pLatelEts And MigRaine iN patEnt foRamen Ovale

Not Applicable

Completed

Conditions: Platelet Aggregation, Spontaneous
Patent Foramen Ovale
Migraine With Aura

Brief Summary: Migraine is a common, chronic neurovascular disorder characterized by attacks of severe headache, autonomic nervous system dysfunction and, in some patients, aura, and disabling neurological symptoms. Worldwide, migraine prevalence is as high as 18% in the general population. Increased frequency of patent foramen ovale (PFO) in migraineurs was first reported in 1998 in a case-control study. Since then, others have described a 60% prevalence of PFO in patients suffering from migraine with aura. The presence of a right-to-left shunt (RLS) is thought to be a potent trigger of migraine attacks, although the mechanism is unknown. Moreover, PFO closure has correlated with improved migraine symptoms in several retrospective uncontrolled studies. The aim of this single-center, prospective study is to assess the impact of PFO closure on migraine attacks over time together with evaluation of potential predictive risk factors.

Detailed Description: The Study will evaluate the results of approximately 100 subjects from a single center study registered in this trial. Subjects who experienced transient ischemic attack (TIA) or stroke with a clinical indication to PFO closure and symptomatic for migraine with/o aura are considered for a migraine score analysis at baseline before PFO closure and during the subsequent follow-up (FU) at 6 and 12-months, together with lab evaluation for platelet reactivity tests (P selectin, Thromboxane B2), Prostaglandin E1 and 2 (PGE1, PGE2), serotonin, cytokines and prostaglandin PGE1 urinary metabolite run under aspirin therapy.

The research questions are as follows:

Does the presence of a large PFO have any impact on migraine with aura?

Do migraineurs with aura and PFO have higher biomarkers of platelet activation than control patients? and are they at higher risk of stroke and TIA recurrences based on high on clopidogrel platelet reactivity?

What is the effect of PFO severity on monthly migraine frequency and aura frequency?

What is the result of PFO closure in migraineur patients with PFO? Do Migraine with aura patients with large PFO have higher platelet activation and better migraine resolution after PFO closure?

Recruitment & Eligibility

Inclusion Criteria

Patients older than 18 years with more than 2 criteria:
Previous Stroke or TIA (transient ischemic attack)
positive MRI for ischemic events -
PFO with a baseline R-L shunt > 10 microembolic signals (MES) and > 20 MES during/after Valsalva Manoeuver
Atrial septal aneurysm (ASA) or residual Chiari network or Eustachian Valve
positive Thrombophilic screening (MTHFR/prot C/Prot S)
Ability to sign the informed consent for the study participation

Exclusion Criteria

Patients older than 70 years
Paroxysmal Atrial fibrillation
Carotid, vertebral or basilar artery stenosis> 50% on duplex imaging
Inadequate temporal bone windows (signals) for transcranial Doppler insonation
medication overuse headache
history of cognitive dysfunction, epilepsy, brain injury
use of continuous positive airway pressure (CPAP) within 6 months of study enrollment
Left Ventricular Ejection Fraction (LVEF) < 30%
Moderate/severe mitral valve regurgitation
Known Allergy to aspirin
Known allergy to nickel
Severe chronic kidney disease (GFR < 30 ml/min)
Beck depression inventory score > or= 29
State-trait anxiety inventory score exceeding cut-off for are and sex

Keywords: PFO, migraine, migraine with aura, aura, platelets

Arm && Interventions

Group	Intervention	Description
Migraine evaluation in PFO patients	patent foramen ovale closure	Patients symptomatic for migraine with/o aura and addressed to patent foramen ovale closure (Occlutech Figulla Flex II PFO occluder device) for a previous ischemic event, will receive dual antiplatelet therapy (DAPT) for 2 months after procedure and aspirin alone subsequently. Patients will undergo evaluation of platelet reactivity, serotonin and cytokines before PFO closure with a dedicated device and at 6 months follow-up and these results compared to those of a control, group of healthy subjects treated with aspirin alone

Primary Outcome Measures

Name	Time	Method
Change in Migraine Characteristics	The outcome data were evaluated at 6-months and 12-months after PFO closure and compared to baseline	The evaluation in absolute numbers of patients fully responders, non-responders or with a moderate benefit on migraine symptoms after PFO Closure was performed
Migraine Assessment by Anzola's Score	Baseline, 6 months and 12-months after PFO closure	The change in migraine severity, incidence and duration with or without aura as measured by the Anzola's score (The score is the expression of the sum of each corresponding value referring to migraine duration, frequency and the presence or absence of aura). The minimum value was 2 and the maximum 9; the higher the value, worse is the migraine classification. Anzola's score: Duration 0=No pain 1=\<6 hours 2=6-12 hours 3=\>12 hours Frequency 0=No pain 1=1-4/month 2=5-9/month 3=\>10/month Aura 0=No aura 1=Aura in ≥1 attack

Secondary Outcome Measures

Name	Time	Method
Platelet Activation (I)	baseline and 6 months after PFO closure	Platelet Thrombin generation potential in migraineurs and healthy subjects
Platelet Aggregation (I)	baseline and 6 months after PFO Closure	Platelet aggregation was measured on PAP-8 aggregometer (BioData). Briefly, PRP aliquots (250µL) were pipetted into a siliconized glass cuvette, stirred at 1200 rpm at 37°C and stimulated with arachidonic acid (1mM), collagen (2µg/ml), ADP (5µM), TRAP-6 (5µM). Light transmission was recorded for 5 min after stimuli addition and platelet aggregation was reported as maximal percentage of light transmission. Aspirin-treated patients were considered drug responders when platelet aggregation was less than 20% after arachidonic acid (1mM) stimulation.
Platelet Activation (II)	Baseline and 6 months after PFO closure	Platelet Thrombin generation Potential in Migraneurs and Healthy subjects
Clinical Outcomes	In hospital, six and 12 months follow-up	Absence of TIA and stroke recurrences after PFO closure and during the follow-up
Platelet Activation (III)	baseline and six months after PFO closure	Platelets' endogenous thrombin generation potential in Migraneurs and Healthy subjects
Platelet Activation (IV)	Baseline and six-months after PFO closure	Platelets' functional activity measured as the amount of thrombin generation