The foramen ovale is a natural interatrial channel, delimited inferiorly by the thinner flap-like septum primum and superiorly by the thicker septum secundum (Jeanrenaud & Kappenberger 1991, Movsowitz et al. 1992). During fetal life this anatomic configuration permits a functional RLS of placental oxygenated blood. As long as the pressure in the right atrium exceeds that in the left atrium, blood flows from right to left. At birth, with the development of the pulmonary circulation, the pressures are reversed and the increased pressure in the left atrium forces the septum primum to close the foramen ovale. Fusion of this membrane with the septum secundum usually follows by means of fragile fibrous adhesions during the first years of childhood. When fusion does not occur, an oblique tunnel-like opening persists between the septa, known as PFO. This differs from an atrial septum defect (ASD), which is not a valve-like structure but rather a true defect in the septum (Movsowitz et al. 1992). According to an autopsy study of 965 normal hearts, the size of the PFO varies between 1 and 19 mm, with a mean diameter of 4.9 mm (Hagen et al. 1984).

PFO usually allows RLS, but it may also allow left-to-right shunting, despite its valve-like morphology, especially when associated with left-sided cardiac lesions (Wu et al. 1993), although only rarely without such a pathology (Schneider et al. 1996). RLS through a PFO may occur under several sets of physiological conditions, such as sporting effort, blowing the nose, decompressing the ears, straining at stool, sexual intercourse, coughing and even trumpet playing (Gautier et al. 1991, Evers et al. 1998). It may occur also during positive end expiratory pressure ventilation and diving. Interestingly, RLS across a large PFO may occur during heavy exercise, producing clinically important arterial desaturation in some healthy adults (Wilmhurst et al. 1994). The VM causes a transient rise in right atrial pressure above the left atrial pressure, reversing the interatrial pressure gradient, with resultant RLS across the PFO during the straining phase (Movsowitz et al. 1992). More frequently, RLS occurs immediately on the release of the VM. It has been postulated that, on the release of the VM, systemic venous blood rushes into the right atrium, reversing the interatrial pressure gradient or exacerbating it if it already exists in the straining phase (Lynch et al. 1984). Furthermore, it has been shown that transient reversal of the interatrial pressure gradient may occur during each cardiac cycle (Langholz et al. 1991). This probably explains the echocardiographic findings of alternate bulging of an atrial septal aneurysm into the left and right atria with each cardiac cycle, and the fact that RLS has been shown to exist in the presence of PFO without any provocative manoeuvre or pulmonary hypertension (Lechat et al. 1988, Webster et al. 1984).

Pathological conditions that predispose a subject to RLS in the presence of a PFO include those in which there is a reversal of the interatrial pressure gradient or in which abnormal right atrial flow dynamics exist. Right atrial pressure may exceed left atrial pressure under conditions that raise the intrathoracic pressure, right ventricular failure (right ventricular infarction, cardiomyopathy), pathological conditions of the pulmonary artery causing right ventricular hypertension (pulmonic stenosis, pulmonary embolism, chronic obstructive lung disease, high altitude pulmonary oedema), pulmonary valve stenosis, diseases of the tricuspid valves and during cardiac tamponade (Movsowitz et al. 1992). RLS with a normal right atrial pressure may occur if an abnormal right atrial blood flow exists (cases of right atrial mass, presence of Chiari`s network or after pneumonectomy) or with multifactorial causes, as in platypnoea-orthodeoxia syndrome (Langholz et al. 1991, Movsowitz et al. 1992, Schneider et al. 1995).

Diagnostic methods
PFO cannot be identified by history, physical examination or chest x-ray. One study has suggested that “crochetage”, a (notch) pattern in the inferior limb leads, could be an electrocardiographic sign associated with its presence (Ay et al. 1998), but others have not been able to reproduce these findings (Tembl et al. 1998). Routine right and left cardiac catheterisations do not usually allow a definite diagnosis (Movsowitz et al. 1992).

Echocardiography
TEE is still regarded by many as the gold standard for the detection of PFO. As a PFO is not a discontinuity in the septum but a valve-like structure, intravenous administration of echo contrast material is usually required to detect RLS. Commonly used contrast agents include air-saline microbubbles, or galactose or oxypolygelatin suspensions. As stated earlier, shunting is present under resting conditions in some persons. A provocation test is usually necessary to reverse the pressure gradient across the interatrial septum, however, and this can be either coughing or a Valsalva Maneuver (VM) . The colour Doppler technique has been used. Contrast and colour Doppler TEE techniques for the detection of PFO have been validated in an autopsy study (Schneider et al. 1996).

Transcranial Doppler
With the huge advances in TCD technology in recent years many practioners are realizing that TCD is now the becoming the new gold standard in PFO detection. The contrast transcranial Doppler (TCD) ultrasound technique is based on the detection of microbubble-induced embolic signals within the intracranial arteries, usually the middle cerebral artery. Intravenous contrast medium injections are performed at rest and after VM in a similar manner to that adopted in TEE. The major advantage of using TCD is that the patient remains fully conscious and is therefore able to cooperate with instructions.
Using TCD both MCAs are monitored at a depth of 50 to 60 mms and initially recorded for at least 10 minutes to detect any spontaneous emboli. Two 10ml syringes are prepared, each with 9 ml saline along with 1 ml air. A suspension of microbubbles is produced by back and forth exchanges of the saline-blood mixture via a 3-way stopcock with another syringe containing 1 ml of air. Two injections of the bubble contrast are made, the first with normal respiration and a second with the Valsalva Maneuver (VM). It may be helpful to monitor the subclavian vein with a separate 4 MHz Doppler to observe the arrival of microbubbles

The number of microemboli detected during each phase of the study is then compared. Typically results may look like shown below
Rest 30, Strain 30, Result = Normal
Rest 30, Strain 300, Result = Possible PFO
Rest 300, Strain 300, Result = Possible ASD
Diseases linked to patent foramen ovale
Ischaemic stroke
Several case-control studies have compared the frequency of PFO in patients with ischaemic stroke with that in controls (for reviews, see Overell et al. 2000, Chant & McCollum 2001).

In their recent meta-analysis, Overell et al. (2000) found eight positive and seven neutral or negative results of such comparisons, further analysis of which revealed that when the ages of the patients were considered, a significant difference in mean age emerged between the positive (44.8 years) and neutral or negative series (61.1 years). In nine studies which included young stroke patients aged 55 years or less (Webster et al. 1988, Lechat et al. 1988, Chen et al. 1991, de Belder et al. 1992, Cabanes et al. 1993, Jones et al. 1994, Job et al. 1994, Zahn et al. 1995, Del Sette et al. 1998), PFO was present in 40.3% of the subjects overall as compared with 17.8% of the controls, giving a significant odds ratio (OR) of 3.1 (Overell et al. 2000). Only three studies have been performed on older patients, aged above 55 years of age (de Belder et al. 1992, Jones et al. 1994, Zahn et al. 1995), and these gave an overall prevalence of PFO in the patients (16.3%) that did not differ from the control figure (13.6%) (Overell et al. 2000).

There are nine well performed case-control studies that compare the prevalence of PFO in cryptogenic stroke to that in stroke of known causes among young patients aged 55 years or less (Lechat et al. 1988, Webster et al. 1988, Jeanrenaud et al. 1990, Di Tullio et al. 1992, Cabanes et al. 1993, Ranoux et al. 1993, Job et al. 1994, Jones et al. 1994, Yeung et al. 1996). Here the meta-analysis showed a significantly higher prevalence of PFO in cryptogenic stroke (55.7%) as compared with stroke of known aetiology (17.1%), giving a significant OR of 6.0 (Overell et al. 2000). In older patients, the three studies that exist (Di Tullio et al. 1992, Jones et al. 1994, Yeung et al. 1996) point to a non-significant difference in PFO between cryptogenic stroke (27.1%) and stroke of known origin (14.0%) (Overell et al. 2000).

There have been five comparisons of the prevalence of PFO among young cryptogenic stroke patients (aged 55 years or less) and non-stroke controls (Lechat et al. 1988, Webster et al. 1988, Cabanes et al. 1993, Job et al. 1994, Jones et al. 1994), the overall prevalence of PFO being significantly higher in the cryptogenic stroke cases (54.6% vs. 19.9%), with an OR of 5.0 (Overell et al. 2000). In contrast to this, the two available comparisons of the same kind among persons aged over 55 years (Vella et al. 1991, Jones et al. 1994) show no difference in the prevalence of PFO between the cryptogenic stroke cases (11.6%) and controls (13.4%).
In conclusion, the current evidence clearly shows a significant association of PFO with ischaemic stroke in general, and especially with cryptogenic stroke, among patients younger than 55 years. No firm conclusions can be made among older patients because of the limited data. There are several reports (Homma et al. 1994, Job et al. 1994, Steiner et al. 1998) demonstrating a more significant association of a large PFO than a small one with stroke, and it has been shown that stroke patients with a large PFO show more brain imaging features of embolic infarcts than those with a small PFO (Steiner et al. 1998). These results suggest a “dose-response” relationship and support a causality link between PFO and ischemic stroke (Overell et al. 2000). No prospective study has been made of the PFO-stroke association, however.

Migraine
There have been several suggestions of an association between PFO and migraine with aura (Del Sette et al. 1998, Anzola et al. 1999, Wilmhurst & Nightingale 2001). Interestingly, it has been suggested that there may be a subgroup of patients who have severe migraine associated with major RLS in whom closure of the PFO may improve or abolish the migraine (Wilmhurst et al. 2000).

Obstructive sleep apnoea
There is an increased prevalence of PFO in patients with obstructive sleep apnoea. RLS across the PFO can contribute to significant systemic arterial hypoxaemia after a VM in up to a third of these patients (Shanoudy et al. 1998).

Pulmonary embolism
Kasper et al. (1992) observed that the presence of PFO was associated with significant arterial hypoxaemia and a high incidence of cerebral and peripheral ischaemic events in patients with haemodynamically significant pulmonary embolism. In a further study, the group found patients with a PFO and major pulmonary embolism to have a particularly high risk of death or arterial thromboembolic complications (Konstantinides et al. 1998).

Chronic obstructive pulmonary disease
Patients with severe chronic obstructive pulmonary disease have an increased prevalence of PFO relative to controls, and their PFO has more pronounced systemic arterial oxygen desaturation associated with it than is observed without PFO (Soliman et al. 1999).

Gas embolism
PFO may act as a pathway for the arterialisation of venous gas bubbles. RLS through a PFO is thought to be associated with neurological, cutaneous and cardiorespiratory decompression sickness as a result of paradoxical gas embolism (Wilmhurst et al. 1989). Furthermore, the presence of a large RLS has been shown to be associated with multiple brain lesions in magnetic resonance imaging (MRI) in the case of sport divers (Knauth et al. 1997). On the other hand, it has recently been found that diving itself is associated with the presence of ischaemic lesions rather than diving in the presence of a PFO (Schwerzermann et al. 2001), although divers with a PFO have an increased risk of decompression sickness events and suffer more ischaemic lesions in the brain than do divers without a PFO. PFO may also be associated with hypobaric decompression sickness in high altitude aviators and astronauts (Kerut et al. 2001). Venous air embolism, a complication of surgery above the level of the heart in which non-collapsible veins are present at the operative site, may serve as an embolic source of paradoxical embolism through the medium of a PFO. Although rare, this may be a serious complication of posterior fossa surgery (Movsowitz et al. 1992).

Fat embolism
Paradoxical fat embolism can occur during invasive intramedullary orthopaedic procedures. In a survey of 111 consecutive operations on 110 patients for fractures of the femur and tibia or hemiarthroplasty of the hip, Christie et al. (1995) observed paradoxical embolisation in four cases. All of them involved major embolic phenomena, leading to pulmonary hypertension before the embolic material was observed to be passing through a PFO.

Platypnoea-orthodeoxia syndrome
This rare syndrome refers to dyspnoea induced by assuming an upright position and relieved by returning to a recumbent position (platypnoea), or accentuated arterial hypoxaemia experienced in a standing position that is improved by lying down (orthodeoxia). It has been shown to be associated with PFO and RLS through the lesion despite normal pressure in the right side of the heart. It has been claimed that surgical closure of the PFO leads to clinical improvement. (Robin & McCauley 1997).

Transient global amnesia
One study has suggested that paradoxical embolism in patients with a PFO may play a role in causing transient global amnesia (Kl?tzsch et al. 1996).