By Claudine HAMEL-DESNOS, Caen, France Is ultrasound foam sclerotherapy contraindicated in patients with migraine? By Claudine HAMEL-DESNOS, Caen, France

Should we treat varicose veins using UGFS* in patients with migraine? Meier B et al. Eur Heart J 2012;33:705-713 Foam Patent foramen ovale MIGRAINE There could be an association between migraine with aura and right-to-left shunts. These shunts usually occur through a large persistent foramen ovale (PFO). Because PFOs do not have hemodynamic effects and cardiac examination is normal, their presence is often not suspected. PFOs are suspected of being involved in neurologic troubles after foam sclerotherapy. Since there is an association between migraine and PFOs, the question of the relevance of the treatment of varicose veins by foam sclerotherapy is raised. *Abbreviations: PFO, patent foramen ovale; UGFS, ultrasound-guided foam sclerotherapy Neurological disturbances?

Kurth K, Tzourio C, and Bousser MG. Editorial « The results of NOMAS can be seen as the strongest evidence against an association between migraine or migraine with aura and PFO » Kurth K, Tzourio C, and Bousser MG. Editorial

How does foam progress? In vitro, 2 ml of 3% sodium tetradecyl sulphate are deactivated by only 1 ml of blood in a short period of time (15 s) The sclerosing agent does not reach the brain circulation Only “bubbles” remain Watkins M.R. Deactivation of sodium tetradecyl sulphate injection by blood proteins. Eur J Vasc Endovasc Surg. 2011;41:521-525.

Neurological disturbances Visual (1.4%) Migraine (4.2%) Transient ischemic attacks Stroke Mostly case reports Good recovery Jia X, Mowatt G, Burr JM, Cassar K, Cook J, Fraser C. Systematic review of foam sclerotherapy for varicose veins. Br J Surg. 2007;94(8):925-936.

What’s a migraine?

The International Headache Society migraine without aura: diagnostic criteria At least 5 attacks fulfilling criteria B-D Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) At least two of the following characteristics: Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg walking or climbing stairs) At least one of the following symptoms: Nausea and/or vomiting Photophobia and phonophobia Not attributed to another disorder Migraine is characterized by episodes of head pain that is often throbbing and frequently unilateral and may be severe. In migraine without aura, attacks are usually associated with nausea, vomiting, or sensitivity to light, sound, or movement. When untreated, these attacks typically last 4 to 72 hours. A combination of features is required for the diagnosis, but not all features are present in every attack or in every patient. The International Classification of Headache Disorders. Cephalalgia. 2004;24:S9-S160.

The International Headache Society migraine with aura : diagnostic criteria At least 2 attacks fulfilling criteria B-D Aura consisting of at least 1 of the following, but no motor weakness: fully reversible visual symptoms including positive features (eg, flickering lights, spots, or lines) and/or negative features (i.e, loss of vision); fully reversible sensory symptoms including positive features (i.e, pins and needles) and/or negative features (i.e, numbness); fully reversible dysphasic speech disturbance At least 2 of the following : homonymous visual symptoms and/or unilateral sensory symptoms at least 1 aura symptom develops gradually over ≥5 min and/or diferent aura symptoms occur in succession over ≥5 min each symptom lasts >5 and <60 minutes Headache fulfilling criteria B-D for migraine without aura begins during the aura or follows the aura within 60 minutes Not attributed to another disorder The International Classification of Headache Disorders. Cephalalgia. 2004;24:S9-S160.

Pathophysiology of migraine associated with Ultrasound-Guided Foam Sclerotherapy (UGFS)

Pathophysiology of migraine with aura (AM) Extensive cortical depression (propagated): Depolarization wave from the occipital cortex to the forehead (may be limited): occipital = visual troubles parietal = paresthesias frontal = speech troubles Endothelin-1 (powerful vasoconstrictor) = triggers AM The pathophysiology of visual disturbances is not established. Some clues, based on clinical analysis, indicate that they could correspond to migraine with aura (AM) and that they should not be confused with cerebrovascular accidents.

Visual disturbances= AM Foam →release of endothelin-1 Endothelin and foam Visual disturbances= AM Foam →release of endothelin-1 Varicose vein endothelium is damaged by foam and releases endothelin-1, which reaches the cerebral cortex via the PFO, triggering an aura. Visual disturbances are not transient ischemic attacks The objective of the study by Gillet et al was to validate the hypothesis that visual disturbances (VDs) occurring after foam sclerotherapy correspond to AM and are not transient cerebrovascular events. The results of clinical assessments showed that VDs presented clinical features of MA with headache in 50% of patients and without headache in the remaining 50%. Disturbances were transient. It is hypothesized that cytokines, such as endothelin released by the action of foam sclerosants acting on the endothelium, reach the cerebral arterial circulation through right-to-left cardiac or intrapulmonary shunts. Endothelin has been shown to initiate one of the pathways leading to migraine with aura. It is suggested that foam bubbles passing through a PFO may trigger endothelin release, which quickly reaches the cerebral cortex, leading to cortical-spreading depression, a depolarizing waveform occurring in the cerebral cortex and shown to be associated with migraine with aura, including visual, speech, and motor disturbances. Gillet et al. Phlebology. 2010;25:261-266. Frullini et al. Phlebology. 2011;26:203-208.

According to expert recommendations: MIGRAINE WITH OR WITHOUT AURA IS NOT A CONTRAINDICATION FOR UGFS

Breu FX, Guggenbichler S, Wollmann JC. 2nd European consensus meeting on foam sclerotherapy 2006. Tegernsee, Germany: Vasa 2008;S/713-729. Berridge D, Lees T, Earnshaw JJ. The VEnous Intervention (VEIN) project. Phlebology. 2009;24 (suppl 1):1-2.

LITERATURE REVIEW

No personal history of migraine described 1023 articles analyzed 41 articles retained reporting the presence of stroke, transient ischemic attacks (TIA) or visual or speech disturbances, migraine, cephalalgia (63% foam and 37% liquid) 12 cases of stroke 9 TIAs 29 cases of migraine (0.27%) No personal history of migraine described The search yielded 1023 articles, of which 41 studies were found to meet the inclusion criteria. A total of 10 819 patients undergoing sclerotherapy were reviewed. There were 12 case reports of cerebrovascular accidents (CVA) with confirmatory brain imaging and nine reports of TIA. There were 97 (0.90%) reports of neurological events overall, including TIA, visual and speech disturbances, and 29 reported cases of migraine (0.27%). Symptoms occurred at times ranging from minutes to several days following sclerotherapy. Eleven patients with TIA or CVA were found to have a right-to-left cardiac shunt, usually a patent foramen ovale. Conclusions: Neurological side-effects following sclerotherapy are a rare occurrence; however, CVA associated with the use of sclerotherapy is clearly documented. The pathologic mechanisms resulting in CVA are likely to be different to those leading to migraine and visual disturbances; however, care should be exercised in patient selection, particularly in those with known cardiac defects. (J Vasc Surg. 2012;55:243-251.) Sarvananthan T, Sheperd AC, Willenberg T, Davis AH. Neurological complications of sclerotherapy for varicose veins. J Vasc Surg . 2012;55:243-251.

Techniques used to create foam varied widely, but the Tessari technique appeared to be the most frequently used . Concentrations of sclerosant used frequently depended on the type of vein treated and the sclerosant utilized, but varied from 0.25% to 5%. The volumes of sclerosant used also varied significantly, and frequently depended on the size and nature of the veins treated; however, in the majority of studies, 20 mL of foam per patient was used. In five studies, more than 20 mL was frequently used; however, no association between the volumes of foam used and the reporting of neurological side-effects was identified. Air was the most frequently used gas; however, CO2 was used in three studies, and O2 was used in one study. The most frequently used ratio of gas-to-sclerosant mixture was 1:4; however, ratios ranged from 1:2 to 1:8. No association between the gas used or the ratio of gas and sclerosant and the number or type of neurological side effects was observed

There are insufficient data to determine the role of: The technique used to generate foam, The gas used, The volumes injected, The type of veins treated, The different types of measures taken to avoid complications

« The pathologic mechanisms resulting in CVA are likely to be different to those leading to migraine and visual disturbances »  « Precautions should be exercised particularly in patients with a known PFO and perhaps those known to suffer from migraine » According to the authors, “It is likely that the pathologic mechanism resulting in CVA is different than that occurring in patients reporting transient visual, speech, and motor disturbances and symptoms of migraine, and it is likely that the majority of the neurological side effects seen are unrelated to true CVAs, which are very rare. The majority of symptoms occurred within minutes to hours after the injection of sclerosant; however, there are cases of symptoms occurring up to 5 days afterward.” Sarvananthan T, Sheperd AC, Willenberg T, Davis AH. Neurological complications of sclerotherapy for varicose veins. J Vasc Surg 2012; 55:243-251.

PRACTICAL RECOMMENDATIONS A symptomatic PFO is a contraindication for UGFS A personal history of migraine is not a contraindication for UGFS. However, it must be reported along with the presence or absence of aura Should migraine with/without aura occur after UGFS: Treat the patient with his/her usual antimigraine treatment (or with NSAI) In case of VDs, do not let the patient drive unaccompanied until the cessation of disturbances The risk/benefit ratio should be reviewed before continuing sclerotherapy treatment (preventative antimigraine treatment?) In case of stroke: assessment (Doppler examination of the supra-aortic vessels, consultation with a neurologist, consultation with a cardiologist, MRI); pharmacovigilance report.

CONCLUSION Neurological disturbances after UGFS should not be overlooked; however, they are usually AM variants Strokes are rare side-effects and are not the result of the same underlying mechanisms; no link with a personal history of migraine has been established; stroke diagnosis must be confirmed Currently, a history of migraine is not a contraindication for UGFS though it may contribute to the development of AM (or AM variant) Further studies are needed