05). Four of six patients with CHVS and migraine (67%) had RLS due to PFO, the rest 2 subjects had normal c-TCD. The underlying mechanism by which some patients develop hyperventilation syndrome is unknown. It often represents a simple manifestation of anxiety, rarely endocrine and respiratory diseases (i.e. hypoparathyroidism,

asthma and pulmonary embolism) or central nervous system disorders (i.e. brainstem lesions). In many patients the cause of CHVS remains, however, unclear [4]. The pathogenetic role of RLS is unknown DNA Damage inhibitor and as far as we know the link between RLS and CHVS has not been reported so far. Patent foramen ovale represents a main cause of cardiac RLS. According to different studies PFO is a common and generally benign finding present on autopsy in approximately 17–29% of population [5]. Direct PFO visualization by TEE is considered the golden standard for PFO diagnosis but contrast TCD of the MCA has similar and high sensitivity (70–100%) [6]. Data from population-based studies showed that prevalence of PFO in the general population is ranging from 11% to 25% by TEE. PFO has been linked with paradoxical embolization of thrombi and other microparticles or vasoactive chemicals leading to cryptogenic stroke and also broad spectrum of neurological diseases (migraine or migraine with aura, transient global amnesia, decompression sickness in sport divers)

[7] and [8]. Anzola et al. reported in TCD Natural Product Library cost study that RLS was present in 48% of individuals with migraine with aura, compared with 20% of healthy controls and 23% of patients with migraine without aura [9]. The present study demonstrated higher prevalence of RLS in CHVS group (64%) than in CG (12%). In over half of all studied patients RLS had been related to PFO, but we also found that AVM was the cause of RLS in 2 patients with CHVS. The prevalence of PFO in all studied CHVS patients (40%) was significantly higher than in CG and expected in the general Fludarabine datasheet population (≈25%). The prevalence of extracardiac shunting via pulmonary AVM in the general

population is not well studied but its presence is believed to be uncommon. In an autopsy study, only three cases of pulmonary AVM were detected in 15,000 consecutive autopsies [10]. High frequency of PFO and AVM in CHVS suggests a possible link with RLS regardless of its cause, however, causal relationship between these conditions is unknown. As postulated in previous reports, RLS may allow venous-circulating, vasoactive chemicals to bypass the pulmonary filter and reach the cerebral circulation to induce a migraine and possibly hyperventilation attack [11]. This concept is, however, not supported by the observation that inducing a drop in arterial pCO2 through forced voluntary hyperventilation may provoke CHVS in some but not all patients [12]. Obviously CHVS is related to a variety of mechanisms, which may not be associated with hyperventilation alone.