NeuroNews issue 44 - EU

January 2022 | Issue 44

Featured in this issue:

www.neuronewsinternational.com

10

Michael Chen Improving stroke triage and transport

Profile Salim Hayek page 14

The Diversion-p64 study—the largest prospective study using the p64 flow modulation device (phenox) to date—has demonstrated that the device has a high level of efficacy and carries a low rate of mortality and permanent morbidity. This is the conclusion of a report published in the Journal of NeuroInterventional Surgery by Alain Bonafe (Department of Neuroradiology, Hôpital Gui De Chauliac, Montpellier, France) and colleagues.

I

at an average of 375±73 days, and available for 343 patients (81.7%)—complete aneurysm occlusion and residual neck were seen in 83.7% and 2.3% of cases, respectively, resulting in an 86% (n=295) rate of adequate occlusion.

Safety data were available for 413 patients (98.3%) at the first follow-up and showed a composite morbidity/ mortality rate of 2.42% (n=10). In these patients, the major procedure-related stroke rate was 1.9% (n=8), with all of these being due to thromboembolic complications, and the mortality rate was 0.97% (n=4), with two of these deaths relating to a major stroke within the territory of the implanted device. No further episodes of major stroke or death occurred between the first and second follow-up, with data available for 372 patients, the authors add.

After highlighting the main limitations of the Diversion-p64 study—its non-randomised nature and lack of a control arm—Bonafe and colleagues conclude that the trial met its primary efficacy and safety endpoints. “The results of Diversion-p64 demonstrate one of the lowest rates of morbidity/ mortality seen in any prospective study on flow diversion,” they add. “It can be concluded that the device has a high efficacy and excellent safety profile that is comparable to other devices.”

The results of Diversion-p64 demonstrate one of the lowest rates of morbidity/ mortality seen in any prospective study on flow diversion.”

Patient access to spinal cord stimulation page 20

Global study demonstrates high efficacy and low mortality rates with p64 flow diverter

n an effort to build on existing evidence in treating intracranial aneurysms with the p64, researchers initiated the Diversion-p64 study—a single-arm, international, multicentre, prospective trial to assess the safety and efficacy of the device. Between December 2015 and January 2019, a total of 420 patients (mean age=55±12 years; 86.2% female) met the eligibility criteria and were enrolled at 26 centres across 10 countries. In this patient population, a total of 445 devices were implanted, resulting in a mean number of 1.06±0.47 devices per patient.

Adjunctive coiling was performed in 14% of cases (n=59).

The primary efficacy endpoint in Diversion-64 was complete intracranial aneurysm occlusion (Raymond-Roy Occlusion Classification=one) on follow-up angiography, and the study’s primary safety endpoint was the incidence of major, treatment-related stroke (National Institutes of Health Stroke Scale [NIHSS] score increase=four points) or neurologic death at three–six months, with a secondary safety endpoint at seven–12 months after treatment.

Relaying the study’s results, the authors state that angiographic follow-up data were available for 357 patients (85%) at the first follow-up—performed at an average of 145±43 days. At this point, complete occlusion and residual neck were reported in 71.7% and 4.5% of cases, respectively, leading to 76.2% (n=272) of cases demonstrating adequate occlusion. At the second Bonafe et al angiographic follow-up—performed

Neuromodulation:

Alain Bonafe

Novel stimulation technique could be “gamechanger” in treatment-resistant depression Stanford accelerated intelligent neuromodulation therapy (SAINT)— a novel, high-dose intermittent theta-burst stimulation (iTBS)— was found to be safe and more effective than sham stimulation in a recent randomised controlled trial (RCT). And, according to Nolan Williams, assistant professor within the Department of Psychiatry and Behavioral Sciences at Stanford University Medical Center in Stanford, USA, this technology has the potential to be a “gamechanger” for patients with major, treatmentresistant depression.

“THE CLINICAL RESULTS FROM our study were significant and rapid,” Williams, who also founded the Stanford Brain Stimulation Lab and, as such, played a key role in developing SAINT, told NeuroNews.

“After five days of treatment, 79% of people experienced remission, meaning they were no longer experiencing symptoms of depression or suicidal ideation. Some patients found the treatment to be life-changing.

“Conventional treatments for intractable depression take weeks or even months to begin working, and provide remission Continued on page 2

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January 2022 | Issue 44

Neuromodulation

Novel stimulation technique could be “gamechanger” in treatment-resistant depression Continued from page 1

from depression for only a fraction of people. SAINT group showed significantly greater post-treatment treatments are completed in five days, or less, and could reductions in MADRS scores at all follow-up timepoints help people return to their daily lives more quickly.” (zero, one, two, three and four weeks) and equivalent Williams and his colleagues have published the results results were found for secondary outcomes—score of the RCT in The American Journal of Psychiatry. In changes on the six- and 17-item Hamilton depression their report, they note that iTBS is approved by the US rating scales (HAM-D), and the quick inventory of Food and Drug Administration (FDA) in treatmentdepressive symptomatology-self-report (QIDS-SR). The resistant depression but is also limited by suboptimal authors report no severe adverse events during the trial. efficacy and a six-week duration, with SAINT—a Speaking with NeuroNews, Williams emphasised the high-dose, accelerated repetitive transcranial magnetic “immediate need” for an effective, faster-acting therapy stimulation (rTMS) protocol—being developed to for patients experiencing a mental health emergency. overcome these limitations.

“The FDA granted Breakthrough The authors also report that, while Device designation for the SAINT At positive results have been observed technology, which helps underscore four-week in open-label trials, this is the first the need to provide more effective follow-up time the efficacy of SAINT has been treatment for major depression,” investigated in a double-blinded, he said. “In the USA alone, more Active Sham SAINT treatment sham-controlled trial to determine than 550,000 adults are hospitalised group: group: the placebo effect's contribution. annually for suicidal depression, and A total of 182 patients who the highest peak in suicide attempt had a primary diagnosis of major and completion is immediately after of of depressive disorder, were currently discharge from hospital. Currently, experiencing a moderate-tothese people do not have access to patients responded patients responded severe depressive episode, and an effective, rapid-acting and nonhad moderate-to-severe levels of invasive treatment.” % % treatment resistance, underwent Williams also stated that he and eligibility screening, with 29 his colleagues are currently focusing patients ultimately being enrolled on these types of psychiatric and undergoing 1:1 randomisation emergencies—and propose a of of to receive either active SAINT or an potential treatment model in which identical course of sham stimulation. achieved remission achieved remission SAINT is used to achieve rapid Ten sessions of active or sham remission from depression before iTBS were delivered daily to being followed by a less intensive % % personalised targets in each patient’s maintenance therapy, such as brain on five consecutive days. psychotherapy, medication or brain The study’s primary outcome was stimulation. “But, as we have seen Montgomery-Åsberg depression rating scale (MADRS) with the rest of medicine, those therapies developed for score four weeks after the end of this five-day SAINT emergencies ultimately become treatments for nonprotocol, with response being defined as a ≥50% emergencies if the risk-benefit ratio is good,” he added. reduction from baseline in MADRS score and remission In addition to stating that the rapid effectiveness being defined as a MADRS score of ≤10. of SAINT could significantly shorten the duration of Reporting the results, the authors note that, across the depression-related hospitalisations, thus reducing the four-week follow-up, 12 of 14 patients (85.7%) in the “enormous” human and system-wide cost of extended active SAINT group met the criterion for response and 11 emergency department stays, and the overall time (78.6%) met the remission criterion in at least one of five required for physicians to treat psychiatric patients in post-treatment assessments. In the sham treatment group, the outpatient setting, Williams concluded that “with four of 15 patients (26.7%) responded and two (13.3%) advances in neuromodulation, including ours and remitted at some point during the four-week follow-up. others, there is now hope globally for people with major They further state that patients in the active treatment depressive disorder who are treatment-resistant”.

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12 14

News in brief

The latest stories from the neuro world

n ESCAPE-NEXT TRIAL COULD PAVE WAY FOR “DREAM” THERAPEUTIC COMBINATION: At the LINNC Paris Course 2021, Mayank Goyal discussed the potential held by the ESCAPE-NEXT trial, which will assess the safety and efficacy of the neuroprotective agent nerinetide (NoNO), and may represent a major step towards the “dream” of combining neuroprotection and endovascular therapy for acute ischaemic stroke.

For more on this story go to page 6. n ARTIFICIAL INTELLIGENCE HOLDS MULTIPLE BENEFITS IN STROKE CARE: Time savings, cost reductions and improved patient outcomes are among the key benefits that artificial intelligence can enable in stroke care. Speaking at the 2021 BRAIN conference, Ameer Hassan also reported a 66-minute time saving between angiogram acquisition at a primary stroke centre and arrival at a comprehensive stroke centre using the Viz platform (Viz.ai).

For more on this story go to page 17. n STUDY IDENTIFIES ETHICAL CONCERNS AROUND PAEDIATRIC DEEP BRAIN STIMULATION FOR OCD: A series of semi-structured clinician interviews has revealed prevailing ethical concerns around the use of paediatric deep brain stimulation for obsessivecompulsive disorder (OCD)— including the conditions of patient decision-making and a lack of evidence on possible outcomes.

These findings are published in Brain Stimulation

by Gabriel Lázaro-Muñoz and colleagues.

For more on this story go to page 22.

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January 2022 | Issue 44

Novel Technologies

Novel teleproctoring platform successfully used for neuroendovascular fellowship training A novel augmented reality (AR) platform (Proximie) has been successfully used to teleproctor a neuroendovascular fellow during complex interventional and diagnostic procedures. That is according to a scientific abstract presented at the Congress of the European Society of Minimally Invasive Neurological Therapy (ESMINT 2021; 8–10 September, Nice, France and virtual). In the opening session of ESMINT 2021, Sohum Desai (Valley Baptist Medical Center, Harlingen, USA) presented a single-centre experience involving 10 cases in which a fellow was guided through a variety of neuroendovascular procedures remotely.

D

esai first noted that remote teleproctoring technologies are currently available, and have been used in neuroendovascular surgery before, but that there is limited evidence on this approach—whereby an on-site surgeon is supervised remotely by an attending physician— within fellowship training specifically.

Desai and his colleagues therefore set about investigating the use of an AR platform to guide fellows through neurointerventional procedures.

“This platform is a little bit different to other remote teleproctoring solutions in that it is completely cloud-based, and it can capture and stream feeds from

up to four devices,” Desai added. “In our setting, in the cath lab, we obtained direct feeds from the biplane, as well as additional feeds from two cameras that were set up within the operating room—one was ceiling mounted, and the other was set up within a computer workstation.”

He also detailed that a microphone enabled the attending physician to hear any concerns the fellow had during the procedure, and provide immediate feedback via an intercom system.

Desai noted that the teleproctoring platform comes with several AR tools and overlays—for example, one such tool allowed the attending physician to

Lack of evidence among challenges that must be overcome to realise potential of robotic neurointerventions In spite of the clinical successes observed to date, a lack of high-level safety and efficacy evidence, among other current challenges and limitations, must be overcome in order to realise the potential held by robotics in neurointerventional surgery. This is the concluding view outlined in a systematic literature review published in the Journal of NeuroInterventional Surgery

by Thomas Booth, William Crinnion (both School of Biomedical Engineering and Imaging Sciences, King’s College London, London, UK) and colleagues.

“IT IS PLAUSIBLE THAT ROBOTICALLY performed neurointerventional procedures will eventually benefit patients and reduce occupational hazards for staff; however, there is no high-level efficacy and safety evidence to support this assertion,” Booth, Crinnion et al write. “If robust efficacy and safety evidence emerges, and if proved to be cost-effective, one potential use would be for a fully functioning platform to perform teleoperated intervention—which, if applied to MT [mechanical thrombectomy] in stroke, would accelerate the treatment of eligible patients in locations

label the exact location of where the feed could not stenoses and other features demonstrate what the on an angiogram using an fellow was doing, nor electronic pen, with these instances where the fellow directions also being visible was unable to understand to the operating fellow. what the attending A consecutive series of 10 physician was asking diagnostic and interventional them to do,” Desai noted. neuroendovascular He added that this case Sohum Desai surgeries were performed series, the details of which on eight patients in the have also been published study, Desai stated, including a left in Interventional Neuroradiology, inferior division middle cerebral artery “demonstrates the successful use of an (MCA) balloon angioplasty, and left AR teleproctoring platform to guide and right carotid artery stenting (CAS) a neuroendovascular fellow through procedures. Some 30% of these patients complex neurointerventional procedures were female, and the median patient from a remote setting”. age was 63±18.6 years. Desai reported “The possible wider impact of this that all 10 procedures were a technical work is that this solution can be further success, and no immediate postoperative implemented in residency and fellowship complications or deaths occurred in the training programmes—possibly even case series. to allow visiting professors to give “We found it very easy to use and neuroendovascular fellows a flavour for easy to set up, even for a non-technical different styles of intervention,” Desai person. There were also no instances further concluded.

We found it very easy to use and easy to set up, even for a nontechnical person. There were also no instances where the feed could not demonstrate what the fellow was doing, nor instances where the fellow was unable to understand what the attending physician was asking them to do.”

that are at a considerable distance from the operator.

“Potential platforms currently require considerable refinement. First, to ensure that minimal interventional input is required by an operator within the operating room. Second, to allow the precise use of a wide range of neurovascular microcatheters and devices. Third, to develop haptic feedback systems that directly match manual operator movements; this has the potential to reduce training time, make use of the operator’s preexisting skills, and mitigate risks from catheter and wire damage through the appreciation of subtle catheter and wire movements.”

These conclusions were drawn by Booth, Crinnion and colleagues following a systematic review of existing literature in this space, which included articles published before or on 12 April 2021, and sourced through the

Across 81 robotic neurointerventions

96%

100%

technical success rate

clinical success rate

Medline, PubMed, Embase and Cochrane databases.

After screening a total of 145 articles, the authors note that eight articles—treating 81 patients—met their eligibility criteria and were included for qualitative and quantitative analysis.

They state that seven of these studies reported the use of robotic systems for diagnostic cerebral angiography or carotid artery stenting (CAS), and one case report described the use of a robotic system performing intracranial intervention. Manual conversion was required in three cases across these articles, giving a technical success rate of 96% (78/81). There were also no pertinent morbidity- or mortality-related safety data or complications reported in any of the studies, resulting in a clinical success rate of 100%.

Only one study performed a comparison between robotically assisted and completely manual procedures, they add—and found a significant increase in procedure times associated with robotic CAS. However, Booth, Crinnion and colleagues also temper these largely positive findings by noting that all the evidence identified here falls into the category of level-four evidence, adding that, as such, there is currently no high-level evidence to demonstrate that robotically performed neurointervention is at least non-inferior to manual procedures.

But, despite this low level of existing evidence, they continue, there is still value in discussing these individual studies further—not least because “they represent the current state of the art and form a baseline for further research”. In their report, Booth, Crinnion and colleagues also highlight the various pros and cons associated with the Magellan robotic system (Hansen Medical/Auris Health), the CorPath GRX system (Corindus/Siemens Healthineers), and a further two experimental robotic systems, all of which featured in the eight articles.

Issue 44 | January 2022

Advertorial

5

THIS ADVERTORIAL IS SPONSORED BY PERFLOW

Enabling new possibilities in stroke treatment with Stream technology

also need to get used to the different settings—autolock mode and free mode—that the handle enables.

One of our suggestions would be to take care not to over-expand the device unnecessarily, as we found this can happen when we first started using Stream. As a starting point, you can use four or five ‘clicks’ to open the device in auto-lock mode and, in our experience, it will still function perfectly well without needing to be fully expanded.

The StreamTM family of products (Perflow) is a range of dynamic neurothrombectomy net Overall, you probably need to perform about 10 devices designed to give physicians greater control and visibility when treating ischaemic cases to become completely familiar with the handling stroke. The first clinical use of the Stream17—a lower-profile device intended to improve of the device. But, from then on, it will enable you the treatment of more tortuous patient anatomies—was announced in May 2021, with to have more precise control during thrombectomy preliminary data on Stream technology as a whole being presented even more recently procedures. The difference between the Stream and at the Barts Research and Advanced Interventional Neuroradiology conference (BRAIN a self-expanding stent retriever is like the difference 2021; 13–16 December, London, UK). Kārlis Kupčs and Helmuts Kidikas of the Pauls between driving a car with a manual gearbox or an Stradiņš Clinical University Hospital (Riga, Latvia) discuss their experiences with Stream, automatic transmission. With the Stream, you need and the data their centre has collected on this next-generation stent retriever. to choose what gear you are in, but once you have mastered that skill it opens up more possibilities Could you briefly outline your experience full control over how far, and with how and enables you to offer the patient a with the Stream device to date? much force, the braid will open. This is better chance of reaching the limits We performed our first endovascular thrombectomy especially important in more difficult of what can be achieved—with the Stream device on imaging procedure back in 2006—which was also the first time cases, as that extra control means goal of removing the thrombus software this procedure had ever been done in Latvia—and, we can make adjustments in quickly and effectively. over the course of the past 15 years, we have had the real-time, helping us to remove opportunity to use pretty much all of the thrombectomy the thrombus more safely and Have you seen any devices that are on the market. And, in that time, we sometimes more quickly, which, complications while have gained a lot of experience with these devices, of course, brings benefits for the using the device? performing close to 1,500 cases. patient.

When you are treating We started with the Stream devices in 2019, and we Another great feature of ischaemic stroke, it is were one of the first centres that had the opportunity to the Stream is its radiopacity. impossible to have no use this technology. Up to now, we have deployed them Under fluoroscopic guidance, the complications at all. However, in in more than 40 cases. The majority of these cases have device is fully radiopaque and can our data, the rates of device-related been with the standard device—which has undergone be visualised on imaging software and/or overall complications are several improvements since 2019. More recently, once it has been deployed and no higher than those seen with we have also had the chance to use the Stream XL, opened—which is not the case other stent retrievers. which we use for large vessel occlusions (LVOs), and for most stent retrievers. This Stream17, which is one of the more unique devices on visibility helps to give you a Could you highlight the market right now. better idea of how the device is some key findings interacting with the thrombus, from the data you What are the most appropriate cases and also where the thrombus is have collected on the and anatomies to use this technology in? positioned relative to the device Stream to date?

As you would expect, we use the standard Stream during clot retrieval. The device’s It is important to note that we are Stream devices for standard cases! Specifically, M1 occlusions excellent visibility combined still in the process of collecting and device and also basilar artery occlusions are instances in which with how controllable it is allows analysing these data. the standard Stream performs very well. We have also us, as treating physicians, to apply our However, in terms of recanalisation found that certain, more complex cases, such as when knowledge and experience directly and precisely rates—which we often look at when it comes the thrombus is very hard and cartilage-like, are easier at the occlusion site within the vessel. to device performance—the numbers are really high to handle with the Stream compared to other stent compared to other thrombectomy devices. retrievers because you can manually adjust the device Is it easy to use the Stream?

At the recent BRAIN conference, we presented data and thus the radial force applied to the arterial wall.

As with any stent retriever, there is obviously a demonstrating successful recanalisation (Class 3 or The Stream17 device is one of the smallest learning curve regarding how to handle the specific 2b, thrombolysis in cerebral infarction [TICI] scale) in thrombectomy devices on the market and, as such, device and how best to use all of its functionalities. about 90% of patients treated between February and it can be deployed via microcatheters with an One needs to familiarise themself with the device’s December 2021 (n=41, 51% male, mean age=70 years). inner diameter as small as 0.017 inches, meaning dimensions, its length and the radiopaque markers. You These patients had a mean preprocedure National you can navigate to more distal anatomies like Institutes of Health Stroke Scale (NIHSS) score of 16 M2 or M3 branches, and perform thrombectomies and we observed an average procedure duration of there. And, of course, the advantage of using these 54 minutes. smaller microcatheters is that it makes your distal These data are only from a single centre, however, catheterisation quicker and easier. We have done a and as such we believe that a multicentre study would couple of cases involving posterior cerebral artery now be a very good option to expand the existing body occlusions too, specifically in the P1 and P2 segments, of data on Stream, and its performance as an acute and the Stream17 worked very nicely. ischaemic stroke treatment.

Overall, there are probably not any cases that you could look at and say: “This is not a Stream case”. You Kārlis Kupčs is the head of the Diagnostic Radiology can use Stream for any case—it is just about choosing Institute, and an assistant professor and interventional the right size between the standard device, the Stream radiologist, at the Pauls Stradiņš Clinical University XL and the Stream17.

Hospital in Riga, Latvia.

What features do you appreciate the most on the Stream device?

The Stream is a very special device, because it is one of the only dynamic thrombectomy devices on the market. Whereas many other stent retrievers are selfexpanding—meaning you have no control over how far the stent retriever expands—the Stream gives you

Helmuts Kidikas is an interventional radiologist in the Diagnostic Radiology Institute at the Pauls Stradiņš Clinical University Hospital in Riga, Latvia.

Kārlis Kupčs (L) and Helmuts Kidikas (R)

DISCLAIMER: The Stream device has received CE certification for use in Europe but is currently not available for sale in the USA.

6

January 2022 | Issue 44

Endovascular Therapy

AURORA: Evidence in favour of thrombectomy beyond six hours strengthened by meta-analysis

p<0.0001) and an adjusted common OR—for age, gender, baseline stroke severity, extent of infarction on baseline head computed tomography (CT), and time from onset to random assignment—of 2.54 (1.83–3.54; p<0.0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS score of 0–2) than best medical therapy alone, with 122 of 266 patients (45.9%) achieving this outcome in Evidence favouring endovascular therapy (EVT) in anterior circulation stroke patients the intervention group, and 46 of 238 patients (19.3%) presenting with reversible cerebral ischaemia in the later time window (beyond six hours) achieving it in the control group (p<0.0001). from time last known well has been strengthened by a recent systematic review and No significant difference between the two groups individual patient data meta-analysis. These findings are published in The Lancet by was found when analysing either 90-day mortality or leading stroke neurologists Tudor Jovin (Cooper University Health Care, Camden, USA) and symptomatic intracerebral haemorrhage, the researchers Raul Nogueira (University of Pittsburgh Medical Center [UPMC] Stroke Institute, Pittsburgh, note. No heterogeneity of treatment effect was found USA), and colleagues. across subgroups defined by age, gender, baseline stroke severity, vessel occlusion Benefit of thrombectomy n their report, the researchers note that disability on the modified site, baseline Alberta stroke program beyond six hours: trials examining the benefit of EVT via Rankin Scale (mRS) early CT score (ASPECTS), and thrombectomy in anterior circulation at 90 days, analysed mode of presentation. However, proximal large vessel occlusion (LVO) stroke by ordinal logistic treatment effect was stronger have enrolled patients considered to have regression, while in patients randomly assigned salvageable brain tissue who were randomly key safety outcomes within 12–24 hours (common assigned beyond six hours and up to 24 hours were symptomatic OR=5.86 [95% CI, 3.14–10.94]) Tudor Jovin from time last seen well. intracerebral compared to those randomly As such, they aimed to estimate the benefit haemorrhage and assigned within six–12 hours (1.76 of thrombectomy overall, and in prespecified mortality within 90 days.

[1.18–2.62]; p=0.0087).

Unadjusted common Adjusted common subgroups, through a systematic review and Data from 505 patients “These findings strengthen the odds ratio odds ratio an individual patient data meta-analysis of (mean age=68.6 years; evidence for benefit of endovascular randomised controlled trials (RCTs) involving 51.3% women), 266 of whom were thrombectomy in patients with evidence of endovascular stroke therapy between January in intervention groups and 239 of whom were reversible cerebral ischaemia across the six–24-hour 2010 and March 2021. in control groups, were included from six trials time window and are relevant to clinical practice,” the Raul Nogueira In this research—the AURORA that met the review’s inclusion criteria. authors conclude. “Our findings suggest that, in these (Analysis of pooled data from randomized studies of Primary outcome analysis showed a benefit of patients, thrombectomy should not be withheld on the thrombectomy more than six hours after last known thrombectomy with an unadjusted common odds ratio basis of mode of presentation or of the point in time of well) collaboration—the primary outcome was (OR) of 2.42 (95% confidence interval [CI], 1.76–3.33; presentation within the six–24-hour time window.”

I

2.42 vs. 2.54

ESCAPE-NEXT trial may help realise “dream” of combining neuroprotection and endovascular therapy At the LINNC Paris Course 2021 (14–16 September, Paris, France and virtual), audiences heard that the ESCAPE-NEXT trial (sponsored by NoNO), which has already started enrolling patients and is expected to be completed by August 2022, could represent a major step towards the “dream” therapeutic approach of combining neuroprotection and endovascular therapy (EVT) for acute ischaemic stroke. This viewpoint was presented by Mayank Goyal, director of imaging and endovascular treatment in the Calgary Stroke Program at the University of Calgary’s Hotchkiss Brain Institute (Calgary, Canada).

Should ESCAPE-NEXT confirm the results of ESCAPE-NA1 in patients not receiving alteplase, combining the data should “dramatically reduce” the likelihood of false positive results, he added. The trial is currently ongoing across 88 global sites and has enrolled 81 patients already. The maximum enrolment in ESCAPE-NEXT will be 1,020 patients, with an interim analysis scheduled after enrolment reaches 510 patients.

“Obviously, I have no idea how this story will play out—but, let us jump forward two years and say that the results from the trial are positive,” Goyal proposed. “For the first time, we will have a neuroprotective agent approved

GOYAL BEGAN BY RECAPPING results from the ESCAPE-NA1 study—a multicentre, randomised controlled trial that assessed the safety and efficacy of the neuroprotective agent nerinetide (NA-1; NoNO) in treating acute ischaemic stroke. A subgroup analysis of the trial’s results found that this drug improved clinical outcomes— demonstrated by a 10% increase in modified Rankin Scale (mRS) scores of 0–2 at 90 days—in patients who did not also receive intravenous tissueplasminogen activator (IV-tPA) therapy, or “alteplase”, but this improvement was not seen in patients who received concurrent alteplase and nerinetide treatments.

He also noted that another “interesting journey” is underway in trials investigating the effectiveness

for human use.” He went on to note that this would be a major step forward, as a total of 1,073 of these drugs have been tried and have ultimately failed to date, and may stimulate a significant increase in investment as well as leading to many

of IV-tPA itself, including the recent presentation of results from the SWIFTDIRECT trial at the 7th European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual). While he added that an upcoming meta-analysis of this trial and others may uncover some benefit to EVT alone in certain subgroups, it is likely that the overall status quo of giving stroke patients IVtPA plus EVT will remain unchanged by these findings.

Goyal relayed that presentation of ESCAPE-NA1’s findings to the US Food and Drug Administration (FDA) has now led to a second trial, dubbed ESCAPENEXT, being devised to further assess nerinetide. He claimed that this trial is similar in many ways to the original study, but only includes patients who are not concurrently receiving IV-tPA.

The dream is that—if a stroke is detected at a patient’s house—we give them nerinetide as they are being transported to receive EVT.”

Mayank Goyal

other new drug products being trialled as a result.

“So, as a conclusion, are we on the cusp of a revolution? I hope so, although we will find out for sure in two years’ time,” Goyal stated. “The dream is that—if a stroke is detected at a patient’s house—we give them nerinetide as they are being transported to receive EVT.” He further concluded that it is important to prepare for the practical implications of the ESCAPE-NEXT results because, if nerinetide is approved, physicians will need to consider its role under the context of the already-approved IV-tPA in stroke care more generally.

In a subsequent discussion, Goyal also noted that, if the trial produces positive results and nerinetide is approved for use in stroke, it will likely be used to treat patients who do not qualify for IV-tPA, or it will be given ahead of IV-tPA.

Issue 44 | January 2022

Endovascular Therapy

Mechanical thrombectomy fails to show non-inferiority to bridging thrombolysis in SWIFT-DIRECT trial The preliminary results of the SWIFT-DIRECT (Solitaire with the intention for thrombectomy plus IV t-PA versus direct Solitaire stent-retriever thrombectomy in acute anterior circulation stroke) trial have indicated that, in the treatment of large vessel occlusions (LVOs), direct mechanical thrombectomy failed to demonstrate noninferiority to intravenous tissue-plasminogen activator (IV t-PA) plus thrombectomy—or “bridging thrombolysis”.

T

hese results were presented at the European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual) by Jan Gralla, chair and director of the Department of Diagnostic and Interventional Neuroradiology at the Inselspital, University Hospital of Bern (Bern, Switzerland), and Urs Fischer, chairman and head of the Department of Neurology at the University Hospital of Basel (Basel, Switzerland).

“The quality of data in this trial is very good and it was clear to see that the preintervention reperfusion rate with intravenous thrombolysis was very low—this is basically what we expected based on our clinical experience,” Gralla said. “Nonetheless, the postintervention reperfusion rate was much higher in the IV t-PA arm, so, from my point of view—in the current setting—there is no reason to skip intravenous thrombolysis in LVOs.” “In terms of what we have shown, we have not proven the superiority of bridging thrombolysis over direct mechanical thrombectomy, but this can be seen as a shift towards bridging thrombolysis,” Fischer added. He did, however, also note that there are probably some subgroups within the SWIFT-

DIRECT patient population who will see a benefit from direct mechanical thrombectomy, in addition to those who benefit from receiving IV t-PA prior to the thrombectomy procedure.

“Therefore, the aim in the future will be an individualised treatment approach in acute stroke therapy,” he stated.

The researchers relayed that their primary aim going into the SWIFTDIRECT trial was to determine whether patients eligible for IV t-PA, who are experiencing an ischaemic stroke due to an internal carotid artery (ICA) or M1 occlusion, and have been referred to a stroke centre, will have a noninferior functional outcome at 90 days when treated with direct mechanical thrombectomy, compared to those treated with combined IV t-PA plus thrombectomy. They also noted the trial’s non-inferiority margin was set at 12%.

SWIFT-DIRECT was a prospective, multicentre, 1:1 randomised, openlabel, blinded-endpoint study in which patients in the standard group received intravenous alteplase (0.9mg/ kg) plus mechanical thrombectomy using Solitaire devices (Medtronic), and patients in the intervention group received thrombectomy with Solitaire devices alone. Its primary efficacy

Image credit: UTSW Medical Center

Hispanic stroke patients experience poorer post-thrombectomy outcomes than white counterparts A study conducted by neurology researchers at University of Texas Southwestern (UTSW) Medical Center has found lower-quality functional outcomes for Hispanic ischaemic stroke patients who receive endovascular thrombectomies than for comparable white patients. Outcomes were similar between white and Black ischaemic stroke patients receiving endovascular thrombectomies, the researchers also determined.

“THIS NEW STUDY IDENTIFIES populations that we should focus on in future research to gain a better understanding of the root causes of these disparities,” said the study’s lead author Erica Jones, assistant

7

endpoint was functional rates in both groups as independence— well. However, while measured via a modified successful postintervention Rankin Scale [mRS] reperfusion rates were score of 0–2—at 90 above 90% in both days, with secondary treatment arms, they Urs Fischer Jan Gralla outcomes being were significantly higher mortality at 90 days, in the IV t-PA plus mRS shift, successful reperfusion, and thrombectomy cohort (97% vs. 91%). both symptomatic and asymptomatic Symptomatic intracerebral haemorrhage intracerebral haemorrhages. rates were low in both groups, but A total of 423 patients were recruited at significantly lower in the direct 48 sites across eight different countries in thrombectomy cohort (1.5% vs. 4.9%).

Europe and North America. Some 408 of Gralla qualified the preliminary these patients were included in the final nature of these results by stating that analysis, with 201 being randomised to the database for the trial is yet to be receive direct mechanical thrombectomy closed, meaning the numbers may change (median age=73 years; 52% female), slightly in the future, but that all of the and 207 being randomised to receive IV clinical outcomes are “100% clear”, t-PA plus thrombectomy (median age=72 and the patterns these data indicate years; 50% female). In these groups, 198 “will not change now”. In a discussion and 204 patients received their allocated following this, Fischer noted that the intervention, respectively.

SWIFT-DIRECT researchers are now “Overall, it is extremely important hoping to pool their data with those from to note that outcomes were very good the Improving reperfusion strategies in in both treatment arms, with good ischaemic stroke (IRIS) group—which functional outcomes—indicated by an will begin collaborating in early 2022— mRS score from 0–2—of 62%,” Fischer in order to identify subgroups who may said. “In terms of the primary outcome, benefit from either one of these two 57% of patients in the direct mechanical treatment options for LVO stroke. thrombectomy group had a good functional outcome, compared to 65% of patients in the bridging thrombolysis cohort.” He went on to report a risk difference of -7.3% between the two groups, and a -15.1% lower limit of onesided 95% confidence interval—which fell outside of the 12% non-inferiority margin, and led the researchers to conclude that SWIFT-DIRECT did not show statistical non-inferiority of direct mechanical thrombectomy when compared to IV t-PA plus thrombectomy.

Regarding secondary outcomes, they recounted no differences in mRS shift, mortality at 90 days, or median National Institutes of Health Stroke Scale (NIHSS) score changes at 24 hours, in the two groups—and there were very low rates Urs Fischer of successful preintervention reperfusion

professor of neurology at UTSW Medical Center in Dallas, USA. “With understanding, targeted interventions can be developed to improve access to the best outcomes for all stroke patients.”

These findings, which are published in the Journal of Stroke and Cerebrovascular Diseases, add to the growing body of knowledge on improving stroke treatment in underserved groups—the researchers note—as previous studies have identified racial disparities in stroke outcomes and access to treatment.

In the study, a retrospective review of patients from a prospectively collected stroke registry in Houston, USA was conducted from August 2015 to June 2019.

Patients aged 18 and older who received mechanical thrombectomy, and had race/ethnicity data belonging to the three largest racial/ethnic groups (non-Hispanic white, non-Hispanic Black and Hispanic), were included.

The study’s primary outcome was to evaluate differences in good functional outcome, defined as a 90-day modified Rankin Scale score (mRS) of 0–2, and secondary Erica outcomes were discharge Jones disposition, length of stay

We have not proven the superiority of bridging thrombolysis over direct mechanical thrombectomy, but this can be seen as a shift towards bridging thrombolysis.”

and excellent functional outcomes (90-day mRS score of 0–1).

Among a total of 666 patients who met the inclusion criteria, 45% were non-Hispanic white, 30% were non-Hispanic Black and 19% were Hispanic. The researchers also detail in their report that there were no significant racial differences in pre-morbid mRS scores, arrival National Institutes of Health Stroke Scale (NIHSS) scores, or tissue plasminogen activator (tPA) treatment rates.

They found there was no difference in primary outcomes by race when comparing non-Hispanic white patients to the other racial groups (odds ratio [OR]=1.08 [0.68–1.72]) but that, compared to Hispanic patients, non-Hispanic white patients had a higher likelihood of achieving an excellent functional outcome (OR=2.23 [1.01–4.93])—one of the study’s secondary outcomes.

The researchers conclude that, as such, “further study on disparities in post-acute stroke care is needed”. This research also builds on a study published by Jones et al in the Journal of Stroke and Cerebrovascular Diseases in 2020, which found that—among stroke patients under the age of 50—there was a higher prevalence of modifiable risk factors (including diabetes, hypertension and heart failure) in Black and Hispanic patients, as well as a decreased likelihood of good, early functional outcomes after ischaemic stroke.

Issue 44 | January 2022

Flow Diverters

COATING study “badly needed” to assess surface modification of flow diverters The Congress of the European Society of Minimally Invasive Neurological Therapy (ESMINT 2021; 8–10 September, Nice, France and virtual) saw details of the COATING (Coating to optimise aneurysm treatment in the new flow diverter generation; phenox) study presented by Laurent Pierot, head of the Department of Radiology at the University Hospital of Reims (Reims, France), who is also the study’s principal investigator. And, while a discussion following this presentation saw questions raised about patient acceptance in the study, attendees were in agreement that it is highly necessary to improve on the current understanding of surface modification in the treatment of intracranial aneurysms.

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ierot began by reporting that the COATING study will assess the phenox Hydrophilic Polymer Coating (pHPC)—which is designed to modify the surface of a flow diverter in order to reduce platelet aggregation, and minimise complications like intra-stent thrombosis and distal emboli without the need for dual antiplatelet therapy (DAPT) alongside these devices.

This multicentre, prospective, randomised controlled trial (RCT) will therefore compare the endovascular treatment of unruptured or recanalised intracranial aneurysms using a bare p64/p48-MW flow modulation device (phenox) with DAPT, and a coated p64/ p48-MW-HPC device (phenox) with single antiplatelet therapy (SAPT). The

primary hypothesis of the trial is that the HPC-coated device is non-inferior to the bare device in the treatment of intracranial aneurysms, with the secondary hypothesis being that the coated option is superior to the bare one for the same indication.

Pierot reported that the primary endpoint of the COATING study will be the number of diffusionweighted imaging (DWI) lesions—visualised via magnetic resonance imaging (MRI)—within 48 hours of the index procedure.

Secondary safety endpoints

Role of in silico clinical trials may be to reduce, refine and complement traditional studies

In silico studies involving virtual participants hold great potential in the neurovascular field—and the broader medical industry— with their future role in the generation of scientific evidence likely to be alongside more traditional clinical trials. And, by circumventing some of the ethical and logistical difficulties relating to current inhuman and animal studies, they hold the potential to reduce, refine, and complement, these more conventional methods.

THIS WAS A KEY VIEWPOINT PRESENTED

by Alejandro Frangi, Diamond Jubilee chair in Computational Medicine, Royal Academy of Engineering chair in Emerging Technologies, and scientific director of the Leeds Centre for HealthTech Innovation, at the University of Leeds (Leeds, UK), speaking at the Barts Research and Advanced Interventional Neuroradiology conference (BRAIN 2021; 13–16 December, London, UK).

Frangi began by highlighting the possibility for a “paradigm shift” in the way medical devices, particularly those used in the treatment of cerebral aneurysms, are evaluated. He drew comparisons between the medical sector and the automotive industry, noting that while the latter has introduced “virtual”

will include rates of morbimortality, neurological death or major stroke, intracranial haemorrhage, and declining modified Rankin Scale (mRS) scores, at up to 365 days post-procedure.

The study will recruit a maximum total of 200 patients—100 per randomisation arm—Pierot continued, with enrolment taking place across 25 European centres.

He noted that the first patient was enrolled in France in August 2021, with the last patient randomisation expected to occur in Q4 2022 and a final study report scheduled for Q2 2024.

Randomisation will take place on a 1:1 basis, with patients in both the coated device plus SAPT group and the bare device plus DAPT group receiving routine care alongside their designated treatment approaches. Pierot concluded his presentation by stating that the COATING study is the first multicentre RCT comparing these two specific flow diversion approaches—and will hopefully help to elucidate the effect of surface modification in intracranial aneurysm treatment with these devices.

A discussion following the presentation saw István Szikora (National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary) state that he strongly believes this study is “the only way to go” in order to investigate surface modification in flow diverters, and that it is Laurent Pierot “badly needed”

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by the medical community.

However, he went on to note an ethical concern with the study’s design, as it compares a well-established approach, for which all the associated benefits and potential complications are known, with an approach about which so little is known, and for which the only tangible benefit for the patient is that they need to take fewer medications following implantation. “If I was a patient,” Szikora continued, “I am pretty sure that I would refuse to enter this study—so, I wonder, psychologically, how you can convince patients to enter the study.”

Pierot responded by stating that this is simply “the principle of randomisation”, and that many novel treatment methods have had to be investigated from a similarly uncertain starting point in the past. In addition to noting that no issues arose during enrolment of the first patient last year, he relayed that the study has been approved by an ethical committee— and concurred with Szikora that COATING is the only way of properly evaluating this new approach.

Speaking to NeuroNews following ESMINT 2021, Pierot stated that SAPT does hold potential benefits for patients compared to DAPT, including lower risks of haemorrhagic complications and earlier occurrence of thrombosis in the aneurysm. He added that SAPT may also enable flow diversion technologies to be deployed in the treatment of ruptured aneurysms as well as unruptured aneurysms—another area the COATING study could shed some light on.

approaches, such as aerodynamic modelling and crash larger aneurysm sizes, and hypertension—and even simulations, in recent years, the former has undergone explaining the findings of in-human clinical trials thanks comparatively little change over the past few decades. to advanced computational modelling techniques.

An in silico trial, Frangi told the BRAIN audience, Expanding on this second point, Frangi said FDis a computer-based study performed on populations PASS produced data indicating that—following flow of virtual patients by modelling key features of their diversion—haemorrhagic stroke caused by a delayed anatomy, physics and physiology. Outlining the rupture is more likely to occur in patients with complexpremise further, he said it is akin to having a library shaped aneurysms that have a high aspect ratio or are of anatomical models that is near-limitless in size and large/giant in size, while an ischaemic stroke resulting within which one can conduct virtual implantations—for from a posterior communicating artery (PCoA) example, of flow diverters or coiling devices. aneurysm is more likely to be observed in hypertensive Benefits here include the ability to patients with a distal side branch. Some simulate different physiological conditions of these insights would be “very difficult” (e.g. rest versus stress; normotensive versus to demonstrate or hypothesise on with a hypertensive) and test multiple different conventional trial design, he claimed, adding devices in a single patient—both of which that identification of potential biomarkers for are not feasible with in-human studies, he device failure is therefore another possible added. As such, in silico trials also hold the avenue opened up by in silico models. potential to optimise complex interventions Responding to a query from BRAIN course Alejandro Frangi that combine several devices or introduce director Paul Bhogal (Barts Health NHS coadjuvant drugs alongside a device. This is in Trust, London, UK), Frangi said: “I think, addition to the significant, intrinsic advantage of using a potentially, we will continue to use conventional trials virtual patient population, which is that it carries no risk as confirmatory studies for hypotheses or findings to humans nor compromises animal welfare. generated in silico over large-scale, virtual patient Frangi then moved on to discuss the FD-PASS (Flow datasets, rather than them being the first port of call diverter performance assessment) study, the findings for human evidence on novel designs that have come of which were published in Nature Communications straight from the bench and animal experiments.” in 2021. This saw comparisons drawn between FDCommenting on the shortened timeframes that in PASS—an in silico trial assessing outcomes with the silico trials can enable, Frangi added that FD-PASS Pipeline embolisation device (PED; Medtronic)—and took place over the course of three months, while three conventional studies (ASPIRe, PREMIER and the ASPIRe, PREMIER and PUFS studies each took PUFS) also involving this technology. In addition to between six and eight years to complete—with the predicting the effectiveness of PED successfully, by former also requiring significantly less funding. And, producing similar angiographic aneurysm occlusion he continued, while prior development and validation rates in its virtual, 82-patient cohort to those seen of the computational models used in FD-PASS did take in the conventional studies, FD-PASS was able to several years, those models can now be used for many go a step further by identifying risk factors of PED similar neurovascular devices—essentially, anything failure—including the presence of branch arteries, “stent-like”—in the future.

January 2022 | Issue 44

10 Stroke Care

World Stroke Day 2021: Clinical community calls for improved treatment protocols The World Stroke Organization (WSO) and the Society of NeuroInterventional Surgery (SNIS) were among prominent groups that advocated improved stroke treatment protocols on the advent of World Stroke Day (29 October 2021).

IN A STATEMENT, THE WSO CALLED FOR “urgent improvements” to the treatment of stroke, and increased awareness of symptoms, in light of a study it conducted alongside the World Health Organization (WHO) that found only 35% of hospitals across the globe provide treatment using tissue plasminogen activator (tPA)—despite it being added to the WHO essential medicines list two years ago.

TPA is a highly efficacious and cost-effective treatment, the statement goes on to note, but its

provision is dependent on the establishment urged US lawmakers to update stroke triage of specialist stroke units, which are far and transport protocols. In a statement, less common in low-income countries it also asserted that, if the country’s compared to their higher income stroke system of care looked more counterparts, leading to poorer like its trauma triage system, patients geographies experiencing four times would experience less disability and the rate of stroke-related death and improved survival rates. disability.

“We now have scientifically “People treated with tPA have a proven techniques and devices to of hospitals across 31% higher recovery rate and can treat stroke patients by restoring the globe provide go on to lead independent lives,” said blood flow,” said SNIS president treatment using tPA WSO president-elect Sheila Martins. “It Michael Chen. “Where we have to catch is shocking that 65% of hospitals still do up is in state-level policies that stymie first not provide it. Hospitals must urgently prioritise responders from taking patients to Level 1 stroke the development of stroke units in order to administer centres right away. If we could better organise and tPA. Donors, industry, pharmaceutical companies and centralise state-level stroke triage, more patients could governments need to come together to prioritise stroke be treated sooner, which directly benefits outcomes. care units. We also need training for non-specialist “The trauma system paved the way for patients to get doctors and nurses, particularly in low-income settings, the care they need immediately. This World Stroke Day, to widen access to stroke-ready hospitals.” we need to better organise and centralise care for stroke To tackle this issue and many others, the WSO has patients too.” launched its Roadmap to Quality Stroke Care—a Having already successfully advocated the platform that can be used in all settings to identify introduction of updated stroke treatment protocols areas for improvement—and is urging healthcare across a number of US states—benefitting thousands professionals to join efforts to optimise stroke services. of patients in the process—the Get Ahead of Stroke Another announcement aligned with World Stroke campaign is also currently working to improve stroke Day came from the Get Ahead of Stroke campaign, care via policy changes in Massachusetts, Pennsylvania which—through SNIS, its sponsoring organisation— and Michigan.

Reducing disability and death: What is next for stroke triage and transport?

Michael Chen Comment & Analysis Michael Chen (Rush University Medical Center, Chicago, USA) discusses the growing awareness around the need for timely interventions in stroke care in the USA, and outlines efforts being undertaken by the Get Ahead of Stroke campaign to address this moving forward.

THE NEED TO IMPROVE stroke triage and transport has never been more important. Since 2015, the New England Journal of Medicine has published seven positive studies proving the efficacy of thrombectomy—a minimally invasive, catheter-based procedure to physically remove blood clots within arteries and improve disability after stroke. Patients with severe strokes secondary to large clots blocking a major brain artery have a nearly-75% chance of being dependent or dying. Thrombectomy can reduce the chance of this poor outcome by 50%.

However, thrombectomy is extremely time-dependent. During a stroke, the brain is essentially holding its breath.

Appropriate triage and transport can save the wasted precious hours that would have otherwise been spent at a hospital not equipped to perform thrombectomy. The Get Ahead of Stroke campaign, sponsored by the Society of

NeuroInterventional Surgery (SNIS) and its corporate partners, has been working on passing legislation and protocols state-by-state since 2016 that allow first responders to triage and transport large vessel occlusive (LVO) stroke patients directly to Level 1 stroke centres capable of performing thrombectomy.

The campaign has helped to update protocols in six states (Arizona, Colorado, Florida, North Carolina, Ohio, Tennessee) and several other states have

ONLY

35%

followed suit to change protocols on their own (Delaware, Kentucky, Louisiana, Maine, Maryland, Mississippi, Nebraska, New Hampshire, Utah, Vermont, Washington). The goal is that, once a critical mass of states has adopted LVO stroke assessment, triage and transport into their protocols, surrounding states should quickly follow suit.

Stroke triage and transport that is protocolised also has the best chance of addressing entrenched healthcare disparities. Research from Adam Wallace (Ascension Columbia St Mary’s Hospital, Milwaukee, USA) et al, presented at the 2021 SNIS annual meeting, highlights that Black patients have the highest rate of death due to stroke, and are 30% less likely to be diagnosed with blockage of a large artery in the brain upon arrival and 28% less likely to have a thrombectomy.

By standardising approaches across the country, currently underserved groups including certain racial groups, neighbourhoods and those who are economically disadvantaged may truly have better odds of more efficient and effective stroke treatment.

But, passing legislation that changes local stroke triage and transport protocols is not enough. We are partnering with emergency medical services (EMS) and first responder leaders to find effective ways to educate about stroke assessment, and the importance of triage and transporting severe stroke patients to equipped centres. Given turnover

More so than better designed thrombectomy devices or faster in-hospital workflows, reducing the time it takes for a patient to arrive at a thrombectomy-capable hospital can make the biggest impact on patient outcomes.”

and the fact the large majority of first responder calls are not for stroke patients, educational efforts need to increase. We also must educate the public on stroke symptoms and the importance of calling 911 instead of driving themselves to the hospital—whereby they will lose time, as they could have been assessed in-transit.

As critical stakeholders with a depth of knowledge, EMS also must be engaged in the development of technologies that can further assist in stroke severity detection. There are several technologies to rapidly diagnose an LVO stroke, similar to what an electrocardiogram does for acute myocardial infarction. As an initial tool, Get Ahead of Stroke created a free mobile app, Stroke Scales for EMS, to help first responders assess stroke severity, and in the field, to determine where to transport patients. Other challenges besides sufficient education currently interfere with rapid adoption of effective stroke triage. Financial interests may mean smaller hospitals block first responder transport protocols out of fear of decreasing their admission volumes.

The ability to accurately diagnose a stroke rapidly also makes strict transport protocols difficult to adhere to if the diagnostic information is limited.

Nevertheless, more so than better designed thrombectomy devices or faster in-hospital workflows, reducing the time it takes for a patient to arrive at a thrombectomy-capable hospital can make the biggest impact on patient outcomes.

Efficiently and effectively triaging and transporting patients to Level 1 stroke centres for mechanical thrombectomy from a specialised team would have a disproportionately large benefit to any population of LVO stroke patients.

Michael Chen is a neurointerventionist and professor of Neurology, Neurosurgery and Radiology at Rush University Medical Center in Chicago, USA, and the current president of SNIS.

Issue 44 | January 2022

Stroke Care 11

Flying intervention teams lead to higher EVT rates and reduced time to treatment for rural stroke patients Flying teams of interventionists directly to a primary stroke centre to perform endovascular therapy (EVT)—as opposed to waiting for the patient to be transferred to an intervention centre—may be associated with a higher probability of receiving EVT, a reduced time to treatment of roughly 90 minutes, comparable complication rates and slightly improved functional outcomes at three months.

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his is according to Gordian Hubert, a senior physician in the Department of Neurology and Neurological Intensive Care Medicine at the Munich Harlaching Clinic and head of the TEMPiS (Telemedical Stroke Network Southeast Bavaria) project (Munich, Germany), who presented data from a prospective study carried out in the TEMPiS network at the European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual).

“As we all know, the effect of endovascular treatment is highly time dependent, and we also know that intervention expertise is scarce in rural areas—meaning rural patients experience significant treatment delays and worse outcomes,” Hubert stated. He went on to describe a new approach to treating these stroke patients, which involves a flying intervention team (FIT) travelling directly via helicopter to a primary stroke centre to perform EVT. This differs from the standard model of care whereby patients are transferred from the site of stroke onset to a primary stroke centre for diagnosis, and then transferred on to an intervention centre later to undergo the

thrombectomy procedure.

He claimed that, in addition to removing the need to prepare patients for transfer to a separate intervention centre, and cutting out the time spent admitting patients to the new centre, a key reason why the FIT approach is so much faster than conventional methods is because it allows transportation of the FIT and preparation of the patient for surgery to be done simultaneously. “That allows you to move the start of the therapy forward, and that is where you really gain time,” Hubert stated. “The parallelisation of processes is what really makes the difference here.”

To assess this novel approach, Hubert and his colleagues conducted a prospective cohort study within the TEMPiS network in Germany between February 2018 and January 2021. A total of 15 primary stroke centres participated in the study. Hubert reported that two FITs were available for half of the study period, with the standard model of interhospital transfer being used throughout the other half. This led to 134 EVT-eligible patients (57% female, average age=75 years) being treated with

FIT and 210 EVT-eligible patients (47% logistic regression analysis revealed that female, average age=76 years) being this did not reach statistical significance. treated following transfer.

He went on to state that, for various Hubert noted that, in the study, when reasons, a large number of patients FIT was deployed, patients received ultimately did not receive EVT within EVT 84% of the time—compared to the study and, as such, the researchers just 65% when they were transferred carried out a subgroup analysis looking for the procedure instead. He added solely at patients who received EVT. that the median time taken to decide on “Obviously, those are the ones that a treatment was 62 minutes in the FIT may benefit from shorter time delays,” group and 148 minutes in the transfer Hubert told the audience. Once again, group, which he described as “highly this subgroup analysis revealed a similar statistically significant”. And, while trend towards improved three-month successful recanalisation was more even outcomes in the FIT group, but not to a between the two groups, being achieved statistically significant extent.

94% of the time in the FIT Hubert closed his group and 88% of the time presentation by highlighting in the transfer group, the several limitations of median time from stroke the study, including its onset to recanalisation—the observational design, which “most important” time may have created a risk of metric from the patient’s systemic biases, as well as point of view, according to the difficulties in comparing Hubert—was 240 minutes an existing, unaltered in the FIT group and 338 healthcare structure with Gordian Hubert minutes in the transfer a novel system of care. He group. noted that the Regarding safety mono-regional outcomes, mortality design of the with within three study could flying months, and also be seen intervention to harm the in-hospital and teams periprocedural generalisability EVT complications, of its data. were all similar rates “We need between the more research two groups. and we need with Discussing more data from standard the study’s stroke care other groups primary endpoint— setting this up model functional outcome, in their regions as measured by modified to really Rankin Scale (mRS) scores, know whether at three months—Hubert noted that, we can spread this model of care— while there was a trend towards better and whether it is worthwhile for our outcomes in the FIT group, an ordinal patients,” he concluded.

Stroke study reveals optimal timing and intensity for arm and hand rehabilitation A phase II, randomised clinical trial has found that the optimal period for intensive rehabilitation of arm and hand use after a stroke should begin 60 to 90 days after the event.

The study, conducted by Georgetown University and MedStar National Rehabilitation Network (NRH) researchers, is titled “Critical period after stroke study (CPASS): a phase II clinical trial testing an optimal time for motor recovery after stroke in humans” and has been published in Proceedings of the National Academy of Sciences.

THE SAME INTENSIVE REHABILITATION at less than 30 days after a stroke provided some benefit, but rehabilitation at six months or more after a stroke showed no significant benefit compared to those receiving standard care, a Georgetown University Medical Center press release states.

The release adds that approximately 750,000 new strokes occur each year in the USA, and nearly two thirds of people who have a stroke do not recover complete function in their hands and arms—an impairment that can severely limit everyday activities.

“Our finding demonstrates the existence of a critical period or optimal time when adults are most responsive to rehabilitation after a stroke,” said lead author Alexander Dromerick, professor of Rehabilitation Medicine and Neurology and chair of Rehabilitation Medicine at Georgetown University Medical Center, and vice president for research at MedStar NRH (Washington, USA). “Previous clinical trials have found

few or very small improvements in motor function post-stroke, so our research could be an important breakthrough in finding ways we can make substantial improvements in arm and hand recovery.”

For their trial, the researchers enrolled 72 stroke patients, primarily from the Washington area, within three weeks after their stroke. Participants were randomly assigned to receive 20 extra hours of activityfocused motor skills therapy, starting at different times after stroke, in addition to their regularly prescribed therapies. The additional therapy began either at 30 days post-stroke, at 60 to 90 days post-stroke, or at six months or more post-stroke. The results were compared to a control group that received prescribed rehabilitation therapies but no extra motor rehabilitation training.

“Our results suggest that more intensive motor rehabilitation should be provided to stroke patients at 60 to 90 days after stroke onset,” said Elissa Newport, director of the Center for Brain Plasticity and

84%

65%

Recovery at Georgetown University Medical Center, and corresponding author of the study. “It is well known that a young developing brain shows great plasticity compared to other times in life. Our results show that there may be a similar period of heightened plasticity for stroke patients at a specific time after their stroke.”

The improvement in hand and arm function found in this study was not only statistically significant, but was also large enough to be perceived as functionally meaningful by the patients themselves, the release states.

“Our approach shows that patients can tolerate much more intensive motor training than is traditionally provided if they are free to choose the activities used in their training,” said Dorothy Edwards, professor of Kinesiology and Medicine at the University of Wisconsin-Madison (Madison, USA), and member of Georgetown University’s Center for Brain Plasticity and Recovery. “Knowing there might be a critical period for recovery, there are many techniques one might imagine bringing to bear on understanding and enhancing recovery during this time period.”

The researchers hope that this study will establish a time window in which future research can combine therapy with brain stimulation or medications aimed at helping remaining healthy areas of the brain recover impaired functions, or take over functions lost from the damage inflicted by a stroke. They also plan to design a larger clinical trial to confirm the current findings and to determine the optimum dose of therapy, thereby achieving the best effects during this time-sensitive window, the release concludes.

January 2022 | Issue 44

12 Carotid Interventions

Women face increased risk of stroke and readmission after carotid interventions A recent study has pointed to an increased risk of stroke in both asymptomatic and symptomatic female patients, as well as readmission in asymptomatic female patients, following carotid endarterectomy (CEA) or carotid artery stenting (CAS).

These findings were published online ahead of print in the Journal of Vascular Surgery (JVS).

AUTHORS STEVEN GOICOECHEA (LOYOLA University Medical Center, Chicago, USA) et al write that, historically, CEA has illustrated a higher rate of perioperative adverse events for female patients.

Despite this, they note that recent research portrays evidence to suggest similar outcomes following

CEA between female and male patients. In contrast, however, they stress that few studies have examined sex differences in CAS. In order to address this gap in the literature, Goicoechea et al prospectively collected contemporary data from the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, and performed a retrospective, cross-sectional review.

The research team collected data from a total of 106,658 adult patients (average age=70.9 years, 39.9% female) who had undergone CEA (n=104,412) or CAS (n=2,156) between 2005 and 2017, they communicate in their JVS report. The study’s primary outcomes of interest were 30-day postoperative adverse events in asymptomatic versus symptomatic patients, and female versus male patients, who had undergone CEA or CAS. For asymptomatic patients, female gender was associated with significantly higher rates of cerebrovascular accident (CVA)/stroke (13%, p=0.005), readmission (10%, p=0.004), bleeding complication (32%, p=0.001) and urinary tract infection (54%, p=0.001), as well as less infection (26%, p=0.001). In the symptomatic cohort, female gender was associated with significantly higher rates of CVA/stroke (32%, p=0.034), bleeding complication (203%, p=0.001) and urinary tract infection (70%, p=0.011), but a lower rate of pneumonia (39%, p=0.039).

Goicoechea et al add that female patients under the age of 75 years demonstrated increased rates of CVA

SedLine-guided general anaesthesia may reduce post-carotid endarterectomy delirium A prospective study, published in Frontiers in Neurology by Na Xu and colleagues at Capital Medical University in Beijing, China, has shown that general anaesthesia guided by SedLine brain function monitoring parameters (Masimo), and using the Root patient monitoring and connectivity platform (Masimo), can reduce the incidence of postoperative delirium (POD) in patients undergoing carotid endarterectomy (CEA).

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hrough a combination of SedLine’s patient state index (PSi)—an index based on processed electroencephalogram (EEG)—and the density spectral array (DSA)—which represents the power of the EEG on both sides of the brain—to guide anaesthesia administration, the researchers found a significantly reduced risk of POD following these procedures.

They further conclude that patients “may benefit from the monitoring of multiple EEG parameters during surgery”, according to a Masimo press release.

The researchers note that cerebral blood supply may be “severely disrupted” during CEA, which is considered to be the gold-standard treatment for severe carotid stenosis, and that cerebral function is “highly vulnerable” to even brief changes in oxygen and blood supply, as well as to cerebral vascular diseases like carotid stenosis.

POD is an acute state of mental confusion characterised by alterations in attention and consciousness, and

disorganised thinking. It is a common and serious neurological dysfunction, affecting up to 60% of patients after major surgery, the release adds, and is also associated with worse shortand long-term prognoses, and higher healthcare costs.

Noting that the incidence of POD is associated with the duration of EEG suppression during surgery, the researchers sought to investigate whether monitoring multiple processed EEG parameters simultaneously to guide anaesthesia during a procedure like CEA could positively impact the incidence of POD, compared to the use of a single parameter alone, via a single-centre, prospective, randomised clinical trial.

They enrolled 255 patients scheduled for CEA and divided them randomly into an intervention group (n=127, mean age=62 years) and a standard group (n=128, mean age=63 years).

In the intervention group, general anaesthesia was managed using a combination of SedLine PSi and

(21%, p=0.001) and readmission (15%, p<0.001) compared to male patients, whereas this was not the case in female patients aged 75 years and older.

Lastly, in both asymptomatic and symptomatic patients who received CEA, female patients had significantly higher rates of CVA (13% p=0.006 and 31%, p=0.044, respectively). However, these findings were not found in patients undergoing CAS. In the discussion of their findings, Goicoechea et al write that the current study highlights sex disparities in vascular surgery, including discrepancies in postoperative outcomes and complications that have previously been established. They detail that women and ethnic minorities have historically been underrepresented in vascular surgery randomised controlled trials (RCTs), especially in non-governmental and single-centre trials, commenting that this underrepresentation leads to under-reporting of potentially significant differences in outcomes between male and female patients.

The authors also highlight limitations of their study including its use of retrospective data with potentially missing information and a possible “lack of granularity” in a large database like NSQIP. In concluding, Goicoechea et al stress that the present study emphasises the importance of understanding sex disparities in surgical management of cerebrovascular disease, also stating that RCTs must ensure adequate representation of female patients in order to better understand these differences.

DSA monitoring—designed to reduce the risk of intraoperative EEG burst suppression—and, in the standard group, PSi without DSA monitoring was used. In both groups, patients were also monitored with continuous transcranial Doppler ultrasound and near-infrared spectroscopy (NIRS) designed to avoid perioperative cerebral hypoperfusion or hyperperfusion.

The primary outcome was the incidence of POD, measured using the Confusion Assessment Method, during the first three days after surgery.

Secondary outcomes were postoperative hospital length of stay and other neurologic complications. A team of neurophysiologists independently reviewed the EEG data acquired by

Incidence of postoperative delirium

7.87%

28.91%

in the intervention group

in the standard group

SedLine to calculate the cumulative duration of burst suppression for each patient, the release notes.

The researchers found that the incidence of POD was significantly

lower in the intervention group (7.87% of patients) compared to the standard group (28.91% of patients; p<0.01). Patients in the intervention group also spent significantly less overall time with EEG suppression. In addition, there was no significant difference in the incidence of other neurologic complications.

“Processed electroencephalogramguided general anaesthesia management, consisting of PSi combined with DSA monitoring, can significantly reduce the risk of postoperative delirium in patients undergoing CEA,” the researchers conclude. “Patients, especially those exhibiting haemodynamic fluctuations or receiving surgical procedures that disrupt cerebral perfusion, may benefit from the monitoring of multiple EEG parameters during surgery.”

Patients, especially those exhibiting haemodynamic fluctuations or receiving surgical procedures that disrupt cerebral perfusion, may benefit from the monitoring of multiple EEG parameters during surgery.”

Xu et al

Issue 44 | January 2022

Carotid Interventions 13

TCAR yields “high technical success, with an extraordinarily low stroke and death rate at one year” Outcomes in a cohort of patients who consented to one year of follow-up after transcarotid revascularisation (TCAR; Silk Road Medical) treatment for carotid stenosis in the ROADSTER 2 trial showed a 97.4% rate of technical success, no incidences of ipsilateral stroke and a 2.6% mortality rate, the annual meeting of the Midwestern Vascular Surgical Society (MVSS, 9–11 September 2021, Chicago, USA) heard.

THE PROSPECTIVE, OPENlabel, single-arm, multi-registry study included 155 per protocol participants from 21 US centres, and one in Europe, followed between June 2016 and November 2018 who were evaluated 365 days postoperatively.

The results were presented by Kristine So, a vascular surgery fellow at University Hospitals Cleveland Medical Center in Cleveland, USA, with the research team concluding that “in patients with high-risk factors, TCAR yields high technical success with an extraordinarily low stroke and death rate at one year. Further comparative studies to CEA [carotid endarterectomy] are warranted.” The senior author on the oneyear outcomes study was Vikram Kashyap, chief of the Division

of Vascular Surgery and Endovascular Therapy and the co-director of the Vascular Center of the Harrington Heart & Vascular Institute at University Hospitals Cleveland Medical Center.

The early outcomes section of the ROADSTER 2 study reporting the perioperative outcomes of TCAR up to 30 days were promising, So explained. “Over the course of approximately four years, the technical success reached 99.7%, with the stroke rate, death rate and perioperative MI [myocardial infarction] rate all less than 1%. A composite 30day stroke, death and MI rate Kristine So was also

only 1.7%,” she added.

In the one-year follow-up cohort, So and colleagues found that the patient population included a similar breakdown to the early outcomes group: those with asymptomatic disease numbered 119 (76.8%), and symptomatic patients represented 36 (23.2%). They presented with a variety of high-risk anatomic (43.2%), physiologic (31.6%), or combined actors (25.2%). No patient suffered perioperative MI or stroke.

There were four deaths (2.6%) and no ipsilateral strokes. Of the deaths, three occurred in asymptomatic patients, with one symptomatic. All deaths were from non-neurological causes. These findings were comparable to early outcomes in the

Over the course of approximately four years, the technical success reached 99.7%, with the stroke rate, death rate and perioperative myocardial infarction rate all less than 1%.”

30-day cohort, the researchers noted.

So acknowledged limitations in the study, including the fact there were only 155 patients from the original 632 in ROADSTER 2 who remained in the long-term follow-up study. “Additionally, the follow-up period did not start until about a year and a half following the initiation of the ROADSTER 2 trial,” she added.

“Of the 11 subjects who had initially consented to the long-term follow-up who had been excluded for per protocol deviations—within that, one did suffer from an ipsilateral stroke. That patient was ultimately excluded. These limitations emphasise the need for larger observational and comparative studies.”

So said the research team’s long-term follow-up analysis of the ROADSTER 2 cohort “provides evidence that TCAR is performed with low rates of mortality and ipsilateral stroke. This minimally invasive technique can [be] and is used safely in high-risk patients with extracranial carotid disease. There is, however, still a need for larger comparative controlled trials to confirm the safety and efficacy of TCAR.” The ROADSTER 2 post-approval study was launched to evaluate realworld usage of TCAR—the Enroute transcarotid stent (Silk Road Medical) when used with the Enroute transcarotid neuroprotection system (Silk Road Medical)—in patients with significant carotid disease by physicians of varying experience with the transcarotid technique.

January 2022 | Issue 44

14 Interview

PROFILE

Salim Hayek

Salim Hayek is chief of the Division of Pain Medicine at University Hospitals of Cleveland and a professor in Case Western Reserve University’s Department of Anesthesiology in Cleveland, USA. Having received his medical degree from the American University of Beirut in 1991, he has been practising medicine for over 20 years and has been the principal investigator in more than 40 research projects too. As the current president of the North American Neuromodulation Society (NANS), Hayek discusses his experiences and expectations in this role, and also highlights a number of key trends that are shaping the landscape of neuromodulation and pain management right now.

I have always been interested in helping people; hence, medicine felt like a natural choice. While studying medicine, I became very interested in basic research and ultimately enrolled in a PhD programme at Case Western Reserve University during my anaesthesiology training. Unfortunately, none of the projects at the time in the Physiology and Biophysics Department dealt with pain. Thus, my thesis research focused on the molecular biology and electrophysiology of the ryanodine receptor—an intracellular calcium channel involved in malignant hyperthermia. Nonetheless, I followed the basic science research on pain, in particular in relation to neuraxial delivery.

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

As a graduate student, I followed Tony Yaksh and his pioneering neuraxial research. Though I did not train with him, I consider him a mentor and, to my delight, he and I are currently co-editing a textbook on neuraxial therapeutics. Nagy Mekhail at the Cleveland Clinic (Cleveland, USA) steered me toward clinical research and Michael Stanton-Hicks ignited my interest in neuromodulation. I would be amiss not to mention my chairmen in anaesthesiology during training: Harold Michael Marsh, who encouraged me to pursue basic research, and Helmut Cascorbi, who facilitated it. My PhD thesis advisor, Jianjie Ma, impressed me with his perseverance and hard work as well.

How has the COVID-19 pandemic impacted your time as president-elect of the North American Neuromodulation Society?

The pandemic created novel challenges for the society but also allowed time to reflect on the future as well as the organisational structure of NANS. In particular, committee restructuring and initiatives for member engagement have been introduced. On the other hand, the society had to adapt to virtual meetings and webinars along with challenges related to meeting commitments.

NANS is fortunate to have had the steady hands of immediate past president Peter Konrad, and the vision of former president and current advisor Ashwini Sharan, to steer it during that difficult time. Past presidents of the society and fellow board members have been instrumental in guiding us during these unprecedented challenges too. Also, kudos to the executive director and office staff who have persevered through the pandemic.

What are you hoping to accomplish during your time as president?

NANS has experienced an impressive, rapid growth over the past 15 years, which has paralleled the advances in the field of neuromodulation. With rapid growth comes challenges of standardisation and access, however. Standardisation of education and

certification of trainees and practitioners is a NANS priority. Decentralisation of leadership within the society, and empowering young minds, through special interest groups and committees are important measures for growth and adaptability in modern times. The expansion of NANS to other specialities beyond its traditional reach is also a worthwhile long-term goal.

Inclusion of engineers and basic scientists is critical, as is supporting the initiatives of the independent Institute of Neuromodulation (IoN)—which was started by NANS in 2016. Additionally, heightened focus will remain on advocacy and policy matters to support access to therapy for our patients. Expansion of office staff and accomplishing autonomy in a number of services will be a strategic goal. Work is underway to improve information technology and enhance publication output, and NANS will continue to collaborate with other societies for the betterment of the field.

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

Science advances in measured increments with occasional leaps. In general, neurostimulation advances have outpaced advances in neuraxial delivery. Wireless applications and sensing technologies hold the promise to be gamechangers in the near future. Neuraxial delivery for applications beyond pain and spasticity are very promising too.

Sensing in neuromodulation has been an active area of research in a number of laboratories and promises to change the future of the therapy with closedloop systems. Potential applications are wideranging and promise to revolutionise the field.”

What is your proudest achievement in the field of neuromodulation or anaesthesiology?

My work on intrathecal drug delivery (IDD). While I am a big advocate of neurostimulation and carried out some research in that area, most of my work has focused in on IDD and, in particular, on the role of the adjuvant local anaesthetic bupivacaine. There are very limited data in IDD in general and we have worked to improve this evidence base using both retrospective and prospective data. Along the way, we uncovered other potential

alisonlang.com

What initially attracted you to medicine, and the fields of neuromodulation and anaesthesiology specifically?

applications for intrathecal bupivacaine—particularly in managing facial pain and as a potential means to control blood pressure.

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

Sensing in neuromodulation has been an active area of research in a number of laboratories and promises to change the future of the therapy with closed-loop applications. A closed-loop system potentially allows feedback control to titrate the therapy to the patient’s needs in real time. Potential applications are wideranging and promise to revolutionise the field.

What is the most significant unmet need in the field right now?

Not unlike many other specialities, neuromodulation

Issue 44 | January 2022

Interview 15 would benefit from high-level evidence in clinical research. While significant progress has been made over the past decade in the quality and quantity of research publications in the field, the vast majority of high-impact studies have been industry sponsored.

NANS, through IoN, has collaborated with the International Neuromodulation Society (INS) and IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials) to produce a document that will hopefully act as a framework for the design of future studies on spinal cord stimulation (SCS). This work has been recently published in Pain.1 Adoption of such design considerations in future clinical neuromodulation research promises to improve ongoing efforts in the generation of high-quality information that will ultimately benefit our patients.

What do you think needs to be done to enable better, more equitable access to neuromodulation therapies for patients?

Collectively, we need to do a better job at educating patients and referring physicians on the potential of neuromodulation to improve many of the afflictions that are deemed refractory otherwise. NANS has embarked on a number of marketing initiatives in the past but more needs to be done by all stakeholders.

What advice would you give to people embarking on a career in the field of neuromodulation and anaesthesiology?

Nowadays, young graduates are barraged by data, products and engagement opportunities in neuromodulation. However, they need to carefully weigh their options as they navigate the field. It is important to critically evaluate the presented evidence and not be swayed by marketing. Continued participation in high-quality educational initiatives, such as those offered by NANS, is the cornerstone for a solid foundation in neuromodulation. In addition, engagement in volunteerism through NANS allows for service accomplishments and opportunities for growth in the field.

What are your interests outside of the field of medicine?

I played a little bit of tennis growing up, but I was never a good athlete. And, though I enjoy running outdoors, I have been hampered by a recurrent knee meniscal tear. I enjoy watching my kids compete in sports; three are hockey players and one is a swimmer.

I also enjoy travelling to Europe with my wife and playing online chess.

References: 1. Katz N, Dworkin R H, North R, et al. Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations.

Pain. 2021; 162(7): 1935–56.

Fact file Current appointments:

2012–present: Professor, Department of Anesthesiology, Case Western Reserve University, Cleveland, USA 2006–present: Chief, Division of Pain Medicine, University Hospitals of Cleveland, USA

Education:

2004: Fellow of Interventional Pain Practice, World Institute of Pain, Budapest, Hungary

2001: PhD, Case Western Reserve University 1991: MD, American University of Beirut, Lebanon

Honours (selected):

2022–present: President, North American Neuromodulation Society 2020: Distinguished Service Award, European Society of Regional Anesthesia and Pain Medicine (Spain Chapter)

2019: Presidential Commendation Award, American Academy of Pain Medicine 2017: Clinical Excellence Award, West Virginia Society of Interventional Pain Physicians 2015–2017, 2020, 2021: Top Doctors, Cleveland Magazine/ Castle Connolly

January 2022 | Issue 44

16 New Research

Incidence of brain complications among hospitalised COVID-19 patients revealed in global study The largest multi-institutional international study to date on brain complications associated with COVID-19 has found that approximately one in 100 patients hospitalised following SARS-CoV-2 infection will likely develop complications of the central nervous system.

These can include stroke, haemorrhage and other potentially fatal complications.

THE STUDY WAS PRESENTED AT THE annual meeting of the Radiological Society of North America (RSNA; 28 November–2 December 2021, Chicago, USA and virtual).

“Much has been written about the overall pulmonary problems related to COVID-19, but we do not often talk about the other organs that can be affected,” said the study’s lead author Scott Faro, professor of radiology and neurology, and director of the Division of Neuroradiology/Head & Neck Imaging, at Thomas Jefferson University in Philadelphia, USA. “Our study shows that central nervous system complications represent a significant cause of morbidity and mortality in this devastating pandemic.”

Faro initiated the study after discovering that existing literature on central nervous system complications in hospitalised patients infected with COVID-19 was based

on a relatively small number of cases.

He and his colleagues analysed nearly 40,000 cases of hospitalised COVID-19-positive patients from seven US and four western European university hospitals. These Nearly 40,000 patients had been admitted hospitalised between September COVID-192019 and June 2020. Their positive average age was 66 years and patients there were twice as many men as women. The most common cause of admission was confusion and altered mental status, followed by fever.

Many of the patients had comorbidities, including

40,000

hypertension, cardiac disease and diabetes.

There were 442 acute neuroimaging findings that were most likely associated with the viral infection.

The overall incidence of central nervous system complications in this large patient group was 1.2%.

“Of all the inpatients who had imaging, such as MRI [magnetic resonance imaging] or a CT [computed tomography] scan of the brain, the exam was positive approximately 10% of the time,” Faro added. “The incidence of 1.2% means that a little more than one in 100 patients admitted to the hospital with COVID-19 are going to have a brain problem of some sort.”

The most common complication was ischaemic stroke, with an incidence of 6.2%, followed by intracranial haemorrhage (3.72%) and encephalitis (0.47%). The researchers also discovered a small percentage of unusual findings, such as acute disseminating encephalomyelitis—an inflammation of the brain and spinal cord—and posterior 442 acute reversible encephalopathy neuroimaging syndrome, which mimics many of findings the symptoms of a stroke. associated “It is important to know an with the virus accurate incidence of all the major central nervous system complications,” Faro concluded.

“There should probably be a low threshold to order brain imaging for patients with COVID-19.”

442

Study indicates efficacy of hyperbaric oxygen therapy in reversing Alzheimer’s activators A new study, published in Aging, marks the first time nonpharmaceutical clinical exploration has proved efficacious in reversing the main activators of Alzheimer’s disease—according to a press release from Aviv Clinics. Using a specific protocol of hyperbaric oxygen therapy (HBOT), cerebral blood flow (CBF) was increased in elderly patients by 16–23%, alleviating vascular dysfunction and amyloid burden.

THE STUDY—WHICH WAS part of a comprehensive research programme directed towards ageing and accompanying ailments as a reversible disease—holds promise for a new strategic approach in the prevention of Alzheimer’s by not only targeting its biomarkers or symptoms, but also by addressing the core pathology and biology responsible for advancement of the disease, the release adds.

This comprehensive research was led by study co-authors Shai Efrati, Uri Ashery, Ronit Shapira, Pablo Blinder and Amir Hadanny, and conducted at the Sagol School of Neuroscience at Tel Aviv University in Tel Aviv, Israel, and the Sagol Center for Hyperbaric Medicine and Research at Shamir Medical Center in Be’er Ya’akov, Israel.

Based on combined data from an animal model of Alzheimer’s, where effects on brain tissue were evaluated directly, as well as humans assessed with the use of high-resolution magnetic resonance imaging (MRI) and computerised cognitive tests, correlating

results displayed beneficial effects of HBOT on patients suffering from mild cognitive impairment (MCI)—the stage before dementia. Each patient received 60 HBOT sessions over a 90-day period, showcasing substantial improvements in cognitive functions, with memory, attention and information-processing speed exhibiting the strongest results.

Vascular dysfunction, the release notes, is a crucial element in the development of Alzheimer’s and cognitive decline. Amyloid beta deposits in the brain blood vessel walls are the most common vascular pathology in Alzheimer’s, while reduced blood flow to the brain and its related decrease in oxygen supply (hypoxia) can precede the clinical onset of dementia and correlates with the degree of cognitive impairment in Alzheimer’s.

“After dedicating our HBOT research to exploring its impact on the areas of brain functionality and age-related cognitive decline, we have discovered for the first time HBOT induces degradation and clearance of pre-

Elevated blood flow, improved oxygenation in patients with cognitive impairment

By treating vascular dysfunction, we are mapping out the path toward Alzheimer’s prevention.”

Shai Efrati

existing amyloid plaques (treatment), and the appearance of newly formed plaques (prevention),” said Ashery.

“Elderly patients suffering from significant memory loss at baseline revealed an increase in brain blood flow and improvement in cognitive

performance, demonstrating HBOT’s potency to reverse core elements responsible for the development of Alzheimer’s disease.”

“By treating vascular dysfunction, we are mapping out the path toward Alzheimer’s prevention,” added Efrati, research group leader and medical advisor to Aviv Clinics. “More research is underway to further demonstrate how HBOT can improve cognitive function and become an influential tool in the imperative fight against the disease.”

The release also states that Aviv Clinics has developed a unique medical treatment protocol that includes HBOT, cognitive and physical training, and nutritional coaching, to enhance brain and body performance in ageing adults, which is currently available in Central Florida and Dubai.

Issue 44 | January 2022

Artificial Intelligence 17

Time savings, cost reductions and improved patient outcomes all key benefits of AI in stroke care Artificial intelligence (AI) and the role it can play in improving acute ischaemic stroke treatments took centre stage at the Barts Research and Advanced Interventional Neuroradiology conference (BRAIN 2021; 13–16 December, London, UK). Ameer Hassan, head of the Neuroscience Department, and director of Endovascular Surgical Neuroradiology and Clinical Neuroscience Research, at the Valley Baptist Neuroscience Institute in Harlingen, USA, reported benefits relating to patient outcomes as well as time and cost savings following the introduction of a novel, AI-powered smartphone application at his centre.

H

assan, who is also president of the Society of Vascular and Interventional Neurology (SVIN), started his presentation by noting that the current utilisation of mechanical thrombectomy is “much lower than it should be” in the USA. He cited recent data that indicate as many as 20% of acute ischaemic strokes are caused by a large vessel occlusion (LVO)—and yet rates of thrombectomies, which are widely considered to be the gold standard in LVO stroke treatment, range from 8–9% to as low as 2% in some US regions.

Discussing the various patient volumerelated challenges that this may lead to, Hassan highlighted lengthy treatment times in transferred patients, hospital bed shortages, healthcare provider burnout, and increased costs due to delays in delivering thrombectomies. After asserting the importance of treating more patients more quickly, he went on to state that AI solutions “really do make a difference” on this front.

One way of implementing these solutions is during the detection phase

prior to a patient being transferred to the cath lab for a thrombectomy procedure, Hassan told the BRAIN conference audience. “If we can detect [a stroke] earlier, rapidly triage, synchronise our care coordination, and then transfer the patient, we could get them treated much more quickly,” he said.

Hassan went on to compare the standard stroke workflow in many referral centres—a complex process that can take more than two hours, and involves multiple stages and specialists—with a synchronised stroke care model using the Viz intelligent care coordination platform (Viz.ai). The latter process, he said, deploys AI analysis, and uses a smartphone application to alert multiple specialists of the LVO diagnosis within minutes, potentially cutting the detection timeline down to as little

Artificial intelligence can calculate personalised risk of having another stroke Artificial intelligence (AI) can be used to give stroke patients a personalised and more accurate assessment of their risk of suffering a recurrence, according to a new study presented at the European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual).

EXPERTS BELIEVE THE STUDY WILL HELP to identify the most important factors for preventing stroke recurrence and has the potential to help prevent many thousands of strokes each year in Europe, and in doing so prevent many deaths and cases of disability, a European Stroke Organisation (ESO) press release states.

According to previous research, one in four stroke survivors will have another stroke—and yet up to

as 39 minutes. free life. So, if we say that Elaborating on these each minute of delay in claims, Hassan presented receiving a thrombectomy a report, entitled “Early results in a loss of four experience utilizing artificial days of disability-free life, intelligence shows significant and 10 days of functional reduction in transfer times independence [0–2 modified and length of stay in a hub and Rankin Scale score], 66 spoke model”, that has been minutes could mean nearly published in Interventional 265 days of additional Neuroradiology. The report disability-free life and 660 recounts a multicentre, days of additional functional retrospective study evaluating independence.” the impact of Viz on the time Quipping that “time is between computed tomography money—not just brain”, (CT) angiogram acquisition at a Hassan noted that those 66 primary stroke centre and arrival minutes could also be worth at a comprehensive stroke centre just under US$70,000 in cost reduction in among 43 LVO stroke patients. savings as well, due to each neuro-ICU length Comparing these timelines at minute-long delay prior to of stay the Valley Baptist Neuroscience receiving a thrombectomy Institute over two time periods— procedure holding an pre-Viz implementation (February economic value of US$1,059, 2017 to November 2018) and poston average. Discussing the 2.5days of additional day reduction in overall length Viz implementation (November disability-free life of stay observed in the study, 2018 to May 2019)—researchers observed a 66-minute time he also told the audience that saving, on average (171 this reduction could be worth vs. 105 minutes; 39% roughly US$12,300 to the reduction), which also hospital itself as well. resulted in a 55% In addition to touching cost saving reduction in neuroon data from other centres intensive care unit (ICU) that have deployed Viz in length of stay (3.5 days; their stroke care protocols, 6.4 vs. 2.9 days), including significant time for patients who savings and improved clinical underwent a outcomes at Mount Sinai mechanical Health System (New York, thrombectomy.

USA), and a door-to-device “Patient time of less than 90 minutes outcomes are in all thrombectomy cases at time-dependent—we Sky Ridge Medical Center (Lone Tree, already know this,” USA), Hassan concluded by stating that Hassan continued. this novel technology “directly correlates “Every minute saved to better outcomes—including increased Ameer Hassan leads to more disabilityaccess to care for stroke patients”.

80% might be prevented with the right treatments and lifestyle changes.

The study used calculations based on both nonmodifiable risk factors, such as age and ethnicity, and modifiable lifestyle risk factors and habits like smoking, weight, blood pressure and cholesterol, diet, obesity, physical activity levels and treatment compliance, as well as socio-economic factors. These can be used to make a more accurate prediction of an individual’s risk of having a stroke recurrence within three months or one year, and after more than one year, helping to prevent a recurrence and improve patient treatment adherence.

The research, conducted by scientists from Vall d’Hebron University in Barcelona, Spain, used a dataset of 41,325 patients admitted with a stroke diagnosis in 88 public hospitals over the course of six years, and fed them into an AI-based model that was able to provide a reading for individualised risk of stroke recurrence at three and 12 months.

Lead author Giorgio Colangelo, AI research manager at Vall d’Hebron University Hospital’s Institute of Research (VHIR), said: “We were able to use AI to predict the stroke recurrence at three and 12 months on an individual level, and knowing this risk has clinical value for doctors and for patients. Risk factors included high blood pressure and raised cholesterol, atrial fibrillation or sleep apnoea. We also determined and quantified what the most relevant risk factors are, and which of them each patient can modify in his or her lifestyle.”

Marta Rubiera, neurologist at Vall d’Hebron

66-minute time saving with AI platform

55%

265

$69,894

University Hospital and coordinator of the study, added: “We hope the data may be used to create a much more personalised prediction of if, and when, patients might have another stroke, and that—by explaining the impact of individual risk factors—it will make patients more likely to comply with any treatment prescribed or lifestyle changes suggested, reducing the likelihood of having another stroke.”

Marc Ribo, interventional neurologist at Vall d’Hebron University Hospital and chief scientific officer at Nora Health, which also participated in the study, stated: “Patient awareness and empowering self-care are crucial to reduce the risks of recurrent stroke. This study will help inform the personalisation of a recently developed app, Nora, and greatly improve patients’ risk management.”

We were able to use AI to predict the stroke recurrence at three and 12 months on an individual level, and knowing this risk has clinical value for doctors and for patients.”

Giorgio Colangelo

Issue 44 | January 2022

19

Intermittent theta-burst stimulation found to be effective and welltolerated in Alzheimer’s patients

Regarding the study’s results, they state that the active group displayed greater associative memory improvements compared with the sham group.

Specifically, they report a marked improvement in associative memory scores in the active group on day 15 (1.56 to 2.54; The findings of a randomised controlled trial (RCT) have indicated that accelerated 72.83% normalised change) that was intermittent theta-burst stimulation (iTBS), administered to the left dorsolateral not observed in the sham group (1.39 to prefrontal cortex (DLPFC), is an effective and well-tolerated therapeutic approach 1.20; -10.46% normalised change). Similar in patients with Alzheimer’s disease. The results of this trial are published in Brain findings were observed at the eight-week Stimulation by Xingqi Wu, Yanghua Tian and Kai Wang (Department of Neurology, follow-up between the active (1.56 to 2.28; The First Affiliated Hospital of Anhui Medical University, Hefei, China), and colleagues.

47.24% normalised change) and sham (1.39 to 1.17; -4.99% normalised change) groups. he ameliorating effects [of iTBS] were more anatomical image and a frameless neuroFurthermore, higher mini-mental state effective and robust among patients with navigation system (Brainsight, Rogue Research) examination (MMSE) scores at baseline mild Alzheimer’s disease than those with in all stimulations. Outcomes were then assessed were associated with greater associative severe Alzheimer’s disease,” Wu, Tian and Wang et al on day 15 (week two) and eight weeks after the memory improvements at weeks two and write. “In summary, our findings provide RCT evidence cessation of treatment (week 10).

10. For the independent iTBS group, this Top: for the potential use of iTBS in the encoding function of The researchers detail that associative correlation predicted improvements in Xingqi Wu, Yanghua associative memory and cognitive enhancement among memory was the only a priori primary outcome associative memory (p<0.001) and identified Tian and patients with Alzheimer’s disease. Future studies should of the study, and was estimated using a facetreatment responders with 92% accuracy.

Kai Wang investigate the efficacy across multiple centres and cued word association test at baseline and repeated Responses to most of the neuropsychological characterise the neural mechanisms involved in these at the end of treatment. Secondary outcomes tests conducted in the study were markedly improvements.” included changes in clinical symptoms and multiimproved in the active group too. In particular, the The researchers note that, based on promising domain cognition tests at weeks two and 10, while Montreal cognitive assessment (MoCA) and MMSE results from recent studies, high-frequency repetitive adverse events, such as painful scalp sensations, eyelid scores in the active group increased by 2.8 and 2.3 transcranial magnetic stimulation (rTMS) administered twitching, tinnitus, epilepsy, and epileptic seizures, points, respectively, at week two, while there was no to the DLPFC has the potential to ameliorate associative were recorded throughout the study by self-report. significant change in the sham group. memory deficits in Alzheimer’s disease patients. In Eight participants reported adverse events, with addition, they state that sequencing is a key factor five patients reporting painful scalp sensations—three affecting rTMS efficacy, and iTBS—a novel rTMS in the active group and two in the sham group—two protocol—has improved cognitive processing more patients in the active group reporting eyelid twitches, efficiently than traditional rTMS protocols in prior and one patient in the sham group reporting tinnitus. studies, but that there are a lack of existing RCT data in All these events were tolerable, the researchers add, this space. and diminished gradually after treatment cessation. No As such, they set out to investigate the efficacy of cases of epilepsy or epileptic seizures were recorded. accelerated iTBS in enhancing associative memory The researchers conclude that, in this RCT, among Alzheimer’s patients using a randomised, accelerated iTBS of the left DLPFC effectively double-blinded, placebo-controlled, parallel trial. alleviated deficits in the encoding function Between August 2018 and January 2020, 60 patients of associative memory—an effect that was sustained for were enrolled, with 47 ultimately completing the trial. eight weeks after treatment cessation. “In the present These patients were divided into two groups to study, accelerated iTBS of the DLPFC demonstrated an receive either active or sham iTBS over the left DLPFC effective and well-tolerated complementary treatment for 14 consecutive days. Therapy was performed using for patients with Alzheimer’s disease, especially for the Rapid transcranial magnetic stimulator (Magstim), individuals with relatively high MMSE scores,” Wu, Wu, Tian, Wang et al with coil placements being guided by the participants’ Tian and Wang et al add.

“T

In the present study, accelerated iTBS of the DLPFC demonstrated an effective and welltolerated complementary treatment for patients with Alzheimer’s disease, especially for individuals with relatively high MMSE scores.”

Mouse study suggests neuromodulation of certain nerve cells can help regenerate lost heart muscle Johns Hopkins Medicine researchers say they have new evidence from mouse experiments that manipulating certain nerve cells, or the genes that control them, with neuromodulation might trigger the formation of new heart muscle cells and restore heart function after heart attacks and other cardiac disorders.

MORE SPECIFICALLY, THEY believe the results of their study—which are published in Science Advances—

shed new light on how some neurons regulate the number of heart muscle cells.

“Our study sought to examine the role of so-called sympathetic neurons on heart development after birth, and what we found is that by manipulating them there could be tremendous potential for regulating the total number of muscle cells in the heart, even after birth,” said the study’s lead author Emmanouil Tampakakis (Johns Hopkins University School of Medicine, Baltimore, USA).

The research team created a genetically modified mouse model by blocking sympathetic heart neurons in developing mouse embryos and analysed the drivers of heart muscle cell proliferation through the first two weeks after birth.

They found a significant decrease in the activity of a pair of genes—the period 1 and period 2 genes—already known to control the circadian cycle.

And, after removing those two circadian genes in mouse embryos, the researchers saw increased neonatal heart size and a larger number of heart muscle cells by

up to 10%. This suggests that the effect of sympathetic nerves on heart muscle cells is likely mediated through these two circadian or ‘clock’ genes.

People who survive a heart attack can lose up to one billion heart muscle cells, and Tampakakis stated that there is scientific evidence that hearts tend to recover faster after an attack when the total number of cells to begin with is higher. By manipulating sympathetic nerves and clock genes via neuromodulation, researchers believe the heart could be made to respond to injury much better.

“Neuromodulation is a pretty new concept in cardiology, and we believe

these are the first reports that associate clock genes with new growth of heart muscle cells,” said Chulan Kwon (Johns Hopkins University School of Medicine, Baltimore, USA). “Our study, maybe for the first time, shows what is happening if you block the supply of nerves to the heart, and provides new insights for developing neuromodulation strategies for cardiac regeneration.”

Tampakakis added that his team is working on further experiments to characterise the different groups of neurons that supply the heart, and demonstrate how those nerves develop and adjust over time and after heart injury.

Our study, maybe for the first time, shows what is happening if you block the supply of nerves to the heart, and provides new insights for developing neuromodulation strategies for cardiac regeneration.” Chulan Kwon

January 2022 | Issue 44

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Current gaps and barriers in patient access to spinal cord stimulation Maricela Schnur Comment & Analysis Maricela Schnur (St Luke’s Hospital, Duluth, USA) highlights a handful of socioeconomic disparities, racial differences, and psychological and psychiatric factors, that currently present difficulties in patient access to spinal cord stimulation (SCS).

B

arriers and gaps in the delivery of healthcare have been welldocumented. These barriers— which prevent uniform healthcare delivery—are complex and involve a multitude of factors, such as geography, affordability, education and training of the provider, and perceptions of both patients and providers, among others.

Most of these factors have not even begun to be fully elucidated.

Unfortunately, these barriers most certainly exist within the field of chronic pain and affect the ways in which SCS is offered to and ultimately undertaken by patients. Three specific areas cause significant gaps in the offering of this modality: socioeconomic disparities, racial differences, and psychological/ psychiatric factors.

Over the past decade, SCS has seen

a large increase in the advancement of its technology, as well as the indications for its use, with an increase in ease for those providers who are interested in undergoing education and training of these devices. However, the total population of patients undergoing implantation of these devices has not yet been well-studied, and what drives one patient to be offered a device versus another is unclear too.

In the field of chronic pain, postlaminectomy syndrome is a disorder that is treated through a variety of techniques—including SCS. One study, from Mark Jones (Weill Cornell Medical College, New York, USA) et al, retrospectively examined the Medicare limited data set (LDS) from 2016–2019 for those patients given a diagnosis of post-laminectomy syndrome or chronic

pain syndrome who then subsequently underwent placement of a spinal cord stimulator device.1 Race/ethnicity and Medicare/Medicaid dual eligibility (examined as a proxy for income) were reviewed, and showed that minorities and dual-eligible patients were less likely to undergo placement of an SCS device. This study highlights the racial and socioeconomic disparities in a large outpatient setting, common to which most spinal cord stimulators are placed.

Two well-known chronic pain physicians as well as racial diversity advocates, Johnathan Goree (University of Arkansas for Medical Sciences, Little Rock, USA) and Stephanie Vanterpool (University of Tennessee Graduate School of Medicine, Knoxville, USA), recently published a plan for concise outreach efforts to directly address these racial and socioeconomic disparities.2 They outline plans for provider outreach, patient outreach and pipeline outreach.

Also included in this plan are increasing educational efforts in the field of neuromodulation for those practicing or planning to start practice in underserved areas. Additional recommendations include medical societies and organisations partnering with community-based outreach platforms or online education to provide patients in these areas with education in neuromodulation offerings, as well as encouraging a diverse student population to go into the field of chronic pain.

In addition to socioeconomic and racial disparities, psychological and psychiatric barriers to SCS also exist.

Prior to undergoing SCS, most patients are required to undergo psychological testing to identify barriers that may lead to less-than-optimal outcomes postplacement.3 One possible barrier in this area remains the limited number of

New protocol may reduce need for psychological assessments prior to neuromodulation therapy Researchers at Toronto Western Hospital in Canada have proposed a protocol that may precede in-person assessments prior to patients receiving neuromodulation therapies.

Their protocol incorporates a short mental health checklist and pre-defined cut-offs on validated questionnaires to assess whether an in-person assessment—done by a psychologist—is necessary for each patient.

FOLLOWING THESE EFFORTS, MAGGIE Xiao, Fung Ping Wong, Amol Deshpande, Anuj Bhatia, Hemkumar Pushparaj, Kathryn Curtis, Pranab Kumar and Jamal Kara of Toronto Western Hospital (Toronto, Canada) received a Best of Meeting Abstracts Award from the American Society of Regional Anesthesia and Pain Medicine (ASRA) during its annual pain medicine meeting (18–20 November 2021, San Francisco, USA).

The authors also presented their abstract outlining a study of this new protocol, entitled “Can a protocol replace mandatory psychological assessment for workup of neuromodulation therapies for pain?”, during the meeting.

Neuromodulation therapies are an advancing area of chronic pain management that work by blocking pain signals from reaching the brain and can provide

substantial relief in patients for whom conservative therapies have failed. Before implantation of a neuromodulation device, patients commonly undergo an in-person psychological assessment to evaluate potential treatment outcomes. However, the predictive value of psychological testing is not straightforward

This can help reduce wait times and optimise the utilisation of healthcare resources.”

Xiao, Wong, Deshpande et al

providers available to perform presurgical psychiatric assessments as well as the lack of standardisation amongst these assessments. Furthermore, in the patients that require further psychological treatment prior to consideration of SCS, there are significant barriers that lead to delays in accessing the care required to move forward.

Thankfully, since the start of the pandemic, the accessibility and availability of telemedicine visits with medical providers, among many specialities, has increased. This will likely have a positive impact on ease of access for psychiatric care in areas in which finding care providers for mental health has typically been difficult.

Additionally, the creation of a uniform process and/or screening tool to evaluate patients may allow other providers, such as those in primary care, that do screenings for depression and other psychiatric illnesses to include this in their preoperative clearance for patients.

These barriers to the placement of spinal cord stimulators are likely just a few areas that need to be examined and intervened upon in order to improve access.

References: 1. Jones, M R; Orhurhu, V; O’Gara, B, et al. Racial and Socioeconomic Disparities in Spinal Cord Stimulation Among the Medicare Population. Neuromodulation.

2021; 24(3): 434–40.

2. Goree, J; Vanterpool, S. The need for outreach in Pain and Neuroscience. ASPN Newsl. 2020; 5: 5–7.

3. Stephens, K A; Ward, A. Patient selection for spinal cord stimulators: mental health perspective. Curr Pain Headache Rep. 2014; 18(3): 398.

Maricela Schnur is an interventional pain physician at St Luke’s Hospital in Duluth, USA. She is the Neuromusculoskeletal Dyad Director and is active in several societies, including the North American Neuromodulation Society (NANS) and Women Innovators in Pain Medicine (WIPM).

and the process can cause undue delays—as outlined by an ASRA press release.

In the study, patients who screened positive for evident, unresolved psychological conditions underwent an in-person psychological assessment, and patients who screened negative proceeded directly to a neuromodulation trial as part of a fast-track group.

Of the 171 patients who underwent neuromodulation trials for pain at the study centre from July 2017 to December 2020, 57 patients (one in three) bypassed an in-person psychological assessment.

No significant differences in pain reduction outcomes were found between the psychological assessment and fast-track groups. In addition, 72% of patients in the psychological assessment group and 70% of patients in the fast-track group had a successful neuromodulation trial. Follow-up data in 110 patients showed 60% of patients in the fast-track group and 53% of patients in the psychological assessment group had good pain control at six-to-12 months.

The results suggest an algorithm incorporating validated psychological questionnaires and a mental health checklist can be used to identify patients who do not need a formal in-person psychological assessment without a negative impact on outcomes of neuromodulation therapies for pain, the release concludes. “This can help reduce wait times and optimise the utilisation of healthcare resources,” the authors stated.

Issue 44 | January 2022

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Passive recharge burst spinal cord stimulation provides sustainable improvements in pain and psychosocial function Passive recharge burst spinal cord stimulation (B-SCS) can alleviate pain intensity, psychological distress, and improve physical function and health-related quality of life out to two years, according to the latest data from the TRIUMPH study.

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his prospective, international, multicentre, single-arm, postmarket study—the 24-month findings of which were recently published in Spine by Timothy Deer (The Spine and Nerve Centre of the Virginias, Charleston, USA) and colleagues— aimed to assess the long-term safety and efficacy of spinal cord stimulation using a passive recharge burst stimulation design for chronic intractable pain in the trunk and/or limbs.

According to the researchers, B-SCS “uniquely mimics neuronal burst firing patterns in the nervous system and has been shown to modulate the affective and attentional components of pain processing”.

Study participants received a permanent spinal cord stimulation

implant—either a Prodigy, Prodigy MRI or Proclaim Elite implantable pulse generator (Abbott)—and returned for follow-up at six, 12, 18 and 24 months. The latest 24-month data show that the significant improvements in physical, mental and emotional functioning that were seen at six months were also maintained out to two years.

Pain catastrophising scale (PCS) scores dropped below the population norm.

Meanwhile, health-related quality of life on EQ-5D improved across all domains and the mean index score was within one standard deviation of the population norm.

Pain reduction, as measured by a numerical rating scale, was found to be statistically significant (p<0.001) at all timepoints. Patient-reported pain relief, a stated percentage of improvement in pain, was consistent at all timepoints at 60%.

Patients also reported significant improvements across all other measures including activity levels and impact of pain on daily life. At 24 months, 84% of subjects said they were satisfied and 90% said they would recommend the procedure.

In addition, patients were able to decrease their chronic pain medication intake for all categories; 38% reduced psychotropic and muscle relaxants, 46% reduced analgesic, anti-convulsant and non-steroidal anti-inflammatory drugs, and 48% reduced opioid medication.

Reductions in chronic pain medication intake

38%

46%

48%

psychotropic and muscle relaxants

analgesic, anticonvulsant and non-steroidal antiinflammatory drugs

opioid medication

Timothy Deer

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January 2022 | Issue 44

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Patient assent and lack of evidence among key ethical concerns identified in paediatric deep brain stimulation for OCD A study intended to gain insight into prevailing ethical issues surrounding the use of deep brain stimulation (DBS) in adolescents with obsessive-compulsive disorder (OCD) has found that concerns relating to the conditions of patient decisionmaking, a lack of evidence on the outcomes and potential unknown effects of DBS in this patient population, and the importance of exhausting other treatment options before considering DBS, all featured prominently.

THIS STUDY, WHICH INVOLVED conducting semi-structured interviews with 25 clinicians to discuss DBS use in adolescent OCD patients, is published in Brain Stimulation by Gabriel LázaroMuñoz, an assistant professor in the Center for Bioethics at Harvard Medical School in Boston, USA, and colleagues.

“We identified OCD clinicians’ perspectives about the most pressing ethical issues when considering DBS for adolescents with OCD and examined considerations that appear to be exacerbated when using paediatric DBS for psychiatric, compared to movement, disorders,” LázaroMuñoz et al write in their report. “To better understand the ethical and policy implications of the translation of DBS for OCD, further biomedical research and ethical examination of these pressing issues are needed.

Particular attention should be paid to the effective development and implementation of DAs [decision aids] for paediatric DBS, clinician participation in

data registries to expand the evidence base, and the establishment of clear guidelines for patient selection.”

The authors note that refractory OCD among adults was the first psychiatric indication of DBS to receive a US Food and Drug Administration (FDA) Humanitarian Device Exemption (HDE), and that—given this approval and the encouraging evidence that has since emerged—exploration of DBS for OCD may be expanded to adolescents in the future. There is already a precedent for the transition of DBS in adults to children in the case of dystonia, they add, but temper this by stating that the risk-benefit analysis of paediatric DBS for OCD may be more complex and raises different ethical questions to paediatric DBS for dystonia.

As such, Lázaro-Muñoz and colleagues set about investigating these ethical issues via semi-structured interviews with a total of 25 clinicians specialising in child and adolescent OCD, all of whom were trained in and had experience treating minors with refractory OCD. In their report, the authors also note that they sought to ensure these clinicians represented a range of clinical backgrounds—including psychiatrists, psychologists, and licensed professional counsellors—and that the sample consisted of clinicians practising in various US regions.

These interviews, which were an average of 50 minutes in length, were transcribed verbatim, coded with MAXQDA 2018 software, and subsequently analysed using thematic, qualitative content analysis in order to identify emergent themes. According

to Lázaro-Muñoz et al, this analysis of the clinicians’ responses identified five pressing ethical issues: ■ Conditions of decision-making, such as adolescents’ capacity to assent (noted by 80% of clinicians) ■ Evidence, unknowns, and risk-benefit analysis, including the lack of robust clinical trials and potential effects on brain development (68%) ■ Bias, undue influence and conflicts of interest that could potentially affect patient referral for paediatric DBS (28%) ■ Access to paediatric DBS—specifically financial and geographical barriers (24%) ■ Refractory status and exhaustion of other treatments prior to considering paediatric DBS (20%) The authors also note that two of these five concerns—those relating to bias, undue influence and conflicts of interest, and to patient access—were highlighted as being relevant to both paediatric and adult DBS, while the remaining three were seen as being exacerbated in the paediatric DBS setting. In addition, when the clinicians were asked whether paediatric DBS therapy for psychiatric disorders raises different concerns to paediatric DBS for movement disorders, 44% described differences, 40% described both similarities and differences, and four clinicians (16%) maintained there were no differences.

As well as stating that “we need to be attentive to the ethical challenges that may emerge, and be prepared to take action to help ensure the wellbeing of children and adolescents” as this indication for DBS continues to be expanded, Lázaro-Muñoz et al conclude that strategies to address these concerns include implementation of validated decision support tools and further research into the outcomes of paediatric DBS for OCD to help establish clear guidelines for patient selection.

Gabriel Lázaro-Muñoz

Issue 44 | January 2022

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Research shows brain rhythm changes occur within minutes of DBS surgery for depression

Image credit: Mount Sinai Health System

New research published in Translational Psychiatry presents evidence that brief intraoperative exposure to therapeutic deep brain stimulation (DBS) at the time of implantation surgery induces rapid and consistent electrophysiological brain state changes within minutes—shedding light on the mechanism of action by which DBS is able to ease depressive symptoms and, potentially, paving the way for this therapeutic approach to treatmentresistant depression to be enhanced in the future.

T

hese intraoperative brain state changes—which were indexed by a decrease in beta power, measured at the site of stimulation, in a study—are seen in individual subjects and are correlated with a significant and sustained decrease in depressive symptoms outside of the operating room without additional stimulation. As such, this research may help to establish beta power reduction as a novel biomarker for DBS treatment optimisation.

This is according to data from a collaborative study at Emory University in Atlanta, USA and the Icahn School of Medicine at Mount Sinai in New York City, USA led by Helen Mayberg (Icahn School of Medicine at Mount Sinai, New York, USA). The research is part of an ongoing National Institutes of Health (NIH) BRAIN Initiative-funded grant.

“We generally think of depression treatment as taking weeks or months to show stable and meaningful changes

Single-patient study offers promise for individualised depression treatment

in core clinical features of the illness,” approach further, and inform the design said Mayberg. “This study shows of future studies. reproducible and consistent changes in “What we found was that, within a brain readout over the first minutes minutes of stimulation inside the of optimised stimulation in the operating room, there operating room in individual was a change in the beta patients. This provides new brain rhythm,” said the mechanistic understanding of Translational Psychiatry the ‘depression switch’ that report’s co-first author Allison moves a patient from a state Waters (Icahn School of of sustained mental pain and Medicine at Mount Sinai, New Helen Mayberg York, USA). “Patients who immobility to relief, and the renewed capacity to move and showed larger changes then engage.” experienced greater relief from DBS of the subcallosal their depression in the week cingulate (SCC; Area 25) has after surgery.” been repeatedly demonstrated “This research provides as a promising intervention individuals who have struggled for patients suffering from with depression a sense of treatment-resistant depression hope through advancements Allison Waters by reliably eliciting acute in existing technology,” said behavioural changes and longJohn Ngai, director of the term antidepressant responses. However, NIH BRAIN Initiative. “We are making the exact means by which it achieves immense strides in better understanding this is not known for certain—leading debilitating brain and mental health researchers to hunt objective biomarkers conditions through these discoveries, linked to DBS treatment efficacy in and look forward to seeing how DBS order to optimise this experimental will continue to improve people’s lives.”

Despite its small sample size, a study in which a patient received closed-loop, deep brain stimulation (DBS) therapy has demonstrated positive clinical outcomes and indicates the potential held by individualised, biomarker-driven neuromodulation for treatment-resistant depression. This is according to a study report authored by Katherine Scangos (Weill Institute for Neurosciences/ Department of Psychiatry, University of California, San Francisco, USA) and colleagues, and published in Nature Medicine.

adaptation, preserves battery life and reduces sideeffects. However, they continue, closed-loop therapy requires a symptom-specific biomarker that is yet to be identified in patients with major depression.

In their report, they recount a study involving one 36-year-old female patient with severe, treatmentresistant depression in whom a biomarker of major depressive symptoms was identified during a 10-day period of intracranial corticolimbic circuitry mapping using sEEG electrodes (PMT Corporation). Following this, the researchers successfully implemented the biomarker when unilaterally implanting the US Food and Drug Administration (FDA)-approved RNS system (NeuroPace) in the patient’s right hemisphere, and delivered closed-loop neuromodulation therapy over several months.

Scangos and colleagues report that implementation of closed-loop therapy rapidly improved both symptom severity—which was measured daily with the Sixitem Hamilton depression rating scale (HAMD-6) and the visual analogue scale (VAS)—and depression (periodic Montgomery-Åsberg depression rating scale [MADRS]). The patient’s MADRS score decreased from 33 prior to turning on the treatment to 14 at the first during-treatment assessment carried out after 12 days of stimulation, and dropped below 10 (remission) several months later. Similarly, her HAMD-6 and visual analogue scale-depression (VAS-D) scores dropped precipitously the morning after stimulation started, and were lower the week after stimulation was turned on

SCANGOS ET AL BEGIN THEIR REPORT BY noting that DBS is a promising treatment option for neuropsychiatric conditions like major depression and that, due to the complex, underlying neural circuits associated with depressive symptoms, personalised approaches may help to optimise this DBS indication further. They also note that personalisation can be achieved by temporally controlling stimulation—as in closed-loop neuromodulation, whereby a patient’s own physiological activity is used to selectively trigger stimulation only when a certain pathological state is detected.

In addition to this potential for improved success rates in treating depression, they state that closed-loop stimulation also mitigates concerns surrounding neural

The new framework presented in this article could advance biomarker-based neural interfaces, and enhance the mechanistic understanding and treatment of a broad range of neuropsychiatric conditions.” Scangos et al

compared to the previous week, the authors add.

To evaluate whether their algorithm triggered stimulus delivery linked to patient symptoms, and not randomly, the researchers used dynamic time warping (DTW) to nonlinearly align daily symptom severity (VAS-D) and biomarker detection count time traces over two months, and calculated their relative post-alignment distance.

They found that fluctuation in daily symptoms was significantly associated with fluctuation in the number of device-detected biomarker events—suggesting their biomarker detection algorithm was far better at detecting symptom severity changes than random chance.

“In conclusion, we show the successful development of a personalised biomarker of depression-specific symptoms and implementation of closed-loop therapy for MDD [major depressive disorder],” Scangos et al write. “Success was predicated on a clinical mapping stage before chronic device placement, a strategy that has been utilised in epilepsy to map seizure foci in a personalised manner but has not previously been performed in other neuropsychiatric conditions. During this stage, we developed a comprehensive, multimodal framework for selection of sensing and stimulation brain targets. Our approach included personalised stimulusresponse mapping, pairing of resting-state signals with clinical symptom measures, and identification of functionally and structurally connected subnetworks across the corticolimbic network.”

The authors note that their research cannot evaluate if this specific biomarker of depression is present in all patients, and go on to acknowledge limitations of the study including its small sample size—which makes it hard to know whether these results will generalise—and the fact clinicians were not always blinded to stimulation location or parameters. However, they add that “the intent of this study was not to address the efficacy of closed-loop neuromodulation for MDD, which would require a double-blind, randomised controlled, adequately powered study”.

“In this study, we established proof-of-concept for a new, powerful treatment approach for neuropsychiatric disorders,” they conclude. “The new framework presented in this article could advance biomarkerbased neural interfaces, and enhance the mechanistic understanding and treatment of a broad range of neuropsychiatric conditions.”

January 2022 | Issue 44

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Multiple daily doses of iTBS provide no additional benefit in treatmentresistant depression In patients with treatment-resistant depression (TRD), multiple sessions of intermittent theta-burst stimulation (iTBS) do not accelerate responses to the therapy, nor do they improve depressive symptoms. This is the key finding of the CARTBIND (Canadian rTMS treatment and biomarker network in depression) study—a randomised, sham-controlled comparison of once- versus twice-daily iTBS for depression published in the journal Brain Stimulation.

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he study, authored by Daniel Blumberger (Department of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada) and colleagues, highlights the urgent need for more scalable and tolerable treatment methods for patients suffering from TRD. The authors write that repetitive transcranial magnetic stimulation (rTMS) is an established, evidence-based treatment for TRD, but that iTBS can be administered in one tenth of the time of rTMS (~3 minutes vs. 37.5 minutes) yet achieves similar or greater effects on neural plasticity and depressive symptoms. Therefore, Blumberger et al set out to investigate the impact of multiple iTBS sessions per day in patients with TRD. Patients were recruited from across three Canadian academic health sciences centres—the Centre for Addiction and Mental Health and the University Health Network, both of which are affiliated with the University of Toronto, and the University of British Columbia Hospital—between April 2016 and February 2018. To be eligible, participants had to fall between the ages of 18 and 59 years, and have a confirmed diagnosis of major depressive disorder. Additionally, patients had to meet the following criteria: failed to achieve a clinical response to an adequate dose of an antidepressant based on an antidepressant treatment history form (ATHF) score ≥3 in the current episode or were unable to tolerate two separate trials of inadequate dose and duration; had a score ≥18 on the Hamilton depression rating scale (HRSD-17); had no increase or initiation of any psychotropic medication in the four weeks prior to screening; were able to adhere to the schedule; passed the adult safety screening (TASS) questionnaire, and had

Study indicates safety and efficacy of remote electrical neuromodulation in chronic migraine The publication of a new study in Pain Reports, detailing the assessment of a novel, drug-free treatment option for chronic migraine, indicates it is a safe and efficacious therapy option. The prospective, multicentre, open-label trial evaluated remote electrical neuromodulation (REN) with Nerivio (Theranica)—a smartphonecontrolled, prescribed wearable device for the acute treatment of migraine.

RESULTS FROM THE STUDY’S 99 CHRONIC migraine participants demonstrated favourable efficacy of REN, with nearly 60% of the participants experiencing pain relief at two hours after the treatment and close to 65% of those experiencing sustained pain relief even 24 hours post-treatment, according to a Theranica press release. More than 20% of the participants experienced disappearance of their headache

normal thyroid functioning based on pre-study blood work.

The primary outcome measure was changes in HRSD-17, from baseline to day 10 of treatment, with the secondary outcome measure being the change from baseline to day 30 of treatment. In this study, remission

HSRD-17 scores at 10 days Once-daily treatment resulted in:

Twice-daily treatment resulted in:

-6.66

-6.46

points

points

was defined as an HRSD-17 score of less than eight and the response was defined as a decrease in HRSD17 score of 50% or less. These outcome measures were analysed at both day 10 and day 30 of treatment.

Blumberger et al assessed a total of 265 patients, of which 208 were eligible for the study. These patients (pain freedom) at two hours post-treatment as well.

Additionally, post two-hour improvement in nausea, photophobia, phonophobia and functional ability were demonstrated. Only one of the 99 participants (1%) reported a mild, local device-related adverse event— which was independently resolved shortly after the treatment.

“Chronic migraine is characterised by headaches experienced on at least 15 days per month,” said Brian Grosberg (Hartford Healthcare Headache Center, West Hartford, USA), who served as the study’s primary investigator.

“People with chronic migraine not only have a higher frequency of migraine attacks, but their attacks tend to be more severe than episodic migraine patients.

They typically need to take more medications, usually cocktails of preventive and acute medications.

“The challenge is to relieve the migraine symptoms while avoiding the risk of medication overuse headache (MOH) and other complications. Non-pharmacological interventions, such as REN, help meet this need by providing a drug-free treatment option. As a clinically validated, non-pharmacological acute treatment option for people with migraine, Nerivio is an excellent fit for fulfilling this need.”

Worn on the upper arm at the onset of a migraine attack, Nerivio alleviates migraine symptoms without the need for medications by utilising REN to trigger an endogenous analgesic mechanism, known as conditioned

were randomised to either receive once-daily iTBS with one sham treatment (n=105; control, one-time 1200 pulses daily group) or twice-daily iTBS (n=103; accelerated, two-time 600 pulses daily group). In the once-daily group (60% female) and twice-daily group (66% female), the average ages were 41.2±11.5 years and 40.7±11.1 years, respectively. The age of depression onset was earlier in the twice-daily group at 20.7±10.5 years compared to 21.9±10.2 years in the once-daily group. Additionally, the baseline HRSD-17 was 23.2±4.0 in the twice-daily group and 23.1±3.8 in the once-daily group.

A total of 198 participants completed the treatment on day 10, with 185 completing six weeks of treatment. At one, four and 12 weeks, 175, 157, and 141 participants received follow-up, respectively. The results revealed no significant difference in changes in the HRSD-17 scores from baseline to day 10 between the two groups (p=0.84)—however, a significant difference was seen in both the twice-daily (estimated adjusted difference -6.46 points, p<0.001) and once-daily (estimated adjusted difference -6.66 points, p<0.001) groups individually.

Furthermore, there were no significant differences in changes in HRSD-17 between the groups from baseline to day 30 (p<0.001), although a significant change in HRSD-17 scores from baseline to day 30 for both the twice-daily group (estimated adjusted difference -10.52 points, p<0.001) and the one-daily group (estimated adjusted difference -9.05 points, p<0.001) was observed.

The authors note that there are several limitations to this study that may have affected the outcomes. The 30day length of treatment may have led to an expectancy effect and negatively biased early treatment effects, while the doubling of sessions resulted in prompting for—and as such potential over-reporting of—sideeffects, Blumberger et al write.

The authors conclude that, while it is important to consider patient expectations in comparisons of brain stimulation techniques such as this, remission and responses rates did not differ between the two study groups, and an acceleration in response was not observed when controlling for number of pulses and operator contact. As such, the study’s concluding findings ultimately stress that doubling sessions of iTBS does not yield a more rapid reduction in depressive symptoms, nor does it lead to improved outcomes in TRD patients. pain modulation (CPM). The device is controlled by a smartphone app, allowing the patient to set the intensity of their treatment.

Nerivio has received US Food and Drug Administration (FDA) authorisation and a CE mark for the use of this technology in acute treatment of episodic and chronic migraine in adult and adolescent patients, and, the release adds, already serves close to 25,000 people with migraine in the USA.

The challenge is to relieve migraine symptoms while avoiding the risk of medication overuse headache and other complications.

Non-pharmacological interventions, such as REN, help meet this need by providing a drug-free treatment option.”

Brian Grosberg

Issue 44 | January 2022

Market Watch 25 pivotal study, published in The Lancet, Vivistim users showed statistically significant improvements in upper-limb impairment and function as compared to intense rehabilitation therapy. The study achieved its FDA-specified primary and secondary endpoints, and quality of life data showed 65% of patients reporting clinically significant improvements in their ability to perform activities of daily living as well.

Product News Boston Scientific launches FAST therapy in spinal cord stimulation

Boston Scientific has announced the European launch of FAST (Fastacting sub-perception therapy) for its WaveWriter Alpha spinal cord stimulation (SCS) systems—which are indicated as an aid in the management of chronic intractable pain.

FAST has been clinically proven to demonstrate rapid, significant and sustained pain relief. It generates rapid analgesia by precisely targeting the axons that engage a surround-inhibition effect—a new proposed mechanism of action for SCS. While traditional paraesthesia-free therapy can take up to a few days to achieve pain relief, FAST is designed to allow patients to experience paraesthesia-free pain relief in minutes.

“FAST is a clear advancement in helping patients find pain relief,” said Jarek Maciaczyk (Rheinische FriedrichWilhelms-Universität Bonn, Bonn, Germany). “Typically, we had to wait a few days to assess the full impact of SCS, but with the targeting and stimulation parameters of FAST we can provide paraesthesia-free pain relief within minutes, which helps to evaluate the impact of the treatment in a much shorter timeframe and gives the patients back quality of life almost instantly.”

Biomodex launches synthetic clot product for neurovascular training

Biomodex has announced the launch of Thrombotech—a new, hydrogel-based synthetic clot product that can be used for neurovascular training with the company’s Evias Plus training solution in the treatment of ischaemic stroke.

Thrombotech is designed to mimic the density and texture of an actual human blood clot, and is available in three textures that mimic real clots: soft (red blood cell-rich clots), medium (red blood cell/fibrin clots), and hard (fibrin-rich clots). It can be inserted into a Biomodex 3D-printed blood vessel

Medtronic receives CE mark approval for radial artery access portfolio Vivistim system

cartridge that plugs into the Evias Plus station.

Physicians can then practice retrieving the clot using aspiration and mechanical thrombectomy techniques, with a distal clot filter allowing them to see if this has been achieved effectively.

Biomodex debuted Thrombotech at the Congress of Neurological Surgeons (CNS) annual meeting (16–20 October 2021, Austin, USA).

MicroTransponder gains FDA approval for vagus nerve stimulation system to improve stroke rehabilitation

MicroTransponder has received US Food and Drug Administration (FDA) premarket approval for the Vivistim paired vagus nerve stimulation (VNS) system, which is designed to improve the effectiveness of rehabilitation therapy for stroke survivors with moderate-tosevere upper extremity impairment six months after stroke.

The Vivistim system couples VNS with rehabilitation therapy to help improve stroke-related arm and hand deficits. More specifically, it delivers gentle electrical pulses and strengthens neural connections during standard rehabilitation exercises—making this inclinic therapy more effective, according to preclinical data.

Vivistim can also be activated by the user at home during rehabilitation exercises or activities of daily living they wish to improve.

In the 108-subject VNS-REHAB

Medtronic has received CE mark approval for its radial artery access portfolio, which includes the Rist radial access selective catheter and the Rist 079 radial access guide catheter—a device specifically designed for accessing the neurovasculature to treat stroke, brain aneurysms, and other conditions, through the radial artery versus access through the transfemoral artery.

The Rist 079 radial access guide catheter is 510(k) cleared by US Food and Drug Administration (FDA) and has been in use at limited sites in the USA. “With excellent navigability, this first-of-its-kind device will allow clinicians to reach distal locations while still achieving excellent stability to the system,” said Alejandro Tomasello (Vall d’Hebron Hospital, Barcelona, Spain).

“The radial artery access portfolio works well in tandem with Phenom PLUS, Phenom 021 microcatheter for stent deployment or Phenom 027 microcatheter for flow diverter deployment, which is a fantastic setup for the Pipeline Vantage embolisation device with Shield technology treatments [all Medtronic].”

Insightec announces FDA approval of Exablate Neuro device to treat Parkinson’s disease

Insightec has announced that the US Food and Drug Administration (FDA) has approved the Exablate Neuro device for treating advanced Parkinson’s disease patients suffering from mobility, rigidity or dyskinesia symptoms.

Exablate Neuro uses focused ultrasound waves to precisely target and ablate the globus pallidus internus

(GPi) during a pallidotomy. The surgical treatment is incisionless, does not require brain implants, and is designed to carry a lower risk of infection than invasive surgery. It is intended for use in cases where medication has induced side-effects or not been well-tolerated.

“This approval is significant in that it adds focused ultrasound as an incisionless surgical option to treat motor symptoms of Parkinson’s disease,” said Howard Eisenberg (University of Maryland, Baltimore, USA).

Evasc Neurovascular announces new generation of eClips bifurcation flow diverter

Evasc Neurovascular has announced the third generation of its eClips device—a flow diverter designed to provide more effective treatment of intracranial bifurcation aneurysms and therapy options for a wider range of aneurysms, with simplified deployment and shorter delivery times.

The new device is classified as a flow diverter with a leaf density of 35%, which is 60% higher than the existing eClips devices. As a result, the eClips bifurcation device does not require coiling. It can also cover a neck length of up to 6mm.

eClips bifurcation flow diverter

“We are excited to see the latest innovation in Evasc Neurovascular’s eClips devices, which will lead to better outcomes for patients and remarkable device delivery time—usually within 10 minutes,” said Leif Sørensen (Aarhus University Hospital, Aarhus, Denmark).

This newest generation of eClips is intended for more effective treatment of intracranial bifurcation aneurysms with a shapeable delivery wire, a smaller size that is compatible with 0.021inch- and 0.027-inch-inner diameter (ID) microcatheters, and electrolytic detachment, according to Evasc Neurovascular.

Third Annual Sun Valley Stroke Conference

Register Now

Evolving Paradigms for Stroke Care

March 10-13, 2022

A conference for medical providers involved in stroke treatment and research.

Presented by St. Luke’s Neurosciences in partnership with the University of Tennessee Health Science Center and the University of California San Diego School of Medicine

Featuring Recognized Stroke Experts Edward Duckworth, MD | John Perl II, MD | Dan Abenroth, MD | Alexander Khalessi, MD, MBA Andrei Alexandrov, MD | Adam Arthur, MD | Lucas Elijovich, MD | Anne Alexandrov, PhD Brian Jankowitz, MD | Ajay Wakhloo, MD | Robert Spetzler, MD

Third Annual Sun Valley Stroke Conference Sun Valley, Idaho, United States Register online at stlukesonline.org/svsc For more information, email: SVSC@slhs.org

January 2022 | Issue 44

26 Market Watch

Clinical News Robocath successfully performs first carotid stenting in France with R-One robot

Robocath has announced its successful first robotic carotid stenting procedure at Rennes University Hospital. This breakthrough in the neurovascular field was performed on 16 November 2021 using Robocath’s R-One robot, operated

by François Eugène (Rennes University Hospital, Rennes, France) and his team.

The procedure was part of a clinical study—which is the first stage of a research programme launched in July 2021 by Robocath and Rennes University Hospital in partnership with Philips France. The study aims to enrich current and future generations of robotic platforms with the long-term view of improving the treatment of cerebrovascular incidents.

“I am honoured to be one of the first operators in the world working in neurovascular robotics,” said Eugène.

“Until now, there were no clinical investigations in Europe in this area, despite all its potential benefits. Every year, 5.5 million people around the world die from a stroke, and one in two stroke victims live with lifelong consequences.

The reason for this is a lack of comprehensive health coverage, due to a shortage of qualified operators and hospitals capable of performing this type of procedure. Strokes must be treated quickly but also with extreme precision.

“Robotics can operate with millimetre accuracy and offer new possibilities in terms of movement, as well as bringing more comfortable working conditions.

In time, I am sure that robotic assistance will provide the population with optimal stroke treatment and equality of access to care in France, as well as in other countries facing the same public health issues.”

NeuroPace gains FDA nod to launch pivotal study of idiopathic generalised epilepsy treatment

NeuroPace has announced receipt of investigational device exemption (IDE) approval from the US Food and Drug Administration (FDA) to initiate the NAUTILUS pivotal study—which will assess the company’s RNS (responsive neurostimulation) system in treating patients with drug-resistant idiopathic generalised epilepsy.

The prospective, single-blinded, multicentre, randomised trial is projected to start enrolling patients in 2022.

This IDE approval follows news from March 2021 that NeuroPace had received Breakthrough Device designation status from the FDA for the potential use of its RNS system to treat idiopathic generalised epilepsy.

The system delivers personalised, targeted treatment at the seizure source in patients with drug-resistant focal

RNS neurostimulator

epilepsy and, because it is a closedloop technology, can also monitor and respond to a patient’s unique brain patterns to administer realtime therapy—ideally before clinical symptoms occur.

Brainomix announces new study demonstrating benefits of e-Stroke software

Brainomix has announced the findings of a new study in which implementation of the company’s e-Stroke software resulted in faster treatment times and enabled more stroke patients to achieve functional independence. These results were presented at the 13th World Stroke Congress (WSC; 28–29 October 2021, virtual) by Kiruba Nagaratnam (Royal Berkshire Hospital, Reading, UK).

To assess the impact of e-Stroke on the mechanical thrombectomy referral pathway, and its capacity to facilitate faster diagnoses and decision-making, Nagaratnam compared data from patients referred for a thrombectomy procedure before e-Stroke was introduced in the Royal Berkshire Hospital in March 2020 to those admitted after this time.

This comparison revealed a significant reduction in overall door-in-doorout time, from 140 minutes down to 79 minutes—an improvement of more than one hour—and found that 48% of patients achieved functional independence (modified Rankin Scale [mRS] score of 0–2) following the adoption of e-Stroke, compared with 16% prior to implementation.

“After the introduction of the Brainomix system, a higher percentage of patients achieved functional independence—something we attribute mainly to the reduction in door-indoor-out time, as the AI [artificial intelligence] system helped our stroke team identify large vessel occlusions faster, thus enabling the referral and transfer process to be initiated sooner,” said Nagaratnam. “Overall, Brainomix’s software has allowed us to deliver a more efficient pathway, make faster treatment decisions and achieve better outcomes for our patients.”

Imperative Care enrols first patient in trial evaluating Zoom 88 large distal platform Imperative Care has announced that the first patient has been enrolled in the prospective, multicentre Imperative trial.

Overall, the study will enrol 262 patients at up to 30 US sites, and includes

investigators from several ischaemic stroke care specialities—including neurosurgery, interventional radiology and interventional neurology.

It intends to evaluate the clinical benefits of direct aspiration for the treatment of ischaemic stroke with the Zoom 88 large distal platform—a 0.088inch, large-bore intracranial aspiration catheter technology that is currently US Food and Drug Administration (FDA)cleared for neurovascular access.

Additionally, the trial will gather data on the clinical benefits of the full Zoom stroke solution, the company’s ischaemic stroke product portfolio, which includes the Zoom 88 large distal platform, four Zoom aspiration catheters in various sizes, and a pump with accessories.

“This trial will help neurointerventionists better understand the impact of large-bore aspiration, particularly in regard to first pass effect and procedure time,” said Maxim Mokin (University of South Florida, Tampa, USA), who performed the first case in the Imperative trial.

The case report is published in the Journal of NeuroInterventional Surgery (JNIS) and was authored in collaboration with Pedro Lylyk (Clínica La Sagrada Familia, Buenos Aires, Argentina), who is conducting this firstin-human study of the eShunt system at his centre. The ongoing clinical trial, ETCHES I, is evaluating the device as a treatment for CH with additional study data set to be available in 2022.

“We are very pleased to have JNIS publish the first patient case report,” said Adel Malek (Tufts Medical Center, Boston, USA), who co-authored the report and is also the co-founder of CereVasc. “The details and outcome of this case are encouraging signs about the potential of the eShunt system to address a common neurological condition with a long history of poor treatment options.”

The eShunt device represents a minimally invasive treatment for CH and is intended to offer the potential for significant benefits over current treatment options regarding failure rates, infection risks, and associated costs.

Rapid Medical to initiate trial expanding thrombectomy treatment across distal regions of the brain

Wyss Center, Inselspital Bern announce clinical trial of long-term brain monitoring technology

Rapid Medical has announced US Brain signal recording with the Wyss Food and Drug Administration (FDA) Center for Bio and Neuroengineering’s investigational device exemption (IDE) novel brain monitoring technology is approval for what it claims is the first being carried out for the first time in ever trial to expand interventional stroke patients as part of a clinical trial at the treatment to distal regions of the brain.

University Hospital Bern, Inselspital in The DISTALS study, which Rapid Bern, Switzerland.

Medical plans to initiate either in The first-in-human study represents a Q4 2021 or early in Q1 2022, is a step towards the validation of Epios—a pivotal, international, multicentre, minimally invasive, long-term brain randomised controlled trial evaluating monitoring system intended for people the safety and effectiveness of distal with drug-resistant epilepsy. It will thrombectomy with the company’s look to assess the feasibility, safety, Tigertriever 13 device. and electroencephalographic (EEG) While this device has already been recording ability, of the Epios subscalp used to treat nearly 1,500 patients sensing electrodes, and test the tools in Europe and the Middle East, the developed to insert the leads based on DISTALS study aims to extend its usage required locations and patient-specific to a greater range of ischaemic stroke anatomy. patients by focusing on far territories “People with epilepsy often do in the brain, such as M3 blood vessels, not remember having a seizure, and allowing intervention within 24 which can undermine treatment hours of symptom onset. optimisation,” said Maxime Baud “We are especially pleased to receive (Inselspital, Bern, Switzerland). unprecedented FDA IDE approval “Monitoring brain activity can give for a study with DISTALS focus,” an accurate seizure count, but the said the study’s principal investigator standard tool for monitoring brain Jeffrey Saver (University of California waves—electroencephalography Los Angeles, Los Angeles, USA). caps—cannot be used beyond two “With the ever-growing benefits of weeks in the hospital. Epios fills mechanical thrombectomy, we this unmet need for long-term hope to offer better recoveries to a Tigertriever brain monitoring in everyday much broader patient population.

13 device life.”

Rapid Medical has been at the This study is already forefront of enabling that progress.” underway and is expected to continue until the end of September 2022, CereVasc announces with further clinical trials of the publication of first-in-human full Epios system being planned. In case report with eShunt September 2021, the Wyss Center also system announced CE mark Class I medical CereVasc has announced the publication device approval for its Epios Cloud of a case report detailing the first software—a web-based application treatment in a study of its eShunt for the online storage, processing and system—an investigational device review of neural signals, including ultraintended to treat communicating long-term data recorded by emerging hydrocephalus (CH). remote brain monitoring devices.

Issue 44 | January 2022

Market Watch 27

Medtronic recalls Pipeline Flex embolisation devices over risk of delivery system fractures

Industry News North Carolina updates stroke triage and transport protocol

North Carolina has updated its emergency stroke care protocol—a move applauded by the Get Ahead of Stroke campaign. The protocol, which went into effect on 15 October 2021, will change the way first responders triage and transport severe stroke patients across the US state, and aims to reduce death and disability by improving timely access to minimally invasive mechanical thrombectomy procedures.

The updated protocol advises emergency medical services to utilise a stroke severity tool and score when conducting initial assessments of a stroke patient, and recommends transporting them directly to a Level 1 stroke centre if a high likelihood of large vessel occlusion (LVO) is found.

Prior to this update, North Carolina did not have specific guidance in place to help ensure these particular patients were triaged and transported to a Level 1 stroke centre for treatment.

The Get Ahead of Stroke campaign is currently supporting similar protocol changes in the states of Massachusetts,

Michigan and Pennsylvania as well.

Nevro announces plans to appeal jury decision in spinal cord stimulation case Nevro Corporation has provided an update on its position following a Delaware jury’s decision to award Boston Scientific US$20 million over patent infringements.

The jury found that Nevro infringed two Boston Scientific patents (7,891,085 and 8,019,439) directed to ways of manufacturing spinal cord stimulation (SCS) leads, which Nevro obtains from a third-party supplier, according to a press release from the company.

“We disagree with the finding by the jury and plan to appeal,” said Kashif Rashid, Nevro’s general counsel.

Two other Boston Scientific lead patents (8,646,172 and 8,650,747) were not infringed, the jury also determined.

The Nevro press release states: “This decision has no commercial implications or would otherwise impose any restrictions on any current or future Nevro products, and the jury award is an amount of money that will not have a material impact on Nevro’s business.”

Calendar of events 13–15 January North American Neuromodulation Society (NANS) Annual Meeting Orlando, USA conference.neuromodulation.org

9–11 February International Stroke Conference (ISC) New Orleans, USA professional.heart.org/en/meetings/ international-stroke-conference

Medtronic has issued a recall of its Pipeline Flex embolisation device and Pipeline Flex embolisation device with Shield technology products due to a risk of the delivery system’s wire and tubes fracturing and breaking off during placement, retrieval, or movement, of the stent inside a patient.

According to a statement from the US Food and Drug Administration (FDA), the recall of these devices is limited to the Pipeline Flex embolisation device in the USA—with a total of 8,825 devices being recalled. Outside the USA, however, the recall applies to both the Pipeline Flex embolisation device and the Pipeline Flex embolisation device with Shield technology, which gained FDA approval in April 2021.

The FDA has identified this as a Class I recall—the most serious type of recall—as use of these devices may cause serious injuries or death.

There have been 59 reported device malfunctions, 10 serious injuries and two deaths related to this recall to date.

Detailing the recall further, the FDA states that fractured pieces of the Pipeline Flex embolisation device’s delivery system could be left inside the patient’s brain bloodstream, potentially causing continued blockage of blood

vessels, stroke, or death, and it is possible that attempts to retrieve the fractured pieces may make the patient’s condition worse.

Magnus Medical raises US$25 million in Series A financing for novel depression treatment

Magnus Medical has raised US$25 million via a Series A financing round co-led by JAZZ Venture Partners and Red Tree Venture Capital.

In addition, the company has announced receipt of Breakthrough Device designation from the US Food and Drug Administration (FDA) for its individualised, rapid-acting, noninvasive neurostimulation technology designed to treat major depressive disorder in people who have not improved sufficiently following antidepressant medication or other treatments.

The results from a recent randomised controlled trial assessing Stanford accelerated intelligent neuromodulation therapy (SAINT)—the technology Magnus’ system is based on—were evaluated by the FDA as part of the criteria for granting this Breakthrough Device designation.

SAINT was developed at Stanford University in Stanford, USA and has been licensed exclusively to Magnus for commercialisation.

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.

28 February–4 March European Stroke Course in Minimally Invasive Neurological Therapy (EXMINT 4.2) Virtual www.esmint.eu/training-education/exmint

2–7 April American Academy of Neurology (AAN) Annual Meeting Seattle, USA www.aan.com/events/annual-meeting

11–13 April World AVM Congress New York City, USA https://avm2022.org

26–28 April Charing Cross (CX) Symposium London, UK www.cxsymposium.com/cx2022

29 April–2 May American Association of Neurological Surgeons (AANS) Annual Scientific Meeting Philadelphia, USA www.aans.org/meetings

4–6 May European Stroke Organisation Conference (ESOC) Lyon, France

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

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

eso-stroke.org/meetings/eso-conference-2022

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