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A SELECTION OF IMPORTANT ARTICLES IN HEADACHE MEDICINE 2018Mo Levin, MD Professor, Dept of Neurology UCSF

Tom Ward, MD Professor Emeritus, Dept of Neurology Dartmouth

Mo Levin Disclosures

Consulting for Amgen, Lilly, Teva, Alder, Supernus,

Allergan, Biohaven

No speakers bureaus

No stock or ownership in any pharmaceutical or device

company

Royalties - Oxford Univ Press, Anadem Press, Sage

Publ

Member, Board of Directors, IHS (publisher of

Cephalalgia), AHS

• Colleague and friend of Tom Ward for 27 years

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Tom WardDisclosures

• Editor in Chief – HEADACHE

• CEO – DRMLC

No speakers bureaus

Royalties - Oxford Univ Press

Friend of Mo Levin

Owner of a small dog named Dodick

ICHD 3final

version

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Classification Committee IHS, ICHD 3

• ICHD 3 published after 3 year comment period• Primary headaches

– New definition for mig with aura to distinguish TIA

– Vestibular migraine in appendix, along with menstrual migraine

– Persistent aura without MRI changes and NDPH still murky

• Secondary headaches– Post-traumatic HA still requires appearance in 7 d (or within 7d of consc)

– High and low pressure headaches still murky

– Cervicogenic headache causes still debatable

– Psychiatric causes still limted to psychosis and conversion

• Neuralgias –– new definitions for painful neuropathies and facial neuralgias

Cognitive Changes

in Migraine

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Migraine and cognitive performance

• Baena et al - 4208 participants; 19% migraine without aura and 10.3%

migraine with aura. Testing consisted of word list memory test (CERAD-

WLMT), the semantic fluency test (SFT), and the Trail Making Test version B

(TMTB). Pts with important confounders were excluded. Migraine

headaches were associated with poorer cognitive performance. In

particular, migraine without aura was associated with poor cognitive

performance at TMTB.

• Santangelo, et al. - Ninty-one consecutive migraine without aura patients

and 84 healthy subjects underwent a standardized measure of prospective

memory evaluating both time-based and event-based prospective memory,

and the Montreal Cognitive Assessment assessing global cognitive status.

Pts with migraine without aura demonstrated impaired prospective

memory performance compared to healthy subjects, with a greater

impairment demonstrated for the time-based tasks. Depression was not a

factor.

The Trigeminal autonomic

reflex in TACs

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TAR in TACs(V – TNC – SSN – VII/SPG)• Cluster headaches and supposedly TACs in general involve the

trigeminoautonomic reflex. Cause or consequence?

• SPG stim seems to block CH by depolarizing the autonomic neurons?

Moller et al. - Kinetic oscillation stim of the nasal mucosa in CH pts did

produce autonomic symptoms but not CHs

Guo et al - LF stimulation of the SPG induced autonomic symptoms, but no

CH attacks.

So – While afferent (Moller) and efferent (Guo) stimulation of the TAR will

increase parasympathetic outflow but will not provoke a cluster attack.

Cluster is not a peripherally induced phenomenon. (Does not mean that

periph techniques cannot be therapeutic).

Central trigeminal neuralgia

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Neuralgia – a PNS condition?• Neuralgia and painful facial neuropathies are considered to be a

dysfunction in nerve or root entry zone.

• Frolich et al – reviewed 12,210 multiple sclerosis patient recorde,

identified 41 patients with trigeminal neuralgia whose imaging was

analyzed statisticall; They found similar areas to be associated with

trigeminal neuralgia.

• Conclusions: Our study confirms previous data on associations between

multiple sclerosis-related trigeminal neuralgia and pontine lesions, and

showed for the first time an association with lesions in the insular

region, a region involved in pain processing and endogenous pain

modulation.

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CGRP

News in migraine

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Headache’s most down-

loaded article

• The Migraine Attack as a Homeostatic,

Neuroprotective Response to Brain Oxidative Stress:

Preliminary Evidence for a Theory

• Jonathan M. Borkum, PhD

• (Headache 2018;58:118-135)

Background.—Previous research has suggested that migraineurs show

higher levels of oxidative stress (lipid peroxides) between migraine

attacks and that migraine triggers may further increase brain oxidative

stress. Oxidative stress is transduced into a neural signal by the TRPA1

ion channel on meningeal pain receptors, eliciting neurogenic

inflammation, a key event in migraine. Thus, migraines may be a

response to brain oxidative stress. Results.—In this article, a number of

migraine components are considered: cortical spreading depression,

platelet activation, plasma protein extravasation, endothelial nitric

oxide synthesis, and the release of serotonin, substance P, calcitonin

gene-related peptide, and brain-derived neurotrophic factor. Evidence

is presented from in vitro research and animal and human studies of

ischemia suggesting that each component has neuroprotective

functions, decreasing oxidant production, upregulating antioxidant

enzymes, stimulating neurogenesis, preventing apoptosis, facilitating

mitochondrial biogenesis, and/or releasing growth factors in the brain.

Feedback loops between these components are described. Limitations

and challenges to the model are discussed. Conclusions.—The theory is

presented that migraines are an integrated defensive, neuroprotective

response to brain oxidative stress.

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A very common concern

which we don’t like to

discuss!

• Negative Online Patient Reviews in Headache Medicine

• Randolph W. Evans, MD

• Headache: 2018;58:1435-1441

And a cottage-

industry has sprung up to help you, the

“provider”, fix your negative

reviews!

• Patients commonly use online reviews in selecting a

new physician. There have been no studies of online

reviews of headache medicine physicians. To better

understand headache medicine physicians’ attitudes

and opinions about negative reviews, 2 negative

patient reviews were posted to the Southern Headache

Society online discussion group and comments were

requested. Twenty-two anonymous comments are

provided. The strengths and inadequacies of online

physician reviews in other specialties and the possible

actions headache medicine physicians should take for

negative reviews are discussed. A nationwide survey of

online reviews of headache medicine specialists would

be of interest

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Review Article

• Spontaneous Intracranial Hypotension: 10 Myths and

Misperceptions

• Peter G. Kranz, MD ; Linda Gray, MD; Timothy J.

Amrhein, MD

• (Headache 2018;58:948-959

Objective.—To discuss common myths and misperceptions about spontaneous intracranial hypotension

(SIH), focusing on common issues related to diagnosis and treatment, and to review the evidence that

contradicts and clarifies these myths. Background.—Recognition of SIH has increased in recent years.

With increasing recognition, however, has come an increased demand for management by neurologists

and headache specialists, some of whom have little prior experience with the condition. This dearth of

practical experience, and lack of awareness of recent investigations into SIH, produces heterogeneity in

diagnostic and treatment pathways, driven in part by outdated, confusing, or unsubstantiated

conceptions of the condition. We sought to address this heterogeneity by identifying 10 myths and

misperceptions that we frequently encounter when receiving referrals for suspected or confirmed SIH,

and to review the literature addressing these topics. Methods.—Ten topics relevant to diagnosis and

treatment SIH were generated by the authors. A search for studies addressing SIH was conducted using

PubMed and EMBASE, limited to English language only, peer reviewed publications from inception to

2018. Individual case reports were excluded. The resulting studies were reviewed for relevance to the

topics in question. Results.—The search generated 557 studies addressing SIH; 75 case reports were

excluded. Fifty-four studies were considered to be of high relevance to the topics addressed, and were

included in the data synthesis. The topics are presented in the form of a narrative review. Conclusions.—

The understanding of SIH has evolved over the recent decades, leading to improvements in knowledge

about the pathophysiology of the condition, diagnostic strategies, and expanded treatments. Awareness

of these changes, and dispelling outdated misconceptions about SIH, is critical to providing appropriate

care for patients and guiding future investigations going forward.

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A cautionary tale

The Zecuity patch

• Safety Problems With a Transdermal Patch for

Migraine: Lessons From the Development, Approval,

and Marketing Process

• Elizabeth W. Loder, MD, MPH; Melissa Rayhill, MD;

Rebecca C. Burch, MD

• Headache 2018;0:1-19

Objective.—We sought to analyze publicly available information about patient harm associated with an iontophoretic

sumatriptan patch, to identify what went wrong and to suggest ways in which similar problems might be prevented in

the future. Background.—The Zecuity® sumatriptan iontophoretic transdermal system was marketed for acute

treatment of migraine. The patch was withdrawn less than 10 months after its introduction because of multiple reports

of scarring and burning. As of 2018, the FDA Adverse Event Reporting System public dashboard lists a total of 2889

reports of safety problems with the patch, 904 of which were classified as serious. Methods.—For this narrative review,

we examined US Food and Drug Administration documents related to the new drug application for this product and its

approval. We searched Clinicaltrials.gov, PubMed, Google, Facebook, Twitter, and Instagram public posts for relevant

information relating to the patch, its approval, marketing, and complications. Results.—The FDA knew about problems

with burns and scarring prior to approval of the product, and turned down the initial new drug application for this

reason and because of other quality problems with the patch. The reapplication was approved despite continued

concerns of several FDA reviewers about safety. The approval required the manufacturer to comply with

enhanced postmarketing safety reporting. However, product information and labeling did not mention the possibility

of burns or scarring. Approval was based on 1 clinical trial and 2 open label studies in which reporting of adverse events

was suboptimal. The clinical trials had been prospectively registered but outcomes had been changed around the time

the trial concluded. Aggressive marketing efforts and social media activity may have contributed to inaccurate

perceptions of safety and efficacy, but social media also provided a written and photographic record of burns and other

harm suffered by patients who used the patch. Conclusions.—Our review identified several problems with the

development, testing, approval, and marketing of the Zecuity patch. To improve the process of developing headache

treatments, it is important to consider the lessons that can be drawn from an examination of this high-profile failure of

the drug development and regulatory system.

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Views and perspectives

• Linking Cigarette Smoking/Tobacco Exposure and

Cluster Headache: A Pathogenesis Theory

• Todd D. Rozen, MD, FAAN

• Headache 2018;58:1096-1112

Introduction.—To propose a hypothesis theory to establish a linkage between cigarette smoking and cluster headache

pathogenesis. Background.—Cluster headache is a primary headache syndrome grouped under the trigeminal

autonomic cephalalgias. What distinguishes cluster headache from all other primary headache conditions is its inherent

connection to cigarette smoking. It is undeniable that tobacco exposure is in some manner related to cluster headache.

The connection to tobacco exposure for cluster headache is so strong that even if an individual sufferer never smoked,

then that individual typically had significant secondary smoke exposure as a child from parental smoking behavior and

in many instances both scenarios exist. The manner by which cigarette smoking is connected to cluster headache

pathogenesis is unknown at present. If this could be determined this may contribute to advancing our understanding of

cluster headache pathophysiology. Methods/results.—Hypothesis statement. Conclusion.—The hypothesis theory will

include several principles: (1) the need of double lifetime tobacco exposure, (2) that cadmium is possibly the primary

agent in cigarette smoke that leads to hypothalamic-pituitary-gonadal axis toxicity promoting cluster headache, (3)

that the estrogenization of the brain and its specific sexually dimorphic nuclei is necessary to develop cluster headache

with tobacco exposure, and (4) that the chronic effects of smoking and its toxic metabolites including cadmium and

nicotine on the cortex are contributing to the morphometric and orexin alterations that have been previously

attributed to the primary headache disorder itself.

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Related article

• Cluster Headache Clinical Phenotypes: Tobacco

Nonexposed (Never Smoker and No Parental

Secondary Smoke Exposure as a Child) versus Tobacco-

Exposed: Results from the United States Cluster

Headache Survey

• Todd D. Rozen, MD, FAAN

• (Headache 2018;58:688-699)

Objective.—To present results from the United States Cluster Headache Survey comparing the clinical

presentation of tobacco nonexposed and tobacco-exposed cluster headache patients. Background.—

Cluster headache is uniquely tied to a personal history of tobacco usage/cigarette smoking and, if the

individual cluster headache sufferer did not smoke, it has been shown that their parent(s) typically did and

that individual had significant secondary smoke exposure as a child. The true nontobacco exposed (no

personal or secondary exposure) cluster headache sufferer has never been fully studied. Methods.—The

United States Cluster Headache Survey consisted of 187 multiple choice questions related to cluster

headache including: patient demographics, clinical headache characteristics, family history, triggers,

smoking history (personal and secondary), and headache-related disability. The survey was placed on a

website from October through December 2008. Results.—One thousand one hundred thirty-four

individuals completed the survey. One hundred thirty-three subjects or 12% of the surveyed population had

no personal smoking/tobacco use history and no secondary smoke exposure as an infant/child, thus a

nontobacco exposed population. In the nonexposed population, there were 87 males and 46 females with a

gender ratio of 1.9:1. Episodic cluster headache occurred in 80% of nonexposed subjects. One thousand and

one survey responders or 88% were tobacco-exposed (729 males and 272 females) with a gender ratio of

2.7:1. Eighty-three percent had a personal smoking history, while only 17% just had parents who smoked

with secondary smoke exposure. Eighty-five percent of smokers had double exposure with a personal

smoking history and secondary exposure as a child.

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Significant highlights from the survey.—Nonexposed cluster headache subjects are significantly more likely to

develop cluster headache at ages 40 years and younger, while the exposed sufferers are significantly more likely to

develop cluster headache at 40 years of age and older. Nonexposed patients have a statistically significant higher

frequency of a migraine family history. The exposed population is statistically significantly more likely to have a

history of head trauma 19% vs the nonexposed population 10% (P5.02). Tobacco exposed are significantly more likely

to transition from episodic to chronic cluster headache (23% vs 14%, P5.02). Cranial autonomic symptoms as well as

agitation are more common in tobacco exposed. Nonexposed are less likely to have specific cluster headache

triggers. Exposed are significantly more likely to be triggered by alcohol. Tobacco exposed are significantly heavier

caffeine users than nonexposed. Nonexposed are significantly more likely to have cluster headache cycles that vary

throughout the year than exposed (52% vs 40%, P5.02). Exposed are much more likely to develop cluster headache

from 12 am to 6 am than non exposed. Exposed experience significantly more frequent attacks per day and longer

duration cycles than nonexposed. A significantly larger percent of the exposed population (57%) has suicidal ideations

with their syndrome than nonexposed (43%) (P5.003). In regard to disability, both subtypes are disabled by their

headaches, but exposed have more work related disability and lost home-days

from headache. Both subgroups have a poor overall response to preventive and abortive medication outside of

inhaled oxygen and injectable sumatriptan. Conclusion.—Cluster headache sufferers who were never exposed to

tobacco (personal or secondary as a child) appear to present uniquely compared to the tobacco exposed subgroup.

The tobacco exposed clinical phenotype appears to have a more severe syndrome based on attack frequency, cycle

duration, and headache related disability. Tobacco exposure is associated with cluster headache chronification. The

nonexposed subtype appears to have an earlier age of onset, higher rate of familial migraine, and less circadian

periodicity and daytime entrainment, suggesting a possible different underlying pathology than in the tobacco

exposed sub-form.

• Privacy Issues in Smartphone Applications: An Analysis

of Headache/Migraine Applications

• Mia T. Minen, MD, MPH; Eric J. Stieglitz, JD; Rose

Sciortino; John Torous, MD

• Headache 2018;58:1014-1027

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Background.—Headache diaries are a mainstay of migraine management. While many commercial

smartphone applications (apps) have been developed for people with migraine, little is known about

how well these apps protect patient information and whether they are secure to use. Objective.—We

sought to assess whether there are privacy issues surrounding apps so that physicians and patients

could better understand what medical information patients are providing to the app companies, and

the potential privacy implications of how the app companies (and other third parties) might use that

information. Methods.—We conducted a systematic search of the most popular “headache” and

“migraine” apps and developed a database of the types of data the apps requested for input by the user

and whether the apps had clear privacy policies. We also examined the content of the privacy policies.

Results.—Twenty-nine apps were examined (14 diary apps, 15 relaxation apps). Of the diary

applications, 79% (11/14) had visible privacy policies. Of the diary apps with privacy policies, all (11/11)

stated whether or not the app collects and stores information remotely. A total of 55% (6/11) stated

that some user data were used to serve targeted advertisements. A total of 11/15 (73%) of the relaxation

apps had privacy policies. Conclusions.—Headache apps shared information with third parties, posing

privacy risks partly because there are few legal protections against the sale or disclosure of data from

medical apps to third parties.

The End