Transcranial Doppler Ultrasonography

Number: 0353

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses transcranial doppler ultrasonography.

1. Medical Necessity

   Aetna considers transcranial Doppler ultrasonography (TDU) medically necessary when used for any of the following indications: 

   1. Assessing collateral blood flow and embolization during carotid endarterectomy; or
   2. Assessing patterns and extent of collateral circulation in persons with known regions of severe stenosis or occlusion, including persons with Moyamoya syndrome; or
   3. Assessing persons suspected of having patent foramen ovale/paradoxical embolism (symptoms include visual disturbance, weakness, hemiplegia, or slurred speech); or
   4. Assessing persons with suspected brain death; or
   5. Assessing stroke risk of children (2 to 16 years of age) with sickle cell anemia (although the optimal time is unknown, accepted guidelines state that re-screening should be considered approximately every 6 months); or
   6. Detecting arterio-venous malformations (AVMs) and studying their supply arteries and flow patterns; or
   7. Detecting noncardiac right-to-left shunts; or
   8. Detecting microemboli in cerebral artery embolism following stroke or transient ischemic attack; or
   9. Detecting severe stenosis in the major basal intra-cranial arteries for members who have neurological signs or symptoms or carotid bruits; or
   10. Diagnosing and monitoring of reversible cerebral vasoconstriction syndromes; or
   11. Diagnosing dissection of vertebral artery; or
   12. Evaluating and following persons with vasoconstriction of any cause, especially after subarachnoid hemorrhage; or
   13. Evaluating very low birth weight preterm infants with gestational age less than 30 weeks.

2. Experimental and Investigational

   The transcranial Doppler ultrasonography (TDU) is considered experimental and investigational for all other indications, including the following (not an all-inclusive list) because the effectiveness of this approach for these indications has not been established:

   1. Assessing autoregulation, physiologic, and pharmacologic responses of cerebral arteries; or
   2. Brain tumors; or
   3. Diagnosing cerebral vein and sinus thrombosis and other conditions that involve venous pathology; or
   4. Diagnosing or monitoring response to anti-thrombotic therapy in ischemic cerebrovascular disease; or
   5. Epilepsy; or
   6. Evaluating adults with sickle cell anemia; or
   7. Evaluating ataxia, head trauma/skull fracture; or
   8. Evaluating children with neurofibromatosis; or
   9. Evaluating neurocognitive disorders (e.g., depression); or
   10. Evaluating persons with dilated vasculopathies such as fusiform aneurysms; or
   11. Familial and degenerative diseases of the cerebrum, brainstem, cerebellum, basal ganglia and motor neurons (e.g., Parkinson’s disease); or
   12. Following placement of an intra-cerebral arterial stent; or
   13. Guiding targeted adjunctive therapy in cerebral malaria; or
   14. Infectious and inflammatory conditions of the brain; or
   15. Managing traumatic brain injury; or
   16. Migraine headaches; or
   17. Monitoring brain injuries in individuals with left ventricular assist device; or
   18. Monitoring during cardiopulmonary bypass and other cerebrovascular and cardiovascular interventions, and surgical procedures other than carotid endarterectomy; or
   19. Predicting hemorrhagic transformation of ischemic infarction; or
   20. Predicting outcome in vertebrobasilar distribution stroke; or
   21. Psychiatric disorders; or
   22. Screening for carotid artery stenosis in asymptomatic adults; or
   23. Screening for stenosis of cerebral arteries in persons with fibromuscular dysplasia.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
93886	Transcranial Doppler study of the intracranial arteries; complete study
93888	limited study
93890	vasoreactivity study
93892	emboli detection without intravenous microbubble injection
93893	emboli detection with intravenous microbubble injection
Other CPT codes related to the CPB:
61635	Transcatheter placement of intravascular stent(s), intracranial (eg, atherosclerotic stenosis), including balloon angioplasty, if performed
ICD-10 codes covered if selection criteria are met:
D57.00 - D57.819	Sickle-cell disorders [for evaluating children]
G93.1	Anoxic brain damage, not elsewhere classified
G93.5	Compression of brain
H34.00 - H34.9	Retinal vascular occlusions
H53.10	Unspecified subjective visual disturbances
H53.121 - H53.129	Transient visual loss
H53.131 - H53.139	Sudden visual loss
I28.0	Arteriovenous fistula of pulmonary vessels [for detecting noncardiac right-to-left shunts]
I60.00 - I65.9, I67.0 - I69.998	Cerebrovascular diseases
I74.9	Embolism and thrombosis of unspecified artery [paradoxical embolism]
I77.1	Stricture of artery
I77.74	Dissection of vertebral artery
P05.00 - P05.9	Disorders of newborn related to slow fetal growth and fetal malnutrition
P07.00 - P07.32	Disorders of newborn related to short gestation and low birth weight, not elsewhere classified
Q21.10 - Q21.19	Atrial septal defect [patent foramen ovale]
Q25.6	Stenosis of pulmonary artery [for detecting noncardiac right-to-left shunts]
Q25.79	Other congenital malformations of pulmonary artery [for detecting noncardiac right-to-left shunts]
Q28.0 - Q28.9	Other congenital malformations of circulatory system [arteriovenous malformation (AVM)]
R40.4	Transient alteration of awareness
R47.01 - R47.02	Aphasia and dysphasia
R47.1	Dysarthria and anarthria
R47.81	Slurred speech
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
B50.0	Plasmodium falciparum malaria with cerebral complications
C71.0 - C71.9	Malignant neoplasm of brain
C79.31 - C79.49	Secondary malignant neoplasm of brain and nervous system [spinal cord]
D33.0 - D33.2	Benign neoplasm of brain
D43.0 - D43.4	Neoplasm of uncertain behavior of brain and spinal cord
D49.6	Neoplasm of unspecified behavior of brain
E75.00 - E75.19 E75.23, E75.25 E75.29, E75.4	Disorders of sphingolipid metabolism and other lipid storage disorders
F01.50 - F99	Mental and behavioral disorders
F84.2	Rett's syndrome
G00.0 - G09	Inflammatory diseases of the central nervous system
G10 - G12.9, G13.8	Systemic atrophies primarily affecting the central nervous system
G20 - G26	Extrapyramidal and movement disorders
G30.0 - G32.8	Other degenerative diseases of the nervous system
G40.00 - G40.919	Epilepsy and recurrent seizures
G43.001 - G43.919	Migraine
G80.3	Athetoid cerebral palsy
G90.01 - G91.9	Other disorders of the nervous system
G93.7	Reye's syndrome
G93.89 - G93.9, G94	Other and unspecified disorders of the brain
G95.0 - G95.9	Other and unspecified diseases of spinal cord
G99.0 - G99.8	Other disorders of nervous system in diseases classified elsewhere
I63.30 - I63.39, I66.01 - I66.9	Cerebral thrombosis
I72.0 - I72.9	Other aneurysm
I77.3	Arterial fibromuscular dysplasia
Q85.00 - Q85.9	Neurofibromatosis (nonmalignant) [in children]
R56.1	Post traumatic seizures
R56.9	Unspecified convulsions
S02.0xxA – S02.42xS, S02.600A – S02.92xS	Fracture of skull and facial bones [traumatic brain injury]
S04.011A - S04.899S	Injury of cranial nerve [traumatic brain injury]
S06.0x0A - S06.9x9S	Intracranial injury [traumatic brain injury]
Z13.6	Encounter for screening for cardiovascular disorders [screening for carotid artery stenosis in asymptomatic persons]
Z79.01	Long-term (current) use of anticoagulants
Z79.02	Long-term (current) use of antiplatelets/antithrombotics
Z95.811	Presence of heart assist device

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Background

Transcranial Doppler ultrasonography (TDU) is a non-invasive technology that uses a handheld pulsed low-frequency Doppler transducer that enables recording of blood velocities from intra-cranial arteries through selected cranial foramina and thin regions of the skull.  Analysis of the Doppler spectra allows display and calculation of peak systolic, peak diastolic, and mean velocities and pulsitility indices.  Mapping of the sampled velocities as a color display of spectra in lateral, coronal and horizontal views locates the major brain arteries in three dimensions.

Cerebral angiography provides an image of the anatomical configuration of the lesions of the intra-cranial and extra-cranial arteries and their proximal, deep and superficial branches.  Transcranial Doppler obtains information about the physiology of flow through the major basal intra-cranial arteries by measuring velocities and pulsitilities in segments of these arteries.   PET and SPECT scanning, xenon enhanced CT scanning, and MRI spectroscopy yield images or quantitative data about metabolism and perfusion of brain regions but do not give direct data about flow in major supplying arteries (AAN, 1990; AAN, 1991).

Strokes occur in about 10 % of children with sickle cell anemia.  These events can affect motor skills, school performance, as well as overall quality of life.  The treatment, periodic red blood cell transfusions to maintain the level of hemoglobin S below 30 %, lowered the rate of strokes by 90 % in children found to be at increased risk as indicated by elevated transcranial Doppler velocities (greater than or equal to 200 cm/sec time averaged mean velocities).

Adam (2000) stated that non-invasive prediction of risk using TDU made it possible to test primary stroke prevention in a clinical trial comparing chronic blood transfusion with standard care.  A consortium of 14 clinical centers conducted a randomized clinical trial (Stroke Prevention in Sickle Cell Anemia the "STOP" study) to test a strategy to prevent first stroke in children with sickle cell disease (SCD).  Over 2,000 children were screened with TDU and of these, 130 with elevated blood velocity indicating high-risk were enrolled in the trial.  Regular red cell transfusions sufficient to reduce the percentage of Hb S gene product from over 90 to less than 30 of total hemoglobin was associated with a marked reduction in stroke.  The untreated risk of 10 % per year was reduced over 90 % with treatment, an effect sufficient to cause early termination of the trial.  The study led to a Clinical Alert, issued by the National Heart, Lung, and Blood Institute, recommending screening and consideration of treatment in children with SCD and 2 to 16 years of age who are at risk based on TDU, and who have not had stroke.

Miller et al (2001) reported that the STOP trial demonstrated that chronic transfusion is highly effective in reducing the risk of stroke in children with SCD and an abnormal TDU examination result; and compliance with aggressive chronic transfusion reduces the frequency of acute chest syndrome and pain episodes.

Hirsch et al (2002) reported that the value of TDU in children is not in the primary diagnosis of disease but in the follow-up of known vascular processes (e.g., stenoses) or in chronic diseases including angiitis and SCD.

Gorman and colleagues (2009) stated that TDU is used to screen individuals with the major hemoglobin S diseases, SCD and Hb S-beta(0), for significant stenoses in the circle of Willis.  Flow velocities above 200 cm/s have been shown to identify patients at elevated risk for cerebral infarction.  Among TDU's limitations is the inability to insonate the distal extracranial, petrous, and cavernous internal carotid artery (ICA) through the standard transtemporal approach.  These researchers extended the submandibular approach to include infra-siphon portions of the ICA.  Using the extended submandibular approach to evaluate these portions of the ICA, these investigators identified stenotic lesions in 4 patients with SCD out of a population of 131 children with SCD.  Three of the 4 patients had no history of overt stroke or stroke-like symptoms.  Neuroimaging confirmed the stenotic lesions, and also revealed watershed infarction as well as discrete areas of silent infarction.  All 4 children had neuropsychological impairment.  The authors concluded that the submandibular approach, when added to a standard transcranial Doppler examination, may increase the sensitivity of this technique to identify important potential sources of cerebral infarction.  Moreover, they stated that further study is indicated.

In an editorial that accompanied the afore-mentioned article, Jordan and Strouse (2009) stated that limitations of this study included the small number of children with increased ICA velocity, inability to evaluate the temporal relationship between abnormal TDU and the development of stenosis on MRA, and the lack of concurrent TDU and MRA.  If the goal of TDU screening is to identify children with SCD–related vasculopathy who are at high risk for stroke, then in an ideal study, all children should have both TDU and MRA.  It is unknown how many children with a normal TDU might have an abnormal MRA.  Of the 4 children with an abnormal TDU in the current study, 1 child had only mild ICA narrowing confirmed by MRA.  In 2 children, the elevated TDU velocity was not as expected, with increased TDU velocity on 1 side and stenosis identified by MRA on the other.  In the Stroke Prevention (STOP) Trial, all 11 children with ischemic stroke had increased velocities (200 cm/s) on the same side as the cerebral infarct.  This TDU technique could provide information about vasculopathy and stroke risk in children with SCD with little additional cost or effort if added to the routine TDU screening.  Thus, this work should be confirmed and extended by rigorous study in a larger population.  An important aspect of future studies will be to show a temporal relationship between elevated TDU velocities in the cavernous and petrous ICA segments, vessel stenosis, and neurological outcome.

Pavlakis and associates (2010) stated that TDU is used to predict stroke risk in children with SCD, but has not been adequately studied in children under age 2 years.  These investigators performed TDU on infants with SCD enrolled in the BABY HUG trial.  Subjects were 7 to 17 months of age (mean of 12.6 months).  Transcranial Doppler ultrasound examinations were successfully performed in 94 % of subjects (n = 192).  No patient had an abnormal TDU as defined in the older child (time averaged maximum mean TAMM velocity greater than or equal to 200 cm/sec) and only 4 subjects (2 %) had velocities in the conditional range (170 to 199 cm/sec).  Transcranial Doppler ultrasound velocities were inversely related to hemoglobin (Hb) concentration and directly related to increasing age.  The authors concluded that determination of whether the TDU values in this very young cohort of infants with SCD can be used to predict stroke risk later in childhood will require analysis of exit TDU and long-term follow-up, which is ongoing.

Transcranial Doppler bubble ultrasound has been used to evaluate patients suspected of having patent foramen ovale when a transesophageal echocardiography is contraindicated or is unavailable.

Three methods have been used to diagnose patent foramen ovale.  All procedures use a contrast solution of agitated saline that contains air bubbles.  This bubbly solution is injected into a vein during normal respiration and in conjunction with some repetitive action such as a cough or performing a Valsalva maneuver, which should open the patent foramen ovale flap.  Blood flow following injections is compared during the flap-opening maneuver versus the resting condition.

Three-dimensional trans-esophageal echocardiography (TEE) is the most sensitive of measurement methods, but the most uncomfortably invasive since a probe is placed in the back of the throat, which must be anesthetized for optimal imaging of the inter-atrial septum.  Bubble contrast transthoracic echocardiography, or TTE, uses electronic imaging measure across the chest.  Transcranial Doppler, or transcranial Doppler (TCD), uses a sonographic imaging from the of the right middle cerebral artery in the head.  The sensitivity of TCD varies from 68 % to 89 % relative to contrast TEE, and its specificity from 92 % to 100 % when studying stroke populations.  Advantages of TCD are that it is safe, causes little patient discomfort, and can be performed without fasting or sedation.

The 2002 practice parameter on neuroimaging of the neonate by the American Academy of Neurology (AAN) stated that cranial ultrasonography plays an established role in the management of preterm neonates of less than 30 weeks' gestation (Ment et al, 2002).  Furthermore, an assessment on TDU performed by the AAN (Sloan et al, 2004) stated that it provides important information and may have value for detection of intracranial steno-occlusive disease.  On the other hand, the assessment indicated that available data do not support the use of TDU for:

1. diagnosing or monitoring response to anti-thrombotic therapy in ischemic cerebrovascular disease;
2. predicting outcome in vertebrobasilar distribution stroke;
3. predicting hemorrhagic transformation of ischemic infarction;
4. detecting impaired cerebral hemodynamics distal to high-grade extracranial internal carotid artery stenosis or occlusion; and
5. evaluating adults with sickle cell anemia.

The U.S. Preventive Services Task Force (2007) examined the evidence on the natural history of carotid artery stenosis (CAS); systematic reviews of the accuracy of screening tests; observational studies of the harms of screening and treatment of asymptomatic CAS; and randomized, controlled trials of the benefits of treatment for CAS with carotid endarterectomy.  The U.S. Preventive Services Task Force recommended against screening for asymptomatic CAS in the general adult population.  (Grade D recommendation: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits).

The Report of the Therapeutics and Technology Assessment Subcommittee of the AAN considered that TCD is probably useful for detection of cerebral MES in various cardiovascular and cerebrovascular disorders and procedures (Sloan et al, 2004). The report found that the clinical utility of TCD is established in the following indications:

1. Screening of children aged 2 to 16 years with sickle cell disease for assessing stroke risk, although the optimal frequency of testing is unknown;
2. Detection and monitoring of angiographic vasospasm spontaneous subarachnoid hemorrhage; more data are needed to show if its use affects clinical outcomes.

The AAN report (Sloan et al, 2004) found that TCD is able to provide information for the following indications, but its clinical utility, compared to other diagnostic tools, remains to be determined:

1. Intracranial steno-occlusive disease: TCD is probably useful for the evaluation of occlusive lesions of intracranial arteries in the basal cisterns (especially the internal carotid artery [ICA] siphon and middle cerebral artery [MCA]). The report stated that the relative value of TCD compared with magnetic resonance angiography (MRA) or computed tomography angiography (CTA) remains to be determined. Data are insufficient to recommend replacement of conventional angiography with TCD;
2. Cerebral circulatory arrest (adjunctive test in the determination of brain death): If needed, TCD can be used as a confirmatory test, in support of a clinical diagnosis of brain death.

The AAN report (Sloan et al, 2004) found that TCD is able to provide information for the following indications, but its clinical utility for these indications remains to be determined: 

1. Cerebral thrombolysis: TCD is probably useful for monitoring thrombolysis of acute MCA occlusions). The report stated that more data are needed to assess the frequency of monitoring for clot dissolution and enhanced recanalization and to influence therapy;
2. Cerebral microembolism detection: TCD monitoring is probably useful for the detection of cerebral microembolic signals in a variety of cardiovascular and cerebrovascular disorders and procedures. The report stated that data do not support the use of this TCD technique for diagnosis or monitoring response to antithrombotic therapy in ischemic cerebrovascular disease;
3. Carotid endarterectomy (CEA): TCD monitoring is probably useful to detect hemodynamic and embolic events that may result in perioperative stroke during and after CEA in settings where monitoring is felt to be necessary; (iv) Coronary artery bypass graft (CABG) surgery: TCD monitoring is probably useful during CABG for detection of cerebral microemboli. TCD is possibly useful to document changes in flow velocities and carbon dioxide (CO2) reactivity during CABG surgery. Data are insufficient regarding the clinical impact of this information;
4. Vasomotor reactivity (VMR) testing: TCD is probably useful for the detection of impaired cerebral hemodynamics in patients with severe (greater than 70 percent) asymptomatic extracranial ICA stenosis, symptomatic or asymptomatic extracranial ICA occlusion, and cerebral small-artery disease. Whether these techniques should be used to influence therapy and improve patient outcomes remains to be determined;
5. VSP after traumatic subarachnoid hemorrhage (tSAH): TCD is probably useful for the detection of VSP following tSAH, but data are needed to show its accuracy and clinical impact in this setting;
6. Transcranial color-coded sonography (TCCS): TCCS is possibly useful for the evaluation and monitoring of space-occupying ischemic middle cerebral artery (MCA) infarctions. More data are needed to show if it has value versus computed tomography (CT) and magnetic resonance imaging (MRI) scanning and if its use affects clinical outcomes.

The AAN report (Sloan et al, 2004) found that TCD is able to provide information in the following settings, but other diagnostic tests are typically preferable: 

1. Right-to-left cardiac shunts: Whereas TCD is useful for detection of right-to-left cardiac and extracardiac shunts, transesophageal echocardiography (TEE) is superior, as it can provide direct information regarding the anatomic site and nature of the shunt;
2. Extracranial ICA stenosis: TCD is possibly useful for the evaluation of severe extracranial ICA stenosis or occlusion, but, in general, carotid duplex and magnetic resonance angiography (MRA) are the diagnostic tests of choice;
3. Contrast-enhanced TCCS: Contrast-enhanced TCCS may provide information in patients with ischemic cerebrovascular disease and aneurismal subarachnoid hemorrhage (aSAH). Its clinical utility versus CT scanning, conventional angiography, or nonimaging TCD is unclear.

Ritter and colleagues (2008) compiled available studies using microembolic signals (MES) detection by TDU in varying sources of arterial brain embolism.  These researchers investigated prevalences of MES and whether MES detection is of proven use for risk stratification.  Studies reporting prevalences of MES and the risk of cerebral ischemic events were pooled for patients with symptomatic or asymptomatic carotid stenosis, intra-cranial artery stenosis, cervical artery dissection, and aortic embolism.  Microembolic signals were reported in 43 % of 586 patients with symptomatic and in 10 % of 1,066 patients with asymptomatic carotid stenosis.  Presence of 1 MES indicated an increased risk of future events [odds ratio (OR): 7.5, 95 % confidence interval (CI): 3.6 to 15.4, p < 0.0001 for symptomatic, and OR: 13.4, 95 % CI: 6.5 to 27.4, p < 0.0001 for asymptomatic disease).  Microembolic signals were reported in 25 % of 220 patients with symptomatic versus 0 % of 86 patients with asymptomatic intra-cranial stenosis (p < 0.0001).  Of 82 patients with cervical artery dissection presenting with transient ischemic attack (TIA) or stroke, 50 % had MES compared with 13 % of 16 patients with local symptoms (p = 0.006).  In patients with aortic embolism, patients with plaques greater than or equal to 4 mm morefrequently had MES compared with patients with smaller plaques (p = 0.04).  Data were insufficient to reliably predict future events in patients with intra-cranial stenosis, cervical artery dissection, and aortic embolism.  The authors concluded that MES are a frequent finding in varying sources of arterial brain embolism; and MES detection is useful for risk stratification in patients with carotid stenosis.

Jovanovic et al (2008) noted that approximately 1/3 of ischemic cerebrovascular diseases have embolic properties.  Because of that, transcranial Doppler (TCD) test for detection of MES, as the only one method for detection of microemboli, is a very important test for the evaluation of cerebral artery embolism.  Cerebral emboli are particles of thrombus or atheromatous plaque, platelet aggregates, lipid or air particles in cerebral circulation, which can occlude arterioles and cause TIA or stroke.  Most frequently, they derive from exulcerated plaques of the carotid bifurcation or the aortic arch, from the atrial thrombus, prosthetic heart valves, as well as during carotid endarterectomy, arterial stent, aortocoronary by-pass.  For MES detection, bilateral monitoring of a. cerebri mediae (ACM) is performed with each probe held in place over a temporal bone.  Microembolic signals are represented as brightly colored embolic tracks as they pass through the insonated arteries.  A computer hard disk provides continuous recording that is replayed for counting embolic signals.  Color intensity or acoustic range indicate the size and structure of MES.  Microembolic signals in the range of one ACM indicate the source of embolism on the ipsilateral carotid artery, while the bilateral detection of MES suggests a cardiogenic source.  Indications for TCD detection of MES are the evaluation of pathogenesis and risk for embolic stroke or TIA and assessing the source of embolism.  These researchers started applying this method 2 years ago.  They had examined 78 patients and detected MES in 23 patients (28.7 %). 

Woitalla and colleagues (2010) stated that Imaging of the brain structure with trans-cranial ultrasound has become an important tool for the diagnosis and differential diagnosis of Parkinson's Disease.  In up to 90 % of parkinsonian patients, abnormal echogenity of the substantia nigra (SN) could be demonstrated.  Particularly in the early diagnosis in subjects with only very mild extra-pyramidal features and in the differential diagnosis to other neurodegenerative disorders with parkinsonian features, such as the parkinsonian variant of multi-system atrophy (MSA-P) and progressive supranuclear paralysis (PSP) ultrasound has a high diagnostic yield.  Because of a prevalence of about 10 % in the normal population, the evidence of an abnormal echogenity of the SN has to be interpreted carefully in the context of a clinical examination.  Although there are a number of studies indicating that in some of these subjects a vulnerability of the nigro-striatal system can be found, the meaning of an abnormal echogenicity of the SN in the healthy population needs to be further elucidated in already ongoing research projects.

Singh et al (2004) noted that blunt carotid artery injury (BCI) is a rare but potentially devastating injury.  When undiagnosed it can result in severe disability or death.  A Medline-based literature search was performed using key words "blunt carotid injury" and cross-referenced with further original papers obtained from the references from this search.  The incidence of BCI is very low.  However, given the serious consequences of a missed injury, recent efforts have focused on targeted screening for this injury in trauma patients.  Conventional angiography remains the investigation of choice but may be superseded in the future by non-invasive methods such as magnetic resonance angiography or CT angiography.  Operative intervention is rarely required and anti-coagulation remains the treatment of choice where dissection or pseudoaneurysm is diagnosed.  The role of anti-platelet therapy is currently being investigated.  Endovascular management using stents has been described but medium- to long-term results are not yet available.

Sloan (2006) stated that all neuromonitoring techniques, although imperfect, provide useful information for monitoring cardiothoracic and carotid vascular operations.  They may be viewed as providing complementary information, which may help surgical technique and, as a result, possibly improve clinical outcomes.  As of this writing, the efficacy of TDU and near-infrared spectroscopy monitoring during cardiothoracic and vascular surgery can not be considered established.  The author concluded that well-designed, prospective, adequately powered, double-blind, and randomized outcome studies are needed to determine the optimal neurologic monitoring modality (or modalities), in specific surgical settings.

Kincaid (2008) stated that since its introduction in 1982, TDU has become an important diagnostic and monitoring tool in patients with surgical disease.  It has applications in the peri-operative period, as well as in the intensive care unit.  It is therefore appropriate for the anesthesiologist to maintain an understanding of its current utility.  Transcranial Doppler has an established role in diagnosing cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage and for guiding transfusion therapy in children with sickle cell disease.  It has application in the pre-operative evaluation of patients with cerebrovascular disease, as well as that of an intra-operative monitor in carotid endarterectomy and carotid stenting.  It is useful for detecting right-to-left shunts in settings in which trans-esophageal echocardiography is not desirable.  Its value in settings such as traumatic brain injury, hepatic failure, and migraine headache has yet to be fully clarified.  The author concluded that although there are several settings in which TDU has well-established usefulness, there are many more in which it is likely valuable, such as traumatic brain injury, ischemic stroke, and fulminant hepatic failure.  The author stated that further research is needed in these fields to elucidate the exact role for TDU.

Edmunds et al (2011) stated that the American Society of Neurophysiologic Monitoring (ASNM) and American Society of Neuroimaging (ASN) Guidelines Committees formed a joint task force and developed guidelines to assist in the use of TCD monitoring in the surgical and intensive care settings.  Specifically, these guidelines:

1. delineate the objectives of TCD monitoring;
2. characterize the responsibilities and behaviors of the sonographer during monitoring;
3. describe methodological and ethical issues uniquely relevant to monitoring.

The ASNM and ASN strongly support the positions that

1. acquisition and interpretation of intra-operative TCD ultrasonograms be performed by qualified individuals,
2. service providers define their diagnostic criteria and develop on-going self-validation programs of these performance criteria in their practices.

The authors agreed with the guidelines of other professional societies regarding the technical and professional qualifications of individuals responsible for TCD signal acquisition and interpretation (Class III evidence, Type C recommendation).  On the basis of current clinical literature and scientific evidence, TCD monitoring is an established monitoring modality for the:

1. assessment of cerebral vasomotor reactivity and autoregulation;
2. documentation of the circle of Willis functional status;
3. identification of cerebral hypo- and hyper-perfusion, recanalization and re-occlusion; and
4. detection of cerebral emboli (Class II and III evidence, Type B recommendation).

An UpToDate review on "Moyamoya disease: Etiology, clinical features, and diagnosis" (Suwanwela, 2012) states that "[t]ranscranial Doppler ultrasonography (TCD) provides a noninvasive way to evaluate intracranial hemodynamics and large artery stenosis".  Furthermore, the American College of Radiology-American Institute of Ultrasound in Medicine's practice guideline for the performance of TCD ultrasound for adults and children (2007) listed "detection of vasculopathy such as moyamoya" and "detection of right-to-left shunts using agitated saline injection" as one of the recommended indications for children and adults, respectively.

In an international multi-center study, Tsivgoulis and colleagues (2011) prospectively evaluated the safety of TCD with "bubble studies" (TCD-BS) for identifying right-to-left shunt (RLS).  Consecutive patients with cerebral ischemia (ischemic stroke or transient ischemic attack (TIA)) were screened for potential ischemic cerebrovascular events following injection of microbubbles during TCD-BS for identification of RLS at 3 tertiary care stroke centers.  TCD-BS was performed according to the standardized International Consensus Protocol.  Trans-oesophageal echocardiography (TOE) "bubble studies" (TOE-BS) was performed in selected cases for confirmation of TCD-BS.  A total of 508 patients hospitalized with acute cerebral ischemia (mean age of 46 +/- 12 years, 59 % men; 63 % ischemic stroke, 37 % TIA) were investigated with TCD-BS within 1 week of ictus.  Right-to-left shunt was identified in 151 cases (30 %). TOE-BS was performed in 101 out of 151 patients with RLS identified on TCD-BS (67 %).  It was positive in 99 patients (98 %).  The rate of ischemic cerebrovascular complications during or after TCD-BS was 0 % (95 % CI by the adjusted Wald METHOD: 0 to 0.6 %).  Structural cardiac abnormalities were identified in 38 patients, including atrial septal aneurysm (n = 23), tetralogy of Fallot (n = 1), intra-cardiac thrombus (n = 2), ventricular septal defect (n = 3) and atrial myxoma (n = 1).  The authors concluded that TCD-BS is a safe screening test for identification of RLS, independent of the presence of cardiac structural abnormalities.

Stolz (2008) stated that ultrasound examination of cerebral veins and sinuses is a new application that has been developed in the recent years.  In the acute phase of cerebral vein and sinus thrombosis, occlusion of dural sinuses may be diagnosed by TCCS after echo contrast agent application demonstrating a filling defect.  Collateral venous flow can be assessed by both TCD and TCCS.  However, ultrasonographic techniques are not sensitive enough to exclude cerebral venous thrombosis, but they may complement other imaging techniques.  In the follow-up, sonographic findings are related to the functional outcome.

An UpToDate review on “Etiology, clinical features, and diagnosis of cerebral venous thrombosis” (Ferro and Canhao, 2013) states that “Transcranial Doppler ultrasonography and transcranial power or color Doppler imaging, with or without the use of contrast, are noninvasive techniques that have potential utility for the diagnosis of CVT and for follow-up, but more information is needed to determine the true clinical value of these methods.  In pediatric patients, transfontanellar ultrasound may support the diagnosis of CVT”.

The American College of Radiology’s “Appropriateness Criteria® ataxia” (Broderick et al, 2012) rendered TDU for evaluating ataxia associated with various causes a “1” or “2” rating (Rating scale: 1, 2, and 3: Usually not appropriate; 4, 5, and 6: May be appropriate; 7, 8, and 9: Usually appropriate).

The American College of Radiology’s “Appropriateness Criteria® head trauma” (Davis et al, 2012) rendered ultrasonic transcranial with Doppler for evaluating head trauma/skull fracture a “1” rating (Rating scale: 1, 2, and 3: Usually not appropriate; 4, 5, and 6: May be appropriate; 7, 8, and 9: Usually appropriate).

In a meta-analysis, Mojadidi et al (2014) determined the accuracy of TCD for the diagnosis of intra-cardiac RLS and compared with TEE as the reference.  These investigators performed a systematic review of Medline, the Cochrane Library, and Embase to look for all the prospective studies assessing intra-cardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies.  A total of 27 studies (29 comparisons) with 1,968 patients (mean age of 47.8 ± 5.7 years; 51 % male) fulfilled the inclusion criteria.  The weighted mean sensitivity and specificity for TCD were 97 % and 93 %, respectively.  Likewise, the positive and negative likelihood ratios were 13.51 and 0.04, respectively.  When 10 microbubbles was used as the embolic cut-off for a positive TCD study, TCD produced a higher specificity compared with when 1 microbubble was used as the cut-off (p = 0.04); there was, however, no significant change in sensitivity (p = 0.29).  The authors concluded that TCD is a reliable, non-invasive test with excellent diagnostic accuracies, making it a proficient test for detecting RLS.  They stated that TCD can be used as a part of the stroke work-up and for patients being considered for patent foramen ovale (PFO) closure.  If knowledge of the precise anatomy is required, then TEE can be obtained before scheduling a patient for transcatheter PFO closure.

The American Institute of Ultrasound in Medicine’s practice guideline on “Transcranial Doppler ultrasound for adults and children” (2012) listed “detection of right-to-left shunts’ as one of the indications for a TCD ultrasound examination of adults.

An UpToDate review on “Evaluation of carotid artery stenosis” (Furie, 2016) does not mention transcranial Doppler ultrasonography as a diagnostic tool.

Parkinson’s Disease

Li and colleagues (2016) stated that a large number of articles have reported substantia nigra hyper-echogenicity in Parkinson's disease (PD) and have assessed the diagnostic accuracy of transcranial sonography (TCS); however, the conclusions are discrepant.  In a systematic review and meta-analysis, these investigators consolidated the available observational studies and provided a comprehensive evaluation of the clinical utility of TCS in PD.  A total of 31 studies containing 4,386 participants from 13 countries were included.  A random effects model was utilized to pool the effect sizes.  Meta-regression and sensitivity analysis were performed to explore potential heterogeneity.  Overall diagnostic accuracy of TCS in differentiating PD from normal controls was quite high, with a pooled sensitivity of 0.83 (95 % CI: 0.81 to 0.85) and a pooled specificity of 0.87 (95 % CI: 0.85 to 0.88).  The positive likelihood ratio, the negative likelihood ratio and diagnostic OR were calculated 6.94 (95 % CI: 5.09 to 9.48), 0.19 (95 % CI: 0.16 to 0.23), and 42.89 (95 % CI: 30.03 to 61.25), respectively.  The findings of this systematic review and meta-analysis suggested that TCS has high diagnostic accuracy in the diagnosis of PD when compared to healthy control.  Moreover, they stated that  large cohorts of high-quality prospective studies are needed to confirm the value of TCS in the diagnosis of PD.

This study had 2 major drawbacks:

1. although these researchers carefully explored the heterogeneity by meta-regression and sensitivity analyses, notable heterogeneity was still observed, which can be due to random variation between individual studies, and
2. failure to acquire unpublished data or studies not published in English or Chinese for language limitation may affect the validity of these results.

Sakalauskas and colleagues (2018) noted that transcranial ultrasonography (US) is a relatively new neuroimaging modality proposed for early diagnostics of Parkinson disease (PD).  The main limitation of transcranial US image-based diagnostics is a high degree of subjectivity caused by low quality of the transcranial images.  These investigators presented a developed image analysis system and examined the potential of automated image analysis on transcranial US.  The system consists of algorithms for the segmentation and assessment of informative brain regions (midbrain and substantia nigra) and a decision support subsystem, which was equipped with 64 classification algorithms.  Transcranial US images of 191 participants (118 patients with a clinical PD diagnosis and 73 healthy control participants) were analyzed.  The diagnostic sensitivity and specificity achieved by the proposed system were 85 % and 75 %, respectively.  The authors concluded that digital transcranial US image analysis was challenging, and the application of a such system as the sole instrument for decisions in clinical practice remained inconclusive.  However, they stated that the proposed system could be used as a supplementary tool for automated assessment of US parameters for decision support in PD diagnostics and to reduce observer variability.

Furthermore, an UpToDate review on “Diagnosis and differential diagnosis of Parkinson disease” (Chou, 2019) states that “Neurodiagnostic testing is almost always unhelpful in the evaluation of suspected PD.  The AAN systematic review and practice parameter published in 2006 found insufficient evidence to support or refute the value of certain ancillary tests for distinguishing PD from other parkinsonian syndromes, including MRI, ultrasound of the brain parenchyma, 18F fluorodeoxyglucose (FDG) positron emission tomography (PET), urodynamics, autonomic testing, and urethral or anal electromyography (EMG).  While these techniques have continued to advance, the diagnosis of PD remains predominantly clinical”.

Reversible Cerebral Vasoconstriction Syndrome

An UpToDate chapter on reversible cerebral vasoconstriction syndromes (Singhal, 2016) states that "Transcranial Doppler ultrasound has been used for diagnosis; however, normal results do not exclude this diagnosis. This noninvasive bedside tool has utility in monitoring the progression of vasoconstriction "

Levin and associates (2016) stated that reversible cerebral vasoconstriction syndrome (RCVS) is a vascular headache disorder characterized by severe headaches with vasospasm of cerebral arteries.  While TCD has been widely applied and validated in studying vasospasm of intracranial vessels, the role of TCD in the diagnosis and monitoring of RCVS is less well established.  These researchers determined the reliability of TCD for diagnosis and monitoring of RCVS.  Patients admitted to an inpatient neurology service between 2011 and 2014 with a discharge diagnosis of RCVS were retrospectively analyzed for demographics, neuroimaging, and functional outcomes.  Baseline and follow-up TCD flow velocities in the middle cerebral artery (V-MCA) were compared relative to the final diagnosis.  The cohort consisted of 15 patients (93 % females; mean age of 46.7 +/- 12.4 years); initial TCD evaluation was performed 10.9 +/- 6.6 (range of 1 to 24) days after headache onset; 14 patients (93.3 %) had increased flow velocities by initial TCD in at least 1 major cerebral blood vessel (MCA, ACA, PCA, vertebral, basilar); TCD V-MCA reached a mean peak of 163 cm/s 3 to 4 weeks after the onset of thunderclap headache.  The authors concluded that TCD is a non-invasive neuroimaging modality that may have potential for the initial diagnosis and subsequent monitoring of patients with suspected RCVS.  They stated that further studies of larger numbers of patients are needed to evaluate the utility of TCD in diagnosing and monitoring patients with RCVS.

This study had several drawbacks:

1. due to the small retrospective nature of our chart review, these researchers were unable to standardize the timing with which patients received their neuroimaging relative to headache onset,
2. although these investigators  tried to blind the sonographers to clinical data, some unintentional disclosure of vascular imaging was possible,
3. TCD may be limited by TCD technique and operator dependency,
4. the generalizability of these findings may be limited by selection bias in that the authors only included patients with known RCVS who had also undergone assessment with TCD; they did not have data about patients with RCVS who did not undergo TCD.  Thus, they could not determine the specificity of TCD for RCVS, and
5. these researchers did not have a control group to account for potential TCD abnormalities in asymptomatic individuals.

Traumatic Brain Injury

LaRovere and colleagues (2016) reviewed clinical studies using TDU in children with severe traumatic brain injury (TBI) in the pediatric intensive care unit (PICU).  These researchers identified 16 articles from January 2005 to July 2015 that met inclusion (TBI, 5 or more cases in case series, subjects less than 18 years old, TDU performed in PICU) and exclusion criteria (age not stated, data from subjects less than 18 years not separated from adult data, less than 85 % study population less than 18 years in mixed population with adults); TDU parameters were used to evaluate auto-regulation, intra-cranial pressure, and vasospasm, and to predict neurological outcome.  Incidence of impaired auto-regulation varied in severe TBI from 25 % to 80 %.  Altered TDU flows and pulsatility index variably predicted intra-cranial hypertension across studies.  Sonographic vasospasm in the MCA occurred in 34 % of 69 children with severe TBI.  Outcomes appeared to be related to altered TDU-derived flow velocities while in the ICU.  The authors concluded that TDU may be a useful tool to evaluate auto-regulation, intra-cranial pressure, and vasospasm following TBI in the PICU.  They stated that further research is needed to establish the gold standards and validate the findings in children; TDU may then impact day-to-day management in the PICU, and potentially improve outcomes in children with severe TBI.

Brain Trauma Foundation guidelines on traumatic brain injury (Carney, et al., 2016) found one Class 3 study of TDU for TBI. The guidelines stated that the body of evidence is insuffiicent to support a Level III recommendation given that this was a single-center Class III study.

Evaluation of Basilar Artery Stenosis or In-Stent Re-Stenosis

Transcranial Doppler (TCD) ultrasonography is a useful tool for evaluating cerebrovascular disease; however, it is often inaccurate. In patients with basilar artery disease, the reported sensitivity is 72% and the specificity is 94%. TCD ultrasonography is helpful in follow-up once an initial evaluation has demonstrated the lesion. The flow direction detected by TCD ultrasonography, in combination with CT angiography, may be useful before performing invasive angiography, to help predict the area of stenosis or occlusion (Cruz-Flores, 2017; Kermer, et al., 2006).

Koh and colleagues (2017) stated that there are contradictory reports concerning the validity of transcranial sonography (TCD and TCCS) for examinations of the basilar artery.  These researchers investigated sensitivity and specificity of transcranial sonography for the detection of basilar artery stenosis and in-stent re-stenosis compared to cerebral angiography.  These researchers analyzed data of 104 examinations of the basilar artery.  The association between sonographic peak systolic velocity (PSV) and degree of stenosis obtained by cerebral angiography was evaluated applying Spearman's correlation coefficient.  Receiver Operating Characteristics (ROC) curves and areas under the curve (AUC) were calculated for the detection of a greater than or equal to 50 % stenosis defined by angiography.  Optimal cut-off was derived using the Youden-index.  A weak but statistically significant correlation between PSV and the degree of stenosis was found (n = 104, rho = 0.35, p < 0.001); ROC analysis for a detection of greater than or equal to 50 % stenosis showed an AUC of 0.70, a sensitivity of 74.0 % and a specificity of 65.0 % at the optimal cut-off of 124 cm/s.  Results were consistent when analyzing examinations done in stented and un-stented arteries separately (TCD versus DSA/CTA in un-stented artery: AUC = 0.66, sensitivity 61.0 %, specificity 65.0 %, TCD/TCCS versus DSA in stented artery: AUC = 0.63, sensitivity 71.0 %, specificity 82.0 %).  Comparing TCCS measurements exclusively to angiography, ROC analysis showed an AUC of 1.00 for the detection of an in-stent re-stenosis of greater than or equal to 50 % with a sensitivity and specificity of 100 % when a PSV of 132 cm/s was used as a cut-off value.  The authors concluded that the validity of TCD in the assessment of basilar artery stenosis or in-stent re-stenosis was poor.  Moreover, they stated that first results for TCCS were promising, but due to the small sample size, further studies with larger samples sizes are needed.

Guiding Targeted Adjunctive Therapy in Cerebral Malaria

O'Brien and colleagues (2018) evaluated neurovascular changes in pediatric patients with cerebral malaria.  African children with cerebral malaria were enrolled and underwent daily TCD examinations through hospital day 8, discharge, or death.  Neurologic outcomes were assessed 2 weeks after enrollment.  A total of 160 children with cerebral malaria and 155 comparison patients were included.  In patients with cerebral malaria, TCD flow changes characterized as hyperemia were observed in 42 (26 %), low flow in 46 (28 %), microvascular obstruction in 35 (22 %), cerebral vasospasm in 21 (13 %), and isolated posterior hyperemia in 7 (4 %).  Most had a single neurovascular phenotype observed throughout participation.  Among comparison patients, 76 % had normal TCD findings (p < 0.001).  Impaired autoregulation was present in 80 % of cases (transient hyperemic response ratio 1.01 ± 0.03) but improved through day 4 (1.1 ± 0.02, p = 0.014).  Overall mortality was 24 % (n = 39).  Neurologic deficits were evident in 21 % of survivors.  Children meeting criteria for vasospasm were most likely to survive with sequelae, and children meeting criteria for low flow were most likely to die.  Auto-regulation was better in children with a normal neurologic outcome (1.09, 95 % CI: 1.06 to 1.12) than in others (0.98, 95 % CI: 0.95 to 1) (p ≤ 0.001).  The authors concluded that several distinct changes in TCD measurements were identified in children with cerebral malaria that permitted phenotypic grouping.  Groups had distinct associations with neurologic outcomes.  These researchers stated that validation of pathogenic mechanisms associated with each phenotype may aid in developing TCD as a portable, easy-to-use tool to help guide targeted adjunctive therapy in cerebral malaria aimed at causative mechanisms of injury on an individual level.

Furthermore, UpToDate reviews on “Clinical manifestations of malaria in nonpregnant adults and children” (Breman, 2019) and “Treatment of severe malaria” (Taylor, 2019) do not mention transcranial Doppler ultrasonography as a management tool.

Detection of Micro-Emboli Following Stroke or Transient Ischemic Attack

Best et al (2016) stated that identification of patients who will benefit from carotid endarterectomy is not entirely effective, primarily utilizing degree of carotid stenosis.  These investigators examined if micro-embolic signals (MES) detected by transcranial Doppler ultrasound (TCD) could provide clinically useful information regarding stroke risk in patients with carotid atherosclerosis.  They carried out a meta-analysis of prospective studies.  Three analyses were proposed examining MES detection as a predictor of: stroke or transient ischemic attack (TIA), stroke alone, and stroke or TIA; but with an increased positivity threshold.  Subgroup analysis was used to compare pre-operative (symptomatic or asymptomatic) patients and peri- or post-operative patients.  A total of 28 studies reported data regarding both MES status and neurological outcome.  Of these, 22 papers reported data on stroke and TIA as an outcome, 19 on stroke alone, and 8 on stroke and TIA with increased positivity threshold.  At the median pre-test probability of 3.0 %, the post-test probabilities of a stroke after a positive and negative TCD were 7.1 % (95 % confidence interval [CI]: 5 to 10.1) and 1.2 % (95 % CI: 0.6 to 2.5), respectively.  Furthermore, the sensitivities and specificities of each outcome showed that increasing the threshold for positivity to 10 MES per hour would make TCD a more clinically useful tool in peri- and post-operative patients.  The authors concluded that TCD provided clinically useful information regarding stroke risk for patients with carotid disease and was technically feasible in most patients.

Spence (2017) noted that with modern intensive medical therapy, the annual risk of ipsilateral stroke in asymptomatic carotid stenosis (ACS) is now approximately 0.5 %; thus, even the relative low risks reported from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial do not justify routine intervention in most (90 %) of the patients with ACS.  Therefore, It is necessary to identify the approximately 10 to 15 % of patients with ACS who have a stroke risk high enough to justify intervention; TCD embolus detection has been shown in 2 prospective studies (one with 468 patients and the other with 467 patients) to identify patients at high risk and distinguished them from those who would be better served by medical therapy.  There is no valid reason why carotid intervention should be performed in ACS without first identifying that the patient's risk of stroke was higher than the risk of intervention.  The best validated way to do this is by TCD embolus detection, and the cost of TCD equipment and training is approximately the same as the cost of 2 carotid stenting procedures in the U.S.; therefore, this procedure should be used more widely.

Mitchell et al (2017) examined the relationship between symptomatic status, TCD micro-emboli presence and plaque histopathology findings.  TCD was performed on 60 patients (37 symptomatic, 23 asymptomatic) before undergoing clinically indicated carotid endarterectomy.  The frequency of MES was not significantly different between symptomatic and asymptomatic subject groups (p = 0.88) and there were no differences observed in the macroscopic or histopathology scoring of these plaques (p-values all > 0.05).  The presence of micro-emboli was associated with an ulceration score (regardless of symptomatic or asymptomatic status, p = 0.034), with a 1-level increase in ulceration rating associated with an odds ratio (OR) of 5.86 (95 % [CI]: 1.55 to 43.4).  The authors concluded that this study, unlike much of the literature, demonstrated that in patients with advanced carotid atherosclerosis, there was no difference between symptomatic and asymptomatic subjects in high intensity transient signals (HITS) frequency or plaque composition.  This study, similar to others, did demonstrate that higher macroscopic ulceration scores were associated with the presence of MES on TCD.  These findings suggested that both symptomatic and asymptomatic subjects (with clinical indications for carotid endarterectomy) may have plaque with similar features of instability and the ability to create emboli.  Therefore, identifying new ways to measure plaque instability may provide important information for optimizing treatment to prevent future stroke.

Chen et al (2019) stated that in recent years, increasing attention has been paid to cryptogenic stroke (CS) caused by the PFO.  These researchers compared contrast transthoracic echocardiography (cTTE) and contrast TCD (cTCD) to examine if cTTE is more suitable and reliable than cTCD for clinical use.  From March 2017 to May 2018, patients who suffered from migraines, stroke, hypomnesis, or asymptomatic stroke found casually were included in this trial.  Patients with CS were semi-randomly divided into 2 groups (cTTE and cTCD) according to the date of the out-patient visit.  Patients with either of the examination above found positive were selected to finish TEE.  In this study, the sensitivities of group cTTE-positive (group cTTE+) and group cTCD-positive (group cTCD+) did not have any statistical difference (89 % versus 80 %, p = 0.236).  Focusing on group cTCD+, these investigators found that the semi-quantitative shunt grading was not correlated with whether a PFO was present or not (p = 0.194; however, once the PFO has been diagnosed, the shunt grading was shown to be related to the width of the gaps (p = 0.032, p deviation = 0.03).  The authors concluded that both cTTE and the cTCD could be used for preliminary PFO findings.  The semi-quantitative shunt grading of cTCD and cTTE could suggest the size of the PFO and the next course of treatment.  The cTTE may be more significant to a safe PFO (a PFO does not have right-to-left shunts).  These researchers stated that combining cTTE and TEE could help diagnose PFO and evaluate CS risk.

Mattioni et al (2020) noted that an occlusion or stenosis of intra-cranial large arteries can be detected in the acute phase of ischemic stroke in approximately 42 % of patients.  The approved therapies for acute ischemic stroke (AIS) are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to re-canalize an occluded intra-cranial artery.  The reference standard for the diagnosis of intra-cranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, CTA and MRA, or contrast-enhanced (CE)-MRA.  Transcranial Doppler (TCD) and transcranial color Doppler (TCCD) are useful, rapid, non-invasive tools for the evaluation of intra-cranial large arteries pathology.  Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, these investigators systematically reviewed the literature for studies examining the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intra-cranial stenosis and occlusion in individuals presenting with symptoms of ischemic stroke.  They limited their searches from January 1982 onwards as the TCD technique was only introduced into clinical practice in the 1980s.  These investigators searched Medline (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018).  Moreover, they perused the reference lists of all retrieved articles and of previously published relevant review articles, hand-searched relevant conference proceedings, searched relevant websites, and contacted experts in the field.  These researchers included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or CE-MRA (reference standards) in individuals with AIS, where all subjects underwent both the index test and the reference standard within 24 hours of symptom onset.  These investigators included prospective cohort studies and randomized studies of test comparisons.  They also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analyzed retrospectively.  At least 2 review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, evaluated methodological quality (using QUADAS-2), and examined heterogeneity; and they contacted study authors for missing data.

A comprehensive search of major relevant electronic databases (Medline and Embase) from 1982 to March 13, 2018 yielded 13,534 articles, of which 9 were deemed eligible for inclusion.  The studies included a total of 493 subjects.  The mean age of included subjects was 64.2 years (range of 55.8 to 69.9 years).  The proportion of men and women was similar across studies; 6 studies recruited subjects in Europe, 1 in South America, 1 in China, and 1 in Egypt.  Risk of bias was high for subject selection; but low for flow, timing, index and reference standard.  The summary sensitivity and specificity estimates for TCD and TCCD were 95 % (95 % CI: 0.83 to 0.99) and 9 5% (95 % CI: 0.90 to 0.98), respectively.  Considering a prevalence of stenosis or occlusion of 42 % (as reported in the literature), for every 1,000 individuals who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95 % CI: 4 to 71) and 29 (95 % CI: 12 to 58) will be wrongly diagnosed as harboring an intra-cranial occlusion; however, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to subjects examined within 6 hours.  The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good.  The authors concluded that this review provided evidence that TCD or TCCD, administered by professionals with adequate experience and skills, could provide useful diagnostic information for detecting stenosis or occlusion of intra-cranial vessels in individuals with AIS, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available.

Furthermore, an UpToDate review on “Initial evaluation and management of transient ischemic attack and minor ischemic stroke” (Furie and Rost, 2021) states that “Neurovascular evaluation -- The single most important issue to resolve in the initial evaluation of TIA and ischemic stroke is whether or not there is an obstructive lesion in a larger artery supplying the affected territory.  Noninvasive options for evaluation of large vessel occlusive disease include MRA, CTA, carotid duplex ultrasonography (CDUS), and transcranial Doppler ultrasonography (TCD).  The choice among these depends upon local availability and expertise as well as individual patient characteristics and preferences”.

Evaluation of Neurocognitive Disorders

Senel et al (2020) stated that geriatric depression is a special condition associated with a chronic course, treatment resistance and vascular processes; however, its neurobiology has not been fully elucidated.  There is no study in geriatric depression evaluating deep brain structures with transcranial sonography (TCS), which is a low-cost, non-invasive and practical tool.  These researchers examined the changes in the echogenicity of brainstem raphe (BR), substantia nigra (SN) and ventricular diameters by TCS in association with cognitive dysfunctions in patients with geriatric depression.  Echogenicity of BR and SN were evaluated and transverse diameters of the 3rd ventricle and frontal horns of the lateral ventricles were measured by TCS in 34 patients with DSM-5 major depression and 31 healthy volunteers aged 60 years and older.  Cognitive functions were examined by using Mini Mental State Examination, Montreal Cognitive Assessment Tool, Clock Drawing Test and Subjective Memory Complaints Questionnaire.  Although depressed patients had more subjective memory complaints than controls, they had similar cognitive performances.  Reduced echogenicity (interrupted/invisible echogenic line) of BR was found to be significantly higher and the ventricular diameters were larger in the depressed group.  There was no difference between the groups in terms of SN echogenicity.  There was no correlation between ventricular diameters and depression severity or cognitive functions.  The authors concluded that the findings of this study are important in terms of pointing out neurobiological changes related to geriatric depression, which are in parallel with the results of the studies in younger patients with depression.  Moreover, these researchers stated that long-term follow-up studies are needed for accurate differentiation of neurocognitive disorders.

Right VAD Implantation Following Left VAD Implantation

Kiernan and associates (2017) examined pre-implant risk factors associated with early right VAD (RVAD) use in patients undergoing continuous-flow-left VAD (LVAD) surgery.  Patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent primary continuous-flow-LVAD surgery were examined for concurrent or subsequent RVAD implantation within 14 days of LVAD.  Risk factors for RVAD implantation and the combined endpoint of RVAD or death within 14 days of LVAD were evaluated with stepwise logistic regression.  These investigators compared survival between patients with and without RVAD using Kaplan-Meier method and Cox proportional hazards modeling.  Of 9,976 patients undergoing continuous-flow-LVAD implantation, 386 patients (3.9 %) required an RVAD within 14 days of LVAD surgery.  Pre-implant characteristics associated with RVAD use included interagency registry for mechanically assisted circulatory support patient profiles 1 and 2, the need for pre-operative ECMO or renal replacement therapy, severe pre-implant tricuspid regurgitation, history of cardiac surgery, and concomitant procedures other than tricuspid valve repair at the time of LVAD.  Hemodynamic determinants included elevated RAP, reduced pulmonary artery pulse pressure (PAPP), and reduced stroke volume (SV).  The final model demonstrated good performance for both RVAD implant (area under the curve, 0.78) and the combined endpoint of RVAD or death within 14 days (area under the curve, 0.73).  Compared with patients receiving an isolated LVAD, patients requiring RVAD had decreased 1- and 6-month survival: 78.1 % versus 95.8 % and 63.6 % versus 87.9 %, respectively (p < 0.0001 for both).  The authors concluded that the need for RVAD implantation after LVAD was associated with indices of global illness severity, markers of end-organ dysfunction, and profiles of hemodynamic instability.  These researchers noted that the risk factors identified in this model should supplement the clinical judgment of a multi-disciplinary team during patient selection and pre-operative planning for LVAD surgery.

In a systematic review and meta-analysis, Reid and colleagues (2021) examined the current evidence on outcomes for patients undergoing RVAD implantation following LVAD implantation.  Studies examining in-hospital as well as follow-up outcome in LVAD and LVAD/RVAD implantation were identified via Ovid Medline, Web of Science and Embase.  The primary endpoint was mortality at the hospital stay and at follow-up.  Pooled incidence of defined endpoints was calculated by using random effects models.  A total of 35 retrospective studies that included 3,260 patients were analyzed; 30 days mortality was in favor of isolated LVAD implantation 6.74 % (1.98 % to 11.5 %) versus 31.9 % (19.78 % to 44.02 %; p = 0.001) in LVAD with temporary need for RVAD.  During the hospital stay the incidence of major bleeding was 18.7 % (18.2 % to 19.4 %) versus 40.0 % (36.3 % to 48.8 %) and stroke rate was 5.6 % (5.4 % to 5.8 %) versus 20.9 % (16.8 % to 28.3 %) and was in favor of isolated LVAD implantation.  Mortality reported at short-term as well at long-term was 19.66 % (CI: 15.73 % to 23.59 %) and 33.90 % (CI: 8.84 % to 59.96 %) in LVAD, respectively versus 45.35 % (CI: 35.31 % to 55.4 %; p ⩽ 0.001) and 48.23 % (CI: 16.01 % to 80.45 %; p = 0.686) in LVAD/RVAD group, respectively.  The authors concluded that implantation of a temporary RVAD was associated with a worse outcome during the primary hospitalization and at follow-up.  Compared to isolated LVAD support, bi-ventricular mechanical circulatory support led to an elevated mortality and higher incidence of AEs such as bleeding and stroke, which may be a functional expression of a dysbalanced hemodynamic status.

Transcranial Doppler Ultrasound for Monitoring Brain Injuries in Individuals with Left Ventricular Assist Device

Fan and colleagues (2021) noted that despite the common occurrence of brain injury in patients with LVAD, optimal neuromonitoring methods are unknown.  These researchers carried out a systematic review of PubMed and 6 electronic databases from inception to June 5, 2019.  Studies reporting methods of neuromonitoring while on LVAD were extracted.  Of 5,190 records screened, 37 studies met the inclusion criteria.  The neuromonitoring methods include transcranial Doppler ultrasound (US) for emboli monitoring (TCD-e) (n = 13) and cerebral autoregulation (n = 3), computed tomography and magnetic resonance imaging (CT and MRI; n = 9), serum biomarkers (n = 7), carotid US (n = 3), and near-infrared spectroscopy (n = 2).  Of 421 patients with TCD-e, thromboembolic events (TEs) were reported in 79 patients (20 %) and micro-embolic signals (MES) were detected in 105 patients (27 %).  Ischemic stroke was more prevalent in patients with MES compared to patients without MES (43 % versus 13 %, p < 0.001).  Carotid US for evaluating carotid stenosis was unreliable after LVAD implantation.  Elevated lactate dehydrogenase (LDH) levels were associated with TEs.  Significant heterogeneity exists in timing, frequency, and types of neuromonitoring tools.  The authors concluded that TCD-e and serial LDH levels appeared to have potential for examining the risk of ischemic stroke.  Moreover, these researchers stated that future prospective research incorporating protocolized TCD-e and LDH may assist in monitoring AEs in patients with LVAD.

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References