NeuroNews issue 46 – EU

May 2022 | Issue 46

Jury still out on TCAR

What is the link?

79%

21%

For

Featured in 4 this issue: COVID-19 and stroke

Against

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ESOC 2022: Global studies shed new light on clinical outcomes with tenecteplase

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page 14

New frontiers explored in brain stimulation therapies

Owing to the multitude of perceived pharmacological advantages it offers—including high fibrin specificity, long half-life and simple administration route—interest in the intravenous thrombolytic drug tenecteplase is growing all the time. And, while clinical data on its efficacy and safety have been relatively limited to date, a number of late-breaking trials presented during the recent European Stroke Organisation Conference (ESOC 2022; 4–6 May, Lyon, France) sought to rectify this. Studies spanning Europe, Canada and Australia expanded on the existing body of evidence regarding this relatively new alternative to alteplase—the current gold standard in acute ischaemic stroke patients receiving intravenous thrombolysis (IVT). he first of these studies was delivered on behalf of the AcT randomised controlled trial (RCT) investigators on the opening day of ESOC 2022. The investigators noted at the outset of their presentation that alteplase is the current, global gold standard in IVT and, while phase 2 studies have indicated potential benefits with tenecteplase, its safety and effectiveness remain unknown.

The phase 3, multicentre, prospective AcT trial attempted to build on this knowledge base, they claimed, randomising thrombolysis-eligible acute ischaemic stroke patients on a 1:1 basis to receive either intravenous alteplase at 0.9mg/kg or tenecteplase at 0.25mg/kg. Its primary endpoint was a modified Rankin Scale (mRS) score of 0–1 at 90 days, while secondary endpoints included several functional, quality-of-life and process metrics. Safety outcomes included 90-day mortality, symptomatic intracerebral haemorrhage (ICH) within 24 hours, peripheral bleeding requiring blood transfusion and orolingual angioedema.

Across 22 Canadian study sites, a total of 1,600 patients were

Profile Pedro Lylyk

randomised, with 806 being included in the tenecteplase group (median age=74 years; 47.4% female) and 771 being included in the alteplase group (median age=73 years; 48.4% female) for intention-to-treat (ITT) analysis, with no significant differences in any baseline characteristics between the two groups.

Reporting the results—which the triallists said are considered preliminary data, undergoing peer review at the time of writing—they stated that AcT met its non-inferiority threshold, with 36.9% of patients in the tenecteplase group achieving a 90day mRS 0–1 compared to 34.8% in the alteplase group, for an unadjusted risk difference of 2.1% across the ITT population.

They added that the 90-day mortality rates were 15.2% and 15.6% in the tenecteplase and alteplase groups, respectively, with 24-hour rates of symptomatic ICH being 3.4% and 3.1%, respectively. In addition, they reported no significant differences in any secondary outcomes between groups, and said perprotocol and further sensitivity analyses yielded similar results.

Continued on page 2

THIS EDITION OF NEURONEWS features a myriad of indications within which neuromodulation technologies are thought to offer genuine therapeutic promise but, as yet, have been subject to relatively limited clinical research.

A randomised controlled trial assessing the use of transcranial direct current stimulation in young patients with autism spectrum disorder is among the highlights from these new frontiers, following publication in Brain Stimulation by Yvonne Han (Hong Kong) et al.

Having also been the subject of major clinical research in the recent past, other promising applications of neuromodulation technologies, including in treating the negative symptoms of schizophrenia, using transcranial magnetic stimulation, and in alleviating the burden of heart failure, using vagus nerve stimulation, feature as well.

In addition, Marom Bikson (New York City, USA) and Jesse Dawson (Glasgow, UK) offer their thoughts on how the landscapes of longCOVID and stroke rehabilitation, respectively, are set to be altered by neuromodulation moving forward.

To read about these breakthroughs and insights, and much more from the world of neuromodulation, turn to page 19.

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May 2022 | Issue 46

Tenecteplase

ESOC 2022: Global studies shed new light on clinical outcomes with tenecteplase Continued from page 1

Delivering their concluding message at ESOC, the AcT investigators said this large RCT showed 0.25mg/ kg of tenecteplase to be non-inferior to alteplase in terms of 90-day functional outcomes after stroke, with a similar safety profile. “Therefore, in our opinion, and based on these results, tenecteplase is a very reasonable alternative to alteplase in patients meeting standard indications for IVT—across every subgroup,” they stated. They also noted that these preliminary data are undergoing peer-review scrutiny and are expected to be published in a journal in the coming weeks.

Tenecteplase in Europe

Late-breaking data from two more RCTs assessing tenecteplase in ischaemic stroke featured at ESOC 2022, with the first of these being delivered on behalf of the Norwegian NOR-TEST 2A investigators. The triallists began by noting that the previous NOR-TEST study showed similar effectiveness and safety to alteplase in minor stroke and, following on from this, the NORTEST 2A trial aimed to evaluate whether 0.4mg/kg of tenecteplase is non-inferior to 0.9mg/kg of alteplase in moderate or severe stroke. Its primary endpoint was no significant disability and independence in all activities, assessed as mRS 0–1, at 90 days after stroke.

Having included and randomised 216 patients, the trial was terminated prematurely due to an increased number of symptomatic ICHs in the tenecteplase group compared to the alteplase group (6% vs 1%). Also, the investigators reported that mortality was increased (15.6% vs 4.8%) and the proportion of patients with a favourable outcome (mRS 0–1) at 90 days after stroke was lower (32.3% vs 51.5%) with tenecteplase. Thus, 0.4mg/kg of tenecteplase yielded worse safety and functional outcomes than alteplase in moderate or severe stroke—leading the researchers to conclude that further assessment involving lower tenecteplase dosages, such as in the upcoming NOR-TEST 2B study, is warranted.

Speaking to ESOC TV at the event, the AcT investigators said preliminary data from their trial and NOR-TEST 2A could be seen to complement one another in delivering much-needed evidence on tenecteplase. They claimed that positive outcomes seen with 0.25mg/kg dosages in AcT and the safety concerns observed with 0.4mg/kg in NOR-TEST 2A combine to signal the amount required to safely provide clinical benefit, and may “shut the door” on explorations

into that higher dosage of tenecteplase—a point that the NOR-TEST 2A investigators said is “completely possible”. The AcT triallists noted that, having demonstrated non-inferiority, with a trend towards benefit versus alteplase, preliminary data from their trial suggest it succeeded in its goal of providing results that could ultimately trigger a shift within clinical practice guidelines, and that tenecteplase may be suitable as the default IVT option across many patient subgroups.

A second European RCT involving tenecteplase was presented during the final day of ESOC 2022, with results from the TWIST trial being disclosed for the first time. TWIST aimed to investigate whether IVT with 0.25mg/kg of tenecteplase, administered within 4.5 hours after ‘wake-up’ time, results in a better functional outcome in patients who wake up with an acute ischaemic stroke, as compared to no thrombolytic treatment. A total of 288 patients were randomised to receive tenecteplase and 290 were randomised to the control group in TWIST. No significant difference was found between the two groups in terms of the primary outcome (ordinal shift analysis across 90-day mRS scores) and—while a higher proportion of patients achieved an mRS 0–1 with tenecteplase (45% vs 38% in the control group)—this difference was not statistically significant. Regarding safety outcomes, the TWIST triallists found a similar 90-day death rate between the two groups, while the proportions and risk estimates of symptomatic ICH in the tenecteplase group were no higher than those reported in previous stroke studies.

Across the globe

Elsewhere at ESOC, audiences were presented with results from TASTE-A—a phase 2 RCT that set out to determine whether tenecteplase (0.25mg/kg) would result in a superior outcome over alteplase (0.9mg/kg) when used by mobile stroke units (MSU) administering IVT. The study included 104 patients presenting to an MSU within 4.5 hours of symptom onset in Melbourne, Australia and its primary outcome was the extent of perfusion lesion on imaging upon arrival at the receiving hospital. In addition, secondary outcomes included time from MSU arrival to treatment, National Institutes of Health Stroke Scale (NIHSS) changes and 90-day mRS. Detailing their results, the TASTE-A investigators said stroke patients treated with tenecteplase had a significantly smaller perfusion lesion on average compared to those treated with alteplase. Patients treated with tenecteplase also had a significantly higher chance of ultra-early clinical improvement (NIHSS change) and were treated significantly faster than those treated with alteplase (median of seven minutes). There was no difference in the incidence of symptomatic cerebral haemorrhage or any other safety concerns, they said.

To also read about the latest developments regarding alteplase-based IVT, turn to page 9.

News in brief

The latest stories from the neuro world

n “WE CAN FINALLY SAY WE HAVE CONQUERED THE BASILAR ARTERY TERRITORY—IT WAS ABOUT TIME!”: Raul Nogueira delivered late-breaking data from the ATTENTION study at the 2022 European Stroke Organisation Conference, reporting improved rates of independent and functional outcomes, and lower overall disability and mortality rates, at 90 days with endovascular therapy versus best medical management.

For more on this story go to page 7. n WOMEN LESS LIKELY TO RETURN TO WORK AFTER SEVERE STROKE, NEW STUDY FINDS: According to new research published in Stroke by Marianne Hahn and colleagues, about one third of people who had a severe % ischaemic stroke and underwent a mechanical thrombectomy resumed work three months after stroke treatment, while women were about half as likely to return to work after a severe stroke compared to men.

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For more on this story go to page 8. n RECOMMENDED USE OF SPINAL CORD STIMULATION HAS NOT LED TO INCREASED UPTAKE: Only a small proportion of neuropathic pain patients in England who are potentially eligible for spinal cord stimulation have received this intervention over the past decade, as per a retrospective cohort study conducted by Rui Duarte and colleagues and published in Neuromodulation: Technology at the Neural Interface.

For more on this story go to page 21.

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5/6/2022 3:22:33 PM

May 2022 | Issue 46

COVID-19 and Stroke

Alarming trends and alarmist myths: What is the link between COVID-19 and stroke?

Over the course of the past two years, the accepted understanding of how COVID-19 spreads and functions has improved vastly, with preventative vaccines and therapeutic drugs enabling patients to be treated more effectively. However, the relationship between the virus and many other severe conditions, such as stroke, is still shrouded in uncertainty. Early data from stroke patients with COVID-19 were divisive and, while several studies have since attempted to build on this, many questions remain unanswered. Here, NeuroNews gathers European and US perspectives from two physicians spearheading global research efforts to elucidate the link between COVID-19 and stroke.

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he first COVID-19 case in New York was confirmed on 1 March 2020. By the end of that month, cases in the city were in the tens of thousands and New York City had become the worst affected region anywhere in the USA. Amidst the widespread panic surrounding a virus about which so little was known at the time, researchers at Mount Sinai Health System moved quickly to alert the world to a concerning early observation at their centre—large vessel occlusion (LVO) stroke as a presenting feature of COVID-19 in younger patients.

Speaking to NeuroNews, Johanna Fifi (Mount Sinai Health System, New York, USA), one of the authors who published this preliminary finding from five patients (aged <50 years) in the New England Journal of Medicine (NEJM) in April 2020, notes that their report was far from being universally accepted at first.

“When New York City became one of the centres of the pandemic, we had a huge spike in infections and we were able to see this pattern over the course of two weeks of these younger patients coming in with stroke, and it sparked some scepticism from other parts of the country, because they were not seeing that,” she says.

According to Fifi, many other US centres were in fact seeing a decline in strokes—something that is now thought to have been caused by significantly fewer stroke presentations, particularly in more minor cases. A recent population study from Alberta, Canada, published in the Canadian Medical Association Journal, found a marked decrease in the number of stroke admissions compared to pre-pandemic numbers, and concludes that this is unlikely to indicate true declines in stroke occurrence but more likely reflects “pandemic-related hospital avoidance”. An alternative explanation offered by Fifi is that people generally being less active, among other lockdown-related lifestyle changes, may have reduced the stroke rate in some populations, although more evidence is needed to confirm this.

“We saw an overall increase in young people with LVO stroke, because COVID-19 causes clots to form that block the large vessels in the head and neck, and this was affecting slightly younger people who do not normally have strokes,” Fifi continues.

“Elsewhere in the USA, and in other countries, there were lower infection numbers, so they just were not seeing this group of younger patients coming in. Some people wrote editorials on this, and one in particular suggested we were being alarmist, but—once COVID-19 spread across the rest of the country— people were able to look at their numbers, and that pattern was confirmed in numerous other cities and by big collaborations as well.” The publication Fifi references here is a letter published in Neurosurgery in September 2020, entitled “Dismantling the Apocalypse Narrative: The Myth of the COVID-19 Stroke”, which concluded that “there is currently no evidence supporting COVID-19 as a risk factor for stroke, independently of sepsis”.

Global perspectives

As Fifi points out, it did not take long for this early finding to be verified by other groups across “hundreds” of academic papers and a more comprehensive report was published by Fifi and colleagues in The Lancet Neurology in September 2020. It alludes to findings from several thrombectomy case series in COVID-19 patients, including at Rothschild Foundation Hospital (Paris, France), in which the mean patient age is “younger than the typical population having this procedure”, as well as a retrospective cohort study at NYU Langone Health (New York, USA) that found COVID-19 patients with imaging-confirmed stroke were seven years younger, on average, than those in a control group who tested negative for SARS-CoV-2.

Despite a relative wealth of evidence on this phenomenon during the first few months of the pandemic, however, research into this and other aspects of the COVID-19-stroke relationship has since slowed, according to Richard Perry (University College London Hospitals, London, UK). “Not as much progress has been made as we might have hoped,” he tells NeuroNews. “There was a flurry of publications in 2020 and early-2021, but remarkably little in the way of new, more long-term clinical data has emerged since then.” Perry also notes that the current literature in this space is “extremely patchy”. “I think, without a shadow of doubt, recruitment biases have been a major contributing factor in creating these huge inconsistencies, where—for example—one study says LVOs are more common and then another study says they are not,” he claims, adding that variations in the data seen between different countries are more likely to relate to the study populations or healthcare settings involved, as opposed to actual geographical discrepancies.

Much like Fifi and her team at Mount Sinai in the USA, Perry has been at the forefront of efforts from within the UK to elucidate the link between COVID-19 and stroke. He was the lead investigator for the case-control SETICOS study, which collected data from 13 hospitals in England and Scotland in mid-2020. It included 86 patients with evidence of COVID-19 at the time of stroke onset, and compared them to 1,384 stroke patients admitted during the same timeframe who never had evidence of COVID-19. The vast majority of strokes in both patient groups were ischaemic, as opposed to haemorrhagic, in nature.

Findings from SETICOS were published in the Journal of Neurology, Neurosurgery and Psychiatry in November 2020. Presenting these findings at last year’s European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual), Perry said: “COVID-19 does appear to have a significant impact on stroke.” He reported that the proportion of ischaemic strokes was higher in the COVID-19

group and that, looking at those ischaemic strokes, COVID-19 cases were associated with a greater stroke severity on admission, a higher mortality rate during admission, and more severe disability on discharge.

“There was also an association between COVID-19 and the finding of multiple LVOs on CT [computed tomography] angiography,” he added.

“The main thing that comes out very consistently is that, if you have COVID-19 at the time of your stroke, your outcome is worse—there is no doubt about that,” Perry continues. “One can argue about what mechanisms are behind this, but that is a very, very consistent finding across all of the studies.”

This view is endorsed by Fifi, who adds that there are various large epidemiological studies showing that stroke in COVID-19 is different from other strokes, and the outcomes of COVID-19-related stroke are often worse than those seen in stroke patients without COVID-19 from the same patient cohorts. “This is also the case with other viruses, but it is increased with COVID-19—with a risk that is potentially seven times higher compared to influenza,” she states. “This is very well-accepted at this point, more than two years on from when it was first noted.”

Alarming trend or alarmist myth?

Discussing the “very famous” NEJM report from Mount Sinai on younger LVO stroke patients with COVID-19, Perry

Johanna Fifi

notes that his own stroke unit published a similar cases series of six patients around the same time—but believes such publications now serve as “a lesson in being very careful not to overinterpret small case series”. “We now have a better level of evidence, through cohort studies with proper COVID-19-negative controls, from which to draw conclusions,” he adds. “In our study [SETICOS], the age distribution of the COVID-19-positive and COVID-19-negative patients was identical, so it cannot be the case that patients who have COVID-19 at the onset of their stroke are a completely different population with a younger median age.

“I think that, among patients presenting to a stroke unit through the usual patient pathways, those with COVID-19 are not younger. There does seem to be a difference with regard to the frequency of LVOs, but this varies from one study to another, and it is not as straightforward as we perhaps thought it might be at the time of those early reports. Our study did not show any difference in the overall frequency of LVOs. We did find a significantly higher proportion of patients with multiple LVOs in our COVID-19 group, but I do not know whether that will be confirmed in other studies.”

Fast-forward to April 2021—a full year on from

Image_credit

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Issue 46 | May 2022 the publication of those initial case reports—and a review paper in Trends in Neurosciences, which Fifi was also the lead author for, can be seen to corroborate this more tentative viewpoint. Here, the researchers acknowledge limitations surrounding their previously reported experience, as well as noting that the high prevalence of COVID-19 in New York City at the time those studies were performed “raises the possibility that COVID-19 infection in the young stroke patients described previously may have been incidental”. They further state that, in elderly patients, the presence of diabetes, hypertension and many other traditional risk factors for stroke—even at differential rates between COVID-19 positive and negative cohorts— makes elucidating the exact role of COVID-19 in stroke pathogenesis difficult. “Further study of large cohorts is necessary to understand the extent to which COVID-19 infection precipitates stroke as well as the underlying pathogenesis,” they conclude.

The greater breadth of evidence both Fifi and Perry call for could be seen to have emerged in the early part of 2022, however. An international, multicentre study published in Neurosurgery in March—which claims to be the largest study on LVO stroke and COVID-19 to date—came to the conclusion that LVO stroke patients with COVID-19 were younger, and generally healthier, than those not infected with the virus. Conducted through a global collaboration led by

COVID-19 and Stroke

Further evidence required

Perry has his reservations regarding studies like this that assess COVID-19-associated stroke against historical controls. “Such comparisons are flawed because of an unavoidable bias,” he says. “Patients with mild stroke stayed away from the hospital, certainly during the first phase of the pandemic. Thus, the average stroke is more severe in pandemic patients than pre-pandemic patients—regardless of their COVID-19 status. So, taken at face value, such studies will tend to show that COVID-19 causes more severe strokes even if, in fact, it does not.”

While he contests the evidence upon which COVID-19 has been linked to LVO stroke in younger, healthier patients, Perry feels that alternative studies, such as SETICOS, and analyses conducted by other US groups in New York and Chicago, as well as European teams in Paris and Madrid, offer more telling insight. He attributes this to their use of contemporaneous control groups. “These studies can tell us about the impact COVID-19 has on stroke,” he asserts.

“Strokes—whether ischaemic or haemorrhagic— appear to be much more severe in patients with COVID-19, with a higher mortality,” Perry adds, reaffirming data from the SETICOS study. He also notes that most of the existing information relates to ischaemic stroke, and that haemorrhagic stroke is a more difficult topic to study. “We have done a meta-analysis of existing published data, which shows that outcomes [in haemorrhagic strokes] are much worse,” he states. “However, the question of whether COVID-19 increases the risk of intracerebral haemorrhage is potentially confounded by intensive care unit-related treatments for severe COVID-19, which may increase that risk too.”

Perry is also quick to emphasise that the question of whether COVID-19 actually ‘causes’ stroke is a distinct matter, and one that is “very difficult” to assess. “There are hints that, in a small minority of patients with COVID-19 at the onset of their stroke, the stroke was ‘caused by’ the virus, but that is hard to prove,” he says. “There may be a small subgroup of patients whose strokes are caused by COVID-19-related Richard Perry mechanisms, and they may need a different treatment approach—particularly with regard Thomas Jefferson University to antithrombotic agents. This is perhaps the most (Philadelphia, USA), the important question of all for future research.” retrospective analysis evaluated a total of 575 acute LVO patients across 50 comprehensive stroke centres. Some 194 of these patients had COVID-19, while 381 (a control group of LVO stroke patients who received a mechanical thrombectomy between January 2018 and December 2020) did not.

An examination of these data revealed that, on average, patients with COVID-19 were nearly 10 years younger than those without (mean age=62.5 vs 71.2 years), and the COVID-19 group also contained twice as many people under the age of 50 years. In general, those in the COVID-19 group had fewer cerebrovascular risk factors, and were more likely to experience unfavourable outcomes, with higher morbidity/mortality rates being observed compared to the non-COVID-19 group. The study’s corresponding author, Pascal Jabbour (Thomas Jefferson University, Philadelphia, USA), noted that “many neurosurgeons” saw that COVID-19-positive stroke patients were often younger, had multiple large vessels blocked, and frequently had worse outcomes than their usual Future research directions patients, at the start of the pandemic, adding: “This On this front, Perry and Fifi are well-aligned. Both international study confirms those early, alarming allude to the important role future research will observations.” play in elucidating the myriad of mechanisms by

Image_credit

Without a shadow of doubt, recruitment biases have been a major contributing factor in creating these huge inconsistencies, where—for example— one study says LVOs are more common and then another study says they are not.”

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which COVID-19 may influence and/or cause stroke symptoms. “Funding to support basic investigations into the pathogenesis of stroke in COVID-19 would be helpful,” Fifi states. “And, the mechanisms by which COVID-19 induces thrombus formation are important to fully elucidate.” She also notes that these investigations could be even more complex, and will entail laboratory studies and further pathologic data to gain an improved understanding of the virus itself.

Similarly, Perry outlines five key areas that are among numerous factors thought to play a role in this relationship—mainly based on blood and cerebrospinal fluid tests in severe COVID-19 patients.

These include coagulopathy, angiotensin-convertingenzyme (ACE)2 receptors, infection of endothelial cells/endotheliitis, inflammatory mechanisms like increased interleukin levels and platelet activation, and cardiac factors, such as myocardial injury or arrhythmias. “It would be lovely to have a simple story and be able to say it is just coagulopathy, or it is just ACE inhibition, but I am increasingly convinced that it will never be as simple as that,” Perry notes.

“We have this plethora of mechanisms and they are all contributing to a certain degree in different situations—which means it is also going to be difficult to come up with a rational treatment strategy.”

Perry thinks large, dedicated trials, involving COVID-19 groups and non-COVID-19 control groups of stroke patients, are now key, and could yet help to establish which of these baseline variables are more predictive of poor outcomes. He notes that expanded data from SETICOS and other international collaborations will likely be vital on this front. Fifi claims that, in addition to being younger, patients who are COVID-19-positive at the time of their stroke are also more commonly male, and part of an ethnic minority group, as per a Stroke case series from New York in 2020. Further research is required to tease out whether these discrepancies are a product of biological or socioeconomic factors, she adds.

While the underlying link between COVID-19 and stroke is yet to be fully unravelled, Perry and Fifi both believe increasing stock should be placed in optimising the treatment of COVID-19-positive patients too.

Building on one of the concluding messages from her team’s 2021 Trends in Neurosciences paper, which was that “significant work remains to be done to better understand the pathogenesis of COVID-19related stroke and for designing optimal primary and secondary prevention strategies”, Fifi asserts that “major funding” is required to move this area forward.

“Some investigations regarding the initiation of anticoagulation or antiplatelet therapy in COVID-19 are ongoing, specific focus on the prevention of stroke—along with [other indications such as] heart attacks and deep venous thrombosis—are welcome, and the risks and benefits of medications like aspirin in mild COVID-19 need to be fully elucidated,” she concludes.

Perry states: “Personally, I do believe that there is a subgroup of patients whose stroke is truly caused

by COVID-19-related coagulopathy, and I strongly suspect these patients should be anticoagulated rather than given antiplatelets.” He concedes, however, that this suspicion is not clearly supported by any existing datasets and, until the aforementioned patient group has been identified—possibly via widescale population studies—there is “no reason at all” to think patients with COVID-19-associated stroke should not receive procedures like intravenous thrombolysis or mechanical thrombectomy, in line with existing treatment criteria. Perry also feels the UK RECOVERY trial, which claims to be the world’s largest clinical study evaluating COVID-19 treatments, with more than 40,000 participants across 185 sites, could shed some much-needed light on an area that is still largely swathed in darkness.

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May 2022 | Issue 46

Endovascular Therapy

DISTAL: A landmark trial looking to elucidate endovascular treatment outcomes in MeVO stroke In December 2021, University Hospital Basel (Basel, Switzerland) enrolled the first patient worldwide in the DISTAL study—a multicentre randomised controlled trial (RCT) evaluating the clinical efficacy of endovascular therapy (EVT) in acute ischaemic stroke patients with an isolated medium vessel occlusion (MeVO).

More specifically, its primary objective will be to determine whether these patients experience superior long-term functional outcomes, measured via the modified Rankin Scale (mRS) at 90 days and with a superiority margin of 14%, when treated with EVT plus best medical therapy (BMT) versus BMT alone.

According to the DISTAL core team, this international, pragmatic, 1:1 randomised trial with blinded-endpoint assessment aims to provide conclusive, real-world information on the efficacy and safety of EVT in MeVO stroke patients. Here, they discuss the finer details and broader ambitions of the study with NeuroNews.

Have EVT outcomes for other indications, such as large vessel occlusion (LVO) stroke, been subject to more clinical research than MeVO thus far—and why is this?

Absolutely, however it could also be seen as the natural evolution of establishing evidence for the endovascular treatment approach. Back in 2010, we were all convinced that EVT is the gamechanger for stroke patients with an LVO, but then the socalled ‘unhappy triad’ was published in 2013: three RCTs showing no beneficial effect of EVT on clinical outcomes.

This put us back to square one. We had to learn the lessons from these trials and refine the techniques as well as the target population. Largest effect sizes were observed in patients with LVO strokes, which were then chosen as the target population for further pivotal trials. Consequently, the trials proved an overwhelming treatment effect of EVT on the clinical outcome of these selected patients. Now, for patients with MeVOs, we are in the same situation we found ourselves in a decade ago—we hypothesise that it might be beneficial to treat these patients endovascularly, but randomised evidence is lacking.

Therefore, we started the DISTAL trial.

What is the current unmet need with regard to MeVO stroke? Why is it important to shed more light on EVT outcomes in these patients?

As of now, the only evidence-based treatment for MeVO stroke patients is intravenous thrombolysis. However, we all know that intravenous thrombolysis has a rather narrow time window and a rapidly decreasing efficacy, as well as relevant contraindications, leaving many patients with a MeVO stroke without an effective treatment option. The outcome of a MeVO stroke can be devastating and may lead to lifelong disability or death. It is therefore of utmost

importance to establish an effective treatment option for these patients.

Why was mRS selected as the primary outcome measure in the DISTAL trial?

Despite its limitations, the mRS is currently the most established outcome parameter in stroke trials and its use is also supported by stroke patients. We consulted the largest patient organisation for stroke survivors in Switzerland (Fragile Suisse) and they acknowledged that achieving a good functional outcome, measured with the mRS, is of very high relevance to patients in the setting of MeVO. However, we are aware that the mRS does not capture minor clinical deficits, which may have a major impact on the quality of life for individual patients. The change in clinical deficit from baseline to follow-up, measured with the National Institute of Health Stroke Scale (NIHSS) score, would eventually have been more sensitive to capture stroke-related deficits, but the NIHSS is not a patientcentred outcome.

Secondary endpoints, however, include the change in NIHSS from baseline to follow-up, quality of life, cognitive function, all-cause mortality, percentage of brain saved on imaging, and place of residence one year after the stroke. The latter of these was a suggestion from Fragile Suisse, as they pointed out that returning home—and staying home—is of utmost importance to patients. Cognitive function, meanwhile, was chosen as a secondary endpoint because it is very sensitive to subtle differences.

We will use the percentage of brain saved as the main imaging outcome since it is a direct image-based measurement of the treatment effect.

We have opted against using final infarct volume as an imaging outcome parameter due to the heterogeneity of the sizes of the territories supplied by different MeVOs. Since the percentage

of brain saved is derived from the final infarct volume, it is reasonable to assume that, as the final infarct volume, it can be used as a surrogate for functional outcome. Multiple studies have shown a strong correlation between final infarct volume and functional outcome. And, in patients with occlusions of the posterior cerebral artery especially, this outcome will be of high value, since it is known that clinical assessment tools such as mRS and NIHSS underestimate clinically relevant sequelae of these occlusions.

What are the safety endpoints in the study, and how will you minimise potential complications associated with EVT?

The main safety endpoint will be the occurrence of symptomatic intracranial haemorrhage after randomisation.

Retrospective studies have shown similar rates of symptomatic intracranial haemorrhage in patients treated either with EVT or BMT only. In our experience, using dedicated materials and techniques significantly reduces the risk of complications and downsides of EVT. As with the SAVE (Stent retrieverassisted vacuum-locked extraction) technique for LVOs before, we are now in the process of publishing refined techniques as video cases, in dedicated journals, and on our ‘One Stop In Stroke’ YouTube channel. Additionally, discussions about materials and techniques are an important part of our site screening and initiation visits as we strive to achieve the highest technical standards within the trial.

What are your goals in terms of timelines for DISTAL?

At time of writing, 14 patients have been randomised in the trial. Our main goal

is to initiate as many sites as possible within the next few months, and we plan to enrol a total of 526 patients across ≥40 global sites over a period of 36 months. In Switzerland, we already have five recruiting sites, and we have obtained ethical approval to expand into Germany this year. Ethical approval in Belgium, Spain, Finland, Israel and Portugal is pending as well. Our aim is to finish enrolment at the end of 2024 and present our results in mid-2025.

What impact could this trial’s results have within the stroke care field?

If the trial shows superiority of EVT, it could have an impact on future guidelines and clinical practice. As with the LVO trials of 2015, there are multiple MeVO trials starting now, so we can expect good evidence within the next few years. EVT could eventually become the standard of care for MeVO patients, improving their quality of life and reducing their burden of stroke.

Furthermore, individual patient data meta-analyses will be performed with other, similar trials evaluating the efficacy of EVT in MeVO patients—for example, the DISCOUNT trial in France and the ESCAPE-MeVO trial in Canada.

We intend to perform individual patient data meta-analyses of all published trials, and we think that combining our results with such studies, which are also using mRS as their primary endpoint, will help to corroborate the evidence for EVT in MeVO patients. This would also allow us to perform subgroup analyses for different patient cohorts i.e. type and site of vessel occlusions, different time windows, and other important baseline factors. In addition, the effect of different technical approaches and the safety of the used devices can be evaluated with this pooled dataset.

The DISTAL core team Left to right: Marios Psychogios, Alex Brehm, Luzia Balmer and Urs Fischer

Issue 46 | May 2022

ATTENTION results indicate “we have finally conquered the basilar artery” with endovascular therapy

BAO stroke patients presenting 12 hours or less from the estimated time of BAO. The prospective, open, blinded-endpoint RCT took place across 36 comprehensive stroke centres in China, with follow-up at 24–72 hours, 5–7 days/discharge, and 90 days.

In addition to the primary endpoint of a favourable outcome at 90 days, secondary endpoints included overall degree of functional disability (ordinal mRS shift) and rates of excellent outcomes (mRS 0–2), as well as National Institutes of Health Stroke Scale (NIHSS) scores at the earlier follow-up timepoints, THIS YEAR’S EUROPEAN STROKE while 90-day mortality, symptomatic intracranial Organisation Conference (ESOC 2022; 4–6 May, Lyon, haemorrhage (ICH) rates at 24 hours, and procedureFrance) saw results from ATTENTION—a multicentre related complications, were the safety endpoints. randomised controlled trial (RCT) evaluating the From February 2021 to January 2022, ATTENTION benefit of endovascular therapy (EVT) in basilar artery enrolled and randomised 342 patients, with 226 and occlusion (BAO) stroke—presented for the first time.

114 ultimately being included in the EVT plus BMM Raul Nogueira (University of Pittsburgh, Pittsburgh, analysis (median age=67 years, 65.9% male) and the USA) delivered these data, reporting improved rates BMM-only analysis (median age=68 years, 71.9% of independent and functional outcomes, and lower male), respectively. Nogueira noted that roughly one overall disability and mortality rates, at 90 days with third of patients in both groups received intravenous EVT versus best medical management (BMM). thrombolysis, and there were no significant differences Nogueira began by noting that, in spite of the in terms of comorbidities or stroke aetiology. “overwhelming” proof of its benefit in treating anterior Regarding the trial’s results, Nogueira reported a circulation large vessel occlusion (LVO) strokes, successful recanalisation rate (final modified treatment it remains unknown whether EVT offers the same in cerebral infarction [mTICI] 2b–3) with EVT of advantages in acute BAOs—despite “Herculean” 93.3%. He then delivered the crux of his efforts seen in the BEST and BASICS trials. He also presentation—a 90-day rate of mRS noted positive signals seen with EVT in these studies, 0–3 averaging 22.8% in the BMM and said they “paved the way” for ATTENTION group, compared to 46% in the EVT by demonstrating the importance of consecutive group. “This resulted in an adjusted recruitment, fast enrolment and minimal crossover, and risk ratio of 2.1, yielding a p-value confirming the ideal target population. of less than 0.001,” Nogueira The objective of the ATTENTION study, stated, drawing a round of Nogueira said, was to evaluate whether EVT with applause from the ESOC Raul BMM is superior to BMM alone in achieving audience. “Ladies and Nogueira presenting favourable outcomes (modified Rankin Scale gentlemen, I think we at ESOC [mRS] 0–3) at 90 days in acute ischaemic

Endovascular Therapy

7

can finally say we have conquered the basilar artery territory—it was about time!” he added.

Nogueira also noted that the number needed to treat in the study was just four, and EVT showed a statistically significant benefit across the board with regard to ATTENTION’s secondary efficacy endpoints too. “Specifically, there was a lower rate of overall disability [common odds ratio=2.8] favouring the intervention, and [independent] functional outcomes were higher at 33.2% with EVT versus 10.5% with BMM [adjusted risk ratio=3.2],” he reported.

“Moving on to imaging outcomes, patients were 2.5 times more likely to have a patent vessel following EVT compared to controls—and this was statistically significant,” Nogueira continued. “There was a trend towards more asymptomatic ICHs in the EVT group, and statistically significantly more ICHs that were symptomatic, at 5.3% versus 0% [with BMM]. But, despite that, 90-day mortality was significantly lower with EVT than in controls, at 36.7% versus 55.3%.”

Nogueira stated that the benefit of reducing disability with EVT in BAO stroke “appears to be within the same range as that observed in the anterior circulation”.

He added that, in contrast to most anterior circulation EVT trials, however, ATTENTION also demonstrated a potential benefit in terms of mortality. “We can finally say that the overwhelming efficacy of EVT persists in the posterior circulation,” Nogueira concluded.

We can finally say that the overwhelming efficacy of EVT persists in the posterior circulation.”

May 2022 | Issue 46

Stroke Care

Women less likely to return to work after severe stroke, new study finds According to new research published in Stroke, about one third of people who had a severe ischaemic stroke— and underwent a mechanical thrombectomy to remove their large-vessel blood clot— resumed work three months after stroke treatment. In addition, women were about half as likely to return to work after a severe stroke compared to men in the study.

“RETURNING TO WORK AFTER a severe stroke is a sign of successful rehabilitation. Resuming pre-stroke levels of daily living and activities is highly associated with a better quality of life,” said lead study author Marianne Hahn (Johannes Gutenberg University, Mainz, Germany). “In contrast to most return-to-work studies, we included a

large cohort of only people treated with mechanical clot removal; they are a subgroup of stroke patients at high risk for severe, persisting deficits.”

Researchers examined data from the German Stroke Registry—Endovascular Treatment Study Group. The analysis included more than 600 patients (28% women), aged 18 to 64 years, who had a large-vessel ischaemic stroke between 2015 and 2019. All study participants were employed prior to their stroke and were treated with mechanical thrombectomy, while more than half of the study participants also received intravenous thrombolysis.

Researchers compared the people who returned to work 90 days after being treated with mechanical thrombectomy to those who did not resume work.

After accounting for age, sex, health conditions, type and severity of stroke, and treatment characteristics, the analysis found: About one third of the stroke survivors resumed work three months later.

The amount of persistent functional deficits after stroke was the main reason people were not able to return to work.

Women were 58% less likely to return to work three months after mechanical thrombectomy compared to men.

Individuals who were treated with both mechanical thrombectomy and intravenous thrombolysis were almost twice as likely to return to work compared to the individuals who had undergone mechanical thrombectomy only.

“After examining the data further, we the workforce after a major stroke. More also found that women in our cohort intensive and supportive vocational were younger at the time of rehabilitation programmes may their stroke, were more be valuable to help women likely to be non-smokers return to work, they state. and were more likely “There is more to have no existing to re-employment significant disability after mechanical when discharged from thrombectomy than the hospital compared to functional outcomes,” the men in our study,” Hahn Hahn continued. “Targeted added. “Despite having more vocational and workplace Marianne of these favourable characteristics rehabilitation interventions Hahn for return to work, we did not have been shown to observe a higher re-employment rate improve rates of return to work. And, among women before considering these previous studies have also found that differences.” returning to work is associated with The researchers note further study increased wellbeing, self-esteem and life is needed to explain the discrepancy satisfaction.” between men and women re-entering The study authors believe their findings may be transferrable to other countries with similar healthcare and rehabilitation systems. However, confirmation and in-depth analyses of national policies are necessary to explain the observation—since there may be differences, such as social services and benefits, which have been shown to influence return to work. % The study was also limited, they note, in that the data lacked detailed information about types of jobs and available employment opportunities.

The German Stroke Registry does not include social determinants of health, and whether an individual was reemployed at the same job, or working full- or part-time. The researchers claim Women were 58% less likely to return these limitations may help explain and to work three months after mechanical play a role in whether people returned to thrombectomy compared to men work after a severe stroke.

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‘Brain-age’ biomarkers predict stroke recovery more accurately than chronological age in new study Stroke experts have identified how radiomics—an emerging, image-quantifying technology—can be used to extract biomarkers from clinical brain magnetic resonance imaging (MRI) scans in stroke patients and estimate their relative ‘brain age’. The technique demonstrates that using relative brain age, rather than chronological age, can enhance stroke surveillance and improve predictions around post-stroke recovery, according to a study presented at the European Stroke Organisation Conference (ESOC 2022; 4–6 May, Lyon, France).

THE STUDY ANALYSED 4,163 ISCHAEMIC stroke patients across the USA and Europe. It showed that stroke patients with ‘older-appearing’ brains, characterised by a higher predicted brain age than chronological age, were more likely to suffer from hypertension, diabetes mellitus, or have a history of smoking or prior stroke. Patients with older-appearing brains were also less likely to achieve a favourable post-stroke outcome in comparison with their younger-looking counterparts.

Led by Martin Bretzner (Harvard Medical School, Boston, USA), the research team considered that, while chronological age measures the amount of time a person has lived, it is less likely to precisely capture how ‘well’ a patient has aged. By estimating the age of a patient’s brain, this novel biomarker-based approach provides insight into the resilience of a brain to time and cardiovascular risk factors, and how well patients recover from stroke.

The technique—radiomics—leverages advanced mathematical analysis to explore neuroimaging data available to clinicians, allowing experts to predict patients’ relative brain age compared to other stroke survivors and analyse their overall brain health.

“Age is one of the most influential determinants of post-stroke outcomes, but little is known about the impact of neuroimaging-derived biological brain age,” said Bretzner. “Our results show that quantifying relative brain age in stroke patients can be beneficial in assessing a patient’s brain health globally, and useful in predicting how well the patient will recover from a stroke. It would also be very easy to communicate on this biomarker with clinicians and patients, as everyone instinctively understands the negative implications of an accelerated brain-ageing process.”

In addition, the study found that relative brain age impacted stroke outcomes independently from

chronological age and stroke severity. Having previously suffered from a stroke was the most influential clinical factor that impacted relative brain age, followed by diabetes.

“These findings stress the importance of minimising cardiovascular risk factors, and also highlight how cardiovascular health and brain health are tightly intertwined,” added Bretzner.

“Identifying potentially modifiable risk factors that impact brain health by using radiomics and relative brain age as a biomarker could lead to the development of stroke prevention interventions, and aid recovery. We hope that this research will serve as a support to identify fragile stroke patients that require more intensive prevention techniques, treatments and surveillance in the future.”

Our results show that quantifying relative brain age in stroke patients can be beneficial in assessing a patient’s brain health globally, and useful in predicting how well the patient will recover from a stroke.”

Image credit: Markus Schmidt

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Issue 46 | May 2022

Stroke Care

Preliminary data indicate improved neurological outcomes with alteplase versus placebo

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s per early findings from the CHOICE thrombectomy procedure improves post-reperfusion randomised controlled trial (RCT), the use outcomes. of adjunct, intra-arterial alteplase—among CHOICE was a phase 2b, double-blind, placebopatients with large vessel occlusion (LVO) acute controlled RCT performed from December 2018 ischaemic stroke and angiographically successful through May 2021 in seven stroke centres across reperfusion following thrombectomy—may lead Catalonia, Spain. The study included 121 patients to a greater likelihood of an excellent neurological with LVO acute ischaemic stroke treated with outcome at 90 days, as compared to a placebo. thrombectomy within 24 hours after stroke onset, and However, the study’s authors note in The Journal of with an expanded treatment in cerebral ischaemia the American Medical Association (JAMA) that early (eTICI) angiographic score of 2b50 to 3. termination of the trial limits the scope of Chamorro and colleagues relay that 61 these findings, which should be considered participants were randomised to receive “preliminary until replicated”. intra-arterial alteplase (0.225mg/kg; Lead author Ángel Chamorro (Hospital maximum dose, 22.5mg) infused over the Clinic of Barcelona, Barcelona, Spain) and course of 15-to-30 minutes, while 52 patients colleagues begin their JAMA report by noting received a placebo treatment. The primary that “it is estimated that only 27% of patients Ángel Chamorro outcome was the difference in the proportion with acute ischaemic stroke and LVO who of patients achieving an “excellent” score of undergo successful reperfusion after mechanical 0 or 1 on the modified Rankin Scale (mRS) at 90 days thrombectomy are disability-free at 90 days”. They in all patients treated as randomised. In addition, the further note that an incomplete microcirculatory study’s safety outcomes included rate of symptomatic reperfusion might contribute to these suboptimal intracranial haemorrhage and death. clinical benefits—and, through the CHOICE trial, The CHOICE study was terminated early for they therefore set out to investigate whether treatment “inability to maintain placebo availability and with adjunct intra-arterial alteplase after a successful enrolment rate because of the COVID-19 pandemic”,

Study findings encourage direct EVT over bridging thrombolysis in select stroke patients A retrospective study involving more than 200 patients has indicated that ‘bridging thrombolysis’ may not be associated with improved functional outcomes in stroke patients who achieve complete recanalisation—as compared to treatment with endovascular therapy (EVT) alone. As such, researchers conclude that their findings encourage ‘direct EVT’ approaches, particularly in patients with a higher likelihood of successful EVT. WRITING IN THE JOURNAL OF Clinical Medicine, Gabriel Broocks (University Medical Center HamburgEppendorf, Hamburg, Germany) and colleagues speculate that significantly increased oedema volume and risk of symptomatic intracerebral haemorrhage (sICH) as secondary injury volumes could be a major reason for a lack of clinical benefit in this patient cohort.

Intravenous thrombolysis (IVT) with alteplase is a standard of care in ischaemic stroke, the authors note, while recent trials investigating direct EVT approaches have shown conflicting results. However, they continue, the effect of IVT on secondary injury volumes in patients with complete recanalisation has not been analysed to date. The researchers therefore hypothesised that IVT is associated with worse functional outcome and aggravated secondary injury volumes when administered to patients who subsequently attained complete reperfusion after EVT.

Broocks and colleagues analysed anterior circulation ischaemic stroke patients with complete post-EVT reperfusion—defined as a thrombolysis in cerebral infarction (TICI) scale score of 3 after thrombectomy—admitted to a single tertiary stroke centre between January 2013 and January 2021. Their study’s primary endpoints were the proportion of patients with functional independence (modified Rankin Scale [mRS] score 0–2 at day 90), and secondary injury volumes, including oedema volume on follow-up imaging— measured using quantitative net water uptake (NWU)—and the rate of sICH. A total of 219 patients (median age=74 years; 48% female) were included, with 128 of these (58%) receiving bridging IVT with alteplase prior to a thrombectomy. Reporting their results, the authors note that no differences in median National Institutes of Health Stroke

9

the authors detail in JAMA. From a population of 1,825 acute ischaemic stroke patients treated with thrombectomy at the seven study sites, 748 patients (41%) fulfilled the angiographic criteria, 121 (7%) were randomised (mean age=70.6 years; 47% women) and 113 (6%) were treated as randomised.

Some 36 of 61 participants (59%) had an excellent 90-day mRS score with alteplase compared to 21 out of 52 (40.4%) with placebo. The authors describe this as a “significant” adjusted risk difference of 18.4%. In addition, the proportion of patients with symptomatic intracranial haemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo. Chamorro and colleagues add that 90-day mortality was 8% with alteplase and 15% with placebo.

As such, they conclude that the use of adjunct intra-arterial alteplase compared to placebo resulted in a greater likelihood of excellent neurological outcome at 90 days—while also acknowledging limitations of the CHOICE RCT, and subsequently the generalisability of its findings.

Speaking to NeuroNews following publication of these results, Chamorro said: “The CHOICE-2 trial is already planned to validate these exciting results and will start early next year. If confirmed, the new paradigm of lysing patients with ‘clean vessels’ will be [introduced] in the guidelines. In Spain alone, which has a population of 47 million people, the significance of these results would be that approximately 1,000 more stroke survivors will be completely free of long-term disability, as well as about 7,000 in the USA. Only five patients will have to be treated with alteplase post-thrombectomy to make one more disability-free.”

Scale (NIHSS) scores at 24 hours were observed between bridging IVT and direct EVT patients (10 vs 13, p=0.75), while median 90-day mRS scores were also similar (4 vs 3, p=0.61).

They detail that the proportion of patients with functional independence was 28% for bridging IVT compared to 34% for direct EVT (p=0.35).

And, no significant treatment effect of IVT on functional independence as an endpoint was observed, after regression adjustment for age, NIHSS, Alberta stroke programme early CT score (ASPECTS), occlusion location, and time from onset to imaging (p=0.11), with an adjusted proportion of functional independence of 28% for bridging IVT versus 38% for direct EVT. Patients with bridging IVT had higher total infarct volumes (48ml vs 37ml, p=0.04) and higher oedema volumes (6ml versus 4ml, p=0.039) than those who underwent direct EVT. The rate of sICH was higher in patients with bridging IVT (26% vs 7%, p=0.01), with IVT having a significant effect on the occurrence of sICH (p=0.029) after regression adjustment—indicated by an adjusted proportion of sICH of 19% versus 7.8% in direct EVT patients.

In addition to concluding that IVT was not associated with improved functional outcomes compared to direct EVT, but was significantly and independently associated with increased rates of sICH and oedema volume as secondary injury volumes, the Gabriel Broocks

authors state that important predictors of outcome in TICI 3 recanalised patients were age and NIHSS, while ASPECTS, time from onset to imaging, and time from imaging to recanalisation, were not independent predictors. This “emphasises the importance of complete recanalisation as a major determinant of outcome”, they assert.

“To our knowledge, this is the first study that investigated the effect of bridging IVT on functional outcome and secondary injury volumes using quantitative imaging biomarkers in a patient collective exclusively consisting of complete reperfusion cases,” Broocks and colleagues write.

“Considering the rising frequency of successful vessel recanalisation over time [...], the importance of optimising treatment strategies for these patients is suggested by the high proportion of patients with poor outcomes despite successful EVT, as described in a recent meta-analysis (i.e. 45% mRS 3–6 in TICI 2b/3). The early identification of stroke patients who might not benefit from IVT could therefore be important to further improve functional outcome.

The present study might give further insights into the effect of IVT on lesion pathophysiology in the setting of complete vessel recanalisation, and might help to tailor individual adjuvant treatment options.”

The authors conclude that future studies should analyse the identification of baseline variables to guide IVT, and investigate IVT’s impact in relation to the degree of reperfusion for patients with posterior circulation stroke.

May 2022 | Issue 46

10 Carotid Artery Stenosis

CAROTID

Carotid stenting demonstrates comparable short- and long-term results to endarterectomy POOLED PATIENT-LEVEL DATA FROM more than 2,500 asymptomatic, non-octogenarian subjects have shown that carotid artery stenting (CAS) achieved comparable short- and long-term results to carotid endarterectomy (CEA). The findings of this analysis have been published by Jon Matsumura (University of Wisconsin, Madison, USA) and colleagues in the Journal of Vascular Surgery (JVS).

The study authors begin by detailing that asymptomatic carotid stenosis is the most frequent indication for CEA in the USA. Published trials and guidelines support CEA indications in selected patients with longer projected survival and in instances where periprocedural complications are low, they note, while transfemoral CAS with embolic protection is a newer treatment option.

With this in mind, they set out to compare outcomes in asymptomatic, non-octogenarian patients treated with

CAS, versus those treated with CEA, via a widescale Myocardial infarction: 0.6% with CAS and 1.7% analysis of patient-level data. with CEA (p=0.01) Matsumura and colleagues report that a total of 2,544 Death: 0.1% with CAS and 0.2% with CEA (p=0.62) patients with ≥70% asymptomatic carotid stenosis, who Any stroke or death: 2.7% with CAS and 1.6% with were randomised to receive CAS or CEA in addition CEA (p=0.07) to standard medical therapy, were included in their They go on to note that, after this period, the rates of study. ipsilateral stroke were “similar” between the This was based on data from two large, two groups (2.3% with CAS vs 2.2% with randomised trials. One of these enrolled CEA; p=0.97).

1,091 patients (548 CAS; 543 CEA) and the This led Matsumura and colleagues to other enrolled 1,453 asymptomatic patients conclude that, in a pooled analysis of two who were less than 80 years of age (1,089 large, randomised trials of CAS and CEA in CAS; 364 CEA). asymptomatic, non-octogenarian patients, Independent neurologic assessment and CAS ultimately achieved comparable shortroutine cardiac enzyme screening was Jon Matsumura and long-term results to CEA. performed, the authors detail.

Speaking to NeuroNews following The prespecified, primary composite endpoint of publication of these data in JVS, Matsumura said: their study was any stroke, myocardial infarction or “The impact of this large study is that it uses the best death during the periprocedural period, or ipsilateral available evidence—prospective, randomised controls, stroke within four years after randomisation. intention-to-treat analysis, federal regulatory oversight, The authors report their results, stating that there independent neurologic exams and biochemical was “no significant difference” in the primary endpoint screening. between CAS and CEA (5.3% vs 5.1%; hazard “In addition, it studies the largest population ratio=1.02; 95% confidence interval, 0.7–1.5; p=0.91). (asymptomatic, non-octogenarian patients) with severe In terms of the periprocedural rates for each component carotid stenosis receiving interventional treatment in part of this composite endpoint, they also detail the the USA. following: “It has direct relevance for patient care, treatment Any stroke: 2.7% with CAS and 1.5% with CEA guidelines and payor policy. It is also highly congruent (p=0.07) with the recently published international trial, ACST-2.”

Charing Cross audience as-yet unconvinced by data supporting transcarotid artery revascularisation Audience polling during the Acute Stroke Challenges session at this year’s Charing Cross Symposium (CX 2022; 26–28 April, London, UK and virtual) revealed scepticism regarding the benefits of transcarotid artery revascularisation (TCAR) in the treatment of symptomatic carotid artery stenosis. This followed a debate that saw Michael Stoner (University of Rochester Medical Center, Rochester, USA) and Gert J de Borst (University Medical Center Utrecht, Utrecht, The Netherlands) go head-to-head over the quality of evidence supporting TCAR as compared to carotid endarterectomy (CEA) and carotid artery stenting (CAS).

STONER PRESENTED FIRST, arguing in favour of the motion that “TCAR is a safe and effective alternative to transfemoral CAS or CEA in the treatment of patients with symptomatic internal carotid artery stenosis”. He noted that one of the “theoretical advantages” of TCAR is distal embolic neuroprotection—something he feels has been demonstrated in the PROOF and DW-MRI-US studies, while the multicentre ROADSTER and ROADSTER 2 trials, and the Vascular Quality Initiative (VQI) registry, have all shown low 30-day stroke rates among symptomatic patients.

The speaker claimed that the ipsilateral stroke rates seen between 31 and 365 days in ROADSTER and ROADSTER 2 (0.6% and 0%, respectively) show long-term efficacy with TCAR, and other small case series from the USA have corroborated this. Examining data from the VQI registry further, Stoner highlighted findings published in The Journal of the American Medical Association, which include 3,658 symptomatic patients, and reveal a 2.6% rate of stroke or death at

30 days in patients treated with TCAR compared to 4.8% in patients treated via CAS. Pivoting to a propensity scorematched analysis from the same dataset, Stoner noted “matched” 30-day stroke/ death rates between TCAR and CEA, as well as “improved” 30-day stroke/death rates with TCAR compared to CAS. He concluded his argument in favour of the motion by stating that prospective case and case-control studies demonstrate safety and efficacy with TCAR, as well as early advantages over CAS and statistically insignificant differences versus CEA, in patients with appropriate anatomies (symptomatic and high-risk asymptomatic carotid stenoses). “We recommend maintaining guideline-based revascularisation with

For % Against %

regard to timing,” Stoner added, but conceded randomised controlled trial (RCT) data are currently unavailable.

The riposte to this was then provided by de Borst, who began by addressing the “elephant in the room” his opponent had already alluded to—the current lack of RCTs directly comparing TCAR to CEA or CAS. In addition, he noted that the vast majority of the datasets presented by Stoner were dominated by asymptomatic patients. Highlighting further concerns with the existing body of evidence on TCAR, de Borst claimed it is mostly derived from companysponsored, single-arm studies, while three quarters of all the included patients originate from the VQI registry— limiting generalisability—and there is an under-reporting of anatomic suitability and exclusion criteria too.

De Borst touched on further shortcomings of the current TCAR literature, in particular the fact that, despite the procedure being developed to prevent embolic complications, evidence supporting its efficacy here is “very modest”, with no high-quality studies available as things stand. “We have clear data on the efficacy and safety of surgery [CEA] in symptomatic patients, and we also know that stroke risks and the rate of new DW-MRI [diffusion-weighted magnetic resonance imaging] lesions are higher in transfemoral stenting, but we do not have any data on these aspects in TCAR,” he added.

His concluding message was that,

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“TCAR is a safe and effective alternative to transfemoral CAS or CEA in the treatment of patients with symptomatic internal carotid artery stenosis”

while CAS has “evolved considerably” over the past two decades, CEA remains the safer option for the majority of patients, and across all periods after the onset of symptoms. De Borst also said current evidence may seem “promising”, but independent, investigator-driven studies comparing TCAR to CEA in recently symptomatic patients are needed to establish its true value.

After this debate, a show of hands from the audience revealed that very few of the hundreds in attendance had performed TCAR before, with Stoner suggesting this is consistent with the procedure’s more limited European availability. And, upon being quizzed on the possible reasons why uptake of TCAR is still relatively low in the USA compared to other carotid artery stenosis treatments as well, he said this is likely a result of logistical barriers, such as all asymptomatic patients needing to be treated within the VQI registry, and also economic factors, including Centers for Medicare and Medicaid Services (CMS) reimbursement issues and the fact that— at least in the short term—CEA is the far cheaper option.

When pressed by Stoner on data that may “change his tune” regarding TCAR, de Borst said that RCTs, or at least prospective, high-quality registry evidence involving patients selected on the same criteria, are required. “That basis is lacking,” he continued. “There are some pros and some cons, but I think the strong points of TCAR could easily be evaluated in a prospective setup.

Really, the question is: Why don’t we do it?”.

Following Stoner’s admission that there are “undeniable selection biases” in much of the existing data, the majority of the CX audience was ultimately swayed by de Borst’s arguments, with 79% voting against the motion.

Issue 46 | May 2022

Carotid Artery Stenosis 11

Carotid stenosis in women: Should the approach differ?

Seemant Chaturvedi Comment & Analysis The existing evidence on whether women with carotid stenosis experience inferior treatment outcomes compared to men is mixed—and this uncertainty is reflected in the current clinical guidelines. Seemant Chaturvedi (Baltimore, USA) assesses this evidence and outlines how it may impact treatment approaches.

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ne of the leading causes of ischaemic stroke is internal carotid artery (ICA) atherosclerosis.

While several studies have been devoted to studying carotid interventions, such as carotid endarterectomy (CEA) or carotid artery stenting (CAS), many of the studies devoted to analysing the effects of intensive medical therapy are outdated.

Another area where the decisionmaking data are suboptimal concerns ICA stenosis narrowing in women. Early studies, such as ACAS (Asymptomatic Carotid Atherosclerosis Study), showed a reduction with CEA in asymptomatic

men but not in women. Similarly, early trials dedicated to symptomatic ICA stenosis showed reduced benefit in women compared to men. In an analysis of patients with 50–99% stenosis who received either CEA or medical therapy, the number needed to treat to prevent one stroke was nine for men, and 36 for women.

These observations led to questions about whether the biology of carotid disease differs in men versus women.

Pathologic studies regarding CEA plaque specimens showed lower macrophage infiltration in plaques from women. In addition, smooth muscle content was higher in women. These

Randomised trial suggests carotid endarterectomy does not affect dementia risk

Carotid endarterectomy (CEA) does not appear to either reduce or increase the risk of dementia, despite having been shown to reduce stroke risk. This is according to 20-year results from the ACST-1 trial, published in the European Journal of Vascular and Endovascular Surgery.

ACST-1 (ASYMPTOMATIC CEA on incident dementia”. carotid surgery trial) showed In the present study, the that surgery for asymptomatic researchers randomly allocated carotid stenosis significantly all UK and Swedish patients reduces long-term stroke risk, in ACST-1 (n=1,601/3,120) to Alison Halliday (University either immediate CEA (n=796) of Oxford, Oxford, UK) and Alison Halliday or deferral of CEA (i.e. no colleagues write. They note, intervention was performed however, that the effect of CEA on later unless or until triggered by ipsilateral dementia is “uncertain”. transient ischaemic attack or stroke; The investigators underline the n=805), and followed them for 16–26 fact that prolonged follow-up of trial years, to study effects on dementia. The participants is now possible with the median follow-up was 19.4 years. linkage of national electronic records.

Halliday and colleagues report In addition, they note that dementia that dementia was recorded in 107 records have a good positive predictive immediate CEA patients and 115 value for clinical diagnosis, though they allocated delayed surgery. A total of are likely to underestimate the true risk.

1,290 patients died, 1,091 before any The combination of these factors, the dementia diagnosis, they add. authors write, “provides the opportunity The investigators found that dementia to investigate the longer-term effects of incidence rose with age and with female

findings led to the opinion that plaques from women could have a more stable phenotype. The more stable phenotype may be related to the trial observation that women had less benefit from CEA. Radiologic studies have also shed light on differences in carotid stenosis between men and women. Plaque imaging studies have identified a lower rate of intraplaque haemorrhage and lower frequency of lipid-rich necrotic core in plaques from women. Once again, these findings may be related to the observation that women have a lower stroke risk while being treated with medical therapy.

When putting this all together, are the data sufficient to recommend a different approach for women with carotid stenosis?

Some argue that the enrolment of women with carotid stenosis has been suboptimal in clinical trials (ranging from 25–35%) and that we should not reach clinical decisions based on subgroup analysis. Others argue that the pathologic and radiologic data resonate

well with clinical observations, and that the data should not be ignored.

Proponents of this view argue that carotid intervention should be offered less frequently to women.

Finally, clinicians should consider whether a separate women’s carotid stenosis trial is worthwhile. Such a trial could test intensive, modern medical therapy versus intensive medical therapy plus revascularisation. This trial would be unique in the current stroke prevention landscape and could settle a controversial issue.

Further reading: 1. Marulanda-Londone E, Chaturvedi S. Carotid stenosis in women: Time for a reappraisal. Stroke Vasc Neurol.

2016; 1(4): 192–6.

2. Gasbarrino K, Di Iorio D, Daskalopoulou S S. Importance of sex and gender in ischemic stroke and carotid atherosclerotic disease. Eur Heart J. 2022; 43(6): 460–73.

Seemant Chaturvedi is the Stewart J Greenebaum endowed professor of Stroke Neurology and director of the UMMS Stroke Program at the University of Maryland School of Medicine in Baltimore, USA.

Some argue that the enrolment of women with carotid stenosis has been suboptimal in clinical trials and that we should not reach clinical decisions based on subgroup analysis.

Others argue that the pathologic and radiologic data resonate well with clinical observations, and that the data should not be ignored.” sex (men, 8.3% aged <70 years allocated and, as such, at trial entry vs 15.1% aged ≥70; intervention and control groups women, 15.1% aged <70 years were matched for known at trial entry vs 22.4% aged confounders at recruitment. ≥70 years), and was higher in In addition, they write that Dementia those with pre-existing cerebral the use of electronic health diagnosed in records reduces potential bias, infarction (silent or with prior symptoms, 20.2% vs 13.6%, because the electronic health respectively). record includes participants In addition, the authors relay who may not respond to active that dementia risk was similar follow-up. in both randomised groups: Halliday and colleagues 6.7% vs 6.6% at 10 years, also recognise some and 14.3% vs 15.5% at 20 limitations. They years, respectively. acknowledge that faceThe dementia hazard to-face interviews of who underwent ratio was 0.98 (95% participants throughout immediate CEA confidence interval [CI], follow-up would have 0.75–1.28; p=0.89), with no been the “ideal method” to heterogeneity in the neutral detect cognitive impairment effect of immediate CEA on and dementia, but this was not dementia related to age, possible. carotid stenosis, blood They also go on to pressure, diabetes, state that dementia may country of residence, or be under ascertained medical treatments at using electronic records who were allocated trial entry (heterogeneity and that there was no delayed surgery values: p>0.05), Halliday consistent dementia and colleagues detail. ascertainment over time.

Considering the In addition, the researchers main strengths of their remark that the study research, Halliday and confidence interval did not colleagues highlight the fact exclude a proportional benefit that early CEA was randomly or hazard of about 25%.

107 patients 115 patients

Issue 46 | May 2022

Neurosurgery 13

Artificial intelligence tutoring outperforms expert instructors in neurosurgical training AGAINST THE BACKDROP OF REMOTE learning technologies becoming increasingly important within medical training during the COVID-19 pandemic, a new study has found that—in a remote environment—an artificial intelligence (AI) tutoring system can outperform expert human instructors.

The Neurosurgical Simulation and Artificial Intelligence Learning Centre at The Neuro (Montreal Neurological Institute and Hospital, Montreal, Canada) recruited 70 medical students to perform virtual brain tumour removals on a neurosurgical simulator in a randomised clinical trial. Students were randomly assigned to receive instruction and feedback by either an AI tutor or a remote expert instructor, with a third control group receiving no instruction.

An AI-powered tutor called the virtual operative assistant (VOA) used a machine learning algorithm to teach safe and efficient surgical techniques, as well as providing personalised feedback, while a deep learning-based intelligent continuous expertise monitoring system (ICEMS) and a panel of experts assessed student performance. In the other group, remote instructors watched a live feed of the surgical simulations and provided feedback to the students.

The researchers found that students who received VOA instruction and feedback learned surgical skills 2.6 times faster and achieved significantly higher (36%) performance scores compared to those who received instruction and feedback from remote instructors. And, while the researchers expected students instructed by VOA to experience greater stress and negative emotion, they found no significant difference between the two groups in that regard.

Concluding their study, which has been published in The Journal of the American Medical Association, the researchers state: “In this randomised clinical trial, VOA feedback demonstrated superior performance outcome and skill transfer, with equivalent OSATS [Objective Structured Assessment of Technical Skills] ratings, and cognitive and emotional responses compared with remote expert instruction, indicating advantages for its use in simulation training.”

The researchers also claim that, in addition to offering an effective way to increase neurosurgeon performance, VOA may enable improved patient safety while reducing the burden on human instructors.

“Artificially intelligent tutors like the VOA may become a valuable tool in the training of the next

“Largest ever” study on traumatic brain injury highlights global inequality in causes and treatment

Neurosurgery experts from the University of Cambridge (Cambridge, UK) have led what is claimed to be the largest ever study examining the surgical management of traumatic brain injury, highlighting regional inequalities in both major causes and treatment of such injuries.

FINDINGS FROM THE GLOBAL Neurotrauma Outcomes study, which was funded by the National Institute for Health and Care Research (NIHR), is published in The Lancet Neurology and provides data intended to assist in decision-making and improving outcomes for patients with traumatic brain injury globally.

Angelos Kolias (Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), NIHR Global Neurotrauma Research Group associate director, said: “The results show that overall mortality is low, reflecting the life-saving nature of surgery for traumatic brain injuries.

Many of these patients would have died without an operation. However, we also need to address deficits in prehospital management and long-term rehabilitation.”

David Clark (University of Cambridge, Cambridge, UK) added: “A particularly important finding is that outcome is influenced more by hospital characteristics than country of origin, raising the possibility that changing the systems and processes of care in individual hospitals might be able to improve mortality. The paper sows the

generation of neurosurgeons,” said Rolando Del Maestro (Montreal Neurological Institute and Hospital, Montreal, Canada), the study’s senior author. “The VOA significantly improved expertise while fostering an excellent learning environment. Ongoing studies are assessing how in-person instructors and AI-powered, intelligent tutors can most effectively be used together to improve the mastery of neurosurgical skills.”

“Intelligent tutoring systems can use a variety of simulation platforms to provide almost unlimited chances for repetitive practice without the constraints imposed by the availability of supervision,” added Ali Fazlollahi (Montreal Neurological Institute and Hospital, Montreal, Canada), the study’s first author.

“With continued research, increased development, and dissemination of intelligent tutoring systems, we can be better prepared for ever-evolving future challenges.”

Intelligent tutoring systems can use a variety of simulation platforms to provide almost unlimited chances for repetitive practice without the constraints imposed by the availability of supervision.”

In addition, quality of care was generally less favourable in lower HDI settings, including delays to surgery and a lack of postoperative monitoring equipment and intensive care. The very high HDI tier had the highest proportion of operations in which the most senior surgeon present in the operating theatre was a fully qualified neurosurgeon, while the medium HDI tier had the lowest proportion.

The study also found significant variations between hospitals in the outcome of patients. One such variation was the rate of mortality, which was found to be 20% in the very high HDI tier, 16% in the high HDI tier, 22% in the medium HDI tier and 7% in the low HDI tier. After case-mix adjustment, the researchers found that the odds of mortality were greater in the medium HDI tier (odds ratio [OR]=2.84) and high HDI tier (OR=2.26), but not the low HDI tier (OR=1.66), relative to the very high HDI tier.

Alexis Joannides (Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK), NIHR Global Neurotrauma Research Group informatics lead, said: “The contribution of several clinicians and researchers from several hospitals

seeds for discussion and change.”

The paper focuses on types of cases, the way they are managed, and death rates, and was compiled using data submitted by 159 hospitals from across 57 countries to a central database, which the researchers then analysed.

The study included a total of 1,635 records. Researchers stratified countries into four tiers—very high, high, medium, and low—according to their Human Development Index (HDI), which takes into account factors like life expectancy, education and income.

The prospective, observational cohort study determined that patients in the low HDI tier were often young and tended to suffer skull fractures due to assault, but were classified as ‘mild’ traumatic brain injury cases. In the medium and high HDI tiers, patients were also young, but most had moderate-to-severe traumatic brain injury caused by a road traffic collision and Very high extradural haematoma. In the HDI tier very high tier, patients tended to be older and presented with a moderate or severe traumatic % brain injury associated with a fall and acute subdural haematoma.

20

Mortality rates High HDI tier

Medium HDI tier

16%

22%

across the world has been possible due to the infrastructure and collaborations supported by the NIHR. The database and data management process used in the study have now laid the foundation for a global registry of traumatic brain injuries that we have established to support ongoing quality improvement and research in the field of traumatic brain injury.”

Peter Hutchinson (University of Cambridge, Cambridge, UK), director of the NIHR Global Neurotrauma Research Group, added: “This is the largest study in the world looking at the surgical management of head injuries, and will be of practical value to clinicians and others planning strategies for the future. The collaboration across such a vast number of hospitals and countries, together with the support of the World Federation of Neurosurgical Societies and continental neurosurgical societies, has been phenomenal.”

Concluding their report in The Lancet Neurology, the researchers write: “Patients receiving emergency neurosurgery for traumatic brain injury differed considerably in their admission characteristics and management across human development settings. Level of human development was associated with mortality. Substantial opportunities to improve care globally were identified, including reducing delays to surgery. Between-hospital Low HDI variation in mortality suggests tier changes at an institutional level could influence outcome and comparative effectiveness % research could identify best practices.”

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May 2022 | Issue 46

14 Interview

PROFILE

Pedro Lylyk

Pedro Lylyk’s work and achievements in the neurosurgical field have spanned several decades, and range from a momentous intracranial stent placement in 1996, to leading the first in-human study of a novel hydrocephalus treatment in 2022—with more than 10,000 brain aneurysms and arteriovenous malformations (AVMs) treated in between. Since the mid-1980s, Lylyk has dedicated his career to the development and improvement of therapeutic options in endovascular neurosurgery, as well as the training of young physicians from all over the world. He is also currently the director and CEO of ENERI (Equipo de Neurocirugía y Radiología Intervencionista) and Clínica La Sagrada Familia in Buenos Aires, Argentina, in addition to several other titles and appointments.

Here, Lylyk gives NeuroNews a window into his career and discusses how the field of neurosurgery has changed in this time.

I wanted to be a doctor for as long as I can remember.

I knew from the very beginning that neuroscience and the brain were so interesting, and that there was a lot to understand, develop and emerge. After finishing my residence in neurosurgery, I shared with my mentors the concept of treating diseases through minimally invasive therapy—an evolving technique at that time!

Who have your mentors been and how have they impacted your career?

My mentors were Raúl Carrea, who is a paediatric neurosurgeon, and Charlie Drake, in neurosurgery, Julio Castaño, a neurologist, and Fernando Viñuela in interventional neuroradiology. I have tried to combine the best of all of these fields in this new speciality. All of them were inspiring and generous teachers, not only in neurosciences, and they also showed exemplary leadership, ethics and commitment. I have been lucky to be able to learn from my friends and colleagues from all around the world, exchanging ideas and experiences, sharing specialist seminars, proctoring, observing cases, researching and taking part at numerous meetings, symposia, discussions and conferences.

You are recognised as having placed the first intracranial stent in 1996— could you describe the procedure, and how you gained this achievement?

I was performing a very difficult case of acute posterior inferior cerebellar artery (PICA) dissection and there was no other option. Luckily, our team included interventional cardiologists, with whom we discussed the emergency case, and we decided that we would give the patient a chance by implanting a coronary stent—to which the family agreed. This was in 1996 and the patient is perfect to this day.

How did your fellowship training in North America influence you as a neurosurgeon?

I did my neurosurgery fellowship at the Western Ontario University in London, Canada and the University of California, Los Angeles (UCLA) in Los Angeles, USA. To this day, I remember Charles Drake’s advice, telling me that endovascular neurosurgery would promise a bright future!

In your experience, how do neurosurgical practice and research differ in South America compared to other parts of the world?

Our experience in Latin America is very good. We have been trained in Europe and North America and,

today, we train many people from a variety of different countries in Latin America. The current state of the medical education and available opportunities in Latin America face major challenges, however, due to a lack of resources, and the fact that funding and access are quite different depending on the given health system or country.

Why did you decide to develop an endovascular neurosurgery and interventional radiology training programme at your centre, and how successful have these programmes been?

Since Fernando Viñuela, and other young and enthusiastic neuroradiologists, had founded SILAN (Sociedad Iberolatinoamericana de Neurorradiología Diagnóstica y Terapéutica), I decided we should create our own centre—the International Center of Endovascular Training (ICET). The goal was to receive and teach Ibero-Latin American physicians for a period of at least one year, together with three other universities in Buenos Aires, as the training of doctors in interventional neuroradiology in Latin America was an imperative need. Today, we also receive people from several other countries, including China, India, Japan, and places in Europe. I am very proud and grateful to all of them.

The younger generations must study hard, and take advantage of many innovations and interactions between different fields, while the study of the anatomy, physiology and pathology is also very important.”

What do you feel has been the most important development in the field of neurosurgery during your career?

There have been three particularly important milestones, in my opinion: The Guglielmi detachable coil (GDC), which was introduced in the 1990s and drove the endovascular treatment of brain aneurysms After this, intracranial stents, as a treatment for stenosis of the intracranial or carotid arteries

Alisonlang.com

What initially attracted you to medicine, and the field of neurosurgery specifically?

More recently, flow diverters and intrasaccular flow disrupters have provided a new option for treating intracranial aneurysms Also, today, we crucially have a better understanding of brain diseases and the best way to take care of these patients.

What is the most significant unmet need in neurosurgical care right now?

The field of interventional oncology has to evolve— this will be one of the biggest challenges to overcome in the near-future.

What is your proudest achievement in neurosurgery?

The early treatment of newborn patients with vein of Galen aneurysms (a rare form of AVM in which the embryonic precursor to a vein at the base of the brain dilates, causing too much blood to rush to the heart).

Issue 46 | May 2022

Interview 15

My team and I have performed these treatments over the course of many years, with a challenging yet improved technique, at our centre in Buenos Aires.

Besides your own work, what is the most interesting piece of neurosurgery research you have seen in the past year?

Besides endovascular neurosurgery, the most interesting outlook for the future is the development of new techniques for non-vascular diseases like hydrocephalus by endovascular means. This is a new and exciting project that I am working on today with my colleagues Adel Malek and Karl Hellman from CereVasc and Tufts University (Somerville, USA).

As the principal investigator for the first-in-human ETCHES I study, I have already published a case report detailing the first treatments of communicating hydrocephalus with the eShunt system (CereVasc) in the Journal of NeuroInterventional Surgery, and the first normal-pressure hydrocephalus patient was also recently treated with the device at Clínica La Sagrada Familia.

What advice would you give to people embarking on a career in neurosurgery?

Our field has been growing up very fast, but there are still many opportunities to learn and improve.

The younger generations must study hard, and take advantage of many innovations and interactions between different fields, while the study of the anatomy, physiology and pathology is also very important. The new generation has to think out of the box in order to improve the quality of life of our patients as well.

What are your interests outside of the field of medicine?

Outside of medicine, my interests are the study of history, playing tennis, and travelling with my family—my wife, Sandra Boreisink, and my three wonderful children, Ivan, Pedro Nicolás and Natalia.

Since my childhood, I have been a dancer in the Ukrainian ballet in Argentina and have ended up being its director. Today, I greatly enjoy opera and watching classical ballet at the Teatro Colón in Buenos Aires. As a Ukrainian descendent, I am also proud to be the honorary consul of Ukraine in Buenos Aires, and I have chaired the Argentine Central Ukraine Representation (RCU-Representación Central Ucrania) since 2011.

Fact file Current appointments

Neurosurgeon, director and CEO, ENERI (Equipo de Neurocirugía y Radiología Intervencionista) and Clínica La Sagrada Familia, Buenos Aires, Argentina Chair of Neurosurgery and Hemodynamics, University of Buenos Aires (UBA) Professor and chair, Department of Vascular Medicine, Universidad del Salvador (USAL) Professor and chair of Endovascular Surgery, Universidad de Ciencias Sociales y Empresariales (UCES)

Education

MD, Faculty of Medicine, UBA Residency in Paediatric Neurosurgery, Ricardo Gutiérrez Children’s Hospital Fellowship in Diagnostic Neuroradiology, Therapeutic and Endovascular Neurosurgery, University of Western Ontario, London, Canada and University of California Los Angeles (UCLA), Los Angeles, USA

Honours (selected)

2009: Master of Neurosurgery, World

Federation of Neurosurgical Societies (WFNS) 2011: “Outstanding Personality of Science”, legislature of Buenos Aires 2015: First Tribute to Men and Women of Health, Health Prize, UCES 2018: First non-Spanish doctor distinguished as honorary member, Official College of Physicians, La Coruña, Spain

May 2022 | Issue 46

16 Aneurysm Treatments

DEVICES

Guidewire-less neurovascular navigation system shows promise in rabbit aneurysm model A NEW CONCEPT FOR NAVIGATING the neurovasculature, performed without the aid of a guidewire, has demonstrated its ability to be manoeuvred through tortuous vessels, braided stents and occlusions, and to deliver and move coils, in preclinical investigations involving a rabbit aneurysm model. Details of the study, which utilised the Bendit 17 and Bendit 21 steerable microcatheters (Bendit Technologies), are published in the Journal of NeuroInterventional Surgery (JNIS).

“Our in vivo experience with the Bendit microcatheter supports the effectiveness of its bending and torquing capabilities for navigation and positioning, coupled with its stability in the bent position,” lead author Alejandro Berenstein (Icahn School of Medicine at Mount Sinai, New York, USA) and colleagues report in JNIS. “The Bendit has the potential to treat aneurysms for which conventional microcatheters are not suitable, such as sidewall aneurysms requiring directional control and tip positioning while delivering intrasaccular devices.”

Providing a backdrop for their investigations, the authors note that the endovascular treatment of intracranial vascular diseases, such as aneurysms, is often challenged by unfavourable vascular anatomy.

They also claim, however, that the Bendit steerable

microcatheter is designed with bending and torquing capabilities for improving navigation and stability during device delivery—with or without a guidewire.

They set out to assess two of these microcatheter devices—the Bendit 17, which has an inner diameter of 0.0165 inches, and the Bendit 21, which has an inner diameter of 0.021 inches—in the treatment of bifurcation and sidewall aneurysms that had been surgically created in six New Zealand rabbits. In their preclinical study, the researchers attempted to navigate Bendit devices through the vasculature of these animal models and enter the aforementioned aneurysms without a guidewire. Berenstein and colleagues detail that various positions within the aneurysm were selectively explored, and angiographic imaging was used to visualise catheterisation, navigation, vascular manipulations, and the placement of coils, stents and intrasaccular devices.

“We successfully navigated the Bendit microcatheters to all aneurysms without a guidewire,” they report. “We successfully recanalised a nearly occluded carotid artery and navigated the Bendit through a braided stent. In contrast, we were unable to navigate a comparator device [Headway 21; Microvention/Terumo] with a guidewire as effectively as the Bendit. Coils were introduced at different

Multicentre study indicates WEB flow disrupters can safely be used in sidewall aneurysms As per the findings of a multicentre, retrospective study, use indications for the Woven EndoBridge (WEB) intrasaccular flow disruption device (Microvention/Terumo) can be safely extended to include sidewall intracranial aneurysms.

THE STUDY’S AUTHORS detail in Radiology that no significantly different outcomes were associated with this off-label use of the device—as compared to its US Food and Drug Administration (FDA)-approved use in wide-neck bifurcation aneurysms. “The correct characterisation of the sidewall aneurysm location, neck angle and size is crucial for successful treatment and lower retreatment rate,” Nimer Adeeb (Louisiana State University Health Sciences Center, Shreveport, USA) and colleagues write.

To compare angiographic and clinical outcomes between the treatment of sidewall and bifurcation aneurysms, the authors conducted an analysis of the WorldWideWEB Consortium—a synthesis of retrospective databases spanning 22 academic institutions across the Americas, Europe and Australia—to identify patients with intracranial aneurysms treated using the WEB device. The consortium was co-led by Adeeb and Adam Dmytriw (Massachusetts General Hospital, Boston, USA).

Across 671 patients, a total of 683

intracranial aneurysms met the study’s inclusion criteria, Adeeb and colleagues report. Those aneurysms were divided into bifurcation and sidewall groups— and the bifurcation group included 572 aneurysms (median patient age=61 years; 69.8% female), while the sidewall group included 111 aneurysms (median patient age=62 years; 78.4% female). Propensity score matching (PSM) was then performed, resulting in 91 bifurcation/sidewall aneurysm pairs.

Detailing the results of the study, the authors state that no significant difference was observed in deployment success, complication rates, median length of procedure, or use of adjunctive coil placement, between the two groups.

They add that immediate adequate WEB aneurysm occlusion was higher in the sidewall group compared with the bifurcation group (66.1% vs 43.3% of aneurysms, respectively) but, at the last follow-up, no significant difference was observed in adequate WEB aneurysm occlusion rates (89% vs 85%). Retreatment was needed in 7.2% of aneurysms in the bifurcation group versus 10.9% in the sidewall group.

locations within the aneurysm and could be pushed, pulled, and repositioned with the Bendit tip. Finally, we used the Bendit to deliver intrasaccular devices— designed for terminal aneurysms—to treat sidewall aneurysms.”

Discussing further benefits they observed in these devices, the authors add that the Bendit allows for the precise placement and repositioning of coils within the aneurysm, with the device remaining stable in the bent position. When delivering coils, this stability— along with the ability to micro-torque with more or less articulation—permits better packing density as well as avoiding compartmentalisation and the need to recatheterise poorly packed areas, they claim, noting that this contrasts with coil delivery using conventional, guidewire-assisted microcatheters, whereby it is not uncommon for the microcatheter tip to move.

“The stability of the tip in the bent position prevents the Bendit from being ejected from the aneurysm during device deployment and eliminates the need for additional devices, such as a stent or balloon, to protect the aneurysm orifice,” Berenstein and colleagues write.

When the Bendit tip does get out of position, they continue, it can easily be repositioned without having to withdraw coils or use a guidewire—saving a great deal of time during procedures. Berenstein and colleagues also note that, in their study, after aggressive manipulation of the device within the vessel, there was no evidence of spasm, vessel damage or dissection, or thrombosis observed on angiography or histology. “Therefore, the Bendit has the potential to expand indications for different intrasaccular devices to include sidewall aneurysm embolisation,” they state, but conclude that “the clinical safety and efficacy of the device need further assessment”.

They also note that the majority and angiographic outcomes for of patients had an independent the WEB device versus flowfunctional status at discharge, diverting stents for treatment as per the modified Rankin of sidewall aneurysms by using Scale (mRS) and—while matched cohorts.” complications were higher in Adeeb is also the lead the bifurcation group than the author for a recent retrospective sidewall group (8.4% vs 2.7% of Nimer Adeeb cohort analysis that homed in on procedures, respectively)—there bifurcation aneurysm data from was no significant difference observed the WorldWideWEB Consortium to in terms of haemorrhagic complications, compare treatment outcomes using the technical complications and mortality.

WEB device across various aneurysm There was also no recorded incidence locations. A total of 572 aneurysms were of aneurysm rerupture in the study included, and the researchers note the sample. Following PSM, no significant rate of adequate aneurysm occlusion difference was seen in rates of long-term was significantly higher for basilar aneurysm occlusion, retreatment, or tip (91.6%) and internal carotid artery complications, between the two groups.

(ICA) bifurcation (96.7%) aneurysms, “Currently, several endovascular and lower for anterior cerebral artery options are available for treatment of (ACA) bifurcation (71.4%) and anterior intracranial aneurysms, and more are communicating artery (AComA; 80.6%) likely to be available in the near future,” aneurysms.

Adeeb and colleagues write. “Some Writing in the Journal of of those treatments may ultimately NeuroInterventional Surgery, Adeeb be a better fit for certain aneurysm and colleagues conclude: “To our locations, including sidewall aneurysms, knowledge, this is the most extensive compared with WEB. However, the study to date that compares the goal of this study is to address the treatment of different intracranial growing trend of off-label use of WEB bifurcation aneurysms using the WEB for treatment of sidewall aneurysms device. Basilar tip and ICA bifurcation compared with bifurcation aneurysms in aneurysms showed significantly higher a large, matched cohort. Future studies rates of aneurysm occlusion than should focus on comparing the clinical other locations.”

The correct characterisation of the sidewall aneurysm location, neck angle and size is crucial for successful treatment and lower retreatment rate.”

Issue 46 | May 2022

Advertorial 17

THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC

It takes two: The benefits of direct ‘double stentriever’ thrombectomy in M1/TICA occlusions Mechanical thrombectomy may be the standard of care for acute ischaemic strokes caused by a large vessel occlusion (LVO), but even this established and trusted procedure fails to achieve adequate recanalisation in close to one third of cases, and at an even lower rate after the first pass. However, the practice of deploying two stentrievers simultaneously as a first-line intervention for clots that are refractory to treatment with a single device has shown promise and is now gaining traction—with Pedro Vega (Hospital Universitario Central de Asturias, Oviedo, Spain) and colleagues recently publishing initial experiences of this approach in Clinical Neuroradiology. Here, Vega discusses his team’s findings, and usage of the Solitaire X stentriever and Phenom 21 microcatheter (both Medtronic) as part of this novel technique.

D

etailing this ‘double stentriever’ likelihood of successful thrombectomy.” thrombectomy technique, Vega says: In the study, Vega and his colleagues “An 8Fr balloon catheter is positioned also observed three cases of symptomatic in the ICA [internal carotid artery], and a intracerebral haemorrhage (7.9%), and no 0.014-inch guidewire is advanced through a vasospasms. At 90 days, 16 patients (41%) 0.021-inch microcatheter to the target vessel. were functionally independent, registering Pedro Vega After passage through the clot, intra-arterial a modified Rankin Scale (mRS) score of contrast medium is injected to verify the position of 0–2, and nine (23%) had died. In addition, 15 of 27 the microcatheter distal to the clot. Then, a second patients (55.5%) in the first-pass TICI 2b/3 subgroup microcatheter is placed distally in the same artery or had a good clinical outcome (0–2 mRS) at 90 days. in another branch of the main artery. The stentrievers As such, Vega and colleagues conclude their Clinical are deployed by withdrawing the microcatheters in a Neuroradiology report by stating that their findings parallel or Y configuration, and contrast material is suggest first-line double stentriever thrombectomy is injected to evaluate flow after placement of the safe and effective for M1/TICA occlusions. devices. The proximal balloon guiding catheter is inflated one or two minutes later to arrest blood flow, Chosen devices and the opened stentrievers are removed Vega tells NeuroNews that the Solitaire X—which simultaneously with aspiration using a 60ml syringe.” features a unique, parametric design intended to According to Vega, the approach is particularly enable dynamic clot integration—was among the effective as a first choice of treatment in proximal most commonly used stentrievers in the study, with occlusions, especially when the thrombus is located 4×40mm and 6×40mm variations of the device being in arterial bifurcations. “This technique is especially utilised in a total of 19 patients. “While it is hard to say useful in these clots, because they have a tendency to for certain, it makes sense to think that Solitaire’s jump from one branch to another when thrombectomy overlapping structure allows for better interlocking of is performed with a single device,” he notes. “The the two devices, increasing the effectiveness of the increased radial force from a second stentriever might technique,” he says. “I would definitely recommend also be especially beneficial in hard, fibrin-rich thrombi using it as part of the double stentriever procedure. The that are difficult to penetrate with a single device.”

Solitaire has proven over the years to be a dramatically effective extractor device, whether used on its own or Initial experiences with another device.” And, when asked about the extra ‘Rescue therapy’ using two stentriever devices has been cost of deploying two devices instead of just one, Vega reported previously, demonstrating good results. As notes that an effective technique like this holds the such, Vega and his colleagues undertook a singlepotential to improve first-pass recanalisation rates— centre, prospective study to assess whether the potential avoiding the need for expensive rescue therapies and benefits of a two-device approach translate when it is increasing the percentage of functionally independent used as a first-line treatment for acute occlusions of the patients at 90 days, thus reducing costs in the mediumM1 segment of the middle cerebral artery (MCA) and/ and long-term. “A cost-effectiveness study would have or terminal internal carotid artery (TICA). Between to be carried out to demonstrate this,” he adds.

May and October of 2020, 39 patients (median age=79 Moving on to discuss the fact that one specific years, 58.9% female) were analysed. Study outcomes microcatheter product, the 160cm version of the included successful recanalisation, first-pass effect, Phenom 21, was used in every procedure during procedure times, number of device passes, symptomatic this study, Vega highlights the various benefits the intracerebral haemorrhage, National Institutes of device holds. “Phenom 21 is our microcatheter of Health Stroke Scale (NIHSS) score at discharge, and choice for mechanical thrombectomy in proximal 90-day functional independence and mortality. vascular occlusions due to its good navigability and The study produced largely positive results, with all trackability, among other advantages,” he states.

39 patients experiencing successful recanalisation—a final modified thrombolysis in cerebral infarction (mTICI) score of 2b/3—and 27 patients (69%) had an mTICI score of 2c/3 after the first pass. Discussing the latter of these findings, Vega says: “Advantages of using a second device include better integration of the thrombus, thanks to increased radial force from the second stentriever, and more complete coverage of it. Integration of the clot increases the retrieval force transmitted to the thrombus and improves the

“Working with a good microcatheter guarantees the success of the intervention.” Similarly, Vega notes that the use of a balloon guide catheter is his centre’s access system of choice in any thrombectomy procedure, adding: “It is the technique that demonstrates the greatest capacity to block and reverse flow, which has been shown to reduce thromboembolic complications and increase the success of thrombus extraction. It is a key point for the success of the double stentriever technique.”

Future directions

“The most notable benefit is that the percentage of patients in whom a TICI 2c/3 is obtained after the first pass is significantly increased,” Vega claims, homing in on the crux of why he uses the double stentriever approach in M1/TICA occlusions. “I would say that it is undoubtedly a very effective rescue technique when we are unable to extract the thrombus after the first or second pass. Our preliminary results in this series of patients suggest that it is an effective and safe technique if used as a first intention in occlusions located in the TICA and in the M1 segment as well. I would probably recommend that other physicians start using the technique in rescue cases to become familiar with it in order to gradually expand use indications.

The next step would be to use it in occlusions located in arterial bifurcations (TICA, MCA and BA [basilar artery]) and in long thrombi located in the M1 segment. However, the generalisation of the use of the technique as a first intention in all cases should be done with caution until more results are available.”

Delving further into the generalisability of the study at hand, Vega concedes several limitations, including its relatively small size, and lack of patient randomisation or a control group. He notes that additional data are necessary before double stentriever thrombectomy can be included in international guidelines as a first-line option for proximal occlusion, and randomised controlled trials comparing the use of single versus double stentriever thrombectomy will further clarify the effectiveness, safety and cost of the latter. Vega also believes that it is essential to carefully assess the possible risks and benefits of this approach before attempting it in individual patients. “In any case, the results are very promising and we are working on the development of an international, multicentric study to demonstrate that our results hold up,” he concludes. “I am sure that, in the near future, we will demonstrate with the highest level of scientific evidence that it is the most effective technique.”

Pedro Vega is the head of Interventional Neuroradiology in the Department of Radiology at Hospital Universitario Central de Asturias in Oviedo, Spain.

DISCLAIMER: The data and content included in this presentation express only the clinical perspective of the presenter. They are completely independent and do not necessarily reflect the opinions of Medtronic.

Solitaire X

May 2022 | Issue 46

18 Robotics

MIT engineers develop joystickoperated robot to help surgeons treat stroke remotely Engineers from the Massachusetts Institute of Technology (MIT) in Cambridge, USA have developed a telerobotic system to enable surgeons to quickly and remotely treat patients experiencing a stroke or aneurysm.

THE ROBOTIC SYSTEM, THE movement of which is controlled through magnets, has been designed to remotely assist in endovascular stroke interventions.

With a modified joystick, surgeons in one hospital may control a medical-grade robotic arm at another location to safely operate on a patient during the ‘golden hour’ for treatment—a critical window of time considered key in saving a patient’s life and preserving their brain function.

“We imagine, instead of transporting a patient from a rural area to a large city, they could go to a local hospital where nurses could set up this system,” said Xuanhe Zhao (MIT, Cambridge, USA), co-author of a Science Robotics report detailing these findings. “A neurosurgeon at a major medical centre could watch live imaging of the patient and use the robot to operate in that golden hour. That is our future dream.”

Endovascular surgery is a specialised, minimally invasive procedure that involves carefully twisting and guiding a thin wire through a patient’s vasculature to a target

location without damaging vessel walls in the process. Robotic systems, which usually involve motor drives that advance and retract a wire while twisting it through the patient’s blood vessels, are currently being explored as assistive technologies in endovascular surgery. “But, having a robot twist with the same level of sophistication [as a surgeon] is challenging,” noted lead author Yoonho Kim (MIT, Cambridge, USA). “Our system is based on a fundamentally different mechanism.”

The team’s new system builds on demonstrations from 2019 that involved steering a magnetically controlled thread through a life-sized silicone model of the brain’s blood vessels. They did so at the time using a handheld magnet that

they manually manipulated. For their more recent study, the researchers took to Massachusetts General Hospital in Boston, USA, installing the robotic arm and a life-sized phantom model in a cath lab, and setting up the joystick as well as a monitor displaying a live video of the model in a control room. From there, an operator watched the video while using the small joystick knob and buttons on a mouse to remotely navigate the vessels in the model.

With just one hour of training, neurosurgeons were able to remotely control the robot’s arm to guide a wire through this maze of vessels and reach target locations in the model.

The team also used the robotic system to clear simulated clots—via standard endovascular techniques—in difficult-toreach areas of the model.

The MIT team envisions that its teleoperated robotic system could be installed at smaller hospitals and remotely guided by trained surgeons at larger medical centres, helping more patients to receive time-critical stroke treatments while also protecting operators from radiation exposure. “The neurosurgeons can operate the robot in another room or even in another city without repeated exposure to X-rays,” Zhao added.

The neurosurgeons can operate the robot in another room or even in another city without repeated exposure to X-rays.”

Ethics of remote surgeries In an exclusive interview, NeuroNews recently caught up with Jeffrey Saver (University of California, Los Angeles [UCLA] Medical Center, Los Angeles, USA) to discuss the multitude of ethical considerations regarding the use of robotic technologies in neurointerventional surgery.

Saver outlined a number of potential barriers that the global neurointerventional community must reckon with as interest in robot-assisted procedures and remote stroke care continues to grow—including informed patient consent, conflicts of interest, and the diffusion of responsibility.

A four-part video series on this subject is now available in full, and each episode can be viewed online at neuronewsinternational.com/ tag/ethics-of-remote-surgerieswith-jeffrey-saver.

Issue 46 | May 2022

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Multisession tDCS alongside cognitive remediation promotes social functioning in autism patients In a randomised, sham-controlled clinical trial, multisession transcranial direct current stimulation (tDCS) paired with concurrent cognitive remediation training has been shown to promote social functioning in individuals with autism spectrum disorder (ASD). These findings, derived from a total of 41 ASD patients aged 14–21 years, are published in the journal Brain Stimulation.

“T

o the best of our knowledge, this was the first double-blind RCT [randomised controlled trial] to investigate the clinical, neuropsychological and neurophysiological effects of tDCS with left DLPFC [dorsolateral prefrontal cortex] cathode placement and right supraorbital region anode placement, delivered with concurrent, computerised cognitive remediation training, in adolescents and young adults with ASD,” co-first author Yvonne Han (The Hong Kong Polytechnic University, Hong Kong) and colleagues write in their report.

“By matching individuals on age, IQ, sex, and handedness, in the active and sham tDCS groups—which were also matched for baseline ASD symptom severity and current social functioning—we demonstrated that our protocol was a safe and efficacious treatment.”

To assess the clinical effects and neurophysiological mechanisms of prefrontal tDCS alongside cognitive remediation training, the researchers randomly assigned study participants to either active or sham Yvonne tDCS groups. Patients received Han 1.5mA (milliampere) of prefrontal tDCS with the Starstim device (Neuroelectrics) for 20 minutes over two consecutive weeks. TDCS was delivered concurrently with a computerised cognitive remediation training programme.

The authors detail that individuals undergoing sham tDCS received the same cognitive remediation training and underwent the same tDCS protocol as those in the active group—except for the 20-minute stimulation.

To measure the change in overall social functioning and inflexible behaviours before and after treatment, the Social Responsiveness Scale—2nd Edition (SRS-2) was used as the primary outcome measure. The underlying cognitive processes of social functioning, as well as prefrontal restingstate functional connectivity (rsFC), were also measured.

A total of 46 patients were randomised at the start of the trial, with 20 active group patients (mean age=17 years; 18 males) and 21 sham group patients (mean age=17 years; 20 males) ultimately being available for analysis.

Han and colleagues report that results from these 41 participants indicated that multisession, prefrontal tDCS “significantly enhanced the social functioning of ASD individuals”, demonstrated by highly significant reductions in the total SRS-2 score in the active group versus nonsignificant reductions in the sham group.

“This improvement

was associated with enhanced emotion recognition and cognitive flexibility,” they write. “Specifically, this tDCS protocol optimised information processing efficiency and the optimisation showed a trend to be associated with enhanced rsFC in the right medial prefrontal cortex.”

A significant group-by-time interaction was also found between the active and sham tDCS groups regarding SRS2 restricted, repetitive behaviour (RRB) subscores, with post-hoc paired sample t-tests revealing highly significant RRB score reductions in participants in the active group and nonsignificant reductions in participants in the sham group.

And, although the group-by-time interaction effect for SRS2 social communication index (SCI) subscores was nonsignificant, post-hoc paired sample t-tests revealed highly significant SCI score reductions in the active group versus nonsignificant reductions in the sham group.

Han and colleagues detail that—while significantly more participants in the active tDCS group experienced short-term itchiness over the stimulation site compared to participants in the sham tDCS group—this was resolved within 10 minutes after each treatment session. No other significant differences in side-effects were observed between the two groups.

The authors note that their results are consistent with previous preliminary studies in that multisession tDCS, delivered concurrently with cognitive remediation training, yielded “large and significant effects” on social communication and RRBs in individuals with ASD. They add that their finding of prefrontal tDCS enhancing the rsFC of the brain’s right medial prefrontal regions (a major hub that enables socially relevant information to be processed in response to different social situations more efficiently) is consistent with a prior meta-analysis of neuroimaging studies as well.

However, Han and colleagues note that, “despite contributing significantly to understanding the effects of tDCS on ASD”, several factors could limit the generalisability of their study—including a relatively narrow range of ages and IQ scores in its patient population, the inclusion of female participants, and a small sample size. As such, they conclude that their data should be regarded as preliminary until they have been verified by larger-scale studies and future RCTs.

Active tDCS group

Post-treatment

Pretreatment

Post-treatment

Pretreatment

SRS-2 MEAN TOTAL SCORE

Sham tDCS group

Today’s neurologists “privileged” by rapid development of neuromodulation technologies “THE NEUROLOGIST TODAY IS privileged to be in the midst of a time of rapid development of personalised and flexible technologies that deliver data and provide powerful therapeutic options for patients with neurologic disorders.” This is the concluding message of an article recently published in Neurology, entitled “Neuromodulation in 2035”.

In their article, Tim Denison (University of Oxford, Oxford, UK) and Martha Morrell (Stanford University, Stanford, USA) aver that, by 2035, “advances in our understanding of neuroanatomical networks and in the mechanism of action of stimulation, coupled with developments in material science, miniaturisation, energy storage, and delivery, will expand the use of neuromodulation devices”.

“There is enormous opportunity to improve technology, and explore new [...] applications, including for poststroke motor rehabilitation, memory disorders, mood disorders, brain and spinal cord trauma, prolonged disorders of consciousness, and Alzheimer’s disease,” they continue.

In addition, the authors highlight emerging technical and therapeutic capabilities in neuromodulation—from responsive, ‘closed-loop’ systems and adaptive stimulation methods that use time-based biological rhythms, to developments in biomarker data, neural network models and focused ultrasound.

Denison and Morrell allude to several important considerations en route to achieving this, however, including data security and privacy, healthcare economics, regulatory challenges, patient acceptance and involvement, and “fundamental ethical principles” as well as potential legal and social concerns.

“Current neuromodulation treatments have proven benefit, a number will demonstrate benefit soon, and others will follow,” they conclude.

Current treatments have proven benefit, a number will demonstrate benefit soon, and others will follow.”

May 2022 | Issue 46

20

Sham-controlled studies indicate effectiveness of TMS for negative schizophrenia symptoms A SYSTEMATIC REVIEW AND METAanalysis published in Nature Schizophrenia has concluded that data from sham-controlled studies to date indicate the effectiveness of transcranial magnetic stimulation (TMS) in treating the negative symptoms of schizophrenia. In addition, this analysis’ authors— Søren Østergaard (Aarhus University Hospital, Aarhus, Denmark) and colleagues—state that, “although it appears that targeting the L-DLPFC [left dorsolateral prefrontal cortex] and using a stimulation frequency >1Hz are the most efficacious settings, the optimal treatment parameters are yet to be established”. Østergaard and colleagues begin by noting that pharmacological treatment is a “cornerstone of care” in schizophrenia and other psychotic disorders.

However, they continue, while the ‘positive’ symptoms associated with schizophrenia, such as delusions and hallucinations, respond relatively well to these medications, drugs are somewhat less effective in treating the absence/lessening of normal functions, or so-called ‘negative’ symptoms, including affective flattening, alogia, apathy and social withdrawal.

As such, “identification and development of efficacious treatments of negative symptoms is a priority”, the authors claim, noting that a non-invasive neuromodulation technique like TMS could offer hope in this regard. TMS is currently approved by the US Food and Drug Administration (FDA) for the treatment of major depression—a mental health condition that can cause similar deficits in normal functioning to those seen in schizophrenia.

In light of recent trials, some of which have involved the use of novel stimulation parameters or neuronavigation to improve targeting, Østergaard

and colleagues conducted a systematic review and quantitative meta-analysis of double-blind, randomised controlled trials (RCTs) evaluating TMS as a treatment for negative symptoms in schizophrenia patients.

This involved searching MEDLINE, EMBASE, Web of Science, and PsycINFO for relevant studies in May 2021. Only studies involving adult participants (aged ≥18 years) were included, while co-initiation of other treatments with TMS, such as pharmacological therapies, was the main exclusion criterion. Østergaard and colleagues ultimately identified 57 studies, with a total of 2,633 participants and spanning 15 different countries, that were eligible for inclusion in their meta-analysis. The authors report that all of the patients in these studies had schizophrenia or schizoaffective disorder, and the majority of eligible trials involved rTMS (n=48), while theta-burst

Although it appears that targeting the left dorsolateral prefrontal cortex and using a stimulation frequency >1Hz are the most efficacious settings, the optimal treatment parameters are yet to be established.”

Neuromodulation offers hope for patients with long-COVID

Marom Bikson Comment & Analysis With increasing focus being placed on the long-term impact COVID-19 can have, and the demand for effective treatments also growing concurrently, Marom Bikson (New York City, USA) outlines the potential neuromodulation holds regarding this unmet need.

THERE IS AN URGENT NEED to best understand and develop treatments for long-COVID, or neuro-COVID, more formally called post-acute sequelae of SARS-CoV-2 infection (PASC). PASC can be defined by persisting (>1 month) symptoms following COVID-19 illness. It affects up to 20% of survivors, often with debilitating consequences and, as yet, who is susceptible to PASC and what causes it remains to be determined.

While PASC symptoms vary between individuals and can appear as a constellation of symptoms, its impairment of brain functions defines its core syndrome. Central fatigue and cognitive dysfunction, or ‘brain fog’, are

the most reported symptoms, and often disable otherwise healthy individuals (i.e. preventing their return to work).

Given the prevalence of PASC, and its long-lasting and debilitating nature, there is an urgent need to develop treatments—even as questions on how PASC develops are researched.

Neuromodulation includes a range of medical devices that apply energy to the body for therapeutic purposes. Most commonly, this involves application of electrical stimulation to the brain or nerves.

Some neuromodulation devices are implanted, like pacemakers for the brain, while others require repeated visits to medical centres, or are battery-

stimulation (n=9) and deep-TMS (n=2) were seen less commonly. The effect of TMS on negative symptoms versus sham controls in each study was quantified by the standardised mean difference (SMD) with 95% confidence intervals and pooled across studies using an inverse variance random effects model.

Outlining individual study results, the authors state that 18 studies showed a statistically significant superior effect of TMS compared to sham treatment, while one study found a statistically significant superior effect with sham treatment. The remaining studies did not show a statistically significant difference between their treatment groups. There was “considerable heterogeneity” between the included studies, Østergaard and colleagues also report.

The pooled analysis of these results showed statistically significant superiority of TMS (SMD=0.41)—corresponding to a number needed to treat of five. In addition, follow-up data from at least four weeks after the end of treatment yielded an SMD of 0.27, the authors write. The effect in participants with predominantly negative symptoms was substantial (SMD=0.50), while no effect on depressive symptoms was observed (SMD=0.02). The SMD seen with different types of TMS did not differ in a statistically significant way either, according to Østergaard and colleagues.

Regarding stimulation sites, stimulation of the L-DLPFC had a statistically significantly larger effect when compared to other sites (SMD=0.55 vs SMD=0.04), although this may have been confounded by the “considerable methodological heterogeneity” in the ‘other sites’ category, the authors claim. They also state that, while stratified analyses suggested that TMS targeting the L-DLPFC and using a stimulation frequency >1Hz was most efficacious, the optimal treatment parameters “are yet to be established” in clinical trials.

powered and can be used at home.

Because neuromodulation devices can exert powerful therapeutic effects on the nervous systems and because, in non-COVID patients, neuromodulation treatments target many of the same symptoms reported in PASC, medical researchers are anxious to test neuromodulation for long-COVID. Several trials of neuromodulation for COVID-19 are already running or have been completed. These have focused largely on two forms of battery-powered neuromodulation. The first applies electricity to either the neck or the ear in order to activate the vagus nerve.

The vagus nerve is a branch of the nervous system connecting the brain to many peripheral organs and among the many functions it controls is antiinflammatory responses. If COVID-19 involves an extreme and undesired anti-inflammatory response, vagus nerve stimulation (VNS) might reverse or treat COVID-related disorders.

A second form of neuromodulation being tested for PASC is a wearable cap that directs energy to the brain— referred to as transcranial direct current stimulation (tDCS). Early trials suggest tDCS may benefit individuals suffering from PASC, and NYU Langone Health in New York, USA is among the medical centres now offering tDCS services.

Low-intensity neuromodulation techniques, such as VNS and tDCS, are considered safe and well-tolerated, so much so that they are used in healthy

volunteers in experiments on normal brain function. This will favourably factor into condensing the risk versus benefit of any new treatment. Ongoing and expanded studies are needed to prove if neuromodulation is effective for PASC, including understanding which type of treatment should be used for which patients.

Because COVID-19 is ubiquitous and will become endemic, PASC is especially troublesome in regard to cumulative disease burden. While vaccines and drugs are US Food and Drug Administration (FDA)-approved to moderate short-term symptoms, protection against PASC is unclear.

The success of neuromodulation for PASC will depend on identifying device- and symptom-specific mechanisms. Given the unknowns about PASC itself, one method for doing this is to measure biomarkers of disease progression and response to treatment.

Ultimately, home-based neuromodulation should be integrated with wearable health monitors and telemedicine, thereby supporting fully remote comprehensive treatment protocols.

Marom Bikson is the Shames Professor of Biomedical Engineering at the City College of New York in New York City, USA. Bikson’s laboratory works to translate basic research on brain function into the development of new medical devices.

Issue 46 | May 2022

21

Recommended use of SCS in neuropathic pain has not led to increased uptake over past decade

potentially eligible for SCS, and patients receiving an SCS-related procedure, the authors relay, adding that data were retrieved nationally and per region between the financial years of 2010– 2011 and 2019–2020.

They found that there were 50,288 adults in England attending secondary care with neuropathic pain in 2010–2011, increasing to 66,376 in 2019–2020, and the number of patients with neuropathic pain undergoing an Only a small proportion of neuropathic pain patients in England SCS procedure increased on a year-towho are potentially eligible for spinal cord stimulation (SCS) have year basis until 2018–2019. “Notably, received this intervention over the past decade, as per data from there was a reduction in the number of a retrospective cohort study published in Neuromodulation: patients who received a new permanent Technology at the Neural Interface. Based on this finding, the implant of an SCS device [...] for the study’s authors conclude that the recommendation for SCS to be year 2019–2020,” Duarte et al write. used routinely in the management of neuropathic pain has not “Despite a more than twofold increase resulted in an uptake of this therapeutic approach since 2010. in the number of new SCS implants being performed between “OUR RESULTS SHOW THAT new SCS implant has remained 2010–2011 and 2019–2020, only a minority of patients with constant at 0.9% of the total nationally, less than 1% of neuropathic pain are considered patients with neuropathic pain people with neuropathic pain for SCS in England,” Rui Duarte since 2014–2015.” received an SCS device, with (University of Liverpool, Liverpool, They begin their report limited evidence of an increase UK) and colleagues write, discussing by detailing that SCS is a in this proportion over time.

Rui Duarte their findings. “Although there was recognised intervention for Interestingly, since 2014–2015, some regional variation, the overall the management of chronic neuropathic the number of SCS screening trials proportion of patients with neuropathic pain—and has been recommended by [...] has been consistently lower than pain receiving an SCS was <2% of those the UK National Institute of Health the number of new implants. This may with neuropathic pain in the period and Care Excellence (NICE) as a suggest an increase in the use of on-table 2010–2020. Although the absolute management option for this indication trials instead of a two-stage procedure number of new permanent SCS implants since 2008. With their study, Duarte of SCS screening trial followed by has increased over the years, given the and colleagues aimed to assess SCS implantation.” background increase in neuropathic pain uptake across the National Health The authors go on to note that there prevalence, this does not represent an Service (NHS) in England up to 2020. was an increase of 133% in new SCS improvement in uptake. The proportion Hospital episode statistics were obtained implants from 2010–2011 to 2019– of patients with neuropathic pain with a for patients with neuropathic pain 2020—but these estimates remain at less

than 1.4% of the regional estimates of eligible patients with neuropathic pain.

They add that some variability across English regions was observed, with SCS implant rates as low as 0.1% being seen in the Midlands, and a high of 1.9% of potentially eligible neuropathic pain patients being reached in the SouthWest region in 2015–2016, suggesting inequity in access to this treatment modality. An increased uptake of new implants over the full study period was observed in London and Yorkshire, as well as the North-East, North-West and South-East regions.

Discussing their findings, Duarte and colleagues state that—while not all neuropathic pain patients are eligible for SCS—overall prevalence rates of the condition are lower in their study when compared to the 7–9% previously reported. They also suggest that the reduction across SCS implant figures they observed in 2019–2020 was likely due to pressures on the UK healthcare system caused by the COVID-19 pandemic.

In addition, they state the low number of SCS implants per year and low uptake over the years “may be explained by a potential lack of awareness of current SCS guidelines and consequent low referral rates for this intervention”—as opposed to a low number of patients being suitable SCS candidates. The authors conclude that further research is required to investigate possible reasons for, and also mitigate against, inequalities in access to SCS in England.

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Issue 46 | May 2022

23

Neuromodulation for poststroke recovery advancing on several fronts Jesse Dawson Comment & Analysis As a principal investigator for the pivotal VNS-REHAB study, which supported the first US Food and Drug Administration (FDA) premarket approval of a vagus nerve stimulation (VNS) system for stroke rehabilitation therapy last year, Jesse Dawson (Glasgow, UK) is playing a key role in evaluating the potential held by neuromodulation for post-stroke recovery. Here, Dawson outlines the promising future proffered by this technology, and others.

T

here are a number of exciting developments in this space.

Neuromodulation as a concept is well-suited to use during both the acute and rehabilitation phases after stroke.

Broadly speaking, neuromodulation involves the alteration of nerve activity through targeted delivery of a stimulus, which could be either electrical or a drug.

There are numerous advantages to this approach. First of all, the stimulus can be highly targeted and delivered to a specific nerve, and—in the case of electrical stimulation—it can be highly reversible and very specifically timed.

There is also ease of dose optimisation and the potential for direct measurement of whether the required response is being elicited. Further, there is the potential for closed-loop systems, where

the stimulation is delivered in response to an input, such as that from an electroencephalography (EEG) system or perhaps even a brain-computer interface (BCI).

In recent years, randomised controlled trials of VNS paired with rehabilitation, transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), pharyngeal electrical stimulation and sphenopalatine ganglion stimulation in people with stroke have been reported.

The use of VNS paired with rehabilitation has recently been approved by the US FDA for the treatment of chronic upper-limb deficits after ischaemic stroke. A recent randomised, phase 3 trial showed that this technique led to improvements

Current literature suggests promise held by electrical stimulation therapies for cerebral vasospasm ELECTRICAL STIMULATION technologies, and in particular spinal cord stimulation (SCS) and sphenopalatine ganglion stimulation, offer a promising adjunct to existing therapies for cerebral vasospasm after subarachnoid haemorrhage—as per a recent, systematic literature review.

Writing in Neuromodulation: Technology at the Neural Interface, the study’s authors— Janine-Ai Schlaeppi (University Hospital Bern, Bern, Switzerland) and colleagues—note that cerebral vasospasm is a severe and potentially lethal complication in patients with subarachnoid haemorrhage.

“Its pathogenesis is still not completely understood,” they state. “The efficacy of current treatments, such as triple-H therapy or calcium channel blockers, is unsatisfactory, and a new therapy model would therefore be valuable.

“Electrical stimulation may have a considerable influence on cerebrovascular innervation.”

in upper-extremity impairment and function in people with moderate-tosevere arm weakness an average of three years after ischaemic stroke. A clinically meaningful response—defined as an improvement greater than or equal to six points on the Fugl-Meyer assessment, upper limb (FMA-UE)—was seen in approximately half of people treated with VNS compared to approximately a quarter of people treated with rehabilitation alone.

However, several questions regarding implementation of the technique in clinical services remain. These include whether the technique is of use for people with intracerebral haemorrhage (ICH) or in people with the most severe arm weakness. And, cost-effectiveness data are also lacking. In addition, highquality randomised studies of noninvasive VNS are needed.

So far, trials of TMS- and tDCS-based approaches in stroke rehabilitation have not demonstrated improved clinical outcomes, despite promising

This is a really interesting and exciting area, with one technique already approved by a major regulatory body.” experimental evidence showing effects on plasticity and learning. Pharyngeal electrical stimulation may improve symptoms of dysphagia and facilitate decannulation following tracheostomy.

This will now be studied further in wider groups of patients in large clinical trials.

A further, very promising technique is the use of sphenopalatine ganglion stimulation. The sphenopalatine ganglion is a large parasympathetic ganglion, located in the pterygopalatine fossa, posterior to the middle turbinate.

Post-ganglionic parasympathetic fibres travel with the trigeminal nerve to provide vasomotor input to the anterior circulation, including meningeal and dural vessels. Sphenopalatine ganglion stimulation therefore aims to enhance collateral blood flow in the anterior intracerebral circulation. Post-hoc analyses from a large trial suggest this may improve functional outcome in people with cortical ischaemic stroke who do not receive thrombolytic therapy and who receive the optimal amount of stimulation.

In summary, this is a really interesting and exciting area, with one technique already approved by a major regulatory body. There is still much to learn about how to optimise these techniques both in terms of their use, such as stimulation parameters, and of course patient selection. I am very confident, however, that further breakthroughs will happen in the coming years.

Jesse Dawson is a professor of Stroke Medicine at the Institute of Cardiovascular and Medical Sciences, and associate at the School of Medicine, Dentistry and Nursing, at the University of Glasgow in Glasgow, UK. He is also a consultant physician in the Queen Elizabeth University Hospital, the clinical lead for the Scottish Stroke Research Network, and chaired the 2021 European Stroke Organisation Conference (ESOC).

DISCLOSURES: Dawson was a principal investigator for the VNS-REHAB study—a randomised, blinded, pivotal device trial evaluating the Vivistim system (MicroTransponder).

“Most studies were conducted in animals—15 under physiological conditions and 11 in animals with subarachnoid haemorrhage. Eight studies in humans were identified that examined the stimulation effect on CBF under physiological conditions.

“Only two studies looked at patients after subarachnoid haemorrhage: one applied SCS, and the other, transcutaneous In an effort to provide an electrical neurostimulation.” overview of the studies that have Schlaeppi and colleagues applied electrical stimulation in add that different mechanisms models of cerebral vasospasm leading to stimulation-induced to date, Schlaeppi and her coCBF increases that were authors performed a systematic discussed in these studies review of the existing literature, included ‘reversible functional searching PubMed and Ovid Embase sympathectomy’, activation of for the following keywords: ‘electric brainstem vasomotor centres, stimulation’, ‘cerebral vasospasm’, involvement of central ascending Janine-Ai Schlaeppi ‘subarachnoid haemorrhage’, pathways, release of neurohumoral ‘sympathetic’, and ‘parasympathetic’. factors, and interaction with sympathetic, Additional papers were identified from the reference parasympathetic and trigeminal innervation. lists of the articles identified in the literature search, “The results indicate that electrical stimulation is they also note. a promising procedure for prevention and treatment Detailing their findings, the authors write: “Increased of cerebral vasospasm,” Schlaeppi and colleagues cerebral blood flow (CBF) is a widely observed effect conclude. of SCS and sphenopalatine ganglion stimulation in “Further experiments and prospective clinical models of physiological conditions or experimental studies are needed to establish its potential usefulness cerebral vasospasm. as a therapy or prevention option.”

May 2022 | Issue 46

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USING A ONE-MILLIMETRE-SIZED WIRELESS implant to stimulate peripheral nerves from within blood vessels has the potential to treat neuropathic pain that is resistant to traditional medical therapy, according to a team of multi-institutional researchers led by Sunil Sheth (University of Texas Health [UTHealth] Houston, Houston, USA).

Sheth was co-principal investigator of a study published recently in Nature Biomedical Engineering reporting the design and in vivo proof-ofconcept testing of an endovascular, wirelessly powered, battery-free millimetric implant for the stimulation of specific peripheral nerves that are difficult to reach via conventional surgeries.

After receiving a grant from the National Institutes

of Health (NIH) in 2019, researchers teamed up to create these implantable nerve stimulators for use in place of opioids for pain management. The implants— which are roughly the size of a grain of rice—are small enough to be placed on stents, and delivered within blood vessels adjacent to specific areas of the central and peripheral nervous system.

In Nature Biomedical Engineering, the researchers detail that the device can be delivered through a percutaneous catheter and leverages magnetoelectric materials to receive data and power through tissue via a digitally programmable, 1mm×0.8mm system-on-achip. Implantation of the device directly on top of the sciatic nerve in rats, and near a femoral artery in pigs (with a stimulation lead introduced into a blood vessel through a catheter), allowed for wireless stimulation of the animals’ sciatic and femoral nerves, they report.

“We are getting more and more data showing that neuromodulation, or technology that acts directly upon nerves, is effective for a huge range of disorders—depression, migraine, Parkinson’s disease, epilepsy, dementia etc. But, there is a barrier to using these techniques, because of the risks associated with doing surgery to implant the device, such as the risk of infection,” Sheth said. “If you can lower that bar and dramatically reduce those risks by using a wireless, Sunil endovascular method, there Sheth are a lot of people who

Pilot study supports “emerging paradigm” of neuromodulation in selected heart failure patients Parasym has partnered with the University of Oklahoma (Norman, USA) to announce “ground-breaking” research into treating heart failure with neuromodulation. In a pilot randomised controlled trial, the Parasym device was used to significantly improve cardiac mechanics and quality of life, and produced reductions in inflammatory markers in a patient population that historically has very few treatment options available. These positive results pave the way for “a new era” of heart failure treatment, a Parasym press release states.

STAVROS STAVRAKIS (University of Oklahoma College of Medicine, Oklahoma City, USA), the principal investigator for the trial, said: “In this patient population, neuromodulation with low-level transcutaneous vagus nerve stimulation over three months resulted in a significant improvement in global longitudinal strain, inflammatory cytokines and quality of life. Our results support the emerging paradigm of non-invasive neuromodulation to treat selected patients with heart failure with preserved ejection fraction.”

According to the company, until Parasym developed this “first-ofits-kind” device, there had been no clinically validated, non-invasive, non-pharmacological options for people who suffer from heart failure and its range of life-altering symptoms, as well

as the subsequent quality-of-life impact.

While current treatment advises lifestyle changes and medication— which are not without side-effects— ‘electroceuticals’ like neuromodulation hold the potential to “revolutionise” therapeutic paradigms in heart failure, as they hold the capacity to provide highly targeted treatment without drug interaction or side-effects, the release adds.

The results from the clinical trial using Parasym’s neuromodulation device demonstrate that Parasym, which the company claims is the only non-invasive, low-risk and minimal side-effect option in this space, has significantly improved the quality of life for patients suffering from heart failure. The device works by stimulating the vagus nerve and sending signals to the brain, which favourably

could benefit from neuromodulation.”

Previous research has shown electrical stimulation to be an effective treatment for reducing neuropathic pain when doctors target the spinal cord and dorsal root ganglia (DRG). However, as per a UTHealth press release, existing DRG stimulators require open surgery to implant bulky devices, including a battery pack and pulse generator. In addition, traditional pharmacological therapies in this space carry the risk of opioid addiction.

With their newly developed technology, the Texasbased researchers say they have found a way to perform minimally invasive bioelectronic therapy that helps with more precise placement of the implant and enables more predictable outcomes. Ultimately, Sheth hopes to seek regulatory approval of the device from the US Food and Drug Administration (FDA). “We are doing some longer-term studies to ensure this approach is safe and that the device can stay in the body for a long time without causing problems,” he added, also estimating that this process is likely to take “a few years”.

We are doing some longer-term studies to ensure this approach is safe and that the device can stay in the body for a long time without causing problems.”

alters the nervous system and reduces inflammation of the heart.

In addition, the results showed that the patients who took part in the placebo-controlled study experienced measurable improvements from as little as three months of using the device for less than one hour per day.

The study revealed significant improvements in levels of the proinflammatory cytokines interleukin-8 (IL-8) and tumour necrosis factor-alpha, indicating that the treatment had a significant antiinflammatory effect, as well as in global longitudinal strain—a “core indicator of cardiac mechanics”, according to Parasym.

“Importantly, patients also

Parasym device in use

reported improved quality of life and in their day-to-day activities, which is something that surgery and medication struggle to deliver,” the press release states. “Furthermore, as the neuromodulation device is noninvasive, patients can use it in addition to medication, should they want to.

This approach fills a gap by addressing the patient’s overall quality of life, as well as improving their mental health, which is impacted by living with the condition.”

These findings have also been published in the Journal of the American Heart Association by Stavrakis and colleagues from the University of Oklahoma Health Sciences Center.

Image credit: UTHealth Houston

Millimetric implant offers promising alternative to opioids or surgery in pain management

Issue 46 | May 2022

NeuroMODULATION NEWS Cefaly publishes study data indicating effectiveness of e-TNS migraine treatment

was based on a double-blind randomised controlled trial, the EVOKE study, which saw the Evoke system Cefaly Technology demonstrate has announced superior pain the results of a relief compared clinical study to open-loop SCS demonstrating that at 12 months, with two-hour treatment no increase in pain with its external trigeminal medication. In addition, nerve stimulation (e-TNS) 24-month EVOKE study data, Cefaly device—a non-invasive published in JAMA Neurology, device worn on the forehead— show that these clinical is a safe and effective Cefaly device outcomes were durable at two alternative to pharmaceuticals years, with zero explants due for the acute treatment of migraine to loss of efficacy. attacks in the out-of-hospital setting.

Nagy Mekhail (Cleveland Clinic, “The Cefaly device provides Cleveland, USA), lead author and patients with a non-medication medical monitor for the EVOKE study, option for the prevention and acute said: “The ground-breaking technology treatment of migraine,” said study behind the Evoke system’s ability author Deena Kuruvilla (Westport to intelligently measure spinal cord Headache Institute, Westport, USA). activation has had many of us excited “It is especially helpful to add to a for a long time. More exciting than the medication regimen or use for people technology, though, is the unparalleled who have had a negative experience quality of the evidence backing this with migraine medications.” system, which demonstrates pain relief The TEAM study was a prospective, coupled with clinically significant double-blind, randomised, shamimprovements in physical and controlled clinical trial of two-hour emotional functioning, sleep quality, e-TNS treatment for acute migraine and health-related quality of life.” attack, conducted in an at-home scenario. It spanned nine months and INS to host “Innovations in was conducted at 10 centres across the Neuromodulation” event at USA, enrolling 538 patients aged May congress 18–65 years with episodic migraine.

With an educational event entitled Pain freedom at two hours, pain “Innovations in Neuromodulation”, the relief at two hours, absence of all International Neuromodulation Society migraine-associated symptoms at two (INS) will attempt to bring together hours, sustained pain freedom and pain industry leaders, innovators and relief at 24 hours, and resolution of the investors to discuss commercialisation most bothersome migraine-associated from a global perspective at its symptom, were all higher in patients 15th world congress this month (21–26 who received e-TNS as compared May 2022, Barcelona, Spain). to the sham group. In addition, no As per an INS press release, this serious adverse events were reported. educational event—taking place on These findings have been published in 22 May—will highlight presenters’ Scientific Reports. perspectives on innovation advantages and challenges in their respective Saluda Medical receives locales. It will feature presentations FDA approval for Evoke by emerging companies, including SCS system to treat chronic BIOS Health, Neuromod Devices, intractable pain Spark Biomedical, MicroTransponder, Saluda Medical has announced receipt NXTSTIM, Synergia Medical, of full approval from the US Food Neuroelectrics, RebrAIn and and Drug Administration (FDA) for Thermaquil. the Evoke spinal cord stimulation INS president Marc Russo (Hunter (SCS) system, which is indicated for Pain Specialists, Newcastle, Australia) the treatment of chronic intractable and president-elect Konstantin Slavin pain of the trunk and/or limbs, (University of Illinois Chicago, including unilateral or bilateral pain Chicago, USA) will lead a session associated with failed back surgery entitled “Neuromodulation syndrome, intractable low back pain, without Borders”, while and leg pain. electroCore chief medical The Evoke SCS system is capable officer Peter Staats of instantaneously reading, recording will front the topic of and responding to evoked compound “Neuromodulation action potentials (ECAPs)—the nerves’ from the response to stimulation—to provide Ground Up: precise, continually optimised therapy Bootstrapping that is adjusted more than 100 times Marc per second.

Russo Premarket approval of the device

Market Watch 25 a Pandemic”.

Other subjects to be examined include the challenges and pitfalls of conducting clinical trials in Latin America and Asia, how best to shorten the commercialisation pathway, and the benefits of establishing a ‘MedTech precinct’.

Medtronic announces first patient implants of investigational TNM therapy

Medtronic has announced that the first patients have been implanted in the TITAN 2 pivotal study—which will evaluate the safety and efficacy of its investigational tibial neuromodulation (TNM) device in overactive bladder (OAB) patients. The minimally invasive, implantable technology stimulates the posterior tibial nerve near the ankle, transmitting electrical impulses that regulate neural activity of the bladder.

“Implantable TNM has the potential to offer relief to millions who suffer from bladder incontinence through a new approach that will provide greater convenience and more options for physicians and patients,” said Una Lee (Virginia Mason Medical Center, Seattle, USA), national principal investigator for TITAN 2. “The first patient implants in the TITAN 2 study marks the beginning of what may be an important part of the future for better bladder control.”

The TITAN 2 study is a prospective, multicentre, pivotal trial intended to examine the safety and efficacy of Medtronic’s implantable TNM device in people with OAB. The study will include a maximum of 130 patients from up to 30 US sites.

Upon successful completion of TITAN 2, Medtronic will prepare its submission to the US Food and Drug Administration (FDA) for approval of the device in OAB patients.

drug-resistant epilepsy,” said Steven Wolf and Patricia McGoldrick (Boston Children’s Health Physicians, New York, USA). “The RNS system has demonstrated unprecedented seizure reduction and improved quality of life in adults with drug-resistant focal epilepsy. Through this clinical study, we are looking forward to evaluating the RNS system in an expanded population of adolescent patients who have uncontrolled focal seizures, despite taking medications.”

The RESPONSE trial is a prospective, open label, single-arm, pivotal study designed to demonstrate that the RNS system is safe and effective as an adjunctive therapy in individuals aged 12 through 17 years with medically refractory, partial-onset epilepsy. The device is approved by the US Food and Drug Administration (FDA) and is designed to deliver personalised, targeted treatment at the seizure source using responsive, closed-loop technology.

Axonics announces comprehensive launch of F15 recharge-free SNM system

Axonics has announced the comprehensive launch of the Axonics F15 across the USA. The functional life of this newly developed, fully rechargefree sacral neuromodulation (SNM) system has been validated at more than 15 years at typical stimulation parameters, and more than 20 years at lower energy settings.

“The Axonics recharge-free system is a welcome advancement for patients suffering from bladder and bowel dysfunction,” said Taylor Moore (Arkansas Urology, Little Rock, USA).

“My initial implants of the new device have gone well, with low amplitudes achieved at the time of implant suggesting longevity in the body of

RNS system

NeuroPace announces first treatment in pivotal study evaluating RNS system in adolescents

NeuroPace has announced that the first patient was recently treated in the RESPONSE clinical trial, which is evaluating the safety and effectiveness of its RNS system in adolescent patients with drugresistant focal epilepsy. The procedure took place at Westchester Medical Center in New York, USA. “More than one million people are living with

around 20 years.

“Clinical outcomes with the Axonics rechargeable SNM system have exceeded our expectations and we anticipate similar results with the Axonics F15. We are pleased to now offer patients a non-rechargeable option that provides significant longevity in the body, constant current stimulation, and a remote control that is rechargefree and easy for patients to use.”

The Axonics F15 system also received US Food and Drug Administration (FDA) approval in March.

May 2022 | Issue 46

26 Market Watch

Industry News Synchron enrols first patient in US study of endovascular brain-computer interface Synchron has announced the first patient enrolment in the US COMMAND clinical trial at Mount Sinai Hospital in New York, USA, which will assess the company’s endovascular brain-computer interface (BCI)—the Stentrode device—in patients with severe paralysis.

The trial is being conducted under what Synchron claims is the first investigational device exemption (IDE) awarded by the US Food and Drug Administration (FDA) to a company assessing a permanently implanted BCI. COMMAND, an early feasibility study funded by the National Institutes of Health (NIH), will primarily assess safety and begin to explore quantified efficacy measures with Stentrode, which is implanted into the brain’s motor cortex through the jugular vein via a minimally invasive procedure and translates brain activity into a standardised digital language to allow patients to complete everyday tasks on hands-free external devices.

This follows presentation of the SWITCH trial at the American Academy of Neurology (AAN) annual meeting (2–7 April 2022, Seattle, USA), which was conducted in Australia and demonstrated the long-term safety of this technology in four patients. Researchers monitored participants for one year and observed zero adverse events that led to disability or death.

Study data indicate positive outcomes with “exciting new treatment option” in ischaemic stroke

Data from a multicentre clinical study supporting the use of Anaconda Biomed’s Advanced Neurovascular Access (ANA) catheter system for treating ischaemic stroke have been published in Stroke. The company’s mechanical thrombectomy system achieved a high rate of complete recanalisation and favourable 90-day outcomes in the SOLONDA trial— which aimed to validate earlier testing indicating statistically significant improvements in revascularisation rates at both the first and third pass.

“The ANA system represents an exciting new treatment option in ischaemic stroke, where time is brain,” said lead author and principal investigator Alejandro Tomasello (Hospital Vall d’Hebron, Barcelona, Spain). “Achieving the highest degree of reperfusion with the minimum attempts, ideally in a single pass, has been described

as a robust predictor of favourable outcome. The ANA system performed very well in this regard.”

SOLONDA was a 125-patient, prospective trial designed to assess system safety, as well as reperfusion measured using the modified treatment in cerebral infarction (mTICI) score and functional outcomes on the modified Rankin Scale (mRS). The trial’s steering committee decided to terminate the study after enrolment of 74 patients, at which point an interim analysis found “overwhelming evidence” confirming that safety and performance objectives were already met, according to Anaconda.

Wallaby acquires phenox to accelerate global expansion in neurovascular space Wallaby Medical has announced that it has acquired phenox GmbH and its broad portfolio of neurovascular devices—as well as phenox’s femtosecond laser technology specialist, femtos GmbH—for a total consideration of approximately €500 million including milestone payments.

The acquisition is one of the largest cross-border transactions in the medical device industry globally in recent years, as per a press release from Wallaby, and will enable the combined company to become a global leader in providing a wide range of neurovascular technologies and solutions globally, including in the USA, China, Europe, Japan, and other international markets.

Michael Alper, CEO of Wallaby, will become CEO of the combined organisation, while phenox founder Hermann Monstadt will assume the role of managing director of phenox.

All current phenox product brands will be retained.

The two firms have been strategic partners since 2019, and phenox has been the exclusive distributor for Wallaby’s Avenir coil system in US and European markets, as well as for Wallaby’s Esperance aspiration catheters in the USA.

Silk Road announces FDA approval of expanded indications for Enroute transcarotid stent system

Silk Road Medical has gained US Food and Drug Administration (FDA) approval of expanded indications for its Enroute transcarotid stent system to include patients at a standard risk for adverse events from carotid endarterectomy (CEA).

To now, the stent had only been approved for use in patients with anatomic Alejandro or physiological Tomasello

criteria that put them at a high risk of complications from more invasive surgical procedures.

Silk Road had previously submitted a premarket approval supplement, which included data extracted from the Vascular Quality Initiative.

The surveillance data included in the submission represented realworld outcomes in 20,264 patients considered to be at standard surgical risk. Those data demonstrated that the use of Silk Road’s transcarotid artery revascularisation (TCAR) system is statistically non-inferior to CEA in terms of stroke and death outcomes, while showing a ninefold reduction in cranial nerve injury (2.7% vs 0.3%, p<0.001).

“Pairing the right patient with the right treatment results in significantly improved physician and patient experiences and outcomes,” said Marc Schermerhorn (Beth Israel Deaconess Medical Center, Boston, USA). “I speak for the vascular community in welcoming this label expansion for TCAR and recognising this as a vital advancement in the treatment paradigm for patients at risk of stroke.”

who treated the patient with the Bobby device. “We were pleased with the excellent performance of the Bobby balloon guide catheter with the Sofia plus 6Fr aspiration catheter, Headway microcatheter, Traxcess EX guidewire [both Microvention/Terumo] and the 6×40 stent retriever revascularisation device.”

Aidoc gains FDA 510(k) clearance for AI-supported triage and notification of brain aneurysms

Aidoc has received US Food and Drug Administration (FDA) 510(k) clearance for the triage and notification of brain aneurysms with a new software solution that flags and communicates suspected positive cases.

The newly approved technology is intended to deliver a care coordination workflow that is tailored to radiologists, neuroendovascular surgeons and neurologists who need to treat multiple differing types of patients—from the emergency room or an outpatient setting, at the hub, or transferred from the ‘spoke’.

This recent clearance adds to Aidoc’s repertoire of neuro solutions that also includes artificial intelligence (AI)based solutions for M1 large vessel occlusions, intracranial haemorrhage and C-spine fractures.

Cerus Endovascular receives FDA clearance for 027 microcatheter products Bobby balloon guide catheter

Microvention enrols first patient in STRAIT study evaluating new balloon guide catheter

Microvention, a wholly owned subsidiary of Terumo, has announced the successful completion of its first patient enrolment in a multicentre, prospective, observational study called STRAIT. The European Union (EU) study will evaluate the safety and performance of the company’s new Bobby balloon guide catheter in the endovascular treatment of acute ischaemic stroke.

Bobby is currently approved in Europe and North America and has been designed to streamline balloon preparation while improving navigability and ensuring compatibility with the Sofia plus 6Fr aspiration catheter (Microvention/Terumo).

The first STRAIT study patient was enrolled at the site of its principal investigator, Tobias Boeckh-Behrens (Technischen Universität München [TUM], Munich, Germany).

“A severe stroke case with a left carotid occlusion was successfully treated with the use of Bobby, resulting in a first-pass TICI [thrombolysis in cerebral infarction] 3, 20 minutes after groin puncture,” said Christian Maegerlein (TUM, Munich, Germany),

Cerus Endovascular has received US Food and Drug Administration (FDA) 510(k) clearance for its 027 microcatheters, available in two lengths, expanding on a product portfolio that includes the already FDA-cleared 021 microcatheter platform.

The company now expects to submit for CE marking of both sizes under the new European Union (EU) Medical Device Regulation later this year— while a limited US market release of the 027 microcatheters is expected to begin in the second quarter of 2022, with the 021 microcatheters platform to follow shortly thereafter.

The company also recently announced that it is expanding the size offerings of its Contour neurovascular system platform. The newer additional sizes currently in development (3mm, 18mm and 22mm) with the intention of allowing for the treatment of aneurysms up to 18mm in diameter.

Avicenna.AI signs distribution agreement with Sectra for neurovascular AI solutions Avicenna.AI has announced a signed distribution agreement with medical imaging information technology and cybersecurity firm Sectra. The agreement will see Avicenna’s artificial intelligence (AI) solutions for neurovascular pathologies offered through the Sectra Amplifier Marketplace—a platform for contracting, purchasing and servicing

Issue 46 | May 2022

Market Watch 27

Industry News AI applications validated and verified for use at point of care.

Avicenna’s CINA solutions use deep learning to identify, detect and quantify life-threatening pathologies from computed tomography medical images. These US Food and Drug Administration (FDA)-cleared and CE-marked tools are designed to CorPath GRX system be integrated within clinical workflows, automatically triggering and reporting algorithm results through systems already used by radiologists.

The AI tools to be included in Sectra’s Amplifier Marketplace include CINA-ICH for identifying suspected intracranial haemorrhage and CINA-LVO for large vessel occlusion detection—both of which are approved in the USA and European Union (EU)—and CINA-ASPECTS, which was developed to enable faster,

more consistent and more precise interpretation for the assessment of acute ischaemic stroke and is available in the EU only.

Corindus relocates Massachusetts headquarters to accommodate company growth Corindus, a Siemens Healthineers company, has announced the opening of its new headquarters at 275 Grove Street in Newton, USA. Siemens Healthineers relocated the Corindus headquarters from its previous location in Waltham, USA to accommodate company growth, doubling the size of the current location from 35,000 to 77,000 square feet.

The new facility marks the first of 15 new offices or major facility expansions that Siemens Healthineers has planned in the USA, and will serve as the global ‘Centre for

Calendar of events 14–18 May American Society of Neuroradiology (ASNR) Annual Meeting and Symposium Neuroradiologicum (SNR) New York City, USA asnr.org/annualmeeting

21–26 May International Neuromodulation Society (INS) World Congress Barcelona, Spain neuromodulation.com/ins-congress

Excellence’ for its endovascular robotic technologies, which are primarily used in the treatment of coronary artery and neurovascular diseases.

It also features a fully equipped ‘Customer Experience Centre’ that simulates the robotic setup in a hospital cath lab and control room, and will include remote capabilities over various types of connections. In addition, the new office will provide physicians and cath lab personnel with the opportunity to participate in interactive demonstrations of the CorPath GRX system and future innovations.

Bendit receives FDA 510(k) clearance for 0.021-inch steerable microcatheter Bendit Technologies has received US Food and Drug Administration (FDA) 510(k) clearance of its Bendit21 microcatheter for treatment in the neuro, peripheral and coronary vasculature. This clearance was received several months after the successful first use of the Bendit21 microcatheter in the USA in two lifesaving procedures, according to the company.

“The Bendit technology presents a transformative paradigm in endovascular navigation that will revolutionise the way we access the vasculature, and will improve treatments throughout the arterial

and venous systems, especially in the brain,” said Alejandro Berenstein (Mount Sinai Health System, New York, USA).

The Bendit21 steerable microcatheter features advanced steering and ‘torqueability’ manoeuvring capabilities that are intended to enable navigation with or without guidewires, more precisely, and accurately, through all vasculatures—potentially expanding indications, enhancing safety and saving procedure time.

First patient treated in normal-pressure hydrocephalus trial of CereVasc’s eShunt system

CereVasc has announced treatment of the first patient in its clinical study of the eShunt system in patients with normal-pressure hydrocephalus.

The company gained approval from the National Administration of Drugs, Foods and Medical Devices (ANMAT) to conduct this second eShunt study in Argentina.

The trial has been initiated under the leadership of Pedro Lylyk (Clínica La Sagrada Familia, Buenos Aires, Argentina), who said: “Our experience with the eShunt system in patients with hydrocephalus secondary to postaneurysmal subarachnoid haemorrhage has been promising with encouraging initial results.”

Please be advised that the events listed below are subject to change. Please check the relevant website for further details as the event may be cancelled, postponed, or become a virtual event.

30 May–1 June LINNC Paris Paris, France

linnc.com/Course-information/ LINNC-Paris-2022

6–9 June Leipzig Interventional Course (LINC) Leipzig, Germany leipzig-interventional-course.com/ visitors/linc-2022

10–12 June Women Innovators in Pain Management (WIPM) Annual Conference Nashville, USA

25–29 July Society of NeuroInterventional Surgery (SNIS) Annual Meeting & Fellows Course Toronto, Canada

7–9 September European Society of Minimally Invasive Neurological Therapy (ESMINT) Congress Nice, France

25–28 June European Academy of Neurology (EAN) Congress Vienna, Austria

21–25 August World Federation of Interventional and Therapeutic Neuroradiology (WFITN) Congress Kyoto, Japan

14–18 September European Society of Neuroradiology (ESNR) Annual Meeting Lisbon, Portugal

wipmsoc.org/2022-conference

ean.org/congress2022

snisannualmeeting.org

site.convention.co.jp/wfitn2022

esmint.eu/esmint-congress

esnr.org/en/45th-esnr-annualmeeting

NeuroNews is a trusted, independent source of news and opinion in the neurointerventional and neurosurgical world.

Sign up for a free print subscription* and e-newsletter subscription** www.neuronewsinternational.com *Available for US and EU readers only ** Available worldwide

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Dr. Alex Mortimer Southmead Hospital, Bristol, UK Photographs taken by and on file at Penumbra, Inc. Bench test results may not be indicative of clinical performance. Image used with permission. Consent on file at Penumbra, Inc. Individual results may vary depending on a variety of patient-specific attributes and other factors.

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Product availability varies by country. Renderings for illustrative purposes only. Individual results may vary depending on patient-specific attributes and other factors.

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Copyright ©2022 Penumbra, Inc. All rights reserved. The Penumbra P logo, POD, POD400, and PAC400 are registered trademarks or trademarks of Penumbra, Inc. in the USA and other countries. 23130, Rev. A 02/22 EU

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