Transcranial Doppler Ultrasound: Incremental Diagnostic Role in Cryptogenic Stroke Part II.

Transcranial Doppler (TCD) ultrasonography is a noninvasive ultrasound study, which has been extensively applied in both outpatient and inpatient settings. Its main use in current clinical practice is the research for "Paradoxical Embolism," due to migration of thromboembolic material from systemic venous circulation to the left cardiac chambers and arterial circulation through cardiopulmonary shunts such as patent foramen ovale which represents an important cause of cryptogenic stroke, especially in patients under 55 years of age. In this review, we shall describe the incremental diagnostic role in cryptogenic stroke for this imaging modality. TCD not only can be used to detect right-left cardiopulmonary shunts but it also allows to classify the grade of severity of such shunts using the so-called "Microembolic Signals grading score."

INTRODUCTION

The American Academy of Neurology Therapeutics and Technology Assessment Subcommittee states that Transcranial Doppler (TCD) ultrasonography main clinical indications include ischemic cerebrovascular disease, neurointensive care, and periprocedural assistance during carotid and intracranial vascular interventions.[1]

Our discussion in this second part of our review of TCD clinical applications will focus on its role in the research of the so-named “Paradoxical Embolism” through patent foramen ovale (PFO) which represents an important cause of cryptogenic stroke, especially in patients under 55 years of age.[23]

Moreover, TCD also allows to classify the grade of severity of such shunts using the so-called “Microembolic Signals (MES) grading score.”[45]

PARADOXICAL EMBOLISM: PATENT FORAMEN OVALE AND CRYPTOGENIC STROKE

PFO can be considered a remnant of the fetal circulation. During fetal life, foramen ovale allows the transit of blood flow from the right cardiac chambers to the left cardiac chambers determinating a so-called right-left shunt (RLS). Hence, PFO represents a persistence of such fetal communication between the right and left atrium; it appears as an oblique, slit-shaped defect which functionally looks like a tunnel. The cause of its incomplete closure after birth is not known, but it appears to be associated with multigenic inheritance. In some patients, such interatrial communication can be associated with a thinner and redundant interatrial septum which shows mono- or bi-directional movement during the cardiac cycle (atrial septal aneurysm [ASA]).

The frequency of such a lesion in the general adult population varies between 25% and 30%. the prevalence and size of the defect are similar for males and females and decreases progressively with age.[567]

In detail, PFO is diagnosed in 34% of patients at 30s old, into 25% between 30s and 80s old, and finally into 20% over 80s old and this trend is inversely related to the dimensions of the defect.

In fact, the average dimensions increase progressively from 3.4 mm in the first decade of life to 5.8 mm after the ninth decade.[8]

The explanation of this phenomenon is probably that larger defects tend to persist while those of smaller dimensions go toward spontaneous closure with time.[8]

Most individuals with a PFO remain completely asymptomatic lifelong, but in some cases, it has been associated with several clinical manifestations due to transient RLS, such as decompression sickness in scuba divers or platypnea-orthodeoxia syndrome.[910]

The most important potential manifestation related to PFO is represented by cryptogenic stroke due to paradoxical embolism, and migraine and vascular headache although the causal relationship between PFO and migraine is not yet completely understood and is still the object of research.

The clinical significance and the pathogenic role of PFO in patients with cryptogenic stroke are still a matter of debate. about 40% of ischemic strokes that occur in people under the age of 55 are cryptogenic.[311] Cryptogenic stroke is defined as an ischemic stroke which takes place without any clearly identifiable etiology from cardioembolic source or large vessel atheromasia. This kind of cerebrovascular accident has an embolic origin and typically shows a distribution pattern that is not consistent with small vessel involvement.

The prevalence of PFO is higher among subjects hit by a cryptogenic stroke. in a prospective study (the PFO-ASA study) were included 581 patients with a cryptogenic cerebrovascular ischemic accident of <55 years of age (mean 42), 37% had PFO, and 9% had PFO associated with ASA.[11]

In the PFO in cryptogenic stroke, the study was found an analogous prevalence of PFO (39%) in 250 patients with a mean age of 59 years.[12] Moreover, patients with cryptogenic stroke showed a significantly higher rate of large PFOs compared to patients with a stroke of known cause (20% vs. 9.7%).[12]

The pathophysiological mechanism underlying stroke of cryptogenic origin in PFO carriers is probably represented by a paradoxical embolism in the setting of a transient RLS.

In detail, when the right atrial pressure is higher than the pressure in the left atrium, a transient RLS possibly occurs through a PFO that becomes a pathway for the passage of emboli from venous to arterial circulation (paradoxical emboli).

Thus, a transitory occurrence of interatrial right-to-left pressure gradient can cause paradoxical shunting and can commonly be elicitated using specifical maneuvers in patients with no baseline RLS (including both subjects without net shunt at all or with a left-to-right shunt). In particular, a short-lived right-to-left gradient can be present in normal individuals during early ventricular systole and after the release of maneuvers which raise intra-abdominal pressure (such as Valsalva maneuver [VM], defecation, cough, and lifting or pushing heavy objects).

In a community-based study of 148 subjects, carriers of a PFO, 57% showed resting RLS and 92% showed elicitable RLS after VM or cough.[13]

In summary, PFO represents a possible cardioembolic source responsible of cryptogenic stroke and a risk factor for neurological events, especially in subjects under 55 years of age.

ROLE OF THE TRANSCRANIAL DOPPLER METHODOLOGY AND DIAGNOSTIC ACCURACY

The diagnosis of PFO in order to achieve a clinical significance should provide both anatomic description and a physiologic assessment of a potential RLS. The first is usually obtained by transesophageal echocardiography (TEE) or by intracardiac echocardiography, while the physiologic assessment of an RLS is usually obtained using contrast transthoracic echocardiography (c-TTE) or TCD ultrasonography. A definite ultrasonographic diagnosis of temporary RLS requires the use of contrast enhancement. In clinical practice, the most frequently used ultrasonographic contrast medium is represented by the agitated saline solution. In fact, the different density present at the interface separating gas-containing microbubbles from surrounding tissue modifies the “acoustic impedance” of such interface. Higher the impedance higher the echogenicity at the same level. Moreover, gas microbubbles work very effectively as contrast medium since they are 100,000 times less dense than blood.[14]

Traditionally, TEE supported by agitated saline contrast-enhancement (c-TEE) has always been considered the gold standard technique both for a demonstration of a RLS through a PFO and for morphological description of the interatrial septum. It should be noted that microbubbles with a diameter smaller than 9 μm are not able to pass through the pulmonary capillary network, so the finding of any micro-bubble after intravenous contrast administration is diagnostic for RLS.

Contrast enhancement for the research of paradoxical interatrial shunting has been applied also to c-TTE [Figure 1], with a reported sensitivity and specificity similar to that of c-TEE.[1516] this was also due to the introduction of harmonic imaging, which improved the image quality of TTE.[17]

Figure 1

Transthoracic echocardiography showing high-grade right (a) to left (b) shunt with evident microbubbles in the left heart after intravenous contrast administration

However, a more extensive analysis of the different diagnostic methods for the identification of PFO and their relative diagnostic accuracy has been already published in a previous issue of this journal, so from now on our discussion will focus exclusively on TCD.[18]

Contrast enhanced TCD (c-TCD) has gained a growing role for the diagnosis of transient RLS, for it allows to recognize the passage of intravenously injected microbubbles directly in cerebral circulation. As stated above about TTE, also with c-TCD the finding of a single micro-bubble in cerebral arterial circulation, usually in middle cerebral artery (MCA), is considered diagnostic of RLS.

c-TCD represents a low cost, widely available, noninvasive imaging technique of easy interpretation, which also permits to semiquantitatively estimate the severity of venous-arterial shunt.[19]

In order to highlight RLS a contrast medium, usually agitated saline is injected into a peripheral vein, usually right antecubital vein in three boluses, at the same time the Doppler signal is recorded while the patient performs a VM.

In detail, the contrast agent is obtained by combining 9 mL of normal saline solution with 1 mL of air and then it is usually shaken up about 10 times through a system constituted by two 10 mL syringes linked by a 3-way stopcock. The agitated solution is then administrated into the antecubital vein by an 18-gauge.

The patient is then invited to perform a forced expiration against the closed glottis for a minimum of 10 s (VM).

When a RLS is present, the air microbubbles constituting ultrasonographic contrast medium will directly pass from venous to systemic circulation and will be visualized in cerebral arterial vessels as so-called MES.

In addition, it is possible to evaluate the entity and functional relevance of a paradoxical RLS through the MES grading score, based on the number of Doppler signals provoked by microbubbles that reach MCA [Figure 2 and Table 1]. Moreover, the entity of RLS is directly associated with the risk of stroke.[567891011121314151617181920]

Figure 2

Right to left shunt with microembolic signals. (a) Low-grade shunt; (b) moderate-grade shunt; (c) high-grade shunt (shower); (d) curtain effect

Table 1

Grade of transient right-to-left shunting based on microembolic signal grading score

Grade transient shunt	Microembolic signals
No shunt	0
Low-grade shunt	1-10
Moderate-grade shunt	11-25
High-grade shunt	>25 (shower) or uncountable (curtain effect)

It should be noted that when the number of microbubbles passing through a RLS is very low, they may not be able to reach the MCA giving a false negative result of absent RLS. However, on the other hand, the clinical relevance of such small entity of shunt is uncertain. A very large amount of microbubbles reaching MCA is responsible on the Doppler spectrum of the so-called “Curtain effect” characterized by impossibility to distinguish on Doppler spectrum a single MES.

In the work of Serena et al. “Curtain Effect” is characteristically found in patient hit by cryptogenic stroke, so the identification of this Doppler aspect in a subject could denote a higher risk of cerebrovascular events, thus providing useful information for the clinician in order to differentiate “innocent” from “harmful” shunts.[21]

Nowadays, there is no consensus about a definite time interval from contrast administration until the recording of the first MES on MCA Doppler spectrum which can be considered specific for PFO diagnosis. In a recent work, 26 patients with stroke (16 with PFO vs. 10 without PFO, diagnosed by c-TEE) after a positive cTCD test were evaluated for three parameters: The amount of MES, latency time (LT) before the first MES, and the duration time of MES, looking for any difference between PFO carriers and no-PFO. The presence of more than 9 MES with an LT of less than 9 s (so-called rule of nine) could be considered a marker for PFO diagnosis by c-TEE providing a specificity and positive predictive value of 100%.[22]

PFO detection can be increased by asking patient to cough or by releasing a sustained VM since, in practical terms, in the release phase of these strain maneuvers a RLS can be elicitated when the right atrial chamber is filled with blood from the abdominal cavity, while the left atrial chamber is still volume depleted before passage of increased blood return through pulmonary circulation, VM should be always performed for the research of RLS, it is started 5 s after agitated saline administration (because it represents the average time interval required for the injected solution to reach the right atrium from the cubital vein).[23] The effectiveness of VM strength can be assessed through peak flow velocity of the MCA Doppler spectrum.[16]

Mojadidi et al. have published an extensive bivariate meta-analysis of 27 prospective studies with a total of 1968 patients comparing PFO detection with TCD to the c-TEE as the gold standard.[24] Starting from these data, they could determinate sensitivity in PFO identification for TCD (index test) and TEE (considered reference test) according to type of contrast medium, different provocative maneuvers, different quantitative microembolic cutoffs, different time of onset of provocation maneuver, and insonation of a single or both middle cerebral arteries. No difference in sensitivity and specificity was found between each contrast medium (agitated saline, Echovist, and gelatin-based solutions, P > 0.05). No significant difference between cough or Valsalva as provocative maneuver was evident (P > 0.7). When a cutoff number of 10 microbubbles instead of 1 was chosen to define TCD positivity study, specificity showed a significant improvement from 89% to 100% (P = 0.04); nevertheless, this approach did not result in a substantial change in sensitivity (from 98% to 97%, P = 0.29).

Duration of Valsalva strain, more or less than 5 s, did not show a significant influence sensitivity or specificity of TCD (P > 0.50). Finally, a not significant trend toward an improvement of specificity when a single MCA was insonated instead of both (95% specificity vs. 89%, respectively, P = 0.09), while no significant difference was seen regarding sensitivity (P = 0.15).

In conclusion, Mojadidi et al. found an overall sensitivity of 97% and a specificity of 93% for detection of RLS with c-TCD compared with c-TEE.[24] Increasing the number of microbubbles needed for a positive TCD from 1 to 10 resulted in a predictable significant improvement in specificity. TCD showed a good diagnostic performance with an overall likelihood ratio + of 13.51 and likelihood ratio − of 0.04 and a disease probability of 93-94% after a positive test and of 4% after a negative test.[23]

Hence, in the context of a cryptogenic stroke, the clinician is called to choose the best diagnostic technique between c-TCD, c-TEE, or c-TTE in order to detect a RLS.

TEE provides a detailed morphological description of interatrial septum and is able to identify anatomic characteristics of a PFO. In particular, a diameter >4 mm or the presence of an associated ASA are the risk factors for stroke recurrence. These c-TEE high-risk findings may be useful in guiding management toward an interventional strategy instead antithrombotic treatment in patient hit by a cryptogenic stroke.[25] On the other hand, recently published data suggest that TEE should not be considered the true gold standard imaging technique for the detection of RLS. In fact, in the case of really small shunts (of 1–3 bubbles), c-TCD may show a better sensitivity because such a small number of microbubbles may be missed on a single tomographic echocardiographic view.[26] Moreover, TEE is a high cost, semi-invasive technique characterized by poor patient's compliance; it is not always available, and contrast administration may be inconclusive or be followed by falsely negative results, mainly due to inability of the patient to carry out an effective VM.[162627282930]

Zito et al. directly compared c-TCD, TEE, and TTE accuracy for PFO diagnosis in a group of patients affected by cryptogenic stroke or migraine. They found a better sensitivity for TEE over TTE and a very high concordance of TCD with TEE, being positive in 97% of subjects that showed PFO at TEE examination, with reported 94% sensitivity, 96% specificity, 89% negative predictive value, and 98% positive predictive value.[31]

On the other hand, a lower sensitivity of c-TEE compared with c-TTE and c-TCD was reported by the work of González-Alujas et al. (86% sensitivity for TEE, vs. 100% for TTE and 97% for TCD, P < 0.001), while here was no significant difference in sensitivity between TTE and TCD.[25] These results may have a clinical impact because they confirm that TEE is not the most accurate diagnostic technique as it was commonly considered in the past years.

Higher sensitivity shown by c-TCD is also due to its positive results also in the presence of extracardiac shunts, such as pulmonary arteriovenous malformations. It should be reminded that TCD is not able to show the exact anatomic position of the RLS although LT from contrast injection in antecubital vein to the appearance of MES in the setting of an intracardiac shunt is about 11 s, while in the presence of a pulmonary arteriovenous, malformation is reported to be about 14 s.[32] Interestingly as reported in the work of González-Alujas et al. c-TTE performed simultaneously with TCD was able to confirm the presence of an arteriovenous pulmonary malformation in a positive TCD, showing the entrance of microbubbles in the left atrium from a pulmonary vein.[25]

Therapeutic options

Following the acute ischemic event, long-term secondary prevention of stroke recurrence is recommended after Cryptogenic Stroke either by medical therapy or percutaneous closure of PFO. Medical therapy consists of antiplatelet therapy with aspirin or oral anticoagulation therapy with a Vitamin K Antagonist. To date, there is no clear evidence from RCTs favoring any class of antithrombotic agents over the other, but according to the latest American Heart Association/American Stroke Association (AHA/ASA) guidelines for secondary prevention of stroke,[33] oral anticoagulation is indicated for patients with an ischemic stroke or transient ischemic attack (TIA) and both a PFO and a venous source of embolism (Class I, level of evidence A). For what concerns the choice between medical therapy versus percutaneous closure of PFO three randomized clinical trials (CLOSURE I, PC Trial and RESPECT) failed to show the superiority of device closure in the secondary stroke prevention.[343536]

Thus, the latest AHA/ASA guidelines state that percutaneous closure might be considered over antithrombotic only in the setting of PFO and deep venous thrombosis (DVT) depending on the risk of recurrent DVT (Class II b, level of evidence C). Whereas, for patients with a cryptogenic stroke or TIA and a PFO without evidence for DVT, AHA/ASA guidelines do not support a benefit for PFO closure (Class III, level of evidence A). For a detailed discussion of the different management options for PFO carriers after cryptogenic stroke, we refer the reader to the extensive review by Falanga et al. published in a previous issue of this journal.[37]

Recommendations

American Academy of Neurology confers a class II indication for both c-TCD and TEE for interatrial shunt detection.[32] On the other hand, Italian stroke guidelines (SPREAD) consider TCD a better screening tool than TEE in the population of patient with suspect shunt through a foramen ovale.[38]

In a consensus document published on behalf of Italian Society of Interventional Cardiology by Pristipino et al. in 2010, TCD was proposed as the first-choice screening tool for RLS in the setting of a cryptogenic stroke in subjects 55 years old or younger, while in patients older than 55 TEE was recommended as the first-line test.[39]

CONCLUSION

Our suggestion in the setting of a cryptogenic ischemic stroke is to use c-TCD as a first line screening tool, due to its diagnostic accuracy, similar to that of c-TEE,[31] and its better tolerability. TEE may be considered as a complementary imaging technique for a more detailed anatomic definition of the interatrial septum, especially when PFO closure instead of oral antithrombotic therapy is contemplated [Figure 3].

Figure 3

Diagnostic algorithm including transcranial Doppler in the setting of cryptogenic ischemic stroke

Finally, TCD is also useful for follow-up of patients after PFO closure in order to identify those with residual shunting, due to its repeatability and its sensitivity for the detection of small entity residual shunts.[4041]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.