NeuroNews Issue 39 - September 2020

September 2020 | Issue 39

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Featured in this issue:

Thomas Oxley Endovascular brain-computer interfaces

Trends after unruptured aneurysm treatment page 7

from

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2006

2016

Two new studies presented at the Society of NeuroInterventional Surgery (SNIS) 17th annual meeting (4–7 August), which was held virtually this year, have described outcomerelated racial disparities among patients who experience strokes.

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terms of good discharge modified Rankin Scale (mRS) score (p=0.27). For mRS 0–2, there was no significant difference noted (14.8% vs. 16.7%),” he reported. However, symptomatic intracranial haemorrhage (sICH) was significantly higher for African Americans (11.1% vs. 3%, p<0.001), and mortality was significantly higher in African Americans compared to other races (51.9% vs.

28.6%, p=0.03).

In terms of comorbidities, Dmytriw stated that diabetes was significantly higher in African American cases versus others (37% vs. 66.7%).

However, regarding smoking, atrial fibrillation, prior anticoagulation, coronary artery disease, congestive heart failure, hypertension, Adam Dmytriw hyperlipidemia,

Dorsal root ganglion stimulation evokes motor responses in patients with complete spinal cord injury Bilateral L4 dorsal root ganglion (DRG) stimulation has been shown to evoke strong and reproducible motor responses in the upper leg in patients with chronic motor complete spinal cord injury (SCI). In their paper published in Neuromodulation, authors Sadaf Soloukey and colleagues from Erasmus MC, Rotterdam, The Netherlands, refer to their study as the “first of its kind” to demonstrate the potential of the DRG as a new target for reproducible and potentially weight-bearing muscle recruitment in this particular cohort of patients.

THE TEAM IN ROTTERDAM write that current strategies for motor recovery after SCI aim to facilitate motor performance through modulation

of afferent (=sensory) input to the spinal cord using epidural electrical stimulation (EES). However, while the DRG itself represents the first relay

to

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New studies shed light on racial disparities in stroke outcomes, including COVID-19 patients he first study from the North American Neurovascular COVID-19 (NAN-C) Consortium, presented by Adam Dmytriw of Harvard University (Boston, USA), specifically examined stroke patients with COVID-19. He told the online audience that mortality rates in African American stroke patients with COVID-19 were significantly higher than all other races combined in North America among the hospitals participating. Additionally, he said the study showed that the mortality rate of COVID-19–positive stroke patients was greater than previously reported in patients with COVID-19 or stroke alone.

The investigators analysed 69 cases of acute stroke in patients positive for SARS-CoV-2, including 27 African American patients and 42 patients of other backgrounds, including Caucasian, Hispanic and Asian. “All patients presented to 14 major hospitals in the USA and Canada, from 14 March–14 April 14, 2020,” stated Dmytriw.

“Regarding stroke functional outcomes, there was no difference between African Americans and other races in

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Overall rate of in-hospital mortality decreased

in

in

Profile: Jens Fiehler Culture shifts in medicine page 14

cerebrovascular accident, peripheral vascular disease, or chronic kidney disease, no significant differences were observed between races.

“With respect to presenting SARS-CoV-2 symptoms, we found no difference in exposure history, asymptomatic cases, fever, cough, dyspnea, nausea or vomiting, chills, malaise, or lethargy. The African American cohort had a similar mean NIHSS [National Institutes of Health Stroke Scale] score of 16.3 compared with 14.9 in other races (p=0.63). The doorto-CT time was also similar (23 vs. 19 minutes), and the proportion of patients presenting with a large vessel occlusion was not significantly different (40.7% versus 47%),” he added.

Lastly, while the team observed that 14.8% of African American patients received intravenous tPA compared to 31% in other races, Dmytriw said it was not significantly different in this sample.

Addressing the SNIS audience, he reiterated that the preliminary data suggest there may be a mortality difference amongst stroke patients of African American background afflicted with COVID-19.

Speculating on reasons as to why, he said: “Underlying biological, genetic, or epigenetic characteristics can predispose [people] to health differences,” but added that social determinants such as access to healthcare, and geographical differences pertaining to both population and other location-based factors may also be contributory.

Moving forward, the team, which is co-led by Ambooj Tiwari of New York University (New York, USA) aims to continue recruitment of more hospitals across North America, and

station of these afferent inputs (neurons that receive sensory information), it has yet to be targeted for this purpose.

Hence, Soloukey and colleagues set out to determine whether DRG stimulation can facilitate clinically relevant motor responses in motor complete SCI. Five patients were implanted with DRG leads placed bilaterally on level L4 for five days. Based on personalised stimulation protocols, the team aimed to evoke dynamic (phase 1) and isotonic (phase 2) motor responses in the bilateral quadriceps muscles. On days one and five, EMG-measurements (root mean square [RMS] values) and clinical muscle force measurements (MRC scoring) were used to measure motor responses and their reproducibility.

“In all patients, DRG-stimulation

Continued on page 2

evoked significant phase 1 and phase 2 motor responses with an MRC ≥4 for all upper leg muscles,” report the authors.

This led to a knee extension movement strong enough to facilitate assisted weight bearing, they added. Moreover, the team reported that no significant differences in RMS values were observed between days one and five of the study, which indicated that motor responses were reproducible.

Delving into rationale behind their research, Soloukey et al state that SCI is “one of the most devastating” injuries to the human central nervous system, as it can lead to a multitude of problems, including loss of autonomic control, muscle atrophy, spasticity and sensory and motor impairments. According to Continued on page 18

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September 2020 | Issue 39

Racial disparities

New studies shed light on racial disparities in stroke outcomes, including COVID-19 patients Continued from page 1

to investigate coagulation-related parameters. Speaking to NeuroNews, Tiwari says: “Our preliminary findings cannot be tied to any one specific factor, but as the consortium grows, hopefully our confidence in the major elements at play will also grow.”

Racial disparities in acute stroke thrombectomy management

The second study, presented by Vineeth Thirunavu, Northwestern University Feinberg School of Medicine, Chicago, USA, detailed several racial disparities after mechanical thrombectomy for stroke with respect to postprocedure management and outcomes.

Specifically, Thirunavu explained that minority groups, including Hispanics, Asians and African Americans, exhibited worse immediate post-procedural outcomes and

News in brief

disease on African Americans. “Some studies have also looked into other minority groups […] but that research has focused on differences in the utilisation and access to mechanical thrombectomy; not a lot of research carried out has been on outcomes after mechanical thrombectomy, in terms of mRS scores or National Institutes of Health Stroke Scale [NIHSS] scores,” he added.

Therefore, according to Thirunavu, the current study utilised real-world evidence from the NVQI-QOD registry, enabling the team to study racial disparities in a large group of patients throughout the USA. In total, he reported that 3,261 patients from 23 US centres across 17 states, over a five-year time period (January 2015–March 2020), were included.

He pointed to a slide displaying the population breakdown by race. It showed that 2,484 patients were Caucasian,

The latest stories from the neuro world

n ENDOVASCULAR BRAIN-COMPUTER INTERFACE IMPROVES FUNCTION IN PARALYSED PATIENT: Late-breaking data presented at the Society of NeuroInterventional Surgery’s annual meeting denotes that a novel wireless endovascular braincomputer interface, known as the Stentrode, may improve capacity to perform activities in daily living and functional independence in patients with severe paralysis.

For more on this story go to page 4 n HIGH-RESOLUTION INTRAVASCULAR IMAGING IN NEUROINTERVENTION: Matthew Gounis and Ajit Puri discuss the evolution of high-frequency optical coherence imaging. Now designed specifically for application to the neurovasculature, they detail how the novel modality can guide neurointerventional surgery to achieve optimal deployment of flow diverters, stents, and intrasaccular devices.

For more on this story go to page 6 a greater length of in-hospital and intensive care unit (ICU) stays.

“Race seems to be implicated in length of treatment for acute ischaemic stroke,” he told the online audience.

However, he said that the registry yielded an “interesting finding” in that in-hospital mortality for African Americans appears to be lower compared to their Caucasian counterparts. “This finding does not necessarily correlate with the findings that you would expect with longer length of stay and more ICU days.”

Thirunavu added that in terms of outcome variables— mRS score and 90-day mRS—no difference in the rate of favourable outcome between races was observed, when excluding mRS scores of six.

Speculating as to why in-hospital mortality for African Americans was significantly lower, he said: “It could be a cultural thing, or not staying on the support of care, but we really have to do more research to see at what level these disparities are occurring at. Is it at a patient level, a genetic level, or are healthcare providers treating patients differently?”.

Thirunavu added that since endovascular therapy has become the standard of care for stroke, research has focused on the disproportionate burden of stroke and cerebrovascular

Race seems to be implicated in length of treatment for acute ischaemic stroke.”

563 African American, 109 Hispanic and 105 Asian. He admitted that there might be a slight underrepresentation of Hispanics in the cohort.

“We used a robust set of outcome variables; we were able to look up days to follow-up, and in-hospital mortality.

In addition to the initial statistical analysis, we looked at regression models which controlled for a number of factors” Thirunavu explained.

However, he pointed to a caveat with the outcome variables, acknowledging that the registry contains some limited data. “Only 33% of patients that are alive at 90 days had mRS scores reported; two thirds of the data are still up for grabs, and we do not know how those individuals faired,” he told viewers, and further emphasised that mRS, especially at 90-days, is an important outcome variable after mechanical thrombectomy.

n SNIS 2020: THE STROKE TRIALS Recovery ARCADIA YOU NEED TO CREST2 KNOW ABOUT: Acute Interventions: Though held Devices EXCELLENT EVT Indication virtually this year, Expansion COMPLETE PROST the Society of TIGER TESLA INSIGHT TENSION NeuroInterventional LASTE ENDOLOW Surgery’s annual MOSTE Acute BAOCHE meeting began Interventions: MR CLEAN LATE Drugs MOST by providing an TIMELESS MR CLEAN MED Systems outline of the most MR CLEAN NO IV of Care SWIFT DIRECT RACECAT game-changing TRIAGE BEST-MSU stroke trials that The stroke trials you need to are either currently know about Prevention ARCADIA ongoing, or recently CREST2 completed. From acute interventions to the expanding indications of endovascular therapy, Sunil Sheth (Houston, USA) presents a thorough update of the neurointerventional research underway across the globe.

For more on this story go to page 10

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September 2020 | Issue 39

Novel technology

SNIS

SNIS 2020: Endovascular braincomputer interface improves function in paralysed patient According to late-breaking data presented at the Society of NeuroInterventional Surgery’s (SNIS) 17th Annual Meeting, a wireless endovascular brain-computer interface (BCI) “may improve capacity to perform activities in daily living and functional independence” in patients with severe paralysis.

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his conclusion was reached by Thomas Oxley (University of Melbourne, Melbourne, Australia) and Peter Mitchell (Royal Melbourne Hospital, Melbourne, Australia), who together presented the firstin-human examination of the stentrode, an implantable brain-computer interface, during the virtual meeting.

“We have demonstrated that the signal can be used to drive the mouse and keyboard to utilise Windows 10 in a patient who had failed upper limb control, and that instrumental activities of daily living may be a useful scale for BCI efficacy outcomes,” said Oxley.

He began by telling the SNIS online audience that this technology is now eight years in the making. Oxley’s team in Melbourne have developed a stent-electrode (known as a stentrode) device that is implanted in the venous system, enabling patients with paralysis to control external devices in an attempt to improve activities of daily living.

Oxley explained that for BCIs, the hope is that the technology can assist patients that have paralysis.

Paralysis can be due to a range of conditions, he noted, which can affect anywhere from the subcortex to the brainstem, to the spinal cord or the peripheral nerves.

Delving further into the background, he added: “The concept with the BCI is that if there are three elements within these patients that you have to satisfy—one is that they have preserved motor cortex (detectable on functional MRI); two is that they have an upper limb paralysis, which is assessed by a neurologist; and three, that the paralysis has resulted in a functional impairment—then a BCI may enable those patients to regain control over external devices that they could not otherwise control.”

Describing the system itself, he told viewers that it is a fully implanted intravascular array that sits in the superior sagittal sinus and records from the motor cortex. After the electrocorticography signal is detected, an algorithm is used to convert this into “intended attempted movement”, which is in turn converted into functions aimed at taking control over the mouse and keyboard. This then assists patients with upper limb paralysis to “utilise control over personal devices,” Oxley stated.

“We intend to capture that clinical improvement in scales including activities of daily living.”

“This is a first-in-human study. The first patient that we are about to present is a 75-year-old male who has motor neuron disease, or ALS [amyotrophic lateral sclerosis], which is upper limb predominant, with lower motor neuron features. He is able to speak but has weakening vocal cords, and is dependent on his wife for all activities of daily living. He has been unable to independently use the telephone, computer, and do finances,” Oxley said.

He told viewers that the neurointervention procedure that was performed at the Royal Melbourne Hospital was first proceeded by assessing the access approach, and whether to go right or left by review of computed tomography (CT) and a structural MRI. “Functional MRI was then used to identify the motor cortex and allow coregistration to DSA [digital subtraction angiography] targeting during the procedure,” Mitchell noted, adding that Thomas Oxley the jugular vein access and superior sagittal sinus deployment was via a percutaneous direct puncture, and retrograde catheterisation of the superior sagittal sinus was done using a benchmark guide catheter system.

According to Mitchell, the team were able to place the

The neurointervention procedure

Preclinical work

Peter Mitchell took over to explain to the SNIS audience the implantable components of the device.

“The stentrode head is a self-expanding array; 16 sensors record the signal with 4mm spacing. This is connected via the stentrode flexible lead, which passes through the venous system, and then subcutaneously, to see the Internal Telemetry Unit (ITU).”

We are looking at outcomes that we have agreed upon with the FDA, including three- and 12-month thrombosis and change in vessels.” device within 1mm, and a stable stent and lead position was confirmed at three months. There was no evidence of complication, he added, as no thrombosis or stenosis was observed at three months.

Oxley confirmed that the team carried out “a lot” of animal work leading up to this first-in-man study.

He said: “The majority of the work laid out by the US FDA [Food and Drug Administration] was to demonstrate safety around thrombosis.”

The main learning from this, according to Oxley, was that endothelialisation was the biggest determinant of

thrombosis. “We demonstrated that in animal studies, 95% device endothelialisation in the sinus occurred after 45 days. For that reason, we have pursued a dualantiplatelet therapy out to 90 days, and a single agent beyond 90 days,” he confirmed.

Decoding motor intent

Once the device is in and turned on, Oxley explained that a training exercise is undertaken with the patient, to identify different attempted types of movement. These can include left, right, ankle, and quad-movements, he posited. Following this, the machine learning algorithm is trained to classify these particular movements. “Then, we turn those into inputs on a mouse or a keyboard,” Oxley told the audience.

“For our first patient, he was still able to use eye-tracking for the cursor, so we utilised the first several outputs for left-click or zoom functioning, which in combination with his eyes, gave him control over Windows 10, and he was able to regain function.”

Assessing performance

“The way we assessed the performance was primarily around typing,” Oxley asserted.

The team evaluated selection accuracy (click accuracy), which the patient was averaging at around 91%.

Oxley said that the patient was selecting keys on the keyboard to type at a correct-characters per minute rate of 13. “He utilised the system to conduct text messaging, emailing, online shopping, and online banking, which he was unable to do before. This resulted in an

improvement in his activities of daily living.”

Next, Oxley displayed a video of the patient sending his wife a text message. “He was not able to do this before,” he explained, adding that his wife always had to be there. “She is now able to leave the house because he can access her via WhatsApp by opening the app and sending her a message.”

A future for stentrode

Concluding the presentation, Oxley told the online viewers: “This is obviously only the first patient; we have a lot of work to do.”

He argued that the team are not making any claims on safety yet, and put forward that they have approval to implant the stentrode in five more patients in Melbourne, which they are currently moving through. “We are looking at outcomes that we have agreed upon with the FDA, including three- and 12-month thrombosis and change in vessels. In our first patient, we have three and six-month data, and there has been no stenosis.”

Lastly, Oxley confirmed that the next steps are to launch a feasibility study—also in the USA—and then within three years “to hopefully launch a pivotal trial to demonstrate this technology in a subset of patients with paralysis”.

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September 2020 | Issue 39

Commentary

High-resolution intravascular imaging in neurointervention Matthew Gounis Ajit Puri Comment & Analysis High-frequency optical coherence imaging can guide neurointerventional surgery to achieve optimal deployment of flow diverters, stents and intrasaccular devices, write Matthew Gounis and Ajit Puri. Here, they discuss the evolution of the technology, and detail their institution’s experience developing the novel modality, which they have designed specifically for application to the neurovasculature.

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n a recently published article Nature Communications volume 11, article number: 2851 (2020), we have introduced a technology designed for high-resolution intravascular imaging of the cerebrovasculature. The foundational technology is optical coherence tomography (OCT), which uses nearinfrared light to interrogate the arterial lumen and reconstruct cross-sectional images of the blood vessel from the backscattered light.

More than a decade has passed since this technology was introduced to image coronary artery disease, providing detailed information about atherosclerotic plaques with approximately 18µm spatial resolution, allowing precise sizing of stents during treatment.

As clinical evidence has mounted, OCT has been shown to affect clinical decisions in nearly 50% of coronary interventions, as well as reduce major in-hospital cardiac adverse events and mortality. However, the existing platform cannot reliably be used in the intracranial circulation.

Although there are scattered case reports that describe OCT in neurovascular applications, the design of the system is not optimised to allow routine use in the highly tortuous

the encasing catheter, which can cause image distortion or, more commonly, catastrophic failure of the device.

In collaboration with Gentuity LLC (Sudbury, Middlesex County, USA), the University of Massachusetts Medical School (Worcester, USA) has engaged in a National Institutes of Health funded programme to develop a novel highfrequency optical coherence imaging (HF-OCT) technology designed specifically for application to the neurovasculature.

With a profile of 0.0155” (1.2 Fr), the HF-OCT imaging catheter has similar performance characteristics as a microguidewire, including a shapable coil spring tip. The described experiments entailed patient-specific, whole circle of Willis vascular phantom testing to ensure that contrast flushing protocols deployed would not differ from standard protocols used for rotational angiography.

In order to image the arterial lumen, blood has to be momentarily cleared so as not to attenuate the laser. Since the device acquires images at 250 frames per second, it is possible to acquire 8cm of vascular imaging within approximately 2–3 seconds. We found that the standard contrast injection protocols deployed

Figure 1: (A) High-resolution cone beam CT shows very nice apposition of a flow diverting stent; however, HF-OCT imaging (B) reveals flow-diverting stent malapposition at the same cross-section as (A). Inset in B1 demonstrates visualisation of small platelet aggregates on the surface of the device (~80 microns). (C) shows the flow diverter jailing two side branches with no platelet adherence to the device; whereas in (D) HF-OCT imaging of the same location show small thrombus accumulations over the surface of the flow-diverter strut (arrow) 120 microns (D1) in size. Scale bars on HF-OCT image are equal to 1mm.

intracranial vasculature due to the large profile of the device, relatively rigid construction with transitions at the wrong locations, and most importantly— nonuniform rotation of the lens due to contact friction of the torque wire with

Study finds clot permeability linked with first-attempt success of aspiration thrombectomy to open blocked brain vessel

clinically for rotational angiography provided sufficient blood clearance for optimal imaging. Subsequently, in vivo modelling in a porcine brachial artery with elevated tortuosity demonstrated that imaging with uniform illumination

THE COMPASS TRIAL FOUND BOTH aspiration thrombectomy and stent-retrieval thrombectomy techniques to be equally safe and effective as first-line approaches for treating emergent large vessel occlusions (ELVO). Now, a multicentre study led by the University of South Florida Health (USF Health) Department of Neurosurgery and Tampa General Hospital, Tampa, USA, reports that clot perviousness, or permeability – the ability for contrast used during the initial imaging workup to seep through a clot, as estimated by CT imaging – is associated with

was possible and the individual layers of the arterial wall could be reliably visualised.

Neurovascular devices, such as flow diverters and stents were deployed in the animal model and interrogated with HF-OCT at a resolution approaching 10µm, standard digital subtraction angiography, as well as high-resolution cone-beam CT. We found that inter-rater reliability to assess flow diverters and stent malapposition or acute thrombus formation along the surface of the device was significantly superior with HFOCT as compared to the other imaging modalities.

Finally, cadaveric intracranial atherosclerosis specimens were imaged with HF-OCT and compared with histological analysis from a blinded pathologist. Agreement on plaque characterisation (fibrotic, necrotic lipid core, or micro-calcifications) was concordant between HF-OCT and histopathological analysis.

Unlike the coronary and peripheral circulations, in situ analysis to study vascular disease is currently not possible for the intracranial circulation.

Thus, longitudinal data for plaque development, vasculopathies, or degeneration of the wall in aneurysms does not exist. This technology, which is nearing clinical introduction, can shine light on cerebrovascular pathology.

With sizing of devices for specific lesions approaching the resolution of our angiography equipment, highresolution intra-vascular imaging can provide precise sizing for personalised intervention. HF-OCT can guide neurointerventional surgery to achieve optimal deployment of flow diverters, stents and intrasaccular devices, and provide clinically viable information to prevent complications and potentially prognosticate clinical/angiographic outcomes. Mirroring the role of OCT in coronary artery interventions, clinical research exploring novel devices will certainly benefit with HF-OCT. Matthew Gounis is the director of the New England Center for Stroke Research and Professor of the Department of Radiology at UMass Memorial Medical Center, Worcester, USA. Ajit Puri serves as co-director of the New England Center for Stroke Research, Chief of NeuroInterventional Radiology at UMass Memorial Medical Center (Worcester, USA), and is an Associate Professor of Radiology at the University of Massachusettes Medical School.

“first-pass success” in ELVO patients initially treated with the aspiration thrombectomy approach.

Findings from this posthoc analysis of 165 eligible patients enrolled in the COMPASS trial were published in the Journal of Neurointerventional Surgery.

First-pass success means achieving complete reopening of a blocked artery in the first attempt with a thrombectomy device. The treatment success of the stent retriever-first approach for a large vessel occlusion stroke was less dependent on clot perviousness, the study found.

Issue 39 | September 2020

Treatment advancements have helped reduce mortality rates from unruptured brain aneurysms Mortality rates after treatment of unruptured intracranial aneurysms have substantially decreased in the past decade, according to new findings presented at the Society of NeuroInterventional Surgery’s (SNIS) 17th Annual Meeting (4–7 August).

ADDRESSING THE VIRTUAL audience, Shahram Majidi, assistant professor of Neurosurgery at Mount Sinai Hospital (New York, USA), further concluded that a higher rate of morbidity and mortality was observed in patients aged 80 years or older, as well as those with multiple comorbidities and who were treated with microsurgical clipping.

“Decision-making for the management of unruptured intracranial aneurysms remains complex and controversial,” stated Majidi, discussing the background to the research. He added that recent studies suggest an increasing trend in treatment of unruptured intracranial aneurysms in the USA. This led Majidi and his colleagues to investigate trends in mortality and morbidity after treatment of unruptured intracranial aneurysms in the USA between 2006 and 2019. The team reviewed The Nationwide Inpatient Sample (NIS) database to identify patients who

10-year trends underwent aneurysm treatment during hospitalisation.

“We used ICD-9-CM codes from 2006 to the third quarter of 2015, while data from the fourth quarter of 2015 and all of 2016 were classified using the ICD-10CM,” noted Majidi.

According to Majidi, patients’ demographics, comorbid conditions, length of hospital stay, rate of in-hospital mortality, discharge destination for each treatment group (microsurgical clipping and endovascular embolisation) were also recorded. Majidi explained to the viewers that microsurgical clipping involves an open brain surgery, whereas endovascular embolisation is a minimally invasive procedure. He noted that poor clinical outcome was defined as discharge to a skilled nursing facility, or hospice, instead of home or acute rehabilitation facility.

Majidi reported that a total of 105,496 electively treated from patients with an unruptured intracranial aneurysm were identified. The overall rate in of in-hospital mortality decreased from 0.9% in 2006 to 0.2% in 2016. Overall, 83% of the patients had favourable clinical outcomes.

Pointing to a graph depicting trends in utilisation of microsurgical clipping and endovascular embolisation, he told viewers: “Endovascular embolisation accounts for up to 66% of the treatment, while less than 40% of the patients were treated with microsurgical techniques.”

Discussing patient demographics, those treated microsurgically—noted Majidi—were younger, more

likely to be hypertensive and a smoker, more likely to be treated in a rural hospital, and were more likely to have a higher comorbidity index.

He added that patients who underwent endovascular embolisation had a significantly higher rate of favourable clinical outcome, compared to microsurgical clipping group (91% vs.

74%) and an average of three days’ shorter hospital stay (2 vs. 5).

“Overall mortality rate among endovascularly treated patients was 0.3% versus 0.5% in microsurgically treated patients,” Majidi asserted.

In terms of the limitations to the study, he said: “The NIS administrative database is prone to reporting inconsistency and coding errors, and it also lacks sophisticated clinical details, which is a major drawback.

“Also, the outcomes are limited to inpatient mortality and discharge to destination due to the lack of sufficient granularity in the outcome data collected in in NIS.” Nevertheless, he concluded: “Our research indicates that treatment of unruptured brain aneurysm has become exceedingly safer over the last 10 years due to advancement in both microsurgical techniques and endovascular technology.

“While overall clinical outcomes have been significantly improved, we found a higher rate of favourable hospital outcome and lower mortality rate among endovascularly treated patients compared to microsurgical clipping.”

Overall rate of in-hospital mortality decreased

0.9%

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September 2020 | Issue 39

Stroke update

SNIS

Bridging therapy independently predicts haemorrhagic complications in atrial fibrillationassociated stroke Exposure to bridging therapy independently predicts haemorrhagic complications—without improving functional outcomes—in patients with atrial fibrillation (AF) associated stroke.

The findings from this retrospective registry analysis were presented by Feras Akbik (Emory University, Georgia, USA) during a late-breaking abstract session at this year’s virtual Society of NeuroInterventional Surgery’s annual meeting (SNIS; 4–7 August).

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ddressing the online audience, Akbik discussed the rationale behind his research: “Atrial fibrillation is a common and particularly morbid stroke aetiology. In the pre-thombolysis era, these strokes were associated with larger territories of hypoperfusion and infarction, worse functional outcomes, and increased mortality. Even in the thrombolytic era, these patients had increased rates of symptomatic intracranial haemorrhage after IV [intravenous] tPA [tissue plasminogen activator], and still had larger territories of infarction, and, interestingly enough, were less likely to recanalise than other stroke mechanisms.”

Given this, he posed the question: “In the setting of the endovascular era: what is the role for IV tPA in these patients?”

The concerns, he said, are “relatively similar” for any other stroke aetiology. “There is thought to be a limited benefit of IV tPA in the setting of large vessel occlusion.

There is obviously the concern about IV tPA-associated haemorrhage after recanalisation. This is particularly notable given the high rates of recanalisation at most thrombectomy-capable centres.”

Akbik acknowledged that there is also the issue of taking a proximal clot, thrombolysing it, pushing it further, and “making what was previously a retrievable clot, now irretrievable”. He argued that the neurointervention field is yet to acquire these answers until randomised data is produced.

Speaking on the datasets available thus far, he said: “SKIP was inconclusive, but DIRECT MT, which was published just a few months back, showed noninferiority in a relatively small Chinese cohort. There are ongoing trials, MR CLEAN NO IV and SWIFT DIRECT.” However, Akbik told the SNIS audience that by taking a step back, regarding how practice will change,

“we have to keep in mind that IV tPA has been the cornerstone for the last 20 years, until certain trials came out in 2015.” He argued that it is going to take “a lot” for people to move away from this, and added: “It may not be enough to show non-inferiority or any kind of equivocal data; it may be more important to ask: who gets harmed by bridging therapy?

When considering the potential risks of bridging therapy, Akbik asserted, “These are all enriched in the AF patients. So the question remains: does bridging therapy have a differential outcome in these patients?

Are they less likely to benefit, or more likely to get harmed?”

In order to answer these questions, the team leveraged the Stroke thrombectomy and aneurysm (STAR) registry. STAR is an international thrombectomy registry across four continents with over 40 sites included. At the time of this analysis, the team had 4,169 anterior

The current findings highlight the need for randomised trials to assess this high-risk subgroup.” circulation mechanical thrombectomies over a threeyear period (2015–2018); a third of which—according to Akbik—had AF, and a third of which had exposure to bridging therapy.

The team first dichotomised the data by AF versus nonAF. “The former are a little older, more likely to be female, and have more vascular risk factors, which is consistent with the general AF stroke literature,” noted Akbik.

William Mack becomes 25th SNIS president The Society of NeuroInterventional Surgery (SNIS) has announced that William Mack (Los Angeles, USA) has become the new president of the organisation. The announcement was made during the society’s’ 17th annual meeting (4–7 August), which was held virtually.

THE CHANGE MAKES RICHARD Klucznik (Houston, USA) the SNIS immediate past president and means Mack will lead the SNIS’s initiatives to

advance excellence in minimally invasive neuroendovascular care.

“The field of neurointervention is flourishing, driven by the brightest

Looking at their presentation, he said AF patients are more likely to have a higher stroke scale score, a lower Alberta Stroke Program CT Score (ASPECTS), and are less likely to get IV tPA. “But angiographically,” he said, “they have similar outcomes. They have equivalent reperfusion, and equivalent complication rates including haemorrhage.”

In contrast to this, Akbik stated that when looking at bridging therapy patients, “it is a different story”.

When examining AF patients exposed to bridging therapy, he said there was a significant increase in haemorrhagic complications, with the absolute risk increase of over 2% more than patients who were not exposed to bridging therapy.

“Now, the question is, what about the confounding variables such as time to presentation? We controlled for this under multivariate assumptions, as well as age and other variables.

Even in this analysis we found that IV tPA is the only variable that stands out as a predictor with an odds ratio of around two,” Akbik said.

Pivoting to functional outcomes, he claimed there also appears to be Feras Akbik a difference. Regarding the shift analysis in the modified Rankin Scale (mRS) curve, Akbik told the audience that there was a “shift in the positive direction” with the mRS in non-AF patients exposed to bridging therapy. Despite this, he noted that when looking at the AF patients, no shift, or benefit, was observed. “There does not appear to be any bang for our buck in terms of bridging therapy in these patients,” he added.

When the team dichotomised the functional outcomes (good versus bad) via a multivariate analysis, they reported a similar benefit in the non-AF cohort, but again, no benefit in AF patients.

Lastly, Akbik alluded to certain caveats of the study.

“One is the inherent retrospective biases that come with a registry analysis; two is the mechanisms—it is a comorbid AF versus a TOAST aetiology—so this makes it harder to suss out in a big registry dataset like this. Thirdly, the angiographic and haemorrhagic outcomes are all locally (not centrally) adjudicated.

Finally, there is a lack of antithrombotic data in the registry at present.”

He added: “I would point out that the AF patients on anticoagulants, where you worry about bleeding, are those who are least likely to get bridging therapy.”

minds who continue to adapt and innovate to meet the challenges of a rapidly changing world,” said Mack in the society’s announcement.

“I look forward to both the challenges and opportunities to come in the year ahead and promise to drive forward SNIS’s mission of William Mack championing patients and improvements to systems that will help them receive timely and appropriate care.”

The SNIS noted that in addition to his clinical work at the University of Southern California, Mack is the principal investigator and director of the cerebrovascular laboratory in the Zilkha

Neurogenetic Institute.

His scientific interests focus on translational efforts to treat ischaemic and haemorrhagic stroke, and his laboratory investigations concentrate on the pathophysiology of stroke and inflammatory modulation.

Using the information and experience gained in the laboratory, Mack is working to develop new technologies, techniques, and therapies to directly improve the clinical care administered to stroke patients.

The president-elect of SNIS is Michael Chen (Chicago, USA) and J Mocco (New York, USA) has been elected vice president.

Issue 39 | September 2020

Advertorial

9

THIS ADVERTORIAL IS SPONSORED BY EVASC

eCLIPs: Enabling coil retention and flow diversion for the treatment of cerebral aneurysms The successful treatment of wide-neck bifurcation aneurysms remains a challenge for even the most experienced physicians in the neurointervention field. Developing at a branching point of an artery, the high-velocity blood flow at this location creates a large amount of pressure on the aneurysm. Given this demanding anatomy, it is not surprising that coils struggle to stay retained, and aneurysms reopen over time.

SINCE 2008, EVASC HAS BEEN developing the eCLIPs, a novel endovascular device designed to treat cerebral aneurysms, which has now been used clinically in a challenging set of wide-neck aneurysms. In order to optimise coil retention and enhance flow disruption, eCLIPs combines properties from both stents and flow diverters.

Here, speaking to NeuroNews, Leif Sørensen from Aarhus University Hospital (Aarhus, Denmark) outlines his clinical experience with the device, and details how its design has contributed to the low recurrence rates that he and his team have observed so far.

What are the eCLIPs’ distinguishing features?

Have they overcome any limitations of other devices?

The usual way to treat bifurcation aneurysms is to place small coils into the aneurysm and occlude it through coils, or other intrasaccular contents.

However, because you have this waterhammer effect, where the bloodstream is hammering into the aneurysm at least 60 times a minute, these coils tend to compress, and you have a certain degree of reopening of the aneurysm.

What we really want is to have the bloodstream pushed, or diverted away from the aneurysm, out into the branches. This is exactly what the eCLIPs is doing. It has two effects: it

helps to cover the neck so the coils are retained inside the aneurysm while also providing a flow diversion effect.

How does the design permit these benefits?

The eCLIPs is made of two sections; one that covers the aneurysm neck, and the other we call the anchor segment, which prevents migration. The neck-bridging leaf segment is designed like a feather.

Unlike standard stents that have very open constructions, this design produces flow disruption, and mitigates the waterhammer effect, and thus, the tendency to compress the coils. This design feature allows the neck-bridging leaf to act as a platform for neo-endothelial growth, permanently exteriorising the aneurysm from the circulation (Marotta et al. J Neurosurg. March, 2017 https:// thejns.org/doi/abs/10.3171/2016.10.

JNS162024). This is what distinguishes

Leif Sørensen

to enter into the aneurysm through the small rib structures to deploy the coil inside.

How many cases have you treated so far using the eCLIPs?

Locally, we have implanted the device in around 20 patients over the last few years, and I have also been proctoring cases in several hospitals around Europe.

You recently presented at the Society of NeuroInterventional Surgery’s virtual meeting.

Could you tell us about this data?

This was a particularly challenging group of aneurysms, as they all had a very wide neck and short distance between the neck and dome (low aspect ratio). They would be a difficult set to treat no matter what device you use, as they were so open.

With the eCLIPs, we have had no recurrences. In fact, the aneurysms are becoming more closed over time.” this device from others on the market.

The anchor section is the part that is placed at one of the two branches at the T-crossing. It will make contact with the vessel wall, and through this, will secure the clip. It allows the treating physician

But, because it is possible to deploy the eCLIPs outside of the neck of the aneurysm, as the device is not bothered by the size of the neck, you can get both coil retention and a flow diversion effect.

In this particular cohort of difficult

aneurysms, we have 19 patients where we now have a complete follow-up data-set, and we have seen no recurrences (De Vries J, et al. J NeuroIntervent Surg 2020;0:1–6. doi:10.1136/ neurintsurg-2020-016354). If you measure how tight the aneurysms were coiled at the end of the operation and look at them around 11.5 months after the operation, we can see that within the aneurysms that were not closed, nearly all of them were completely closed at the first follow-up. They have gone from a not-so-favourable to a favourable group.

With standard techniques, you usually get a lot of recurrences. But with the eCLIPs, we have had no recurrences. In fact, we have observed the opposite; the aneurysms are becoming more closed over time.

Did these results surprise you?

In theory, based on the design of the device, we should be observing results as good as this. But to see that it works in practice is very fulfilling.

Do you believe that the eCLIPs will offer a new standard of care?

Yes, or at least I hope so. I am so happy with this device. I really hope we can have it on the market because there is a need for this.

Of course, you need to train in order to use it, because there are some technical difficulties you have to overcome when treating aneurysms with the eCLIPs, as well as some anatomical demands that the treating physician should be aware of. I am working with the company and carrying out some workshops, but in addition to this, training in a bench model, or an animal model, will help with the learning curve.

There is also a new version of the product that has been launched, and it has recently received CE mark. While it encompasses the same design, the delivery system is a little different, and it allows the treating physician to use all catheters to deliver the device. I have had less experience using this new device, but it looks as though it should be easier to use.

In order to optimise coil retention and enhance flow disruption, eCLIPs combines properties from both stents and flow diverters

September 2020 | Issue 39

10 Stroke trial update

SNIS

SNIS 2020: The stroke trials you need to know about From acute interventions to endovascular therapy indication expansion, Sunil Sheth from McGovern Medical School at UTHealth, Houston, USA, kick started the Society of NeuroInterventional Surgery’s 17th annual meeting (SNIS; 4–7 August, virtual event) by outlining an array of recently completed, and ongoing stroke trials.

“I

f I do not include your favourite trial, please forgive me,” he said. “Our goal today is to cover the full range of acute ischaemic stroke studies. From start to finish I will try to have representation from trials around the globe.”

He explained to the audience that he has organised the trials by the segment of care; trials pertaining to prevention of stroke, systems of care, acute interventions, endovascular therapy indication expansion, and stroke recovery trials.

Prevention

The first trial Sheth highlighted was ARCADIA (Artrial cardiopathy and antithrombotic drugs in prevention after crypotogenic stroke). In this study, patients with embolic stroke of uncertain source (ESUS) are randomised to aspirin or apixaban. Sheth said it aims to answer the question: Which of these approaches is better at reducing the risk of subsequent or first-time stroke? The key criteria are ESUS, and evidence of atrial cardiopathy.

Next, he said that CREST2 (Carotid revascularisation and medical management for asymptomatic carotid stenosis trial)—a follow-up of CREST1—is investigating whether carotid revascularisation is in fact beneficial in preventing stroke. “The patients in this trial get randomised to either medical therapy or stenting endarterectomy. They have to have ≥70% stenosis and it has to be treatable. Like ARCADIA, this trial is enrolling, also with a target completion date of 2022,” Sheth explained.

Stroke systems of care

Pointing to trials pertaining to systems of care, he discussed RACECAT—a prehospital stroke trial. “In Barcelona, Marc Ribo’s group is trying to answer the question: Which is the better routing strategy in the prehospital environment?

Is it going from EMS [emergency medical services] directly to a primary stroke centre, or from EMS—bypassing the primary stroke centre—and going directly to a comprehensive stroke centre?

“The patients are being prescreened and have to have some suspicion of LVO [large vessel occlusion] with a Rapid Arterial Occlusion Evaluation [RACE] score >4, and the trial is being conducted

in areas where the local hospital cannot perform thrombectomy. This is a trial that is very close to being completed, and I am looking forward to those results.”

The TRIAGE (Treatment strategy in acute ischaemic large vessel stroke: prioritise thrombolysis or endovascular treatment) trial is similar, he said. In Denmark, patients are being randomised in the prehospital setting—either going directly to a primary stroke centre for IV (intravenous) tissue plasminogen activator (tPA), and then to a comprehensive stroke centre, versus going directly to the latter.

The last trial regarding optimising stroke systems of care he discussed was the BEST-MSU (Benefits of stroke treatment delivered using a mobile stroke unit) trial. Here, patients were randomised to either getting mobile stroke unit care versus standard EMS care, and had to be eligible for IV tPA. “They enrolled their final patient last week, so they are now completing their follow-up and we should be hearing from them soon.”

Our goal is to cover the full range of acute ischaemic stroke trials [and] I will try and have representation from trials around the globe.”

Acute Interventions: Drugs

The next set of trials are interventional trials that involve medical therapies, Sheth told the SNIS online audience.

“The first is MOST [Multi-arm optimisation of stroke thrombolysis]; a trial randomising patients that get IV tPA to receive either argatroban, eptifibatide, or placebo,” he said, adding that patients receive the study drug within one hour of IV tPA, and thrombectomy is allowed in these patients.

In addition, the TIMELESS (Tenecteplase in stroke patients between 4.5 and 24 hours) trial is randomising patients to either a single bolus dose of

tenecteplase or placebo. Sheth noted that these patients, who are not IV tPA eligible, are randomised between 4.5 to 24 hours of stroke onset. However, they have to have an LVO, and their imaging criteria must include a mismatch on CT perfusion and MRI. Like the MOST trial, TIMELESS is currently enrolling.

Sheth next introduced the first of several MR CLEAN follow-up trials.

“MR CLEAN MED, a medical trial with

patients must be IV tPA eligible (within 4.5 hours), and have to have an LVO. “One of the unique aspects of this trial, like the original MR CLEAN trial, is that delayed consent is allowed, so you can screen and enrol, and randomise patients without consent upfront. Because of this, they have been enrolling very well; faster than expected, so the trial should be completed very soon,” Sheth highlighted.

Another trial looking to answer the

Recovery

ARCADIA CREST2

Acute Interventions: Devices EXCELLENT COMPLETE PROST TIGER INSIGHT

EVT Indication Expansion TESLA TENSION LASTE ENDOLOW MOSTE BAOCHE MR CLEAN LATE

Acute Interventions: Drugs

MOST TIMELESS MR CLEAN MED MR CLEAN NO IV SWIFT DIRECT

Systems of Care

The stroke trials you need to know about Prevention a 2x2 factorial trial, includes patients with thrombectomy that was planned (with an LVO), getting randomised either to receive 300mg aspirin, or not, and/or a heparin bolus dose drip, or not.

This is an open-label study, so these are patients who are getting thrombectomy, with the drugs infused at the time of groin puncture, or right after IV tPA is completed.” He added that the study started in 2018, and is a third of the way through enrolment.

In terms of the MR CLEAN NO IV trial, Sheth told viewers that this explores the question of whether or not IV tPA is useful when patients are also getting thrombectomy. Key criteria includes that

RACECAT TRIAGE BEST-MSU

ARCADIA CREST2

same question is the SWIFT DIRECT (Bridging thrombolysis versus direct mechanical thrombectomy in acute ischaemic stroke) trial, which is randomising patients to thrombectomy (with Solitaire; Medtronic) with or without IV tPA. Again, these are IV tPA-eligible patients with LVO, and an Alberta Stroke Program Early CT score (APECTS) ≥4. The estimated completion of this trial is 2022.

Endovascular therapy indication expansion

Issue 39 | September 2020 Sheth displayed the first set of four trials to the SNIS viewers, describing them as the “so-called large core trials”, which are exploring whether thrombectomy is helpful in patients that are presenting with an established moderate to large stroke. TESLA (Thrombectomy for emergent salvage of large anterior circulation ischaemic stroke) is testing thrombectomy versus medical management for patients with large cores, which is defined here as an ASPECTS [Alberta stroke program early CT score] 2–5 in patients up to 24 hours of stroke onset. In this study, internal carotid artery (ICA) or M1 occlusions are allowed, but tandem occlusions are being avoided. Currently over 40/300 patients have been enrolled.

“Then we have the TENSION trial out of Europe, which again explores thrombectomy versus medical management for large core,” Sheth explained. However, while the study has similar inclusion criteria to TESLA, large core is defined as ASPECTS 3–5. Sheth said it has a larger sample size (n=655), with around 93 patients enrolled so far.

Regarding the remaining large core trials, Sheth said the LASTE (Large stroke therapy evaluation–ASPECTS 0–5) trial, part of the IN EXTREMIS cohort, defines large core as ASPECTS 0–5, up to 6.5 hours after stroke onset, and also includes ICA or M1 occlusions, while the SELECT 2 trial is similar, but a “major difference” is that CT perfusion is required in these patients.

“At the opposite end of the spectrum, we have the low National Institutes of Health Stroke Scale [NIHSS] studies,” Sheth said.

First, he introduced the ENDOLOW (Endovascular therapy for low NIHSS ischaemic strokes) trial, which examines thrombectomy (with Embotrap; Cerenovus) versus medical management (with possible thrombectomy rescue) in patients with ICA or M1 occlusions that have an NIHSS score 0–5. “Imaging criteria for this trial is ASPECTS ≥6,” Sheth added, “and there are also some CT perfusion and MRI criteria as well.

The trial is currently enrolling, estimated to be completed by next year.”

According to Sheth, the MOSTE (Minor stroke therapy evaluation— NIHSS 0–5) trial is also looking into thrombectomy versus medical management, with possible thrombectomy rescue within 24 hours, with ASPECTS screening as an inclusion requirement.

“In terms of the endovascular therapy indication-expansion trials, we also have a Chinese endovascular trial (BAOCHE), investigating whether or not basilar artery occlusion patients benefit from thrombectomy, which is still an outstanding question, at least from a clinical trial point of view,” he told the SNIS audience.

Lastly, he explained that the MR CLEAN LATE trial is a late time window trial. He proposed that it is different from DAWN and DEFUSE 3 as CT perfusion is not required.

Instead, the imaging requirement is CT

Stroke trial update 11 angiography collateral grading.

Acute interventions: Devices Next, Sheth alluded to a number of studies looking at devices, which are mostly industry sponsored. The EXCELLENT trial, sponsored by Cerenovus, is studying the Embotrap through a prospective registry. The COMPLETE study is looking at the Penumbra aspiration catheters and the 3D separator. Sheth said this trial is now complete, and the results should be out soon. PROST by Phenox is looking at their Preset device versus the Solitaire (Medtronic) device. “This is not a registry,” Sheth explained, “but a randomised trial between two treatment

approaches.”

The TIGER trial that Rapid Medical has recently completed investigated their Tigertriever as a prospective study.

According to Sheth, Imperative Care’s trial is coming soon, which seeks to compare their Zoom aspiration catheters to Solitaire or Trevo (Stryker). Finally, he said the INSIGHT study by Penumbra is a registry for thrombus collection in thrombectomy and intracerebral haemorrhage evacuation.

Stroke recovery trials

“There are a whole suite of recovery trials, but I am going to focus on two,” Sheth told the audience. PISCES III (Investigation of neural stem cells

in ischaemic stroke) involves testing a stereotactic injection of stem cells into a region adjacent to the infarct, versus sham surgery. Key criteria for this, according to Sheth, include some residual arm function, stroke within six to 24 months, and sufficient language function. Enrolment for PISCES III is complete.

The concluding trial of his talk referred to one examining transcranial direct current stimulation (tDCS) and task-specific practice for post-stroke neglect. The design involves comparing bilateral parietal tDCS versus bilateral primary motor cortex tDCS, versus sham plus task-specific practice. In terms of its status, Sheth said it is still enrolling.

September 2020 | Issue 39

12 SNIS coverage

SNIS

Increased intracranial and systemic VCAM1 reduces per cent change in stroke-scale score after endovascular therapy Increased intracranial and systemic levels of VCAM1 have been found to independently correlate with a smaller percentage change in National Institutes of Health Stroke Scale (NIHSS) score in large vessel occlusion (LVO) stroke treated with mechanical thrombectomy. This finding was reported by Benton Maglinger, University of Kentucky College of Medicine (Lexington, USA) during a late-breaking abstract session at the virtual Society of NeuroInterventional Surgery (SNIS). Moreover, he stated that both the intracranial and systemic VCAM1 levels were higher in hypertensive patients compared to those without.

THE STUDY, WHICH SET OUT TO EXAMINE changes in leukocyte distribution in intracranial versus systemic blood collected during mechanical thrombectomy, started with the established BACTRAC (Blood and clot thrombectomy registry and collaboration) protocol and modified the tissue collection protocol to isolate lymphocytes for flow cytometry and to bank the thrombus and plasma. According to Maglinger, the researchers first established the protocol in healthy controls using venous blood samples, and later utilised it for thrombectomy cases.

“What happens is that when a surgeon goes to perform mechanical thrombectomy, they advance the device distal to the clot, and sample some intracranial blood—as well as some systemic arterial blood from the carotids, to serve as an internal comparative control for each patient,” Maglinger explained. He told the online audience that at present, the team have over 130 patients enrolled in the BACTRACT study, and it is currently being expanded across the globe.

Discussing the background to the research, Maglinger said: “VCAM mediates leukocyteendothelial cell adhesion and has been shown to play

a role in atherosclerosis, endothelial integrity and function, as well as stroke recurrence.” He noted that the study takes a “novel approach” at sampling both the intracranial and system arterial blood during an emergent large vessel occlusion stroke.

The team also use proteomic and linear regression analyses to investigate intracranial and systemic levels of VCAM, which, Maglinger stated, may be used to predict the per cent change in an NIHSS score from admission to discharge.

In terms of the cohort that contributed to the current findings, Maglinger said that the team collected data from 25 patients. “Some of the demographics that we capture will be part of the study moving forward,

This modification to the existing protocol provides the opportunity to study changes in local leukocyte populations.”

51% of neurointerventional non-physician staff report burnout

A survey of US neurointerventional non-physician procedural staff demonstrates a self-reported burnout prevalence of 51%.

According to Patrick Brown of Wake Forest Baptist University (Winston-Salem, USA), who presented the data at the Society of NeuroInterventional Surgery’s (SNIS) 17th Annual Meeting (4–7 August; virtual meeting), this figure was driven more by interaction with leadership and physician staff than by thrombectomy procedural volume and stroke call. He also highlighted that attrition among neurointerventionalist non-physician procedural staff is high.

GIVEN THE “HEAVY TOLL” THAT burnout takes on healthcare providers, Brown told the SNIS audience that the team sought to assess the prevalence and risk factors for burnout among neurointerventional non-physician procedural staff, such as nurses and technologists. Research investigating burnout within this cohort is important, he conveyed, due to the increasing demand of thrombectomy.

The team sent out a 41-question online survey containing questions including the Maslach Burnout Inventory-Human

Services Survey for Medical Personnel.

According to Brown, it was distributed to neurointerventional nurses as well as radiology technologists at 20 endovascular capable stroke centres around the USA. Brown said that the team received 244 responses; a response rate of 64%. Median composite scores for emotional exhaustion were 25 (15–35), depersonalisation (2–11) and personal accomplishment 39 (35–43).

In total, 51% of respondents met the established criteria for burnout. However,

such as sex, body mass index, comorbidities, infarct volumes, the collateral scores, and the TICI scores, and the infarct time,” he explained.

Pointing to a graph depicting per cent change in NIHSS due to protein expression levels of VCAM1, Maglinger outlined: “It shows that increased systemic levels of VCAM1 are moderately predictive of the per cent change and the NIHSS from admin to discharge; there is a lower percent change the higher the VCAM for systemic blood.

“In terms of the intracranial blood, the same relationship applies: the higher the VCAM levels in the intracranial blood, the smaller the per cent change in NIHSS observed is.”

Regarding hypertensive patients, he added that this population had significantly higher systemic levels of VCAM1 as compared to non-hypertensive patients.

This, Maglinger noted, also applies to the intracranial samples; the hypertensive patients had higher levels of intracranial VCAM1 compared to their nonhypertensive counterparts.

“As far as future directions go,” he began, “we are going to investigate the relationship between VCAM1 and infarct volume, as well as infarct time.”

Maglinger explained that currently, some studies have shown that obesity increases the basal levels of certain inflammatory cytokines that induce VCAM1 and effect vascular endothelial function.

Ultimately, he concluded that these data may help elucidate biomarkers which can be used for prognostics as well as adjunctive therapies to mechanical thrombectomy.

In an SNIS press release, co-senior author and principal investigator of the study, Justin Fraser, and Ann Stowe (both at the University of Kentucky, Lexington, USA) commented: “This modification to the existing BACTRAC protocol provides the opportunity, for the first time, to study changes in local leukocyte populations with flow cytometry in the arteries undergoing ischemic stroke in the human condition.”

They reiterate that efficient processing of lymphocytes with subsequent flow cytometry analyses will provide important insight into the neuroinflammatory microenvironment of the occlusion during stroke.

Brown explained that there was no significant relationship between hospital thrombectomy volume, call frequency, call cases covered, or length of commute.

Regarding the multiple logistic regression analysis, feeling under appreciated by hospital leadership and working with difficult or unpleasant physicians were “strongly associated” with burnout.

Moreover, at participating centres, nurse and technologist attrition was 25% over the last year, while—according to Brown—the analysis also indicated that over 50% of respondents had strongly considered leaving their position over the last two years.

Coincidentally, the percentage of US neurointerventionalists that meet criteria for burnout is similar, at 56%. This statistic was presented by Kyle Fargen, also from Wake Forest Baptist Health (Winston-Salem, USA) at the SNIS meeting last year (22–25 July, 2019,

49%

Miami, USA).

Similarly, he reported that their analyses revealed that feeling underappreciated by departments or institutions are independent predictors of burnout for neurointerventionalists, while additional payments for stroke call is protective against burnout.

Moreover, Fargen said that physicians that covered more than one hospital on call had a two times higher odds of burnout compared to those that covered a single hospital Fargen also discussed the statistics associated with the topic: “Suicide is a leading cause of death in male residents and the second leading cause in female residents. Ten per cent of medical students report suicidal ideation [and] about 400 doctors commit suicide every year. As a population, we are about twice as likely as the general population to do so.” He added, “Whether you believe in [burnout] or not, it has become a huge talking point in the medical community.”

51%

Issue 39 | September 2020

Prehospital triage 13

Educating EMS in the setting of evolving stroke triage algorithms and emerging technology During a didactic sessions titled “Farther, Better, Faster: New Frontiers in Stroke Management”, at the virtual Society of NeuroInterventional Surgery (SNIS) 17th Annual Meeting (4–7 August), Robin Novakovic highlighted the importance of educating emergency medical services (EMS) when it comes to optimising stroke systems of care and personalising this approach within a specific area, as she ultimately acknowledged that “decision making in the field is very complex”.

G

iven that emergency medical responders are often the first medical professionals with direct patient contact, Novakovic said their initial assessment, treatment and decisions on diversion and routing will have significant consequences on their subsequent care, and can “seal their fate and impact their outcome”. She added that a stroke system of care that can reduce stroke related deaths by 2–3% annually could translate into 20,000 fewer deaths in the USA. “Once you understand how your area is divided into a system of care, then you can start implementing and designing a regional stroke plan,” Novakovic told viewers, adding that her team’s stroke plan for their region in Texas is currently under revision in view to accommodating the latest guidelines.

“In your regional stroke plan it is important that you are outlining for EMS exactly how you want them to care for the patient, [for example] the proper way for positioning and stabilising the patient should they encounter shock, hyperglycaemia, or seizures,” she noted. The next steps involve educating the EMS on how to interview the patient, family, or witnesses, in order to hone in on the systems and establishing the time last known well, Novakovic asserted.

“At this point,” she added, “it is important for EMS to obtain mobile numbers for next of kin. In our area, we are looking to improve prehospital notification so the stroke team can start contacting family even before the patient arrives [at the hospital].”

In terms of instructing the EMS team on “simpler things” such as recognising stroke, Novakovic told the online SNIS audience: “You need to educate them on what stroke mimics look like. We want to start getting some past medical history as well; some of these may be exclusion criteria for tPA [tissue plasminogen activator] or even thrombectomy, and this is a good opportunity to hone in on some of these elements.”

She explained that a history of head trauma or recent surgeries, the presence of pre-existing disabilities, whether they come from a nursing home and/or able to walk independently are factors that are important to know.

Regarding medication, Novakovic noted that it is important for EMS to identify whether the patient is on anticoagulants and, if possible, to record when the last dose was taken. “Once you get past some of the early assessments, you want to start looking into using stroke screening tools,” she added.

Not all strokes are created equal

“We want to now specify whether a patient may have a large vessel occlusion [LVO], as this could affect where we take a patient,” Novakovic stated. Alluding to recently updated guidelines regarding the severitybased stroke triage algorithm for EMS, known as the Mission: Lifeline Stroke algorithm, she added: “We want to encourage EMS to have an on-scene time of less than 15 minutes while they are trying to gather all the information, stabilise the patient, and try to screen for stroke.”

When triaging patients on the way to the emergency department (ED), Novakovic emphasised the importance of education EMS on the recommended metrics that they should be looking for, as well as outlining what type of fluids to use and what to do if hypoglycaemia is detected.

However, she acknowledged that beyond this, it is “critical” that EMS call for prenotification to the receiving hospital for a possible stroke alert. “We know that patients that have access to an ED and have received a prehospital notification are going to have faster door-to-CT times, door-to-needle times, as well as symptom-to-needle times that are shorter, and more patients tend to be treated.”

Time windows and triage

The current algorithm extends out to 24-hours for symptom onset—now used to differentiate whether a patient goes to a thrombectomy capable centre or to the nearest stroke centre, Novakovic asserted.

“It is important to remember that as we are guiding EMS, it is still preferable, in the setting of the current guidelines, to transfer a patient to the nearest stroke centre if they are going to possibly disqualify for thrombolytic therapy,” she said, yet highlighted that if they are not going to disqualify, then they could be transported to a comprehensive stroke centre, even bypassing one that may be closer.

“Decision making in the field is very complex, and for the best patient outcome, it really relies on appropriate interpretation of key data. This includes whether there is an underlying large vessel occlusion; what the distance is to the nearest thrombectomy versus stroke centre; traffic patterns, as well as the efficiency of the primary stroke centre in performing imaging, starting thrombolytic therapy; their door in, door out times. All of these things need to be taken into

consideration,” Novakovic added.

Discussing thrombectomy-capable certifications, she said that these are intended for regions that have ready access to comprehensive stroke centres. “These algorithms and guidelines suggest that comprehensive stroke centres really are the preferred destination when patients have a suspected LVO, and when they are within an acceptable transport time. If there is no comprehensive stroke centre that is available, then a thrombectomy capable centre should be preferred over nearby primary stroke centres.”

Acceptable delays

“What are the acceptable delays that we should accept when creating our algorithms and instructing EMS?”, Novakovic posed to the SNIS audience. While the older algorithm incorporated a delay of 15 minutes, the latest revision, according to Novakovic, talks about a 30-minute transport time from the scene to the nearest comprehensive stroke centres as “acceptable”.

This is based on evidence that suggests that patients with large vessel occlusions should be redirected to comprehensive stroke centres if the additional delay to IV tPA is less than 30 minutes in urban areas, and 15 minutes within rural areas, she added.

“Even the Mission guidelines have begun to tackle this difference between suburban, urban and rural areas, and it has become important in your stroke system of care that you define your type of area, because there are distinctions between how you are going to transfer or recommend transferring and bypass,” Novakovic notes, adding that the Mission: Lifeline Stroke algorithm defines these areas based on population, and highlights what to look for, enabling decision-making regarding transfers in each particular area.

Evolving communication strategies

“What is important to remember”, Novakovic surmises, “is that triage algorithms risk becoming overly complex for stroke.”

She said that acute ischaemic stroke accounts for around 5% for EMS transports, ED visits, and hospital admissions. Thus, in terms of what the future holds for optimising stroke systems of care, Novakovic posits that newer devices such as communication tools may soon come into play. “These include apps which allow the EMS to work with the ED providers and create this open loop of communication.”

September 2020 | Issue 39

14 Interview

Profile

Jens Fiehler

Virtual education offers unparalleled, and relatively inexpensive opportunities, but the joy of interacting in-person with colleagues and, frankly, appreciating a fine vintage after sessions, are both hard to replicate online, Jens Fiehler, professor and chairman, Diagnostic and Interventional Neuroradiology, University Medical Center HamburgEppendorf, Hamburg, Germany, and vice-president of the ESMINT conference, tells NeuroNews.

What first attracted you to the field of neuroradiology?

I still remember the university lecture as a student when I learnt that specialists can puncture patients in the groin and access a brain aneurysm from there to place small platinum coils “that cost as much as a small Mercedes-Benz”. In that moment, the question of my future specialisation was answered.

How have your mentors in the field influenced you?

The mentor who most profoundly influenced me was certainly Hermann Zeumer, who was the first interventionalist to treat acute stroke by intra-arterial fibrinolysis in the early Eighties. He is a very practical no-nonsense physician, a philosopher and visionary at the same time. His dedication to patients and his thoughts on strategy influenced me a lot. There were also other influential mentors in the neurointerventional space that I had the pleasure of working with, such as James Byrne. My early scientific work on ischaemic stroke imaging and my scientific thinking in general was very much influenced by neurological mentors Joachim Röther and Cornelius Weiller.

How has the pandemic changed ESMINT’s approach to delivering education?

We saw a rapid increase in the number of participants in our webinars. Our beloved annual conference in Nice in early September has gone completely online.

We are developing virtual concepts for our training courses ECMINT and EXMINT to be prepared for any situation. Even before the onset of the COVID-19 pandemic, we started exploring livestreaming from angiosuites for teaching and proctoring, to address the need for support during acute procedures. Using a specifically designed remote proctoring technology, we started a training programme for acute stroke cases in Romania (EastMINT) and this month we commenced the e-fellowships in Milan, Basel and Stockholm, connecting these renowned mentor sites with selected trainees across Europe (eFellowship). With COVID-19, the relevance of both projects increased exponentially and we are very excited about the future development of these programmes.

What are the positives and negatives of delivering virtual education in the field of neurointervention?

The positive is the achievable scale. With one webinar, you can reach 500 people easily and inexpensively.

People from remote and less-wealthy regions can participate more easily and keep up with new medical developments. And with livestreaming capabilities, we can even provide educational support during acute procedures to anyone, anywhere.

The major disadvantage is missing personal discussions and camaraderie between the lectures and – let’s face it – the wine in the evening! Many joint projects and good ideas are developed in unexpected moments.

What has been the most important development in the neurointerventional field during your career?

The most important development was the discovery of effectiveness of stent-retrievers for the treatment of large vessel-occlusion stroke. By some “stroke” of luck, my practical interest in neurointerventions and my favourite scientific subject merged with this breakthrough therapy.

What technological advances do you see shaping stroke treatment over the next 10 years, or beyond?

A key development will be the increasing adoption of electronic communication connecting interventionalists to roll-out new devices in a safer way. Further, I believe robotics will play a serious part one day, but it is going to be a long road. Certainly, we will see many more studies with neuroprotective agents, such as in ESCAPE- NA1. Some of them will hopefully be positive. Perhaps the stenting of symptomatic nonstenotic carotid arteries will be another arena where we can help our patients.

Even before the onset of the COVID-19 pandemic, we started exploring livestreaming from angiosuites for teaching and proctoring, to address the need for support during acute procedures.”

What advice would you give to those beginning their neuro career?

There are many ways of doing things right. Start with strictly following one beaten path in your practical processes, but question everything, right from the beginning.

Be aware of your biases and the biases of your teachers. We all have them.

Use standards and routines to free your mind for creative stuff in research and beyond.

Be disciplined.

Synthesise your learnings and find your own way later.

Try to understand the truth behind the obvious.

Treasure the scientific method of formulating hypotheses and trying to falsify them. Do it as strictly as you can.

Try balancing textbook (yes!) learning and digesting neurointerventional tweets the same day. Master this skill.

Grasp your chances, seize the day, be entrepreneurial.

What are the biggest research questions that you would like to see answered in the neurointerventional field?

It is not so much a specific question that I would like to be answered, but rather a shift in neurointerventional culture that I would like to see completed. I really look forward to moving the needle from anecdotal observations and case series, secondarily rationalised, towards an empirical approach for rigorous testing.

Could you tell us about a particularly memorable case you have had, and what you learned from it?

Unfortunately, there were quite a few real disasters that taught me very specific lesions individually but made me approach my decision making with more humility.

I learnt the most from these cases, not from successes.

I have shared several of them in neurointerventional morbidity and mortality meetings. This is where

Issue 39 | September 2020

Interview 15

The most important development was the discovery of effectiveness of stentretrievers for the treatment of large vesselocclusion stroke. By some some “stroke” of luck, my practical interest in neurointerventions and my favourite scientific subject merged with this breakthrough therapy.” science and clinical judgement must come together.

It is of course, also important to remember that we neurointerventionalists really positively influence the lives of our patients.

Outside of medicine, what are your hobbies and interests?

I am fascinated by mechanical wristwatches, including their technique and history. With regard to sport, I am a keen runner, and my greater pleasure is lifting heavy weights and stems from, feeling their resistance and the cold metal. Unfortunately, I do not play an instrument, but I am interested in music, especially melodic death metal. I think it is the true continuation from the classic European composers. I like reading management books, but also enjoy re-reading classics, such as the works of Leo Tolstoy and also modern science fiction, for instance the work of Cixin Liu. My interest in cars and motorbikes has been replaced lately by a disturbing interest in do-it-yourself home improvement in our family holiday home.

Fact file Current appointment:

2009–present Professor and chairman, Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Education:

2006 PhD, Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf

2005–07 Board certifications for Radiology, Neuroradiology, and Quality Management in Medicine

Organisation of scientific meetings (selected)

2019/20 Vice-President, 12th ESMINT congress, Nice, France 2016 President, 8th ESMINT congress 2010–2018 Organiser of ESNRCourse in Hamburg

Fellowships and awards (selected)

2019 Fellow of the European Board of Neurointervention (EBNI) 2017 Honorary Member of the Mongolian Society of Neuroradiology 2016 Fellow of the European Stroke Organisation (FESO) 2016 Honorary lecture 2016 at the IROS, Salzburg, Austria

September 2020 | Issue 39

16 Novel techniques

Endovascular treatment of vein of Galen aneurysm malformation in neonatal patients deemed feasible A new study has demonstrated that endovascular treatment of vein of Galen aneurysmal malformation (VGAM) in neonatal patients with severe pulmonary hypertension is feasible, and can improve chances of survival.

AT THE SOCIETY OF NeuroInterventional Surgery (SNIS) 17th annual meeting, which was held virtually, Kirill Orlov (Center of Neurosurgery, Meshalkin Institute, Novosibirsk, Russia) concluded that the technique “reduces the severity of pulmonary hypertension, thus lowering the risk for developing critical heart failure or multiple organ

failure”. Orlov also told to the viewers that endovascular treatment also allows patients to “cross the critical line on their way to survival” He further surmised that to be treated with endovascular surgery, patients need to undergo meticulous selection, and surgical treatment should be used only if they have the mural subtype of vein of Galen malformations. The study’s abstract states: “The initially poor patient’s condition (the Bicêtre score <8), the choroidal subtype of malformation, and concurrent cardiac malformations are the factors preventing the favourable outcome of endovascular treatment of vein of Galen malformations in neonates.”

Discussing the rationale behind their research in Russia, Orlov explained that vein of Galen aneurysmal malformation is a rare congenital cerebrovascular disorder whose natural course has almost no favourable outcomes (<1%).

Given this, he said their objective was to analyse the outcomes of endovascular treatment of neonatal patients with vein of Galen aneurysmal malformation (VGM) during the first days of their life.

During the period between January 2013 and February 2020, 52 patients with vein of Galen malformations were operated on at the National Medical Research Center. Eleven of these patients, according to Orlov, were younger than 10 days when surgery was performed.

Twelve endovascular embolisation sessions were conducted via a transarterial approach. Cyanacrylate glue

was used in 10 cases (mural VGMs); in one case, Phil 25 non-adhesive liquid embolic system was used and two embolisation stages were performed (choroidal VGM).

Orlov noted that patients were hospitalised in an intensive care unit (ICU) having the Bicêtre score of 10–12. Prior to surgery, all patients underwent cardiac ultrasonography (that involved measuring pulmonary artery pressure)

The findings mark a promising advancement of treatment in a case where there have been few paths forward to date.” and neurosonography that involved measuring the linear blood flow velocity in the vein of Galen and afferent vessels.

All patients had pronounced pulmonary hypertension; linear blood flow velocity in the vein of Galen was ≥0.6 m/s.

Novel tandem stents thrombectomy technique a “safe and effective” rescue treatment A novel tandem stents thrombectomy technique “seems to be a safe and effective” rescue treatment for acute large vessel occlusion (LVO) that is resistant to conventional attempts, concludes a study recently published in the Journal of NeuroInterventional Surgery.

T

he authors, Haowen Xu and colleagues from Zhengzhou University First Affiliated Hospital, Zhengzhou, Henan, China, included nine patients in their retrospective case series (six male; mean age: 65.2 years; median National Institutes of Health Stroke Scale [NIHSS] score: 18). The middle cerebral artery M1 segment and terminal internal carotid artery were occluded in six and three patients, respectively.

The investigation aimed to assess the feasibility, safety, and angiographic and clinical outcomes of the tandem stents thrombectomy technique.

“The technique was performed as a rescue treatment after unsuccessful stent thrombectomy alone in four cases, and stent thrombectomy plus aspiration in five cases,” Xu and colleagues write. They report that recanalisation, defined as modified treatment in cerebral ischaemic (mTICI) 2b/3, was achieved in all patients.

Moreover, no procedure-related complications occurred, except that reversible vasospasms were observed in three patients, while one patient developed haemorrhage transformation after the procedure, but was asymptomatic. The team reported that three patients had good clinical outcome (modified Rankin Scale [mRS] score 0–2 at 90 days), and two patients (22.2%) died.

Speaking to the rationale behind the study, Xu and colleagues state that while successful recanalisation

of an occluded cerebral artery is strongly associated with improved clinical outcome and reduced mortality, standard stent thrombectomy fails to achieve successful recanalisation in 10–35% of patients. “In these refractory cases,” they write, “various rescue treatments, such as direct aspiration, intra-arterial fibrinolysis, stent placement, and balloon angioplasty have been reported to achieve successful recanalisation, while rates of effective recanalisation following these rescue treatments are still not satisfied.”

Given this, the team set out to describe a novel treatment using tandem stents thrombectomy technique for large and/or stubbornly rooted thrombus that is refractory to single stent thrombectomy and even combined with aspiration.

“This technique consists of deployment of two stents in tandem, placing the distal portion of the second stent 5–10mm beyond the thrombus and the tip of the first stent, and then pulling back both stents together. To the best of our knowledge, this technique has not been previously reported,” the authors write.

Delving into the potential advantages and disadvantages of the tandem stents thrombectomy technique, the authors acknowledge that it is beneficial in terms of removing large and/or stubbornly rooted thrombi. “The proximal portion of the second stent is

The team assessed linear blood flow velocity (LBFV) in the vein of Galen intraoperatively in all patients.

“The operative treatment stage was completed when the blood flow velocity in the vein of Galen decreased to 25–50% of the initial value,” Orlov said, adding that echo imaging showed that pulmonary hypertension was significantly reduced in 10 patients during the postoperative period, except in a patient with a choroidal subtype of vein of Galen malformation.

“Favourable outcomes were observed for eight (72.7%) patients. Two (18.8%) patients developed complications, both being caused by intracranial haemorrhage. Two patients who had been operated on died (16.6%),” he reported.

Despite this, Orlov commented: “This technique reduces the severity of pulmonary hypertension, thus lowering the risk for developing critical heart failure or multiple organ failure, and allows babies to cross the critical line on their way to survival. These findings clearly indicate a new feasible treatment option for VGAM, marking a promising advancement of treatment in a case where there have been few paths forward to date.”

overlapped within the first deployed stent, which may prompt the degree to which stent retrievers penetrate the thrombus with their struts, increasing the efficacy of clot retrieval.”

Further, they note that if the distal stent used is the Revive SE device (Codman), then due to its design— with a closed end—the incidence of clot migration/ distal embolisation during the stent withdrawal may be decreased. Xi et al add: “Because the two stents are placed and deployed in tandem, the tandem stents thrombectomy technique might be a less traumatic procedure for the vessel wall than crossing or the parallel Y-Solitaire thrombectomy technique. In our case series, no vessel trauma or dissection occurred during stent retrieval with the tandem stents thrombectomy technique.”

Despite the technique’s advantages, the authors acknowledge that it remains a “relatively complex” endovascular technique, especially when compared with conventional mechanical thrombectomy. According to the team, it requires a higher level of operator experience, which they speculate “may limit the use of this technique”. Lastly, they write that the increased cost of two stent retrievers is another disadvantage.

However, the team in Taipei conclude that while preliminary, the results show the technique to be a “safe and effective” alternative rescue technique to treat acute LVO refractory to conventional mechanical thrombectomy, and they call for further prospective studies to verify this technique.

The technique might be a less traumatic procedure for the vessel wall.”

September 2020 | Issue 39

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Dorsal root ganglion stimulation evokes motor responses in patients with complete spinal cord injury Continued from page 1

the authors, these motor impairments originate from a disconnection between descending pathways and spinal circuits caudal (below) to the lesion, which they say deprives these circuits of synaptic input necessary for the generation and control of motor responses.

While the team write that the importance of the role of afferent input for motor recovery in SCI has been reported before in EES-related studies, the DRG itself has not been targeted as a source of stimulation to evoke motor responses in patients with SCI as of yet.

“The DRG actually harbours the first-order neurons of the sensory pathway and is as such responsible for a range of afferent processes,” they note. However, apart from a preliminary study in rats and cats, there has been no report in the literature of the potential ability of DRG stimulation to evoke motor responses, let alone in patients with SCI. […] Therefore, exploring the potential of DRG stimulation to evoke motor responses after SCI would fill in a current lacuna in literature and clinical practice.”

Selectivity advantages of DRG stimulation have led to superiority in terms of clinical outcome, as compared to EES.”

Discussing the current findings, Soloukey and colleagues highlight that DRG stimulation using the stimulators and leads available on the market for chronic pain “allowed for strong and reproducible isotonic motor responses in the upper leg muscles of patients with chronic motor complete SCI”. They maintained that these responses were enough to potentially enable weight bearing.

Advantages of DRG stimulation

The authors propose that investigating new targets such as DRG for neuromodulation in an SCI setting can be advantageous for a multitude of reasons.

First, they write that the percutaneous technique of the surgical placement of the DRG leads is considered “less invasive” than the laminectomy necessary for EES when using paddle electrodes.

According to the team, the lead-placement over the DRG in the neuroforamen also enhances the physical stability, decreasing the risk of lead migration due to postural changes as seen in EES, while remaining equally as safe as EES. Additionally, they write that the opportunity to place the lead over the DRG may also promote further spatial selectivity, as it would facilitate stimulation to each spinal level separately, which remains a challenging but essential frontier in EES. “In the context of chronic pain, these selectivity advantages of DRG stimulation have led to superiority of the DRG in terms of clinical outcome,compared to EES,” the team surmise, adding that other animal experiments targeting the DRG for sensory feedback (so-called “microstimulation” of the DRG) have

confirmed the level of selective recruitment which can be achieved.

A future for DRG stimulation

Soloukey and colleagues speculate that the most likely room for further improvement of selectivity lies in increasing the limited spatial selectivity inherent to the quadripolar DRG leads. This, they say, could “further facilitate harnessing of DRG-somatotopy using microstimulation techniques”.

With the potential advantageous aspects to DRGstimulation in mind, it is warranted to consider future research looking into DRG stimulation as a means for regaining of standing and/or walking. Theobvious trade-off of EES as compared to DRG-stimulation in this effort is the fact that multilevel DRG stimulation with spatially selec-tive leads will have to be enabled in order to recruit all relevant muscles involved in locomotion. First of all, multiple leads will have to be implanted bilaterally which might cancel out the previously mentioned minimally invasive nature of lead placement. Additionally, pulse generators currently available on the market will need to be adjusted to facilitate the multilead stimulation. Combination placements of both SCS and DRG-leads to increase recruitment selectivity in clinically relevant levels (e.g., for postural stability or bladder control), would be an additional interesting possibility to investigate.

Given the array of benefits that the modality can offer, the authors maintain that future research looking into DRG stimulation as a means for regaining of standing and/or walking is warranted. “The obvious trade-off of EES as compared to DRG-stimulation in this effort is the fact that multilevel DRG stimulation with spatially selective leads will have to be enabled in order to recruit all relevant muscles involved in locomotion,” they state.

Above: Standing measurements being taken from a patient

Left: Sadaf Soloukey

Overview of the experimental design as used in this study. On day 1, patients received surgical implantation of two DRG leads, which were placed bilaterally on level L4. On days 1 and 5, EMG and clinical measurements were performed. At the end of day 1, patients were sent home with both DRG–leads activated at a submotor threshold stimulation level, and a patient diary to fill in during the submotor threshold stimulation period at home (marked orange). On day 5, the ability for assisted weight bearing was also tested with both DRG leads activated according to optimal isotonic stimulation parameters. At the end of day 5, leads were removed in an outpatient clinical setting at the department of pain medicine (as no surgery/admission was necessary for this).

“In the context of chronic pain, these selectivity advantages of DRG stimulation have led to superiority of the DRG in terms of clinical outcome, compared to EES.”

September 2020 | Issue 39

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RNS system reduces seizures and improves quality of life in those with epilepsy: Findings from two pivotal studies Two seminal studies of the RNS system have demonstrated the system’s ability to reduce seizures and improve quality of life in people living with refractory epilepsy.

THE FIRST STUDY, CARRIED OUT BY DILEEP R Nair (Cleveland Clinic Foundation, Cleveland, USA) and colleagues, details nine-year results of a multicentre, long-term treatment investigation, which have now been published in Neurology. The authors concluded that adjunctive brain-responsive neurostimulation provides “significant and sustained reductions in the frequency of focal onset seizures”, while writing that the RNS system was well tolerated, and implant related adverse events were low.

Nair et al enrolled adults treated with brain-responsive neurostimulation within two-year feasibility or randomised controlled trials into a long-term prospective open label trial (LTT), in order to assess safety, efficacy and quality of life over an additional seven years. The team found that at nine-years, the median percent reduction in seizure frequency was 75%, while responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency.

Nair’s team also reported that 18.5% of patients experienced ≥1 year of seizure freedom, with 62% seizure free at last follow-up and an average seizure-free period of 3.2 years (range: 1.04–9.6 years).

They added: “Overall quality of life, epilepsy targeted and cognitive domains of QOLIE-89 remained significantly improved. There were no serious adverse events related to stimulation and the sudden unexplained death in epilepsy rate was significantly lower than predefined comparators.”

A complementary study recently published in Epilepsia also retrospectively evaluated the real-world safety and effectiveness of the RNS system. “Safety was similar and clinical seizure outcomes exceeded those of prospective clinical trials, corroborating effectiveness of this therapy,” the authors, Babak Razavi (University of Stanford, USA) and colleagues, write. Given the findings, they speculate that clinical experience has helped inform more effective programming.

According to Razavi et al, the RNS system is a direct-brain responsive neuromodulation system that is US Food and Drug Administration-approved for adults with medical intractable focal onset seizures from controlled clinical trials. To retrospectively evaluate the system’s safety and efficacy, eight comprehensive epilepsy centres conducted a chart review of patients treated with the RNS system for a least a year, in accordance with the indications for use.

In total, 150 patients met the criteria for analysis. Razavi and colleagues reported that the median reduction in seizures was 67% at one year, 75% at two years, and 82% at three years or more, and 74% at the last follow-up (mean= 2.3 years).

“Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up,” they stated, adding that seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, MRI findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment.

Razavi and the team noted the infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural haemorrhage.

Explaining the “robust real-world responses”

Razavi and colleagues allude to several possible explanations for the rapid and robust real-world response to treatment with direct brain-responsive neurostimulation they observed in the current study, relative to the initial clinical trials.

They speculate that part of the differences lies in the fact that patients in the real world may have less severe epilepsy than patients who choose to participate in clinical trials. However, they write: “This is not the likely explanation in this case, because demographics and disease‐related characteristics of the real-world patients were very similar to the patients in the RNS system clinical trials, including age, duration of epilepsy, baseline seizure frequency, region of seizure onset, types and locations of leads, and the percent of patients previously treated with VNS [vagus nerve stimulation] or resective surgery.”

Another potential explanation the authors highlight is that accumulated experience in the clinical trials has informed more efficient and effective detection and stimulation programming strategies, which have evolved with clinical experience. Razavi and team note that in the initial clinical trials, study protocols required at least 10 visits over the first 24 months after implantation, and programming was often changed at each of these visits. Whereas, in current clinical practice, patients are usually seen six to eight times over the first 24 months and stimulation is not generally adjusted at every visit.

They add: “Contemporary practice recognises that a change in clinical seizure frequency

Neurostimulator leads wof the RNS system

may not be evident for two to four months after a reprogramming.” In light of this, they argue that more frequent programming may obscure a favourable seizure response.

“Charge density, which is a function of the current amplitude and the stimulation pathway configuration, was also different, with more gradual increase in current and lower overall charge density in the real-world patients than in the early clinical trials,” Razavi and colleagues write.

Another difference between the clinical trials and present-day practice, according to the authors, is that detection is programmed so that stimulation is delivered in response to activity typically preceding seizures, such as a run of epileptiform spikes or changes in amplitude or rhythmicity, rather than clearly developed electrographic seizures. They inform readers that “stimulating into well-developed electrographic seizures may not always disrupt electrographic seizure activity, perhaps because the seizure has already propagated beyond the region that can be impacted by spatially limited stimulation”.

“It is possible,” the investigators continue, “that delivering acute disruptive stimulation into abnormal electrographic activity—not only seizures—is effective because of providing longer-term neuromodulation.

This hypothesis is supported by the observation that the total duration of stimulation received was a median of 4.5 minutes per day in the real-world patients, which is significantly greater than in the Pivotal trial population at two years postoperatively, although substantially less than with open-loop scheduled stimulation approaches.”

In a recently published NeuroPace press release, Vikram Rao, a fellow author of the paper, comments: “These real-world outcomes are even better than those reported in the clinical trials supporting FDA approval and underscore the unique advantages of the RNS system for people living with refractory epilepsy.”

Remarking on Nair et al’s paper, Martha Morrell— also principal investigator of the study—adds: “This study is the culmination of over a decade of research with leading epilepsy centres across the country.”

“The robust clinical evidence affirms the long-term benefits of the RNS system, establishing it as part of the standard of care in the treatment of refractory epilepsy. It is exciting to realise that we are just at the beginning of harnessing the power of the data captured by the RNS system.

With growing clinical experience, and with advanced artificial intelligence research applied to our dataset of 4.5 million ECoG records, we can expect continued improvement in the efficacy of the RNS system.”

Issue 39 | September 2020

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Optimising deep brain stimulation parameters in OCD “sensitive” to symptom timecourse and side-effects Although the response rate of therapy-refractory obsessive compulsion disorder (OCD) rests at around 60% for deep brain stimulation (DBS) treatment, the authors of a recent investigation sought to understand how optimising the modalities’ parameters could enhance its therapeutic effects. While Maarten van Westen and colleagues from the University of Amsterdam (Amsterdam, The Netherlands) ultimately concluded that “decision-making in stimulation parameter optimisation needs to be sensitive to the particular time-courses on which various symptoms and side effects change”, they allude to specific directions for future research.

D

iscussing the rationale behind the study, the authors write that DBS offers “unique opportunities” for personalising patient care. Yet, they state that no guidelines on how to choose effective and safe stimulation parameters in those with OCD are currently available. “Our group gained relevant practical knowledge on DBS optimisation by treating more than 80 OCD patients since 2005,” van Westen et al write, which they say is the world’s largest cohort.

Adjustments in stimulation parameters were performed in a fixed order, the team note. First, electrode contact activation was determined by the position of the electrodes on postoperative imaging.

Second, voltage and pulse width were increased stepwise, enlarging both the chance of symptom reduction and of inducing side effects.

The team in Amsterdam found that clinical evaluation of adjustments in stimulation parameters needs to take into account: 1) the particular temporal sequence in which the various OCD symptoms and DBS side-effects change; 2) the lack of robust response predictors; 3) the limited sensitivity of the Yale-

Brown Obsessive–Compulsive Scale to assess DBS-induced changes in OCD symptoms; and 4) a patient’s fitness for additional cognitive-behavioural therapy (CBT).

Directions for future research

First, the authors reiterate that the YaleBrown Obsessive-Compulsive Scale is “inappropriate” to adequately assess the DBS-induced changes in OCD symptoms. They put forward that more precise assessment tools are needed to guide decision-making in stimulation parameter optimisation, which they argue might be achieved by a “dimensional instead of categorical approach”.

Moreover, they state that future studies should look for ways to evaluate DBS effects that remain close to what patients experience. “Given that various OCD symptoms change over different time courses, repeated interviews on different stages in the treatment course might reveal relevant changes in patients’ lived experience which can become general signs of improvement,” van Westen and colleagues explain.

Secondly, the team acknowledge that stimulation parameters are currently

New research offers a minimally invasive approach to deep brain stimulation

Jim Cornfield

Viviana Gradinaru is the 2020 grand prize winner of the Science and PINS Prize for Neuromodulation for her work to develop better delivery vectors and light-sensitive proteins that together enable precise, minimally invasive alteration of nerves.

THE ABOVE-MENTIONED STRATEGY OPENS up the potential for less -, or non-invasively, reaching targets deep in the brain, to treat brain disorders. Its application in a mouse model of Parkinson’s disease also shows it could be a way to treat brain disorders by targeting the peripheral nervous system.

By moving beyond the brain-centric strategies commonly applied in neuroscience, the approaches

optimised through a fixed sequence of adjustments. This, they write, is a time-consuming process which typically takes several months. Thus, van Westen and team argue that moving forward, studies need to look for patient-specific predictors to directly select effective stimulation parameter settings.

“We expect that with increased precision in targeting of electrodes, as is currently investigated using tractography, fewer adjustments will be required to select effective stimulation parameters.

A more direct selection of effective stimulation parameters might also be achieved by identifying particular patient profiles. These might be based on OCD symptom dimensions and the DSM 5 specification of good versus poor insight,” they write. Comorbidity profiles may also be relevant, the team add, which is the case for impulsivity and a comorbid bipolar or borderline personality disorder.

Thirdly, the investigators posit that “an extremely relevant issue” relates to the tapering-off effect of DBS. “Currently,” they state, “patients who get DBS remain tied to their clinicians for regular checkups and battery-replacements for the rest of their lives. It would be relevant to investigate in which patients, at which pace and to what degree tapering off stimulation is effective and safe.”

They continue by arguing that at present, there is no data available on the nature and time course of relapse symptoms. “We only know that when the

This contribution will benefit many centres with a smaller number of, and less experience, with DBS for OCD.”

Gradinaru developed may help overcome hurdles associated with existing treatments for brain disorders— many of which have failed to pass clinical trials.

Gradinaru, a professor of neuroscience and biological engineering at the California Institute of Technology, has recently studied how deep brain stimulation via optogenetics, which uses light to control neurons that have been genetically modified, can treat brain disorders. Her work has revealed that researchers need to be able to access relevant cell populations with less invasive, more precise tools including those that could penetrate the blood-brain barrier (BBB)— protectingthe adult brain; this would allow vectors to be delivered without surgery and invasive intracranial injections.

Those seeking to fully understand brain diseases also need to intervene earlier, which would require them to look beyond the central nervous system, for example to the peripheral nervous system.

In 2016, Gradinaru led development of a novel tool called “CREATE” that allowed scientists to deliver adeno-associated viral (AAV) vectors, harmless viruses that most people carry, across the blood-brain barriers of adult mice. Here, as described in her prize-winning essay, she and colleagues sought to improve the

DBS is switched off abruptly, a rebound effect can be observed: a decrease in mood to a level below the baseline measurement at the beginning of the treatment. It is unclear whether this is a transient phenomenon, as we studied it for a maximum of seven days.” van Westen and colleagues also point to the need for randomised controlled trials that systematically compare efficacy and safety of stimulation parameters. They write: “It would be interesting to compare optimisation strategies across centres, both those that use the same brain target and those that target the electrodes at a different structure.

“This requires that reports on clinical trials provide more details on their optimisation methods,” they add. For example, van Westen and team say that in the future, investigators may look at similarities and differences in optimisation in DBS for other conditions, such as Parkinson’s disease, where an acute sign for evaluating efficacy of stimulation parameters is available and where patients regularly suffer from psychiatric side effects, and major depressive disorder, where acute signs are also lacking and clinicians similarly observe that it takes time for patients to become aware of DBS-induced change.

Commenting on the van Westen et al’s paper, Alon Mogilner, NYU Langone Health, New York, USA, said: “While DBS for OCD has been approved by the US FDA [Food and Drug Administration] via the HDE mechanism for over a decade, the numbers of actual implants, both US and worldwide, is less than that would be expected given the prevalence of the disease. The reasons for this are unclear, but likely include the lack of standardisation of programming parameters. This contribution, the largest single-centre retrospective review of OCD DBS implants, describes their experience with programming, and will be of benefit to many centres with a smaller number of, and less experience, with DBS for OCD.”

light-sensitive nature of the protein cargo, or opsins, delivered by AAVs designed to treat brain disease. In doing so, they developed opsins with “exceptional” light sensitivity. Tested in mice, the opsins worked when the light sources used to direct them were placed on a thinned skull, rather than implanted directly in the brain via optical fibres, the more traditional and invasive route.

Pairing engineered AAVs with designer opsins selected by machine learning for their unprecedented light sensitivity allowed the vectors to penetrate large tissue volumes in the brains of mice, Gradinaru showed.

Viviana Gradinaru

September 2020 | Issue 39

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New protocol for managing a national intrathecal pump service during COVID-19 deemed “safe and efficient” In a recently published paper, Anil K Patel and colleagues of Beaumont Hospital (Dublin, Ireland) detail their experience managing a national intrathecal pump service during COVID-19, and offer a protocol that they say presents a “safe and efficient” pathway for ITP management during a pandemic.

THE INVESTIGATORS FIRST SCREENED their intrathecal pump database for patients most at risk of harm. These patients were risk-assessed for COVID-19 infection, and were subsequently enrolled in a protocol to optimise the safety and efficiency of their pump replacement or refill.

Patel and colleagues reported that 31 of 51 database patients were deemed to be high risk of intrathecal pump failure during the pandemic. “Thirty patients were successfully refilled with only one patient refusing to leave their house for refill,” they write, adding that no significant adverse outcomes occurred.

In the paper published in Neuromodulation, the team in Dublin write that the first case of COVID-19 was diagnosed in Ireland on the 29th February, and the situation escalated to an ultimate “lockdown” of the Irish population on the 27th March.

“We started screening patients on the 3rd March, and our refills started on the 5th March and completed by the 31st March. The refill date for patients was brought forward by an average of 38 days. A delay in this process could have resulted in some patients being COVID-19 positive by the time they were due for refill, with a potentially difficult decision on how to proceed,” Patel et al explain.

Moreover, the authors put forward that at this stage

of the pandemic, these high-risk patients should be “cocooning” with the rate of infection at its peak. The team noted that their staff availability was reduced, as some members were enrolled on intensive care rosters with limited time to commit to intrathecal pump management.

“In theory, home refills are a good option; but in practice, during a serious pandemic, we feel the risk to clinical team members, the patient, and other residents is too high,” Patel and colleagues write.

They highlighted the fact that the refill is being performed in a foreign environment with no clinical waste disposal mechanisms, no designated areas for donning/doffing, and no clinical backup.

Given this, they say the question of what happens if the patient refuses to attend hospital but then requires urgent admission due to a complication (e.g., pocket refill) also needs to be addressed.

The authors underline the importance of protecting clinicians during the pandemic, which they said “probably merits greater emphasis in the NSUKI [ ] guidelines”. Continuing on this point, Patel and

A critical response to the use of non-invasive vagus nerve stimulation to treat COVID-19 “Due to its non-invasive nature and ease of use, there is increasing interest for transcutaneous vagus nerve stimulation [tVNS] as a modulation technique. However, like many emerging fields in medicine, tVNS is hampered by a proliferation of small-scale uninformative and underpowered studies,” write Andreas Berger and Martina D’Agostini (University of Leuven, Leuven, Belgium) in a letter to the editor of Neuromodulation.

T

he authors allude to a specific case series also recently published in the journal, which details the effects of cervical tVNS on symptoms of COVID-19. They write that this case series is a prime example of a study that has reported positive effects that remain unreplicated, and refer to the device manufacturers’ involvement in the study as a “potential point of concern”.

The paper being critiqued, a case series published by Peter Staats (electroCore, Basking Ridge, USA) and colleagues, concluded that non-invasive vagus nerve stimulation (nVNS) might provide clinical benefits in patients with COVID-19 via “multiple mechanisms”.

Subsequently, in an interview with NeuroNews, Staats said that he and his

team believe there is a “strong scientific and clinical foundation for the hypothesis that nVNS can improve disease outcomes in patients with COVID-19”. He maintained that the robust established safety and tolerability of the modality strengthens the case for additional investigation and use of nVNS to fight the pandemic.

However, responding to the article, Berger and D’Agostini write: “While the manuscript does not contain a description of how the researchers came into contact with the two patients, it seems clear that both patients were already familiar with the tVNS device and Case 2 had already used the device to treat his asthma-related complaints. […] While neither patient was blind to the treatment, there is no

colleagues add: “Intrathecal pump teams are often small groups of clinicians with limited or no backup in the wider hospital community. If team members become ill, there is a serious threat to the care of patients.

“Our protocol advocates two team members in the room and all preparation complete before entering the room, thus reducing contact time to a minimum.

Guidelines recommend less than 15 minutes’ contact with individuals to limit your risk of infection.”

However, they acknowledge that while 15 min is an arbitrary cut-off, the key message is to reduce exposure time to a minimum. The team’s protocol also recommends that the “Refiller” and patient engage in clinical contact, whereas the “Programmer” acts as a buddy, supporting the “Refiller” at a distance, in order to remain “clean”.

“The Programmer also isolates the ‘Refiller’ from making contact with, and contaminating, the external environment until they are fully ‘doffed,’” note Patel et al, adding that the patients who presented on an ambulance trolley were easier to refill, and there was a greater distance between the “Refiller” and the patients face.

Lastly, the team admits that “technically”, it would be safer to limit the number of people in the room; but, the carers presence is useful in positioning the patient for refill and in helping to manage anxiety.

“We made the decision to keep all patients in the mobility vehicle they arrived in and we allowed carers to be present during refill,” Patel and colleagues affirmed, as they maintain in their concluding remarks that their protocol resulted in the “safe and efficient refilling and replacement of pumps in all consenting patients with intrathecal pumps” that attended their service.

Guidelines recommend less than

15 MINUTES’

contact with individuals to limit your risk of infection

mention of potential expectancy biases in the manuscript.”

The authors argue that important details about the treatment are not provided, such as which stimulation parameters had been used, how decisions regarding the stimulation procedure were made, and how symptoms improvement was examined specifically.

“While the report mentions an unspecified ‘immediate and consistent symptoms relief’”, they add, “and an improved ability to clear the lungs for patient two, it provides no indications to suggest that cervical tVNS had any treatment benefits for patient one. […] It remains unclear whether tVNS had any effects on the speed of their recovery.”

Berger and D’Agostini state that from a scientific or clinical standpoint, Staats et al’s case reports “provide no new information about the feasibility or efficacy of tVNS as a treatment add-on for respiratory symptoms associated with COVID-19”.

The authors also put forward that the “low informational value of the study, combined with the fact that it was written by employees of electroCore, makes this study seem more like a commercial rather than a scientific publication.”

Discussing these financial interests further, they note that four of the authors own stocks in the company (electroCore) that produces the neuromodulator used in the study. Berger and D’Agostini argue that financial conflicts of interest can lead to a systematic bias in the literature, as

companies may be incentivised to publish favourable results.

Despite acknowledging this, the authors emphasise that they do not principally disagree with collaborations between researchers and industry. “We do, however, urge researchers to be mindful of the importance of robust, slow science, and avoid bloating the scientific literature with studies that are uninformative, underpowered, or not preregistered.”

The letter concludes: “Given the industry sponsorship can be considered as bias-inducing, researchers who are funded by the industry should place particular importance on ensuring high levels of transparency and scientific rigour.”

nVNS and PTSD

Separately, in late August, electroCore announced publication in Brain Stimulation highlighting nVNS’ potential role in the treatment of post-traumatic stress disorder (PTSD).

The paper reports on a double-blind sham-controlled study of nineteen participants who had experienced trauma but did not have the diagnosis of PTSD and highlights the ability of nVNS to decrease the fear associated with emotional stress.

The authors hypothesised that nVNS could mitigate the stress associated with traumatic triggers compared to a sham device based on its ability to decrease the level of neural activity in areas of the brain believed to be responsible for the negative reaction.

Issue 39 | September 2020

Market watch 23 patients and staff.

Industry News

RapidAI receives FDA clearance of Rapid LVO for identification of suspected large vessel occlusions

RapidAI has announced that Rapid LVO has received US Food and Drug Administration (FDA) clearance for detecting suspected large vessel occlusions (LVOs).

Rapid LVO helps physicians speed up triage or transfer decision-making.

The company state that the technology can work in as few as three minutes, with Rapid LVO using a vessel tracker in conjunction with assessment of brain regions with reduced blood vessel density to identify suspected LVOs with a sensitivity of 97% and a specificity of 96%. Stroke team members are also immediately notified when a suspected LVO is detected.

“LVOs are the most disabling and deadly ischaemic strokes,” said Greg Albers, professor of neurology at Stanford University, director of the Stanford Stroke Center and cofounder of RapidAI. “The ability to identify LVOs rapidly facilitates more effective treatment. This is why we are very excited about the FDA clearance of Rapid LVO, a significant step forward in stroke diagnostics and care.”

A company press release states that Rapid is the only clinically validated platform available and considered by many to be the gold standard for advanced cerebrovascular imaging.

Wallaby Medical raises funds to accelerate device development for stroke treatment

Wallaby Medical announced it has recently closed a series B+ financing round worth more than US$20 million.

The company focuses on developing and commercialising medical device products for treating stroke. Wallaby Medical’s first product, the Avenir coil system, is a neuroembolic coil system for treating intracranial aneurysms and other neurovascular abnormalities.

According to the company, Avenir has received US Food and Drug Administration (FDA) 510(k) clearance, CE mark approval, and regulatory approval in Japan and is commercially available in more than 12 countries.

Wallaby has several other products

currently in development.

The funding round was led by a new investor, Citic Med Funds, with participation from existing investors Maison Capital, Qianhai Fund of Funds, and Chang‘an Capital. Hua Cai, general manager of Citic, will be joining Wallaby’s board of directors.

“We are excited and grateful to bring on Citic to our Wallaby team,” commented Michael Alper, CEO of Wallaby Medical. “We feel the resources they bring will help ensure success in our key market, China, which makes up 40% of the global incidence of stroke.”

Stryker’s Neuroform Atlas stent approved to treat aneurysms of the posterior circulation

Stryker announced that it has received US Food and Drug Administration (FDA) approval for an expanded indication of its Neuroform Atlas stent system as an adjunctive stent for use in the posterior circulation of the neurovasculature. In May 2019, the device was approved for use in the anterior circulation.

FDA clears SOMATOM On.site from Siemens Healthineers for CT exams at the bedside

The US Food and Drug Administration (FDA) has cleared the SOMATOM On.site, a mobile head computed tomography (CT) scanner from Siemens Healthineers that enables a critically ill patient to receive CT head imaging in the intensive care unit (ICU) while remaining in bed.

Performing a CT head examination at the patient’s bedside can eliminate costly transports to the radiology department, which involve high staffing requirements and potential patient risk.

“The SOMATOM On.site transforms the delivery of care for critically ill patients who require a CT head scan,” says Douglas Ryan, vice president of Computed Tomography at Siemens Healthineers North America. “The system delivers reliable and consistent image quality demanded by healthcare professionals in the ICU, neurology, and radiology departments. Additionally, bedside imaging helps to reduce patient transports, thereby reducing the risk of infection while improving workforce efficiency.”

A press release from the company states that the SOMATOM On.site offers easy scan setup, fast workflow, and integrated patient support accessories, for convenient and consistent patient positioning in the scanner. An intelligent user interface concept, myExam Companion helps the radiologic technologist navigate the examination for consistent results.

An integrated drive camera enables real-time viewing on the built-in Touch UI display for easy manoeuvring by the technologist. The scanner’s unique telescopic gantry design allows the radiation source to move away from the patient during scanning, while the base and the front cover of the gantry remain stationary. Moreover, the company states that the SOMATOM On.site system design—with the telescopic, selfshielded gantry and attachable front and back radiation shields—reduces scatter radiation compared to CT scanners without this design and provides radiation protection for neighbouring

Neuroform Atlas

According to the company, the approval makes more feasible the long-term treatment of aneurysms in the posterior circulation, which rupture more frequently and are generally more difficult to treat.

Stryker advised that the Neuroform Atlas is a self-expanding nitinol stent indicated for use with neurovascular embolisation coils in the anterior and posterior circulation of the neurovasculature for the endovascular treatment of patients ≥18 years of age with saccular wide-necked (neck width ≥4mm or a dome-to-neck ratio of <2) intracranial aneurysms arising from a parent vessel with a diameter of ≥2 and ≤4.5mm. The stent is positioned across the aneurysm neck to hold metal coils in place and occlude the aneurysm.

The premarket approval (PMA) application for the expanded indication was granted based on clinical trial evidence proving the safety and efficacy of the device. The trial’s anterior and posterior cohorts were composed of a total of 298 patients.

Sam Zaidat, director of the Neuroscience and Stroke Center at Mercy Health System in Toledo, USA, is a co-principal investigator of the US Neuroform Atlas investigational device exemption trial.

“The Atlas posterior PMA trial data shows a compelling advancement in the treatment of wide-neck posterior aneurysms,” commented Zaidat in the company’s announcement. “Posterior stent-assisted coiling with Neuroform Atlas achieved an impressive high rate of complete occlusion in this very challenging location at 76.7%. Equally impressive was the 4.3% primary safety rate.”

Co-principal investigator Brian Jankowitz, who is director of Cerebrovascular Surgery at the Cooper

Neurological Institute in Camden, USA, added, “Complete occlusion, or complete blocking of blood flow, is the gold standard in determining long-term aneurysm healing. With the additional challenges that come with treating posterior circulation aneurysms, we never would have anticipated reaching occlusion rates that rival those found in the anterior circulation. Now with Neuroform Atlas, those same high rates are achievable.”

Cerus Endovascular and Balt enter strategic distribution agreement for devices treating intracranial aneurysms

Cerus Endovascular and AB Medica, a subsidiary of Balt, has announced that they have entered into a strategic distribution agreement providing AB Medica with the exclusive rights to market and sell the newly CE marked Contour Neurovascular System and the Neqstent Coil Assisted Flow Diverter devices in Germany.

“Our partnership with Balt will provide significantly increased awareness and more rapid penetration of both the Contour Neurovascular System and the Neqstent device within Germany, the largest market within

the European Union (EU),” stated Stephen Griffin, president of Cerus Endovascular.

“Physicians in Germany have indicated their desire for greater access to our products and have, therefore, been very supportive of our decision to partner locally with AB Medica. We are excited to begin working closely together and eventually, to extending the distribution agreement into other key EU countries.”

Thomas Liebig, professor at the Institute for Diagnostic and Interventional Neuroradiology at Ludwig-Maximillian’s Universität München (LMU) and principal investigator of the CERUS clinical trial of the Contour Neurovascular System, noted, “I am delighted with the progress that Cerus has made thus far in Germany. At LMU, we performed the first case with the system in Germany back in 2018 and have been using the device consistently since CE mark was granted.”

“Balt has a long history of delivering innovative devices to the hands of physicians. With this partnership with Cerus, we are happy to continue with this tradition and look forward to providing two new unique products to physicians in Germany,” said Pascal Girin, CEO of Balt.

September 2020 | Issue 39

24 Market watch

Industry News

Tigertriever XL

Rapid Medical’s Tigertriever XL receives CE mark approval

Rapid Medical has announced CE mark approval for Tigertriever XL stentriever.

The company noted that the first patients have been treated successfully with the neurovascular device.

According to the company, the device is the latest addition to the Tigertriever family of stentrievers, which are adjustable, fully visible clot retrievers designed to treat ischemic stroke. The Tigertriever XL features a length of 53mm and an adjustable diameter that can conform to any vessel diameter up

to 9mm. It is delivered via a standard microcatheter with an internal diameter of 0.021 inches.

“Tigertriever XL is a very important addition to the ischemic stroke market,” commented Sebastian Fischer, senior Interventional Neuroradiologist at Bochum University Hospital, Germany, in the company’s announcement.

He continued: “For the first time, we have a tool that can be adjusted to these dimensions and is dedicated to retrieving large clot loads. This is an important addition to our current toolset since it can potentially reduce the number of passes required to remove large stroke-causing clots, for example, in the internal carotid artery.”

CerusEndo MC 021 microcatheter wins CE mark

Cerus Endovascular has announced that it has received CE mark approval for its CerusEndo MC 021 microcatheter, designed to allow physicians to access tortuous neurovasculature and deliver therapeutic devices to intended targets.

The CerusEndo MC 021 microcatheter, which already received approval from the US Food and Drug Administration (FDA), is the first of Cerus Endovascular’s microcatheter offerings to gain European regulatory

approval. The device will be available in multiple distal flexible profiles and is designed to offer superior proximal support, which translates to enhanced deliverability and responsiveness in physicians’ hands. According to a company press release, feedback from numerous physicians during the development of the device was extremely encouraging when performing benchtop evaluations in highly tortuous anatomical simulations compared to other commercially available catheters.

In the company news release, Stephen Griffin, president of Cerus Endovascular, comments: “We remain committed to meeting the everincreasing needs of the interventional neuroradiologist community. Our team has identified a range of increased performance demands required of a goto intracranial access microcatheter.

“As a result, we have expanded our key 021 platform so that it can deliver a wider range of devices than it was originally designed for including stents, braided flow diverters, and stentrievers, for treatment of both haemorrhagic and ischaemic strokes. In particular, the 021 ensures predictable stability and control when delivering larger and braided devices through the device lumen.”

US FDA Clears AI-based MRI interpretation assistants from Siemens Healthineers The US Food and Drug Administration (FDA) has cleared two additional Siemens Healthineers artificial

intelligence-based software assistants in the AI-Rad Companion family. Both new software assistants free radiologists from routine activities during magnetic resonance imaging (MRI) examinations, a media release from Siemens says.

The AI-Rad Companion Brain MR for Morphometry Analysis automatically segments the brain in MRI images, measures brain volume, and marks volume deviations.

The AI-Rad Companion Brain MR for Morphometry Analysis supports brain volumetry, which involves measuring the volume of gray matter, white matter , and cerebrospinal fluid in various segments of the brain and comparing the results to normal volumes. In typical clinical presentation and when combined with independent confirmation, reduced volume may indicate Parkinson’s disease, Alzheimer’s disease, or other forms of dementia. Previously, segmentation and comparison to the norm were performed manually or semiautomatically.

Based on AI algorithms, the AI-Rad Companion Brain MR for Morphometry Analysis can automatically identify roughly 30 brain segments on MRI images, measure their volumes, and compare the results to data in a normative reference database for brain morphometry from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The AI-Rad Companion Brain MR for Morphometry Analysis feeds the results into a report where deviations from the norm are marked automatically.

Issue 39 | September 2020

Market watch 25

Industry News Study says telerehabilitation efficacy and cost prove similar to traditional face-toface management

Virtual medical and rehabilitation appointments during COVID-19 could be paving the way to be a new norm, according to a recent review paper co-authored by Brodie Sakakibara (Kelowna, Canada) with the Centre for Chronic Disease Prevention and Management (CCDPM).

The paper, which examined six different clinical trials launched across Canada, has determined that virtual appointments, in the form of telerehabilitation, also work for people recovering from a stroke.

“Telerehabilitation has been promoted as a more efficient means of delivering rehabilitation services to stroke patients while also providing care options to those unable to attend conventional therapy,” says paper co-author Sakakibara. “These services can be provided to remote locations through information and communication technologies and can be accessed by patients in their homes.”

To learn how effective telerehabilitation can be, the Canadian Heart and Stroke Foundation initiative launched six different clinical trials examining stroke telerehabilitation programmes across the country. People recovering from a stroke were provided with interventions ranging from lifestyle coaching to memory, speech skills and physical-exercise training.

“Researchers from each of the six trials came together to write a review paper describing their experiences conducting a telerehabilitation study, and to report on the facilitators and barriers to the implementation of telerehab services within a research context,” says Sakakibara.

Sakakibara adds that the study authors determined there are important lessons learned from each of the six trials, noting that the efficacy and cost of telerehabilitation is similar to that of traditional face-to-face management and that patients mostly reported satisfaction with the telerehabilitation when therapists were trained appropriately, and when there was some social interaction.

Overall, clinicians prefer face-to-face interactions but will use telerehabilitation when face-to-face is not feasible.

However, since seniors are a key target group for stroke rehabilitation, as stroke is associated with aging, the technology needs to be easy to use and suit the needs of the end users.

“The older adult of today, in terms of technology comfort and use, is different than the older adult of tomorrow,” says Sakakibara. “While there might be some hesitation of current older adults using technology to receive health and rehab services, the older adult of tomorrow likely is very comfortable using technology. This represents a large

opportunity to develop and establish the telehealth/rehabilitation model of care.”

Sakakibara notes COVID-19 has amplified the necessity for telehealth and telerehabilitation for many Canadians, especially those in remote areas and for the estimated 70% of stroke victims who are no longer able to drive.

“Prior to the outbreak, telehealth/ rehabilitation was highly recommended in Canadian stroke professional guidelines, but was underused,” he says.

“Now in response to COVID-19, the use of telerehabilitation has been accelerated to the forefront. Once these programmes

are implemented in practice, it will be part of the norm, even when the outbreak is over. It is important that we develop and study telerehabilitation programmes to ensure the programmes are effective and benefit the patients.”

Viz.ai receives Medicare New Technology Add-on Payment

CMS has granted Viz.ai the first New Technology Add-on Payment (NTAP) for artificial intelligence (AI) software. NTAP, part of the CMS Inpatient Prospective Payment System (IPPS), was set up to support the adoption of cutting-edge technologies that have demonstrated substantial clinical improvement and ensure early availability to Medicare patients. Viz.ai provides software that improves clinical and financial outcomes by streamlining

acute care, leading to shorter time to treatment, improved patient outcomes, reduced length of stay, and increased number of procedures.

“Since using Viz at our centre, we have seen a decrease in time to treatment and an improvement in patient outcomes. This software should be considered now the gold standard for all systems treating stroke,” Adam Arthur, professor of Neurosurgery University of Tennessee Health Sciences Center and Semmes-Murphey Clinic.

CMS has selected Viz.ai’s stroke software, Viz LVO, formally known as Viz ContaCT, as the first AI software to receive a Medicare New Technology Add-on Payment. Viz LVO has been granted a New Technology Add on Payment of up to $1,040 per use in patients with suspected strokes.

September 2020 | Issue 39

26 Market watch

Industry News Medtronic announces US launch of its InterStim Micro neurostimulator

Medtronic has announced that its recently US Food and Drug Administration (FDA)-approved InterStim Micro neurostimulator for sacral neuromodulation (SNM) therapy is now available in the USA. Cleveland Clinic (Cleveland, USA) performed the first patient implant in the nation with the new device.

The company’s press release explains that sacral neuromodulation sends electrical impulses to the sacral nerves located in the lower back to improve bladder and bowel control. Unlike oral medications that target the muscular component of bladder control, SNM offers control of symptoms through direct modulation of the nerve activity, normalising the communication between the bladder and the brain.

“Effective long-term bladder and bowel control is needed for almost 55 million adults in the USA who often experience regular accidents and/or frequency issues that are associated with overactive bladder (OAB) and faecal incontinence (FI),” said Sandip Vasavada, professor at the Glickman Urological and Kidney Institute and section head Female Pelvic Medicine and Reconstructive Surgery, Cleveland Clinic. “A new FDA-approved option for these patients is a step forward.”

About InterStim Micro: At 2.8 cm3, it is 50% smaller than the market’s other rechargeable SNM device, making it the world’s smallest.

Allows patients to choose how and when they want to charge their device—from a quick charge once a week, or as infrequent as once per month, depending on the patient’s preference or device settings.

Features SureScan MRI technology, which enables full-body MRI conditional scans.

Does not require impedance checks prior to an MRI scan, providing more efficiency inpatient care versus the other SNM system on the market.

Can recharge from zero to 100% in less than an hour, making it the fastest battery available.

Reduces the need for battery replacement surgeries due to its life of 15 years.

“Patients unfortunately limit their lives socially, professionally and personally due to OAB and FI,” said Howard Goldman, professor and vice chairman of Quality and Patient Safety, Glickman Urological and Kidney Institute, Cleveland Clinic. “With this newly FDA-approved device, we have a new option and can offer more patients sacral neuromodulation therapy and improve their quality of life.”

Brooke Story, vice president and general manager of the Pelvic Health & Gastric Therapies business, comments

in the press release: “We created our entire InterStim portfolio in partnership with physicians backed by a 25-year track record of experience in sacral neuromodulation including over 325,000 implanted patients, five-year clinical data and more than 1,000 peer-reviewed articles.”

satisfaction questionnaire. Therapy responders at follow-up were identified as patients with at least a 50% reduction in urinary urgency incontinence episodes compared to baseline.

The company note that completion of two-year follow-ups concludes the ARTISAN-SNM study. The news release also acknowledges that due to COVID-19, upcoming medical meetings and conferences have been cancelled or restricted to virtual meetings. However, it states that detailed study results will be presented to interested parties by study investigators via an Axonicshosted webinar to be announced in the coming weeks.

Axonics

Axonics announces two-year results from its ARTISANSNM study Two-year results of Axonics’ ARTISANsacral neuromodulation (SNM) study demonstrate that patients implanted with the r-SNM system continue to receive clinically meaningful and statistically significant improvements in urinary urgency incontinence symptoms and quality of life.

The pivotal study was designed to evaluate the safety and efficacy of Axonics’ r-SNM system. According to the company, at two years, 88% of all implanted patients were therapy responders, consistent with the 89% therapy responder rate reported at one-year. Eighty per cent of patients achieved >75% improvement, with 37% being completely dry. The press release also reports that there were no serious adverse or unanticipated device-related events.

“The responder rate from the ARTISAN-SNM study continues to be the highest success rate reported in SNM literature and confirms sustained efficacy,” said Karen Noblett, a urogynecologist and chief medical officer of Axonics. “Americans with urgency incontinence are undertreated and struggle to find long-term relief. The persistent robust response and patient satisfaction with the Axonics r-SNM system demonstrates that there is an easy to use, highly efficacious treatment available to those suffering from this condition.”

The ARTISAN-SNM study is a 129-patient single-arm, prospective, multicentre, unblinded pivotal clinical study. The study was conducted in 14 centres in the USA and five centres in Western Europe. All patients diagnosed with urinary urge incontinence were implanted with a tined lead and the Axonics miniaturised rechargeable neurostimulator in a non-staged procedure. Efficacy data was collected using a three-day bladder diary, a validated quality of life questionnaire (ICIQ-OABqol), and a subject

Synchron

Stentrode brain-computer interface receives breakthrough device designation from US FDA

The US Food and Drug Administration (FDA) has granted breakthrough device designation to the Stentrode brain-computer interface for its fullyimplantable medical device that can translate brain activity or stimulate the nervous system from the inside of a blood vessel, without the need for open brain surgery.

The device, manufactured by Synchron, has already been implanted in patients with upper-limb paralysis and is currently being evaluated for its ability to enable patients with paralysis to regain functional independence by control of digital devices through thought alone.

The breakthrough devices programme is a voluntary programme for certain medical devices and certain device-led products, that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions, with the aim to provide timely access to these devices and lower the burden required for Medicare reimbursement.

“As this is a first-of-its-kind device, we look forward to working closely with the FDA to prioritise development of the Stentrode and ensure access for patients with paralysis, as well as lay the groundwork for future indications for brain-computer interfaces,” said interventional neurologist Thomas Oxley (Mount Sinai Health System, New York, USA), who is also CEO of Synchron.

The Stentrode is the only investigational, implantable device that does not require open brain surgery and is designed so that patients can train their brains to wirelessly control external systems without the need for using their hands or voice, a media release states.

Safety and efficacy data from a

currently-active first-in-human clinical trial will be used to finalise the protocol for a pivotal FDA-enabling study that will guide evaluation for US marketing approval. Future research will evaluate the use of the device in patients with paralysis due to spinal cord injury, amyotrophic lateral sclerosis (ALS), stroke, and muscular dystrophy.

Similar to the procedure utilised for implantation of cardiac pacemakers, implantation of the Stentrode is a minimally-invasive procedure during which the device is delivered to the brain through blood vessels, instead of open brain surgery.

The technology relies on a braincontrolled handsfree app platform called brainOS to translate the brain activity into a standardised digital language, directly through thought, to control apps that restore communication and limb function. In addition, brainPort, a fully internalised, wireless solution implanted in the chest provides high-resolution neural data transmission.

Preclinical studies have demonstrated the Stentrode’s long-term safety as well as its ability to pick up specific electrical frequencies emitted by the brain. The company, in collaboration with the University of Melbourne, has published their scientific results in top ranking journals including Nature Biotechnology, Nature Biomedical Engineering, and the Journal of Neurosurgery.

FDA approves Abbott iOSCompatible app for the management of chronic pain Abbott announces it has received approval from the US Food and Drug Administration (FDA) for the use of its Patient Controller app on compatible personal Apple smartphone devices.

According to Abbott, this approval allows patients living with neurological conditions, including chronic pain or movement disorders, the ability to manage therapy directly from their personal smartphone.

The approval eliminates the need to carry a separate patient programmer device, which streamlines the patient’s experience and integrates therapy management into their life. “This is an important step in the integration and connection of digital health tools that ultimately help patients live fuller, healthier lives,” the press release states.

“For physicians who are prescribing and implanting neuromodulation technologies, the ability to integrate therapies into one’s everyday life is key,” said Alexander Escobar, clinical assistant professor of anesthesiology and pain medicine at The University of

Issue 39 | September 2020

Market watch 27 conditions remotely, and this has never been more evident than in today’s pandemic where virtual care is necessary,” said Keith Boettiger, vice president, Neuromodulation, Abbott.

Product News Toledo, Toledo, USA. He added: “The COVID-19 global health crisis has demanded access to virtual treatment options, especially for those individuals with chronic medical conditions that may have difficulty coming to see their physician or would prefer not to leave their own home. To ensure our patients are receiving the care they need in the appropriate setting, close follow up is critical. Physicians have the ability to remain engaged with their patients through the Apple device, allowing them to interact and treat debilitating chronic pain.”

“The ability to support the changing needs of individuals living with debilitating chronic conditions, like Parkinson’s, without them having to leave their homes is vitally important in today’s world,” said Drew Falconer, director of the Parkinson’s and Movement Disorders Center, Inova Health System in Virginia, USA. “Abbott’s NeuroSphere Digital Care solution, including the new Patient Controller app, allows patients to handle one single device and using the

FaceTime application, interact with their provider teams in a convenient, easy-touse interface; an important attribute for those with tremors or have challenges with mobility.”

The Patient Controller app will be integrated into Abbott’s broader NeuroSphere Digital Care connected care management platform, which became available in May. It is compatible with Abbott’s suite of neuromodulation technologies, including Infinity DBS system for patients with Parkinson’s disease or essential tremor, Proclaim XR SCS System for patients living with chronic pain, and Proclaim DRG Neurostimulation System for patients with chronic pain in the lower limbs caused by complex regional pain syndrome or causalgia. This integration across all Abbott neuromodulation technologies allows physicians to more easily treat the individual needs of each patient within their practice who have an Abbott device and Apple smartphone.

“Patients are seeking digital options to better engage with their healthcare providers and manage their chronic

New study tests “first-of-itskind” EEG device

Methodist Le Bonheur Healthcare (MLH) is the first hospital system globally to participate in a landmark study using a first-of-its-kind EEG device.

A press release states that EEG (electroencephalogram) tests are conducted to detect problems in the brain that may be associated with certain brain disorders such as seizures, tumours or

strokes. A typical EEG test consists of multiple electrodes attached to a patient’s scalp with adhesive. Those electrodes have several wires connected to an amplifier which further connects to a computer that measures and records the results.

The setup and removal of a typical EEG test takes between 20–30 minutes. This new US Food and Drug Administration (FDA)-approved product, called zEEG from Zeto, can be set up in less than five minutes; which offers a more efficient and comfortable experience for the patient, a company release states.

The patient wears equipment that looks like a high-tech bicycle helmet. The electrodes do not need to be glued to the patient’s scalp, do not leave any residue on the patient and there are no wires connected to an amplifier or computer.

The EEG and video recording are uploaded to the cloud where a specialist can read them at their own convenience.

The ZETO Instant EEG has been beneficial in the midst of the unprecedented COVID-19 pandemic.

Due to the convenience of this EEG technology, personal protective equipment (PPE, the release adds, and exposure time for healthcare workers is reduced significantly. The ZETO Instant EEG uses single-use electrodes which also reduces the risk of contamination.

Calendar of events

Event details correct at time of publication.

Please check www. neuronewsinternational. com/events for updates in the wake of COVID-19.

26–29 August The World Institute of Pain (WIP) 10th World Congress Rome, Italy (also offered virtually)

7–11 October 11th World Congress for Neurorehabilitation Virtual

wip-rome2020.org/

www.wcnr-congress.org/

9–11 September 12th ESMINT Congress 2020 Nice, France

23–25 October International Neuromodulation Society Interim Meeting Mumbai, India

www.esmint.eu/

5–7 October SLiCE: Stroke Live Course Montpellier, France www.slice-worldwide.com/

September

2019 | Issue

Georgios

t T trial se RESILIENstroke to shape of care in systems untries co ing develop

convey the nt ing country the treatme in a develop that 35% of 20% of ectomy trialectomy”. Given red to just the first thromb ical thromb 0–2 compa says, “We have the score of results of had of mechan , USA) The final we have efficacy l, Atlanta Scale (mRS) reality.” d Rankin Memorial Hospita [and] by doing so, “overwhelming our same stent, d a modifie l barriers es that share nt with arm achieve G Nogueira (Grady ic Raul al and politica other countri scular treatme controls, financial, logistic e many acute ischaem of endova e and influenc misation and Sheila an therapy with overcom to impact medical Nogueira NT (Rando opportunity from the RESILIE tion versus best first presented by Brazil) at the Europe exclusively oaspira on) trial were Alegre, These data Porto Martins thromb do Sul, and/or occlusi Italy). Now, of action retriever l do Rio Grande May, Milan, NT team’s plan to large vessel stroke due sidade Federance (ESOC; 22–24 on the RESILIE Martins (Univer ation Confere an update to provide Stroke Organis NeuroNews results. positive speaks to the trial’s following

35

Matis:

“Disruptive” media

social Page 24

er: Patrick Brouw

Profile

Page 16

utility of The clinical pound evoked com entials action pot by data is echoed and ke from Evo Avalon Evoke and

the from both e the importance es New data reiterat measur hysiological es.

Avalon studies e neurop ance of objectiv ly meaningful outcom the perform and clinical evaluated spinal cordSaluda These studies closed-loop of the first (SCS) system (Evoke;es the stimulation objectively measur tion and that to stimula Medical) strated response spinal cord’s have in turn demon n, sleep, both studies in pain, functio improvements of life. and quality y to

we use physiolog FIRST time, employing evoked “FOR THE When to control decisions.

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2 tells on page cover the es.” will need Continued the procedur on the first steps, Martins or more, we the Ministry hospitals, g Expandin stage is for that the next these 20 centres initially. for NeuroNews only write a policy to approve “We will of Health says, she this, Following

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neuromodulation.com/interimmeeting

7–9 November ESO-WSO: Joint European Stroke Organisation and World Stroke Organisation Conference Virtual

2021 19–20 March LINNC Seminar 2021 – Americas Edition Miami, USA

eso-stroke.org/events/eso-wso-

Edition

LINNC-Seminar-2021-Americas-

conference-2020

8–10 November LINNC: Live Interventional Neuroradiology & Neurosurgery Course Paris, France LINNC-Paris-2020

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