Sonothrombolysis in acute stroke- Dr Pallav Jain

1. SONO-THROMBOLYSIS IN ACUTE
STROKE
PRESENTER- DR.PALLAV JAIN
DM RESIDENT(NEUROLOGY)
GMC,KOTA

2. Introduction
• IV-rTPA remains the only approved drug therapy.
• Rates of the recanalization are often unsatisfactory.
• Improving the efficacy of systemic thrombolysis to achieve complete
recanalization has been the focus of research.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

3. Introduction
• Mechanical thrombectomy has been established as an interventional reperfusion
therapy for patients with ELVO.
• Stroke centers with endovascular treatment capability are scarce.
• Any novel reperfusion therapy that may enhance the lytic effect of tPA will have a
substantial impact.
 Sonothrombolysis for Acute Ischemic Stroke:A Critical Appraisal Georgios Tsivgoulis

4. Sonothrombolysis
Adjunct use of ultrasound during thrombolysis as an augmentation technique
that can facilitate clot dissolution.
Sonolysis
Some AIS patients may not satisfy the inclusion criteria of IV thrombolysis.
• In such cases, isolated ultrasound exposure has been tried.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

5. • Sonothrombolysis has shown promising results for becoming a rapidly available,
noninvasive, and portable tool.
• IVT augmentation with an ultrasound device- lower cost relative to specialized
endovascular procedure.
 Arvind Sharma.Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

6. • In the setting of acute ischemic stroke, various ultrasound protocols have been
tested with different devices,with or without the concomitant use of ultrasound
contrast material.
• After years of clinical research, much is known regarding the safety profile of low-
intensity(<700mW/cm2) and high-frequency (2 MHz) sonothrombolysis.
• Efficacy remains to be proven
 Sonothrombolysis for Acute Ischemic Stroke:A Critical Appraisal Georgios Tsivgoulis

7. Alexandrov et al. first reported in 2000
• High IVT recanalization rates with concurrent diagnostic TCD monitoring
• Treated patients had higher rates of favorable clinical recovery during TCD
monitoring at 24 h.
• This initial observation was replicated by other centers in the following years
 Alexandrov AV et al. High rate of complete recanalization and dramatic clinica recovery during tPA infusion when
continuousl monitored with 2-MHz transcranial Dopple monitoring. Stroke. 2000;31:610–614

8. • Development of ultrasound-enhanced thrombolysis stems from the clinical
observation that patients who received TCD monitoring during IVT recanalized
more frequently.
• Most clinical research has been done during IVT using diagnostic TCD.
 Sonothrombolysis for Acute Ischemic Stroke:A Critical Appraisal Georgios Tsivgoulis

9. Sonothrombolysis
• Process of delivering tPA to the binding sites at deeper layers of thrombus and
mechanically stretching the thrombus and promoting enzymatic activity which
results in augmentation of the residual blood flow and faster thrombus
dissolution.
• Arvind Sharma.Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

10. Mechanism
Ultrasound-
mechanical and
pressure wave
transient and
repeated
thinning of the
fibrin threads.
potentially
separates the
strands of fibrin
microstreaming
of blood flow
though the clot
enhancing
better and
faster clot lysis.
conformational
changes-
reversible
disaggregation
of uncrossed-
linked fibrin
fibers.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of
Stroke Medicine 1(1) 12-18, 2018

11. Other plausible mechanisms
• Microcavity formation in the shallow layers of thrombus
• Superficial vasodilation
• Promoting nitric oxide release.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

12. Acoustic windows
• For the purposes of sonothrombolysis, acoustic energy can be delivered through
acoustic windows on the skull.
• 1–2 MHz is employed- sufficient penetration and satisfactory Doppler signal.
 José C. NavarroSonothrombolysis. Manual of Neurosonology.2016

13. The four commonly employed acoustic windows in adults are—
1. Temporal - the flow velocities in MCA, ACA, PCA, and PCOM
2. Orbital - ophthalmic artery (OA) and internal carotid artery (ICA)
3. Suboccipital - allows insonation of the vertebral (VA) and basilar (BA) arteries.
4. Submandibular - evaluate the distal cervical ICA.
 José C. Navarro.Sonothrombolysis. Manual of Neurosonology.2016

15. Trans-temporal Insonation
• A red color signal (toward the probe)
between 40 and 65mm - ipsilateral
MCA.
• A blue signal between 65 and 80 mm -
ipsilateral ACA.
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

16. • The ultrasound probe is slowly oriented posteriorly by 10 to 30 degrees.
• Flow signals directed toward the probe - P1 PCA
• Away from the flow - P2 segment of the PCA
• Both segments are visualized at depths of 55-70 mm.
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

17. Suboccipital insonation
• Place the transducer just below and medial to the mastoid process.
• Ipsilateral VA between the depths of 50 to 75 mm - signals always away from the probe.
• By turning the probe slightly upward and medially from the depths of 75 to 110 mm -
BA may be insonated.
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

18. • May also be obtained through the
transforaminal window - transducer
just below the occipital protuberance
and toward the nasal bridge.
• The flow from the BA is away from
the probe.
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

19. • The normal spectral waveform - A sharp systolic upstroke and stepwise
deceleration with positive end-diastolic flow.

22. Lesion amenable to intervention (LAIT)
Defined as an occlusion or near-occlusion or ≥ 50% stenosis or thrombi in an
artery (or arteries) supplying brain area(s) affected by ischemia.
The key USG findings for the diagnosis of a lesion amenable to intervention with
thrombolysis:
• One of four abnormal TIBI waveforms in the vessel supplying a territory affected
by ischemia
• Evidence of flow diversion or collateralization to compensate for this lesion
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

23. In the absence of flow diversion or collateralization, other findings can point to the
presence of thrombus and its location
• increased velocities consistent with the presence of a stenosis
• embolic signals
• blood flow pulsatility changes in vessels proximal and distal to the suspected
obstruction
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

24. The diagnostic yieid is particularly high when performed early after the symptom
onset.
• More than 70% of patients who have significant and fixed neurological deficits
show an arterial occlusion if examined within the first 6 h of symptom onset.
 John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

25. Steps of sonothrombolysis
• Patients satisfying the inclusion and exclusion criteria for tPA administration will receive
the recommended dose of intravenous tPA
• TCD examination should begin to promptly find the acoustic window and identify the
different intracranial arterial segments
• Worst residual flow is identified as the lowest TIBI flow grade or lesions amenable to
intervention in the affected vessel.
• Store digitally as the baseline signal
 José C. NavarroSonothrombolysis. Manual of Neurosonology.2016

26. • Once the lowest TIBI flow grade has been identified and stored, the ultrasound-
monitoring probe should be fixated with the headframe to avoid probe
movements and related artifacts during sonothrombolytic treatment.
• The contact between the probe and the skin should be firm to ensure maximum
transmission of acoustic energy to the occlusion site.
 José C. Navarro Sonothrombolysis. Manual of Neurosonology.2016

28. • The continuous TCD monitoring should be performed for 120 min, while signals
received should be digitally stored every 30 min to observe for worsening or
improvement of TIBI flow grades.
• A repeat examination of baseline TCD monitoring is recommended after the
completion of IV thrombolysis at 24 hours.
• This may help in establishing a persistent recanalization, partial recanalization, or
reocclusion
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

29. Monitoring of Recanalization
• Beginning of recanalization can be timed and quantified using TIBI criteria
• Changes can be well monitored following the TIBI flow pattern for occlusion and
recanalization.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18,
2018

30. Recanalization- monitoring the following parameters:
• A change in the waveform by 1 or more TIBI residual flow grades
• Microembolic signal starts to appear (high intensity transient signals)
• Improvement of the mean flow velocity by almost 30% or more.
• Doppler signals indicating changes (30% or more) in the pulsatility indexes and
amplitude of the systolic peaks.
 Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18,
2018

32. • The appearance of highest TIBI flow grade is an indication of complete
recanalization.
• Monitoring studies during systemic thrombolysis revealed that
recanalization occurred around the median time of 17 min and maximum
TIBI flow grade was achieved at 35 min after the bolus of rTPA
 Christou I, Alexandrov AV, Scott Burgin W, et al. Timing of recanalization after tissue plasminogen activator therapy
determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31(18):1812-1816

33. Timing of recanalization
• Sudden- in which there is an abrupt appearance of normal or stenotic flow
• Stepwise- where flow improvement is observed over 1 to 29 min
• Slow- wherein recanalization is observed in more than 30 min.
 Christou I, Alexandrov AV, Scott Burgin W, et al. Timing of recanalization after tissue plasminogen activator therapy
determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31(18):1812-1816

34. • Rapid or sudden recanalization- associated with better short term improvement
• Slow (30 min or more) or partial flow improvement with dampened TIBI signals
has less favorable outcome
 Christou I, Alexandrov AV, Scott Burgin W, et al. Timing of recanalization after tissue plasminogen activator therapy
determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31(18):1812-1816

35. Limitations of Sonothrombolysis
• Operator dependent
• Insufficient acoustic window leads to an inability of monitoring the
intracranial arteries.
• The attenuation varies between patients .
 Arvind Sharma.Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine 1(1) 12-18, 2018

36. CLOTBUST (Combined Lysis of Thrombus in Brain Ischemia Using Transcranial
Ultrasound and Systemic tPA)
• Phase II, multicenter international randomized clinical trial which included 126 patients.
• Compared iv tPA vs. iv tPA plus 2-MHz transcranial Doppler monitoring for 2 h in acute
ischaemic stroke patients with middle cerebral artery occlusion within a 3 h time
window.
• A significant clinical recovery and complete reperfusion of the occluded artery was noted
in 49 % of the patients treated with iv tPA and ultrasound vs. 30 % of the iv tPA alone,
without an increase of intracerebral bleedings

40. CLOTBUST-ER
• Phase III RCT
• Total of 676 patients were enrolled
• Preliminary results :good safety profile (2.1 % vs. 1.5 % sIch rates in
the active and sham monitoring group, respectively)
• But no clinical benefit in terms of improvement of 3-month functional
outcome.
• Publication of the final analysis is awaited.

41. Microsphere-potentiated sonothrombolysis
Consists of the intravenous administration of ultrasound contrast in parallel with
sonothrombolysis.
• Ultrasound contrast consists of gas-filled microspheres (μS) that enhance the
reflection of ultrasound waves due to the great difference in echogenicity
between gas and surrounding tissues or fluids.
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis

42. The microbubbles
(microspheres) oscillate and
cavitate when exposed to
pulsed wave ultrasound
thereby releasing more energy
along the insonated tissues.
The momentum of bubble
movement can potentially
increase residual flow around
and through the thrombus
thus helping in mechanical
degradation of clot and
promoting recanalization.
Cintas P, Nguyen F, Boneu B, Larrue V. Enhancement of enzymatic fibrinolysis with 2-MHz ultrasound and microbubbles. J
Thromb Haemost. 2004;2(7):1163-1166

43. Advantages
• Microspheres produce stronger returned echoes and this process is helpful first to
overcome the barrier of insufficient temporal bone windows.
• Transmit more energy from ultrasound beam to thrombus thus further facilitating
actions of sonothrombolysis.
• Lowers the threshold of thrombolysis
• Beneficial effects on microvasculature
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis

47. Ultrasound Without Thrombolysis—Sonolysis
• Sonolysis consists of ultrasound use without thrombolytic drug
• It has been studied in AIS patients with contraindications to IVT.
• Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status Journal of Stroke Medicine
1(1) 12-18, 2018

49. • Microbubbles have their own ability to increase clot lysis in combination with
ultrasound, even in the absence of a thrombolytic drug.
• In an animal study, treatment with microbubbles and transcranial ultrasound
without tPA (sonolysis) resulted in the same improvement as treatment with iv
tPA alone.
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis.2016

50. Intraarterial Sonothrombolysis
• Infusion catheter(EKOS MicroLysUS) carrying a 2.1-MHz ring sonography
transducer at its tip, designed to work simultaneously with intraarterial
thrombolysis.
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis.2016

53. Present status in AIS
At this time, there are no RCT data to support additional clinical benefit of sonothrombolysis
as adjuvant therapy for IV thrombolysis.
2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke.American stroke
association.

55. Pitfalls
Vast majority of sonothrombolysis trials required expertise in neurosonology
• Properly identify intracranial occlusion
• Maintain ultrasound delivery to the site of thrombus
• accurately evaluate the final result as complete, partial, or no recanalization .
Recanalization has been evaluated using ultrasound criteria.
• When compared to digital subtraction angiography in real time, TCD provides an
89 % overall accuracy in detecting complete recanalization and 82 % for partial
recanalization
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis

56. Sonothrombolysis: In the era of mechanical thrombectomy
• The recent success of MT trials has marginalized other endovascular
techniques-intraarterial thrombolysis & sonothrombolysis
Two major advantages
• Retrieval of thrombus instead of dissolving it, leading to less risk of
peripheral embolization
• No thrombolytics are used intraarterially- leading to less bleeding risk.
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis

57. Ample opportunity to apply sonothrombolysis
• Majority of patients with ELVO are brought to nearest hospitals often
lacking endovascular expertise.
• High cost involved in Mechanical thrombectomy.
• Rapidly available, noninvasive, and portable tool.
 Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios Tsivgoulis

58. Future Research
Targeted sonothrombolysis
use of μS as vehicles of antithrombotic molecules to occluded arteries
• In animal study, sonothrombolysis with low IV tPA dose and tPA-tagged
μS showed equal efficacy with full-dose IVT sonothrombolysis
• Targeted therapies are a promising therapeutic approach that might
combine minimal risk and equal or superior efficacy compared to
established treatment modalities
 Hua X, Zhou L et al (2014) In vivo thrombolysis with targeted microbubbles loading tissue plasminogen activator in a rabbit femoral artery
thrombus model. J Thromb Thrombolysis 38(1):57–64

59. Conclusion
• Sonothrombolysis is a promising treatment approach
• Conclusive evidence for sonothrombolysis remains awaited
• Sonothrombolysis may play a pivotal role for AIS patients.
• Rapid advancements in the designs of therapeutic devices and microbubbles hold
promise for a better future for patients with AIS

60. References
Arvind Sharma. Sonothrombolysis in Acute Ischemic Stroke: Current Status
Journal of Stroke Medicine 1(1) 12-18, 2018
Sonothrombolysis for Acute Ischemic Stroke: A Critical Appraisal Georgios
Tsivgoulis.2016
José C. Navarro Sonothrombolysis. Manual of Neurosonology.2016
2018 Guidelines for the Early Management of Patients With Acute Ischemic
Stroke. American stroke association.
John S. Pellerito. Introduction to Vascular Ultrasonography.6TH edition.2016

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