Stroke is a leading cause of death and disability worldwide and represents a major global health burden. Each year, an estimated 12 million strokes occur worldwide, with one stroke related death every 5 seconds.¹ Acute ischemic stroke (AIS) accounts for nearly 90% of all strokes and is caused by a thrombotic occlusion of a cerebral artery.² Of particular concern are large vessel occlusion (LVO) strokes which involve major cerebral arteries and are associated with high mortality when timely reperfusion is not achieved.³

Over the past few decades, acute stroke care has been transformed by the development of effective treatments such as intravenous thrombolytics (IVT) and endovascular therapy (EVT). However, utilization of these resource intensive therapies remains limited, especially in many low and middle income countries (LMIC) where health systems lack the infrastructure and workforce needed for such specialized stroke care. As a result, around 60% of stroke related deaths occur in LMICs.^4,5

Addressing global disparities in stroke care requires innovative, cost effective and resource efficient treatments. One such emerging intervention is sonothrombolysis which uses ultrasound waves to cause or enhance clot breakdown. From a global health perspective, this reperfusion therapy is advantageous as it’s noninvasive and reusable. However, despite over two decades of research on sonothrombolysis, there has been no publication exploring the potential role of this acute stroke treatment within the context of global stroke care.

Therefore, this narrative review aims to a) assess global health barriers to current stroke treatments, b) explain the biophysical mechanism of action and supporting clinical evidence of sonothrombolysis and c) outline key directions for future research.

First line acute treatments for AIS include IVT, with either tissue plasminogen activator (tPA) or Tenecteplase (TNK), as well as EVT. These therapies have transformed acute stroke management and helped overcome the historical therapeutic nihilism once associated with stroke. However, global utilization of these therapies remains limited in practice, largely due to systemic, logistical and financial barriers.

IVT was the first major treatment shown to improve outcomes in AIS with landmark trials in the late 1990s and early 2000s.^6,7 Although 30–40% of patients treated with IVT achieve good functional recovery, the potential impact of this therapy is limited by several important constraints that affect usage in both first world countries as well as globally.⁸ One main limitation is the narrow therapeutic window which requires administration within 4.5 hours of symptom onset. This presents major challenges for timely symptom recognition and emergent evaluation. Even if patients arrive within this window, eligibility is often limited by contraindications such as anticoagulant use or active bleeding. Costs further restrict access as prices for tPA and TNK in the United States range from $6,000 to $9,000.⁹ Collectively, these factors contribute to the low global utilization of IVT with an estimated 7–10% patients receiving the treatment worldwide.⁴

EVT is currently the most effective treatment for AIS, with a number needed to treat of just 5 to achieve full or near-full recovery.³ However, EVT is a resource intensive procedure requiring highly trained neurointerventionalists, advanced imaging, high-cost equipment, and access to catheterization surgical facilities. Even in resource rich places such as the United States, access is still limited as only 27% of rural stroke patients present to a hospital with thrombectomy capabilities.¹⁰ Globally, this disparity is even more pronounced as fewer than 2% of worldwide stroke patients receive MT, with rates 90% lower in LMIC compared to high income countries.^11,12

Despite major therapeutic advances, the clinical benefits of both IVT and MT remain inaccessible to most stroke patients with access concentrated in urban centers of wealthy countries. This inequality highlights the urgent need for an alternative thrombolytic strategy that is accessible to all health care systems, even those with limited resources.

Sonothrombolysis offers a promising and resource-efficient alternative to conventional thrombolytic therapies. This treatment uses the mechanical energy of ultrasound waves to promote thrombolysis. Sonothrombolysis can be administered with minimal technical training and does not need highly specialized personnel or an advanced procedural infrastructure. Recent technological innovations, including wearable ultrasound and handheld and automated targeting systems, have further reduced operator dependence, enabling fully automated delivery.¹³

From a materials perspective, sonothrombolysis devices are compact, portable, and reusable, with current devices comparable in size and weight to a typical bicycle helmet. Many devices operate at the same ultrasound frequencies used in transcranial diagnostic imaging, creating the potential to repurpose existing ultrasound platforms for therapeutic use. Since diagnostic ultrasound is already widely used around the world, this compatibility would help accelerate the implementation of sonothrombolysis.¹⁴

Together, these features of non-invasive, automated, portable, and reusable make sonothrombolysis a practical global thrombolytic therapy. These features align with the infrastructural and operational needs of any strong global health system, positioning it as a promising solution to expand access to acute stroke therapies worldwide.

Sonothrombolysis uses the energy of ultrasound waves to exert mechanical forces on the thrombus to ultimately cause fragmentation and lysis of the thrombosis. Ultrasound consists of longitudinal sound waves with frequencies well above the 20 kHz upper limit of human hearing. In medical applications, diagnostic ultrasound typically uses frequencies between 2 and 20 MHz. These waves propagate through media such as tissue or bone as alternating cycles of compression and rarefaction and transmit energy to the surrounding particles. In both diagnostic ultrasound and sonothrombolysis, pulsed wave delivery is typically used and consists of brief ultrasound bursts followed by a listening interval of reflected waves.

Frequency and amplitude are two important features of a wave for energy transfer. Frequency, measured in hertz (Hz), is the number of cycles a wave completes per second, and amplitude is the maximal displacement of a particle during its wave cycle. The frequency is inversely related to its wavelength with higher frequency waves having shorter wavelengths. While wavelength and speed may change as a wave passes through different material, the frequency does not and remains constant. The higher the amplitude, the more energy there is per wave, and the higher the frequency, the more total waves and therefore more total energy over a period of time.

This transmitted energy from ultrasound then interacts with the thrombus through several key mechanical forces to cause thrombolysis.^15-19

The first major sonothrombolysis trial, NOR (Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA), was a Phase II trial that enrolled 126 LVO stroke patients.²² This trial was published in 2004 and helped establish the foundation of ultrasound-enhanced thrombolysis. Utilizing 2-MHz pulsed-wave ultrasound in patients with proximal middle cerebral artery occlusion, CLOTBUST demonstrated a significant increase in the primary endpoint of complete recanalization or early dramatic clinical recovery compared to IVT alone (49% vs. 30%, respectively). Notably, complete early recanalization (within two hours) was achieved in nearly half of the patients receiving sonothrombolysis (46%), compared to only 11% in the control group. Safety outcomes were reassuring as symptomatic intracerebral hemorrhage (sICH) rates were small (4%) and similar between groups. CLOTBUST suggested that sustained radiation effects could be used to improve recanalization and showed that streaming and radiation forces operate at low clinical risk. However, the study was not designed to assess clinical outcomes and despite the promising recanalization results, the effects on functional recovery was limited.²² Importantly, the trial was conducted before the early EVT trials and only 20% of study patients underwent concurrent EVT. This provided a unique opportunity to assess the direct effect of sonothrombolysis without the confounding influence of EVT, as well as highlight its potential in acute stroke care in settings where EVT is not available.

The success of CLOTBUST, especially before the major EVT trials, generated widespread interest in sonothrombolysis. This trial was followed by the Phase III CLOTBUST-ER (Combined Lysis of Thrombus Using Transcranial Ultrasound and Systemic t-PA for Emergent Revascularization) multinational trial which was designed to examine clinical outcomes in sonothrombolysis. Like the previous trial, sonothrombolysis was performed on stroke patients who also received IVT.²³ A new operator- independent ultrasound headset was used to simplify delivery. Ultimately, the primary endpoint of improved functional outcome at 90 days was not met in the 676 patients enrolled as both groups demonstrated a similar median modified Rankin Scale (mRS) score of 3.0. Safety outcomes of sICH were still reassuring as they remained low and comparable at 3%. As seen in Table 1, the limited data from the Phase III CLOTBUST-ER trial reaffirmed what CLOTBUST had shown regarding the low side effects of streaming and radiation forces.

While the CLOTBUST-ER trial abruptly ended much of the excitement for sonothrombolysis, there was significant criticism about the design of the trial. One main limitation of the trial design was that it did not require the presence of LVO on vascular imaging and instead enrollment was based on a National Institutes of Health Stroke Scale (NIHSS) score greater than 9. Since this was a large phase III pragmatic trial, NIHSS was used as surrogate for LVO as routine CT angiography was not yet widely available²³. However, subsequent evidence has clearly demonstrated that NIHSS alone is a poor predictor of LVO and this likely led to many non-LVO strokes patients, ones who would not be expected to benefit from sonothrombolysis, to be included.²⁴ Additionally, this trial was conducted during a pivotal period of stroke care where EVT was rapidly becoming the standard of care in resource rich settings and multiple simultaneous EVT trials being performed worldwide. In a post hoc retrospective analysis of the CLOTBUST-ER trial, investigators from participating centers reported that they preferentially enrolled patients with confirmed LVO into concurrent EVT trials and reserved non-proximal LVO patients, including suspected small vessel disease strokes or medium vessel occlusions (MEVO) on CT angiograms, for this sonothrombolysis trial.²⁵ Since CT angiograms were not required, the percentage of LVO stroke patients included, which was the intended population for this trial, is unknown. Subsequent post hoc analysis excluding the centers that preferentially diverted LVO patients to EVT studies, showed a favorable shift in mean mRS at 3 months in the sonothrombolysis group (2.0 vs. 3.0, although not statistically significant), with higher odds of 3 months functional independence (adjusted odds ratio 1.53, p<0.05).²⁵

During this same time, there was another landmark sonothrombolysis trail, the NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) trial, which examined the role of contrast enhanced sonothrombolysis.²⁶ This phase III trial enrolled 183 patients with AIS who were eligible for IVT and randomized them to contrast enhanced sonothrombolysis (CEST) vs IVT alone. These methods had the greatest potential for both clot busting and serious side effects. The NORSASS trial relied on cavitation, rather than acoustic or streaming forces, carrying a higher risk of ICH. Promisingly, results showed no significant safety differences between CEST vs. IVT groups. However, there were similar limitations to this trial as it included both LVO and non-LVO strokes, with only 19% having confirmed LVO and just 11% having proximal occlusions. Overall, there was no significant difference in the primary clinical endpoint of early neurological improvement at 24 hours (51% in CEST vs. 46% in IVT alone). Among patients with confirmed arterial occlusions, the findings were more encouraging as partial or complete recanalization was achieved in 62% of the CEST group compared to 37% in the IVT alone group.²⁶ To date, there have been no studies on sonothrombolysis in either LMIC settings or in patients without access to acute reperfusion therapies.

Clinical trials investigating sonothrombolysis have been promising, though still inconclusive, regarding its potential as a reperfusion therapy. While studies have consistently demonstrated higher rates of recanalization, this has yet to translate into clear improvements in functional outcomes. However, this apparent discrepancy between reperfusion and clinical results should be viewed in the context of the resource rich countries where the trials were conducted, as patients with LVO stroke typically proceed to EVT, limiting the ability to detect a direct clinical benefit from sonothrombolysis.

As worldwide incidence of stroke continues to rise, there are many important future areas of research for sonothrombolysis. This includes ultrasound technology as well as clinical research.

Advances in ultrasound technology will be critical for improving the safety and efficacy of sonothrombolysis. Initial devices have been quite basic relying on a single frequency, fixed-position ultrasound delivery system. Dynamic targeting systems that use different ultrasound source positions and use varying frequencies need to be developed and tested to optimize mechanical forces on the thrombus while limiting harmful standing waves. Equally important are safety measures such as real-time feedback systems that monitor for intracranial acoustic exposure and adjust energy output accordingly. Safety protocol refinements such as adaptive duty cycles, automated shutoff thresholds, and individualized sonication profiles will improve the risk-benefit balance. Studies examining the usage of frequencies that match the resonance of a thrombus are needed to help improve thrombolysis rates as well as time to recanalization.

Clinical research will need to prioritize testing on patient populations who are most likely to benefit clinically from sonothrombolysis. These should include stroke patients with confirmed proximal LVOs as opposed to a heterogenous group of stroke patients including small vessel or MEVOs. Patients in LMIC settings should be prioritized to determine if sonothrombolysis has a role in areas without access to EVT. Additionally, the effect of sonothrombolysis both as an adjunct to IVT and as a standalone need to be examined.

Further work is required on optimizing the implementation of sonothrombolysis therapy in LMIC. We propose that this would not require novel machinery because sonothrombolysis can repurpose existing TCD ultrasound systems already widely available across stroke centers. Adding standardized TCD-based protocols to pre-existing stroke checklists and quality-improvement cycles can complement thrombolytic therapies without major infrastructure upgrades.

As both the technology and clinical understanding evolve, optimizing ultrasound parameters and trial design will be essential steps toward making sonothrombolysis a practical, global health therapy.

Sonothrombolysis represents a compelling opportunity to expand access to acute stroke reperfusion therapies on a global scale. Its noninvasive nature, relative affordability, and potential for operator-independent application make it particularly attractive for LMICs, where current standard-of-care therapies like EVT remain out of reach for most patients. While early trials have been limited by patient selection and evolving standards of care, the consistent findings of improved recanalization rates suggest a therapeutic potential. By prioritizing targeted research in high-risk LVO populations in under-resourced health systems, and advancing ultrasound delivery technologies, sonothrombolysis has the potential to bridge critical global disparities in stroke care by delivering noninvasive reperfusion to the millions of patients currently beyond reach of IVT and EVT.