ORIGINAL ARTICLE

Transcranial Doppler Screening for Patent Foramen Ovale

Closure in Cryptogenic Strokes in Young: A Single Center
Experience from South India
Deepti Bal1, Atif Iqbal Ahmed Shaikh2, Murali Rayani3, Sanjith Aaron4*, Viji Samuel Thompson5, John Jose6, Jesu Krupa7, Rohit Ninan Benjamin8,
Joanne Lydia Rajkumar9, Appaswamy Thirumal Prabhakar10
Received: 06 May 2022; Accepted: 07 July 2022

A b s t r ac t patients with ESUS compared to the general

population and is known to contribute to
Background: Cryptogenic strokes are common in young adults. Patent foramen ovale (PFO) is
an important cause of cryptogenic ischemic strokes. Transcranial Doppler (TCD) with bubble recurrent strokes. 6 In patients with ESUS,
contrast is a noninvasive bedside tool in screening for PFO and other right to left shunt (R-L shunt). PFO remains an important cause. PFO can
Percutaneous PFO closure in selected patients with a high risk for paradoxical emboli is beneficial. cause ischemic strokes due to multiple
Data on PFO in young cryptogenic strokes from India are limited. mechanisms. The most common mechanism
Aims: To determine the utility of screening for R-L shunt using TCD in young patients with described is paradoxical embolism.6 Rarely,
cryptogenic strokes and to identify clinical predictors of an R-L shunt. in situ thrombus formation can be seen.6 Also,
Materials and methods: This was a hospital-based prospective study conducted between January patients with PFO have more susceptibility to
2013 and December 2019 in a tertiary hospital in South India. All consecutive patients with ischemic arrhythmias.7
stroke and ages between 18 and 45 years were included. TCD with bubble contrast study was The RoPE score combines some of the
performed on all patients. Those who were TCD bubble contrast study positive and had features of clinical and imaging details to help identify
an embolic stroke of undetermined source (ESUS) underwent transesophageal echocardiography cryptogenic strokes more likely to have a
(TEE) to confirm a PFO and to look for its high-risk features. Selected ESUS patients with PFO and pathogenic PFO.8 In younger patients without
associated high-risk features as identified on TEE underwent percutaneous PFO device closure. vascular risk factors and cortically placed
All patients were followed up in the stroke and cardiology clinics.
infarcts if a PFO is identified, it is likely that the
Results: During the study period, 6,197 patients with ischemic strokes were screened for eligibility PFO is the cause of the stroke. Whereas, if a PFO
of which 304 (4.9%) were between the age of 18 and 45 years. Of these, 300 patients with ischemic
is picked up in an older patient with a subcortical
stroke in young underwent the TCD bubble contrast study. R-L shunt was found in 121 (40.3%)
patients. Based on an extensive etiological evaluation, 72 patients were identified to have an cryptogenic stroke who has vascular risk factors,
ESUS and underwent TEE for confirming PFO. Of these, 65 patients had PFO, four were negative, it is likely that the PFO is an incidental finding
and three were found to have extracardiac shunts. Based on clinical findings, imaging features, and not the cause of the stroke.8 There are
and high-risk features on TEE, 29 patients underwent PFO closure. Activity at the time of stroke few features of a PFO and certain associated
onset equivalent to a Valsalva maneuver (p ≤ 0.01), isolated cortical infarction (p = 0.027), and features which can make it a high risk for an
posterior circulation involvement (p = 0.0135) were significantly associated with the presence of ischemic stroke. The combination of atrial septal
an R-L shunt. The patients who had a higher modified anatomical-functional risk of paradoxical aneurysm (ASA) and PFO has the strongest
embolism (AF-RoPE) score, a high-grade shunt on the TCD bubble contrast study had a longer association with a higher risk of cryptogenic
length of the tunnel and had the presence of an interatrial septal aneurysm (p = 0.012) were strokes.9,10 Other features which increase the
referred for PFO device closure.
possibility of the PFO to be the cause of the
Conclusions: R-L shunt is common in cryptogenic ischemic strokes in young. TCD with bubble stroke are large-size PFO (≥2 mm in height),
contrast study is a noninvasive and feasible bedside tool to detect them. Applying the ESUS criteria
long-tunnel PFO (≥10 mm in length), ASA,
in these cryptogenic strokes with a positive TCD bubble contrast study can be then used for
selecting patients for more invasive tests like TEE. High-risk PFOs picked up with TEE can be then hypermobile interatrial septum large R-L shunt
considered for PFO closure for secondary stroke prevention. The history of Valsalva maneuver-like during Valsalva maneuvers, low-angle PFO
activity (such as lifting heavy weights or straining) at the time of stroke onset can be a clinical (≤10° of PFO angle from inferior vena cava), and
predictor for the presence of an R-L shunt. In addition to isolated cortical infarction, the presence the presence of a prominent Eustachian valve
of posterior circulation infarct in ESUS can predict the presence of an R-L shunt. or Chiari’s network.11,12 The AF-RoPE score has
incorporated these high-risk features of PFO
Journal of the Association of Physicians of India (2022): 10.5005/japi-11001-0112
into the existing RoPE score trying to identify

Introduction be due to paroxysmal atrial fibrillation 1,3

Assistant Professor; 2,8Associate Professor;
(AF), atheroembolism, cancer-associated, 4,10

I
Professor, Department of Neurosciences;
schemic stroke continues to remain as
and paradoxical embolism. 5 The term 5,6
Professor; 7Assistant Professor, Department
one of the major causes of disability of Cardiology; 9Senior Resident, Department
paradoxical embolism is used to describe
and death in the Indian setting.1 Despite of Geriatrics, Christian Medical College, Vellore,
an embolus of venous origin entering the
extensive vascular, cardiac, and serological Tamil Nadu, India; *Corresponding Author
systemic circulation through a PFO, atrial
evaluations, the etiology remains unknown How to cite this article: Bal D, Shaikh
septal defect, ventricular septal defect,
in 20–40% of patients.2 These are classified AIA, Rayani M, et al. Transcranial Doppler
or extracardiac communication such as Screening for Patent Foramen Ovale Closure in
as cryptogenic strokes. Cryptogenic strokes
pulmonary arteriovenous malformation. Cryptogenic Strokes in Young: A Single Center
are especially important in young adults. 3
PFO is present in about 25% of the adult Experience from South India. J Assoc Physicians
Cryptogenic strokes can be further classified
population.6 PFO is seen more commonly in India 2022;70(10):52–56.
as non-embolic and ESUS. 4,5 ESUS can

© The Author(s). 2022 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/
by-nc/4.0/). Please refer to the link for more details.
 Transcranial Doppler Screening for Patent Foramen Ovale Closure in Cryptogenic Strokes

patients at high risk for recurrence who may by a trained stroke neurologist. The TCD head in the artery supplying the ischemic region,
benefit with PFO closure.13 Recent studies frame was fixed with a 2MHz Probe (Nicolet® major cardioembolic sources (permanent
have shown the importance of identifying SONARA®, TCD System). The middle cerebral or paroxysmal AF, sustained atrial flutter,
high-risk PFOs and the benefits of PFO closure artery (MCA) was identified through the intracardiac thrombus, prosthetic cardiac
for secondary stroke prevention.14 These temporal window. Continuous monitoring valve, atrial myxoma or other cardiac tumors,
observations are supported by findings of was done to look for any microembolic signals mitral stenosis, myocardial infarction within
the CLOSE and DEFENSE-PFO trials which (MES). Agitated saline (9 mL of saline and the past 4 weeks, left ventricular ejection
included only high-risk PFO patients.15,16 Thus,1 mL air with a few drops of patient’s blood fraction <30%, valvular vegetation’s or
screening for PFO in patients with cryptogenic mixed 20 times using a three-way stopcock) infective endocarditis), and no other specific
stroke is essential for stroke prevention. The was injected through an 18-gauge needle cause of stroke (e.g., dissection, arteritis,
routine transthoracic echocardiography (TTE) inserted into the antecubital vein. Each migraine/vasospasm, and drug misuse).4
is of limited diagnostic power in detecting patient underwent a total of four injections. Those patients who were diagnosed
PFO while TEE is considered the reference The injections were done in the supine to have ESUS and TCD bubble contrast
standard. However, TEE is a semi-invasive and sitting (45° incline) positions, with and study positive underwent TEE. The TEE was
test requiring patient cooperation and often without the Valsalva maneuver. Any MES performed by a trained cardiologist who was
noted was graded according to Spencer’s
mild sedation. Also, it is difficult to perform a part of the cardiology-neurology team. The
Valsalva maneuver during this procedure. TCD logarithmic scale (grade 0: no MES, grade I: patients who were diagnosed to have a PFO
bubble contrast study is a noninvasive, simple, MES count 1–10, grade II: MES count 11–30, were seen by the stroke neurology team and
and easy-to-perform test.17 It has been shown grade III: MES count 31–100, grade IV: MES the interventional cardiologist. The RoPE and
previously that TCD is superior to TEE for the count 101–300, and grade V: MES count more AF-RoPE scores were calculated for those who
detection of R-L shunt in stroke patients.18 than 300).19,20 After extensive evaluation the had a PFO. The decision of PFO closure was
Thus, the aim of our study was to stroke neurologist categorized the patients made after discussing with the patient/relatives
determine the utility of screening for an R-L as those with established etiology of stroke about the risks and benefits of the procedure
shunt using the TCD bubble contrast study in in the young, cryptogenic stroke, and ESUS. taking into consideration the negative workup
young patients with cryptogenic strokes and Embolic stroke of the undetermined for stroke etiology, risk of recurrent strokes,
to identify clinical predictors of an R-L shunt.source was def ined as a non-lacunar high-risk TEE parameters like ASA, PFO size,
infarct (subcortical infarct ≤1.5 cm on and length, and also presence or absence of
CT or ≤2.0 cm on MRI) in the absence of spontaneous shunting. PFO closure was done
M at e r ia l s a n d M e t h o d s the following: extracranial or intracranial under conscious sedation with fentanyl and
This was a prospective observational study atherosclerosis causing >50% luminal stenosis midazolam. All patients received intravenous
between January 2013 and December 2019,
conducted in the Department of Neurological
Sciences of a tertiary-level teaching hospital
in South India. All ischemic stroke patients
between the ages of 18–45 years were
included. The study was approved by the
Institutional Review Board (Mi. No. 13438).
All included patients underwent a detailed
history and physical examination to look at any
clues towards a possible etiology. All patients
had imaging including vascular imaging
with computed tomography angiogram or
magnetic resonance angiogram and 4-vessel
carotid Doppler, TTE, and hematological
evaluation including vasculitis, retroviral,
and venereal disease research laboratory
screening. Full thrombophilia workup was
done which included genetic markers and
protein assays. Fabry’s screening was done
on selected patients. Magnetic resonance
imaging (MRI) scans were performed on
a 1.5T (Magnetom Avanto, Siemens) or a 3T
(Intera Achieva, Philips Medical Systems)
scanner. Computed tomography (CT) scan
was performed on a 64-section scanner
(Discovery750 HD, GE Healthcare). Radiological
images were reviewed from Picture Archiving
and Communication System (PACS, GE) and
lesion location with the vessel involvement
was noted.
All included patients underwent a TCD
bubble contrast study that was performed Fig. 1: Study flow diagram

Journal of the Association of Physicians of India, Volume 70 Issue 10 (October 2022) 53

 Transcranial Doppler Screening for Patent Foramen Ovale Closure in Cryptogenic Strokes

heparin 5000 units prior to the procedure. Table 1: Baseline characteristics of the patients who underwent TCD bubble contrast study
The access was through the femoral vein and Transcranial Doppler bubble contrast study p-value
intracardiac echocardiography/TEE guidance
Positive Negative Total
was used. MP 1 (5 or 6F) and straight tip glide
wire (260 cm) were used for crossing the defect. N = 121 % N = 179 % N = 300 %
Amplatzer PFO Occluder (Abbott, Illinois, United Age 33.0 ± 7.4 31.7 ± 32.2 ± 0.274
States) was used for PFO closure. 21 Patients 7.2 7.3
were followed up in the stroke clinic and in the Sex 0.118
cardiology clinic (for those who underwent PFO
Male 85 70.2 140 73.7 225 75.00
closure). Any further events noted.
Statistical analysis was done using Female 36 29.8 39 26.3 75 25.00
a statistical package STATA (Stata Corp). Risk factors
Variables were compared using univariate Systemic hypertension 33 27.3 46 25.7 79 26.33 0.761
analysis. All factors reaching significance Diabetes mellitus 15 12.4 25 14.0 40 13.33 0.695
were analyzed using a logistic regression Dyslipidemia 14 11.6 18 10.0 32 10.67 0.677
model to perform a multivariate analysis.
Ischemic heart disease 2 1.7 7 3.9 9 3.00 0.321
Two-tailed Fisher’s exact test was used to look
Smoking 22 18.2 31 17.3 53 17.67 0.847
for significant associations.
Alcohol 22 18.2 20 11.2 42 14.00 0.086
Obesity 8 6.6 7 3.9 15 5.00 0.292
R e s u lts Elevated homocysteine 24 19.8 32 17.9 56 18.67 0.669
During the study period, a total of 7,179 patients Atrial fibrillation 0 0.00 0 0.00 0 0.00
were admitted in the neurology unit of
Carotid disease 0 0.00 0 0.00 0 0.00
Christian Medical College, Vellore. Of these,
6,197 (86.32%) were ischemic strokes and Recurrent stroke 15 19 34 0.711
972 (13.68%) were hemorrhagic strokes. The Type of stroke
number of patients with ischemic strokes with
Ischemic 118 97.5 165 92.2 282 94.31 0.051
an age at the time of stroke onset between
TIA 3 2.5 14 7.8 17 5.7 0.088
18 and 45 years was 304. A total of 304 patients
were screened for possible paradoxical Oxfordshire classification
emboli with the TCD bubble contrast study. Total anterior circulation 4 3.3 15 8.4 19 6.33 0.025
However, four were excluded due to technical stroke
difficulty. Thus, 300 patients underwent the Partial anterior circulation 76 62.8 120 67.0 196 65.33 0.509
TCD bubble contrast study. The mean age at stroke
presentation was 32 (7.2) years and 225 (75%) Posterior circulation stroke 38 31.4 34 19.0 72 24.00 0.0135
patients were males. Of the included patients
283 (94.3%) had infarcts and 17 (5.7%) had Lacunar stroke 0 0 0 0 0 0 0
transient ischemic attacks (TIAs). Among the Large vessel occlusion
300 patients who were evaluated, 121 (40.3%)
patients were found to have a positive TCD ICA 4 3.3 7 3.9 11 30.56 0.026
bubble study. The flow of patients recruited MCA 4 3.3 15 8.4 19 52.78 0.077
for the study is given in Figure 1. PCA 0 0 5 2.8 5 13.89 0.23
The baseline characteristics of the patients BA 0 0 1 0.6 1 2.78 0.784
with and without a positive TCD bubble study Cortically located infarcts 48 39.6 42 23.5 90 48.14 0.027
are given in Table 1.
BA, basilar artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery;
The activity at the time of stroke was TIA, transient ischemic attack
documented in 105 (35%) patients. Patients
who lifted heavy weights (p = 0.02), strained
to perform mechanically challenging work, which two of them had additional fistulas over the tunnel, and the presence of an interatrial
or did an activity that was equivalent to the liver, and two of them fulfilled the criteria septal aneurysm (p = 0.012). Eighteen (27.7%)
a Valsalva maneuver (p ≤ 0.01) were likely for Osler–Weber–Rendu syndrome. patients were managed with anticoagulation
to have a positive bubble study. The list of Finally, based on clinical indication and and the rest were on antiplatelet therapy. The
activities at the time of stroke onset is given affordability, 29 patients underwent PFO outcomes of the patients who underwent PFO
in Table 2. closure. The patients with PFO who did not closure in our center have been described by
A total of 72 (59.5%) patients were undergo PFO closure were managed with Thomson et al. 22
identified to have an ESUS and based on clinical dual antiplatelet therapy. The mean RoPE
discretion of the stroke neurologist and RoPE score was 6.8 in the patients who underwent
score, underwent TEE for PFO confirmation. Of PFO closure and in those who were medically Discussion
these, 65 patients had PFO, four were negative managed (p = 0.906). The patients who were Transcranial Doppler bubble contrast study is
and three were found to have extracardiac referred for a PFO device closure had a higher known to be superior to direct imaging of the
shunts. All three extracardiac shunts were AF-RoPE score, a high-grade shunt on the left atrium and can easily be done in an office
pulmonary arteriovenous malformation, of TCD bubble contrast study, a longer length of setting, hence, it is a simple and reliable tool

54 Journal of the Association of Physicians of India, Volume 70 Issue 10 (October 2022)

 Transcranial Doppler Screening for Patent Foramen Ovale Closure in Cryptogenic Strokes

Table 2: Activity at the time of stroke onset in patients with stroke in the young who underwent of the patients fulfilling the ESUS criteria had
TCD bubble study vascular risk factors.
N = 300 Positive Negative p-value Recently, three large randomized
N = 121 N = 179 controlled trials that enrolled 2,307 patients
Push and pull activity 4 2 2 0.700
with ESUS and aged <60 years showed a
significant reduction in the risk of recurrent
Pulling bike 2 1 1 0.412
strokes with PFO closure when compared
Pushing a heavy chair 1 1 0 0.222 with antithrombotic therapy.14,15,32 Patient
Ironing 1 0 1 0.412 selection for PFO closure was guided by
Seizures at onset 26 7 19 0.143 a combination of factors from the clinical
Neck pain 2 0 2 0.242 history, whether the patient fulfilled the
Prolong hours of sitting ESUS criteria, exclusion of other significant
vascular risk factors, imaging findings, and
At work-1 1 1 0 0.222
clinical scores, especially the AF-RoPE score
Travel in bus 1 1 0 0.222
which highlights the high-risk features of
Driving long hours 2 1 1 0.780 a PFO.16 Limitations of our study include
Postflight travel 1 0 1 0.412 limited follow-up on patients and not all
Sitting for a written examination 1 0 1 0.412 patients who were eligible underwent PFO
History of lower limb DVT 1 0 1 0.597 device closure.
Valsalva maneuver before stroke 24 18 6 <0.01
Lifting heavy weights 9 7 2 0.02 C o n c lu s i o n s
Straining activity 13 10 3 <0.01
Right to left shunt is common in cryptogenic
Squatting/toileting 2 1 1 0.780
ischemic strokes in young. TCD with bubble
Aerobic activity contrast study is a noninvasive and feasible
Swimming 1 1 0 0.222 bedside tool to identify them. Applying the
Jogging 1 1 0 ESUS criteria in these cryptogenic strokes
with a positive TCD bubble contrast study can
Riding cycle/bike 4 3 1 0.412
be then used for selecting patients for more
Road traffic accident/fall 0.167 invasive tests like TEE. High-risk PFOs detected
Head injury 1 0 1 on TEE can be then considered for PFO closure
RTA 1 0 1 for secondary stroke prevention. The history
of Valsalva maneuver-like activity (such as
Fall 1 0 1 0.412 lifting heavy weights or straining) at the time
Wake up stroke 11 1 10 0.031 of stroke onset can be an important clinical
During sleep 3 1 2 0.390 predictor for the presence of an R-L shunt.
In-hospital stroke 0 0 0 In addition to isolated cortical infarction, the
Migraine 15 9 6 0.111
presence of posterior circulation infarct in
ESUS can predict the presence of an R-L shunt.
History of lower limb DVT 1 0 1 0.597
Immediate postpartum 1 0 1 0.222
Arrhythmias 2 2 0 0.175 Authors’ Contribution
DVT, deep vein thrombosis; RTA, road traffic accident Study design—Sanjith Aaron, Appaswamy
Thirumal Prabhakar.
Dat a colle c tion — D e epti Bal, Joanne
in the evaluation of cryptogenic strokes.17 This only limited literature on it. 25–28 Our study
Roopkumar, Murali Rayani, Appaswamy
study demonstrates that 40% of cryptogenic reiterates this clinical finding and emphasizes
Thirumal Prabhakar.
strokes in young have positive TCD bubble that this could be an important clinical clue
Data Analysis—Appaswamy Thirumal
contrast study indicating an R-L shunt. This in evaluating patients with stroke in young.
Prabhakar.
is similar to the findings from North India In our study, the presence of isolated
Preparation of manuscript—Deepti Bal, Atif
and other parts of the world.6,23,24 When we cortical infarction and posterior circulation
Shaikh.
looked at the subgroup of young patients strokes were associated with R-L shunt and
Review, intellectual inputs, and critical revision
with ischemic strokes fulfilling the ESUS PFO. These findings are similar to those
of manuscript and supervision—Sanjith
criteria, the TCD bubble contrast study was described in other studies that looked at
Aaron, Appaswamy Thirumal Prabhakar, Viji
positive in 54%. We found a history of Valsalva neuroimaging studies in ischemic strokes
Samuel Thompson, John Jose, Atif Shaikh,
maneuver-like activities such as lifting heavy associated with PFO.29–31
Jesu Krupa, Rohit Benjamin.
weights or straining, at the time of stroke As strokes in the young are a
onset was found to be significantly associated heterogeneous group, the presence of an R-L
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