NeuroNews Issue 36 EU

January 2020 | Issue 36 Demetrius Lopes:

Surface modification

Page 4

Robert M Levy:

Jason Pope:

Profile

Centres of excellence

Page 16

World’s first robotic-assisted brain surgery provokes possibility of remote stroke care Physicians in Toronto, Canada, have performed the world’s first-in-human robotic-assisted brain surgery, using Corindus’ robotic system. In the future, advocates of the robot hope that it will enable experts to remotely operate on stroke and aneurysm patients. Vitor Mendes Pereira, Joint Department of Medical Imaging and Krembil Brain Institute at Toronto Western Hospital, who led the team through this stent-assisted aneurysm coiling case, speaks to NeuroNews about how communication within this new workflow is the greatest challenge, and enthuses about the prospect of remote stroke procedures.

Page 22

“W

e were thrilled to have the opportunity to perform this first case. Robotics adds a lot of precision to neuroendovascular procedures, particularly during stent deployment. In this perspective, what is also exciting is the possibility of performing remote procedures.

“Here in Canada, we have a big problem; we have a country that is too wide, with some populations living around 10 hours away from stroke centres. So for us, the robotic system has huge potential to improve access to care.” Pereira posits that the ultimate goal is to acquire a central hub, as the team in Toronto is currently organising for some centres in remote cities of Canada to become capable of remote procedures. So far, some hospitals in Canada are already set up with the telestroke programme—according to Pereira—meaning they are already connected to the stroke network, enabling an easier transition to remote capabilities.

Remote proctoring is also something that will help diffuse knowledge, says Pereira, and subsequently increase the quality of procedures in general. He adds that when coaching a trainee, it will be very easy to take over if they ever begin to feel uncomfortable.

While the possibility of remote procedures is “one of the most exciting objectives”, Pereira says that other advantages of a robotic system include improved procedural precision at the bedside. “I have a lot of experience with intracranial stents, and perhaps few physicians could place it exactly where they want it.

But with the robot, every time, you can precisely—with millimetre precision—deploy the stent.”

Procedural success

Having acquired Corindus’ CorPath GRX in August 2019, Pereira reports that the team conducted an array of tests, and that, in the four months leading up to the first-in-human case, the team performed at least two

Vitor Mendes Pereira using the CorPath GRX console

Continued on page 2

Non-invasive targeting of deep brain structures now tested in the human brain Attempting to bridge the gap between invasive and non-invasive brain stimulation modalities, Nir Grossman of Imperial College London, London, UK, introduced delegates at the International Neuromodulation Society’s (INS) 14th World Congress (25–30 May, Sydney, Australia) to a technology that affords the steerable targeting of structures deep inside the brain, without “chemical or genetic modification of the [stimulated] brain tissue”.

ACCORDING TO GROSSMAN, the new brain stimulation modality is based on the physical principal of temporal interference. “We deliver multiple electric fields to the brain, at frequencies too high to recruit neural firing, but

which differ by a frequency within the dynamic range of neural firing.”

This technique enables the electrical stimulation of neurons throughout a region where interference between the electric fields results in a periodic

change of the envelope amplitude at the difference of the two frequencies.

“So, if the first was 1,000Hz, for example, the second could be 1,010 or 1,005Hz. These two currents create electrical fields inside the brain, and these electrical fields are superimposed by the neurones inside the brain.”

Grossman told INS delegates that although the physical concept of temporal interference has been known for centuries (it is used to record neuromuscular structure), his team has further developed the concept and made it relevant to the brain. He explained that through temporal interference, it is possible to recruit subcortical structures without the overlying cortex and functionally map a brain region without physically moving the electrodes.

Importantly, he highlights: “Temporal

interference does not replace existing brain stimulation modalities, such as [invasive] deep brain stimulation, or non-invasive transcranial current stimulation. Instead, it adds new capabilities to the existing ecosystem of brain stimulation.”

We deliver multiple electric fields to the brain, at frequencies too high to recruit neural firing.”

Continued on page 21

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January 2020 | Issue 36

Robotic neurointervention

World’s first roboticassisted brain surgery provokes possibility of remote stroke care Continued from page 1

or three experiments every week. Once the date of the procedure was set for 1 November 2019, Pereira performed a rehearsal procedure, alongside the specialist robotic technologists, on a Biomodex three-dimensional (3D)–printed flow model of the specific anatomy of the patient, a 64-year-old female Canadian resident.

At the start of the real procedure, the robotic technologists loaded the devices into the robotic arm as soon as access was completed by the bedside physicians. “Once the guiding catheter was placed, the robotic arm took over. Everything that we would usually do with our hands, we did with the robotic arm during the intracranial part of the procedure,” Pereira explains. “I was controlling the arm with the console, using the joysticks while looking at the screens in front of me. The robotic arm navigated all the devices, from the microcatheter and microwire, to the stent and coils.”

He adds: “We did not experience any procedural complications and the patient was discharged the next day. We only had one unexpected event. When I was deploying the eighth coil, my microcatheter was pushed out of the aneurysm, but I was able to put it back into the aneurysm again using the robotic arm.

We often have to do this manoeuvre manually, but it worked very well with the robotic system.

“After removing the coil, the cassette [of the robotic arm] had to be changed. We changed the sterile part of the robotic arm and we continued the procedure with a new cassette until the aneurysm was completely occluded, but our teams were trained to do this.”

Pereira acknowledges that procedural time “probably increased slightly”, as it represented a new workflow for the team. While he does not believe that the robotic procedure itself has a large learning curve, he says: “There is a big learning curve as a team.” He speculates that in the future, the physician performing the operation may be miles away from the robotic station, with only the console in sight. “When I am coiling an aneurysm manually, for example, I can do the procedure without saying a word. With a robotic procedure, the workflow is different; I have to communicate effectively, and the team has to be in tune [with me], and communicating all the time.”

In relation to what the future holds for this robotic system, Pereira says: “This is the future of our specialty. Next generation robotic systems will

Editor-in-chief:

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Vitor Mendes Pereira using the CorPath GRX console

It is about being able to provide every patient with the standard of care for stroke treatment regardless of their geographic location.” allow more steps of the procedure to be performed by the robotic arm, and certainly, more centres will be comfortable with this technology too. Regarding remote procedures, it will all depend on many factors, including connectivity between centres, and even countries. One may even foresee remote procedures in Africa or South America some time in the future.

Additionally, can you imagine training someone new [in these continents] to perform complex procedures?

Training may take years, but certainly, remote robotics may steamline it, and in turn, expand access to treatment of patients in remote communities.

Early adopters believe this is the future of mechanical thrombectomies

Pascal Jabbour of Thomas Jefferson University Hospital, Philadelphia, USA, also expresses excitement

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The CorPath GRX console

surrounding the possibility of remote procedures.

He tells NeuroNews that his institute is the first in the northeast and the third in the USA to acquire the technology. “Right now, it is approved for carotid stents, and angiograms [in the USA]. Once the intracranial indication comes in, we want to be one of the first to be ready to do that.”

“It is about being able to provide every patient with the standard of care for stroke treatment regardless of their geographic location,” Jabbour emphasises. “All the technology is there, we are just waiting for FDA [US Food and Drug Administration] approval. Then we can begin to train, and then start working on remote procedures.

“I have already worked with the robot in the lab, completing cases intracranially, and it is really amazing.

It will be the future of how we are going to carry out mechanical thrombectomy.”

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January 2020 | Issue 36

Stents and flow diverters

Surface modification: From bench to clinical practice Demetrius Lopes Comment & Analysis Demetrius Lopes has been working on the surface modification of stents and flow diverters, given that thromboembolic and antiplatelet-related complications represent the majority of those reported when using these devices. His aim is to decrease their thrombogenicity and mitigate the need for dual antiplatelet therapy. He outlines the current methods being used to lower thrombogenicity and theorises that future applications of surface modification will move beyond the realm of flow diverters.

T

he introduction of devices with surface modification represents a new chapter for the field of neurointervention. Device surface modification is the practice by which we can modify the physical, chemical or biological characteristics of the surface of a device. There are many reasons for creating coatings and making surface modifications to endovascular devices.

Ultimately, each modification is trying to “enhance” or create a desired feature for safety or performance. Currently, the most widely accepted indications for device coatings and surface modifications are: Lower material thrombogenicity - Electropolishing - Silicon carbide - Heparin - Phosphorylcholine Bioabsorbable stents Corrosion resistance - Passivation - Electropolish - Parylene coating - Material choice, including stainless steel, cobalt-chromium, and nickel titanium.

Increase lubricity - Hydrophobic - Hydrophilic It is crucial we continue to work on improving profiles for device safety in the field of neurointervention. The introduction of flow diverters for the treatment of cerebral aneurysms shifted the focus from intrasaccular embolisation to luminal reconstruction. It took over two decades to bring the concept of flow diversion to clinical practice. The initial trials demonstrated feasibility and safety treating complex cerebral aneurysms such as giant and fusiform types.

Flow diversion also improved cerebral aneurysm long-term occlusion rates. Aneurysm recurrence used to be the Achilles heel of intrasaccular

therapies, such as coils. Intraluminal devices generally require use of a dual antiplatelet regimen to reduce their thromboembolic risk. Thromboembolic and antiplatelet-related complications are amongst the most frequently reported when using stents and flow diverters.

Thrombogenicity in endovascular intervention is a multifactorial issue. At least three main factors play a significant role in thrombus formation, also known as Virchow’s triad of thrombosis: 1. Surface activation - Influenced by intimal damage and device material 2. Flow Disruption - Determined by wall apposition and stent design 3. Hypercoagulable state - Can come about due to a lack of response to antiplatelets or heparininduced thrombocytopenia Thus, the surface modification of flow diverters to decrease their thrombogenicity, and perhaps the need for dual antiplatelets, seems to be a natural next step to advance our field.

Furthermore, as we move into the next generation of flow diverters, we will be faced with new challenges for expansion of indications for ruptured aneurysms and the more distal and smaller vessels.

There are different methods to lower the thrombogenicity of a device. Some examples include: Electropolishing - EP nickel titanium absorb fewer platelets and plasma than stainless steel Silicon carbide - May reduce thrombogenicity.

Heparin coating - Actively prevents thrombus. May affect aneurysm occlusion Phosphorylcholine - Present in the surface of red blood cells. Device surface mimics red cell membrane

OCT demonstration on the endothelialisation process of a surface modified device over time in a porcine model. Day 0 (left) vs. day 14 (right).

PUFS (1Y)

PREMIER (1Y)

Shield (1Y)

Inspire (6M)

Device

Classic

Flex

Shield

Shield

Subjects Enrolled

108

141

204

114

Aneurysm type

Large and Giant

Small and Medium

ALL

ALL

Aneurysm occlusion rate

74%

79%

72%

70%

Major Stroke and Neurological Death

5.6%

2.2%

3.3%

TBD

Table 1: Comparison between studies of Pipeline without (PUFS and PREMIER) and with surface modification (Shield and Inspire).

Initial clinical experience with phosphorylcholine surface modification has demonstrated a good safety profile and no compromise on occlusion rates.”

- Phosphorylcholine surface modification of the Pipeline Flex Embolisation Device (Medtronic; shield technology) was the first commercially available device for clinical use Since there are multiple factors that determine the formation of thrombus in an endovascular implant, it is very challenging to simulate, in the bench, all variables using a single model. Therefore, it is worthwhile to review the possible types of bench testing these devices are being submitted to, prior to clinical trials.

Surface modified device performance test

Delivery test - Resistive forces are measured on the pusher as the implant is delivered through simulated vasculature.

In vitro thrombogenicity assessment - Thrombogram analysis - Human blood loop - Ex vivo primate shunt Animal models (porcine, rabbit) to evaluate thrombogenicity, endothelialisation, parent vessel stenosis, and aneurysm occlusion - Histology (both acute and long-term) - Optical Coherance Tomography (OCT) We have had a very positive experience using OCT in a porcine model to follow the impact in the “healing” process of different surface modified devices.

In our studies, the phosphorylcholine surface modification demonstrated a more evenly distributed concentric neointimal formation and no delay in endothelialisation compared to similar devices without phosphorylcholine surface modification.

At this point, the initial clinical experience with flow diverter with phosphorylcholine surface modification has demonstrated a good safety profile and no compromise on aneurysm occlusion rates (Table 1).

The preclinical testing of flow diverter surface modification has shown promising results. The translation of such results has been confirmed in initial clinical reports. It still remains to be seen if surface modification will decrease thromboembolic complications or antiplatelet medication needs compared to current devices.

The future possibilities with surface modification may also involve applying it to devices beyond flow diverters. We are already seeing new concepts with coatings and surface modification aimed towards decreasing thrombogenicity as well as faster endothelialisation.

Demetrius Lopes is a cerebrovascular neurosurgeon specialising in neuroendovascular therapy. At Advocate Health, he serves as medical director of the cerebrovascular and neuroendovascular programme, and is co-director of their stroke programme.

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January 2020 | Issue 36

Artificial intelligence

Although “unperfected”, AI has the potential to accelerate and synchronise stroke care A recently published systematic review reveals that artificial intelligence (AI) is rapidly being used by major medical centres to identify large vessel occlusions (LVO) and diagnose stroke. While AI has the potential to expedite treatment and address a critical time delay for many patients, the authors, Nick Murray (Stanford University, USA) and colleagues, acknowledge that the software is complex, and there is a wide variation in the performance of different AI products. Noting a “paucity” of randomised controlled trials comparing AI software, the team says that, in order for the field to reap the full benefits of AI algorithms, future studies should standardise methods for both validation and comparison.

T

he team from Stanford University and Johns Hopkins (Baltimore, USA) describe the fundamentals of AI and machine learning (ML) as applied to stroke: “ML is an area of AI-related research that provides tools to discover and develop decisionmaking rules from data. In the case of stroke, the primary goal of any AI or ML algorithm is to reliably identify the presence or absence of a feature, such as LVO, from 3D tomographic images.”

Speaking to NeuroNews, Murray posits that the benefits of stroke diagnostic software using AI are “innumerable”. These include: “Faster stroke diagnosis, faster stroke treatment [and] improved decisions of when and how the stroke should be treated.” Overall, Murray said, “This reduces brain cells lost, which may be the difference between returning to independent functionality and work, and becoming paralysed.”

In their manuscript, published in the Journal of Neurointerventional Surgery, the authors support the consensus that AI tools can alleviate the “unmet” need for immediate and standardised time-sensitive stroke detection and triage. They outline how the clinician can use AI in real-time to improve interpretation of

images. “This understanding is necessary for informed interpretation of the scans of individual stroke patients that use AI software,” they write.

The team reviewed the current landscape of AI in ischaemic stroke diagnostics by characterising the current literature and emerging ML diagnostic technology that has only recently been made available to clinicians. In accordance with PRISMA guidelines, they Nick Murray used PubMed, Medline and Embase to conduct their review, extracting a total of 20 studies that adhered to the criteria.

The team found that AI use in acute LVO stroke diagnostics and triage falls under three categories: automatic stroke core and penumbra size and mismatch quantification, detection of vascular thrombi or occlusions that cause stroke, and prediction of acute complications. Specifically, Murray and colleagues write that ML algorithms eliciting Alberta stroke program early CT score (ASPECTS) most commonly employ a random forest learning (RFL) classifier, while LVO

detection typically uses convolutional neural networks (CNNs). They found that average image feature detection had greater sensitivity with CNN than with RFL (85% vs. 68%, respectively), with some software performing with significantly higher sensitivity.

Nonetheless, of 10 studies reviewed that used RFL, the authors report: “The AI often out-performs single radiologist ASPECTS and is non-inferior or even better than consensus ASPECTS.” They also acknowledged that core and perfusion studies from iSchemaView’s RAPID CT and MR have the highest metrics for AI accuracy, with some datasets showing 100% sensitivity to predict favourable perfusion mismatch.

An advantage of utilising AI algorithms for acute prognosis prediction—according to the team—is the fact that they facilitate immediate treatment planning; whether or not to offer IV tPA or endovascular therapy, or near-term outcome prediction, such as intracranial haemorrhage. The Viz.ai software is noted by the authors to be the only software currently available that automatically detects blood vessel blockages and then alerts the stroke team via an app. The physicians can then activate a helicopter transport to directly bring the patient to a hospital capable of performing thrombectomy. According to Murray et al, Viz.ai’s software has been validated in multiple hospitals to date.

The authors also explain that some versions of AI have good predictive power to assist in interpretation of traditional stroke imaging outcomes. Accordingly, AI may reduce false-negative human errors in image interpretation, in turn increasing the efficiency of stroke triage and minimising morbidity and mortality.

Yet, Murray and colleagues maintain that diagnosis of acute stroke by AI “has not been perfected”, and errors still exist. They allude to peer-reviewed literature that has reported a mean sensitivity metric of 68% for AI algorithms, which “indicates that AI algorithms may miss up to one in three findings on imaging output”.

The investigators propose reasons for the failure of AI in this context: “Radiologic scan abnormalities from pre-existing central nervous injury, inadequate contrast

AI diagnostics may be the difference between stroke patients returning to independent functionality, and becoming paralysed.”

Figure 1: A comparison between acute stroke diagnostic and triage-capable software that incorporate AI for stroke imaging and emergency treatment system activation.

boluses, inability to correct for patient motion, and tortuous vessels that preclude evaluation of the contrast column.” Use of software with the highest performance and automation capability is thus essential, says Murray.

Moreover, the team write that “critical review of the radiological images by a physician remains important”, due to lower specificities reported by some AI algorithms. The authors also argue that while LVO detection methods aim for higher positive detection rates, the “burden on the physician to navigate an increased number of scans containing false positives will be noticed”.

To accommodate these AI advances, validation studies for LVO diagnostics are rapidly developing.

Nonetheless, the investigators maintain that there is a “critical need for a clear definition of ‘ground truth’ against which algorithms are evaluated consistently.”

They emphasise: “Having a consistent set of metrics is essential to improve AI in acute stroke care.”

Further speaking to NeuroNews on what the future holds, Murray speculates: “Patient CT scan imaging needs to be matched with gold standard data from MRI

Issue 36 | January 2020 scans or conventional angiographic images, to detect true final stroke volumes and the presence of LVO. Ultimately, the same stroke imaging dataset should be evaluated by each AI software for a genuine comparison and reporting of accuracy, sensitivity, specificity and dice coefficient; however, this is limited by patient privacy and sharing of proprietary software.”

AI software

Among the array of AI software platforms currently used in healthcare institutions, Murray and colleagues closely compared iSchemaView RAPID, Viz (Viz.ai) LVO and Viz CTP, and Branomix (see Figure 1 for a full software comparison).

Artificial intelligence of AI, mobile automation, and multidisciplinary team communication to synchronise stroke care, with the aim being democratisation of the quality of stroke care across rural and urban areas,” Manoj Ramachandran, co-founder of Viz.ai, tells NeuroNews. He adds: “We will be publishing more peer-reviewed journal articles, building on our previous data that in 95.5% of cases, Viz.ai saved time to stroke treatment compared to the standard of care, saving an average of 51.4 minutes and reducing the standard deviation from ±41.14 to ±5.95, meaning care becomes faster and more standardised.

“We have placed security at the centre of our platform, investing heavily in testing our systems for

weakness and ensuring maximum protection from possible patient data breaches. Having signed a major distribution deal with Medtronic, Viz.ai is now installed in 300+ hospitals in the USA and will enter the global stroke market outside the USA in the near future, having successfully closed our series B funding round recently.”

According to Ramachandran, AI and the modernisation of technology will aid the automation of processes that have historically been manual. “To truly synchronise care,” he says, “the focus needs to be on all aspects of the clinical workflow, allowing a rapid activation of geographically distributed, multidisciplinary teams [which will] lead to faster treatment and better outcomes”.

There is a need for a clear definition of ‘ground truth’ against which algorithms are evaluated consistently.”

Of these, they acknowledge that AI for LVO detection is in different stages of validation, while certain features can differ significantly based on the software platform. Specifically, they highlight that iSchemaView and Brainomix (indirect form) AI do not directly detect LVOs, but instead infer their presence based on asymmetry in collateral blood vessel density.

Brainomix (direct form) and Viz.ai offer direct LVO detection, although “only Viz.ai has reported validation metrics”, the team writes. Moreover, AI for both direct LVO detection and automatic emergency LVO treatment system activation is available only through the Viz.ai platform (see Figure 2).

“Viz.ai has been focused on combining the power

7

Figure 2: Viz.ai stroke triage software. From left to right, the process map depicts the treatment course.

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January 2020 | Issue 36

Innovation

Novel device seeks to overcome paralysis by “bypassing” nervous system Synchron recently announced the first successful implant of its minimally-invasive neural interface technology (Stentrode) as part of a trial evaluating the safety and efficacy of the technology for restoring communication in people with severe paralysis. The technology uses modular training software (BrainOs) to control assistive technologies through thought. The company’s CEO Thomas Oxley (Synchron, Campbell,) spoke to BIBA Briefings about the Synchron brain-interface system, describing it as a “bypass” for the nervous system.

Why is there a need for a device, such as Stentrode, to restore communication in patients with severe paralysis?

It is very clear from patients with severe paralysis who are not able to communicate that the lack of communication is far and away the most important [negative] element in terms of quality of life.

However, currently, we do not have a technology that truly overcomes spinal or brainstem injury. Stephen Hawkins, for example, had to use a small muscle in his cheek to activate a single switch to communicate.

With this technology, he wrote A Grand Design at about a rate of one word per minute.

If you took the concept of using a switch to communicate to the extreme by having multiple switches, with no limitations on the number of “switches”, then you could have a very efficient form of communication. People with disabilities as severe as Hawkins, or even milder, could have a similar level of communication as a person without any communication disabilities.

How does the Stentrode, in conjunction with the Synchron Brain-Computer interface, seek to restore communication?

We are creating a “technology bypass” that wirelessly connects the motor cortex in the brain to the brainOS app platform. The aim with the platform is to overcome the three primary features of paralysis— speech deficit, upper limb failure, and lower limb failure—and the first application is speech.

To do that, we are placing an interventional stent electrode— which we are calling “Stentrode”— into the command centre of the brain; the motor cortex. We then train patients to activate the Stentrode by “thinking” a specific set of thoughts.

Stentrode

Thomas Oxley

How does your system differ from other neural interface devices, such as Elon Musk’s Neuralink and BrainGate, in development?

It is less invasive. The main difference is that the other technologies out there require a craniotomy; so, part of the skull needs to be removed to get to the brain. Our system, however, uses neurointerventional techniques to implant the system through the blood vessels. Though, unlike traditional neurointerventional techniques, we are targeting the venous system rather than the arterial system.

The system wirelessly sends the information from the stent to the brainOs platform. How are you ensuring the cybersecurity of the system?

The security of the system is a major area of concern that we are taking very seriously. There are lessons that we can learn from other companies that remotely access information from devices implanted into the brain (such as cochlear implants). It is not a novel problem.

What data are already available for the system?

Twenty-five scientific studies on the system have been published in international peer-reviewed

journals. We have looked at the risks of stenosis, thrombosis, endothelialisation, and the signal quality over time [demonstrating the long-term safety of the system].

The largest study was published in Nature Biotechnology in 2016 and was an extensive work; it took us years to put that data together.

functional MRI, to ensure the motor cortex is intact and functioning.

Additionally, a neuroradiologist has to assess the vascular system to ensure that it is appropriately structured for the implant into the motor cortex. Patients do need to have a life expectancy that is greater than 12 months.

What are the aims of the ongoing feasibility trial?

Are you in discussions with the US Food and Drug Administration (FDA) about market approval?

A critical part of the study will be to characterise which patients could benefit from the technology, but the primary endpoint is the safety of the system. In terms of safety, we will be monitoring the patient to determine the potential risks, including haemorrhage and thrombosis, with the system. The secondary endpoints will be the quality and the stability of the signal over time.

With the data from the study, we will begin to adjust our artificial intelligence algorithms as we learn how we can best clarify the signal that comes of the stent and use it to control the apps.

What is the inclusion and exclusion criteria of the study?

In Australia, we have approval for five patients with a range of conditions: stroke-related paralysis, motor neurone disease, spinal cord injury, and muscular dystrophy.

All patients must have a positive

BIBA Briefings

Yes, our broad goal is to get FDA approval; therefore, we have been in discussions with them for a couple of years. We have designed an extensive trial programme that is seeking to demonstrate the safety and efficacy of our system in the way that the FDA requires for approval.

The FDA actually published, in February 2019, a guidance document (Implanted braincomputer interface devices for patients with paralysis or amputation) about getting approval because of the number of braininterface technologies in the pipeline. They have communicated clearly what is needed to demonstrate safety, so we are working through that very long and extensive checklist.

It is too early to say when we would have market approval. It will be a number of years.

BIBA Briefings is an online platform (www.bibamedtech.com/bibabriefings) that gives an in-depth analysis of the latest market intelligence from BIBA MedTech Insights (www.bibamedtech.com). It also reviews the latest industry news and pipeline developments.

For editorial enquiries, please contact Dawn Powell: dawn@bibamedical.com For sales enquiries (including BIBA MedTech Insights), please contact Merveille Anderson: merveille@bibamedical.com

10

January 2020 | Issue 36

GA vs. procedural sedation

General anaesthesia associated with better clinical outcome compared to procedural sedation for thrombectomy patients In a recently published systematic review and meta-analysis, the use of protocol-based general anaesthesia (GA) in acute ischaemic stroke patients undergoing thrombectomy was significantly associated with less disability at three-months, compared with procedural sedation. However, the authors, Silvia Schönenberger and colleagues from Germany, Sweden, and Denmark write that the findings should be interpreted “tentatively”, given that the individual studies were single-centre trials, and disability was the primary outcome in only one trial. The paper has been published in the Journal of the American Medical Association (JAMA).

ACCORDING TO THE authors, the rationale behind this investigation was driven by the previous association between GA during thrombectomy and poor neurological outcome in nonrandomised studies. “Because mechanical thrombectomy has become the mainstay of therapy for patients with acute large vessel occlusion stroke, the need to clarify the optimal anaesthetic strategy is imperative,” they write.

Through aggregating individual patient data from three single-centre trials, Schönenberger and colleagues obtained data from 368 patients (mean age: 71.5, 163 [44.3%] women). The

median National Institutes of Health Stroke Scale (NIHSS) score for the cohort was 17 (14–21), while 183 (49.7%) patients received GA and 184 (50.3%) received procedural sedation.

A total of 70.5% of the GA group and 71.4% of the procedural sedation group received intravenous thrombolysis with recombinant tissue-type plasminogen activator prior to mechanical thrombectomy.

In terms of functionality at three months—the primary endpoint—the authors reported a mean modified Rankin Scale (mRS) score of 2.8 (95% confidence interval [CI], 2.5–3.1) in the

Surpass Evolve Flow Diverter System

See package insert for complete indications, contraindications, warnings and instructions for use.

Intended use/indications for use The Surpass Evolve Flow Diverter System is indicated for use for the treatment of saccular or fusiform intracranial aneurysms arising from a parent vessel with a diameter ≥2.0mm and ≤5.0mm.

Surpass Streamline Flow Diverter See package insert for complete indications, contraindications, warnings and instructions for use.

Intended use / Indications for use The Surpass Streamline Flow Diverter is indicated for use in the endovascular treatment of patients (18 years of age and older) with unruptured large or giant saccular wide-neck (neck width ≥ 4 mm or dometo-neck ratio < 2) or fusiform intracranial aneurysms in the internal carotid artery from the petrous segment to the terminus arising from a parent vessel with a diameter ≥ 2.5 mm and ≤ 5.3 mm.

AXS Infinity LS Long Sheath See package insert for complete indications, contraindications, warnings and instructions for use.

Intended use/indications for use The AXS Infinity LS Long Sheath is indicated for the introduction of interventional devices into the peripheral, coronary, and neuro vasculature.

This document is intended solely for the use of healthcare professionals.

A physician must always rely on his or her own professional clinical judgment when deciding whether to use a particular product when treating a particular patient. Stryker does not dispense medical advice and recommends that physicians be trained in the use of any particular product before using it in a procedure. The information presented is intended to demonstrate the

GA group, which was significantly less (p=0.02) than the mean mRS score for the procedural sedation group, at 3.2 (95% CI, 3.0–3.5). Among adverse events, which were prespecified prior to analysis, Schönenberger and colleagues report that only hypotension (p<0.01) and blood pressure variability were significantly more common in the GA group.

Of importance, the authors noted that, “These findings are in contrast with the results of previous retrospective studies that reported worse functional outcome in patients with acute ischaemic stroke who received general anaesthesia compared with those who received procedural sedation.” They add that GA may be associated with a more optimal procedural condition for performing mechanical thrombectomy because of the absence of patient movement.

To initially guide their study selection, the investigators looked into randomised clinical trials of adults with an NIHSS score of at least 10 and anterior circulation acute ischaemic stroke.

Then, individual patient data from three single-centre, randomised, parallel-group, open-label treatment trials with blinded endpoint evaluation that met inclusion criteria were analysed, using fixed-effects meta-analysis.

Specifically, these trials were: SIESTA (Sedation versus intubation for endovascular stroke treatment), ANSTROKE (Anaesthesia during stroke) and GOLIATH (General of local anaesthesia in intra-arterial therapy).

Of note, the latter recently won the

European Society of Minimally Invasive Neurological Therapy (ESMINT) award for best European publication in the Journal of NeuroInterventional Surgery (JNIS).

In support of the current review, the authors also allude to a post hoc analysis of SIESTA that suggested advantages for several technical aspects and a shorter procedure time with GA. Regardless, Schönenberger and colleagues conclude that further research is needed to “identify clinical and radiologic factors that could predict when a primary GA is necessary to reduce the number of emergency conversions from procedural sedation to GA.” Further, they emphasise—given the likelihood that patient populations and anaesthetic strategies differ from country to country—that a large, multicentre trial which includes “at least a basic agreement on standards of procedure and physiology parameter targets” is necessary.

breadth of Stryker product offerings. A physician must always refer to the package insert, product label and/or instructions for use before using any Stryker product. Products may not be available in all markets because product availability is subject to the regulatory and/or medical practices in individual markets. Please contact your Stryker representative if you have questions about the availability of Stryker products in your area. The Stryker products listed above are CE marked according to the Medical Device Directive 93/42/EEC. Stryker or its affiliated entities own, use, or have applied for the following trademarks or service marks: AXS Infinity LS, Stryker, Surpass Evolve, Surpass Streamline. All other trademarks are trademarks of their respective owners or holders.

The absence of a product, feature, or service name, or logo from this list does not constitute a waiver of Stryker’s trademark or other intellectual property rights concerning that name or logo.

Surpass Evolve is not approved for use in the USA. FDA approval is pending.

Issue 36 | January 2020

Flow diverters

THIS ADVERTORIAL IS SPONSORED BY STRYKER

How Surpass Evolve is making headlines across the world Once considered a novel endovascular approach to treating cerebral aneurysms, flow diverters have increased in popularity over recent years, with technology continuing to advance. Recently, international neurovascular meetings have seen a number of physicians from Europe, Canada, and Australia present their early experiences with Stryker’s latest entrant into the field of flow diversion: Surpass Evolve.

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onsiderable engineering changes and simulation testing by leading physicians around the world have led to the development of Surpass Evolve. Among other things, this included reducing the number of wires and modifying the braid angle to achieve an implant with optimal mesh density, implant opening, and conformability. Saleh Lamin of Queen Elizabeth Hospital, Birmingham, UK, reiterated these developments at the European Society of Minimally Invasive Neurological Therapy (ESMINT) annual meeting (4–6 September, Nice, France), acknowledging that one of the key differences from Surpass Streamline is the braid angle: “It is steeper, which allows for more radial force, expansion, and better opening.”

From bench to bedside in Canada

Vitor M Pereira of Toronto Western Hospital, Toronto, Canada, the first physician to carry out first-in-human cases using Surpass Evolve, described the translation of the device from laboratory to clinic at the ESMINT meeting. During the development of the device, his team had the opportunity to carry out multiple simulated experiments in silicone models. “This gave us a lot of confidence in terms of the deployment,” Pereira said.

The team in Toronto has now completed Vitor M Pereira 14 cases in total, from small paraclinoid aneurysm cases to giant fusiform aneurysm lesions. Pereira presented a case involving tortuous anatomy: a 64-year old patient with a partially thrombosed fusiform aneurysm. He said they decided to treat because of the enlargement of the aneurysm, which was gradually increasing. “One thing we saw was that, because of the loop inside the aneurysm, we had to navigate the device around this ‘twist’, but as we pushed, the twist resolved itself,” he explained. He added that, Surpass throughout this complex case, the Evolve device was “very stable”, and it was “easy to recapture the distal portion of the wire”.

After administering steroids to the patient and placing them on anticoagulants for 48 hours, the early MRI follow-up was positive, noted Pereira. The aneurysm was already occluded, and the team did not observe any flow within the aneurysm. “We are always conservative in these lesions,” he added, “but we have been successful in this case, and we can already see that the aneurysm

has thrombosed.”

In terms of three-month follow-up, Pereira posited that he has observed “probably seven or eight cases,” and all aneurysms were completely occluded, for the small paraclinoid cases. In relation to large cavernous lesions, he said: “Even within a month, they were also completely thrombosed.” He acknowledged that bench tests are needed to demonstrate the performance of the device, but irrespective of this, he maintained that his team is seeing earlier thrombosis based on their collective experience.

Pereira alluded to an experiment carried out in Toronto, examining aneurysm flow after flow diverter placement. Using a machine that measured mean aneurysm flow amplitude (MAFA), Pereira and colleagues found that the 64-wire Surpass Evolve elicited 15–20% lower MAFA score, versus a 48-wire device. This suggests that a greater number of wires may lead to more flow diversion and a higher chance of thrombosis. According to Pereira, this has also been recognised clinically.

He concluded: “I think the pushability and trackability is remarkable. I have been using long devices, 5x30mm and 5x40mm, but I have not felt this difference when using Evolve; [...] it is like you are pushing a 3mm device. Even in complex, large neck aneurysms, the device has behaved very well.”

Pereira’s advice to colleagues wishing to use Surpass Evolve is to start with cases that have straight or less complex anatomy, such as small neck or paraclinoid aneurysms. Having some preclinical experience on the bench—on patient-specific models—will also help.

He explained that the manipulations that are needed in order to open the device require a change in technique.

At the distal portion, he said, “resheathing can be easily done when you need to precisely place the device. Be careful not to push the device. […] I have been unsheathing more than

11

AP-002810 pushing, adapting my technique for Evolve.”

Early European experience

Affiliated with the first site in Europe to work with Surpass Evolve, Lamin shared his early clinical experience with ESMINT delegates: “The main impression I get is that [Evolve] has easy trackability and reliable distal opening.” Although acknowledging that the number of cases performed was limited, he explained that his team observed no major clinical sequelae, while the device displayed very good visibility and wall apposition. “It is less cumbersome than Saleh Lamin the previous Streamline device, as it is catheter deliverable,” he added.

First Australian cases

At the World Federation of Interventional and Therapeutic Neuroradiology’s 15th congress (21–24 October, Naples, Italy), Hal Rice of Gold Coast University Hospital, Southport, Australia, also shared his experience with Surpass Evolve. He spoke to NeuroNews about how flow diversion has changed his practice: “We have been doing flow diversion since 2007 in Australia [and] what we have found is that our practice has changed from less than 5% of patients receiving flow diversion therapy to close to 50%, where appropriate, being successfully treated with flow diversion.”

Rice’s team in Southport treated their first case with Surpass Evolve in April 2019.

Now, 13 patients in total have been treated—all of whom had anterior circulation aneurysms, including paraophthalmic, paraclinoid, and wideneck saccular aneurysms. Hal Rice Referring to the sixmonth angiographic follow-up in this cohort, Rice said: “It has been a really positive experience.”

He corroborated the key benefits of Surpass Evolve put forward by Pereira and Lamin. “The first is trackability, the device is very stable and tracks well in tortuous anatomy, which is a limitation of other devices. That stability means you have more confidence using the device. The second benefit is the opening of the stent. With improved radial force, it has a much more reliable opening and greater apposition to the vessel wall; without good wall apposition, we do not observe good healing. The third advantage is recapturing—you can easily recapture the device so you can reposition it.”

Rice speculated that there are two cohorts of physicians globally who will reap the benefits of Surpass Evolve: those with a lot of experience with flow diverting stents, and those who are new to the field. Regarding the former, he said that many see a huge improvement with Surpass Evolve, and it is “a lot easier to use compared to other devices”.

For colleagues who do not have a benchmark of the previous challenges of flow diversion, Rice surmised: “It will mean the learning curve to use flow diverting stents will be a lot shorter.”

The opinions and views of those cited in this article do not necessary reflect those of Stryker.

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January 2020 | Issue 36

Award-winning oral papers

First-pass success reduces hospitalisationrelated and annual care costs in six European countries The first European study to evaluate the economic impact of firstpass effect (FPE) found that FPE patients not only benefit clinically, they also endorse favourable economic outcomes. At the 15th Congress of the World Federation of Interventional and Therapeutic Neuroradiology (WFITN; 21–25 October, Naples, Italy), Tommy Andersson of Karolinska University Hospital, Stockholm, Sweden, and AZ Groeninge, Kortrijk, Belgium, concluded: “Based on these results, FPE may represent a new and valid goal for endovascular therapy in acute ischaemic stroke.”

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he clinical and economic impact of first-pass success was assessed from a European cost perspective in conjunction with Cerenovus, using the results from the ARISE II (Analysis of revascularisation in ischaemic stroke with EmboTrap) study. The investigators found that both hospitalisation-related and annual care costs were in favour of the FPE patients, a finding that persisted throughout the six countries they

studied: France, Germany, Italy, Spain, Sweden and the UK. In terms of the first-pass success rate in the target population, Andersson said that of the 227 patients included in ARISE II, 172 achieved a modified treatment in cerebral ischaemia (mTICI) score of 2c–3. Of these, 91 patients achieved first-pass success (FPE group), whereas for 81 patients multiple passes were needed (non-FPE group), giving

rise to a 53% rate of FPE among patients in whom mTICI 2c–3 was achieved. He added that baseline characteristics were balanced across most variables between these two groups.

“Cost consequences were compared between the FPE group versus the non-FPE group, at two separate timehorizons,” Andersson said. Regarding hospitalisation-related economic impact, cost savings were derived from hospital length of stay and devices/methods used. The estimated cost savings for the FPE group were SEK28,727 in Sweden, €2,164 in Germany, £1,711 in the UK, €2,884 in Italy, €1,563 in France, and €4,513 in Spain.

Andersson also reported the annual care economic outcomes, which described the cost savings within the first year after stroke. Again, first-pass success led to further cost savings of SEK12,777 in Sweden, £2,041 in the UK, €694 in Italy and €2,140 in France.

Importantly, Andersson highlighted that the average cost for annual care in this first year following stroke incrementally increased as the modified Rankin Scale (mRS) score of the patient group increased. For example, costs for those achieving an mRS of 0 were €12,870 in France, and even though a significantly lower percentage incurred an mRS of 5, costs rose to €40,313 per patient for this cohort.

Hospitalisation-related economic outcomes. Courtesy of WFITN presentation. Full manuscript to be published soon.

Use of optical coherence tomography deemed feasible after first-in-human analysis

Results of the first-in-human analysis of acute interactions and healing process after flow diverter implantation using optical coherence tomography (OCT) imaging was presented by Boris Pabón, Angioteam-Angiosur, Medellín, Colombia, at the 15th Congress of the World Federation of Interventional and Therapeutic Neuroradiology (WFITN; 21–24 October 2019, Naples, Italy).

HAVING EVALUATED THREE patients at the time of presentation, Pabón said: “The ultimate objective was to evaluate the feasibility and success of OCT technology after deployed intracranially and extracranially, and to describe the acute findings, and after six weeks.”

During the acute phase, the investigators assessed both the safety and feasibility of the procedure, as well as anatomic and technical considerations. The latter included evaluating each procedure in terms of wall apposition, stent conformability, strut symmetry, and acute thrombosis phenomena events. Additionally, through early (six weeks) and late (six months) follow-up, Pabón and colleagues evaluated the rate of occlusion, evidence of endothelial healing at different levels of the device, and its relation with pathological segments.

Discussing his experience with OCT, Pabón told delegates at WFITN, that while “OCT is a challenging procedure requiring a highly experienced neuroendovascular team”, it is feasible. He added that the technology is a reliable method to detect micro intrastent thrombosis, prolapse of thrombogenic material, apposition of the stent, conformability, fibrin bridges and neoendothelium. Pabón also reported that the team observed no adverse events.

Speaking of the sensitivity analyses addressing the variability of different key parameters of the cost calculation, Andersson said: “The results were consistent with the main analyses regarding hospitalisation-related and annual care costs.” He added that variations in the total length of stay or increasing/decreasing the costs by 20% did not alter the direction of the results.

Andersson concluded: “Patients in the FPE group had improved functional outcomes, a trend towards lower mortality, and a faster and more complete recovery, which all led to reduced hospitalisation-related and annual care costs in every country that we studied.”

Now, speaking to NeuroNews, he outlines the importance of FPE: “It is clear that FPE leads to better clinical outcome which now has been shown to also save costs but we still do not

First-pass success may represent a new and valid goal for endovascular therapy.” fully understand exactly why it is so important.

“FPE mostly leads to a shorter procedure time, but that is probably not the complete truth. For instance, if it takes 45 minutes to achieve FPE, does it still have the same beneficiary effect? That may very well be the case, and consequently, we need to develop even better techniques and strategies to be able to remove difficult clots, including those rich in dense fibrin and platelets, regularly, with only one pass.

We realise, as time goes on, that when performing a thrombectomy, we have to immediately ‘throw in everything’ to achieve FPE. It is good for the patient and it probably saves money.”

“In the near future, routine use of OCT may direct dual antiplatelet therapy based on individualised analysis,” Pabón said. Now speaking to NeuroNews, he adds, “The community are really excited about these findings, because you can evaluate both the mechanical factors, and the biological response after stent deployment. I consider this new technology a new diagnostic tool. You can evaluate the delivery and presence of some conditions as well as the follow-up, and [subsequently] make judgements as to whether to continue or stop treatment.”

Pabón explains that while conventional digital subtraction angiography and MRI are common modalities used to image cerebral vasculature, they have limitations pertaining to image-resolution, which means their potential to evaluate the biological healing process is restricted.

OCT is currently more established in coronary plaque characterisation and coronary stenting, Pabón says, but emerging indications in the diagnosis of different peripheral vascular conditions (including cervical carotid bifurcation visualisation) led to an “international interest” in evaluating the possibility to reach the intracranial vasculature.

“Now, we are waiting for neuro-dedicated OCT. People are working on it, it is coming soon,” confirms Pabón.

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January 2020 | Issue 36

ESMINT coverage

MR CLEAN II trials are expanding into France The recent European Society of Minimally Invasive Neurological Therapy (ESMINT; 4–6 September, Nice, France) meeting saw Adriaan CGM van Es of Erasmus Medical Center in Rotterdam, the Netherlands, present an update on the MR CLEAN II trials currently underway. While MR CLEAN LATE and MR CLEAN NO IV are progressing well in terms of patient inclusions, he said MR CLEAN MED is lagging, and for this reason, the trial will expand into France.

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urther updates he alluded to were in regards to the inclusion criteria used for MR CLEAN LATE, a

multicentre randomised controlled trial (RCT) investigating endovascular therapy in the time window 6–24 hours after

symptoms onset. van Es said: “If you look closely at the populations included in DAWN and DEFUSE 3, you can see that the infarct core was very small: 18ml and 25ml for DAWN and DEFUSE 3, respectively.” Now, those with a small infarct core (<25ml) on CT perfusion, as well as an ischaemic tissue-to-core ratio of ≥1.8 and a National Institutes of Stroke Scale (NIHSS) score of over 10 are being excluded from the trial.

Generally speaking, van Es acknowledged the “liberal” inclusion and exclusion criteria for MR CLEAN LATE, given that even collateral grade 1 is sufficient to enter the study. He said that the investigators will include a maximum of 100 patients with poor collateral

flow. In terms of technique, he added that any device can be used, employing a stentriever, aspiration or combined technique. Pointing to the progression of the trial, van Es proposed that the inclusion rate is “picking up”; since the first patient was enrolled in February of 2018, there have been 146 inclusions (as of August 2019).

The second trial he discussed was MR CLEAN MEDICINE: a multicentre RCT of endovascular treatment examining the effect of periprocedural medication—heparin, antiplatelet agents, both or either. While the study was previously a 2×3 factorial design, with the intervention being administration of aspirin (300mg loading dose) or no aspirin, in combination with unfractionated heparin (low dose, intermediate dose or no dose), van Es said, following the interim safety assessments, that there has been an unanimous decision to stop recruitment for the intermediate dose of heparin arm.

According to van Es, the safety and monitoring board for the MR CLEAN II trials is led by Peter Rothwell from the University of Oxford, Oxford, UK. An interim analysis is carried out after each five symptomatic intracerebral haemorrhage’s (ICH) and/or after 10 deaths. It was after the fourth safety analysis when the decision was made to terminate the intermediate dose, meaning the trial’s design was adapted to a 2×2 factorial design.

Explaining the rationale behind this pharmacological intervention, van Es said: “As we all know, successful recanalisation does not always lead to restored tissue perfusion. However, this incomplete microvascular reperfusion is reversible, and can potentially be influenced by pharmacological therapy.”

He added that microemboli can be derived from the proximal thrombus— locally formed by activated coagulation or by endothelial damage caused during endovascular therapy.

Further, another process that contributes to incomplete microvascular reperfusion, van Es said, is the formation of cellular plugs that block capillaries. “We call them neutrophil extracellular traps [NETS], and they consist of thrombocytes, erythrocytes, leucocytes and fibrin. Specifically, these NETS do not respond to rt-PA.” He put forward that these NETS can be targeted with heparin. While the risk for symptomatic ICH is approximately 2%, van Es noted that there is no RCT data on the effect of heparin during EVT. Although recognising that the team is behind schedule in relation to recruitment, van Es said: “We are very happy that we can expand the study into France, and that we can start [recruiting] in six new centres in May; in Nancy, Nantes, Bordeaux, Montpellier and two in Paris.”

Lastly, van Es alluded to the MR CLEAN NO IV trial, which looks into whether skipping IV thrombolysis before endovascular therapy leads to a 10% absolute increase in good outcome, in particular, by avoiding intracranial haemorrhage. “To summarise the

Issue 36 | January 2020

There has been an unanimous decision to stop recruitment for the intermediate dose of heparin arm.” trial, it compared direct intra-arterial thrombectomy with a combined approach of IV thrombolysis (rt-PA 0.9mg/kg) plus intra-arterial thrombectomy,” he told delegates at ESMINT. The team’s aim is to include 540 patients using a very “pragmatic” inclusion and exclusion criteria. MR CLEAN NO IV uses deferred consent, meaning that patients can be randomised first, and asked for consent up to 90 days following randomisation.

Speaking on what motivated this study, van Es said that “quite a few” observational studies are suffering from confounding variables—considering

ESMINT coverage that the patients not receiving IV thrombolysis are likely to have contraindications, such as an elevated INR, recent surgery or a late presentation.

According to van Es, this led the team in the Netherlands to conduct their own systematic review on the topic. They found 24 studies, with one post hoc analysis from an RCT, four prospective cohort studies and 19 retrospective cohort studies. “When these data are combined with unadjusted odds ratios, the data seem in favour for the group receiving IV thrombolysis and endovascular therapy. However,” he added, “if you look at the odds ratios that have been adjusted for confounders, there is a small favour for IV thrombolysis and endovascular therapy—which is not significant anymore.”

Moreover, van Es told delegates that if you look at studies including only patients without contra-indications for IV thrombolysis, the data favour endovascular therapy alone, but again, this finding is also not statistically significant. “So simply, we can conclude that we are still not sure what to do,” surmised van Es.

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Adriaan CGM van Es presenting the MR CLEAN II trials at ESMINT 2019

With the first patient enrolled into MR CLEAN NO IV on 24 January 2018, 242 further patients have entered into the trial as of August 2019. van Es

confirmed: “This trial is moving quite well, we have more inclusions that what we projected at this point, so we are very happy.”

Multimodal imaging identifies stroke patients most likely to benefit from mechanical thrombectomy “Target mismatch patients experience a large benefit of reperfusion, when we translate the biological effect into outcome,” JeanMarc Olivot (Hospital Centre, University of Toulouse, Toulouse, France) told delegates at the European Society of Minimally Invasive Neurological Therapy (ESMINT; 4–6 September, Nice, France). In light of this, he put forward that penumbral imaging helps to identify acute ischaemic stroke patients most likely to benefit from reperfusion.

THESE FINDINGS, PRESENTED by Olivot, were a result of the FRAME (French acute cerebral multimodal imaging to select patients for mechanical thrombectomy) trial; a prospective multicentre cohort study. Explaining the study’s rationale, Olivot said, “Infarct progression is highly variable within the first six hours after stroke onset. We know that target mismatch (TMM) identifies the patients who have salvageable tissue independent of the time from symptom onset. [Also] we know that patients with target mismatch as inclusion criteria seem to have the most benefit from mechanical thrombectomy within six hours.”

Alluding to the recently published HERMES metaanalysis, Olivot acknowledged that 90% of patients enrolled in studies such as SWIFT PRIME and EXTEND IA had a target mismatch. He added that the HERMES investigators also mentioned that patients who had no penumbra (no mismatch), did not seem to benefit from mechanical thrombectomy. Moreover, he highlighted: “As the target mismatch definition differs according to [previously published] studies, and as there has been no prospective estimation of the impact of the prevalence of target mismatch on baseline imaging assessed blindly of clinical outcome, there is currently no demonstration that mechanical thrombectomy has to be limited to the subgroup of patients based on imaging criteria.”

Yet, Olivot read out the current stroke guidelines (ESOC-PICO-9) to the delegates, which stated that for adult patients with anterior circulation large vessel occlusion-related acute ischaemic stroke, presented from 0–6 hours from time last know well, advance imaging is not necessary for selection. However, Olivot posited that the quality of this evidence was moderate, and weak in strength.

Given the gap in the literature and their conflicting view of the guideline, Olivot explained that the FRAME investigators sought to investigate the relationship between the success of mechanical

thrombectomy performed within the the target mismatch group, and 19 in six hours, the rate of good functional the no target mismatch group.” Other outcome (modified Rankin Scale 0–2) at statistically significant differences three months, and the presence or absence regarding medical history included of target mismatch on pretreatment hyperlipidemia, which was 32% in the multimodal imaging. target mismatch group and 15% for “We insisted on no limit in terms of those with no target mismatch, and the National Institutes of Health Stroke percentage of smokers in the no target Scale [NIHSS] and no limit in terms of mismatch group was double that of the ASPECTS [Alberta stroke program early target mismatch patients.

CT score),” said Olivot, speaking on the In relation to the imaging-core lab inclusion criteria. In terms of the target readings, Olivot highlighted, “What was mismatch definition, the investigators very different was the size of the core. used that derived from EXTEND IA: 61% of The median core lesion in the target core volume <70ml; mismatch ratio >1.2 the target mismatch group was 13.3, and in the no and mismatch volume >10ml. Treating mismatch had a target mismatch group, it was 102, so physicians were blinded to perfusion good outcome almost 10 times larger.” maps and core volume measurement at versus 35% in The results, Olivot said, were positive. the time of the treatment decision, Olivot the no target “We are happy to see that we validated explained. Automatically processed maps mismatch our hypothesis: 61% of the target were sent to a study server using RAPID mismatch had a good outcome versus (iSchemaView) software and clinical outcomes were 35% in the no target mismatch.” It was highly significant assessed by independent raters. even after adjustments, he added. The researchers also “We hypothesised that 60% of the patients with target stratified based on the occurrence of reperfusion: “Target mismatch would have a good outcome, and 35% with mismatch patients did benefit from reperfusion, 65% no target mismatch would have a good outcome at three of them had a good outcome after reperfusion versus months,” stated Olivot.

38%,” Olivot said. This compared to 35% versus 3% Of the 220 eligible patients that were enrolled, two among non-target mismatch patients. were excluded, leaving 218 to undergo multimodal In conclusion, Olivot and his team found that the imaging prior to treatment. Seventy-one per cent prevalence of target mismatch within three hours after (n=155) of the cohort had a target mismatch, while 29% onset was “not that high”, at 71%. “We saw that 22% (n=63) had no target mismatch. Within the latter group, of patients had a large core … and almost 20% of the 48 (76%) had a core of over 70ml. patients within three hours have almost no penumbra left.

The mean age for patients with a target mismatch “Target mismatch patients have experienced a large tended to be older, Olivot said (72.1 years vs. 65.3 benefit from reperfusion. Non-mismatch patients did not years in no target mismatch group), while they were appear to benefit from reperfusion. So penumbral imaging also less likely to be transferred (16% vs. 29%). helps to identify patients who are most likely to benefit The baseline NIHSS was also different, “Sixteen for from mechanical thrombectomy.”

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January 2020 | Issue 36

Interview

Profile

Jason Pope

Jason Pope is the president and CEO of Evolve Restorative Center in Santa Rosa, USA, and serves as president of the Californian Society of Interventional Pain Physicians. Here, he talks to NeuroNews about how he has seen the field evolve over the past decade, his hopes for the future, and why neuromodulation is “the best kept secret in medicine”.

How have you seen the field of neuromodulation develop over your years practising?

Neuromodulation has been around since 1967. First there was the influence of hardware, but over the last three to eight years, there has been more influence and innovation in software, such as the application of electricity to the spinal cord. Now, not only are people empowered by randomised prospective controlled studies, they are also empowered by collecting their own data, and seeing how well the device performs in their hands and their practices.

How have you seen these technological advances shape research and treatment?

It is surrounded by some of the best data that we have; it should not be salvage pain care, but pain care for refractory cases. Unfortunately, we do not see that acceptance with some of the labelling we have here in the USA. Some of our payers are slow to appreciate the clinical data.

To combat this, we need to develop a data sharing strategy to further demonstrate that neuromodulation works away from an industry sponsored study. Having the ability to share those outcomes in a validated manner is important, and doing so requires being able to speak a common language, so all the data that is being acquired is done so in the same manner. Then you can compare patient populations around the world. This is critical for the survival of our space.

When I was first exposed to neuromodulation, there were only three companies, and it was more of a onesize-fits-all strategy. I think we will begin to see medical devices created for certain indications, so we will have specialists within the world of neuromodulation that will reach for certain therapies based on what they are trying to treat.

If we empower those physicians by marrying the results from the clinical trials with how they are actually performing practice, it will elevate the standard of medical practice while ultimately enabling patients to do better. A lot of the innovation in our space has come from physicians trying to find gaps in their practice and end up reaching for the bench side and industry to help fill those gaps.

Is there anything else on your wish list for the future development of neuromodulation therapy?

What has been the most practicechanging advance thus far?

The advent of DRG stimulation has allowed for a treatment that will significantly change a prognosis.”

I think there are two. One that has significantly changed my practice is the advent of dorsal root ganglion (DRG) stimulation. Chronic regional pain syndrome (CRPS) was one of those syndromes that was really difficult to manage, and the prognosis was somewhat poor.

Now, the advent of DRG stimulation has allowed for a treatment that will significantly change someone’s prognosis. Being involved in the ACCURATE study, and seeing it in clinical practice now, is probably one of the most gratifying things.

I also think that the concept of looking inward within practice, to see how well your patients are performing, is important. In the USA and elsewhere, it is sometimes very difficult to gauge from a longitudinal perspective how well patients are performing with a particular medical device. And, if you wait for the patient to tell you the device is not performing, sometimes it is too late, and it is difficult to assimilate such data. Having the ability to track data inwardly within the practice, and doing so in a way where there is validated measures and endpoints, I think is really critical.

On the contrary, what has been the biggest disappointment you have seen?

When you look at the opioid epidemic in the USA that we are currently battling, some of the regulatory strategies surrounding the placement of neuromodulation in the pain care algorithm still seems to be fairly late. Even with the labelling that we have with a lot of devices, it remains a last resort therapy, and it is certainly not that.

I think cost-effectiveness is always important. We have made strides in the neuromodulation world looking at the periphery, not only central neural axial stimulation, but also peripheral nerve stimulation. Having companies that have created technology specifically for the periphery was a huge win for us too.

I also think we need to appreciate that all ships rise with the tide. The language between one therapy and another detracts from the overall success of our space.

We need to focus on having a common voice within the neuromodulation world, because it still remains the best kept secret in medicine. There are many who do not

know about the field of neuromodulation, so to always talk about it kindly, is very critical.

Outside of your research, what has been the most interesting paper or presentation you have seen in the last year?

I like the work that Saluda Medical has done with the Evoke study. They have created a strategy where you can give the spinal cord the exact amplitude of stimulation that is required to elicit a response. I think the feedback strategy is really innovative.

Also, we tend to publish in our own journals.

To see that they have an acceptance in other journals, such as Lancet Neurology, is really important.

Expanding the readership may expand the footprint of neuromodulation. This credits them for the exhaustive science they have done and the robustness of their data.

The work by Stimgenics is also very exciting.

Purposeful stimulation of the supporting glial cells to institute a change in neuronal activity is very space-altering.

What research are you working on at the moment?

We are doing a study looking at intrathecal therapy. We are trying to compare conservative medicine management to targeted drug delivery in the non-cancer, chronic pain population.

In total, 15 practices are participating in a prospective randomised comparative of intrathecal therapy versus conservative medical management in the USA. We are in the middle of enrolment and we are activating sites currently. I am hopeful that we will have a preliminary slice of data to share with the space next year.

You have been on mission trips to Liberia, Kenya and Mexico. What motivated you to go, and what have you learnt from these experiences?

My motivation was to see how medicine is practised in different environments. Myself and my wife went through World Medical Mission to Kijabe (Kenya) and we spent about three months there. I practised as an anaesthesiologist and my wife taught at the nursing school. One of the takeaways was how wasteful medicine can be (in first-world countries), and I think is it important to be efficient in where we place our resources when we take care of patients.

I think that there is a huge opportunity to improve on the waste of medicine. When we were in Kijabe, we would wash anaesthesia circuits and reuse laryngeal

Issue 36 | January 2020

Interview

17

Fact File

Professional experience

2018–Present: President and CEO, Evolve Restorative Center, Santa Rosa, USA 2007–Present: Regulatory and Marketing Vice President, Anaesthetic Gas Reclamation, LLC, Nashville, USA 2018–Present: President and Co-Founder, Celeri Health, Inc 2016–Present: Co-Founder, Neural Integrative Solutions, LLC

Society positions

2017–Present: President, California Society of Interventional Pain Physicians 2019–Present: President-elect, American Society of Pain and Neuroscience 2017-Present: Board of Directors, International Neuromodulation Society 2015–Present: Board of Directors, North American Neuromodulation Society

Current research

mask airways and endotracheal tubes, and we did so in a sterile way, because the resource was very limited.

Yet, when you look at infection rates in those hospitals versus other hospitals, they are very much the same. I think there is an opportunity to create more economic ways to engage in medicine in the USA. The piece of the medicine pie within most governments is only so big, if we become more efficient in how we disperse those funds, we may be able to take care of more people.

Do you have a fantasy experiment, regardless of cost or ethics?

I think it would be interesting to carry out a clinical study looking at targeted drug delivery and sampling the concentration of medication along the neuraxis. In order to do that you would have to place ports or catheters to sample the cerebrospinal fluid at the various levels of the spinal cord. I think it would be able to give us more

granular data and insight into the pharmacokinetics of the cerebrospinal fluid space, outside of the computer model or translational medicine from animal data.

However, this would be a difficult study to perform because I do not know any person who would sign up to get five, six or eight sampling catheters within their intrathecal space. But it would be very interesting to do.

What are the major questions in the field of neuromodulation that remain unanswered?

In terms of the mechanism of action, there is a lot of debate surrounding how spinal cord stimulation works based on of the strategy that is employed. I still think we have a lot of basic science to do regarding that.

I think looking at the influence of temperature on peripheral nerve and spinal cord stimulation would also be interesting; I am sure there will be an opportunity to see some advances in thermal treatment of neural tissue.

Also, everyone is looking at the influence of electrical energy on neural tissue, but looking at the supportive structures around the neural tissue is also innovative.

PROSPER: Post-market, randomised, controlled, prospective study evaluating intrathecal morphine (IT) versus conventional medical management (CMM) in the noncancer, refractory, chronic pain population PROLONG: Prospective, multicentre, openlabel, post-market study PRESS: Post-market registry for evaluation of the superion spacer REALITY: Long-term real-world outcomes study on patients implanted with a neurostimulator

Mission trips

October 2012: Lead Anaesthesiologist, Children Surgery International, Hermosillo, Mexico January 2010: Lead Anaesthesiologist, Children Surgery International, Liberia, Africa March 2009: Lead Anaesthesiologist, World Medical Mission, Kijabe, Kenya

Education

2009–2010: Pain Management Fellowship, Department of Pain Management, Anesthesiology Institute, Cleaveland Clinic, USA 2005–2008: Aesthesiology Residency, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, USA 2000–2004: Doctor of Medicine, Indiana University of Medicine, Indianapolis, USA

Issue 36 | January 2020

Endovascular therapy

Superior clinical outcomes for endovascular therapy candidates triaged directly to a comprehensive stroke centre For patients with emergent large vessel occlusion (ELVO or LVO) eligible for endovascular therapy, prehospital triage to a more distant comprehensive stroke centre (CSC) compared with a closer primary stroke centre (PSC) was associated with significantly shorter time to thrombectomy, better clinical outcomes and no delay to alteplase. Within a matchedpairs model, this association held true for the entire cohort, report Mahesh V Jayaraman, Ryan A McTaggart and colleagues from Warren Alpert Medical School of Brown University, Providence, USA.

P

ublished in the Journal of NeuroInterventional Surgery, Jayaraman et al write in their paper: “In a densely populated setting, […] seven additional minutes of prehospital transport was associated with nearly an hour faster time to endovascular therapy, and a 16–26% absolute increase in functional independence.”

Between January 2016 and December 2017, a portion of the region (Rhode Island, Providence, USA) in which the study was conducted allowed field triage for patients who met severity criteria to a more distant CSC as opposed to the closest PSC. During these two years, 232 patients met inclusion criteria, and in turn, 144 were taken to the closest PSC and 88 to the more distant CSC. “The median additional transport time to the CSC was seven minutes,” write the authors. They also found that times from scene departure to alteplase and arterial puncture were faster in the direct group (50 vs. 62 minutes, 93 vs. 152 minutes, respectively; p<0.001).

Among patients who were independent before the stroke, the odds radio for less disability in the direct group was 1.47 (95% confidence interval [CI] 1.13–1.93, p=0.003), and 2.06 (95% CI 1.10–3.89, p=0.01) for the matched pairs. Moreover, the rate of symptomatic intracranial haemorrhage was 10/144 (7%) in the transfer group, and 1/88 (1%) in the direct group (p=0.06).

In light of the findings, McTaggart and colleagues believe, “these results will drive much needed change to regional stroke care delivery; better point-of entry protocols not only save lives but every minute reduction in time to endovascular therapy is estimated to save the healthcare system more than US$1,059.”

The study investigators provide additional background to the study. “Our region has a population of nearly 1.5 million people in Rhode Island and southeastern Massachusetts, and all 16 PSCs in our region use a standardised protocol to transfer patients to a single CSC where all endovascular therapy is performed,” they write.

Yet, with a portion of the region implementing a severitybased, field triage algorithm that directed emergency medical services to bypass closer PSCs to take patients directly to the CSC, the authors could compare the times to treatment and outcomes of patients.

The following criteria were used to identify eligible patients: a new, disabling neurological deficit (scoring

≥6 on the National Institutes of Health Stroke Scale [NIHSS]), initial non-contrast CT demonstrating lack of large completed infarction (scoring ≥6 on the Alberta Stroke Programme Early CT score [ASPECTS]), occlusion of the intracranial internal carotid or middle cerebral artery, the closest hospital from the scene was a PSC, as well as availability of 90-day clinical follow-up.

McTaggart and colleagues acknowledged that, in terms of demographic variables, there were higher rates of hyperlipidaemia in the transfer group (54% vs. 39%, p=0.02). Yet, the remainder of the demographics failed to elicit any significant differences between the two groups.

We need to critically re-evaluate why, where, and how we are accrediting stroke centres in the new mechanical thrombectomy era.”

Discussing the results further, the authors write that many may argue that the findings are not applicable to other regions. However, they referenced the STRATIS (Systematic evaluation of patients treated with neurothrombectomy devices for acute ischaemic stroke) registry, which includes 985 patients across 55 sites in the USA, 65% of whom incurred a stroke within 25 miles of the hospital where endovascular therapy was performed, and 40% within 10 miles. Thus, they surmised: “It is likely that there are many other regions that are similar to ours.”

Regardless, McTaggart and colleagues recognise that the optimal time parameters to determine triage to a more distant centre are unknown. According to the authors, a recent decision analysis has suggested that time to CSC, as well as time from onset, play a role in determining an optimal triage radius, and proposed that, Ryan McTaggart

Early clinical experience with Cascade shown “safe and effective”

In a case series depicting early clinical experience with Cascade (Perflow, Israel)—a temporary neck bridging device for embolisation of intracranial aneurysms—treatment of wide-neck ruptured intracranial aneurysms has been deemed safe and effective, without the need for adjuvant antiplatelet therapy.

WHILE THE AUTHORS, Stanimir Sirakov of University Hospital St Ivan Rilski, Sofia, Bulgaria, and colleagues

write that long-term follow-up data in larger cohorts are needed to confirm these preliminary findings, they report

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for early presenting patients, the bypass threshold may increase up to 56 minutes. Further research to optimise the threshold for triage may be warranted, they write.

Nonetheless, based on this work and their recent research trying to optimise door-in, door-out times for LVO stroke at the regional PSCs (McTaggart et al, Stroke, 2018 49 [12]: 2969–2974), the Rhode Island Ambulance advisory board recently voted to eliminate the 30-minute threshold from the field triage protocol— all suspected LVO patients in Rhode Island are taken directly to the CSC (Level 1) stroke centre.

In relation to particular drawbacks of the study, McTaggart et al alluded to a lack of documented field severity score for all patients. “As a point of reference, during the study period, a total of 1,170 patients with a final diagnosis of acute ischaemic stroke were brought by the emergency medical services directly to the CSC, and, of these, 147 (12.6%) underwent thrombectomy,” write the authors. Therefore, they suggest that it is “beyond the scope of this work” to determine the accuracy of emergency medical services assessment and rates of over-or under-triage.

Furthermore, they acknowledged that the nonrandomised nature of their study somewhat limits its validity. Referring to the randomised controlled trial currently underway in Barcelona, RACECAT (Direct transfer to an endovascular centre compared to transfer to the closest stroke centre in acute stroke patients with suspected LVO), McTaggart and team write that a similar trial in the USA may be “logistically difficult”, given the “fragmented nature of the healthcare system”.

In turn, they explain that their matched-pairs design with mixed modelling of pre-stroke and 90-day score, and matching according to time to CSC and NIHSS score, provides a strong alternative to randomisation for the observational data.

While concluding that the results should be interpreted with caution, in regions where the distribution and workflow metrics of stroke centres are not similar, McTaggart and colleagues write, “Prehospital triage may be the last remaining, yet modifiable, bottleneck within an otherwise optimised stroke system of care.”

“The most important link in the stroke chain of survival in Rhode Island is, by far, the ability of our emergency medical service professionals to leverage their ability to make important field triage decisions for stroke patients just as they do for trauma patients,” McTaggart tells Vascular News.

He adds: “Emergency medical service professionals need to be focused on doing what is right for patients, rather than navigating the geopolitics of stroke; we need to critically reevaluate why, where, and how we are accrediting stroke centres in the new mechanical thrombectomy era.”

that 75% (9/12) of cases achieved complete obliteration (Raymond-Roy 1) of the intracranial aneurysm.

Further results include that intentional residual neck (Raymond-Roy 2) was left in three cases (3/12), while none of the patients received any oral or intravenous antiplatelet therapy perioperatively. The authors also note that no thromboembolic complications, device-related spasm, vessel perforation, or coil entanglement occurred in any of the treated patients.

With the findings published in the Journal of Neurointerventional Surgery (JNIS), the investigators described their

initial single-centre experience with this new device, focusing on aneurysm obliteration, parent vessel interaction, and thromboembolic complications.

According to Sirakov and colleagues, Cascade is designed to provide temporary support during coil embolisation. The device is composed of 42 interwoven nitinol and platinum wires which form a net-like compliant structure with variable cell porosity.

Cascade also has an “ultra-thin wire braid structure” which allows easy adjustment of the braid through controlled expansion and partial resheathing, the authors add.

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Issue 36 | January 2020

Non-invasive targeting of deep brain structures now tested in the human brain Continued from page 1

Validating the modality in mice

The team first set out to validate that the temporal interference of electric fields can drive action potential activity in a living mouse brain. “We positioned two electrodes on the skull of the mouse, each one paired with another electrode that sat on the thorax of the animal …

We recorded activity of single neural calls in the brain using whole-cell patch clamp recording.” Grossman and colleagues found that through the application of two frequencies (2,000 and 2,010Hz), the neurons began to fire at the different frequency—10Hz in this case—in a similar way to if 10Hz was applied.

After confirming that envelope modulation change could drive action potential activity, the investigators sought to test if it was possible to utilise temporal interference by stimulating neurons in the hippocampus of living mice, without recruiting neurons of the overlying cortex. “We positioned the electrodes on the skull again, over the area corresponding to the hippocampus.

We stimulated for 20 minutes and then waited for 90 minutes to allow the expression of early genes like c-Fos … and, using immunohistochemistry, we characterised the changes in neural activity,” Grossman said.

He explained that the electrical fields, at a low frequency range (10Hz) created a strong gene expression in the cortex underneath the electrodes, but more importantly, the currents were sufficiently strong enough to drive activity within the hippocampus, while the electrical fields at a high-frequency range (2,000Hz) did not induce gene expression. However, it was only when the investigators changed the frequency of one of the currents, applying 2,000Hz and 2,010Hz, that a strong activation was observed within the hippocampus, with no expression in the overlying cortex. “This indicated selective recruitment of this deep structure [the hippocampus] in a non-invasive way,” concluded Grossman. Then, by altering the ratio of currents delivered to a set of immobile electrodes placed over regions of the motor cortex, Grossman explained that it is possible to steerably evoke different motor patterns in mice.

Temporal interference in the human brain

Through validating the concept of temporal interference in an array of animal experiments, Grossman told INS delegates that the next step was to test whether this method can safely record activity in the human brain.

After positioning the electrodes in a “trapezoid configuration” around the motor cortex of healthy subjects, Grossman and team applied temporal

Temporal interference adds new capabilities to the existing ecosystem of brain stimulation.” interference stimulation and recorded, concurrently, functional MRI activity.

“We stimulated for about 30 seconds, with 30 second intervals in between, before applying 10Hz stimulation as a control, 2Hz as a sham control, and temporal interference through current ratios’ of 1:1, 3:1, and 1:3, and repeated this four times in a random order.”

According to Grossman, the investigators were specifically interested in the effect of stimulation in the brain region underneath the electrode. Thus, they used structural MRI to create a personalised anatomic model, and simulated the distribution of the field to define an area as the region of interest. “We divided it into the frontal side of our region of interest, and the dorsal side.”

Through temporal interference, 2,010Hz of stimulation was applied to one electrode pair on the human subject, and 2,000 on the other pair, both receiving one milliamp of current.

Grossman posited, “Our simulation shows that the envelope modulation is located somewhere in the middle of the region of interest. Indeed, in this subject, a significant cluster is at the sulcus, within the middle of the region of interest. At the group level, we do not see a difference in the activation between the frontal side and the dorsal side of the region of interest.”

Nevertheless, when the study investigators decreased the current in the front electrode pair to 0.5, with the other at 1.5 (keeping the current sum fixed), the envelope modulation was steered frontally. “In this subject, we saw that a significant cluster has moved to the frontal side of the region of interest, and at the group level, we saw a large activation at the frontal region of interest compared to the dorsal one.

“When we did the opposite, the envelope modulation was steered dorsally,” Grossman explained; an effect the team also observed at the group level.

Ultimately, Grossman put forward that the hope for this technique, “since no chemical or genetic manipulation of brain tissue occurred”, is that it will be adopted in clinical research and “perhaps in therapy where it can find its highest impact”.

A graphical abstract, first published in Cell, illustrating envelope modulation.

An INS discussion

After discussion was opened up to the floor, an INS delegate posed the question, “Do you foresee a time in the future where we will be looking at deep brain stimulation as a historical artefact, or something that may be more invasive and aggressive then we need for advancing brain therapies?”.

“My perspective on this,” began Grossman, “is that the way we perceive disorders is on the circuit level, so there are many nodes or networks of the circuit that are involved. Therefore, you look for a node that will affect the whole. […] Some of the more subcortical ones are more efficient in engaging the whole circuit, and therefore [are] more beneficial for us to target.

“With that in mind, if we can improve the efficacy of cortical stimulation, we can affect the network or the circuit as a whole. When we do it non-invasively, at least at the moment, we have a weaker field that reach the neurons; we operate at subthreshold level, and also, the accessibility to the rest of the network is potentially more limited.”

Also on the panel, Dirk de Ridder from the University of Otago, Dunedin, New Zealand, replied, “As a clinician, there are two important factors that need addressing. One is that with this interference, you can only create tonic stimulation. So, if you wanted to apply other stimulation designs, that might not yet be possible. But the second, which is a problem for all noninvasive stimulation, is that the effects are transient in general. Except maybe with depression, if you apply Nir Grossman

The way we perceive disorders is at the circuit level. If we can improve the efficacy of cortical stimulation, we can affect the network or circuit as a whole.” long-term stimulation.

“So in the first instance,” de Ridder speculated, “yes, it might be better as a prognostic indicator, rather than a device that will remove deep brain stimulation from our arsenal.”

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January 2020 | Issue 36

Centres of excellence for neuromodulation: A critical proposal Robert M Levy Comment & Analysis While recognising that excellence derives from experience, Robert M Levy suggests that the neuromodulation community can better protect the field’s “desire to ensure excellence for patients and healthcare economies”. Here, he makes a case for establishing centres of excellence for neuromodulation therapies. Although acknowledging the benefits that this will bring, for both patients and healthcare providers, Levy writes, “I expect that not everyone will support this proposal due to self-interest or economic concerns”.

A

s a field, neuromodulation has struggled with methods to increase the efficacy of our procedures, decrease the associated risks, and improve patient outcomes.

By achieving the latter, we further legitimise our field, improve patient satisfaction and demonstrate the costeffectiveness that is necessary to drive reimbursement, in turn improving patient access to neuromodulation procedures. One important way to improve results in our specialty is to ensure that neuromodulation practitioners have, indeed, practiced.

And practiced quite a lot.

In his book, Outliers, Malcolm Gladwell points to the correlation between the level of practice and excellence. “The idea that excellence at performing a complex task requires a critical minimum level of practice surfaces again and again in studies of expertise. In fact, researchers have settled on what they believe is the magic number for true expertise: 10,000 hours.”1 While Gladwell discusses excellence in sports, music and computer science, this correlation appears to hold for virtually any discipline. He quotes Daniel Levitin, a neuroscientist whose research focuses on the development of excellence: “The emerging pictures from such studies is that 10,000 hours of practice is required to achieve the level of mastery associated with being a world-class expert—in anything.”2 Gladwell goes on to state that “practice is not the thing you do once you are good.

It is the thing you do that makes you good”. He suggests that it takes about 10 years to develop such excellence.

Though the actual amount of practice required may be debated, the recognition that excellence derives, at least in part, from experience, cannot. Unfortunately, there appears to be a conflict between the way in which neuromodulation is practiced and our desire to ensure excellence for our patients and our healthcare economies. That is to say that

less than 20% of spinal cord stimulator (SCS) implanters, for example, perform 80% of these procedures, leaving 80% of implanters to do no more than 20% of SCS implants. The vast majority of implanters perform less than 12 such procedures a year; possibly too few to ensure quality, much less excellence.3

Centres of excellence in neuromodulation

In the field of neuromodulation, the correlation between high practice volumes and high quality outcomes has not yet been definitively established, even though it has for other procedural fields, including vascular surgery, cardiothoracic surgery, cancer surgery and bariatric surgery.4-18 Yet, it is unlikely that neuromodulation is unique. There are approximately 4,000 implanters of SCS devices in the USA; it is almost a certainty that the outcomes of implanters performing 100 or more procedures per year would be better than those performing 10 or fewer procedures

There is now developing data that suggests that the correlation between surgeon volume and outcomes applies to the field of neuromodulation as well. Sharan and co-workers recently examined adverse events and patient response rate as a function of surgeon experience as part of a 52-week prospective, randomised, controlled multicentre study of peripheral nerve stimulation (PNS).20 Surgeon experience with PNS played a major role in reducing all device-and procedure-related adverse events, including biological, stimulation-, and hardware-related adverse events (p<0.005). Frequently observed device-related adverse events, such as lead migration, infection, pain at the internal pulse generator pocket and/ or the lead implant site, decreased as a function of the experience (p<0.005) by approximately 80%, 60%, and 50%, respectively, when surgeons had performed greater than 10 prior procedures. Treatment response rate improved significantly as a function of experience (p=0.001), with the response rate increased by approximately 20%, 10%, and 13% at the 4-, 12- and 52-week follow-up visits, respectively.

Benefits of neuromodulation centres of excellence

By establishing centres of excellence (COE) for neuromodulation therapies, we can provide significant benefits to our patients and healthcare providers as well. First, the COE would house groups of busy, highly-skilled implanters whose outcomes are likely to be better than local providers performing these procedures only rarely.

Next, the improved quality of the neuromodulation training environment promises to be a second important benefit of the COE concept. In a recent fellowship training programme, I was surprised to find that at least half of the pain fellows had not participated in a single neuromodulation surgery and had seen less than a handful performed by their faculty. Undertaking a neuromodulation fellowship in a practice that perform hundreds of these

The vast majority of [SCS] implanters perform less than 12 such procedures a year; too few to ensure quality, much less excellence.” per year. However, 80% of implanters perform one procedure per month or less. In light of these statistics, it is not surprising that the adverse event rates in neuromodulation—although improving in recent years—continue to occur at too high a rate compared to other similar surgical procedures.19 A not dissimilar situation exists for deep brain stimulation (DBS) procedures. Approximately 500 surgeons perform 13,000 DBS procedures each year. Only 11% of surgeons perform 50% of these cases (averaging about 120 cases per year), with the remaining majority performing on the average of 15 cases per year.

procedures each year would provide a significantly enriched environment for hands on education and training.

A COE model, where hundreds of similar procedures are performed each year would further provide an economy of scale. Many of the costs of a neuromodulation practice are fixed costs that are largely unrelated to volume. These practices require nurses and other mid-level providers, such as medical and surgical assistants, to refill and reprogramme intrathecal drug administration systems or to oversee device trials; perform programming of DBS, SCS and PNS neurostimulation systems; assist with the care of the

patient’s non-surgical needs, or with record keeping, data input and outcomes data development as well as many others.

A high volume neuromodulation practice can spread the cost of these critical personnel across a large number of patients and procedures to make them cost effective. One particularly important need for a high quality neuromodulation practice is access to a psychologist for pre-surgical assessment, patient education and ongoing therapy. The cost of these services is frequently minimally or not reimbursed; a high volume COE model can incorporate the cost of psychological support as part of the cost of doing business without putting the practice at risk. In short, the neuromodulation multidisciplinary team model can be much more easily accomplished within a high volume COE. There are operational issues that are more easily addressed in such high volume practices as well. It is frequently the case that in smaller neuromodulation practices, there are long delays between patient medical evaluation, psychological evaluation, the therapeutic trial and the permanent implant. As a result, only 21% of patients evaluated by neuromodulation physicians as being good candidates for these procedures ultimately undergo the procedure.3 Practices often lose track of patients as they navigate these systems; they are lost to follow-up or they may lose their vigour to pursue therapy and simply suffer in silence.21 In a high volume COE model, case managers who can shepherd patients through the process become potentially cost-effective, and help to ensure that patients reach their goal of receiving potentially effective therapy. Those office personnel involved with obtaining insurance approval, appropriate reimbursement, hospital scheduling, and outcomes data collection can only become more proficient and efficient as a result of a higher volume, ongoing experience. This not only improves patient throughput and office efficiency but also avoids uncomfortable delays, which can result in patient dropout or poor patient satisfaction.

A most important collateral benefit of a high volume COE model is the improved ability to collect and process outcomes data. As health care systems evolve around the world, the ability to provide meaningful outcomes data is becoming the key to obtaining and maintaining appropriate reimbursement, as well as increasing understanding of our therapies and their outcomes. The adoption of and rigorous adherence to a common outcomes database across neuromodulation COEs would allow for pooling of data and large scale validated research programmes.

Of equal importance, I would hope that the resulting reliable outcomes data should demonstrate greatly improved and cost effective outcomes when compared to the large number of small, less experienced and lower volume practices.

The high volume COE model would make it easier for industry to identify important sites for educational and research support. Both industry and

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Issue 36 | January 2020 consumers would benefit; the industry can well expect more “bang for the buck” from their support due to the large volume and great influence of these centres, while patient and health care provider consumers can expect higher quality educational programmes and more expert implanters and teachers.

Further, by consolidating volume into fewer sites, COEs could decrease the service burden of the vendors that supply neuromodulation devices.

I would propose a national health system of neuromodulation CEOs. About 60,000 permanent SCS procedures are performed each year in the USA alone. With an overall estimated trial to permanent implant ratio of 65%, this adds 92,000 spinal cord stimulation trial procedures per year.3 Finally, there are approximately 13,000 permanent deep brain stimulator implants in the USA each year.

Without including peripheral nerve stimulation or peripheral nerve field stimulation procedures, this accounts for at least 165,000 neurostimulation procedures in the USA anually. With 200 centres of excellence throughout the country, each centre would perform over 800 procedures per year not including peripheral nerve or nerve field stimulation procedures. It is hard to imagine that the quality of patient outcomes would not be better than they are now, where the overwhelming majority of implanters perform less than 10 procedures per year.

Defining neuromodulation centres of excellence

We are left with the challenges of defining what makes a neuromodulation COE and who should be responsible for defining and monitoring such centres of excellence. While industry is often called on to make these determinations, I believe that this is improper.

First, industry cannot refuse to sell product to a licensed physician.

Second, the requirement to satisfy the needs of industry stakeholders creates a potential conflict between the objectivity needed for establishing and monitoring

centres of excellence and the need to maximise profits. Third, the medical device industry is not in the business of providing healthcare; doctors can best dictate the requirements for optimal medical care programmes.

Unfortunately, the medical profession in general, and the field of neuromodulation in particular, has been remarkably slow to own up to their responsibilities. Already, governmental agencies or their agents have stepped forward to begin to regulate the practice of neuromodulation.22 I believe that professional regulation by knowledgeable medical societies is preferable than that by governmental agents.

So again, what are the components of a neuromodulation centre of excellence?

I would propose that they include, but are not limited to: 1. Physicians performing more than some critical number of neurostimulation procedures per year.

2. Institutions that provide comprehensive access to US FDA approved neurostimulation procedures (DBS, SCS, PNS, IT DAS).

3. Institutions whose complication rates fall below a critical level.

4. Institutions whose outcomes and patient satisfaction rates are above a critical level.

5. Institutions that collect data using appropriate instruments so that they can produce reliable outcomes and complication data.

6. Institutions that have available all necessary ancillary services (i.e., psychology, physical therapy, etc.).

7. Institutions that demonstrate certain levels of efficiency and proficiency in patient evaluation, screening, trialling and performing surgery.

8. Institutions that provide acceptable long term therapy maintenance.

9. Institutions that consent to regular monitoring of these variables.

As is often the case, however, the devil is in the details. How we define and quantitate each of these variables, and how we choose to measure and monitor them, is the difference between success and failure for a COE programme.

First educational module for neuromodulation ensures field is “future-proof” The first educational module for neuromodulation, a masters-level, e-learning course aimed at nurses and allied healthcare professionals working within the field, received its first cohort of students in September of 2019. However, the story of its launch is not a simple one. Carol Bourke, a nurse with over 10 years’ experience in neuromodulation, talks to NeuroNews about how she set about raising the £60,000 she needed to design and develop the module.

I charge our professional neuromodulation societies to act quickly and decisively to enact these programmes for the sake of our field and our patients.

Conclusion

I expect that not everyone will support this proposal due to self-interest or economic concerns. I expect that most objections will come from medical societies and practitioners bent upon maintaining the status quo and focused on the desires of individual practitioners.

Unfortunately, the time for this type of protectionism has long passed.

In fact, insurance companies are already leading the way in this regard; they have already initiated programmes to increase scrutiny and limit or withdraw reimbursement to practitioners with poor outcomes.22 In this day and age, we must first consider the wellbeing of our patients, second the cost effectiveness of our therapies and finally, the survival of our field.

On the other hand, especially during the current evolution of the healthcare system in the USA and the economic challenges to healthcare around the world, it seems that the field of neuromodulation has something significant to offer both our patients and healthcare payers. By improving outcomes through better patient selection, a higher level of surgical skills and improved post-procedural care and therapy maintenance, we can offer a better level of care to our patients at a significantly lower cost. In the equations used by healthcare systems to determine willingness to pay for a given therapy, we can help by both increasing patient outcomes while also decreasing costs.

The resulting drop in cost per qualityadjusted life year may ensure continued acceptance of neuromodulation therapies and access for our patients.

Robert M Levy currently serves as president of the International Neuromodulation Society and Editor-in-Chief of Neuromodulation: Technology at the Neural Interface.

“Clinically, at the moment, if you are a nurse and work in this area, there is no recognised formal training, and that is how new the field is. It seems ludicrous now, but in a few more years, it is going to seems even more absurd,” Bourke explains.

After receiving endorsement from the International Neuromodulation Society (INS), she worked together with Leeds Beckett University, Leeds, UK, to develop and design the course. Bourke then devised a business case that she took to Nevro, Abbott, Medtronic and Boston Scientific. “I had to do a lot of presentations, but Nevro were the first company to fund the module; they put £16,000 into the pot, and after, Abbott, Medtronic, and Boston followed. Saluda Medical also contributed text and graphics to support some of the learning topics. I ended up with £66,000,” Bourke told NeuroNews.

“I think that part of the reason I secured funding was because the companies realised that if their medical devices are going to stay in patients; if they are going to work, then they need this group of professionals to be educated and use them properly.”

Bourke also explained that it is education that will ultimately ensure the field of neuromodulation remains

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13. Peterson, ED, Coombs, LP, DeLong, ER, Haan, CK, Ferguson, TB. Procedural Volume as a Marker of Quality for CABG Surgery. JAMA 2004;291(2):195-201.

14. Cowan, JA JR, Dimick, JB, Henke, PK, Huber, TS, Stanley, JC, Upchurch, GR Jr. Surgical treatment of intact thoracoabdominal aortic aneurysms in the United States: Hospital and surgeon volume-related outcomes. Presented at the Twenty-ninth Annual Meeting of the New England Society for Vascular Surgery, Rockport, Me, Oct 4-6, 2002.

15. J ustin B Dimick, John A Cowan Jr, James C Stanley,Peter K Henke, MD, Peter J Pronovost, Gilbert R Upchurch Jr Surgeon specialty and provider volumes are related to outcome of intact abdominal aortic aneurysm repair in the united states. Presented at the Thirty-sixth Annual Meeting of the Association for Academic Surgery, Boston, Mass, Nov 7-9, 2002 16. Harmon JW, Tang TG, Gordon TA, Bowman HM, Choti MA, Kaufman HS, Bender JS, Duncan MD, Magnuson TH, Lillemoe KD, Cameron JL. Hospital Volume Can Serve as a Surrogate for Surgeon Volume for Achieving Excellent Outcomes in Colorectal Resection. Annals of Surgery. 1999 Sept;230(3):404-11; discussion 411-3 17. Hollenbeak, CS, Rogers, AM, Barrus, B, Wadiwala, I, Cooney, RN. Surgical volume impacts bariatric surgery mortality: A case for centers of excellence.

Surgery. 2008 Nov;144(5):736-43. Doi: 10.1016/j. surg.2008.05.013. Epub 2008 Jul 21.

18. Dimick, JB, Osborne, NH, Nicholas, L, Birkmeyer, JD. Identifying High-Quality Bariatric Surgery Centers: Hospital Volume or Risk-Adjusted Outcomes. J Am Coll Surg. 2009 Dec;209(6):702-6. doi: 10.1016/j. jamcollsurg.2009.09.009.

19. DeBakey, M. Medical Centers of Excellence and Health Reform. Science. 1993 Oct 22;262(5133):523-5.

20. Sharan, A, Huh, B, Narouze, S, et al. Impact of surgeon experience performing peripheral nerve stimulation surgeries on treatment efficacy and safety. North American Neuromodulation Society Annual Meeting, December, 2013, Las Vegas, NV 21. Levy, RM. Patient Targeted Therapy. Presented at the North American Neuromodulation Society Meeting, Las Vegas, NV, December, 2012.

22. Local Coverage Determination (LCD): Spinal Cord Stimulators for Chronic Pain (L32549).(2013).

“future-proof”: “Right now, a lot of companies themselves are looking after patients with devices in the clinics, which is good if one [clinic] only uses one company. But, in the case of Leeds, where they use more than one, they would need all the [company] representatives in everyday, if they wanted to look after the patients properly.

“Ideally, the nurse have to be able to, at least, do the troubleshooting”, she argues. “They are the ones responsible for education the patients; they get to know the patient very well.”

The e-learning educational module aims to provide students with a critical understanding of the principals and clinical practice of neuromodulation therapies. Bourke highlights: “I already have interest from nurses and allied health professionals in Europe and Australia as well as in the UK,” and speculates that, depending on the feedback, the next course will be available in February 2020.

“Kudos really needs to go to Mark Johnson, director of the Centre for Pain Research at Leeds Beckett University; to the companies that made this happen, to Kim Vanmouwerik and Jenny Jennings, clinical nurse specialist, for their professional and personal contributions, and to the INS which initially endorsed it.”

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January 2020 | Issue 36

Pooled analysis finds dorsal root ganglion stimulation “safe and effective” for multiple chronic pain disorders Dorsal root ganglion (DRG) stimulation is a safe and effective therapy for multiple chronic pain disorders, concludes a pooled analysis published in Neuromodulation. The authors, Frank JPM Huygen (Erasmus University Medical Center, Rotterdam, the Netherlands) and colleagues emphasise that, with the advent of new stimulation modulators in recent years, “it is important that treatments are tailored to specific diagnoses and conditions”. With this in mind, they say that DRG stimulation therapy is most successful for treating focal pain in carefully selected patients.

A

ccording to Huygen and colleagues, chronic pain affects approximately 20–30% of the population in the USA and Europe, and has a wide range of aetiologies. Therefore, the authors aimed to identify differences in the effectiveness of DRG stimulation by pain aetiology or location, and to investigate the generalisability and reproducibility of individual prospective studies following patients for 12 months.

In total, seven studies were identified that met predefined acceptance criteria: one prospective, randomised comparative trial and six prospective, single-arm, observational studies. Within these, 217 patients with a permanent implant at 12-month follow-up were analysed. “The weighted mean pain score for all patients decreased from 7.8 at baseline to 3.4 at 12 months,” highlight the authors. In relation to specific pain aetiologies, the most common was found to be causalgia (n=104; 48%), followed by back pain (n=53; 24%) and complex regional pain syndrome type 1 (n=46; 21).

The most frequently reported areas of primary pain were leg (n=64), foot (n=50), back (n=37), buttocks (n=18), and groin (n=11). For these discrete regions, Huygen et al noted that pain scores at 12 months ranged from 1.7 (groin) to 3.0 (buttocks). In terms of responder rates for primary pain areas, foot and groin areas elicited rates of 80%, with 75% for leg, 70% for back, and 59% for buttocks.

In addition to examining pain scores, patient-reported

outcomes were also measured, which were weighted by study sample sizes and subsequently pooled.

Specifically, Huygen and his team measured quality of life (using the EQ-5D instrument), mood states (through the Profile of Mood States [POMS] and therapy satisfaction) and physical function (Brief Pain Inventory [BPI], Oswestry Disability Index [ODI]).

“Each instrument showed a substantial improvement at the 12-month follow-up visit,” write the authors. EQ5D index was found to increase from 0.38 to 0.69, while mood disturbance decreased from 25.6 at baseline to 7.3.

Pain severity was seen to decrease by 3.1 points on BPI, with pain interference also decreasing by 2.8. Further, Huygen and colleagues put forward that in patients with low back pain, disability reported on ODI was found to reduce from severe disability at baseline (mean: 43.8) to minimal disability (mean: 17.5).

Lastly, the authors acknowledge the most frequently reported procedure- and device-related complications.

Pain at the implantable pulse generator (IPG) pocket site (n=26, 10.2%) was the most common complication,

Each instrument showed a substantial improvement at the 12-month follow-up visit.”

Meta-analysis shows deep brain stimulation improves multiple sclerosisrelated tremor A recently published meta-analysis has provided level III evidence that deep brain stimulation (DBS) may improve multiple sclerosis (MS)-related tremor. The study reports that adverse events in this population of patients are similar to those reported for other indications of DBS. These findings led Nicholas J Brandmeir and colleagues from West Virginia University, Morgantown, USA, to conclude that in patients with debilitating tremor related to MS, DBS should be considered as an effective treatment option based on “the best available evidence”.

ACCORDING TO THE authors, DBS was first used in 1980 to successfully treat MS tremor. Since, multiple studies have been completed to evaluate the effect of DBS on MS tremor. However, Brandmeir and others write, “Many of these studies showed relatively small clinical effects and were composed of very small patient series … and many used

various measurements of tremor severity … making direct comparison of outcomes difficult.”

The team in Morgantown set out to examine the effect of DBS on MS tremor, as measured by a normalised scale of tremor severity. The papers included were read in their entirety, and each paper was graded for risk of bias according to the

DRG leads placed in the lumbar region

while a total of 15 lead fractures and 15 lead migrations (both 5.9%) were reported. Of the 13 infections (5.1%) that occurred across the studies, seven appeared at the IPG site. Yet, Huygen et al argue: “The procedural complications reported across the seven studies in our pooled analysis are in line to those observed for other neurostimulation therapies.”

Further discussing the findings, they allude to the “only randomised controlled study” to assess the efficacy of DRG stimulation: the ACCURATE trial.

Although this trial demonstrated slightly higher effectiveness metrics than the current study, Huygen and team argue, “The [discrepancy] is not unexpected, given the addition of post-market data collected in typical clinical settings and heterogeneous patient populations.”

Concluding their findings, they maintain that DRG stimulation is an effective therapy for multiple chronic pain disorders, and add: “It is a safe and widely used therapy for patients that have failed to receive pain relief and quality of life improvements from other interventions.”

American Academy of Neurology (AAN) standards, note the authors.

After removing papers that were unrelated to the study question, duplicate results, papers without comparison for outcomes, and those based on the same patient cohort, the final number of studies included in the meta-analysis was 13.

Brandmeir and colleagues report that the total number of patients included across all manuscripts was 261, with 129 having received DBS and 132 receiving medical management.

“Of the 13 studies included, the level of evidence of the studies varied,” the authors highlight. Four were level II, five were level III, and four were level IV. The team put forward that the “major factor” contributing to the lower levels of evidence was the fact that no studies had randomised allocation and many studies had unmasked evaluation of outcomes.

Moreover, they report that the number of subjects per study was relatively low, ranging from four to 14.

While they also acknowledge that the adverse event rates varied from 8–50%— with the most common being device infection requiring reoperation—they write

that this rate is similar to that reported in trials for other diagnoses. “This shows that patients with MS and tremor can tolerate DBS surgery and DBS with a similar safety profile to patients with other movement disorders,” Brandmeir et al surmise.

Discussing the results, they point to the fact that despite multiple studies completed on this topic at busy DBS centres, patient cohorts remain small.

This led the team to speculate that a large randomised controlled trial addressing DBS for MS tremor is unlikely to yield sufficient patient numbers to definitely answer the question at hand. “This fact makes the meta-analysis approach appropriate for this clinical question, since level I data is unlikely to be forthcoming.”

Brandmeir et al point to the fact that while the analysis illustrates that DBS improves tremor is MS, the exact magnitude to improvement that can be expected on a given tremor scale is difficult to predict. Thus, they postulate that going forward, it would improve the utility of studies on this topic to use an agreed upon, standardised measure of tremor severity, which would also permit easier generalisability of the results.

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Issue 36 | January 2020

Less than 2% of physicians performing spinal cord stimulation procedures in Florida have “high volume” caseloads “Less than 10 physicians [in Florida, USA] can be classed as ‘high volume’ (≥100 cases) with respect to the performance of spinal cord stimulation procedures,” a study, published in Neuromodulation, concludes. The authors, Richard H Epstein (University of Miami Miller School of Medicine, Miami, USA) and colleagues propose that, although volume is “only one among many criteria” used to designate centres of excellence for other procedures, the potential impact on physician practice as well as patient access should be considered if a specific minimum of annual cases by physicians are to be established.

TO ASSESS THE volume of spinal cord stimulations (SCS) performed by physicians, Epstein et al obtained information from publicly available state databases for all patients undergoing procedures in 2018 at Florida hospitals, as well as hospital-owned facilities and independent ambulatory surgery centres in the same state.

In total, 10,762 SCS cases were analysed. Of these, 10,127 (94.1%) were performed as outpatients, and 637 (5.9%) as inpatients. Regarding medical specialty, Epstein and colleagues discovered that different types of procedures were distributed unevenly

among anaesthesiologists, physiatrists, orthopaedic surgeons, and neurosurgeons.

“Anaesthesiologists performed most (65.2%) of the percutaneous lead placements, [whereas] neurosurgeons or orthopaedic surgeons performed most (95.3%) of the procedures involving a laminectomy or laminotomy,” they write.

Interestingly, the study investigators found that among the 606 physicians who performed at least one SCS procedure, only nine performed at least 100 cases in 2018. During this year, 78.4% of physicians performed, on average, <2 SCS procedures per month. Epstein and colleagues confirmed that 29.4% of

SCS patients were cared for by the latter cohort of physicians, while physicians performing less than four cases per month provided care for 56.9% of all cases. They posit: “Our finding of a high percentage of spinal cord stimulation procedures performed by physicians with a relatively low annual volume is comparable with a recent study investigating conversion rates from neurostimulation trials to permanent

For [US] states with larger percentages of the population living in rural areas, issues related to individual physician volume and patient access would be magnified.” implantation.” In the corresponding study, Epstein and colleagues say that approximately two-thirds of the permanent neurostimulation implants were performed by physicians doing 24 or fewer cases per year.

Given such results, the authors emphasise that the impact of establishing a threshold on the delivery of high quality care to patients “should be considered”.

Composite measures of activity tolerance and pain intensity predict patient satisfaction with spinal cord stimulation A post hoc analysis of data from an exploratory sub-paraesthesia study has enabled the generation of a multivariate model to predict patient satisfaction with spinal cord stimulation (SCS) treatment. Published in Neuromodulation, the results suggest that a composite measure of activity tolerance (walking distance) and pain intensity can predict patient satisfaction with SCS therapy.

“T

his study highlights the utility of composite outcome metrics in evaluating the benefits of SCS for chronic low back and leg pain,” write the authors, Marc Russo of Hunter Pain Clinic, Broadmeadow, New South Wales, Australia and colleagues. The investigators generated a model that predicted patient satisfaction with treatment using evening pain intensity and the interaction between this and walking tolerance time.

While acknowledging that the assessment of success is challenging due to the “inherently subjective nature” of quantifying the chronic pain experience, the authors argue that due to the high prevalence and expense of chronic pain, it is of “significant importance” to use appropriate measures to evaluate treatment success. According to Russo and others, in the USA, chronic pain contributes to an estimated US$560 billion each year in direct medical costs, lost productivity and increased disability. Moreover, they report that chronic pain affects one in six Australians, with a similar prevalence in the USA. Given this, the investigators aimed to explore the interactions between clinical outcome variables of interest in the field of chronic pain and SCS. “We conducted an ex post facto analysis using data collected in a 2014 multicentre exploratory study of sub-perception

SCS programming strategies,” they write. The ultimate objective was to identify relationships between clinical assessments of chronic pain and to build a multivariate model that predicts satisfaction with SCS treatment.

“Such a model may be useful for clinical guidance on the treatment of chronic pain with SCS.” Forty-seven subjects tested multiple sub-perception SCS programmes for three to four days each. At the

New SCS waveforms and devices can be benchmarked against these measures as part of their evaluation process.” end of each programme period, subjects recorded pain intensity, patient satisfaction with treatment, modified patient global impression of change and physical activity tolerance times. Russo et al note that 12 outcomes variables were evaluated. Subsequently, Pearson’s correlation coefficient was used to assess pairwise correlations, and multigenerational mixed effects

They add: “Thresholds affect both the number of physicians who would be able to meet the criteria as ‘high volume’, and the potential impact of patient care, because of travel considerations and access issues related to expected long lag times for appointments with such providers.” Nonetheless, Epstein et al put forward: “In the absence of evidence linking a minimum annual number of cases to meaningful patient outcomes, selecting a threshold presents challenges.”

The investigators note that in order extract the figures presented in the study, they estimated for each office-based spinal cord stimulation trials based on the published Florida conversion factor of 25.6% of the total number such procedures. In addition, the medical specialty of the performing physician was determined based on the national provider identifier.

Epstein and colleagues speculate that a limitation of the study pertains to the fact that the study used data from a US state that is “far more densely populated” than others where interventional pain procedures have been explored. They say, for states with larger percentages of the population living in rural areas, issues related to individual physician volume and patient access would “likely be magnified”. Furthermore, they acknowledge that the data analysed contain neither outcomes nor indications of medical necessity, and in turn, prevent an assessment of procedural volume and either: complications, effectiveness, or appropriateness of this therapy.

modelling was performed to create a model to best explain relationships between those variables.

The majority of subjects in the study presented with chronic predominant low back and/or leg pain; the primary indication for SCS therapy. Russo and colleagues report that the mean overall baseline pain intensity indicated severe pain (8/10), while the mean overall average daily pain intensity with stimulation across all programmes assessed was 4.7/10.

Morning, evening and overall pain intensities were highly correlated, as were patient satisfaction with treatment and patient global impression of change, the authors note.

Ultimately, the study illustrated a significant nonlinear multifactorial relationship between evening pain intensity, daily walking tolerance, and patient satisfaction with SCS. “This relationship may be instructive in evaluating SCS in clinical practice,” highlight Russo and colleagues. They add that any discrepancy between patients reports of satisfaction with treatment, pain intensity, and/or walking tolerance can trigger a further exploration of these issues to ascertain the status of the patient. Moreover, they speculate that SCS can be optimised to produce the greatest decrease in evening pain scores and the greatest increase in walking tolerance time with the expectation that this may lead to improved patient satisfaction with SCS. “New SCS waveforms and devices can be benchmarked against these measures as part of their evaluation process,” Russo and colleagues put forward.

Nonetheless, they theorise that future research should examine additional factors, such as mood, sleep, and other relevant lifestyle factors. “Ideally, future studies would also incorporate objective measures, such as biometric physical data and clinical assessment (clinician global impression of change), to improve the model fit in order to predict patient satisfaction outcomes.”

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Low pain scores following spinal cord stimulation trials found predictive of successful implants Low pain scores after spinal cord stimulation (SCS) trials are predictive of successful SCS implants with high sensitivity, according to a recent study.

Senior author Charles Odonkor and colleagues from Harvard Medical School, Boston, USA, report that post-SCS trial pain scores less than or equal to 4.9 had greater than 50% probability of a successful permanent SCS implant (97.14% sensitivity, 44.5% specificity; ROC=0.71).

FURTHER TO THIS, the authors found that post-SCS trial pain scores between 4 and 7 were associated with a significantly higher probability of a successful SCS implant among patients without spine surgery, compared to those who had previously undergone spine surgery.

Separate gender analyses also evidenced that females with pain scores between 5 and 7 had a higher probability of a successful SCS implant.

The authors acknowledge that several studies have attempted to determine predictors of pain reduction after SCS implantation. In terms of patient demographic factors, lower age, lack of a psychological comorbidity, and a lower BMI have been associated with better SCS outcomes in previous studies. Regarding implantationrelated factors, a shorter interval between onset of

January 2020 | Issue 36 symptoms to implantation, decreased complication rates, an increased area covered by the SCS leads and an increased number of leads have previously been found to increase efficacy.

However, prior to the current study, Odonkor and colleagues emphasise that “it remained unclear to what extent pain reduction during the trial period is associated with long-term success of the permanent implant”. With this in mind, the authors investigated if pain scores obtained during the SCS trial serve as reliable predictors of ultimate success of a permanent SCS implant.

Odonkor and team retrospectively identified 88 patients (57% female, median age: 52.5 years) who underwent both an Charles Odonkor SCS trial and a subsequent percutaneous permanent implantation from 2015–2018. The authors report a mix of paraesthesia-based versus paraesthesia-free programming implants. Pain scores were obtained at baseline, postSCS trial period, and post-permanent SCS implantation.

Successful permanent SCS implant was defined as patients who had more than 50% pain reduction in pain scores (documented as numeric pain rating [NRS] scores).

Of the entire cohort, 70 (79%) had successful permanent SCS implantation. The primary author, Vwaire Orhurhu, also reports that there were no statistical significant differences in demographic variables between patients who receive successful versus unsuccessful SCS implantations, with the exception of overrepresentation of patients with a history of spinal surgery among the subgroup who received unsuccessful permanent SCS implants (p=0.02).In terms of the association between post-SCS trial pain scores and successful permanent SCS

implant, pain scores were significantly lower among patients with successful implants compared to those without (pain scores: 2.14; 95% confidence interval [CI]: 177–2.52 vs. 3.88; 95% CI: 3.11–4.67; p<0.0001).

However, while maintaining that—in the current cohort of patients—males and patients with surgical history with higher pain scores had a lower probability of successful SCS implant compared to females and nonsurgical patients, respectively, the authors allude to several limitations. They write, “As with all other retrospective studies, our work cannot determine a causative relationship between any independent variable and the SCS outcome.”

Odonkor and colleagues put forward that confounding biases, the Vwaire Orhurhu small sample size and the nature of a single-centre study may compromise the study’s generalisability, and findings may not be transferable to other settings.

Furthermore, they highlight an important shortcoming, of which they note is “particularly relevant in studies of patient pain experiences”. Referring to pain as a multifactorial, heterogeneously experienced phenomenon, the authors postulate that the same intervention may yield drastically different results in separate patients. Moreover, they allude to the lack of validity of numeric rating scores as a means of quantifying pain. “Clinicians and researchers should recognise that numeric pain scores are not entirely indicative of clinical pain reduction,” they write.

Thus, Odonkor and team surmise that not only should the measurement of such scores be standardised more systematically, but future studies should aim to consider patients’ perceived responses to pain intervention as an additional measure of success.

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Issue 36 | January 2020

Product News Nevro announces launch of a new medical device for the treatment of chronic pain

Nevro has announced it has received approval from the US Food and Drug Administration (FDA) for the Senza Omnia spinal cord stimulation (SCS) system. The Omnia system is the first and only SCS system designed to deliver Nevro’s proprietary HF10 therapy in addition to all other available SCS frequencies.

The Omnia system is comprised of three new components. The first is a new programmer that will make it easy for physicians to offer a wider array of waveforms across the full SCS frequency spectrum, either separately or paired together.

The second element of the system is a redesigned patient remote that is smaller and more intuitive for patients to use, and enhances their experience. The new remote supports greater programming capacity, allowing the flexibility to expand on the HF10 algorithm by giving physicians the ability to provide additional waveforms.

Lastly, the system comes with an updated and upgradeable implantable pulse generator. Unlike nonrechargeable systems, the Omnia system is designed to last over 10 years no matter what stimulation profile is used, has conditional full body MRI approval and will be upgradeable to future waveforms and frequencies.

“The Omnia system was developed based on feedback from the pain community and has resulted in a product that Nevro is uniquely able to provide. Omnia not only offers HF10, the most studied therapy available in the market that physicians have provided to over 53,000 patients, but it also gives physicians access to all other SCS frequencies, either independently

Senza Omnia spinal cord stimulation (SCS) system

or paired with HF10. With Omnia, our goal is to provide physicians the peace of mind that, when they implant the system, they will have the versatility needed to achieve the best possible outcomes for their patients,” said Keith Grossman, chairman and CEO of Nevro.

In addition to the US approval for Omnia, international approvals are expected in Europe during the first half of 2020, and in Australia during the latter part of 2020.

Axonics announces US Food & Drug Administration approval for its sacral neuromodulation system for urinary clinical indications

Axonics has announced the approval of the Axonics r-SNM system by the US FDA for the clinical indications of overactive bladder (OAB) and urinary retention.

The FDA premarket approval grants Axonics the right to market its product in the USA for the clinical indications of OAB (urinary urge incontinence and urinary urge frequency) as well as urinary retention, representing the largest segment of the market for SNM devices. The FDA approval follows the company’s September approval for the clinical indication of foecal incontinence, which, according to published clinical studies, is a comorbidity reported by as many as onethird of patients presenting with urinary urge incontinence.

The FDA approval was supported by the results of a detailed review of technical data and the positive results of the Axonics ARTISAN-SNM 129-patient pivotal clinical study that met its primary and secondary endpoints and demonstrated 90% efficacy for all implanted urinary incontinence patients at six months, as well as published clinical literature.

The Axonics r-SNM System is the first rechargeable SNM system approved for sale in the USA, Europe, Canada and Australia. It is also the only SNM device approved for patients to undergo a fullbody MRI scan without the necessity of having the device explanted. The FDA approval includes the claim of a 15-year functional life, which is in contrast to the incumbent company’s legacy device which requires replacement on average every four years. In addition, the system includes a patented tined lead, user-friendly accessories, such as a wireless charging system optimised for infrequent charging, a small easyto-use key-fob patient remote control, and an intuitive clinician programmer that facilitates lead placement and stimulation programming. The longlived miniaturised neurostimulator is approximately the size of a USB stick.

Boston Scientific receives CE mark approval for the VERCISE Neural Navigator 3

Boston Scientific has announced it has received CE mark for the Vercise Neural Navigator 3 directional deep brain stimulation (DBS) programming software—the first system that integrates patient-specific 3D brain anatomy and stimulation field modelling into the clinician’s programming interface.

When used in conjunction with the Vercise directional DBS System, this innovation is intended to empower physicians to accurately and efficiently

optimise personalised DBS therapies for their patients.

The Vercise Directional System, with the Vercise Cartesia directional lead, is designed to treat the symptoms of Parkinson’s disease (PD), essential tremor, and primary and secondary dystonia by delivering precisely targeted electrical stimulation in the brain to provide optimal symptom relief and better control of unwanted sideeffects. An estimated 10 million people worldwide are affected by Parkinson’s disease, causing symptoms such as shaking or tremors, muscle stiffness, and slowness of movement. Dystonia is a neurological movement disorder that affects more than half a million men, women, and children across Europe.

“DBS programming can be time intensive as a clinician works through trial and error to identify the right stimulation settings,” said Jens Volkmann, director and chairman of the Department of Neurology at the University Hospital of Wurzburg, Germany. “We now have the ability— with STIMVIEW XT—to visualise lead placement in the patient to see how stimulation settings work in real time.”

The Vercise Neural Navigator 3 programming software features STIMVIEW XT, which is the most advanced, visualisation capability built for DBS programming. A press release from the company states that a study found that overall programming time with the first-generation GUIDE System was significantly shorter than traditional programming time (n=10, p<0.0001).

Shorter programming time is beneficial as it reduces prolonged periods of time used for adjusting the stimulation settings, which can be stressful and tiring for patients.

Medtronic files FDA submission for InterStim Micro neurostimulator and SureScanTM MRI leads

Medtronic has announced that it has filed a premarket approval (PMA) supplement with the US FDA for approval of its InterStim Micro neurostimulator and its InterStim SureScan MRI leads. InterStim Micro is a rechargeable, implantable sacral neuromodulation (SNM) device to treat patients affected by overactive bladder, urinary urge incontinence, unobstructed urinary retention and foecal incontinence. The SureScan leads, which will be used in future implants of the recharge-free InterStim II system and rechargeable InterStim Micro system, are designed to provide fullbody 1.5 and 3 Tesla MRI conditional labeling, pending US FDA approval.

The rechargeable InterStim Micro device works by sending electrical impulses to the sacral nerves, normalising the connections between the brain, bladder and bowel. It is 80% smaller than the current recharge-free InterStim II neurostimulator and could reduce the need for battery replacement surgeries due to its lifespan of 15 years.

Additionally, the SureScan full-body conditional MRI leads will enable

patients to undergo imaging procedures that were not previously indicated under the current US FDA approval for the InterStim II system.

“The FDA submission for InterStim Micro and SureScan MRI leads is a significant milestone for Medtronic and a leap forward in our 20-year history of leadership in sacral neuromodulation,” said Brooke Story, vice president and general manager of the Pelvic Health & Gastric Therapies business, which is part of the Restorative Therapies Group at Medtronic.

This submission, pending regulatory approval from the US FDA, would position the company to achieve approval for the InterStim Micro system and SureScan MRI leads in the spring

InterStim Micro neurostimulator

of 2020, following a standard 180-day review process. The InterStim Micro system and SureScan MRI leads are not yet available for sale in the USA.

FDA approves Abbott’s lowdose spinal cord stimulator for chronic pain

Abbott has received US FDA approval for its Proclaim XR recharge-free neurostimulation system for people with chronic pain. A press release reports that the Proclaim XR platform offers a low dose of Abbott’s proprietary BurstDR stimulation waveform, which has been designed to mimic natural patterns found in the brain. The press release reports that the system works by using low doses of mild electrical pulses to change pain signals as they travel from the spinal cord to the brain. It adds that the delivery of lower doses of spinal cord stimulation helps extend the system’s battery life.

Abbott’s low-energy stimulation is based on finding the lowest effective dose as determined by the treating clinician for selected patients. It delivers BurstDR stimulation intermittently, at low energy levels, while allowing people to experience the same level of superior pain relief. Proclaim XR also uses familiar Apple mobile digital devices and Bluetooth wireless technology to help discreetly manage pain and fit seamlessly into a patient’s lifestyle.

The system was developed based on positive results from Abbott’s BurstDR microdosing stimulation in de novo patients (BOLD) study, which showed 100% of 24 enrolled patients on a lowenergy BurstDR dosing programme experienced pain relief with less than six hours of battery use per day, while approximately 50% of those patients achieved pain relief with the lowest effective dose (less than two hours of battery use per day).

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January 2020 | Issue 36

Clinical News Stimwave launches post-market peripheral neuropathy pain relief randomised controlled trial

Stimwave has announced the launch of a new randomised clinical trial treating painful peripheral neuropathy, known as the “SMOOTH” study.

This study will focus on comparing the commercially available spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) therapy versus sham (device off state) in a prospective, randomised controlled trial with a 12-month endpoint. The study will take place at over 20 sites throughout the USA in conjunction with neuropathy diagnostic testing centres.

“Utilising the innovative Stimwave wireless technology for pain associated with peripheral neuropathy has proven effective for many patients in my practice,” said Ryan Pollina, the SMOOTH study principal investigator and medical director at Blue Water Pain Specialists (St Clare Shores, USA).

“I look forward to conducting this prospective study to generate level 1 evidence for the therapy and to widen the awareness of this novel, drug free, microtechnology option for patients suffering from the debilitating effects of peripheral neuropathy.”

Stimwave has the first FDA cleared wireless Freedom Stimulator devices for SCS and PNS. These devices are the world’s first wireless, fully programmable stimulators for pain management, and represent a lifechanging technological breakthrough for the more than 90 million people in the USA who endure chronic back and leg pain.

Over-the-skin electrical stimulation helps provide movement in quadriplegics

Researchers at The Feinstein Institutes for Medical Research used new closedloop neurostimulation methods and textile-based electrodes to facilitate individual finger movement and grasp force regulation in quadriplegia individuals. Their results were published in Springer Nature, Bioelectronic Medicine.

Approximately 5.4 million people

are living with paralysis in the USA, with stroke and spinal cord injury the two leading causes. Over the skin, or transcutaneous, neuromuscular electrical stimulation is often used in physical rehabilitation for those with paralysis. However, there are limitations for non-invasive stimulation systems, including not being able to target the muscles, muscle fatigue and inconsistent contraction strength.

To address the current rehabilitative boundaries, a team of researchers, led

by Chad Bouton, vice president of advanced engineering and professor in the Institute of Bioelectronic Medicine, partnered with Milad AlizadehMeghrazi, director of research and development at Myant and co-author of the paper. The team developed closed-loop neurostimulation methods and textile-based electrodes using proprietary processes from Myant to form a lightweight wearable sleeve that regulates individual finger forces to facilitate functional movement in paralysed individuals.

“We developed an approach that accurately controls muscle contractions and resulting forces exerted by the fingers,” said Bouton. “This opens up future research possibilities to create portable, rehabilitative devices beyond the laboratory to help those living with paralysis.”

The study consisted of three ablebodied participants and two participants with quadriplegia. The participants had the sleeve placed on their forearm,

An over-the-skin bioelectronic sleeve used to help individuals with paralysis move their fingers

and electrical stimulation was applied to the different electrodes to evoke various movements. Finger extension, flexing, and a cylindrical type grasp was observed in each participant, including the ability to squeeze and support a full (750ml) water bottle.

The results show that through controlled electrical stimulation, along with the use of lightweight textile electrodes, grasp force can be initiated and regulated in quadriplegia. In the future, the methods and technology used could be implemented with an in-brain computer interface to better decode and control hand movements.

“Chad Bouton and his team continue to advance our understanding and application of the science to better help those living with paralysis,” said Kevin J Tracey, CEO and president of The Feinstein Institutes.

Issue 36 | January 2020

Market watch stroke software in the space, Viz.ai is built with a security-first mentality and proven emphasis on protecting patient and facility information. Viz.ai is the first and only AI stroke company to achieve organisational compliance (SOC 2 Type 2) with federal laws restricting health information (HIPPA Attestation certification), in addition to six ISO certifications.” Viz.ai’s acute ischaemic stroke software is now available in over 300 hospitals across the USA.

Product News Philips announces WETRUST multicentre clinical trial to assess impact of direct-to-angiosuite workflow on stroke patient outcomes

Philips has announced a major clinical trial to assess the impact of a directto-angiosuite workflow on stroke patient outcomes. The study will assess whether with Philips’ advanced image-guided therapy platform it is possible to diagnose, plan and treat stroke patients in the interventional suite without requiring an initial CT or MRI exam. The multicentre, prospective, randomised, controlled, open-label, blinded-endpoint trial will be run across eight sites and over 460 patients globally. It will begin in the first half of next year and is expected to be completed in 2022.

Outcomes for stroke patients are closely tied to how quickly they receive treatment: every 30 minutes’ delay before treatment reduces the chance of a good outcome by 14%, and every hour of delay ages the brain by 3.6 years compared to a normally aging brain.

Currently, when a possible stroke patient arrives at the emergency department, they typically first undergo a CT or MRI exam and, in the case of an ischaemic stroke, are then treated in an interventional suite. Several studies have indicated that a direct-to-angiosuite workflow can reduce the time to treatment and improve patient outcomes.

Philips is developing new technology to further improve the CT-like images of the brain created with the X-ray system in the suite. The WE-TRUST (Workflow optimisation to reduce time to endovascular reperfusion in stroke treatment) trial will provide the most comprehensive assessment to-date of the impact of this technology and workflow innovation on time to treatment and patients’ neurological outcomes.

“Significant advances in technology mean that we are now able to identify, plan and treat ischaemic stroke patients in the angiography suite, without the need for a separate CT or MR scan,” said Raul G Nogueira, director, Neuroendovascular Service, Marcus Stroke & Neuroscience Center at Grady Memorial Hospital in Atlanta, USA, and principal investigator for the WETRUST trial. “Now is the right moment to perform a randomised controlled trial to objectively assess the benefits of a streamlined direct-to-angiosuite workflow on patient outcomes.”

“With extensive clinical research demonstrating the benefit of a treatment approach that combines thrombectomy and clot-busting drugs, stroke patient triage and treatment has changed dramatically in recent years,” said Ronald Tabaksblat, General Manager Image Guided Therapy Systems at Philips. “For stroke patients, ‘time

Philips Azurion stroke

is brain’. The WE-TRUST trial will assess the impact of a streamlined direct-to-angiosuite workflow on patient outcomes and has the potential to make a significant impact in this rapidly advancing field.”

The trial will primarily be carried out on Philips Azurion, the company’s platform for interventional procedures, at eight leading stroke sites in Europe and the USA. The primary endpoint of the WE-TRUST trial is patients’ cognitive function at three months after the procedure.

Brainomix AI software improves stroke treatment rates at Budapest University Hospital

Viz.ai launches a range of new AI features

On the 8th November 2019, during a symposium at the annual meeting of the Hungarian Neuroradiology Society (MNRT) in Mátraháza, Hungary, Bence Gunda shared results from his hospital which showed that treatment rates for stroke patients improved and treatment times were reduced following the installation of Brainomix’s e-Stroke Suite.

“The results of our assessment indicated that the treatment rates of both intravenous thrombolysis and mechanical thrombectomy increased once the e-Stroke Suite was installed, with thrombolysis rates increasing from

Viz.ai, the only company with US Food and Drug Administration (FDA) clearance for large vessel occlusion (LVO detection), has added the ability for clinicians to set a desired tMax threshold, which can notify them about hypoperfusion in any part of the vasculature and allows specialists to define the alerts they want to receive.

“Stroke is the second leading cause of death worldwide. Our goal at Viz. ai is to decrease the time to treatment and increase the number of patients receiving life-saving treatment,” said Chris Mansi, CEO and co-founder of Viz.ai.

A press release states, “Unlike other

11.5% to 18.1%, and thrombectomy from 2.8% to 4.8%,” Gunda noted.

“Moreover, there was an improvement in our door-to-needle times, as well as the CT-to-groin-puncture times, both important factors in the treatment pathway for stroke patients,” continued Gunda.

Gunda is a neurologist, and is associate professor at the Department of Neurology at Semmelweis University in Budapest, which treats more than 700 stroke patients each year. According to a press release, Semmelweis is a primary stroke centre, able to deliver intravenous thrombolysis (IVT) to eligible patients. The stroke patients in need of mechanical thrombectomy (MT) treatment are transferred to OKITI in Budapest, where the procedure is performed by a team of trained specialists.

The e-Stroke Suite was installed at Semmelweis in May 2018, enabling the stroke team to automatically assess brain scans from stroke patients using the AI-driven software from Brainomix. To assess the impact of this technology on their stroke service, Gunda conducted an analysis comparing the same period of time in the year prior to the installation of e-Stroke Suite to the period of time when the software was being used.

“The e-Stroke Suite increased our team’s confidence when they are

Viz.ai has announced a number of new features at the Society of Vascular and Interventional Neurology (SVIN) annual meeting in Atlanta, USA (20–23 November, 2019). The latest software, available as a free software update to Viz.ai customers, features customisable alerts based on CT perfusion, proprietary mobile 3D reconstruction, multi-planar reconstruction (MPR), maximum intensity Projection (MIP) reconstruction, and built-in HIPAA compliant direct and group messaging.

In addition, Viz.ai has added an ability to notify and share cases between specialists with the click of a button; this all-in-one mobile application allows stroke teams to synchronise care seamlessly.

29

interpreting brain scans, accelerated our decision-making, and expedited image sharing with the team at OKITI,” Gunda observed. George Harston, chief medical and innovation officer at Brainomix, added: “Their results are indicative of the impact that our technology can have on a stroke network, helping physicians make faster decisions so that more patients can get the optimum treatment.”

Perflow Medical receives CE mark approval of Cascade Agile

Perflow Medical has announced they have received CE mark approval for the Cascade Agile non-occlusive remodelling net (Cascade Agile).

Expanding the Cascade product family, the Cascade Agile optimises control for distal and tortuous vessel anatomy during coil embolisation of intracranial aneurysms.

The Cascade Agile is the latest addition to Perflow’s portfolio of novel neurovascular devices based on a proprietary technology platform, which includes the Stream Dynamic neuro-thrombectomy net (Stream Net) and Cascade Net. The company also announced publication of an article highlighting clinical experience with the Cascade Net as a novel approach for the treatment of ruptured intercranial aneurysms in the September issue of the Journal of NeuroInterventional Surgery (JNIS).

“Multicentre clinical experience with the Cascade Net has been very positive to date. Our focus on providing physicians with more intraoperative control and better information to improve decision-making during complex neurovascular procedures has been well received by the market. And our nimble team continues to ideate and respond to unmet needs in the market, which led to developing the Cascade Agile,” commented Danny Farin, CEO of Perflow Medical. “It is an exciting time, soon we will be publishing our clinical experience with the Stream and Cascade Net, which will fuel our future commercial expansion in and outside of Europe.”

The Cascade product family enables procedural efficiency that is not seen in competitive remodelling devices that necessitate total or partial vessel occlusion. Their unique net design enables continuous blood flow during cerebral aneurysm repair and coiling.

For distal aneurysms with tortuous anatomy, the Cascade Agile’s shorter braid length creates an even more responsive device, which gives physicians the confidence and control they need to safely perform coil embolisation.

Perflow is exhibiting the Cascade Net, Cascade Agile and Stream Net at the World Federation of Interventional and Therapeutic Neuroradiology (WFITN) this week in Naples (Italy). In addition, the company will exhibit at Alice the Course (Essen, Germany), LINNC Asia (Singapore) and SVIN (Atlanta, USA) over the next few months.

The Cascade product family and

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January 2020 | Issue 36

Market watch

Product News Stream Net are commercially available across Europe for the treatment of intracranial aneurysms and acute ischaemic stroke, respectively. Perflow products are not approved for clinical use within the USA.

RAPID platform expands to address haemorrhagic stroke

iSchemaView has launched the newest addition to the RAPID platform, RAPID ICH at the 2019 Congress of Neurological Surgeons (CNS) Annual Meeting (19–23 October, San Francisco, USA). This fully-automated system uses the latest in artificial intelligence to quickly triage non-contrast CT (NCCT) cases and notify clinicians of possible intracranial haemorrhage (ICH). RAPID ICH will enable hospitals and mobile stroke units on the frontlines of stroke patient assessment to better streamline treatment decision-making.

RAPID ICH can detect all types of brain haemorrhages with a sensitivity and specificity greater than 90%. This innovative technology was developed and validated using over 1,000 CT scans from stroke centres worldwide.

This new RAPID module automatically

processes images from a scanner and assesses them for haemorrhage. Results are immediately available to doctors via PACS/Workstation, RAPID Mobile app and email.

“RAPID ICH is the next step in AI-powered imaging technology,” said Greg Albers, professor of neurology at Stanford University, director of the Stanford Stroke Center and co-founder of iSchemaView. “By providing radiologists, neurologists and other clinicians this level of detection for all types of haemorrhages in such a small window of time, from minutes compared to the current standard of care of more than an hour, will promote better and faster decision-making for improved patient care and outcomes. RAPID ICH will be extremely useful to facilitate triage decisions in both primary stroke centres and mobile stroke units.”

The RAPID artificial intelligence framework combines deep learning, machine learning and expert feature extraction. It is the only clinically validated imaging solution for stroke diagnostic support worldwide. This proven platform is being used for more than 350,000 scans per year by thousands of healthcare professionals.

RAPID ICH platform

Insera announces first two stroke patients treated with its cyclical aspiration system

Insera Therapeutics has announced that the first two ischaemic stroke patients have been treated with its flagship cyclic aspiration system, CLEAR. The company received CE mark approval for its flagship product, the CLEAR Aspiration System, in March 2019.

“We used the CLEAR Aspiration System to remove blood clots from two stroke patients, one from the anterior circulation and the other from the posterior circulation. I am extremely pleased with the device and believe the cyclical nature of the aspiration offers unique safety and efficacy advantages over existing devices,” said Vladimir Kalousek, interventional neuroradiologist at the Sisters of Charity Hospital, Zagreb, Croatia.

The CLEAR Aspiration System is a digital vacuum aspiration system that allows operators to employ uniform

suction or cyclical suction patterns. The pump can be optionally operated via an iPad app, which also collects system of care chronology, such as time metrics in the stroke chain of survival, as well as key angiosuite metrics, such as expand Thrombolysis in Cerebral Infarction (eTICI) outcomes.

“Cyclical aspiration was used as primary therapy for the first patient resulting in first pass eTICI 3 outcome (complete vessel re-opening) within six minutes. The first patient had a blood clot resulting in a large vessel occlusion in the M1 segment of the middle cerebral artery, and had a witnessed stroke onset in the early time window. The second patient had a blood clot in the posterior circulation in the basilar artery with extremely tortuous vessels, and had an unknown time of stroke onset as she woke up with stroke symptoms. Cyclical aspiration was used successfully in conjunction with stent retriever technology for removing the entirety of the clot,” added Kalousek.

“Our aspiration technology offers the ability to vary the vacuum suction pressures and intervals within the safe vacuum suction range up to -98.2kPa (-29inHg) with the explicit goal of increasing first-pass recanalisation, reducing vessel vasospasm and resulting clot fragmentation compared to static aspiration (namely uniform suction pressure),” said Vikram Janardhan, chief executive officer of Insera Therapeutics.

Calendar of events 18–21 February ISC: International Stroke Conference Los Angeles, USA

11–14 March Global Stroke Alliance Rio de Janeiro, Brazil globalstroke2020.com/

https://professional.

27–28 March LINNC Seminar 2020 – Americas Edition Miami, USA

heart.org/professional/ EducationMeetings

LINNC-Seminar-2020Americas-Edition

6–8 May World Live Neurovascular Conference Washington DC, USA www.wlnc.org/

12–15 May ESO-WSO: Joint European Stroke Organisation and World Stroke Organisation Conference Vienna, Austria eso-stroke.org/events/esowso-conference-2020

30 May–4 June ASNR: American Society of Neuroradiology 58th Annual Meeting Las Vegas www.asnr.org/annualmeeting/

4–7 August SNIS: Society of NeuroInterventional Surgery 17th Annual Meeting San Diego, USA www.snisonline.org

9–11 September 12th ESMINT Congress 2020 Nice, France www.esmint.eu/

September

2019 | Issue

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