERS
Peter J. Goadsby, MD, PhD, FRS. Continuum (Minneap Minn). April 2024;
30 (2 Headache):488–497.
ABSTRACT
OBJECTIVE:
This article describes the clinical features and treatment of the indomethacin-responsive
headache disorders paroxysmal hemicrania and hemicrania continua.
Both paroxysmal hemicrania and hemicrania continua are treated with indomethacin at the
lowest clinically useful dose. It has recently become clear that some patients with either
condition may respond to treatment with noninvasive vagus nerve stimulation, which can be both
indomethacin sparing and, in some cases, headache controlling. Given the lifelong nature of
both paroxysmal hemicrania and hemicrania continua, brain imaging with MRI is recommended
when the conditions are identified, specifically including pituitary views.
ESSENTIAL POINTS:
Paroxysmal hemicrania and hemicrania continua are indomethacin-responsive headache
disorders that offer a rewarding and unique opportunity to provide marked clinical improvement
when recognized and treated appropriately. These disorders share the final common pathway of
the trigeminal-autonomic reflex, with head pain and cranial autonomic features, and are
differentiated pathophysiologically by the pattern of brain involvement, which can be seen using
functional imaging. They have distinct differential diagnoses to which the clinician needs to
remain alert.
KEY POINTS
• Certain rare headache disorders have an absolute response to indomethacin.
• Indomethacin lowers intracranial pressure, which may produce a false-positive, nonsustained clinical effect
in patients with increased intracranial pressure.
• Indomethacin can elevate lithium levels when the medicines are coadministered.
• Paroxysmal hemicrania and hemicrania continua involve activation of the trigeminal-autonomic reflex with
distinct brain networks of activations seen on functional imaging.
• About one-third of patients with paroxysmal hemicrania also report primary stabbing headache.
• Paroxysmal hemicrania is marked by short-lasting, multiple attacks of strictly unilateral head pain with
marked cranial autonomic symptoms, and an absolute response to indomethacin.
• Hemicrania continua is characterized by a strictly lateralized, persistent, continuous headache often
associated with cranial autonomic features and an absolute response to indomethacin.
• Patients with paroxysmal hemicrania or hemicrania continua should undergo contrasted brain MRI to exclude
a pituitary adenoma.
ARTICLE 12: DIVERSITY, EQUITY, AND
INCLUSION IN HEADACHE CARE AND
RESEARCH
Rashmi B. Halker Singh, MD, FAAN; Jessica Kiarashi, MD. Continuum (Minneap Minn).
April 2024; 30 (2 Headache):498–511.
ABSTRACT
This article reviews the disparities faced by individuals who experience headache disorders and
discusses potential solutions to deliver equitable care. Disparities exist in the diagnosis and
treatment of headache disorders with regard to race, ethnicity, sex, gender, sexual orientation,
geography, and socioeconomic status. Furthermore, research in the realm of headache
disparities is inadequate, and the clinical trial representation of patients from underserved
communities is poor. Many barriers exist to optimizing care for underserved communities and
this article addresses these barriers and presents ways to combat them.
KEY POINTS
• Underserved communities are heavily impacted by disparities in the diagnosis and treatment of headache
disorders.
• Headache disparities are seen with regard to race, ethnicity, gender, sex, sexual orientation, insurance
status, socioeconomic status, and geographic location.
• The scarcity of headache providers in the United States contributes to insufficient headache care.
• Disparities are also seen in the conduct of headache research and there is a lack of representation of many
patient populations in research studies.
• Issues with access to care, health and headache literacy, systemic racism, and implicit bias all contribute to
the perpetuation of headache disparities.
• Other potential ways to mitigate disparities include incorporating cultural sensitivity training, improving
patient-physician communication, and diversifying the physician workforce and leadership.
• Efforts are being made to increase the number of headache specialists and fellowship positions to improve
the issue of access.
Issue Overview
Headache, Volume 30, Number 2, April 2024
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Headache issue,

participants will be able to:
 Apply the principles of evaluating patients with headache in clinical practice

 Identify the extended phenotypic spectrum of migraine, the likely central basis for attack
initiation, the neuroanatomy of key structures involved in migraine neurobiology and
their likely symptomatic correlates, and the neurochemical systems that may have a role
in migraine therapeutics
 Describe the approach to the acute treatment of migraine, including goals of therapy;
review nonspecific and migraine-specific options for the acute treatment of migraine;
discuss how to choose among the various treatment options; review the safety of acute-
treatment options in pregnancy; and consider rescue and inpatient treatment options
 Describe strategies for preventive treatment of migraine including the emerging role of
calcitonin gene-related peptide–targeted therapies and discuss novel paradigms of
preventive treatment
 Discuss best practices for the diagnosis and management of medication-overuse headache
 Diagnose and manage cluster headache, SUNCT, and SUNA
 Describe the epidemiology, diagnosis, clinical presentation, pathophysiology, prognosis,
and treatment of posttraumatic headache attributed to mild traumatic brain injury
 Describe the clinical features, etiology, mimics, management, and prognosis of new daily
persistent headache
 Describe the latest epidemiology, assessment, and management principles pertaining to
children and adolescents presenting with headache
 Distinguish primary and secondary presentations of cranial neuralgias and apply
evidence-based management strategies to clinical practice
 Recognize the existence and treatability of the indomethacin-responsive headache
disorders paroxysmal hemicrania and hemicrania continua
Core Competencies
This Continuum: Lifelong Learning in Neurology Headache issue covers the following core
competencies:
 Patient Care and Procedural Skills
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism

Systems-Based Practice

Contributors
Lakshmi Nayak, MD, Guest Editor

Director, Center for CNS Lymphoma; Associate Professor of Neurology, Dana Farber Cancer
Institute, Harvard Medical School, Boston, Massachusetts
Relationship Disclosure: Dr Nayak has received personal compensation in the range of $500 to $4999 for serving as
a consultant for Genmab, Gilead Sciences, Inc., and Ono Pharmaceutical Co., Ltd. and for serving on a speakers
bureau for Ono Pharmaceutical Co., Ltd. An immediate family member of Dr Nayak has received personal
compensation in the range of $500 to $4999 for serving as a consultant for Brave Bio. Dr Nayak has received
publishing royalties from a publication relating to health care.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nayak reports no disclosure.
Deborah A. Forst, MD
Assistant Professor of Neurology, Harvard Medical School; Neuro-oncology Faculty Member,
Massachusetts General Hospital Cancer Center, Boston, Massachusetts
Relationship Disclosure: Dr Forst has stock in Lilly and has received research support from Conquer Cancer, the
ASCO Foundation, the Palliative Care Research Cooperative Group, and the American Cancer Society Institutional
Research Grants.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Forst discusses the unlabeled/investigational use of
bevacizumab for the treatment of vestibular schwannomas in the setting of NF2-related schwannomatosis and
nivolumab and ipilimumab for the treatment of aggressive adenomas.
Macarena I. de la Fuente, MD
Neuro-oncology Division Chief, Associate Professor, and Program Director, Neuro-oncology
Fellowship, Department of Neurology, University of Miami; Clinical Research Chair, Neuro-
oncology Site Disease Group, Sylvester Comprehensive Cancer Center, University of Miami,
Miami, Florida
Relationship Disclosure: Dr de la Fuente has received personal compensation in the range of $500 to $4999 for
serving as a consultant for Les Laboratoires Servier and Pyramid Biosciences, Inc. An immediate family member of
Dr de la Fuente has received personal compensation in the range of $500 to $4999 for serving as a consultant for
ADC Therapeutics SA and Genentech, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr de la Fuente discusses the unlabeled/investigational

use of vorasidenib in clinical trials for the treatment of brain tumors.
Jerome J. Graber, MD, MPH, FAAN

Associate Professor of Neurology and Neurosurgery; Neuro-oncology Fellowship Director,
University of Washington, Seattle, Washington
Relationship Disclosure: Dr Graber has noncompensated relationships as a member of the board of directors of the
American Society of Neuroimaging, a certification exam committee member with the United Council of
Neurological Subspecialties, an editorial board member for Journal of Pain and Symptom Management, Neuro-
Oncology: Practice, and Practical Neurology, and a member of the Neurology Question of the Day committee with
the American Academy of Neurology (AAN) that are relevant to AAN interests or activities.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Graber discusses the unlabeled/investigational use of
corticosteroids, cyclophosphamide, intravenous immunoglobulin, ixazomib, lenalidomide, plasma exchange, and
rituximab for the treatment of paraneoplastic neurologic syndromes.
Pamela S. Jones, MD, MS, MPH

Assistant Professor, Department of Neurosurgery, Massachusetts General Hospital, Harvard
Medical School, Boston, Massachusetts

Relationship Disclosure: Dr Jones reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Jones discusses the unlabeled/investigational use of
bevacizumab for the treatment of vestibular schwannomas in the setting of NF2-related schwannomatosis and
nivolumab and ipilimumab for the treatment of aggressive adenomas.
Priya Kumthekar, MD
Associate Professor of Neurology and Hematology/Oncology, Feinberg School of Medicine,

Northwestern University, Chicago, Illinois
Relationship Disclosure: Dr Kumthekar has received personal compensation in the range of $500 to $4999 for
serving as a consultant for Janssen, Orbus Therapeutics, and Roche; in the range of $5000 to $9999 for serving as a
consultant for Affinia Therapeutics, BioClinica, Inc., BPGbio, Inc., EnClear therapies, and Servier Laboratories and
for serving on a speakers bureau for Seagen, Inc.; and in the range of $10,000 to $49,999 for serving as a consultant
for Biocept, Inc., BioClinica, Inc., and Novocure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kumthekar discusses the unlabeled/investigational

use of ANG1005, cytarabine, ipilimumab, methotrexate, nivolumab, pemetrexed, pertuzumab, thiotepa, topotecan,
and trastuzumab for the treatment of brain metastases and leptomeningeal disease.
Emilie Le Rhun, MD
Senior Physician, University Hospital of Zürich, Zürich, Switzerland
Relationship Disclosure: Dr Le Rhun has received personal compensation in the range of $500 to $4999 for serving
as a consultant for Les Laboratoires Servier and Pierre Fabre and on a scientific advisory or data safety monitoring
board for Astra Zeneca, Bayer AG, F. Hoffmann-La Roche Ltd., Janssen, Leo Pharma A/S, Les Laboratoires
Servier, and Seagen, Inc. An immediate family member of Dr Le Rhun has received personal compensation in the
range of $500 to $4999 for serving as a consultant for Les Laboratoires Servier, Medac GmbH, NeuroSense
Therapeutics, Novartis AG, and Novocure GmbH and on a scientific advisory or data safety monitoring board for
CureVac SE, Orbus Therapeutics, Inc., and Philogen S.p.A. The institution of Dr Le Rhun has received research
support from Bristol-Myers Squibb. The institution of an immediate family member of Dr Le Rhun has received
research support from Quercis Pharma and Versameb AG.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Le Rhun discusses the unlabeled/investigational use
of ANG1005, cytarabine, ipilimumab, methotrexate, nivolumab, pemetrexed, pertuzumab, thiotepa, topotecan, and
trastuzumab for the treatment of brain metastases and leptomeningeal disease.
Fatema Malbari, MD
Associate Professor and Director of Neuro-oncology, Division of Pediatric Neurology and
Developmental Neurosciences; Associate Program Director, Child Neurology Residency
Program, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
Relationship Disclosure: Dr Malbari reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Malbari reports no disclosure.
David M. Meredith, MD, PhD

Associate Pathologist, Brigham and Women’s Hospital, Boston, Massachusetts; Assistant
Professor, Harvard Medical School, Boston, Massachusetts
Relationship Disclosure: Dr Meredith reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Meredith reports no disclosure.
David J. Pisapia, MD

Associate Professor of Pathology and Laboratory Medicine, Weill Cornell Medical Center,
Cornell University, New York, New York
Relationship Disclosure: Dr Pisapia owns stock in Tesla. The institution of an immediate family member of Dr
Pisapia has received research support from the National Institutes of Health (NIH). The institution of Dr Pisapia has
received research support from the Rhodes Center for Glioblastoma.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Pisapia reports no disclosure.

Lauren Schaff, MD
Assistant Member, Memorial Sloan Kettering Cancer Center, New York, New York; Assistant
Professor, Weill Cornell Medical Center, Cornell University, New York, New York
Relationship Disclosure: Dr Schaff has received personal compensation in the range of $500 to $4999 for serving as
a consultant for Guidepoint and Ono Pharmaceutical Co., Ltd., and in the range of $5000 to $9999 for serving on a
scientific advisory or data safety monitoring board for BTG International, Inc. An immediate family member of Dr
Schaff has received personal compensation in the range of $500 $4999 for serving as an expert witness for
MichieHamlett Attorneys at Law. Dr Schaff has received research support from BTG International, Inc. and Merck
& Co., Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Schaff discusses the unlabeled/investigational use of
chimeric antigen receptor T-cell therapy, ibrutinib, immune checkpoint inhibitors, lenalidomide, and temozolomide
for the treatment of primary central nervous system lymphoma.
Akanksha Sharma, MD
Assistant Professor, Pacific Neuroscience Institute/Saint John’s Cancer Institute, Santa Monica,
California
Relationship Disclosure: Dr Sharma has received personal compensation in the range of $0 to $499 for serving as a
speaker with Project Ronin, and in the range of $500 to $4999 for serving as an advisory board member with the
National Brain Tumor Society and on a scientific or data safety monitoring board for Novocure. Dr Sharma has a
noncompensated relationship as an advisory board member with ElevateMeD, Inc. that is relevant to American
Academy of Neurology (AAN) interests or activities. The institution of Dr Sharma has received research support
from Apollomics, Inc., Chimerix, Inc., Incyte, and Novocure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Sharma reports no disclosure.
Jennie Taylor, MD
Associate Professor of Neurology and Neurological Surgery, University of California, San
Francisco, San Francisco, California
Relationship Disclosure: Dr Taylor has received research support from Mount Sinai University and the University of
Colorado. Dr Taylor has received publishing royalties from a publication relating to health care. The institution of
Dr Taylor has received research support from AbbVie, Inc., Agios Pharmaceutical, Inc., Bristol-Myers Squibb, and
Navio Theragnostics, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Taylor reports no disclosure.
Nancy Wang, MD, MPH

Neuro-oncologist, Pappas Center for Neuro-oncology, Massachusetts General Hospital, Boston,
Massachusetts; Instructor in Neurology, Harvard Medical School, Boston, Massachusetts
Relationship Disclosure: Dr Wang has received personal compensation in the range of $500 to $4999 for serving on
a scientific advisory or data safety monitoring board for Seagen, Inc. The institution of Dr Wang has received
research support from Merck & Co., Inc. Dr Wang has received publishing royalties from a publication relating to
health care.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Wang discusses the unlabeled/investigational use of
anakinra, antithymocyte globulin, and siltuximab for the treatment of immune effector cell–associated neurotoxicity
syndrome.
Mary R. Welch, MD, MS

Associate Professor of Neurology, Columbia University Irving Medical Center, New York, New
York
Relationship Disclosure: Dr Welch reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Welch reports no disclosure.
Self-Assessment and CME Test Writers
Adam Kelly, MD, FAAN

Associate Professor, Department of Neurology, Stroke Division; Associate Professor,
Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York
Relationship Disclosure: Dr Kelly has received personal compensation in the range of $500 to $4999 for serving as a
consultant for Grand Rounds, as an editor, associate editor, or editorial advisory board member for the American
Academy of Neurology (AAN), and as a question writer for various educational offerings with the AAN.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kelly reports no disclosure.
Allyson R. Zazulia, MD
Professor of Neurology and Radiology and Associate Dean for Continuing Medical Education,
Washington University, St. Louis, Missouri
Relationship Disclosure: Dr Zazulia reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Zazulia reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing

neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

Vol 30.2 Headache 2024

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294 Editor’s Preface

296 Approach to the Patient With Headache

325 Pathophysiology of Migraine

344 Acute Treatment of Migraine

364 Preventive Treatment of Migraine

379 Medication-Overuse Headache

391 Cluster Headache, SUNCT, and SUNA

411 Posttraumatic Headache

425 New Daily Persistent Headache

488 Indomethacin-Responsive Headache Disorders

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

498 Diversity, Equity, and Inclusion in Headache Care

SELF-ASSESSMENT AND CME

284 Learning Objectives and Core Competencies

513 Instructions for Completing Postreading Self-Assessment and CME

515 Postreading Self-Assessment and CME Test

527 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Learning Objectives ◆ Describe the clinical features, etiology, mimics,

management principles pertaining to children and

◆ Describe the approach to the acute treatment

◆ Diagnose and manage cluster headache, SUNCT, ◆ Professionalism

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Amy Gelfand, MD, Rebecca Burch, MD, FAHS

Guest Editor Assistant Professor,

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Associate Professor, UT Health MPH, FAAN

Unlabeled Use of Products/Investigational

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Peter J. Goadsby, MD, PhD, FRS Rashmi B. Halker Singh, MD,

Professor of Neurology, King’s FAAN

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Professor, The Saul R. Korey

Unlabeled Use of Products/Investigational

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Stephanie J. Nahas, MD, MSEd, Serena L. Orr, MD, MSc, FRCPC

FAAN Assistant Professor,

Associate Professor of Departments of Pediatrics,

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Chief, Division of Headache, FAHS

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Todd J. Schwedt, MD, FAAN

Professor of Neurology, Mayo

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Nuri Jacoby, MD, FAAN Adam Kelly, MD, FAAN

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Headache Neurology’s Call

It’s no secret that patients with headache disorders are underserved

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CONTINUUM (MINNEAP MINN)

LATEST DEVELOPMENTS: The availability of online resources for clinicians and

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

exclude a secondary disorder, the diagnosis of primary headache disorders is

u Number of lifetime episodes needed to diagnose the headache disorder

u The patient has a headache (which may be further elaborated)

CONDUCTING THE INTERVIEW

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.