Abstract In the last ten years a considerable bulk of evi- dence has accumulated on the relationship between migraine, particularly migraine with aura, and atrial septal defects, particularly patent foramen ovale (PFO). The increased frequency of PFO in migraine with aura, which almost parallels that found in stroke of unknown cause, the fact that in migraine patients PFO tends to be larger than in non-migraine controls and some positive results on migraine severity obtained after PFO closure have spurred speculation on a possible causal relationship. By applying the criteria proposed by Bradford-Hill to establish causal- ity between associated phenomena, we try to demonstrate that PFO is not just a further example of migraine comor- bidity but exerts a causal effect at least in the triggering of aura. Keywords Migraine · Patent foramen ovale · Transcranial Doppler · Causation Foramen ovale is an anatomical structure allowing physi- ologic right-to-left shunt (RLS) during foetal circulation. In over 70% of the general population, it comes to closure after birth. In the remaining 30% of cases, such commu- nication is left “patent”, i.e., “open”, and represents a potential substrate for RLS during adult life [1]. Given its high prevalence in the general population, patent foramen ovale (PFO) cannot be considered a pathology itself. Nevertheless, a consistent body of epidemiological evi- dence has been suggesting a causal relationship between PFO and those strokes where an evident cause cannot be found, particularly in the young population [2]. In this subset of patients, a PFO is found in more than half of cases. Stroke clearly is a pathological condition and sec- ondary prevention has to be pursued by every means, par- ticularly in younger patients. So, there is little doubt that a PFO has to be searched for in young patients with a stroke of unknown origin [2]. But what about the PFO–migraine relation? Indeed, a PFO is as prevalent in migraineurs with aura as in stroke patients of less than 55 years [3, 4]. However, both migraine and PFO are com- mon conditions and it is possible their association is no more than chance. Moreover, migraine is not commonly considered a threat as much as stroke is. Therefore, there is no current indication to screen migraineurs for a PFO. But if a causal link between migraine and PFO was demonstrated, would it change our way of looking at migraine? In 1965, Sir Austin Bradford-Hill proposed, in a semi- nal paper [5], his well known criteria on the concept of causation: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence and analogy. Such criteria can be advocated to demonstrate that the PFO–migraine connection goes far beyond the simple association by chance of two common conditions. The patent foramen ovale–migraine connection: a new perspective to demonstrate a causal relation Gian Paolo Anzola • Sara Mazzucco © Springer-Verlag 2008 Financial Disclosures: G.P. Anzola received honoraria for consulta- tion and lecturing from St Jude Medical and from Cardia. S. Mazzucco: none. G.P. Anzola () Service of Neurology S. Orsola Hospital FBF Via Vittorio Emanuele II 27 25100 Brescia, Italy e-mail: gpanzola@fatebenefratelli.it S. Mazzucco Department of Neurology University of Verona Verona, Italy Neurol Sci (2008) 29:S15–S18 DOI 10.1007/s10072-008-0878-5 MIGRAINE-ISCHAEMIC STROKE COMORBIDITY IN YOUNG AGE