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(Stroke. 1996;27:2251-2255.)
© 1996 American Heart Association, Inc.

Articles

Patent Foramen Ovale and Transcranial Doppler

Comparison of Different Procedures

Elietta Maria Zanette, MD; Giovanni Mancini, MD; Stefano De Castro, MD; Marco Solaro, MD; Domenico Cartoni, MD Flavia Chiarotti, BSc

the Departments of Neurological Sciences (E.M.Z., G.M., M.S.) and Clinical Medicine (S. De C., D.C.), University "La Sapienza," and the Department of Organ and System Pathophysiology, Istituto Superiore di Sanita (F.C.), Rome, Italy.

Correspondence to Prof Elietta M. Zanette, Department of Neurological Sciences, University "La Sapienza," Viale dell'Universita, 30, 00185 Rome, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The capability of transcranial Doppler sonography (TCD) to detect a patent foramen ovale (PFO) has been established. However, which provocative maneuver and what timing of contrast injection are most effective to induce a right-to-left shunt has not yet been determined.

Methods We selected 38 cerebrovascular patients (21 men, 17 women) with positive contrast study for PFO on transesophageal echocardiography. Patients underwent a TCD with bilateral monitoring of the middle cerebral arteries (MCAs) and injection of a contrast solution. The injection was repeated (1) during normal breathing (basal conditions); (2) before Valsalva maneuver (VM); (3) during VM; (4) immediately after VM; and (5) during cough. The latency time and the total number of microbubbles for each side were recorded.

Results TCD found positive results for PFO in 30 patients. Twenty were positive even during basal conditions. The number of positive cases varied according to the timing of the VM in relation to the contrast injection: 28, 25, and 27 cases were positive when the injection was performed before, during, and after VM, respectively, while 26 were positive during cough. There were significant differences in the number of microbubbles in the MCAs between the procedures (P<.001, ANOVA): the highest number was detected in the injection before VM and the lowest number during basal conditions (P<.001, Wilcoxon's test with Bonferroni's correction). The latency time was significantly shorter when the injection followed VM.

Conclusions The injection performed before VM appeared to be the most effective TCD procedure in determining the transit of microbubbles through a PFO and subsequently in the MCAs.

Key Words: echocardiography, transesophageal • foramen ovale, patent • transcranial Doppler • ultrasonics

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In recent years several studies have emphasized the role played by the paradoxical cerebral embolism through either a PFO or an intrapulmonary arteriovenous shunt in the pathogenesis of cryptogenic cerebral infarcts. These studies, conducted primarily on young patients, demonstrated a significantly higher prevalence of PFO in patients with unexplained stroke than in the healthy population, either as an isolated abnormality or associated with an aneurysm of the interatrial septum.^{1 2 3 4}

TEE, although a semi-invasive procedure, has been confirmed as the method of choice for the detection of a right-to-left shunt, particularly during provocative conditions such as the VM or cough.^{5 6 7}

Recent studies have proposed TCD, which is able to detect air or contrast microbubbles passing through the intracranial arteries, as an alternative noninvasive technique for the detection of an intracardiac right-to-left shunt.^{8 9 10 11 12 13 14} However, the most effective provocative maneuver to raise the right atrial pressure to induce the right-to-left shunt has not yet been established, and there is no agreement on the most effective timing between the VM and the injection of ultrasound contrast medium. The latency time of microbubble detection in the MCA from the injection is also still a matter of debate (Table 1).

View this table: [in this window] [in a new window]   Table 1. Review of TCD Studies for the Diagnosis of PFO

The aim of our study was (1) to compare the efficacy of different maneuvers and of different timing of the contrast injection in determining the transit of microbubbles in the middle cerebral arteries and (2) to compare the latency times of the various provocative procedures to assess the optimum observation period.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
For the purposes of our study, we selected 38 consecutive patients who had suffered a recent cerebrovascular episode of unexplained origin and who had a positive contrast study for PFO at TEE (21 men, 17 women; mean age, 52.5±16.3 years; range, 26 to 76 years). All patients had been submitted to the following instrumental protocol: unenhanced cerebral CT scan (in the absence of ischemic lesions at CT, an MRI was performed), color Doppler of extracranial arteries, TCD, TTE, and TEE.

A contrast TCD examination was performed within 24 hours of the TEE. All patients had given their informed consent to this study.

Echocardiographic Protocol
All patients underwent transesophageal studies with a 5-MHz biplane or 5/3.5-MHz multiplane transducers, shortly after a transthoracic examination. The TEE was performed with the patient in the left lateral decubitus position, after a fast of more than 4 hours, with the use of topical hypopharyngeal anesthesia with 10% lidocaine spray. After a complete anatomic and functional examination to search for cardiac sources of emboli, the probe was positioned with the scanning plane at the level of the fossa ovalis. Color-flow mapping before the contrast study was performed in an attempt to detect left-to-right and/or right-to-left shunts. The contrast study, during both TTE and TEE, was performed with a mixture of saline solution (9 mL) and air (1 mL), agitated between two 10-mL syringes, connected by a three-way stopcock. When ready, the solution was immediately injected in 2 to 3 seconds into an antecubital vein to obtain a bolus of air microbubbles.⁸ This procedure was performed during both normal breathing and VM. The patient was asked to start the VM at the time of injection and to release the strain after the complete opacification of the right atrium by contrast solution. All echocardiographic examinations were recorded on a super-VHS videotape and independently reviewed by two cardiologists. The contrast study was considered positive if three or more microbubbles appeared in the left atrium within three cardiac cycles after complete opacification of the right atrium.⁷ The maximum number of microbubbles shunted in the left atrium at rest or during VM was counted off-line in a single freeze-frame. Contrast studies during the VM were repeated if a first injection yielded a negative or a questionable result. Echocardiographic measurements of the functional characteristics of PFO were blindly reviewed by two cardiologists (S. De C. and D.C.). In a previous report by these cardiologists, no significant interobserver variability was found in the TEE measurements, with a high agreement in grading PFO shunting both at rest (Spearman's r=.97) and during VM (Spearman's r=.96).¹⁵

Contrast TCD Protocol
Both MCAs were simultaneously monitored by means of an elastic headband, supporting a pair of 2-MHz probes. A special software for emboli count was used to record and count high-intensity transient signals from each MCA.

The preparation of the contrast solution was the same as that of the contrast echocardiography. The appearance of microbubbles in the MCAs was automatically recorded by the equipment together with the time, side, and intensity (in decibels) of each event (Figure). The test was considered positive when at least one microbubble was detected within 22 seconds of the contrast injection.¹³

View larger version (97K): [in this window] [in a new window]   Figure 1. Off-line display of TCD-recorded high-intensity transient signals, representing microbubbles passing through the MCA of both sides (dark gray line=left MCA; light gray line=right MCA), in a PFO-positive patient at the end of the VM. The time and intensity increase (in decibels) of each high-intensity transient signal are automatically recorded under the Doppler spectrum.

After the injection at rest, during normal breathing (BC), the test was repeated in association with the following provocative maneuvers, with a 2-minute interval between each procedure: (1) before a 10-second VM (IBVM); (2) during a 10-second VM, starting the injection at the 5th second (IDVM); (3) immediately after a VM (IAVM); and (4) during repeated series of 3 to 5 rapid and successive coughs, prolonged for at least 20 seconds.¹⁶

For each procedure, we considered both the time interval (in seconds) and the number of cardiac cycles between the start of the contrast injection and the appearance of the first microbubble in each side (latency time) and the total number of microbubbles for each side during an observation period of 20 seconds after the first microbubble was detected.

All the contrast studies with provocative maneuvers were repeated at least twice when a result was negative or questionable.

All the patients were able to perform an effective VM, preliminarily evaluated, without contrast injection, by a mean flow velocity reduction of at least 25% in phase II.¹⁷

To assess the reproducibility of the microbubble count in the MCAs and of the latency time recording, we repeated the contrast injection during BC in 10 TCD-positive patients.

Statistical Analysis
Data were analyzed by Friedman's nonparametric ANOVA because of the nonnormal distribution of data and the presence of cutoff values for latency times. The ² partitioning of the overall Friedman's ² was used to assess the main effects of maneuvers and side and the effect of their interaction. In view of the nonsignificant effect of side and of maneuverxside, data collected on the two sides were collapsed; the mean for the number of microbubbles and the minimum for the latency time were used. Wilcoxon's nonparametric test for paired data with Bonferroni's correction was used for multiple comparisons. The reproducibility of the microbubble count and of latency time recording were analyzed by means of Wilcoxon's test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The 38 patients included in this study showed PFO-positive results at TEE: 15 both during BC and with VM, and 23 only with VM. TCD found positive results in 30 of these 38 patients, 20 of whom were positive during BC and 10 only during provocative maneuvers. The remaining 8 TCD false-negative cases showed less than 20 microbubbles passing through a PFO at TEE, only during provocative maneuvers.

The timing of the VM in relation to the contrast injection determined a different number of positive cases: the IBVM detected 28 of 30 positive patients, the IDVM 25 of 30, and the IAVM 27 of 30. Coughing was effective in 26 cases. All the patients were able to cooperate adequately when performing the various provocative maneuvers. Two patients were found to be positive for IAVM and cough but negative for IBVM and IDVM, while 3 other patients were positive for only IBVM and negative for the other procedures. These 5 patients with discrepancies between the procedures all showed fewer than 10 microbubbles in the MCAs, and 3 of them were only unilaterally positive at TCD.

In the 20 patients who were positive during BC, the mean number of microbubbles detected in the MCAs was 5.8±12.6 for the right side and 5.7±9.3 for the left side (13 patients showed fewer than 10 microbubbles in each MCA). The mean latency time between the injection and the appearance of the first microbubble was 9.7±4.1 seconds (Table 2).

View this table: [in this window] [in a new window]   Table 2. TCD Results in the Diagnosis of PFO

In 10 of these 20 patients who were positive for PFO in BC, the repetition of the contrast solution injection did not reveal any significant difference between the two tests, either in the number of microbubbles in transit through the MCAs (P=.37, Wilcoxon) or in the latency time (P=.55, Wilcoxon).

The different timing between the VM and the injection determined differences in the number of microbubbles in transit through the MCAs (as shown in Table 2). The Friedman ANOVA showed that these differences between procedures were statistically significant (²=86.23, df=4, P<.001), whereas no significant differences were found between the two sides, either globally or separately within each procedure. Wilcoxon's test for paired data showed that the number of microbubbles detected during BC was significantly lower than that obtained with each of the provocative maneuvers (BC versus IBVM, P<.001; BC versus IDVM, P<.005; BC versus IAVM and BC versus cough, P<.05). Differences between provocative maneuvers were also found to be significant, insofar as IBVM determined a significantly higher number of microbubbles than any of the other procedures (IBVM versus IAVM and IBVM versus cough, P<.001; IBVM versus IDVM, P<.05).

The latency time between contrast injection and detection of the first microbubble in the MCAs varied significantly between the different procedures (Friedman ²=20.97, df=4, P<.001 for latency time expressed in seconds; Friedman ²=9.72, P<.05 for number of cardiac cycles) but did not differ between the two sides, either globally or within each procedure. Wilcoxon's test for paired data showed that the latency time for BC was significantly higher than that measured in IAVM (P<.01 for seconds, P<.05 for cardiac cycles), whereas the other provocative maneuvers gave intermediate values. For detailed data, see Table 2.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data confirm the capability of TCD to detect a right-to-left circulatory shunt, although provocative maneuvers seem to be indispensable to improve TCD efficacy (10 of 30 patients were positive only during provocative maneuvers).

Notwithstanding TCD accuracy in the diagnosis of PFO, which ranges from 68% to 100% in the literature^{8 9 10 11 12 13 14} (TCD sensitivity was 78.9% in our study), 8 of our TEE-positive patients showed negative results at TCD despite all provocative maneuvers. These 8 patients did not show a severe degree of right-to-left shunt: all of them were positive only at VM, during which they showed the transit of fewer than 20 microbubbles in the left atrium. The fact that we sometimes detected microbubbles only unilaterally in some of the tests suggests that the simultaneous exploration of both MCAs might have increased TCD sensitivity in our study. The reproducibility of TCD measurements of both microbubbles and latency times in a subgroup of 10 patients was good, with no difference found between repeated measurements.

A possible explanation for the relatively high number of patients (20) with positive results for PFO even under BC may be that although the mean left atrial pressure is normally higher than the right, a transient inversion of this pressure gradient may occur during normal breathing, permitting a right-to-left shunt if a good interatrial functional communication is present.¹⁸ This hypothesis is supported by the observation that in normal individuals the interatrial septum bows toward the left atrium in midsystole during mechanical expiration.¹⁹

However, which provocative maneuver is preferable (VM or cough) has not yet been sufficiently investigated. Stoddard et al¹⁶ reported that the cough test is superior to VM in diagnosing a PFO during contrast TEE, although this observation has not been confirmed for TCD. Most of the authors used VM as a provocative test, while both VM and cough were used in only one study, which did not mention whether any difference between these provocative maneuvers had been found.¹² Our results showed that cough detected a slightly lower number of positive patients than VM (26/30).

The timing of the contrast solution injection in relation to VM is also still a matter of debate. Most of the authors injected the contrast solution (usually agitated saline) during VM^{8 9 10 11} ; other authors did it immediately before VM,^{12 13} and only one at the end of VM¹⁴ ; in none of these studies were these procedures compared. We made such a comparison in our study and found that the highest number of PFO-positive patients, confirmed by TEE, were detected when the contrast solution was injected before VM (IBVM=28/30), followed by IAVM (27/30) and IDVM (25/30).

The higher number of positive patients for IBVM can be explained by the fact that this procedure determines the highest number of microbubbles in transit through the MCAs. The difference in the number of microbubbles between the various procedures was confirmed by the statistical analysis. The discrepancy in 5 cases between the different procedures may be due to the ubiquitous and random distribution in the systemic circulation of a small number of shunting microbubbles.¹²

We believe it is reasonable to assume that the higher the number of contrast microbubbles shunting through a PFO, the higher the probability of correctly diagnosing the interatrial communication. From a theoretical point of view, these results can be explained by the hemodynamic variations that take place during VM, as reported by several studies on the physiology of VM.^{20 21 22} At the beginning of VM, the rise in intrathoracic pressure results in (1) a relevant increase in the right atrium and pulmonary artery pressure, with a reduction in the flow and velocity of the pulmonary circulation,^{21 22} and (2) a reduced venous return toward the heart.²²

When the Valsalva strain is released, the sharp increase in the venous return to the heart, while the pulmonary district is still deplete, leads to a further rise in right atrial pressure, which can briefly exceed left atrial pressure, thus permitting a right-to-left shunt if a PFO is present, as reported by Langholz et al²³ in a combined study with TEE and cardiac catheterization.

The injection performed immediately before VM should allow the microbubbles to reach the right atrium as a bolus just when the pulmonary circulation slows down. This means the microbubbles have more time to reach and accumulate in the right atrium during VM, so that they can then cross the PFO at the release of the Valsalva strain. If the contrast injection is performed during VM (IDVM), fewer microbubbles can accumulate in the right atrium because of the shorter duration of the slower pulmonary circulation. If the injection is given after VM (IAVM), the number of microbubbles should, in theory, be even smaller in the right atrium, given that they mix with the increased incoming venous flow and fewer microbubbles would therefore cross the PFO. The injection during coughing should be similar to the post-VM injection condition, given that cough represents a sudden, transient increase in the right atrial pressure while microbubbles are reaching the right heart without being concentrated by the VM.

The slowing effect of VM on the circulation and its subsequent acceleration at the release of VM are evident if we consider the latency time for each procedure. The longest mean latency time was obtained in BC, followed by IBVM, cough, and IDVM, while the shortest latency time was measured with IAVM (significantly different from BC), which is influenced only by the post-VM acceleration of the circulation.

Although there were no substantial differences in the number of PFO-positive patients between the various procedures, the contrast injection before VM determined the passage of a significantly higher number of microbubbles through the MCAs. Consequently, this TCD procedure seems to be preferable in assessing a right-to-left shunt in PFO-positive patients. Coughing, on the other hand, may be an alternative provocative maneuver that can be easier for patients who cannot perform the VM correctly.

	Selected Abbreviations and Acronyms

 

BC = basal conditions IAVM = injection after Valsalva maneuver IBVM = injection before Valsalva maneuver IDVM = injection during Valsalva maneuver MCA = middle cerebral artery PFO = patent foramen ovale TCD = transcranial Doppler sonography TEE = transesophageal echocardiography TTE = transthoracic echocardiography VM = Valsalva maneuver

	Acknowledgments

 
This study was supported by the National Research Council, grant CNR93.00465.40. The authors acknowledge Drs Cinzia Roberti and Antonio Salerno for their substantial contribution to the realization of this study and Lewis Baker for English revision of the manuscript.

Received June 11, 1996; revision received July 26, 1996; accepted August 25, 1996.

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