Comorbidities Associated With Migraine and Patent Foramen Ovale (CAMP)
Condition: Migraine With Aura; Patent Foramen Ovale
MeSH terms: Migraine Disorders; Migraine with Aura; Foramen Ovale, Patent
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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?
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Otherwise healthy persons who have a diagnosis of MA, based on the International
        Classification of Headache Disorders Diagnostic Criteria, will be recruited from headache
        and neurology clinics. Potential subjects can self refer if they have a diagnosis of MA.
      
Keywords: Migraine; Migraine with Aura; Aura; Patent Foramen Ovale; Platelets; Sleep Apnea; Cognitive Function