How to use contrast enhanced transcranial doppler toward detection and follow-up of patent foramen ovale

The foramen ovale is not an innocent remnant of fetal circulation. During fetal life, the foramen ovale allows blood flow across the fetal atrial septum, thus supplying a necessary right-to-left shunt. A foramen ovale which has persisted into adulthood is referred to as a persistant foramen ovale (PFO) and is an oblique, slit-shaped defect resembling a tunnel. Autopsy-derived prevalence of probe-patent PFO is approximately 27% overall, and its prevalence decreases with age (1). The reasons for this incomplete closure are not known, but they are likely related to multifactorial inheritance (2). PFO pathology, pathophysiology, and clinical impact should become better understood as multiple approaches to percutaneous closure become available for clinical application.

PFO is a cardiac lesion that causes inter-atrial right-to-left blood shunting during the periods of the cardiac cycle and right atrial pressure to exceed left atrial pressure. It can be implicated in the pathogenesis of several serious clinical syndromes, including paradoxical systemic embolism, such as ischemic stroke (3), myocardium infarction (4), neurological decompression illness in divers (5) and complications of pulmonary embolism (6). Recent evidence further implicates PFO as a possible explanation for the presence of migraine headaches through mechanisms that are not yet fully understood. The presence of a causal relationship between PFO and migraine however needs yet to be confirmed (7)

I - Current Diagnostic Techniques

Contrast echocardiography

Several techniques allow the dection of PFOs (8), however diagnosis is carried out using contrast-enhanced techniques. Indeed, contrast echocardiography, first reported on in 1968 by Gramiak (9), has become an indispensable tool for cardiovascular imaging and the most common contrast agent used for the detection of shunts is agitated saline solution.

The contrast effect of microbubbles relies on the difference in density at the interface between gas-contained microbubbles and surrounding tissue, the result of which is referred to as “acoustic impedance”. The higher the acoustic impedance, the more echogenic the interface. Gas-contained microbubbles are excellent contrast agents as gas is 100,000 times less dense than blood (10). Several echocardiographic techniques, including transthoracic, transesophageal, and/or intracardiac echocardiography, may be used. Transesophageal echocardiography (TEE) with bubble tests is currently considered the gold standard for the diagnosis of right-to-left shunt due to PFO, as well as for morphological characterisation of the inter-atrial septum. Since contrast microbubbles of a diameter = 9µm do not pass the pulmonary capillary circulation, any appearance of intravenously injected microbubbles in the left side of the heart is considered positive for a right-to-left shunt. TEE shows a high correlation with necropsy studies in these cases (11). Nevertheless, TEE has limitations, of which high cost, semi-invasivity combined with patients’ potential low tolerability. TEE is also less widely available. Additionally, contrast injections for TEE detection may lead to inconclusive or false-negative results (12). Various studies have compared contrast enhanced transthoracic echocardiography (c-TTE) with c-TEE and have reported close sensitivity and specificity values (13,14). Furthermore, attention has been given to the extent of shunt as assessed in the cerebral vessels by contrast enhanced transcranial Doppler (c-TCD).

Contrast enhanced transcranial Doppler (c-TCD)

C-TCD is a low cost, easy-to-perform, non-invasive method, the results of which are easy to interpret. TCD allows for a semiquantitative estimation of venous-to-arterial circulation shunts which is backed up by a standardised protocol (15). Nevertheless, the procedure requires for the insonation of one middle cerebral artery at the least. A contrast agent is prepared by mixing in 9 ml of isotonic saline solution to 1 ml of air. The agent is then injected into a cubital vein. The procedure is repeated once. The air-containing echo contrast agent, in the presence of  right-to-left shunt, will bypass pulmonary circulation and induces microembolic signals in the basal cerebral arteries. The monitored Doppler spectra are then stored for offline analysis (e.g., videotape). Proper reviewal of time of occurrence and number of microbubbles is carried out in order to assess the size and functional relevance of right-to-left shunt. A four-level categorisation according to the number of microbubbles (MB) detected in the middle cerebral artery (MCA) is to be applied:

A standard minimal amount of microbubbles which would be suggestive of a clinically relevant right-to-left shunt, however, has yet to be established. This amount probably varies according to interindividual differences in hemodynamics that are currently not fully understood. 'Curtain' refers to a shower of microbubbles, which is identified as such when a single bubble cannot be identified.

From the paper of Serena et al, it appears that the so-called "curtain" pattern is exclusively encountered in cryptogenic stroke patients, and would  providing indication regarding the ability to distinguish "innocent" from "suspected" (ie, potentially harmful) shunts (16).

Additionaly, patent foramen ovale detection can be increased by asking patient to cough. PFO detection can also be more easily detected by releasing a sustained Valsalva manoeuvre (VM) since this procedure will open the foramen when the right atrium fills with blood from the abdomen, while the left atrium is volume depleted prior to blood passing through pulmonary circulation (17). Actually, this manoeuvre is now considered necessary when performing any type of echocardiography. Of note, VM can be applied more comfortably and more reliably during Doppler examination than during TEE.

Furthermore, TCD requires no sedation, rendering patients more cooperative and producing a better strain. VM should be started, upon the examiner’s request, only 5 seconds following injection - that is the mean time required for the contrast solution to progress from the cubital vein into the cardiac chambers: it is not correct to start later or after this time. VM strength can be controlled by peak flow velocity of the Doppler curve (14). A correct VM is useful not only to detect “better” right-to-left shunt. It also can offer important information that will allow differentiating between cardiac and extracardiac shunt. An extracardiac shunt allows the arrival of microbubbles in the MCA both in basal condition and after VM, since it is not influenced by pressure variation.
Best “timing” from contrast injection until identification of the first MB in the MCA has also been offered but this topic remains controversial and there is no consensus regarding this criterion in the literature. It has been reported that in diagnosing PFO, contrast-enhanced TCD has good accuracy compared with c-TEE, reaching a sensitivity of 70-100% and specificity higher than 95% (18-20). In the evaluation of 100 consecutive patients with stabilised ischemic stroke/TIA, cTCD appeared to be more sensitive than cTEE. The latter resulted positive under normal breathing, mostly in cases of significant  right-to-left shunt at cTCD (21). However, no definitive criteria exist to correlate the results obtained from cTCD with diagnoses of PFO obtained by cTEE. In a recently published study, twenty-six stroke patients (16 with PFO vs 10 without PFO) who had previously submitted to cTEE, were evaluated for three markers based on a positive cTCD test. The number of microembolic signs (MES), the latency time (LT) to the first MES and the duration time (DT) of MES were evaluated to look for a difference between the PFO and no-PFO group. It has been demonstrated that the rule of nine (> 9 MES and LT < 9 s) for cTCD can be considered a marker for PFO diagnosis by cTEE, with a specificity and positive predictive value of 100% (22).

The Italian stroke guidelines (SPREAD) recommend (level of evidence D) TCD as a good substitutive method for screening rather than TEE in patients with a suspicious PFO (23). In a regional consensus document, Pristipino et al recommended first-line use of TCD for PFO assessment in patients = 55 years. The use TCD is also considered a good alternative to TEE for patients > 55 years in those centres with high experience in this field of interest (24).
Also of note, TCD appears ideal to follow-up on the closure process following percutaneous procedures and for early identification of those patients who will be left with a significant shunt (25). Indeed, TCD is easily repeatable and sensitive enough to detect minor residual shunts as well (26).

II - Prognosis

Many anatomo-pathologic studies have shown clear and ample differences in PFO morphology. This wide variability regards both size and the association with embryonic variants in the right atrium wall (ie: Tebesian or Eustachian valves and atrial septal aneurysm). In a recently published study evaluating 117 patients, 25 with previous acute cerebrovascular event and 92 with migraine with aura, we demonstrated that not all PFOs have the same prognostic value (7). Our study suggests that the evaluation of two anatomical characteristics (size and presence of embryonic recesses) may allow to better define PFOs.
Indeed, it shows that a “large” foramina as assessed by c-TCD and the evidence of embryonic recesses as assessed by TTE were frequently detected in stroke patients with PFO. These features were however not as common in patients with migraine (large foramina (10%) and embryonic recesses (13%). It is also interesting to note that for an embolus to reach the brain from a peripheral vein, a number of conditions may be relevant, such as 1) the orientation of the caval ostium in the right atrium and 2) the anatomy of supra-aortic vessels. Therefore it may be useless to measure the degree of shunt across the atrial chambers, while the estimate may be carried out usefully in the target organ - the one that needs protected (27).

Conclusion:

C-TCD for evaluation of right-to-left shunt volume, combined to c-TEE to observe anatomic details, could become the gold standard for patent foramen ovale detection in the near future. Furthermore, c-TCD has also been proven useful in the screening phase of and follow-up phase. Lastly, its routine use may also help stratify patients according to their risk profile.