Comorbidities Associated With Migraine and Patent Foramen Ovale (CAMP)
Comorbidities Associated With Migraine and Patent Foramen Ovale (CAMP)
The purpose of the study is to compare the rate of comorbidities associated with migraine
 aura (MA) between persons who have a large circulatory right-to-left shunt (RLS) and those
 who do not have RLS.

 Approximately 50% of individuals who have MA also have RLS due to patent foramen ovale (PFO).
 A PFO is an anatomical opening or flap between the upper chambers of the heart or atria that
 permits blood to pass from the right of the heart to the left side of the heart, without
 first going to the lungs to be filtered and oxygenated. Many health conditions and clinical
 syndromes including stroke, sleep apnea, and migraine have been linked to PFO. Although the
 mechanism is undetermined, it is hypothesized that microscopic blood clots and chemicals such
 as serotonin can pass through the PFO, travel to the brain, and cause headache and aura.

 Persons who have MA are at increased risk for stroke and transient ischemic attacks relative
 to people who do not have migraine. Migraine is also associated with the presence of white
 matter lesions in the brain and mild deficits in cognitive function associated with the
 posterior brain (vision, memory, processing speed). The risk of stroke in migraine is highest
 for women under the age of 45 who have aura and a high number of migraine headache days per
 month. No convincing evidence has been produced to explain the mechanism for the increased
 risk of ischemic stroke in migraine; however, increased platelet activation and aggregation
 is a plausible theory.

 We hypothesize that migraineurs with aura and large RLS (presumably due to a PFO) will be
 more likely to have sleep apnea, increased platelet activation, cognitive deficits,
 alterations in cerebral vasomotor function, and white matter lesions than migraineurs with
 aura who do not have PFO. The results of this exploratory study will generate hypotheses as
 to why subgroups of migraineurs have an increased risk of stroke and the impact of large PFO
 on comorbid conditions associated with migraine aura. Early identification of migraine
 subgroups with a constellation of clinical syndromes that increase risk of neurovascular
 diseases will allow initiation of preventive strategies that may ultimately reduce burden and
 improve the productive quality of life for these individuals.
A two-group observational study will be performed to determine if comorbidities associated
 with MA are more prevalent in the setting of large PFO. Potential subjects will be screened
 to assure that initial inclusion criteria are met (age, diagnosis of MA, monthly migraine
 frequency). Those who meet criteria will complete questionnaires including general medical
 history, migraine and aura frequencies, migraine-related disability, and treatment and
 preventive medications. In addition, subjects will be asked to complete two surveys on
 insomnia and sleep quality. Presence or absence of large PFO will be assessed by transcranial
 Doppler (TCD) bubble test. Subjects will also be screened for arterial variations in the
 Circle of Willis ("fetal origins") and carotid artery stenosis by duplex ultrasound
 examination of the arteries of the head and neck. If a subject is found to have a
 small-to-medium PFO on TCD evaluation, fetal origins, or carotid artery stenosis, s/he will
 be excluded from remaining study procedures.

 Subjects who have either a large PFO or no PFO will undergo measurement of brain blood flow
 dynamics using TCD and carbon dioxide (CO2) stimulation to assess cerebral vasomotor
 reactivity. A blood specimen will be collected to assess three platelet activation biomarkers
 including CD40 ligand (sCD40L), P-selectin, and thromboxane B2 (TXB2). Subjects will be
 screened for sleep apnea using a portable sleep monitor for home use; results will be
 analyzed by a sleep medicine specialist. Finally, each subject will undergo a battery of
 performance -based cognitive function tests that measure visual and auditory memory,
 processing speed, attention, and eye-hand coordination. If magnetic resonance imaging (MRI)
 evaluation has been performed within the past 5 years, the film will be reviewed by a
 neuroradiologist to assess the presence of white matter lesions. Additional MRI will not be
 performed as part of the study. Completion of the study will necessitate up to three clinic
 visits (total 5-6 hours) and the home sleep study.

 The research questions are as follows:

 -  Does the presence of a large PFO have any impact on cognitive function, particularly in
 brain regions supplied by posterior circulation, in migraine aura?

 -  Does cerebral vasomotor reactivity differ between migraineurs with aura, with and
 without large PFO?

 -  Do migraineurs with aura and large PFO have higher biomarkers of platelet activation
 (soluble P-selectin, sCD40L, TXB2) than migraineurs with aura without PFO?

 -  Are there differences in the prevalence and severity of sleep apnea, as assessed by
 apnea-hypopnea index (AHI), in migraine aura, with and without large PFO?

 -  What is the effect of large PFO on monthly migraine frequency (MMF) and aura frequency?
Inclusion Criteria:

 1. Age 18-55 years

 2. Ability to speak, read, and understand English

 3. Documented diagnosis of migraine aura (MA) for a ≥2 year period preceding enrollment,
 confirmed by a neurology healthcare provider (MD, DO, ARNP, PA-C) using the
 International Classification of Headache Disorders criteria. Focal neurologic symptoms
 must precede or accompany the headache (aura) for at least one headache in the 12
 months prior to enrollment.

 4. Average of 4 to 14 migraine days per month for the 3-month period preceding enrollment

 5. Migraine prevention regimen stable for at least 30 days prior to enrollment. This
 criterion does not pertain to acute medications or aspirin- or non-steroidal
 anti-inflammatory (NSAID)- containing medications, which will be held (wash-out) prior
 to blood draw. See below.

 6. Able and willing to complete a washout of aspirin, NSAIDs (including ibuprofen,
 naproxen sodium, ketorolac), combination drugs containing these compounds, or dietary
 supplements containing willow bark (salicylate) prior to blood collection.

 7. Experimental group: Documented large right-to-left shunt (RLS) with >100 embolic
 tracks (ET) at rest or following calibrated or uncalibrated respiratory strain by TCD
 (whichever yields largest number of ET).

 8. Control group: Documented absence of right-to-left shunt (RLS) with <11 ET at rest and
 following calibrated and uncalibrated respiratory strain by TCD (whichever yields
 largest number of ET).

 9. Adequate correction of hearing and/or vision deficits

 Exclusion Criteria:

 1. Pregnancy

 2. Postmenopausal female

 3. Documented right-to-left shunt (RLS) with 11 to 100 ET at rest or following calibrated
 or uncalibrated respiratory strain by TCD (whichever yields largest number of ET)

 4. History of stroke or neurological condition associated with cognitive dysfunction such
 as multiple sclerosis, epilepsy, brain tumor or brain injury

 5. Chronic migraine or medication overuse headache

 6. Prescription use of warfarin or antiplatelet drug such as clopidogrel or aspirin

 7. Inability or unwillingness to complete a washout of aspirin, non-steroidal
 anti-inflammatory drugs (NSAIDs), combination drugs containing these compounds, or
 dietary supplements containing willow bark (salicylate)

 8. Evidence of carotid, vertebral, or basilar artery stenosis >50% on duplex imaging

 9. Evidence of fetal origins or >50% stenosis of intracranial blood vessels on TCD
 imaging

 10. Inadequate temporal bone windows (signals) for TCD insonation

 11. Daily treatment regimen includes topiramate and/or other medication that causes
 significant cognitive or psychomotor impairment based on provider assessment and/or
 self-report (e.g., amitryptiline, divalproex sodium)

 12. Use of continuous positive-airway pressure (CPAP) instrumentation within 6 months of
 study enrollment

 13. Status post PFO or RLS closure/repair

 14. Beck Depression Inventory score ≥29

 15. State-Trait Anxiety Inventory score exceeding cutoff for age and sex