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May migraine post-patent foramen ovale closure sustain the microembolic genesis of cortical spread depression?
Cardiovascular Revascularization Medicine 12 (2011) 217 – 219
May migraine post-patent foramen ovale closure sustain the microembolic genesis of cortical spread depression? Gianluca Rigatelli a,⁎, Paolo Cardaioli a , Fabio Dell'Avvocata a , Massimo Giordan a , Aravinda Nanjundappa b , Sangeeta Mandapaka c , Mauro Chinaglia c a
Adult Congenital and Structural Heart Disease, Cardiovascular Diagnosis and Interventions Unit, Rovigo General Hospital, Via Mozart, 9, 37045 Legnago, Verona, Italy b West Virginia University, Charleston, USA c Neurosciences Department, Rovigo General Hospital, Italy Received 7 August 2010; received in revised form 14 September 2010; accepted 14 September 2010
Abstract
Background: Cortical spreading depression has been suggested to be the main substrate for migraine, but its pathobiology is not completely understood. Recently, the microembolic hypothesis as a promoting factor of cortical spreading depression has been demonstrated in an animal model. Our study is aimed to present a series of patients in whom early migraine attacks immediately after closure procedure predicted migraine with aura resolution on the long term, suggesting a role for microembolization in migraine genesis. Methods: Our study consisted of 42 patients with migraine (36 female, mean age 35±6.7 years, mean Migraine Disability Assessment Score 29.9±9) and previous stroke who underwent transcatheter PFO closure during the last 2 years at the Rovigo General Hospital using different devices selected on the basis of specific anatomies. Procedural, technical, and clinical variables have been recorded and analyzed searching for potential relationships among postprocedural migraine, migraine improvement, and microembolization. Results: Sixteen patients (38%) experienced a migraine attack of mean duration 3.5±2.4 h immediately (b60 min) after closure procedure. These patients more frequently had a severe migraine with aura and a permanent shunt on transcranial Doppler. There were no differences in terms of procedure time, occlusion time, and type of device used. After a mean follow-up of 32.2±10.6 months, only patients with postprocedural migraine attacks reported resolution of aura and a significant improvement in migraine symptoms. Conclusions: Our series seem to indirectly confirm in vivo the experimental animal data of microembolization-driven cortical spreading depression. It also confers the recent hypothesis about air microbubble-induced cerebral deoxygenation linking the micromebolic hypothesis with cortical spreading depression. © 2011 Elsevier Inc. All rights reserved.
Keywords:
Stroke; Patent foramen ovale; Transcatheter closure; Migraine
⁎ Corresponding author. Adult Congenital and Structural Heart Disease, Cardiovascular Diagnosis and Interventions Unit, Rovigo General Hospital, Via Mozart, 9, 37045 Legnago, Verona, Italy. Tel.: +3903471912016; fax: +39044220164. E-mail address: [email protected] (G. Rigatelli). 1553-8389/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.carrev.2010.09.009
218
G. Rigatelli et al. / Cardiovascular Revascularization Medicine 12 (2011) 217–219 Table 2 Procedural and follow-up results
1. Introduction Conflicting studies based on microembolic genesis of migraine have investigated the association of patent foramen ovale (PFO) with migraine [1–2]. Cortical spreading depression has been suggested to be the main substrate for migraine, but its pathobiology is not completely understood. Recently, the microembolic hypothesis as a promoting factor of cortical spreading depression has been demonstrated in an animal model [3]. Microembolization during transcatheter PFO closure is a well-described occurrence at the time of crossing the septum with the guide wire or at the opening of left disk [4]. Our study is aimed to present a series of patients in whom early migraine attacks immediately after closure procedure predicted migraine with aura resolution on the long term suggesting a role for microembolization in migraine genesis.
2. Methods Our study consisted of 42 patients with migraine (36 female, mean age 35±6.7 years) and previous stroke who underwent transcatheter PFO closure during the last 2 years at the Rovigo General Hospital. International Headache Society criterion Migraine Disability Assessment Score (MIDAS) was used to assess migraine with aura incidence and severity routinely in all patients referred to our center (mean MIDAS 29.9±9). The Amplatzer Occluder (AGA Medical Corporation, Golden Valley, MN) was selected in cases of associated atrial septal aneurysm (ASA), whereas the Premere Occlusion System (St Jude Medical Corp.) was used in case of tunnelized (tunnel length N10 mm) PFO without ASA. A 9F 9MHz UltraICE catheter (EP Technologies, Boston Scientific Corporation, San Jose, CA) was used to perform a complete intracardiac study. Heparin 70 U/kg was given to all patients after catheterization in order to obtain an Table 1 Comparison between patients with and without post-op migraine attack Migraine attack + Migraine attack − P Age (years) Male/female Migraine with aura Migraine with no aura Preoperative MIDAS Number of anti-headache drugs a TC Doppler shower pattern TC Doppler curtain pattern PFO size large/medium (TEE) Permanent shunt on TC Doppler ASA (TEE) Eustachian valve on ICE
36.1±4.8 2/14 16/16 (100) 0/16 30.7±9.5 2.7±1.3
34.9±7.3 4/22 10/26 (3.8) 16/26 (61.5) 28.1±9.1 2.5±0.9
ns ns .001 .001 ns ns
4/16 (25) 12/16 (75) 16/16 (100) 14/16 (87.5)
20/26 (76.9) 6/26 (23) 20/26 (76.9) 6/26 (23)
.001 .001 .01 .001
16/16 (100) 14/16 (87.5)
8/26 (30.7) 4/26 (15.3)
.001 .01
ICE, intracardiac echocardiography; TEE, transesophageal echocardiography; TC, transcranial. a Incuding β-blockers, triptan, anti-inflammatory drugs.
Procedural time (min) Amplatzer/Premere Pre-discharge complete occlusion a Follow-up complete occlusion b Follow-up number of anti-headache drugs a Follow-up MIDAS
Migraine attack +
Migraine attack −
P
35.4±15.4 7/9 13/16 (81.2) 15/16 (93.7) 0.6±0.5
35.9±14.8 23/19 21/26(80.7) 24/26 (92.3) 1.4±0.6
ns ns ns ns .01
12±3.5
20±2.8
.01
Including β-blockers, triptan, anti-inflammatory drugs. one patient in the Migr+ group had a moderate shunt and two patients in the Migr− group had a small shunt on follow-up. a
b
activated coagulation time around 250 for the duration of the procedure. All patients were managed with aspirin 100 mg/day 1 week before and for 6 months after the procedure. Follow-up was conducted by means of transesophageal echocardiography at 1 month, and if at least a small shunt was detected, at 6 months; transthoracic echocardiography at 1, 6, and 12 months; transcranial Doppler at 1 month; ECG Holter monitoring at 1 month; and combined cardiologic and neurological visit at 1, 6, and 12 months with MIDAS administration. Residual shunt was assessed by contrast transesophageal echocardiography and transcranial Doppler. Data are expressed as mean±S.D. and as percentages. Variables were compared with Student t and Fisher tests and ANOVA. A significant level was defined when Pb .05. All analyses were performed using SPSS 10.0 (SPSS Inc., Chicago, IL). 3. Results Sixteen patients (38%) experienced a migraine attack of mean duration 3.5±2.4 h immediately (b60 min) after closure procedure. These patients more frequently had a severe migraine with aura and a spontaneous shunt on transcranial Doppler. The procedures time, type of device used, and occlusion times did not differ between the two groups of patients (Table 1). There were no intraprocedural or late complications including no supraventricular arrhythmias. After a mean follow-up of 32.2±10.6 months, patients with postprocedural migraine attacks reported complete resolution of aura and a more significant improvement in migraine symptoms demonstrated by decrease of mean MIDAS and mean number of anti-headache medications (Table 2, Fig. 1). 4. Discussion Different speculations have been argued on the causality of PFO and migraine attacks. The main hypothesis is that the shunt could allow microemboli or substances such as serotonin and norepinephrine to bypass filtration by the lungs and to circulate through the brain provoking migraine. This hypothesis, suggested also by recent series of migraine
G. Rigatelli et al. / Cardiovascular Revascularization Medicine 12 (2011) 217–219
219
Acknowledgments The authors have no conflicts of interest to declare regarding any pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the article. References
Fig. 1. Histogram representation demonstrating differences in mean MIDAS and mean number of anti-headache medications at the follow-up observed in patients with (Migr+) and without (Migr−) migraine attacks immediately after PFO closure procedure.
improvement after transcatheter closure [5–7], has been mitigated in prevalence studies [8–9]. Recently, a certain degree of LA dysfunction, such as impairment of active or passive emptying or perhaps conduit function, has been suggested to be present in patients with PFO, especially in those with ASA [10], contributing to create the hemodynamic conditions for fibrin deposit or microthrombi formation just inside the left atrium, on the atrial aneurysm surface, or within the tunnel. Cortical spreading depression, the main substrate for migraine as investigated by neurobiologists, has not been yet completely understood, being the microemboli genesis only very recently proposed. In the early 2010, Viola et al. [11] demonstrated that areas of cortical hypoperfusion corresponding to the topography of aura symptoms on infrared spectroscopy resulted from decreased metabolic demand. This hypothesis seems to be against the study of Nozari et al. [3] that demonstrated in an animal model how cortical spreading depression may be induced also by microembolic ischemia. Recently, Caputi et al. [12] suggested that microembolization because of microbubbles injection during transcranial Doppler ultrasound might provoke a decrease in cerebral oxygen saturation, thus triggering cortical spreading depression and thereafter migraine with aura attack. Although with many limitations, including the very small sample of patients and the lack of transcranial Doppler monitoring, our series seem to indirectly confirm in vivo the experimental animal data of micromebolization-driven cortical spreading depression and the recent hypothesis about air microbubble-induced cerebral deoxygenation linking the micromebolic hypothesis with cortical spreading depression.
[1] Garg P, Servoss SJ, Wu JC, Bajwa ZH, Selim MH, Dineen A, Kuntz RE, Cook EF, Mauri L. Lack of association between migraine headache and patent foramen ovale. Results of a case-control study. Circulation 2010;121:1406–12. [2] Rigatelli G, Dell'Avvocata F, Ronco F, Cardaioli P, Giordan M, Braggion G, Aggio S, Chinaglia M, Rigatelli G, Chen JP. Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism. JACC Cardiovasc Interv 2010;3:282–7. [3] Nozari A, Dilekoz E, Sukhotinsky I, Stein T, Eikermann-Haerter K, Liu C, Wang Y, Frosch MP, Waeber C, Ayata C, Moskowitz MA. Microemboli may link spreading depression, migraine aura, and patent foramen ovale. Ann Neurol 2010;67:221–9. [4] Morandi E, Anzola GP, Casilli F, Onorato E. Silent brain embolism during transcatheter closure of patent foramen ovale: a transcranial Doppler study. Neurol Sci 2006;27:328–31. [5] Anzola GP, Morandi E, Casilli F, Onorato E. Does transcatheter closure of patent foramen ovale really “shut the door?”A prospective study with transcranial Doppler. Stroke 2004;35:2140–4. [6] Vigna C, Marchese N, Inchingolo V, Giannatempo GM, Pacilli MA, Di Viesti P, Impagliatelli M, Natali R, Russo A, Fanelli R, Loperfido F. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions. A case-control study. J Am Coll Cardiol Intv 2009;2:107–13. [7] Wahl A, Praz F, Findling O, Nedeltchev K, Schwerzmann M, Tai T, Windecker S, Mattle HP, Meier B. Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical therapy. Cathet Cardiovasc Intervent 2009;74:124–9. [8] Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale and migraine: a systematic review. Chephalalgia 2008;28:531–40. [9] Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A, Padovani A. Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationships with clinical phenotype. J Haedache pain 2005;6:328–30. [10] Rigatelli G, Aggio S, Cardaioli P, Braggion G, Giordan M, Dell'avvocata F, Chinaglia M, Rigatelli G, Roncon L, Chen JP. Left atrial dysfunction in patients with patent foramen ovale and atrial septal aneurysm: an alternative concurrent mechanism for arterial embolism. JACC Cardiovasc Interv 2009;2:655–62. [11] Viola S, Viola P, Litterio P, Buongarzone MP, Fiorelli L. Pathophysiology of migraine attack with prolonged aura revealed by transcranial Doppler and near infrared spetroscopy. Neurol Sci 2010; 31:S165–6. [12] Caputi L, Usai S, Crriero MR, Grazzi L, D’Amico D, Falcone C, Anzola GP, Del Sette M, Parati E, Bussone G. Microembolic air load durino contrast-transcranial Doppler: a trigger for migraine with aura? Haedache 2010;50:1320–2.
May migraine post-patent foramen ovale closure sustain the microembolic genesis of cortical spread depression? Gianluca Rigatelli a,⁎, Paolo Cardaioli a , Fabio Dell'Avvocata a , Massimo Giordan a , Aravinda Nanjundappa b , Sangeeta Mandapaka c , Mauro Chinaglia c a
Adult Congenital and Structural Heart Disease, Cardiovascular Diagnosis and Interventions Unit, Rovigo General Hospital, Via Mozart, 9, 37045 Legnago, Verona, Italy b West Virginia University, Charleston, USA c Neurosciences Department, Rovigo General Hospital, Italy Received 7 August 2010; received in revised form 14 September 2010; accepted 14 September 2010
Abstract
Background: Cortical spreading depression has been suggested to be the main substrate for migraine, but its pathobiology is not completely understood. Recently, the microembolic hypothesis as a promoting factor of cortical spreading depression has been demonstrated in an animal model. Our study is aimed to present a series of patients in whom early migraine attacks immediately after closure procedure predicted migraine with aura resolution on the long term, suggesting a role for microembolization in migraine genesis. Methods: Our study consisted of 42 patients with migraine (36 female, mean age 35±6.7 years, mean Migraine Disability Assessment Score 29.9±9) and previous stroke who underwent transcatheter PFO closure during the last 2 years at the Rovigo General Hospital using different devices selected on the basis of specific anatomies. Procedural, technical, and clinical variables have been recorded and analyzed searching for potential relationships among postprocedural migraine, migraine improvement, and microembolization. Results: Sixteen patients (38%) experienced a migraine attack of mean duration 3.5±2.4 h immediately (b60 min) after closure procedure. These patients more frequently had a severe migraine with aura and a permanent shunt on transcranial Doppler. There were no differences in terms of procedure time, occlusion time, and type of device used. After a mean follow-up of 32.2±10.6 months, only patients with postprocedural migraine attacks reported resolution of aura and a significant improvement in migraine symptoms. Conclusions: Our series seem to indirectly confirm in vivo the experimental animal data of microembolization-driven cortical spreading depression. It also confers the recent hypothesis about air microbubble-induced cerebral deoxygenation linking the micromebolic hypothesis with cortical spreading depression. © 2011 Elsevier Inc. All rights reserved.
Keywords:
Stroke; Patent foramen ovale; Transcatheter closure; Migraine
⁎ Corresponding author. Adult Congenital and Structural Heart Disease, Cardiovascular Diagnosis and Interventions Unit, Rovigo General Hospital, Via Mozart, 9, 37045 Legnago, Verona, Italy. Tel.: +3903471912016; fax: +39044220164. E-mail address: [email protected] (G. Rigatelli). 1553-8389/10/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.carrev.2010.09.009
218
G. Rigatelli et al. / Cardiovascular Revascularization Medicine 12 (2011) 217–219 Table 2 Procedural and follow-up results
1. Introduction Conflicting studies based on microembolic genesis of migraine have investigated the association of patent foramen ovale (PFO) with migraine [1–2]. Cortical spreading depression has been suggested to be the main substrate for migraine, but its pathobiology is not completely understood. Recently, the microembolic hypothesis as a promoting factor of cortical spreading depression has been demonstrated in an animal model [3]. Microembolization during transcatheter PFO closure is a well-described occurrence at the time of crossing the septum with the guide wire or at the opening of left disk [4]. Our study is aimed to present a series of patients in whom early migraine attacks immediately after closure procedure predicted migraine with aura resolution on the long term suggesting a role for microembolization in migraine genesis.
2. Methods Our study consisted of 42 patients with migraine (36 female, mean age 35±6.7 years) and previous stroke who underwent transcatheter PFO closure during the last 2 years at the Rovigo General Hospital. International Headache Society criterion Migraine Disability Assessment Score (MIDAS) was used to assess migraine with aura incidence and severity routinely in all patients referred to our center (mean MIDAS 29.9±9). The Amplatzer Occluder (AGA Medical Corporation, Golden Valley, MN) was selected in cases of associated atrial septal aneurysm (ASA), whereas the Premere Occlusion System (St Jude Medical Corp.) was used in case of tunnelized (tunnel length N10 mm) PFO without ASA. A 9F 9MHz UltraICE catheter (EP Technologies, Boston Scientific Corporation, San Jose, CA) was used to perform a complete intracardiac study. Heparin 70 U/kg was given to all patients after catheterization in order to obtain an Table 1 Comparison between patients with and without post-op migraine attack Migraine attack + Migraine attack − P Age (years) Male/female Migraine with aura Migraine with no aura Preoperative MIDAS Number of anti-headache drugs a TC Doppler shower pattern TC Doppler curtain pattern PFO size large/medium (TEE) Permanent shunt on TC Doppler ASA (TEE) Eustachian valve on ICE
36.1±4.8 2/14 16/16 (100) 0/16 30.7±9.5 2.7±1.3
34.9±7.3 4/22 10/26 (3.8) 16/26 (61.5) 28.1±9.1 2.5±0.9
ns ns .001 .001 ns ns
4/16 (25) 12/16 (75) 16/16 (100) 14/16 (87.5)
20/26 (76.9) 6/26 (23) 20/26 (76.9) 6/26 (23)
.001 .001 .01 .001
16/16 (100) 14/16 (87.5)
8/26 (30.7) 4/26 (15.3)
.001 .01
ICE, intracardiac echocardiography; TEE, transesophageal echocardiography; TC, transcranial. a Incuding β-blockers, triptan, anti-inflammatory drugs.
Procedural time (min) Amplatzer/Premere Pre-discharge complete occlusion a Follow-up complete occlusion b Follow-up number of anti-headache drugs a Follow-up MIDAS
Migraine attack +
Migraine attack −
P
35.4±15.4 7/9 13/16 (81.2) 15/16 (93.7) 0.6±0.5
35.9±14.8 23/19 21/26(80.7) 24/26 (92.3) 1.4±0.6
ns ns ns ns .01
12±3.5
20±2.8
.01
Including β-blockers, triptan, anti-inflammatory drugs. one patient in the Migr+ group had a moderate shunt and two patients in the Migr− group had a small shunt on follow-up. a
b
activated coagulation time around 250 for the duration of the procedure. All patients were managed with aspirin 100 mg/day 1 week before and for 6 months after the procedure. Follow-up was conducted by means of transesophageal echocardiography at 1 month, and if at least a small shunt was detected, at 6 months; transthoracic echocardiography at 1, 6, and 12 months; transcranial Doppler at 1 month; ECG Holter monitoring at 1 month; and combined cardiologic and neurological visit at 1, 6, and 12 months with MIDAS administration. Residual shunt was assessed by contrast transesophageal echocardiography and transcranial Doppler. Data are expressed as mean±S.D. and as percentages. Variables were compared with Student t and Fisher tests and ANOVA. A significant level was defined when Pb .05. All analyses were performed using SPSS 10.0 (SPSS Inc., Chicago, IL). 3. Results Sixteen patients (38%) experienced a migraine attack of mean duration 3.5±2.4 h immediately (b60 min) after closure procedure. These patients more frequently had a severe migraine with aura and a spontaneous shunt on transcranial Doppler. The procedures time, type of device used, and occlusion times did not differ between the two groups of patients (Table 1). There were no intraprocedural or late complications including no supraventricular arrhythmias. After a mean follow-up of 32.2±10.6 months, patients with postprocedural migraine attacks reported complete resolution of aura and a more significant improvement in migraine symptoms demonstrated by decrease of mean MIDAS and mean number of anti-headache medications (Table 2, Fig. 1). 4. Discussion Different speculations have been argued on the causality of PFO and migraine attacks. The main hypothesis is that the shunt could allow microemboli or substances such as serotonin and norepinephrine to bypass filtration by the lungs and to circulate through the brain provoking migraine. This hypothesis, suggested also by recent series of migraine
G. Rigatelli et al. / Cardiovascular Revascularization Medicine 12 (2011) 217–219
219
Acknowledgments The authors have no conflicts of interest to declare regarding any pharmaceutical companies, biomedical device manufacturers, or other corporations whose products or services are related to the subject matter of the article. References
Fig. 1. Histogram representation demonstrating differences in mean MIDAS and mean number of anti-headache medications at the follow-up observed in patients with (Migr+) and without (Migr−) migraine attacks immediately after PFO closure procedure.
improvement after transcatheter closure [5–7], has been mitigated in prevalence studies [8–9]. Recently, a certain degree of LA dysfunction, such as impairment of active or passive emptying or perhaps conduit function, has been suggested to be present in patients with PFO, especially in those with ASA [10], contributing to create the hemodynamic conditions for fibrin deposit or microthrombi formation just inside the left atrium, on the atrial aneurysm surface, or within the tunnel. Cortical spreading depression, the main substrate for migraine as investigated by neurobiologists, has not been yet completely understood, being the microemboli genesis only very recently proposed. In the early 2010, Viola et al. [11] demonstrated that areas of cortical hypoperfusion corresponding to the topography of aura symptoms on infrared spectroscopy resulted from decreased metabolic demand. This hypothesis seems to be against the study of Nozari et al. [3] that demonstrated in an animal model how cortical spreading depression may be induced also by microembolic ischemia. Recently, Caputi et al. [12] suggested that microembolization because of microbubbles injection during transcranial Doppler ultrasound might provoke a decrease in cerebral oxygen saturation, thus triggering cortical spreading depression and thereafter migraine with aura attack. Although with many limitations, including the very small sample of patients and the lack of transcranial Doppler monitoring, our series seem to indirectly confirm in vivo the experimental animal data of micromebolization-driven cortical spreading depression and the recent hypothesis about air microbubble-induced cerebral deoxygenation linking the micromebolic hypothesis with cortical spreading depression.
[1] Garg P, Servoss SJ, Wu JC, Bajwa ZH, Selim MH, Dineen A, Kuntz RE, Cook EF, Mauri L. Lack of association between migraine headache and patent foramen ovale. Results of a case-control study. Circulation 2010;121:1406–12. [2] Rigatelli G, Dell'Avvocata F, Ronco F, Cardaioli P, Giordan M, Braggion G, Aggio S, Chinaglia M, Rigatelli G, Chen JP. Primary transcatheter patent foramen ovale closure is effective in improving migraine in patients with high-risk anatomic and functional characteristics for paradoxical embolism. JACC Cardiovasc Interv 2010;3:282–7. [3] Nozari A, Dilekoz E, Sukhotinsky I, Stein T, Eikermann-Haerter K, Liu C, Wang Y, Frosch MP, Waeber C, Ayata C, Moskowitz MA. Microemboli may link spreading depression, migraine aura, and patent foramen ovale. Ann Neurol 2010;67:221–9. [4] Morandi E, Anzola GP, Casilli F, Onorato E. Silent brain embolism during transcatheter closure of patent foramen ovale: a transcranial Doppler study. Neurol Sci 2006;27:328–31. [5] Anzola GP, Morandi E, Casilli F, Onorato E. Does transcatheter closure of patent foramen ovale really “shut the door?”A prospective study with transcranial Doppler. Stroke 2004;35:2140–4. [6] Vigna C, Marchese N, Inchingolo V, Giannatempo GM, Pacilli MA, Di Viesti P, Impagliatelli M, Natali R, Russo A, Fanelli R, Loperfido F. Improvement of migraine after patent foramen ovale percutaneous closure in patients with subclinical brain lesions. A case-control study. J Am Coll Cardiol Intv 2009;2:107–13. [7] Wahl A, Praz F, Findling O, Nedeltchev K, Schwerzmann M, Tai T, Windecker S, Mattle HP, Meier B. Percutaneous closure of patent foramen ovale for migraine headaches refractory to medical therapy. Cathet Cardiovasc Intervent 2009;74:124–9. [8] Schwedt TJ, Demaerschalk BM, Dodick DW. Patent foramen ovale and migraine: a systematic review. Chephalalgia 2008;28:531–40. [9] Dalla Volta G, Guindani M, Zavarise P, Griffini S, Pezzini A, Padovani A. Prevalence of patent foramen ovale in a large series of patients with migraine with aura, migraine without aura and cluster headache, and relationships with clinical phenotype. J Haedache pain 2005;6:328–30. [10] Rigatelli G, Aggio S, Cardaioli P, Braggion G, Giordan M, Dell'avvocata F, Chinaglia M, Rigatelli G, Roncon L, Chen JP. Left atrial dysfunction in patients with patent foramen ovale and atrial septal aneurysm: an alternative concurrent mechanism for arterial embolism. JACC Cardiovasc Interv 2009;2:655–62. [11] Viola S, Viola P, Litterio P, Buongarzone MP, Fiorelli L. Pathophysiology of migraine attack with prolonged aura revealed by transcranial Doppler and near infrared spetroscopy. Neurol Sci 2010; 31:S165–6. [12] Caputi L, Usai S, Crriero MR, Grazzi L, D’Amico D, Falcone C, Anzola GP, Del Sette M, Parati E, Bussone G. Microembolic air load durino contrast-transcranial Doppler: a trigger for migraine with aura? Haedache 2010;50:1320–2.