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December 2020 | Issue 40

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Grant Mair Evaluating artificial intelligence-based stroke scoring software

Profile Timo Krings Future of Neuroradiology page 16

Global drive to increase awareness, action and access to mechanical thrombectomy for stroke patients Mission Thrombectomy 2020+ (MT2020+), a global campaign of SVIN (Society of Vascular and Interventional Neurology), recently published Mechanical Thrombectomy for Acute Stroke.

Building Thrombectomy Systems of Care in Your Region: Why and How—a white paper targeted towards health policymakers. The paper examines the widespread inaccessibility and geographical disparities in receiving mechanical thrombectomy, and calls for sweeping increase in awareness, accessibility to thrombectomy, and action on a worldwide level.

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VIN notes that currently, the US is a global leader in mechanical thrombectomy use, but that the burden of care is almost four to five times greater in many lower- to middle-income countries. According to MT2020 (now re-named MT2020+ due to ongoing work into 2021 and beyond), the data on stroke patients and the level of care they receive are as follows.

Each year, approximately 13.67 million people suffer from strokes worldwide 20–30% of all ischaemic stroke cases are due to a large vessel occlusion stroke, which makes them eligible for mechanical thrombectomy Less than 10% of eligible large vessel occlusion stroke patients receive thrombectomy, leaving Dileep Yavagal

approximately two million people in need for this procedure but unable to receive it.

One of the main goals set forth by the initiative and detailed in the report are to implement public health interventions to double global access to mechanical thrombectomy every two years for the next decade.

Dileep Yavagal, Global Chair MT2020+ and Global Executive Committee (GEC) co-chair and past-president of SVIN, points out that the campaign is well on its way to increasing the annual rate of stroke thrombectomy for eligible patients to 202,000 annually by the end of last year.

“Large vessel occlusion stroke is a longstanding silent global crisis that now has a highly-effective solution since the last five years: mechanical thrombectomy.

However, thrombectomy care is not widely accessible with colossal geographic disparities on a global level,” said Yavagal, “We are calling on public health policymakers to increase physical, financial and diagnostic access to thrombectomy for patients with disabling stroke to prevent a lifetime of suffering and death.”

Continued on page 4

Phagenyx study shows benefits for neurogenic dysphagia patients page 25

Bimodal neuromodulation can significantly reduce tinnitus symptoms, new trial finds In what is being billed as the largest clinical trial of its kind, researchers show that combining sound and electrical stimulation of the tongue can significantly reduce tinnitus symptoms. They also found that therapeutic effects can be sustained for up to 12 months post-treatment.

THE RESULTS OF THE TENT A1 (Treatment Evaluation of Neuromodulation for Tinnitus) trial, published in journal Science Translational Medicine, revealed that a large majority of participants reported reduced symptom severity at the end of 12 weeks of treatment, which persisted for 12 months.

“Results support the safety and potential utility of bimodal neuromodulation for tinnitus,” the authors report.

The clinical trial was conducted between 2016 and 2019 and was designed to track changes in tinnitus symptom severity. The trial investigated the bimodal neuromodulation approach, using Neuromod’s non-invasive stimulation device that delivers sound to the ears and electrical stimulation to the tongue.

According to the company, this represents the largest and longest followed-up clinical Continued on page 2

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December 2020 | Issue 40

New data

Bimodal neuromodulation can significantly reduce tinnitus symptoms, new trial finds

News in brief

Continued from page 1

Neuromod tonguetip device delivers mild energy pulses to the trigeminal nerve

study ever conducted in the tinnitus field with 326 enrolled participants, providing evidence regarding the safety, efficacy and patient tolerability of bimodal neuromodulation for the treatment of tinnitus.

“Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating, affecting 10 to 15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition,” write Brendan Conlon (Neuromod; School of Medicine, Trinity College; Department of Otolaryngology, St. James’s Hospital, Dublin, Ireland) and colleagues.

A total of 86.2% of treatment compliant participants reported an improvement in tinnitus symptom severity when evaluated after 12 weeks of treatment, with many experiencing sustained benefit 12 months posttreatment.

The study was conducted at the Wellcome TrustHRB Clinical Research Facility (St. James’s Hospital, Dublin, Ireland) and the Tinnituszentrum of the University Regensburg, Regensburg, Germany.

The tinnitus treatment device, now branded as Lenire, was used in the study. This device was developed by Neuromod and consists of wireless bluetooth headphones that deliver a sequences of audio tones layered with

wideband noise to both ears, combined with electrical stimulation pulses delivered to 32 electrodes on the tip of the tongue by a proprietary device trademarked as Tonguetip.

The timing, intensity, and delivery of the stimuli are controlled by a handheld controller that each participant is trained to use. Before using the treatment for the first time, the device is configured to the patient’s hearing profile and optimised to the patient’s sensitivity level for tongue stimulation.

In the trial, participants were instructed to use the Lenire device for 60 minutes daily for 12 weeks.

Out of 326 enrolled participants, 83.7% used the device at or above the minimum compliance level of 36 hours over the 12-week treatment period. For the primary endpoints, participants achieved a statistically and clinically significant reduction in tinnitus symptom severity.

A press release outlines that participants in the study were screened and selected based on a predefined list of inclusion and exclusion criteria to ensure the trial had a wide distribution sample of the tinnitus population.

When treatment was completed, participants returned their device and were assessed at three followup visits up to 12 months. A total of 66.5% of participants who filled out the exit survey (n=272) affirmed they had benefited from using the device and 77.8% (n=270) said they would recommend the treatment for other people with tinnitus.

Addtionally, Neuromod has also announced that they have secured a series B €10.5 million financing for the Lenire device, following the success of this study.

The latest stories from the neuro world

n ESO-WSO: ARTIFICIAL INTELLIGENCE FOR AUTOMATIC STROKE INFARCT VOLUME: At this year’s joint conference between the European Stroke Organisation and World Stroke Organisation (ESO-WSO), Kelvin Wong presented findings on Kelvin Wong artificial intelligence being used to calculate stroke infarct volume from MRI images.

Researchers found artificial intelligence correctly labelled segmentation more often than a human expert was able to.

For more on this story go to page 6 n THE FUTURE OF CLINICAL TRIALS: The INSIST project is aiming at making the in silico, computer modelled, stages of clinical trials a possibility. These researchers are using the MR CLEAN database, among others, to create a fully mathematical model to represent the physiology of the human body. This technology builds models of stroke and stroke treatment.

66.5%

For more on this story go to page 11.

of participants benefited from the device

n NEUROSCIENTIST’S PERSONAL ACCOUNT OF TDCS AND EPILEPSY: Sandra Boccard-Binet provides a warning with her personal account of the potentially harmful effects of transcranial direct current stimulation (tDCS) and epilepsy on healthy subjects.

Since her experience with a tDCS, her life has radically changed.

This account is in press in the journal Epilepsy & Behavior Reports, as a self-case report.

This study represents the largest and longest followed-up clinical ever conducted in the tinnitus field.”

For more on this story go to page 25.

Sandra Boccard-Binet

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2021

4

Global stroke treatment

Global drive to increase awareness, action and access to mechanical thrombectomy for stroke patients Continued from page 1

The white paper also provides perspective on: Cost-effectiveness of patient care afforded by successful implementation of mechanical thrombectomy protocols Tracking metrics and analytics made available through the dedicated MT2020 Global Thrombectomy Tracking (GTT) app Educational tools for members of the community Training initiatives for EMS and healthcare professionals Building thrombectomy systems-of-care in the community Improving inter-hospital transfers for mechanical thrombectomy patients The white paper will be disseminated in six continents with the long-term goal being widespread availability of mechanical thrombectomy as the standard of care globally.

SVIN held its GEC meeting in Los Angeles, USA, in early 2020. MT2020+ members presented country- and region-specific analyses of stroke care. These highlight where stroke care is currently positioned in these countries, roadblocks, and how change can be achieved.

India

P N Sylaja (professor of Neurology, and head of the comprehensive stroke care programme in Sree Chitra Tirunal Institute of Medical Sciences and Technology, Kerala, India) presented an update on the access to stroke care across India.

The presentation began with different stroke registries across India. The Trivandrum Stroke Registry showed an incidence of 135 strokes per 100,000 members of the population, with 74.8% of those being ischaemic, and 14.3% being haemorrhagic; in the Ludhiana Stroke Registry, there was an incidence of 162.3 strokes per 100,000 people with 73% of those being ischaemic, and 25.7% haemorrhagic. Finally, the Kolkata Stroke Registry recorded an incidence of 145.3 strokes per 100,000 people, with fatalities reported at 41.08% after 30 days.

An important takeaway was that in rural areas, there are higher rates of fatality related to stroke. In the Trivandrum Stroke registry, the rate of fatality after 28 days was 37.1% in rural cases, compared with 24.5% in urban. According to Sylaja, one barrier regarding the access to stroke care in India is transport, not just in rural areas but also in cities. “Poor availability of transport in rural areas and congestion in urban areas are barriers to immediate hospitalisation and initiation of treatment.” In a study lead by Sylaja herself, published in Stroke in January 2018, it was found that only 1.8% of stroke patients were brought to hospital by paramedics, while 52% used private transportation.

According to Sylaja, a factor in access to rapid treatment is a lack of education about, and understanding of, stroke symptoms. Further, the Indian population often looks towards alternative medicines for the treatment of stroke. This finding was borne out in the results of a study published in Topics in Stroke Rehabilitation in 2012, which looked at complementary and alternative medicines used in stroke treatment in India. Forty six per cent of stroke patients studied were found to use Ayurvedic medication, 15% intravenous therapies, and 11% used herbal medication.

Latin America

Santiago Ortega-Gutierrez (director of

December 2020 | Issue 40 Neurointerventional Surgery, associate clinical professor Endovascular Center, professor of Neurology and of Neurology, Neurosurgery and Radiology at the Interventional Neuroradiology Alexandria University, University of Iowa, Iowa City, USA, and global vice Cairo, Egypt; and president of Middle East North Africa chair of MT2020+) next presented data on stroke care in Stroke and interventional Neurotherapies Organisation Latin America.

[MENA-SINO]), presented the Middle Eastern Over the last three years Ortega-Gutierrez reveals that perspective. dedicated efforts to collaborate with different regions The Middle East and North Africa (MENA) region in Latin America and help with stroke education and encompasses 17 countries, with an estimated population systems development, primarily in Peru, Ecuador and of 411 million. Mansour commented: “In the absence Argentina, have been undertaken. of good quality data on stroke incidence and prevalence According to data he presented, many South from the region, the exact burden of this devastating American countries do not have a national plan for disease is hard to determine. However, the MENA stroke, with the exception of Brazil and Chile. region has a relatively young population, with According to Ortega- Gutierrez, the main more than 40% of the region’s population barriers to stroke care across Latin being below 15 years of age and just 4% America include: lack of awareness being over the age of 65, indicating that of stroke symptoms, stroke not being in the future, the impact of stroke will treated as a priority, delays in arrival become an increasingly huge burden.” and transfers, lack of well-established Mansour reported that the incidence transport, poorly established stroke rate for all strokes ranged between policies, many hospitals being 22.7 and 250 per 100,000 population improperly prepared for stroke care, per year. There was a 75% high malecrowded public hospitals, limited to-female ratio among stroke patients, funding, and limited neurointerventional and the age of a stroke incidence was training. Moreover, Ortega-Gutierrez stated that typically in the sixth, or seventh decade.

MT2020+ plan the ethnic and socioeconomic disparities are Mansour cited a prospective observational to continue their very pronounced. hospital study from Qatar, where only 17.5% work beyond 2020 Ortega-Gutierrez remains optimistic that of ischaemic stroke patients arrived in things could change rapidly. He points to hospital within three hours of stroke onset.

Brazil’s success following the RESILIENT trial, which He also referenced a prospective study conducted in demonstrated the benefit of mechanical thrombectomy the Neurology Department of Istanbul Medical School in Brazilian public hospitals, which was used to in Turkey, where the admission of stroke patients is convince the government to change its policies. “This dependent on the availability of beds. exemplifies that Latin America has an exceptionally Mansour described the stroke care system across the passionate group of physicians, that when provided region as “in its infancy”, and, noted that, despite strides with adequate resources, can improve stroke care and in the last two decades, there are still too few centres overcome then care barriers,” he says. providing intervention. “To the best of our knowledge, before 2012, there were fewer than ten centres that were Africa treating patients with intravenous thrombolysis for acute Mehari Gebreyohanns (Department of Neurology, ischaemic stroke in the whole region, and the rate of University of Texas Southwestern, Dallas, USA) thrombolysis was less than 1%.” presented on the current state of stroke care across Mansour concluded by showing that there has been Africa and saw the main problems as being the some growth in stroke care across the region achieved “extreme” lack of resources, and a concentration of through the MENA-SINO, which began in 2013 with available resources within the cities. a group of neurointerventionalists coming together to Gebreyohanns reflected on some of the barriers that improve ischaemic and haemorrhagic stroke services could hinder the progress in stroke care across the in the region. The organisation is raising awareness continent. Importantly, one of the first stumbling blocks regarding stroke risk factors and identifying the is that there may be no specific medical vocabulary in interventions needed; providing education, endovascular the African languages (of which there are an estimated thrombectomy training and awareness for stroke care 2,000 in the continent) for stroke. Secondly, there is providers; conducting research focused on pragmatic and a significant shortfall in the number of neurologists, locally-relevant solutions for reducing stroke burden; with only one for every five million people, and these building networks of political and professional allies; are concentrated in the capital cities. The systems of and disseminating relevant knowledge. care too are not well developed, Gebreyohanns said, illustrating that these include emergency medical Beyond 2020 services, emergency room triage, and the existence In an exclusive interview Yavagal gave to NeuroNews, of dedicated stroke units and protocols. Thirdly, there on MT 2020+, he notes, “The next steps are very is a lack of availability of drigs, especially of tissue exciting, and we have much work to do.” plasminogen activator (tPA). Then, there is a lack of According to Yavagal, the number of SVIN’s regional what Gebreyohanns described as “basic” equipment, committees is expected to grow to over 100. Existing including CT scanners, MR imaging, and catheter labs, regional committees are currently developing their which are only available in a few big cities. top five interventions for 2021. “Each region needs a Despite these large roadblocks, Gebreyohanns slightly different intervention, for example, educating pointed to signs that things may improve including the pre-hospital personnel to recognise stroke is a big creation of a word for stroke in the Ethiopian language, requirement in low- and middle -income countries.” which would translate to “brain attack”. Other positive Yavagal also emphasises that a more equitable global developments include programmes run by the Bahir Dar access to mechanical thrombectomy rests on the huge Outreach for Neurology Education (BORNE) initiative, task of properly training the medical personnel needed which he founded, that aim to improve the state of to perform mechanical thrombectomy, which is closely stroke care with Bahir Dar University in Ethiopia. linked to the set-up of stroke centres around the world.

Gebreyohanns says this initiative includes institutional Yavagal left with this comment, “multiple relationship building, global neurology elective courses stakeholders from every aspect of public health need for residents, yearly teachings and symposia, skills to come together, along with policy makers and training and cross-training, telemedicine, and web-based governments, to advance MT 2020+ because, we finally skills training. have a very important treatment that actually reduces the disability from stroke. Without a global implementation Middle East and North Africa of this powerful treatment, the benefit will not be Ossama Yassin Mansour (director, Stroke and realised in any good measure.”

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December 2020 | Issue 40

Artificial intelligence

ESO-WSO: AI can be used for automatic segmentation of stroke infarct volume A study presented by Kelvin Wong (Houston Methodist, Houston, US) at the European Stroke Organisation and the World Stroke Organization joint virtual conference (ESO-WSO 2020, 7–9 November), has shown that artificial intelligence (AI) can be used to identify stroke infarct volume from MRI images.

IN FACT, THIS STUDY REVEALS THAT IN cases with a low Dice score, the AI labelled the segmentation correctly more often than a human expert was able to. The study is a collaboration between John Volpi, (director of Eddy Scurlock Stroke Center, Houston Methodist, Houston, USA) and Stephen T C Wong (Houston Methodist Cancer Centre, Houston Methodist Hospital).

The stroke infarction volume in acute ischaemic stroke can be an important variable in predicting a patient’s modified Rankin score (mRs) after 90 days, when used alongside patients’ age and National Institutes of Health Stroke Scale (NIHSS).

This means that being able to segment sections of the brain, through MRI imaging, can be important in assessing a stroke. However, doing this manually can be labour intensive, requires expert training, and plenty of practice.

This study included 875 acute ischaemic stroke patients who received a diffusion-weighted MRI (DW-MRI) at Houston Methodist Hospital in Texas.

Three independent experts would manually segment the infarction volume, with changing infarct size and location, including middle cerebral artery stroke, posterior cerebral artery stroke, and anterior cerebral artery stroke.

A rotation-reflection equivariant UNet model was

NICO.LAB receives FDA clearance for artificial intelligence stroke care solution NICO.LAB has received clearance from the US Food and Drug Administration (FDA) for its artificial intelligence (AI) powered solution in stroke care, StrokeViewer LVO. ACCORDING TO NICO.LAB, StrokeViewer LVO is an AI algorithm for fast triaging of stroke patients. The

The AI model is largely able to automatically segment the brain correctly

trained on 67 cases and validated on 32. This model was then applied to all cases and segmentation results were manually corrected by three independent experts.

The final model used for the study was based on 80% data and tested on 20% data, and the programme’s performance was evaluated using Dice score.

There have been some developments in this area prior to this study, with deep brain learning stroke segmentation with convolutional neutral networks

company claims that StrokeViewer LVO detects the image characteristics of large vessel occlusion and alerts physicians.

The FDA approved the 510(k) application supported by a multicentre clinical study where the performance of the StrokeViewer algorithm was retrospectively evaluated on CT images from 384 patients from multiple US stroke centres. The results from the algorithm were then compared with the results from a panel of experts who also assessed the data to identify the large vessel occlusion. According to NICO. LAB’s press release, the algorithm exceeded the set performance goal.

Merel Boers, CEO and co-founder of NICO.LAB, said: “With our first FDA clearance we are now able to show US physicians how impactful the combination of human and artificial intelligence is. And yes, more will follow as we are fully committed to unlocking the full healthcare potential for every patient.”

NICO.LAB is a Dutch company founded in 2015, from the Amsterdam University Medical Center in the Netherlands. Their StrokeView solution is already in use in Europe and Australia, where they claim it has already been proven to reduce the time from hospital arrival to start of treatment for patients with acute stroke.

Kelvin Wong

(CNN) showing promising results in large studies.

However, these areas show some limitations and obstacles.

The first of these is a general problem in this area, that acute ischaemic stroke lesions often have complicated shapes, and there is a large variation in their size and location, dependent

on the vascular origin.

CNN image results can be confused by mirror flipped or rotated images. Additionally, there are artefacts which appear in the DW-MRI imaging, which can be confused for stroke, although this problem is less apparent in larger lesions.

Data augmentation also presents further issues, as when there are image interpolation artefacts introduced that does not occur within the data, it is not guaranteed that this programme will recognise it.

It therefore seems promising that this study shows that the AI model created is able to automatically segment the brain largely correctly. Furthermore, this model created less complications with regards to imaging orientation, as Wong commented, “in general if the image rotates or reflects, the output or segmentation will be rotated accordingly.”

While the study shows the model as working well, Wong observes some areas of weakness. Firstly, the image quality would affect the ability for the model to create a segmentation, and these were the main causes of error. Secondly, there are some areas, such as the pons, where imaging is particularly dark, which creates a problem in the programme’s ability to identify lesions. Finally, the pure cortical infarct cases were more challenging for the model to segment. Despite this, the model could be promising in creating a less labour intensive route to segmentation of stroke infract volume.

Avicenna.AI stroke detection tool approved for Medicare NTAP Avicenna.AI has announced that its medical imaging artificial intelligence (AI) tool, CINA Head, has qualified for the new technology add-on payment (NTAP) recently approved by the Centers for Medicare and Medicaid Services (CMS).

CINA HEAD ANALYSES COMPUTER TOMOGRAPHY ANGIOGRAM (CTA) images of the brain taking during acute settings, and notifies clinicians when it identifies a suspected large vessel occlusion, potentially reducing time to treatment according to the company. Additionally, CINA Head has been approved by the US Food and Drug Administration (FDA) for use in neurovascular emergencies for the detection of intracranial haemorrhages.

According to the company, CINA Head uses a combination of deep learning and machine learning technologies in order to automatically detect and prioritise acute intracranial haemorrhages and large vessel occlusion (LVO) cases from CTA images in less than 20 seconds, alerting clinicians. The NTAP award is available for radiological computer-assisted triage and notification software systems like CINA Head.

Peter Chang, radiologist and co-founder of Avicenna.AI, California, USA, commented, “AI-enabled CT stroke triage, specifically with LVO detection, is the first deep learning tool to receive the CMS NTAP designation and is eligible for up to $1,040 of reimbursement. CMS only grants NTAP designation to promote the adoption of new technology that provides substantial clinical improvement over standard of care. This will help accelerate the innovation and adoption of deep learning technology by aligning the incentives of both software developers and clinical providers.”

ASPECT score 5: right side acute ischaemic region(s): M2, M4, M5, L, I

Issue 40 | December 2020

Artificial intelligence

Real-world testing of artificial intelligence software used to identify stroke features Grant Mair Comment & Analysis Grant Mair (University of Edinburgh, and honorary consultant neuroradiologist, NHS Lothian, Edinburgh, Scotland), gave a talk entitled, “Large-scale clinically representative evaluation of e-ASPECTS & e-CTA software, the RITeS study (Real-world independent testing of e-ASPECTS software) at the ESC-WSO 2020 conference. He writes on the study’s finding for NeuroNews.

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oftware designed to assist clinicians interpret brain imaging in stroke is increasingly available. Yet there are no agreed standards for assessment and no requirement for software to demonstrate tangible improvement in patient care. Published testing often lacks independence from software developers and datasets may be under-powered and poorly-defined.1 As a major charitable funder of stroke research in the UK, the Stroke Association commissioned research to provide robust, largescale and independent testing of one commercially available option.

Initially designed for automated Alberta stroke programme early CT score (ASPECTS) assessment of non-enhanced CT brain scans in acute ischaemic stroke, e-ASPECTS (Brainomix, Oxford, UK) is now part of a software suite and offers additional automated features including haemorrhage detection on CT, and CT angiography scoring (e-CTA).

The RITeS collaboration comprises researchers from four UK centres and one in Germany. All five centres have extensive experience conducting stroke research, with access to large numbers of imaging studies approved for research.

The RITeS database comprises nine completed national/international clinical stroke trials or registries6–14 with >6,000 unique patients covering the gamut of potential diagnoses underlying acute stroke symptoms (ischaemia, haemorrhage, mimics). All imaging studies in the RITeS database were scored consistently by centralised expert readers, masked to clinical data including other imaging. Inter-rater agreement between experts for ASPECTS and angiography scoring was 0.56 and 0.7015, respectively. Scan assessment occurred before the RITeS study began.

The RITeS study sought a large number of clinically representative acute stroke cases from the RITeS database for a ‘real-world’ evaluation of e-ASPECTS and e-CTA. Primarily, we aimed to

Software and expert human results agreed for 68.7% (2091/3044) of CT and 63.1% (344/545) of CTA.

identified the most appropriate DICOM image set per case (axial orientation, soft tissue kernel, thinnest slices available) and uploaded these to the Brainomix online platform (version 9.0p3). We recorded all scan processing outcomes.

Multiple upload attempts were made if necessary and we tried alternative DICOM image sets if available.

We include 4,117 patients (50.4% female, median age 78 years, median NIHSS 10, median 2.5 hours from symptom onset). Software successfully processed 89.1% (3660/4108) of CT and 81.6% (545/668) of CTA presented.

For assessment of ASPECT scoring, we include 3,044 cases with ischaemic stroke and successfully processed imaging.

In pairwise comparison of human and software results, nearly half (1,409 scans, 46.3%) matched exactly (ASPECT score and side affected), while over two thirds (68.7%) were ±1 ASPECTS point, and over three quarters (82.3%) were ±2 ASPECTS points. For 356 scans (11.7%), humans and software scored the opposing cerebral hemisphere as abnormal. Human-software inter-rater

CT CTA 68.7% 63.1% (2091/3044)

compare ASPECTS results, and also compare CTA results (identification of obstruction) provided by software versus expert humans. Our study will also ultimately include assessment of e-ASPECTS haemorrhage detection, and a clinical impact evaluation, but these components are ongoing.

Our methods were prespecified,16 and include intention-to-analyse testing, ie, we attempted to process all available scans and did not exclude cases where imaging quality was poor, or where processing was unsuccessful.

We aimed for the maximum number of unselected cases from those available with clinical and demographic representation similar to other large pre-specified datasets.3–5 We manually

(344/545)

agreement was 0.50.

For assessment of CTA, we include 545 cases with successfully processed imaging. In pairwise comparison of human and software results, nearly two-thirds (344 scans, 63.1%) matched exactly (183 normal, 149 proximal/12 distal side-matched obstruction). Most mismatches were false negative (82 scans, 15%) or false positive (57 scans, 10.5%) calls by software relative to humans. Humans and software scored the same side but different abnormal vessels in 34 scans (6.2%), while for 13 scans (2.4%) the opposing side was scored abnormal. Human-software inter-rater agreement was 0.48.

RITeS provides a large, independent assessment of e-ASPECTS and

There are no agreed standards for assessment and no requirement for software to demonstrate tangible improvement in patient care.”

7

e-CTA using non-selected clinicallyrepresentative cases. Our study relied on retrospective scan processing and expert opinion delivered non-acutely.

Thus, our results may differ from routine practice where scans are processed prospectively, rapidly evaluated in real-time, and where readers may often be less experienced. For the primary software features of ASPECT scoring on CT and identification of CTA obstruction, e-ASPECTS and e-CTA agreed with human expert reviewers for around two thirds of cases. Software users should be aware that results may differ from expert opinion (18–31% in our analysis). e-ASPECTS and e-CTA should be used strictly within their approved indications to aid clinicians who understand stroke CT interpretation, and not by inexperienced readers.

Grant Mair is the Stroke Association’s Edith Murphy Foundation Senior Clinical Lecturer, University of Edinburgh, and honorary consultant neuroradiologist, NHS Lothian, Scotland. He writes on behalf of the RITeS investigators and reports that this research is funded by the Stroke Association. Mair reports no commercial disclosures.

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14. RIGHT-2 Investigators. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet 2019; 393(10175): 1009–1020.

15. Mair G, von Kummer R, Adami A, et al. Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial. Neuroradiology 2015;57, 1–9.

16. Mair G, Chappell F, Martin C, et al. Real-world Independent Testing of e-ASPECTS Software (RITeS): statistical analysis plan [version 1; peer review: 1 approved]. AMRC Open Res 2020, 2:20 (https://doi. org/10.12688/amrcopenres.12904.1)

December 2020 | Issue 40

10 Acute stroke care

The relevance of a strong healthcare system for acute stroke care during the COVID-19 pandemic Blanca Fuentes María Alonso de Leciñana Exuperio Díez Tejedor Comment & Analysis Blanca Fuentes, María Alonso de Leciñana, and Exuperio Díez Tejedor write about the challenges faced in the management of stroke care throughout the pandemic, and the lessons learned.

Fuentes originally presented on this topic at the joint European Stoke Organisation and World Stroke Organization (ESO-WSO) virtual confrence (7–9 November, 2020).

T

he COVID-19 pandemic has disrupted the normal functioning of hospitals, causing an overload of emergency services and hospital wards with patients infected with SARSCOV-2. As a result, many of the human and material resources usually dedicated to stroke care were reallocated to attend COVID-19 patients. This fact might have negatively affected acute stroke care.

A recent web-based survey conducted by the ESO in March 2020, showed the negative impact on the delivery of stroke care. The survey was completed by more than 400 stroke care providers from 55 countries. A reported 77% of responders affirmed that not all stroke patients were receiving usual care, and this proportion was even higher in Italy and Spain, two of the most heavily affected countries by the first wave of the COVID-19 pandemic in Europe.1 Extended working hours due to lack of personnel, sleep deprivation, the assignation of stroke physicians to new tasks outside of stroke care, and the shortage of personal protective equipment were frequently reported.1,2 To overcome the challenge of the pandemic, most hospitals in affected countries had to reorganise acute stroke resources, balancing two main objectives: first, to provide timely and effective stroke care; and second, to ensure safety and minimise the risk of infection inside the stroke teams.

It is important to highlight that reorganisation involves every component of the stroke care chain,3 starting with the general public by encouraging them to seek prompt medical attention and avoid staying at home for fear of contagion. At the prehospital level, it is essential to stick with stroke code

77%

emergency wards, inpatient wards, stroke units and critical care units.

We should encourage close outpatient management for TIA and minor stroke patients as well as the use telemedicine for follow-up and rehabilitation.

However, the implementation of the expert’s recommendations was not homogenous in the affected regions, since each hospital had to adapt them to their local characteristics and resources.4,5 Therefore, in addition to establishing organisational recommendations, we should evaluate their generalisability and effectiveness in terms of stroke treatment and outcomes.

Several multicentre studies in Europe have reported decrease in stroke admissions, but the good news is that, in the majority of them, the proportions of recanalisation therapies for acute ischemic strokes were kept without significant changes.6–9 even with an increase in the proportion of endovascular treatment in some regions.6 This suggests that the strength of the preCOVID-19 stroke care systems, along with the implementation of the new organisational measures has played an essential role in affording the pandemic challenge.

Nevertheless, as the COVID-19 pandemic has not yet been fully eradicated, and with some countries

of responders affirmed that not all stroke patients were getting the same care

The implementation of the experts’ recommendations was not homogenous in the affected regions, since each hospital had to adapt them to their local characteristics and resources.” priority while also ensuring the personal protection of all of the healthcare professionals evaluating the patients. A COVID-19 symptoms checklist should be implemented at this level for early identification of infected patients.

All health providers must be familiar with the code stroke protocol. This is especially important in those settings hiring temporary or external staff because of the pandemic who may not be familiar with local stroke code protocols.

Different pathways should be followed for patients with and without suspected COVID-19, including the use of different

undergoing new waves, it is also important to monitor the performance of each of the recommended measures to identify any deviation and correct it in the forthcoming waves.

One of the organisational measures that has come into question is the performance of Chest-computed tomography (CT) scan on acute stroke patients for the early detection of the COVID-19 lung involvement, as it seems to be associated to significant delays in door-to puncture-times.7 That recommendation was given at the beginning of the pandemic, to ensure

the better allocation of the acute stroke patients in the COVID or COVID-free wards and pathways. Its rationale was that, at that time, there were large delays in the confirmation of the SARS-COV-2 infection by the polymerase chain reaction (PCR).

The reliability of PCR was initially poor, with many false negatives, which could compromise the safety of the members of the stroke teams and other stroke patients. Fortunately, diagnostic accuracy for the currently available tests is much better now, and there are no reasons for the systematic performance of Chest-CT. This finding is a good example of the importance of monitoring and evaluating the stroke care pathways during COVID-19 pandemic, to identify new needs and to discard some organisational measures that are not needed anymore.

The war against the pandemic is still on-going. The first wave of the pandemic caught us off guard, but we knew how to adapt and deal with it. We have learned our lesson and we may face the new waves with reinforced organisational measures to care for acute stroke.

Blanca Fuentes. Head of the stroke unit, Department of Neurology and Stroke Centre, Hospital La Paz Institute for Health Research-IdiPAZ, La Paz University Hospital-Universidad Autónoma de Madrid, Madrid, Spain.

María Alonso de Leciñana. Coordinator of the Stroke Group, Spanish Society of Neurology, Department of Neurology and Stroke Centre, Hospital La Paz Institute for Health Research-IdiPAZ, La Paz University Hospital-Universidad Autónoma de Madrid, Madrid, Spain.

Exuperio Díez Tejedor. Coordinator of the Ictus Madrid Program, Department of Neurology and Stroke Centre. Hospital La Paz Institute for Health ResearchIdiPAZ, La Paz University HospitalUniversidad Autónoma de Madrid, Madrid, Spain.

References: 1. Aguiar de Sousa D, van der Worp HB, Caso V, et al.

Maintaining stroke care in Europe during the COVID-19 pandemic: Results from an international survey of stroke professionals and practice recommendations from the European Stroke Organisation. Eur Stroke J. Epub ahead of print 2020. DOI: 10.1177/2396987320933746.

2. Alonso de Leciñana-Cases M, Castellanos M, AyoMartín Ó, et al. Stroke care during the COVID-19 outbreak in Spain. The experience of Spanish stroke units. Stroke Vasc Neurol. Epub ahead of print 2020.

DOI: 10.1136/svn-2020-000678.

3. Rodríguez-Pardo J, Fuentes B, Alonso de Leciñana M, et al. Acute stroke care during the COVID-19 pandemic.

Ictus Madrid Program recommendations. Neurologia 2020; 35: 258–263.

4. Bersano A, Kraemer M, Touzé E, et al. Stroke care during the COVID‐19 pandemic: experience from three large European countries. Eur J Neurol 2020; 27: 1794–1800.

5. Fuentes B, Alonso de Leciñana M, Calleja-Castaño P, et al. Impact of the COVID-19 pandemic on the organisation of stroke care. Madrid Stroke Care Plan.

Neurologia 2020; 35: 363–371.

6. Sacco S, Ricci S, Ornello R, et al. Reduced admissions for cerebrovascular events during COVID-19 outbreak in Italy. Stroke 2020; 51: 3746–3750.

7. Fuentes B, Alonso de Leciñana M, García-Madrona S, et al. Stroke acute management and outcomes during the COVID-19 outbreak: a cohort study from the madrid stroke network. Stroke (in Press).

8. Tejada Meza H, Lambea Gil Á, Sancho Saldaña A, et al. Impact of COVID-19 outbreak on ischemic stroke admissions and in-hospital mortality in North-West Spain. Int J Stroke 2020; 15: 755–762.

9. Tejada Meza H, Lambea Gil Á, Sancho Saldaña A, et al.

Impact of COVID‐19 outbreak in reperfusion therapies of acute ischaemic stroke in northwest Spain. Eur J Neurol 2020; 27: 2491–2498.

Issue 40 | December 2020

New study finds diabetes and hypertension may increase risk of COVID-19 brain complications A new study presented at the Radiological Society of North America (RSNA) annual meeting shows that some COVID-19 patients with the pre-existing conditions hypertension and diabetes, may be at an increased risk of complications such and bleeding in the brain and stroke.

THE STUDY LOOKED AT COVID-19 PATIENTS who received either head computerised tomography (CT) or magnetic resonance imaging (MRI) scans

Research updates 11 between January and April of 2020. Of the 81 patients who received a scan, one in five had conditions such as stroke, brain bleeds or blocked blood vessels. Within this group, around half had a history of conditions such as high blood pressure or type two diabetes.

The study was led by Colbey W Freeman, chief resident in the Department of Radiology at Penn Medicine, Philadelphia, USA, Freeman commented, “COVID-19’s effects extend far beyond the chest.” He continued, “COVID-19 is associated with neurologic manifestations, and hypertension and type 2 diabetes mellitus are common in individuals who develop these manifestations. These populations may be at higher risk for neurologic complications and should be monitored closely.”

COVID-19 is known to first attack cells in the respiratory system, which may lead to inflammation of the lungs, putting some patients at risk from pneumonia. While COVID-19 does primarily effect the lungs, according to a press release from RSNA, it is being theorised that the inflammation associated with the infection may be leading to

Colbey W Freeman

INSIST in silico project: The future of randomised controlled trials

The in silico trials for treatment of acute ischaemic stroke (INSIST) consortium began in 2017 and presented its concepts and first results at the joint European Stoke Organisation and World Stroke Organization (ESO-WSO) virtual conference (7–9 November). NeuroNews had an exclusive interview with two of the project’s leaders, Charles Majoie (professor of neuroradiology at the Amsterdam University Medical Center Amsterdam, The Netherlands), co-principal investigator (PI) of the MR CLEAN trial, the MR CLEAN registry, and now co-PI of the MR CLEAN NO IV trial and INSIST, and Alfons Hoekstra, professor of computational science and engineering, director of the Informatics Institute at Amsterdam University (Amsterdam, The Netherlands) and co-PI of INSIST.

M

ajoie explained the aim of their project, “Performing a randomised control trial (RCT) is a huge burden and also very expensive, for researchers as well as patients. Despite good designs, they often fail. So, with INSIST, we aim to generate a platform to perform the trials in silico through computational modelling and simulation technologies.

We now have computer simulations, which are standard technology in many industries like automotive, aeronautics or engineering, but they are really underestimated for the health care setting. INSIST is based largely on existing databases like the MR CLEAN trial and MR CLEAN registry. We have generated a virtual population model, which is an effective covariant distribution model, incorporating all relevant patient parameters that may account for the differences between those individuals. We also generated models to simulate thrombosis and thrombolysis, thrombectomy, and models simulating tissue fate during and following ischaemic stroke. We have also generated a platform for in silico trials.”

Hoekstra added, “We are talking about mathematical models. What we do is try to mimic parts of physiology in the computer and then we are able to do that. We can also model the path of physiology in a computer, in this case a stroke, and we can also model treatment. We have a movie showing a thrombectomy treatment, but this is not an animation. This is completely computed from the basic laws of physics and from the basic laws of physiology and biology. And that is one big thing to realise. And so when we speak about models, this is what we mean.”

Hoekstra continued with some ideas of where the project is now, “a big part of our work is to turn trial data, into real information for the INSIST project. We

the neurological effects. This study looked at blood markers of inflammation, which were high in people with critical results. To this effect, Freeman stated, “While complications in the brain are rare, they are an increasingly reported and potentially devastating consequence of COVID-19 infection.”

The study also found that two-thirds of the patients with critical results were African American, suggesting that these patients also may also require closer monitoring.

This study is ongoing and researchers will continue to publish results as they come in.

These researchers are also investigating incidence of neurologic complications in COVID-19 patients on extracorporeal membrane oxygenation.

On this, Freeman stated, “We have plans to initiate a larger prospective study evaluating delayed, longterm, and chronic neurologic manifestations that may not be known in this early period in the pandemic.”

are getting close to being able to claim that our models are valid, meaning that indeed they represent reality and in this case, the stroke effect and the treatment effect. We are now getting ready to put all our models together to mimic the MR CLEAN trial. So we are basically Charles Majoie trying to, in a retrospective sense, recreate the MR CLEAN trial in the computer.

If our in silico trial produces the same output as the original MR CLEAN trial, we have made a big step and we are quite optimistic that we are going to be able to do that. If that is the case, then we can open up a complete new territory. We can start to ask ‘what if’ questions to the computer. So, what if the MR CLEAN trial was a little bit different? What would be the outcome? If we repeat the MR CLEAN trial, but now with a different device, what would that INSIST look like? We need to try a few ideas that came up in the clinical context before putting that into a real randomised trial. That’s where we are going with this technology.

It will not tell you anything yet about the fate of an individual patient. We are not claiming we can predict

that. This may happen in the future, but that is not the goal of this project. This technology will never fully replace trials. That is impossible. It will help to improve trials. It will help speed up trials.”

Majoie added what some of the benefits of this can be for clinicians, “I think that by trying to simulate thrombectomy, you also get more insight on what is really happening. Every detail is then incorporated in the model, the mechanical properties of the clot, and of the stent itself. So, you can see very good interaction between the stent and the clot. You have got more insight on what is really happening and then you get an idea how to optimise the device to improve the treatment. You can also adapt the design of the trial that you are planning to execute, when you first run it in silico, you could see the problems and the possible failures.”

Hoekstra commented on some obstacles they face, “One big barrier is the certification and accreditation of all this technology. From our very first moment, we interacted with the US Food and Drug Administration (FDA), who are very open to these Alfons Hoekstra ideas, which was a big support for this research.

This resulted in a lobby towards the European Commission that understood the importance of this technology and decided to start to fund these ideas. So, we got a first wave of money to support the idea of in silico trials.”

Hoekstra continued, “the FDA and the European Medicines Agency (EMA), have both declared that in silico techniques are feasible and should be able to perform primary evidence in trials or replace primary evidence for trials, or other experiments. That means that you need to set up a whole chain of protocols for in silico technology to be accredited by FDA or the EMA to allow a piece of software to generate this data.”

The INSIST project is supported by the European Union’s Horizon 2020 research and innovation programme (Grant No. 777072; www.insist-h2020.eu).

12 Advertorial

December 2020 | Issue 40

THIS ADVERTORIAL IS SPONSORED BY MEDTRONIC NEUROVASCULAR

Coil pliability matters: Novel metrics for assessment of in vitro coil softness

differences in coil characteristics by using a model internal carotid artery (ICA) and a synthetic aneurysm, a fixed position of a catheter tip at the level of the neck, a consistent velocity of coil deployment using a motor, and a digital pressure sensor (Futek Advanced Sensor Technology) affixed to one side of the outer surface of the aneurysm to measure the perpendicular component of force as a coil is being deployed. The authors integrated a commercially available automated tracking and measurement system (Interventional Device Testing Equipment) with their customised aneurysm acrylic model. A schematic of the setup is shown in Figure 1.

In addition to the computer-controlled motor for coil delivery, leveled test surface, and synthetic ICA and The deployment of an embolisation coil is “much more art than science” according to aneurysm model, the setup also included a camera to Daniel Sahlein (Goodman Campbell Brain and Spine, Indianapolis, USA). In this article, monitor the deployment. Briefly, a computer-controlled Sahlein considers the importance of embolisation coil pliability, describes a novel test for motor was used to push the coil through a simulated the assessment of coil softness, and considers how this may influence clinical practice. synthetic ICA segment into the model aneurysm. The perpendicular component of force experienced by the mbolisation coils have been widely used for Causes of IAR are likely multifactorial and may be aneurysm wall was tracked over the deployment of the intracranial aneurysm treatment since the related to characteristics of the aneurysm such as single coil and a force displacement curve was obtained introduction of Guglielmi detachable coils in wall thickness or integrity as well as properties of the for each case. An energy metric (effective work done to the 1990s. Platinum coils have typically been used in procedure such as catheter tip position. For deploy the coil) was calculated and reported these endovascular procedures and are commercially example, it is possible that a very soft, small as the average work number (AWN)—equal available in various shapes and sizes. Technological coil can perforate an aneurysm if deployed to the area under the force displacement advancements in coils include the improvement of through a catheter tip that is pinned against curve for each deployment. Specifically the pliability or softness, addition of shapes, modification an aneurysm wall (immediately apposed authors compared framing and finishing coils of the mechanical detachment systems, addition of to the dome). IAR rates as reported in from two manufacturers. Specifically, the coatings, and increased softness of the distal delivery the literature have found no specific authors studied the following coil groups: wire or mandrel.5 Coiling remains the preferred correlation related to coil type (framing, (a) soft coils: Axium™ Prime Detachable treatment for ruptured aneurysms. Flow diversion filling, finishing) and sequence.11,8,16 IAR Coil (Extra Soft) (Medtronic, 2.5mm x 4cm, is currently not indicated for treatment of ruptured rates are somewhat dependent on aneurysm Daniel Sahlein n=20) and Target™ 360 Nano Coil (Stryker, aneurysms due to the potential risk associated with use location10, and size.13 2.5mm x 4cm, n=20), and (b) frame coils: of antiplatelet therapy and questions over the degree Nevertheless, a coil that is more pliable (soft), with Axium™ Prime Frame Detachable Coil (Medtronic, of aneurysm protection following flow diversion and resultant decreased force against the aneurysm wall and 5mm x 15cm, n=20) and Target™ 360 Standard Coil prior to stent construct endothelialisation. While braided less amplitude of that force (more consistent low force), (Stryker, 5mm x 15cm, n=20). endosaccular devices such as the Woven EndoBridge is likely to result in a decreased risk of perforation.

Overall, the force component curves had three (WEB, Sequent Medical) can be used to treat phases. Firstly, an initial low force phase—during the ruptured aneurysms, the device stiffness during initial Finding space initial introduction of the coil when there is enough deployment can result in an aneurysm perforation, Another important coil characteristic is the ability to volume inside the aneurysm sac for the coil to deploy particularly in small and/or off-angle aneurysms.12 fill in the available volume within the aneurysm sac, and bend unimpeded by other coil loops. Then there is Typically, wide neck and medium‒large intracranial colloquially referred to as “finding space”. This is a mid-deployment phase when the peaks and valleys in aneurysms treated with endovascular coiling particularly relevant during multi-coil embolisations the force-displacement curve begin to develop; peaks sequentially utilise framing, filling and finishing coils. but is important in the treatment of small ruptured occur when the coil is pushed against the aneurysm One of the major risks associated with intracranial single-coil cases as well when trying to achieve higher wall and valleys when the coil bends or loops into the aneurysm coil embolisation is intraprocedural packing density.3,15 Mechanical analysis of coils has open space in the aneurysm. This is followed by the aneurysm rupture (IAR) or perforation.2 This risk is been traditionally considered using first order Hookean final phase of deployment—as the coil continues to fill associated with the mechanical characteristics of a principles17 and these calculations do not often the aneurysm model, there is progressively reduced thin and heterogeneous aneurysm wall that is difficult account for higher order effects associated with coil to predict and impossible to measure in a clinical rearrangement in an aneurysm sac. setting.1 Tactile feedback during coil deployment is A recent report in the Journal of Neurological often subjective and the perception may vary widely Sciences18 uses a model of force against an aneurysm between neurointerventionalists and is likely to wall—throughout the length of a coil deployment—to change and become more refined with experience. study comparable, commercially available coils. The Furthermore, visual feedback—watching for coil authors have developed an in vitro system to isolate “accordioning” in the catheter—is used concomitantly by neurointerventionalists and factored variably depending on the size of the aneurysm, the degree of coil occlusion, and the catheter tip position. Adding a layer of complexity to this paradigm, the literature has consistently shown that aneurysm remnants have a risk of rupture11 and that the degree of incomplete treatment is inversely correlated with recurrent rupture risk: i.e. the less the aneurysm is treated, the greater the risk of recurrent haemorrhage.9 The neurointerventionalist, therefore, is left to balance two discrete risks; pack coils more and risk aneurysm perforation, or, embolise less and potentially undertreat—thereby exposing the aneurysm to recurrent haemorrhage. Taken as a whole, the practice is much more art than science.

Nevertheless, the treatment and its associated hazards can be studied scientifically, and effective measures can be taken to mitigate risk. Coils have the potential to introduce undesirable point or localised forces on the aneurysm wall which can lead to an IAR.4,14 The incidence rate of IAR is low but the mortality rate Figure 1 Figure 2 associated with such complications remains high.10

E

Issue 40 | December 2020

Figure 3a

available volume which translates into higher force being detected by the distal force sensor. The peaks and valleys become most apparent in this end phase as a longer coil is deployed within the aneurysm. These characteristics are evident in the deployment of the soft category of coils, the extra soft (ES) Coil and a Nano Coil (Figure 2), which as expected impart less force on the aneurysm wall than the Axium Prime FC and Target 360 Standard framing coils. In addition, there were significant differences between the Axium Prime and Target 360 Standard coils (Figure 3a), in the total perpendicular component of force on the aneurysm wall during deployment—quantified with the AWN. There were also differences in the force gradient between the peaks and valleys, particularly between the framing coils—Axium Prime FC and Target 360 Standard coils (Figure 3a). The increased magnitude of the force gradient shows that the Target 360 Standard coil offered a higher resistance to rearrangement within the aneurysm sac. The lower peaks for the Axium FC coils indicate that the coils rotate more smoothly to facilitate rearrangement within the available aneurysm sac volume.

Although finishing coils are structurally different from the framing coils, similar behaviour is also observed with progressive filling of these coils. In this experiment, the ES coil exhibits lower aneurysm wall forces than the Nano coil and appears to offer less resistance to rearrangement within the aneurysm sac (Figure 3b). These measurements could be somewhat correlated to coil design. For example, the ES coil has a smaller wire diameter (0.0013 inch primary wire and

Taken as a whole, the practice is much more art than science.”

0.0011inch stretch resistant strand diameters) that may allow for smoother transitions and adjustments within the aneurysm sac.

The authors compared the AWN for the coil deployments (Figure 4) using analysis of variance (ANOVA). Not surprisingly, the AWN for the finishing coils was significantly lower than for the framing coils. In addition, the AWN for Axium ES coils was significantly lower than Target Nano coils, and the AWN for Axium FC coils was significantly lower than Target Standard 360 coils (p<0.001, Figure 4).

They also calculated theoretical coil stiffness using an established method.17 Reference is made to a report

Advertorial 13

Figure 3b

Figure 4

coils are more pliable than Nano coils, and (b) Axium Prime FC coils are more pliable than Target Standard 360 coils.18 Although benchtop performance data may not always reflect clinical performance, metrics assessed here are likely to have an impact on procedural efficacy and safety.

Table 1

on estimating the stiffness of a coil from material properties and structural dimensions.

A comparison of this stiffness factor between the coils seems to correlate with the measurement trends for pliability reported by the authors. Also noted in the report is the contribution of other factors beyond the basic stiffness factor calculation such as the thickness of the polypropylene filament and the secondary shape characteristics. These factors together with stiffness calculations are summarised in Table 1. This doesn’t take into account what the authors deem high-order effects such as coil behaviour and its engagement with the aneurysm wall during deployment—a parameter measured by the in vitro model. Nevertheless, results are consistent with the results of the wall force model.

Imparted force

Another important factor to consider clinically is the force imparted with finishing coils towards the end of the coiling procedure. As observed in the forcedisplacement curve, the force (peaks) increase with progressive coil deployment. At this point, the available volumetric space in the aneurysm is fairly limited to allow for extensive coil rearrangements. In this instance, a more pliable coil could possibly conform better to the available volumetric space in the aneurysm and potentially reduce the risk against coil loop herniation into the parent artery, a factor likely to be associated with thromboembolic risk.

This in vitro model is able to study coil characteristics specifically by holding fixed variables such as catheter tip position and rate of coil deployment. Some elements of the in vitro model depart from clinical practice. However, the in vitro setting allows for more controlled direct comparison between coil types and better understanding of the dynamics involved in coil volumetric filling and the forces applied on the aneurysm wall (two characteristics that are clinically relevant).18 The differences between the coils are statistically significant, confirming that: (a) Axium ES

Daniel Sahlein is the fellowship director of the Goodman Campbell Brain and Spine neuroendovascular fellowship training programme, and a consultant, speaker and proctor for Medtronic, and a consultant for Stryker, Microvention and Phenox.

REFERENCES 1. Abruzzo T, Shengelaia GG, Dawson RC, et al. Histologic and morphologic comparison of experimental aneurysms with human intracranial aneurysms.

AJNR Am J Neuroradiol 1998; 19: 1309‒1314.

2. Ahn JM, Oh JS, Yoon SM, et al. Procedure-related Complications during Endovascular Treatment of Intracranial Saccular Aneurysms. J Cerebrovasc Endovasc Neurosurg 2017; 19:162‒170.

3. Babiker MH, Gonzalez LF, Albuquerque F, et al. Quantitative effects of coil packing density on cerebral aneurysm fluid dynamics: an in vitro steady flow study. Ann Biomed Eng 2010; 38: 2293‒2301.

4. Blankena R, Kleinloog R, Verweij BH, et al. Thinner Regions of Intracranial Aneurysm Wall Correlate with Regions of Higher Wall Shear Stress: A 7T MRI Study. AJNR Am J Neuroradiol 2016; 37:1310‒1317.

5. Campos JK, Lien BV, Wang AS, et al. Advances in endovascular aneurysm management: coiling and adjunctive devices. Stroke Vasc Neurol 2020; 15: 5(1): 14‒21.

6. Chang CH, Jung YJ, Kim JH. Intraprocedural rupture management for intracranial aneurysm rupture during coil embolisation by manual common carotid artery compression. J Clin Neurosci 2019; 62: 273‒276.

7. Doerfler A, Wanke I, Egelhof T, et al. Aneurysmal rupture during embolisation with Guglielmi detachable coils: causes, management, and outcome. AJNR Am J Neuroradiol 2001; 22: 1825‒1832.

8. Jindal G, Miller T, Iyohe M, et al. Small Intracranial Aneurysm Treatment Using Target ((R)) Ultrasoft Coils. J Vasc Interv Neurol 2016; 9: 46‒51.

9. Johnston SC, Dowd CF, Higashida RT, et al. Predictors of rehemorrhage after treatment of ruptured intracranial aneurysms: the Cerebral Aneurysm Rerupture After Treatment (CARAT) study. Stroke 2008; 39(1): 120‒125.

10. Kocur D, Przybylko N, Bazowski P, et al: Rupture during coiling of intracranial aneurysms: Predictors and clinical outcome. Clin Neurol Neurosurg 2018; 165: 81‒87.

11. Li H, R Pan, H Wang, et al. Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis. Stroke 2013; 44(1): 29‒37.

12. Ozpeynirci Y, Braun M, Pala A, et al. WEB-only treatment of ruptured and unruptured intracranial aneurysms: a retrospective analysis of 47 aneurysms. Acta Neurochir 2019; 161(8): 1507‒1513.

13. Park YK, Yi HJ, Choi KS, et al. Intraprocedural Rupture During Endovascular Treatment of Intracranial Aneurysm: Clinical Results and Literature Review. World Neurosurg 2018; 114: e605‒e615.

14. Shamloo A, Nejad MA, Saeedi M. Fluid-structure interaction simulation of a cerebral aneurysm: Effects of endovascular coiling treatment and aneurysm wall thickening. J Mech Behav Biomed Mater 2017; 74: 72‒83.

15. Slob MJ, van Rooij WJ, Sluzewski M. Coil thickness and packing of cerebral aneurysms: a comparative study of two types of coils. AJNR Am J Neuroradiol 2005; 26: 901‒903.

16. Sluzewski M, Bosch JA, van Rooij WJ, et al. Rupture of intracranial aneurysms during treatment with Guglielmi detachable coils: incidence, outcome, and risk factors. J Neurosurg 2001; 94: 238‒240.

17. White JB, Ken CG, Cloft HJ, et al. Coils in a nutshell: a review of coil physical properties. AJNR Am J Neuroradiol 2008; 29: 1242‒1246.

18. Zhao R, Liu J, McComas S, et al. In vitro pliability assessment of embolisation coils for intracranial aneurysm treatment. J Neurol Sci 2019; 15; 406: 116432.

This advertorial is sponsored by Medtronic Neurovascular. The views expressed in this article are based on the experiences of the author and do not represent the views of Medtronic.

Disclaimer See the device manual for detailed information regarding the instructions for use, indications, contraindications, warnings, precautions, and potential adverse events. For further information, contact your local Medtronic representative and/or consult the Medtronic website at medtronic.eu © 2020 Medtronic. All rights reserved. Medtronic, Medtronic logo and Further, Together are trademarks of Medtronic.

TM * third party brands are trademarks of their respective owner. All other brands are trademarks of a Medtronic company. UC202110971EE Medtronic International Trading Sarl Route du Molliau 31, Case postale, 1131 Tolochenaz, Switzerland Tel: +41 (0) 21 802 70 00 Fax: +41 (0) 21 802 79 00

Figures 1-4 and Table 1 were reproduced with permission from Journal of the Neurological Sciences Volume 406, 15 November 2019, 116432 https://doi.org/10.1016/j.jns.2019.116432 under license 4938570012208

December 2020 | Issue 40

14 Stroke therapy

Stroke risk disparities in black and white patients related to cardiac difference, new study finds In a new study published in the online issue of Neurology, researchers claim to have found a difference in the left atrium in the hearts of black and white patients, which may play a role in the risk of stroke.

H

oomean Kamel, lead author, vice chair for research and chief of neurocritical care in the Department of Neurology at Weill Cornell Medicine, New York, USA, said, “Black US residents face a higher risk of stroke caused by blood clots to the brain, known as ischaemic stroke, compared with white residents, yet the difference cannot be entirely explained by differences in known risk factors. The difference is especially notable for strokes where the cause cannot be determined. Better understanding of the underlying causes of these strokes is important for addressing these racial disparities.”

The study involved 2,391 black and white patients who suffered an ischaemic stroke. Using electrocardiograms (ECGs) and echocardiograms, researchers looked at the structure and function of the left atrium of the heart.

Researchers, blinded, took measurements of the P-wave terminal force in ECG lead V; they measured the amount of fibrosis, scar-like tissue, in the left atrium and impaired inter-atrial conduction; and, using the echocardiogram, a diameter was taken of the left atrium.

Linear regression was used to examine the association between race and atrial cardiopathy markers after adjustment for demographics, body mass index, and vascular comorbidities.

This study found that the mean diameter of the left atrium for all participants was 3.65cm. The mean for black subjects was 3.58cm, contrasted with 3.69cm in white subjects. Black patients also had more ECG markers of arterial fibrosis.

Researchers claim that these findings show a systemic difference in the structure of the left atrium between black and white patients, and clinicians should be aware that structural or functional changes in the left atrium may not present similarly in all stroke populations.

They added that more research needs to be done on the different manifestations of cardiac disease and the more appropriate use of drugs, which may reduce the racial and ethnic disparities in stroke.

Kamel further commented, “Our findings should not be taken to imply that these racial differences in

These findings show a systemic difference in the structure of the left atrium between black and white patients.”

3.58 VS 3.69 cm

The mean diameter of the left atrium was 3.58cm for black subjects, contrasted with 3.69cm in white subjects. people with stroke reflect innate biological differences.

Our findings suggest that the current standards for diagnosing left atrial disease that can lead to stroke may need to be updated. These standards were established in groups of exclusively white people and may not fully reflect the variety and complexity of how these acquired cardiac issues are manifested in all people.”

ESO-WSO 2020: No reason to withhold thrombectomy for older patients with low ASPECTS score A study presented by Johanna Ospel (University of Calgary, Calgary, Canada) at the European Stroke Organisation and the World Stroke Organization joint virtual conference (ESO-WSO 2020, 7–9 November), has shown that there is no reason to withhold endovascular therapy (EVT) from patients regardless of their age and Alberta Stroke Program Early CT Score (ASPECTS) score.

IT IS OFTEN ASSUMED THAT THE age of a patient and their ASPECTS score interact with each other, when it comes to endovascular decision making.

For example, a younger patient with low ASPECTS may be treated with EVT routinely, however, for elderly patients, treatment with EVT is often avoided.

This study shows no evidence for the practice, as commented by Ospel, “In our dataset, the treatment effect of APECTS does not significantly change across the age spectrum and the other way around.”

The main aims of the study were to assess the combined effect of age and

ASPECTS outcome in acute ischaemic stroke due to large vessel occlusion when treated with or without EVT; and to explore whether there was a difference in EVT treatment effect between age/ ASPECTS subgroups.

The study looked at 1,735 subjects, the median aspect score was eight and the median age was 67.6. A good outcome for patients was seen as having a modified Rankin score (mRs) of 0–2.

Ospel noted that as part of the study they had a low sample size of elderly patients with a low ASPECT score. This can in part be attributed to a sampling

cm

Johanna Ospel

bias on the part of the studies used, which seem more likely to select fitter and younger patients.

While this study did show no need to

Younger patients with low ASPECTS may be treated with EVT routinely, however, for elderly patients, treatment with EVT is often avoided.”

withhold EVT from older patients with low ASPECTS scores, for those patients over 75 with low ASPECTS score, their overall outcome was poor, with high mortality, regardless of treatment with EVT. Ospel observed that this subgroup of patients, older patients with low ASPECTS scores, is an area which may need more study and discussion. This is in part because of the low sample size their study had access to, but also due to wider considerations for this subgroup.

One of these considerations is whether a mRs of 0–2 is really the best measure of this group’s outcome, due to their worse prognosis compared to those who are younger and fitter. In these cases, it might be possible to accept a higher mRs score as the outcome.

Another consideration may be the healthcare resources in an area, as well as health insurance considerations.

Overall, the study suggests that all age ranges and ASPECTS scores may possibly benefit from treatment with EVT, however, raises some questions over whether EVT should be routinely performed on elderly patients, which needs further study and discussion.

In this regard, Ospel finished her presentation by saying, “The answer to this question probably depends on the local healthcare resources and infrastructure, as well as the patients’ wishes.”

December 2020 | Issue 40

16 Interview

Profile

Timo Krings

“The most profound and scaring changes I felt are the impact of increased levels of anxiety and stress on the team,” comments Timo Krings regarding his learnings from COVID-19, which has had a considerable impact on his, and everyone else’s, neurointerventional practice. Krings is currently serving as a professor of radiology and surgery, and programme director of interventional neuroradiology at the Department of Medical Imaging at the University of Toronto (Toronto, Canada). Krings talks to NeuroNews about exciting developments the future might hold for neuroradiology, noting that it would be amazing to one day integrate neuromodulation and neurointervention using ‘stentrodes’.

What initially attracted you to medicine and neuroradiology?

I majored in biology and philosophy and was particularly interested in the interplay between these two fields. When reading Popper and Eccles’ millennial work The Self and its Brain I decided to study medicine, and to move into the neurosciences. I was lucky to study one year abroad at Harvard Medical School where, during my neurology rotation, I witnessed an intra-arterial urokinase thrombolysis done by In Sup Choi at Massachusetts General Hospital in Boston, USA. I remember asking my senior staff at this time what type of specialty you have to pursue to do these types of treatment, and he answered, “interventional neuroradiology”, and the rest is history.

Who were your mentors and what impact have they had on your career?

The three main names that come to mind are: Armin Thron, neuroradiologist in Aachen, Germany, a specialist in spinal vascular anatomy and malformations; the late Pierre Lasjaunias in Bicetre, Paris, France, with whom I did my interventional fellowship (and where I worked as junior staff); and Karel Terbrugge, my predecessor in Toronto who epitomised the successful combination of a diagnostic and interventional neuroradiologist.

All three were extremely generous teachers who not only taught neuroradiology in all its facets, but also ethics and leadership by example. While I am indebted to the above mentioned giants, I have learned also a lot from colleagues—staff and fellows—by observing their cases, or discussing research at conferences.

How has COVID-19 impacted your neurointerventional practice?

COVID-19 has impacted every single aspect of our lives including, therefore, our clinical practice. The direct and most obvious effects on neurointervention were increased door-to-puncture times in acute stroke due to personal protective equipment (PPE) requirements worn by the team, and delays in treatment for acute subarachnoid haemorrhage (SAH) as these patients require, at least in our hospital, a COVID-19 test.

We decreased our elective procedures to not overwhelm the intensive care unit (ICU) and wards.

Interestingly, we also experienced a drop in both acute subarachnoid hemorrhage (SAH) and stroke patients and are wondering whether this is related to side-effects of confinement and the “stay at home— stay away from hospitals” notion that is prevalent in Canada. However, the effects of COVID-19 go beyond the clinical realm: we feel the impact on teaching, with no in-person meetings, no observerships, and no “hands-on” courses that we previously held for flow diversion or stroke at our institution.

We had to cancel our annual interventional neuroradiology meeting, for the first time in the past 20 years, and will hold our Canadian Course of Diagnostic Neuroradiology virtually instead of in person.

Many research studies were put on hold, including recruitment in multicentre stroke trials.

What are the biggest learnings you would like to share with the wider neuro community about your department’s response to COVID-19?

The most profound and scaring changes I felt are the impact of increased levels of anxiety and stress on the team. Neurointerventionalists are accustomed to stress in the form of working long hours at high stakes, however, this stress comes with job satisfaction. The stress and anxiety levels imposed on us because of COVID-19 are different, and we should not underestimate the risk of burnout. As such, my biggest learnings from COVID-19 are that we need to take better care of each other and ourselves, be supportive of members of the team and rely on social networks.

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

The knee-jerk answer to this question for anyone who has lived through the intra-arterial tPA and/or urokinase era is of course stroke thrombectomy using stentretriever or aspiration. It is only 10 years ago that we waited for what felt like hours to infuse the tPA, just to realise the futility of our treatment in a large proportion of cases. In its current state, with success rates at more than 80% and procedural times rarely exceeding 40 minutes, stroke treatment certainly has been one of the most impactful developments in neurointervention.

In addition, I believe that the development of large inner diameter distal access catheters has not only

Artificial intelligence tools to improve stroke workflow or robotics to provide remote care will likely become an ever-prevalent reality in the near future.” enabled stroke thrombectomy, but has changed our ability to treat more and more complex neurovascular diseases with an ever-increasing armamentarium of devices.

These distal access devices have been instrumental, not only for stroke treatment, but have opened the door to safe and accurate deployment of flowdiverters, intrasaccular aneurysm devices, and safer multicatheter approaches for aneurysms or arteriovenous malformations, which we now see as routine procedures.

What has been the biggest disappointment?

The low point of intraarterial stroke treatment was the 2013 International Stroke Conference (ISC) in Hawaii, USA, where three consecutive intravenous versus

intra-arterial stroke trials demonstrated inferiority of intra-arterial stroke treatments. If it had not been for the comeback victory for mechanical thrombectomy in stroke just two years later at the ISC in Nashville, USA, with three overwhelmingly positive trials, stroke patients worldwide would have lost an excellent treatment for their condition. This shows that being in the driver’s seat when it comes to trial design is important.

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

Technological advances will be driven by the demand imposed by the treatment of neurovascular diseases.

Thus, artificial intelligence tools to improve stroke workflow or robotics to provide remote care will likely become an ever-prevalent reality in the near future.

Beyond this, future neurointerventional care will likely necessitate appropriateness criteria for treatment as

Issue 40 | December 2020

Interview 17

well as personalised medicine and quality control. As such, advanced neuroimaging for patient selection, integration of individual health data in treatment plans and collection of big data in common databases will play a significant role in our day-to-day lives. With the identification of somatic mutations in brain vascular malformations and molecular pathways in vascular disease progression, we will move more towards targeted drug treatment approaches rather than looking only at new mechanical devices.

What are your current research interests?

In my current role, I see myself foremost as a facilitator of the excellent work of my colleagues at the Toronto Western Hospital. We are focusing, in collaboration with our colleagues in neurology and neurosurgery, on the prediction of brain bleeding from brain vascular malformations, using a multidiscplinary approach, development of novel methods to treat these lifechanging events and estimating the relative effectiveness of treatments to determine their impact on healthcare.

Do you have a fantasy experiment?

I would like to continue recent preliminary work that we performed on evaluating whether intravascular devices (so-called stentrodes) implanted into the vascular system could be used for non-invasive brain stimulation.

With current catheter technology it is possible to non-invasively navigate into very distal vessels and we have recently mapped the relationship between vascular structures and potential brain stimulation targets. I think it would be amazing to one day integrate neuromodulation and neurointervention.

What are your interests outside of medicine?

I like to spend time with my family. I have two young girls aged eight and 10. We spend the winters skiing, while in the summers we like hiking or other outdoor activities, like canoeing and swimming—the latter I used to do competitively when younger.

Recently, I was ‘forced’ by my kids to enrol with them in a family production of the musical Wicked, although singing is really not my forte. I enjoy traveling, in particular to Europe and Asia. I appreciate watching and listening to ballet and opera, with Swan Lake and Madama Butterfly being my respective favourites, and I admire Chinese art, especially calligraphy.

Fact file Present position

Full professor of radiology and surgery, University of Toronto, Toronto, Canada Head of the Division of Interventional and Diagnostic Neuroradiology at the University Health Network, Mount Sinai Hospital and Women’s College Hospital, Toronto, Canada Chief of radiology, Toronto Western Hospital, Toronto, Canada Clinician scientist at the Krembil

Research Institute, Toronto, Canada David Braley and Nancy Gordon chair in interventional neuroradiology

Research

Author of more than 400 peer reviewed articles, six textbooks and more than 30 book chapters Research in both diagnostic and interventional neuroradiology Co-editor of Clinical Neuroradiology; previous co-editor for Interventional Neuroradiology and associate editor of American Journal of Neuroradiology

Research awards

The Scientific Awards of the German Society for Biomedical engineering and the German Society for Neuroradiology The Lucien-Appel Prize of the European Society of Neuroradiology The Holthusen-Ring of the German Society of Radiology The Lasjaunias Award of the Hereditary Haemorrhagic Telangiectasia Foundation

December 2020 | Issue 40

18 Healthcare economics

Cost of stroke care in Europe could increase to €86 billion by 2040 A report from the Stroke Alliance for Europe (SAFE), shows that if countries continue to fail to invest in stroke prevention, treatments and rehabilitation, the cost of stroke care across Europe could increase to €86 billion by 2040.

T

he study, named ‘At what cost? The economic impact of stroke in Europe,’ was conducted by the health economic team at the University of Oxford (Oxford, UK), in 2017. It included data on all stroke-related costs accrued in EU countries, with the addition of Iceland, Israel, Norway, Switzerland and the UK. According to SAFE, this is the first study to calculate all the costs related to stroke as a whole, including the cost of informal care and losses in productivity.

The total cost of stroke in the countries studied was estimated to be €60 billion. Just under half of that total was spent on healthcare, at €27 billion, with a further €5 billion being spent on social care, nursing or residential care. Outside of those direct costs, €16 billion was spent on informal, unpaid care provided by their loved ones.

Researchers calculated an additional €12 billion which could be attributed to lost productivity due to deaths or disability from stroke in people of working age.

The study estimated that friends and family provided an average of 1,052 hours of informal care for each person with stroke who became severely limited in their daily activities. This meant a total of 1.3 billion hours of informal care was provided by friends and family.

Investigators calculated a total of 438,000 deaths due to stroke across the 32 countries in the study, resulting in an estimated 286,000 potential work years lost. The researchers estimated from this a total of 38 million working days lost to permanent and temporary absence

due to stroke.

Assuming no changes, except for the projected decrease in birth rates, an aging population and reduction in the working age population, researchers estimated that the total number of strokes across the countries they studied in Europe would rise from nine million in 2017, to 12 million in 2040, seeing a rise of 35%.

From this investigators projected that the cost of stroke would increase from €60 billion in 2017 to €75 billion in 2030, €80 billion in 2035 and €86 billion in 2040. This creates a projected increase of 44% of costs in 23 years. Furthermore, researchers note that in some of the countries looked at, that increase could be nearly 100%.

The study also looked at three different interventions across the stroke care, which they state already have clinical evidence supporting their effectiveness: prevention, acute treatment, and rehabilitation in a community setting. Researchers made projections of the cost of these over the next five years.

Prevention was seen as being applied to those who had atrial fibrillation, treated with anticoagulant drugs.

Researchers calculated that the pre-emptive treatment of atrial fibrillation patients with warfarin, blood thinner, would generate a saving of €7 billion.

Within this study the acute treatment of stroke was mechanical thrombectomy. According to the authors, in 2017, within the countries studied, just over one million people aged 20 and over suffered an ischaemic stroke.

Of that group, researchers found that 27% were eligible for mechanical thrombectomy. They estimated that if over five years, all eligible patients received mechanical thrombectomy, then the health and social care costs would be €11 billion, compared to the current figure of €12 billion.

Finally, researchers argue that rehabilitation in a community setting improved the quality of life for stroke survivors. They found that of the 1.4 million people aged 20 or over who suffered an ischaemic or haemorrhagic stroke in 2017, 59% were eligible for community-based rehabilitation. Over their fiveyear projection, community-based rehabilitation was associated with health and social care costs of €31.6 billion compared with €31.8 billion for current practice.

The research was completed before COVID-19. Since the beginning of the pandemic, health services across Europe have been diverted away from noninfectious conditions, including stroke care, therefore we feel that the projected costs in our report are likely to be even higher.”

Ramon Luengo-Fernandez

A specialised news source in the neuro interventional arena

July 2020 | Issue 38 Thrombectomy proved efficacious in Latin America Page 10

Richard P Klucznik:

Profile

Page 16

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COVID-19 causes | Issue 37 April 2020 “widespread disruption” to neuroendovascular Profile research around the globe

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he study, recently published in the Journal of NeuroInterventional Surgery (JNIS), focused on randomised controlled trials (RCTs) and singlearm studies for acute ischaemic stroke and cerebral aneurysms. The survey was developed by a group of September subsequently sent to senior neurointerventionalists, 2020 Issue sites identified through the clinical |trials website, 39 study sponsors, and physician investigators.

Jesse “The survey was sent to 101 institutions, with 65 responding,” state Rai et al, as they added that stroke RCTs were (prior to the pandemic) being conducted at Overall rate Trends after Page 10 www.neu Thomas 40 sites, aneurysm RCTs at 22 sites, stroke single-arm of in-hospital ronews.c Oxley unruptured om Endovascular mortality studies at 37 sites, and aneurysm single-arm studies at decreased aneurysm brain-computer 43 sites.

“Widespread disruption of neuroendovascular trials occurred because of COVID-19,” Profile: treatment interfaces Meyers However, following COVID-19, the authors report conclude the investigators of a survey-based study examining the impact of the pandemic.

Philip M Jens Fiehler Wang: page 7 that enrolment was suspended at 51 (78%) sites; Now, as sites begin to resume clinical research, first author Ansaar T Rai of West Virginia 0.9% 0.2% and Arthur Culture shifts 2006 completely at 21, and partially at 30. Moreover, missed University, Rockefeller Neuroscience Institute (Morgantown, USA), and colleagues amid 2016 York in medicin New throughout the USA call for steps4to mitigate similar challenges that may arise in the future. trial-related clinics, imaging follow-ups and protocol 19 e Page COVIDpage 14 deviations were reported by 27, 24, and 27 sites, respectively. Negative reimbursements were reported at 2 April brought cerebrova and (SNIS) on scular 17 sites. nal Surgery from Italy, China, chronic kidney accident, peripheral to terventio The majority of sites, Rai and colleagues note, were vascular disease, disease, no , and how of NeuroIn neurosurgeons observed significant or between forced to put new trials on hold. The team found that physician the Society and endovascular whether to intubate difference as each ic’s s were “With respect races. hosted by nalists many study coordinators (63%) worked from home, and who to treat, the pandem to presenting 9 were raised, A webinar symptoms s such as known of COVID-1 neurointerventio SARS-Co r of , 31% reported a personal financial impact.

While remote they we found no question V-2 togethe setting asymptom prior, had difference Important pathways in the atic consent was possible for some studies at 34 sites, only in exposure two weeks the USA. or vomiting, cases, fever, cough, history, post-care have done five sites reported that remote consent presented a dyspnea, nausea chills, malaise, optimise what they would American or lethargy. d cohort had option for all studies underway.

The African disclose Twoviable a similar mean Institutes new studies effects. of Health the presente 51 sites with suspended trials, NIHSS [National devastating annualRegarding Stroke Scale] compared meeting d at theenrolment with 14.9 score of 16.3 endovascular (4–7treatment Society of related racial in other races August)without to-CT time NeuroIn , which (p=0.63). was occurred at 61% of sites for stroke,was and dispariti The doorthe proportion also similar (23 vs. es among held virtuallyterventional Surgery 45% of sites for aneurysms. Rai and the 19 minutes), patients of patients (SNIS) occlusion who experien this year, have and he first study presenting was not significant team found this resulted in a total with a large describe 17th from ce strokes. thethat 47%),” he North American d outcom Neurovasc vessel ly different added. of 277 patients with acute ischaemic ular e(40.7% versus COVID-1 Lastly, while presented 9 further (NAN-C) terms stroke, and a 184 patients with by of good discharge Adam Dmytriw the team observed Consortiu University African American m, score (Boston, USA), of Harvard modified Rankin cerebral aneurysms being treated (p=0.27). finds Ansaar patients receivedthat 14.8% of patients with compared specificall For mRS Scale (mRS) blind trial difference y examined to 31% in cord intravenou without consideration for stroke Rai COVID-1 that mortality 9. He told noted (14.8% 0–2, there was no other races, ised, double- oop spinal for not significant s tPA the online significant Dmytriw vs. 16.7%),” A random closed-l Continued on page 2 reported. However, ly different audience with COVID-1rates in African American he Addressin ally superior ed in this sample. said it was symptoma haemorrha ECAP-controlled g stroke patients tic intracrania races combined9 were significant compar ge (sICH) (SCS) statistic the preliminar the SNIS audience, l was significant higher for he reiterated in North Americaly higher than all stimulation nt of chronic pain,12-months, y data suggest participati African ly other that difference ng. among the vs. 3%, p<0.001), Americans (11.1% the treatmeop stimulation. At reached amongst stroke there may be a mortality hospitals the mortality Additionally, he said and American patients of the study patients rate of COVID-1 to open-lo backgroun African showed that significantly higher mortality was was greater d and closed-loop d afflicted in African Speculatin than previously 9–positive stroke compared >83% of responder threshol responder with COVID-1 American g on reasons COVID-1 to other patients reported in high s 9 or stroke 9. as “Underlyi 28.6%, p=0.03). races (51.9% vs. patients relief the ≥50% reliable storm,” Staats tells NeuroNews. the ≥80% and leg pain. alone.experienced ng biological to why, he said: with from The investigato patient , genetic, characteri back >56% reached tightness and dyspnea within five In terms of comorbidi As VNS has been demonstrated analysed or epigenetic stics can predispose patients positive rs chest in overall the North 69 cases of difference ties, Dmytriw threshold these results at Society’s for SARS-Co acute minutes of using the stimulation.

He alsostated that diabetes to block production of cytokines [people] to s,” but Americanin V-2, including stroke in health patients and such as access added that social , PresentingNeuromodulation observed an improved ability to clear hishigher in African was significantly sepsis in animal modelsincluding and in many 27 African 42 patients determina to healthcare American (23–26 January t Caucasian difference versus others othernVNS American , and geographi nts cases lungs when heofused to manage his other medical conditions (including backgroun , meeting Hispanic presiden s presented pertaining (37% Deer, ds, However, and Asian. to 14 major vs. 66.7%). and other to both population cal (NANS) annual PTSD, Sjogrens disease, rheumatoid location-b hospitals inat home. “All patients from regarding USA), Timothy Nerve Center 14 March–14 symptoms ased factors smoking, the USA and dependenceatrial fibrillation contributo Las Vegas, The Spine and USA, April“Avoidance arthritis, and stroke), Staats and his may also Canada, 14, 2020,” of ventilator “Regardin ry. of , prior be ton, g stroke functional stated anticoagul and CEO Dmytriw. in both cases and lack of hospitalisation team hypothesised that nVNS might , Charles difference ation, coronary Moving forward, of the best outcomes, between are “some of the Virginias the team, there wasattributedartery disease, congestive in case 2 cannot be causally provide clinical benefits in patients with African is co-led by American no that these our field and any heart failure, Ambooj Tiwariwhich and argued other races to nVNS, but its is reasonable to respiratory symptoms, such as those An article accepted withininto the journal Neuromodulation has New York of in hyperlipid hypertension, University results seen speculate that nVNS therapy may have exhibited in the novel coronavirus. concluded that, based on two case reports, non-invasive vagus emia, today”.

(New York, USA) ion publicat aims ECAP been a supporting factor, via either The information on the two case nerve stimulation (nVNS) might provide clinical benefits in patients to continue Adam Dmytriw recruitmen the median t of found that mechanisms”. bronchodilation or inhibition of cytokine reports was obtained via email with COVID-19ALSO via “multiple ) amplitude across North more hospitals THE STUDY America, action potentials the in-clinic release,” argue Staats and colleagues. correspondence and phone interviews and compound n fell below clinic. Yet (evoked Continued They add, given the concerns about with the patients. known as a WHILE MOST COVID-19 stimulatiocases of the reaction—otherwise on page 2 outside with open-loop level storm”. were number of intensive care unit beds and According to the authors, in case “cytokine are mild, the authors, Peter Staats patients d the target target when maintaine that the search for an antiviral, or ventilators amid the pandemic, that it 1, the patient used nVNS to aid “While ged (electroCore, Basking Ridge, USA) and p group acknowled the closed-loo almosteffective for SARS-CoV-2, station of is “imperative to consider all viable his recovery at home after hospital a vaccine colleagues acknowledge that,aDeer minority . Moreover these afferent c range was of activation that receive closedinputs therapeutic options”. Thus, they put discharge, and was subsequently able the virus causing COVID-19, remains of patients develop to severe in the therapeuti large vessel with spentmoderate sensory informatio (neurons different— g, but so is the time evoked significant lar has yet to the mostwe also need to put resources forward that “the well-established safety to discontinue use Bilatera of opioids and cough a priority, respiratory symptoms, which tly they say and n), it endovascu nd significan be targeted OVID is devastatin l L4 dorsal vs. 47.9%), andsix J Mocco, motor responses phase 1 and phase for this purpose.

Hence, Soloukey suppressant medications. the root effort to solving this cytokine appeardouble—a to be due to a hyperimmune Continued on page 16 shownIntocase 2, n (95.2% ai Health was an times 2 stroke,” declared with an MRC Mount-Sin evoke strong ganglion (DRG) and colleagues loop stimulatio cord activation level upper leg to determine eon from upper leg need an ≥4 for all those receiving muscles,” stimulat set out and reprodu neurosurg whether DRG report frequent spinalcohort, compared to This led to “Stroke patients can facilitate injury (SCI).in patients with chronic cible motor ion has been stimulatio s carried out a knee extensionthe authors. this York, USA. clinically spinal greater in In their paper strong enough responses relevant motor n many procedure motor completresponses in System, New movemen added, Sadaf Solouke behind this . in motor complete the t But Arguing that semi-elective, he publishe open-loop e spinal weight bearing,to facilitate assisted the mechanics would indicate and y and colleagu or d advocate.”

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Issue 40 | December 2020

Rehabilitation 19

There is no place like home for rehab after stroke, study shows A study published in the 30 September 2020 online issue of Neurology, the medical journal of the American Academy of Neurology, has found that stroke patients who get professional rehabilitation training through remote video consultations from their residence may recover their motor skills better than those who do their rehab in person with a therapist at an outpatient rehabilitation facility.

THE STUDY ALSO FOUND THAT remote rehabilitation may also promote greater brain connectivity.

Chuancheng Ren (Zhongshan Hospital, Fudan University, Shanghai, China), the study author, says that because travel and human contact might not be possible due to COVID-19, “it is important to find out if it is safe and effective for stroke patients to recover at home, using video consultations for their therapy”. He continued, “Our findings are exciting because they suggest remote rehabilitation programmes may be more effective than in-person rehabilitation in two ways: on the physical level, with greater increases in physical mobility, and on the brain level, with increased functional brain activity.”

The study enrolled 52 people who suffered a stroke with paralysis on one side of their bodies, who had their strokes an average of two weeks before the study. Half of those involved were randomly assigned to a homebased telerehabilitation group and the remaining half were assigned to a conventional outpatient group. All the participants did at least 12 weeks of rehab.

For both groups, each session included 60 minutes of occupational and physical therapy, plus 20 minutes of neuromuscular stimulation. All the participants were assessed for both motor function and brain changes at the start of the study, immediately after completion of the rehabilitative sessions and again three months later.

Researchers tested the recovery of motor skills in the arms and legs after stroke and in order to show meaningful improvement, there needed to be an increase of at least 10 points.

The group rehabilitating remotely scored an average of 11 points higher than they did at the beginning of the study, while the group receiving conventional in-person rehabilitation scored on average of 5.3 points higher.

Researchers used resting-state functional imaging to measure changes in the brain and saw that the remote training group increased their resting state brain connectivity compared to the conventional therapy group.

“We believe the convenience of rehabbing at home may have helped study participants stick to their rehabilitation programmes, and that, in turn, may have helped them recover motor skills better than their conventionally treated peers,” Ren said. “Also, the home environment may have given people more opportunities

to participate in and learn from real-life family activities.”

A limitation of the study was there was no control group, the authors write.

POINTS

11

vs

POINTS

5.3

At-home patients 11 points higher than at the beginning of the study vs in-person rehabilitation only 5.3 points higher

December 2020 | Issue 40

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Research shows better cognition with non-invasive vagal nerve stimulation In a study published in Neuromodulation: Technology at the Neural Interface, authors report that they have initial evidence that non-invasive vagal nerve stimulation (nVNS) is linked to better performance on visuospatial reasoning and memory recognition tasks.

THIS STUDY AIMED TO ASSESS WHETHER nVNS enhances complex visuospatial problem solving within a normative sample of healthy patients.

Authors of this study, led by Ruth Klaming, University of California and San Diego healthcare system, San Diego, USA, report that this study, and further research in this area, has potential implications for the treatment and management of cognitive disorders due to incidences such as stroke, traumatic brain injury, or dementia. Klaming said, “Our study has important implications for a potential new approach of treating cognitive disorders with non-invasive neuromodulation in the near future.”

The study included 30 participants, half of which received transcutaneous cervical nVNS, the other half received a sham stimulation in the same area. The nVNS and sham devices were similar in appearance, and produced similar sensations on the skin.

Stimulation lasted two minutes at 24V for nVNS, and at 4.5V for sham stimulation. In both cases stimulation would have a ramp-up period of 30 seconds, followed by 90 seconds of peak stimulation.

Approximately 35 minutes after this stimulation, subjects had to complete a number of tasks. Participants completed a matrix reasoning (MR) task in a magnetic resonance imaging (MRI) scanner, and a forced-choice recognition task outside the scanner.

According to the study, the MR task comprised 30

different matrices, including geometric shapes arranged around specific patterns in a three by three panel.

Fifteen shapes had one dimension of difficulty (shape, colour, or orientation), and 15 had two dimensions of difficulty (colour and orientation, orientation and shape, etc.).

Subjects completed the tasks by selecting one of four shape options and pushing the corresponding button.

Responses were fed into a computer and subjects did not receive feedback if answers were correct or incorrect.

The forced-choice recognition task took place

Our study has important implications for a potential new approach of treating cognitive disorders with non-invasive neuromodulation in the near future.” – Ruth Klaming, lead author

Boston Scientific launches Vercise Genus DBS in Europe Boston Scientific has announced that its Vercise Genus deep brain stimulation (DBS) device has received CE mark approval. This is a fourth generation device and has now been launched with a limited release in the European market.

Vercise Genus DBS

T

approximately 10 minutes after the MR session.

Subjects were presented with images of the shapes from the MR task as well as new shapes and asked to indicate which they had remembered seeing. Subjects were not previously told that they would be tested on the items from the MR task, allowing researchers to assess participant’s incidental learning.

From their research, authors were able to determine that those with nVNS showed higher accuracy on both easy and hard MR items, compared to the sham group.

Additionally, on the forced-choice recognition task, the nVNS group was able to correctly reject more items than the sham group. This study also looked at subjects’ functional MRI scans, to see if nVNS had any effects on brain activation patterns while completing the problem solving task seen on MRI imaging.

While the study team was able to see nVNS providing some sort of cognitive difference, there was not a significant difference in brain pattern activation.

In their discussion, the authors comment, “based on these behavioural observations, we hypothesise that nVNS increased alertness and improved attention, which led to more engagement in the tasks and consequently enhanced higher order executive processes, such as visuospatial problem solving. It is possible that this effect lasted for at least 50 minutes following stimulation and led to more efficient recognition and less errors compared to sham.”

Despite their overall positive findings, the authors note in their conclusion, “these are proof-of-principle findings and further research is needed before nVNS can be implemented in clinical practice.”

he Vercise Genus DBS has been designed to treat symptoms of Parkinson’s disease, essential tremor, and dystonia.

According to Boston Scientific it does this by delivering precisely targeted electrical stimulation to specific sections of the brain providing a certain level of symptom relief.

Jens Volkmann, director and chairman, Department of Neurology at the University Hospital of Würzburg, Würzburg, Germany, said, “Advanced directional stimulation combined with a visualisation system based on a patient’s own brain anatomy now provides the accurate navigation as well as the steering capability we need to optimise therapy outcomes,” This is the fourth generation of this DBS system since 2012, and includes multiple independent current control and the Cartesia Direction Lead and integrated visualisation.

Features for patients, include a low-profile two-in-one extension with the option of abdominal placement, a company release says.

Boston Scientific states that this system allows for personalisation as the system uses multiple independent current control, directional stimulation capabilities, and integrated visualisation of patient anatomies.

Additionally, the new Vercise system incorporates clinician software that

optimises programming with integrated visualisation. The software uses patient imaging through the company’s exclusive partnership with Brainlab.

Maulik Nanavaty, senior vice president and president, Neuromodulation, Boston Scientific, USA comments: “For patients, the Vercise Genus DBS System continues the tradition of small, thin devices, and it provides Bluetooth programming which is important during times of social distancing.”

Nanavaty continued, “Combined with the option of a 25-year rechargeable battery, as well as the expanded MRI conditional feature available on our primary cell devices, patients can find the best option to suit their specific needs.”

Veerle Visser-Vandewalle, Cologne University Hospital, Cologne, Germany, commented, “With neurodegenerative movement disorders, the ability to deliver the right dose of stimulation where it is needed can make a remarkable difference in controlling an individual patient’s symptoms.”

In Europe, the Vercise Genus DBS System is indicated for use in unilateral or bilateral stimulation of the subthalamic nucleus or internal globus pallidus for treatment of levodoparesponsive Parkinson’s disease and essential tremor, which is not being well controlled with medication and for treatment of intractable primary dystonia, for persons seven years of age and older.

December 2020 | Issue 40

22 Advertorial THIS ADVERTORIAL IS SPONSORED BY ABBOTT

Directional DBS with Abbott’s Infinity™ DBS system seeks to overcome historical limitations and advance therapy for movement disorder patients The effectiveness of deep brain stimulation (DBS) for the management of movement disorders such as Parkinson’s disease or essential tremor is well-established. There is a growing body of evidence suggesting there are additional clinical benefits that are achieved with the use of directional DBS (dDBS), beyond those previously established with omnidirectional DBS (oDBS). Research advances have begun to show that dDBS, which seeks to precisely and selectively target stimulation to the desired areas, and so avoid stimulation to unintended zones, may be an important therapeutic step forward.

O

ne device offering directional lead technology is the Abbott Infinity™ DBS system, an integrated platform leveraging Bluetooth and iOS technology to offer patients a more connected and digital therapy experience. According to Abbott, the system combines innovative directional lead technology and a wireless platform with enhanced patient comfort so that patients can be offered the very latest in DBS treatment.

There are three main targets within the brain in which DBS electrodes are typically implanted for movement disorders: the subthalamic nucleus (STN), the ventral intermediate thalamic nucleus (Vim), and the globus pallidus internus (GPi). Target selection is primarily driven by disease state and symptom presentation.

A historic limitation to oDBS systems has been unintentional stimulation of areas outside of the intended target, resulting in some patients being unable to receive the full benefit of DBS. Stimulation of certain structures situated adjacent to the optimal DBS target results in onset of stimulation induced adverse side-effects like muscular contraction eye deviation, dysarthria, parasthesia and ataxia.1 The difference in stimulation amplitude, causing onset of adverse effects, and that result in meaningful symptom relief, is referred to as the therapeutic window (TW).

The amplitude resulting in meaningful symptom relief is referred to as therapeutic current strength (TCS).

Several studies have reported an increase in TW and reduction in TCS with dDBS when compared to oDBS.

PROGRESS results show Infinity™ DBS System use expands therapeutic window in Parkinson’s disease

The PROGRESS prospective, blinded, multicentre study that compared directional with oDBS for Parkinson’s disease, revealed that at three months, dDBS with the Infinity™ DBS System demonstrated 90.7% of patients had a wider TW, exceeding the superiority endpoint of 60% (p<0.001).2 The study was presented at the Congress of the International Parkinson’s and Movement Disorder Society in September 2019 and in September 2020 by the researchers, Alfons Schnitzler (Heinrich-HeineUniversity, Düsseldorf, Germany) et al.2,3 The researchers set out to evaluate the efficacy of

dDBS by assessing the TW for directional versus omnidirectional stimulation for the management of Parkinson’s disease.

Abbott’s Infinity™ DBS system includes a directional lead comprising two levels of traditional ring electrodes and two levels of segmented electrodes in a 1-3-3-1 configuration.

The results from the PROGRESS study showed that 90.7% of patients (185/234) had a wider TW with dDBS compared to oDBS. The increase in TW was 41% on average with dDBS.2 Further, post hoc analysis of the data showed that there was 39% reduction in therapeutic current strength requirement with dDBS to achieve meaningful therapeutic benefit, as compared to oDBS.3 Single segment activation (SSA) produced a wider TW than oDBS in 86% of patients.2 These results were shown to sustain also at 12-month follow-up. In terms of preference, clinicians preferred dDBS in three times as many patients over oDBS, when compared sequentially, and two times as many patients preferred dDBS over oDBS in a blinded fashion.3

Clinical value of dDBS in essential tremor

The PROGRESS study showed benefits of dDBS in Parkinson’s disease, but there are also some advantages with the use of dDBS in essential tremor.

A randomised double-blind study published in the journal Neuromodulation: Technology at the Neural Interface, in July 2020, looked at dDBS in the Vim in order to increase the TW of essential tremor.1 According to authors Sabine Bruno (Heinrich-Heine-University, Düsseldorf, Germany) et al, dDBS was able to widen the TW by 213.2% with the best dDBS, compared with 83.1% with oDBS, and 54.6% with the worst dDBS. The side-effect threshold for these did not differ, but the volume of neural activation was larger for dDBS. These findings led the authors to conclude the,“superiority of dDBS, compared to conventional, oDBS on TW,” in essential tremor patients undergoing Vim DBS.1

STN and GPi have both been shown to be effective DBS targets in the treatment of advanced Parkinson’s disease

In a poster presented to the American Parkinson’s Disease and Movement Disorders Congress in February 2020, Muhammad Anjum (Georgetown University, Washington, DC, USA) et al, while reporting the first clinical case series using dDBS in the GPi for Parkinson’s disease, proposed a novel programming approach.4 The researchers reviewed both nondirectional and directional electrode montages to identify those with the best symptom relief and widest TW. The aim of this study was to retrospectively review the active programming settings and associated volumes of tissue activated (VTA) in Parkinson’s disease patients implanted with Abbott’s DBS system, and explore a programming approach for dDBS in the GPi. Their series suggested that using vertically-stacked single segment activation (V-SSA) as a programming approach could leverage the benefits of directionality in GPi-DBS.4 InfinityTM DBS System

PROGRESS study: Directional DBS results showed2,3:

TW was

90.7 % Three months

41%

39%

wider than omnidirectional DBS

lower TCS

90.7% of patients with directional DBS had a wider TW and the TW was 41% wider than omnidirectional DBS, with 39% less TCS required to achieve symptom relief with directional DBS at 3 months

Issue 40 | December 2020

Advertorial 23

Vim-DBS frequently leads to delayed side-effects limiting the therapeutic benefit for the patient. Reducing therapeutic current strength and improving therapeutic window with directional stimulation is a promising way to take advantage of the full potential of DBS treatment for tremor”

Abbott’s directional leads

Stefan Groiss

Directional programming with Informity™ software

In addition to optimal targeting, optimal programming of the DBS system is critical to therapy outcomes. Tools that simplify directional programming, addressing the perceived complexity of programming directional leads have significant value to clinicians in their practice.5 In a study, published March 2020 in Neurology and Therapy, authors Aristide Merola (Ohio State University, Columbus, USA) et al looked at the different programming approaches and platforms.5 Merola et al point to numerous challenges with visualisationbased programming approaches like brain shift, lead rotations, localisation of individual contacts on the lead, patientspecific anatomy, image registration and patient- Stefan Groiss

TW was

89.3 % 12 months

32% wider than omnidirectional DBS

89.3% of patients with directional DBS had a wider TW at 12 months, with that TW at 12 months being 32% wider itself

specific tissue properties that influence VTA.5 In a review published in Frontiers in Computational Neuroscience by Simeng Zhang (Abbott, Plano, USA) et al, September 2020, the authors concluded that when evaluating the effect of tissue heterogeneity on VTA modeling, both the size and shape of the VTA was affected in the GPi.6Abbott’s Informity™ programming software offers a solution to the issues related to visualisation-based programming by focusing on the individual patient’s stimulation-induced symptom relief and side-effects.

The programme includes tools for simplified documentation and review of these responses to create an action plan of the different stimulation montages, which may be used over time during the therapy. After this, clinicians can rank these montages based on several metrics depending on the needs of the patients and clinician’s practice preferences like maximising TW, minimising power consumption or TW percentage (a metric which helps simultaneously maximise TW and minimise TCS). The ability to reduce TCS may offer additional longevity to recharge-free DBS devices.7

Looking forward

The balance of clinical evidence seems to be in favour of dDBS and the benefits it provides to patients.1-7 A solution like Abbott Infinity™ DBS has the technology and tools to positively impact the clinical outcomes of Parkinson’s disease and essential tremor patients.

REFERENCES 1. Bruno S, Nikolov P, Hartmann CJ, et al, Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window. Neuromodulation: Technology at the Neural Interface, June 2020.

2. Schnitzler A, Mir P, Brodsky MA, et al. Directional versus Omnidirectional Deep Brain Stimulation: Results of a Multicenter, Prospective, Blinded, Crossover Study. Presented at the MDS Virtual Congress; September 2020.

3. Schnitzler A, Mir P, Brodsky MA, et al. Directional versus Omnidirectional Deep Brain Stimulation for Parkinson’s disease: Results of a multi-center, prospective, blinded, crossover study. Presented at the MDS Congress, Sept 2019; Nice, France.

4. Anjum M, Fayed I, Torres-Yaghi Y, et al. Vertically-stacked Single Segment Activation (V-SSA) as a Programming Approach for Directional DBS in GPi First Clinical Case Series. Presented at the 3rd Pan American Parkinson’s Disease and Movement Disorders Congress, February 2020; Miami, USA. 5. Merola A, Romagnolo A, Krishna V, et Current Directions in Deep Brain Stimulation for Parkinson’s Disease-Directing Current to Maximize Clinical Benefit. Neurol Ther. Published online March 2020.

6. Zhang S, Tagliati M, Pouratian N, Cheeran B, Ross E, Pereira E. Steering the Volume of Tissue Activated With a Directional Deep Brain Stimulation Lead in the Globus Pallidus Pars Interna: A Modeling Study with Heterogeneous Tissue Properties. Frontiers in Computational Neuroscience. 2020; 14:1–9.

7. Rebelo P, Green AL, Aziz TZ, Kent A, Schafer D, Venkatesan L, Cheeran B.Thalamic Directional Deep Brain Stimulation for Tremor: Spend less, get more. Brain Stimulation. 2018; 11(3): 600–606.

Rx Only Brief Summary:

Prior to using these devices, please review the Clinician’s Manual for a complete listing of indications, contraindications, warnings, precautions, potential adverse events, and directions for use. The system is intended to be used with leads and associated extensions that are compatible with the system.

Indications for Use:

USA: Bilateral stimulation of the subthalamic nucleus (STN ) or the internal globus pallidus (GPi) as an adjunctive therapy to reduce some of the symptoms of advanced levodopa-responsive Parkinson’s disease that are not adequately controlled by medications, and unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the suppression of disabling upper extremity tremor in adult essential tremor patients whose tremor is not adequately controlled by medications and where the tremor constitutes a significant functional disability.

International: Unilateral or bilateral stimulation of the thalamus, internal globus pallidus (GPi), or subthalamic nucleus (STN) in patients with levodopa-responsive Parkinson’s disease, unilateral or bilateral stimulation of the ventral intermediate nucleus (VIM) of the thalamus for the management of disabling tremor, and unilateral or bilateral stimulation of the internal globus pallidus (GPi) or the subthalamic nucleus (STN) for the management of intractable, chronic dystonia, including primary and secondary dystonia, for patients who are at least 7 years old.

Contraindications:

USA: Patients who are unable to operate the system or for whom test stimulation is unsuccessful. Diathermy, electroshock therapy, and transcranial magnetic stimulation (TMS) are contraindicated for patients with a deep brain stimulation system.

International: Patients who are unable to operate the system or for whom test stimulation is unsuccessful.

Diathermy and magnetic resonance imaging are contraindicated for patients with a deep brain stimulation system.

Warnings/Precautions:

Return of symptoms due to abrupt cessation of stimulation (rebound effect), excessive or low frequency stimulation, risk of depression and suicide, implanted cardiac systems or other active implantable devices, magnetic resonance imaging (MRI), electromagnetic interference (EMI), proximity to electrosurgery devices and high-output ultrasonics and lithotripsy, ultrasonic scanning equipment, external defibrillators, and therapeutic radiation, therapeutic magnets, radiofrequency sources, explosive or flammable gases, theft detectors and metal screening devices, case damage, activities requiring excessive twisting or stretching, operation of machinery and equipment, and pregnancy.

Loss of coordination is a possible side-effect of DBS therapy, exercise caution when doing activities requiring coordination (for example, swimming), and exercise caution when bathing. Patients who are poor surgical risks, with multiple illnesses, or with active general infections should not be implanted.

Adverse Effects:

Loss of therapeutic benefit or decreased therapeutic response, painful stimulation, persistent pain around the implanted parts (e.g. along the extension path in the neck), worsening of motor impairment, paresis, dystonia, sensory disturbance or impairment, speech or language impairment, and cognitive impairment. Surgical risks include intracranial hemorrhage, stroke, paralysis, and death. Other complications may include seizures and infection. Clinician’s Manual must be reviewed for detailed disclosure.

December 2020 | Issue 40

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Axonics announces publication of faecal incontinence neuromodulation implant study Axonics has announced the publication of results of the ARTISAN study, looking at its implantable sacral neuromodulation (SNM) device, the Axonics r-SNM system, for the treatment of urinary and bowel dysfunction.

Patients in the study experienced significant clinical benefits and satisfaction with recharging and therapy using the r-SNM system, Axonics said.

THE STUDY WAS PUBLISHED IN THE Journal of Neuromodulation: Technology at the Neural Interface in October 2020. The ARTISAN study was led by Stefan De Wachter, Antwerp University Hospital, Edegem, Belgium, and Katleen Jottard, Brugmann University Hospital, Brussels, Belgium. There were 15 subjects with faecal incontinence in this study who were each implanted with the Axonics r-SNM System in a single procedure.

The key findings of the study were that 87% of all implanted patients were therapy responders based on a ≥50% reduction in faecal incontinence episodes as documented in their bowel diary. Of that group, 92%

were responding to the therapy six months post-implant; and weekly faecal incontinence episodes were decreased from a median of eight at the baseline, to a median of one and half after six months of therapy, meaning a 79% reduction in weekly faecal incontinence episodes.

There were no unanticipated device or procedure related adverse events.

Additionally, ARTISAN found that after six month 93% of patients indicated that charging the Axonics device was both ‘easy’ and ‘acceptable’.

Karen Noblett, chief medical officer of Axonics and board-certified urogynecologist, commented, “faecal incontinence is a physically and psychologically debilitating condition for patients who often suffer in silence due to embarrassment. The strong outcomes of this study are consistent with Axonics’ pivotal study, ARTISAN, in which urinary incontinence patients who also had faecal incontinence experienced significant reductions in faecal incontinence symptoms and meaningful improvements in quality of life. Axonics congratulates and thanks the study investigators for continuing to expand the body of clinical evidence for Axonics r-SNM system

Focused ultrasound study for epilepsy treatment finishes safety phase NaviFUS has announced the presentation of the initial findings of studies on the company’s focused ultrasound (FUS) technology, which were presented at the seventh International Focused Ultrasound Symposium (9–13 November, virtual).

N

aviFUS announced the presentation of several studies at the congress, which included the preliminary results from its epilepsy neuromodulation clinical trial, which has just finished its safety phase. This study was conducted at the Taipei Veterans General Hospital, Taiwan, involving six patients since October 2020.

According to a press release, investigators observed a notable difference in onset of symptoms and changes in brain activity before and after focused ultrasound treatment in some patients. They reported neurophysiological responses which correspond to these results. These results,

combined with other clinical data, have been used to provide support for the safety and feasibility of NaviFUS’ neuromodulation application.

NaviFUS is now preparing for the next phase of the trial, while concurrently collaborating with international partners at Stanford University, USA. They are actively seeking international collaborators to help with their commercialisation.

Jen Chen, NaviFUS chairman, Taiwan, commented, “To be heavily involved on an international stage and present these exciting preclinical and clinical results is a testament of NaviFUS’ growing imprint in the FUS industry.

To be heavily involved on an international stage and present these exciting preclinical and clinical results is a testament of NaviFUS’ growing imprint in the FUS industry and leading status in clinical FUS applications.” Jen Chen

bowel dysfunction.”

Publication of the results comes after Axoincs applied to the US Food and Drug Administration (FDA) for the purposes of gaining detachable extremity coil magnetic resonance imaging (MRI) labelling for 1.5T and 3.0T MRI scanners.

Guangqiang Jiang, chief technology officer of Axonics, commented, “These additional conditions will provide Axonics with the widest range of MRI conditions in sacral neuromodulation. The benefits of this expansion include (a) better image quality for extremity scans and increased scanning setup flexibility; (b) broader MRI access for patients; and (c) avoiding RF exposure of the entire body, which may be important to patients who are frail, elderly, diabetic, obese, or pregnant as they are less tolerant to thermal stress from RF exposure.”

According to Axonics, an estimated 87 million adults are affected by overactive bladders in the USA and Europe, and an estimated 40 million adults are reported to suffer from faecal incontinence and/or accidental bowel leakage.

Faecal incontinence is a physically and psychologically debilitating condition for patients who often suffer in silence due to embarrassment.”

FDA grants Breakthrough Device Designation for migraine treatment Salvia BioElectronics has received a Breakthrough Device Designation from the US Food and Drug Administration (FDA) for its implantable neurostimulation system for the treatment of drug resistant chronic migraines.

WIM POLLET, CHIEF MEDICAL OFFICER OF SALVIA BioElectronics stated, “The FDA breakthrough device designation of our neurostimulation system reflects the recognition of the large unmet medical need of patients suffering from refractory chronic migraine, and the potential of Salvia’s bioelectronic foil technology to address this. We look forward to working closely with the FDA to expedite the review process to accelerate the development of our therapy.”

The FDA’s breakthrough devices program was established to help patients to have more timely access to medical devices, which could provide them with more effective treatment for their debilitating diseases or conditions.

This designation allows companies like Salvia BioElectronics to have more frequent interactions with FDA regulatory experts when preparing its submissions, and also gives them prioritised reviews.

One in seven people suffer from migraines, and more than 5% of those with this condition suffer from chronic migraines, having on average 22 migraine days per month.

Adding to this, only one in three of drug-refractory chronic migraine patients’ symptoms are helped with the newest generation of anti-migraine drugs, making neurostimulation a possible avenue for these patients.

In September, Salvia BioElectronics announced that it had raised €26 million in new financing from new and existing investors.

This was a series A investment led by Panakès Partners, INKEF Capital and SHS Gesellschaft für Beteiligungsmanagement with participation from BOM Brabant Ventures, Thuja Capital and Dolby Family Ventures. The total raised includes a €5 million deferred risk-bearing Innovation Credit from the Netherlands Enterprise Agency (RVO, part of the Dutch ministry of Economic Affairs and Climate Policy).

Issue 40 | December 2020

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Neuroscientist offers personal account of the harmful effects of tDCS and epilepsy Sandra Boccard-Binet Comment & Analysis Sandra Boccard-Binet is a research scientist at the University of Oxford, Oxford, UK. Her research focuses on deep brain stimulation. Here she writes about her personal experiences with transcranial Direct Current Stimulation (tDCS), an account which is currently in press in the Journal of Epilepsy and Behavior Reports.

B

ack in 2012, my husband-to-be and I had recently moved from France where I was awarded a PhD in Biology, developing a treatment increasing the chemosensitivity of glioblastomas.

I was a newly appointed post-doctoral fellow in neuroscience at the University of Oxford, when a research team we used to collaborate with, started to recruit healthy volunteers for a tDCS study. Being at that time a healthy woman in her early thirties, (therefore a seemingly ideal volunteer), I decided to take part.

Small pads were placed on the top of my head and behind my left shoulder.

The student in charge of the experiment calibrated the tDCS just below the threshold at which I was able to feel a slight tingling when the stimulation was on. Blinded to the on/off status of

the stimulation I performed an Erickson flanker task where I had to observe arrows on a computer screen and indicate as fast as possible the direction of the middle one.

No side-effect was observed during the experiment, not even a headache, and I simply went back to my own research on deep brain stimulation afterwards.

Three weeks later, while walking along a corridor at my workplace, I suddenly had a dream while still being aware that I was awake and walking. I stayed a bit confused for a minute, not being able to swipe my access card the right way.The next days I had similar experiences: while reading outloud at night in bed, and in my car when, luckily, I was not the driver. I mentioned these episodes to my principal investigator, professor of Neurosurgery, who strongly advised me to see one of our neurologists.

As focal seizures were assumed, an electroencephalogram was performed, and an epileptogenic focus was indeed observed in my left temporal lobe. A CTscan and a MRI showed a left calcified thalamus as well as an abnormality in the left amygdala. The latter was believed to be a glioma. Surprisingly, I did not feel happy to see an old friend from my PhD. The news was instead quite devastating to me and for my family, at Christmas time and only six months before my wedding.

Fortunately, after repeated scans, this socalled abnormality remained unchanged along the years and its malignancy was rejected. The cause of my epilepsy was thus not tumoral.

The only remaining probable cause for the triggering of my temporal lobe epilepsy was the tDCS study. First, it was temporally adjacent to the occurrence of the first epileptic seizures. Moreover, tDCS is strongly linked to epilepsy. It is to be avoided by anyone with a family history of epilepsy. Furthermore, its fundamental principle is to send electric current through the brain. The most likely

The only remaining probable cause for the triggering of my temporal lobe epilepsy was the tDCS study.” explanation was that my abnormal but, yet, asymptomatic brain features created a subliminal epileptic background and that the tDCS triggered my temporal lobe epilepsy.

In the scientific literature, tDCS is

New Phagenyx study shows significant benefits for patients with neurogenic dysphagia The largest real-world study of Phagenyx, a form of pharyngeal electrical stimulation, was published in the journal EClinicalMedicine – The Lancet, and showed significant benefits for those suffering from neurogenic dysphagia.

THE STUDY, THE PHARYNGEAL ELECTRICAL stimulation for treatment of neurogenic Dysphagia European Registry (PHADER), was conducted on more than 255 patients from 14 countries, suffering with five different neurological conditions (stroke not needing ventilation; stroke needing ventilation; ventilation acquired; traumatic brain injury; other neurological causes).

Pharyngeal electrical stumilation was administered to patients once daily for three days.

The study finds that treatment with pharyngeal electrical stumilation was associated with an improvement in neurogenic dysphagia, and a reduced risk of aspiration.

Pharyngeal electrical stumilation helped restore neurological control of swallowing. Patients were able to swallow safer, progress to a larger oral diet, have their feeding tubes removed and could be discharged

from hospital.

Shaheen Hamdy, University of Manchester, Manchester, UK, and co-lead investigator stated, “This data is exciting, in that, Phagenyx treatment can be successfully applied in a number of conditions associated with dysphagia and raises additional hope that after mechanical ventilation, dysphagic critically ill COVID-19 patients could recover faster; as seen from recent reports in two European hospitals...”

According to the company, neurogenic dysphagia, affects up to 78% of stroke patients, up to 90% of traumatic brain injury patients, 50–83% of tracheotomised patients, and up to 62% of orally intubated mechanically ventilated patients. Phagenyx reports that this condition can delay patient recovery and

widely described as safe. Only transient side-effects have been reported so far (skin lesions like burns, and mental health issues in depressed patients) apart from the case of a young epileptic boy who experienced a seizure during a tDCS trial. However, it does appear that tDCS has triggered my lifelong temporal lobe epilepsy, even though I was healthy with no family history of epilepsy. And since the tDCS experiment, my life is definitely different from what it used to be. Twice a day I have to take several medications, I still experience a few seizures a month, often suffer from a debilitating fatigue and am not allowed to drive anymore. The impact of my temporal lobe epilepsy on my life, and on my family is massive.

Epilepsy & Behavior Reports recently accepted to publish my self-case-report.

This case report might be the first to be published, but it does not mean that I am the only one experiencing a long-term medical issue associated with tDCS. As such a patient, I wanted my story to be told hoping that other asymptomatic healthy volunteers woud be spared.

As a neuroscientist, I think that it is indispensable that most, if not all, researchers using tDCS are aware of the potential risks seemingly healthy volunteers are exposed to. Preventively scanning them would be the way to safely discard asymptomatic volunteers presenting any abnormal brain feature.

The cost might be high for the study sponsors, however, it has to be balanced by the cost of claimed indemnities and that imposed on our health system. And, most importantly, the safety of volunteer is of a paramount priority.

Sandra Boccard-Binnet is a functional neurosurgery researcher at the University of Oxford, Oxford, UK. The author has no disclosures.

create increased chances of complications such as intensive care unit readmission, which results in a 13-times higher mortality. Other complications can include aspiration pneumonia, at two- to four-and-a-half times higher risk, and reintubation, at two- to four-times higher risk.

Additionally, those patients with neurogenic dysphagia have a lessened quality of life due to reliance on feeding tubes and risk of malnutrition or dehydration.

Neurogenic dysphagia can more than double the length of time patients remain in hospital after being released from the intensive care unit.

Rainer Dziewas, University of Münster, Münster, Germany, and co-lead investigator of PHADER, commented: “These results are fascinating since most patients were treated in a chronic state of illness, where it is usually extremely difficult to achieve any treatment success. PHADER clearly suggests that pharyngeal electrical stumilation may help even in this notoriously difficult situation. However, it is important to mention that patients with dysphagia should be treated as early as possible for best outcomes.”

Issue 40 | December 2020

Viewpoint 27

MEDTECH INSIGHTS

Stryker’s Mark Paul talks COVID-19 and developments in the neurovascular field The pandemic has affected the lives of everyone across the world, but especially those in the medical field. Physicians’ daily practices have changed, and the manufacturers of the medical products used every day have had to adapt, because a pandemic has not stopped the medical need for their products.

M

ark Paul, Stryker’s global president for neurovascular, started his career at Procter & Gamble. It wasn’t until he watched his wife undergoing a caesarean-section, and found himself completely fascinated by the surgery, that he realised he had a passion for the medical world. Shortly after, he made the leap into the medical device industry with a move to Boston Scientific.

As a young sales rep in peripheral vascular, he could not help but go and watch the first neurovascular cases in the region, which at the time included devices such as the Guglielmi detachable coil (GDC). Those early cases introduced a new chapter in the field of cerebrovascular surgery, and Paul knew he was hooked. So when the position for a product manager for the company’s neurovascular division became available, Paul relates that he ran to the CEO’s office in excitement.

In 2011, Stryker acquired Boston Scientific’s neurovascular division, and with this move, Paul became part of the Stryker family.

COVID-19 and its effect on the industry

Over the past ten months, the COVID-19 pandemic has been akin to a “spanner thrown into the works” for the medical

device industry, but a global pandemic “does not stop people from having strokes and does not stop the need for the best possible treatments,” notes Paul.

When the pandemic first hit, Paul’s number one priority became the safety of his huge, global team and their families. On 10 March, Paul sent his team to work from home. However, he was still keeping two other priorities front and centre: to continue supporting physicians around the world by ensuring products were still being made, sterilised and shipped; and continuing to innovate while working from home.

Stryker had to innovate from the factory up. Social distancing had to be built into the design of their facilities, with new Plexiglas dividers being added. The company was also required to change the way they educated clinicians on the use of their technology, adapting to a more digital form of communication. Paul commented, “the silver lining of COVID-19 has been that it has forced us to challenge our paradigms and allowed us to explore new and improved ways to provide physician support and training than we have ever had before.”

Paul goes a step further, explaining that the experience of COVID-19 will likely change the industry in the long term by going forward with a blending

of best practices.

Paul stated, “nothing is better than face-to-face communication, nothing is better than meeting face-to-face to talk about technologies and procedures and patients’ needs, and how to best treat those needs.” However, the pandemic has taught him that this is not always the best use of everyone’s time, and “we do not need to be sending people on airplanes as frequently as we have done [in the past]”.

Paul emphasises that although practices have changed at Stryker, their core aims have remained the same. For Paul, the most important thing has been sticking to the company’s mission of providing complete stroke care solutions and advancing the treatment of those suffering from stroke.

Looking forward, Paul identifies several areas in which he can see growth and improvement. “The vast majority of stroke patients is not receiving treatment, or not receiving treatment in time.” He would dearly like to see improvements on a global scale to reduce the time in which patients are brought in to receive stroke treatment, and fundamental shifts in the scale of patient education and awareness of stroke care.

On a more technical or procedurerelated note, Paul comments that once a patient is within an interventional suite and on the treatment table, there is still room for improvement in endovascular devices and imaging. Finally, he claims post-stroke care is an area with major opportunities for advancement.

The vast majority of stroke patients is not receiving treatment, or not receiving treatment in time.”

Alison Twiner appointed chair of Heart & Stroke National Board of Directors

Heart & Stroke has announced that Alison Twiner has been appointed as a chair on its National Board of Directors. Twiner has served on Heart & Stroke’s National Board since 2014, and was most recently a vice chair.

TWINER IS CURRENTLY A DIGITAL marketing and strategy consultant and advisor at Relentless Venture Fund, an early stage fund focused on technology solutions that optimise health, activity, and longevity. She has experience working with organisations like Facebook, Instagram and Google.

Twiner has been involved with Heart & Stroke since childhood, when she went door-to-door with her family to raise awareness and funds for Alison research, according to a press release from the

Twiner

organisation.

Twiner said, “Heart disease and stroke have touched my family, and so many families in communities across Canada. It is a privilege to come full-circle and continue to volunteer and serve this organisation as the new chair and help find business solutions that give people

Large-scale transformation with artificial intelligence (AI) and robotics also loom on the horizon. Paul says: “I think over the next several years, we are going to see exciting technologies that will dwarf what we have been launching today.”

Paul tells NeuroNews that Stryker has shifted from a pioneering first-to-market spirit to one that is guided by a solid medical research and evidence base.

However, this cannot be achieved without conducting clinical trials, which Paul notes can take years and cost several millions of dollars to undertake. Still, Paul is categorical that this is, “the right thing to do for patient care.” He claims that one of Stryker Neurovascular’s key aims is to constantly meet physicians’ needs, and reveals that their understanding of these needs evolves by closely watching image-guided procedures being performed with their devices and closely tracking outcome data. “Stryker seeks to maintain a high clinical threshold, meaning the investment put into clinical trials is worthwhile,” Paul notes.

Paul comments that through his career the neurovascular field has radically changed. Endovacular treatment approaches for stroke have “gone from [being used in] a handful of cases to being the standard of care.”

Neurovascular medical development is an exciting place to be, and Paul is well placed to watch it happen. As he says, they are, “just getting started.”

Mark Paul

hope. I want to encourage everyone to come together, engage and connect with Heart & Stroke to beat these diseases.”

Twiner replaces outgoing board chair Andrew Pipe, who will now serve as past chair on the Heart & Stroke National Board. According to Heart & Stroke, Pipe is a tireless advocate and world expert in tobacco control who has contributed to efforts to protect youth from vaping, restricting food and beverage marketing to kids, implement front-of-package nutrition labelling, and adopt a national, universal pharamacare programme for Canada.

Doug Roth, the CEO of Heart & Stroke, Toronto, Canada, commented on Twiner’s appointment: “Success in beating heart disease and stroke depends on being able to engage and connect with people across the country on the urgency of our cause. Now, more than ever, that is done through digital platforms.” He continued, “Alison’s expertise supporting organisations in developing strategies for a changing digital world will be exceptionally valuable as we expand how we use technology and new platforms to promote health, save lives and enhance recovery.”

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Alzinova AB announces clinical trials for Alzheimer’s vaccine candidate

Industry News

Wallaby Medical closes US$45 million Series C funding

Wallaby Medical, a medical device company focused on stroke treatment, has announced the closing of US$45 million Series C funding.

This round of funding was led by GL Ventures, the venture capital arm of Hillhouse Capital with participation from Sinovation Ventures.

According to their press release, Wallaby Medical intends to use this funding to further develop their product portfolio, as well as commercialisation in China, which they see as a key market.

Wallaby Medical’s first product, the Avenir Coil System, has clearance from the US Food and Drug Administration (FDA), a CE mark, and approval from Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), as well as being commercialised in over 15 countries, according to the company.

The Avenir Coil System is a technically differentiated neuro embolic coil system for the treatment of intracranial aneurysms and other neurovascular abnormalities.

RapidAI experiences nearly 300% growth

RapidAI has announced growth of nearly 300%. This has been attributed

by RapidAI in a press release to an “international adoption” of AI-powered stroke care.

RapidAI is approved for use in over 60 countries, used in over 1,600 hospitals, and is on track to scan one million patients worldwide by the end of 2020.

Sanjeev Nayak, University Hospitals of North Midlands, Stoke-on-Trent, UK, comments: “I see artificial intelligence as the future in the fast-moving world of diagnostic and therapeutic stroke management.”

Fycompa receives approval from European Commission for use in children with epilepsy

Fycompa or perampanel, an antiepileptic agent, has now been approved by the European Commission (EC) for use in children, according to a press

release by Eisai.

The drug has been approved for adjunctive treatment of partial-onset seizures with or without secondary generalised seizures in patients aged four and older. It has also been approved for use in patients aged seven and older suffering from primary generalised tonic-clonic (PGTC) seizures who have idiopathic generalised epilepsy (IGE).

This approval was based on the results of two studies, study 311 (phase III) and study 232 (phase II). Study 311 evaluated the safety and tolerability of perampanel, while study 232 looked at the pharmacokinetics, efficacy, and long-term safety.

Andras Fogarasi, head of Neurology at Bethesda Children’s Hospital, Budapest, Hungary, and principle investigator on study 311, says, “The day-to-day impact of uncontrolled epilepsy in children can be very difficult for them to understand and manage, affecting all aspects of their lives from a very young age. Providing new treatment options to children must be done with caution, care, and diligence, and I am very happy to have taken part in this study to be able to provide this new treatment option to children, and their families, who are in desperate need of support with their condition.”

Brilinta with aspirin reduced disabling stroke or death in patients with acute ischaemic stroke or TIA

Results from a prespecified exploratory analysis of the positive THALES phase III trial have shown that for patients with acute ischaemic stroke or transient ischaemic attack (TIA), taking Brilinta (ticagrelor) 90mg twice daily along with aspirin for 30 days, reduced the rate of the composite of disabling stroke or death by 17%, when compared with using aspirin alone.

These results reinforce the findings of the THALES phase III trial, showing that ticagrelor alongside aspirin, has a statistically significant reduction in the composite of stroke or death at 30 days in patients with stroke or TIA, than with aspirin alone. This study had 11,000

subjects across 28 countries.

Additionally, this medication combination reduced the risk of severe bleeding events in patients with disabling stroke was 0.4% for aspirin with tricagrelor, compared with 0.1% for aspirin alone. The rate of the composite of non-disabling stroke or death at 30 days was 1.3% in the aspirin plus ticagrelor group and 1.6% in the aspirin only group

Alzinova AB has announced its upcoming clinical study for Alzheimer’s disease vaccine candidate ALZ-101, which will take place in the second quarter of 2021.

The subjects of this phase 1 study will be early Alzheimer’s disease patients.

This is the first-in-human study of the ALZ-101 vaccine, its primary objective is to assess the tolerability or adverse effects. The study will also analyse the immune response, and will be conducted in Finland in cooperation with the Clinical Research Services Turku.

Alzinova AB is a biotherapy company focused on an immunotherapy approach to Alzheimer’s disease.

Kristina Torfgård, CEO of Alzinova AB, commented, “On the basis of the documented preclinical properties of the ALZ-101 vaccine candidate, we are truly looking forward to the clinical development of ALZ-101 into a therapeutic vaccine for patients. To the best of our knowledge, this is the first clinical study that specifically targets the toxic forms of the Aβ peptide, and it will thus be the first of its kind. This is an important step for Alzinova, in a field where the medical need is great.”

Nurami Medical raises an estimated US$6 million in series B funding round

Nurami Medical has raised up to US$6 million in series B funding to finance ongoing clinical trials for ArtiFascia.

Funding will also be used for the regulatory approval process for the US Food and Drug Administration (FDA)

and CE mark. Funding was led by Almeda Ventures, a health-tech focused public research and development partnership.

ArtiFacia is a synthetic dural graft, which is intended to help the healing and repair of the dura after cranial neurosurgery. Nurami claims it does this by boosting dura regeneration, preventing the leakage of cerebrospinal fluid (CSF), and protecting the brain and the central nervous system.

The clinical trial for ArtiFascia will consist of 90 patients, 13 of which have already been implanted with an ArtiFascia graft. This trial will occur in European medical centres, composed of a controlled, blind study.

This is Nurami’s first product, although the company is currently developing other products for the healing and regeneration of soft tissue.

The company was formed in 2014

by Amir Bahar, Nora Nseir Manassa and NGT3VC, a venture capital fund.

The company’s technology consists of biodegradable, synthetic nanofibers, which have sealing properties for soft tissue.

Hannoch Marksheid, co-CEO of

Nurami, stated, “Our first product, ArtiFascia, offers clear clinical and economic benefits to the 600,000 neurosurgeries performed annually, representing a US$1 billion market with an annual growth rate of 6%.”

Keck Medicine to enrol individuals in phase III clinical trial to treat mild Alzheimer’s disease with deep brain stimulation

Keck Medicine, of the University of Southern California, Los Angles, USA, is enrolling individuals in an international phase III clinical trial to study deep brain stimulation as a treatment for Alzheimer’s disease, sponsored by Functional Neuromodulation.

The clinical trial involves approximately 200 patients at 20 sites across the USA, Canada and Germany.

Keck Medicine plans to enrol between eight and 15 patients.

Electrodes will be implanted into the subjects’ brains, connected to a battery pack which is placed under the collarbone. The study uses electrical impulses through the electrode to stimulate the fornix, and aims at analysing the safety and effectiveness of this as a treatment.

This randomised, double-blind study will last four years, split into two stages.

For the first year of the study, subjects will receive either low-frequency stimulation, high-frequency stimulation, or no stimulation—to act as placebo.

Based on what is learned in the first year of the trial, for the last three years all of the subjects will receive what has been determined to be the most effective level of stimulation.

The effectiveness of this treatment will be measured with cognitive tests to assess any improvements in memory and learning abilities.

To qualify for the trial patients must be at least 65, have been diagnosed with mild Alzheimer’s and take Alzheimer’s medication, and have a caregiver or family member who can take them to doctor’s visits.

NeoRhythm to conduct study of its pulsed electromagnetic field headband device

NeoRhythm has been gathering customer feedback on its pulsed electromagnetic field therapy (PEMF) headband device, since its launch in 2019, to conclude the largest PEMF research to date.

Electromagnetic and bioelectromagnetic therapy pioneers Igor Jerman (BION Institute, Ljubljana, Slovenia) and Beverly Rubik (Institute for Frontier Science, Oakland, USA), are leading this first large-scale research on relaxation, focus and sleep.

The study has recruited more than 1,500 participants who use PEMF and will be undertaken in Europe and the USA. The researchers will examine how different circumstances influence PEMF efficacy, the most efficient frequency for

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Market watch 29

Industry News the desired state, and examine the longterm impact of the device.

Several PEMF headbands have found success with users, however, none of the developers behind these have tested them through large-scale independent scientific research, the company said in a press release.

PEMF technology works by emitting harmless rhythmic pulses that encourage the brain to sync. The brain can thus be compelled to go into various modes based on brain wave patterns that the pulses mimic. This can induce sleep, reduce pain, increase energy and focus, stimulate meditation and more.

NeoRhythm

Diadem presents clinical data and commercialisation plans at Alzheimer’s disease international conference

Diadem has announced clinical data and commercialisation plans for its AlzoSure Prognostic Biomarker Test, a blood-based test for the early prediction of Alzheimer’s disease (AD), at the 2020 Alzheimer’s Disease International Conference (ADI, 10–12 December, virtual). The company reported these results at a symposium it hosted on its prognostic biomarker test at ADI. According to a Diadem press release, AlzoSure Predict is a simple, noninvasive plasma-based biomarker test that has been validated in early studies to accurately predict the probability a patient with asymptomatic mild cognitive impairment (MCI) will progress to dementia due to AD. The company’s patented technology measures a conformational variant of p-53 (U-p53), which is over-expressed in Alzheimer’s patients, using an analytical method that includes a proprietary antibody and target sequences developed by Diadem.

Further clinical studies are currently underway and the company plans a global launch in collaboration with strategic partners in 2021.

Diadem CEO Paul Kinnon and Simona Piccirella, vice president of product development and operations, presented an overview of promising initial clinical data showing the potential utility of AlzoSure Predict for identifying which patients will progress from asymptomatic MCI to AD. They also discussed the company’s clinical, regulatory and commercialisation plans.

Symposium panelists included Diadem Medical Advisory Board AD experts Tamas Bartfai, Jeffrey Cummings and Anne Fagan. In an interactive session, they discussed the scientific background of the AlzoSure

Predict biomarker test, its performance to date, and initial clinical validation data. They also explored how AlzoSure tests could fit into and impact the patient clinical pathway, along with their suitability and potential to improve patient treatment and long-term outcomes.

As part of the symposium, Diadem presented early clinical validation data comparing AlzoSure Predict’s prognostic performance with historical diagnostic results. AlzoSure accurately predicted which individuals would experience cognitive decline to Alzheimer’s dementia, achieving positive and negative predictive values (AUC’s) of greater than 90%, regardless of cognitive status (cognitively normal or MCI) at the time of the test.

AlzoSure showed superior ability to predict cognitive decline to Alzheimer’s dementia compared to “gold standard” PiB-PET imaging, and AlzoSure predicted progression to Alzheimer’s dementia significantly better than amyloid and tau-based assays combined, using the same baseline characteristics.

Fagan commented, “The beauty of the biomarker test is that it is available. It is a simple blood test and people are used to that. It can be administered in the physician’s office and serve as the basis for discussions with family members and caregivers. I think it is a very attractive option.”

Cummings said, “We are in the age of biomarkers right now that will hopefully lead us to the age of therapies.”

He concluded, “This is the kind of biomarker test companies are looking for.”

According to the press release, further validation studies of AlzoSure Predict involving about 1,000 individuals are expected to be completed during the first half of 2021.

Kinnon said, “We were pleased at the opportunity to share the encouraging early clinical data and our commercialisation plans for our AlzoSure Predict prognostic assay.”

He continued, “Based on these results, we believe that our ongoing studies will confirm its ability to forecast which patients will go on to develop symptomatic AD up to six years before symptoms appear, well before any current diagnostic is accurate.

We see AlzoSure as a game-changer in Alzheimer’s disease—enabling earlier treatment for patients and the development of more effective AD therapies for administration before brain damage and loss of cognitive function are irreversible.”

Synaptogenix forms new company

Neurotrope announced the completion of an independent spin-off of Neurotrope Bioscience, which has now been renamed as Synaptogenix, trading under

the symbol SNPX. Daniel Alkon, the company’s chief scientific officer commented, “We expect Synaptogenix to benefit from the current environment where global pharmaceutical companies and institutional investors are both seeking opportunities in new neuro-restorative strategies to treat Alzheimer’s disease, as well as other neurodegenerative diseases.” He continued, “The work we have pioneered for the last twenty years on our first in class regenerative therapeutic platform now serves as the foundation for an entirely new emphasis from both the scientific and investment communities. Our lead compound, Bryostatin-1, has demonstrated safety and has shown promising signals of meaningful cognitive improvement over baseline function. This synaptogenesis and prevention of neuronal death are, we believe, critical for treating Alzheimer’s disease, as well as other important neurodegenerative conditions such as multiple sclerosis, Parkinson’s disease, fragile X syndrome, and autistic spectrum disorders.”

Alan J Tuchman, CEO of Synaptogenix, added, “We are very pleased with the progress we are making on our NIH-sponsored phase II Alzheimer’s trial and look forward to further updating the market in the near future. This trial extends the duration of dosing to six months and builds on the valuable lessons we have learned from previous, limited-duration pilot studies.

We are also exploring opportunities for additional NIH grants and hope to conduct early trials for additional neurodegenerative indications in the near future.”

Josh Silverman, chairman of Synaptogenix, stated, “The successful spin off of Synaptogenix, following the recently announced merger between Metuchen Pharmaceuticals and Neurotrope, forming Petros Pharmaceuticals, completes the strategic step of realigning our assets to maximise shareholder value going forward. We are excited and focused on creating value in each of these two companies for our investors in the near term.”

First patients enrolled in Balt STEM trial

Balt announced in a press release that the first patients have been enrolled in the STEM (Squid trial for the embolisation of the middle meningeal artery) for the treatment of chronic subdural haematoma. This marks the first patients enrolled in a prospective, randomised, international trial of a liquid embolic agent for the treatment of chronic subdural haematoma.

David Fiorella, Stony Brook University Medical Center, New York, USA, and co-primary investigator of the STEM trial, USA, commented, “We are excited to have started enrolment in the pivotal STEM trial.” He continued, “We have seen some tremendous preliminary results with this procedure in clinical practice. STEM provides the opportunity to confirm these observations with level one evidence from a randomised

controlled clinical trial. We are optimistic that middle meningeal artery embolisation with Squid will advance the standard of care for chronic subdural haematoma and improve the quality of life for patients with this common and disabling disease.”

Adam Arthur, Semmes-Murphey Neurologic and Spine Institute and University of Tennessee Health Sciences Center, Memphis, USA, co-primary investigator, added, “Having the first patients enrolled in the STEM trial is an important milestone. The results of STEM are critical as they are going to substantially add to our knowledge base on chronic subdural haematomas.

Not only will this trial tell us whether treatment of chronic subdural haematoma with the Squid liquid embolic system is safe and effective, it will also provide tremendous insight into the disease’s natural history and the safety and efficacy of the currently available treatment strategies, which are not yet well characterised.”

According to Balt, the STEM study is the first-of-its-kind, pivotal, multicentre, randomised controlled trial comparing embolisation of the middle meningeal artery with Squid to standard therapy for patients undergoing surgery and patients undergoing medical management.

Balt seeks to use these data to gain US Food and Drug Administration (FDA) approval of the Squid liquid embolic system for this indication.

Meta-analysis of acute migraine treatment devices found evidence in support of the REN method According to a press release produced

by Theranica, a peer-reviewed study published in The Journal of Headache and Pain, has concluded that remote electrical neuromodulation (REN) was the only neuromodulation-based acute migraine treatment with sufficient clinical evidence to conclude that it is effective.

According to the press release, the study examined 38 peer-reviewed studies focusing on the effect of neuromodulation treatment on migraine patients.

Seven of the studies focused on acute treatment and the ability of different devices to deliver either pain relief or pain freedom at two hours.

Secondary outcomes were assessed by improvement in quality of life, the need for rescue medication and the Patient Global Impression of Change Score.

Stephem Silbertein, director of the Headache Center at Jefferson University Hospital, Philadelphia, USA, commented, “As non-invasive neuromodulation is an emerging field in the treatment of migraine, an unbiased systemic review was important to understand what may really be benefitting patients.” He continued, “While the industry should conduct more studies to understand the potential of neuromodulation for migraine treatment, this study certainly helps comparing between the different emerging techniques.”

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Product News

eCLIPs system

Evasc receives CE mark approval for its electric eCLIPs bifurcation remodelling system

Evasc has announced that the Electric eCLIPs bifurcation remodeling system (eB) has been granted a CE mark.

The eB builds on eCLIPs’ highly effective design, incorporating an improved delivery system with a torquable wire, a smaller size that is compatible with 021 and 027 microcatheters, and electrolytic detachment.

Donald Ricci, president and chief executive officer of Evasc, commented: “We have listened to the experts in the neuro field and developed an improved version that is smaller and easier to use.

This will allow treatment for a wider range of aneurysms and shorten delivery times,” he continued, “The previous version showed exceptional outcomes due to the eCLIPs implant’s ability to bridge the neck of the aneurysm and to create a flow diversion effect. This new and improved version retains these favourable characteristics and also allows eCLIPs to gain access to smaller and more distant vessels within the cerebral anatomy.”

Evasc is a privately-held medical device company focused on the development of disruptive endovascular treatments for cerebral aneurysms.

IonicRF, Abbott’s first radiofrequency ablation device, launches in the USA

Abbott has announced that their IonicRF, a minimally invasive radiofrequency ablation device, is now being launched in the USA. This is after the IonicRF device received clearance from the US Food and Drug Administration (FDA).

IonicRF is intended for the management of pain in the nervous system. The non-surgical device uses an electrical current to heat up a small area of tissue, targeting specific nerves and blocking pain signals from reaching the brain. According to studies cited

by Abbott, a single radio ablation treatment’s effects can last from six to 12 months.

Millions of people suffer from chronic pain in the USA. The most common medical complaint worldwide is lower back pain, which could potentially be treated with this device.

IonicRF is Abbotts’ first radiofrequency ablation device, which is currently approved for use in the USA

and Europe.

“Most people who are candidates for radiofrequency ablation have tried other therapies, such as medications and injections, with limited success.

As a result, they are now seeking an alternative solution that does not require surgery or the use of opioid medication,” said Keith Boettiger, vice president, neuromodulation, Abbott. “We are proud to be able to provide the first Abbottdesigned radiofrequency ablation device engineered to deliver safe and effective pain management.”

Jason E Pope, founder and CEO of Evolve Resortation Center, Santa Rosa, USA, comments: “Every patient is different and the source of their pain is unique, making it extremely important to have multiple options available, so treatment can be tailored to individual circumstances.”

Rapid Medical receives CE mark for Comaneci adjustable device

Rapid Medical has announced that its adjustable remodelling mesh device, called Comaneci, has received CE mark approval. Comaneci is intended to treat cerebral vasospasm by mechanically dilating the intracranial vessels.

According to Rapid Medical’s press release, this is the first adjustable mesh device indicated for the endovascular treatment of vasospasm. Over 4,000 procedures have been performed utilising the Comaneci device to assist in the coil embolisation of wide-neck intracranial aneurysms.

During a cerebral vasospasm, spasms cause a narrowing of brain blood vessels, reducing blood flow. The traditional therapy for this problem has been balloon angioplasty, but according to their press release, this treatment carries the risk of balloons blocking blood flow and vessel perforation.

According to the company, the Comaneci device temporarily supports vessels in the brain without occluding blood flow. The device is subsequently expanded, allowing clinicians to gradually increase its applied force, and monitor dilatation.

The company has stated that Comaneci’s adjustable diameter, low delivery profile and excellent visibility has the potential to treat patients more effectively with a lower risk of vessel injury.

Hervé Brunel, senior interventional neuroradiologist at Marseille University Hospital, Marseille, France, said, “Comaneci’s expanded indication for the endovascular treatment of vasospasm will provide physicians with an exciting new treatment option for our patients.”

FDA issues Class I recall for Stryker’s Trevo XP ProVue retriever The US Food and Drug Administration

(FDA) has issued a Class I recall for Styrker’s Trevo XP ProVue retriever.

This device is intended for the removal of blood clots during acute ischaemic stroke.

The Trevo XP ProVue retriver has been recalled due to a risk that the core wire in the device may break or become separated during use. If this occurs during an operation, it may result in the device being left inside a patient’s blood vessel or tissue.

The device being left inside a patient may result in adverse events such as bleeding, additional blockage, disability, and death. There have been 11 reports of injury or illness, and one death.

The devices were manufactured between July 2019 and September 2019, and distributed from September 2019 to July 2020. Stryker itself issued a recall for this product in September 2020.

Cerenovus unveils new clot extractor device in European launch

Cerenovus, part of Johnson & Johnson Medical Devices Companies, has announced the European launch of Cerenovus Nimbus, a device designed to remove tough clots for successful revascularisation in patients with acute ischaemic stroke caused by a large vessel occlusion.

Ischaemic strokes account for 85% of all strokes and up to 46% are caused by a large vessel occlusion (LVO).

Strokes caused by LVO have devastating consequences—they are responsible for 60% of patient dependency due to disability and more than 90% of mortality.

Mechanical thrombectomy (MT), a minimally invasive procedure, is the recommended treatment option for acute ischaemic stroke; however, successful recanalisation is not achieved within three passes or not at all, in approximately 25% of thrombectomy cases due, in some cases, to the inability to remove a tough clot. Each attempt is associated with an increased risk of vessel injury and potential impact on clinical outcomes.

Cerenovus Nimbus has two different design features to maximise tough clot removal: a proximal spiral section and distal barrel section. The spiral section is specifically designed to maximise blood vessel lumen coverage and device-clot interaction, providing engagement with the clot and facilitating dislodgement of resistant clots. Due to the design, Nimbus has the potential to improve reperfusion rates and reduce the number of passes required in tough clot cases, which may lead to improvement in patient outcomes, the company claims.

Hannes Nordmeyer (Radprax Neurocenter, Solingen, Germany) said: “The performance of MT devices varies according to the composition and characteristics of the occluding thrombus and we know that retrieving fibrin rich clots and restoring flow is challenging.

“Having a device specifically designed to retrieve tough clots for successful revascularisation may

improve clinical outcomes and advance stroke treatment.”

Nimbus is the latest addition to Cerenovus Stroke Solutions—a suite of technologies designed with compatibility in mind to help physicians perform mechanical thrombectomy procedures.

Nalu receives FDA clearance for 1.5T full-body MRI scanning in patients with Nalu neurostimulation system implants

Nalu Medical has received US Food and Drug Administration (FDA) 510(k) clearance for an expanded labelling that allows for full-body 1.5 Tesla (T) magnetic resonance imaging (MRI) in individuals with select Nalu spinal cord stimulation (SCS) implants. This clearance is retroactive to currently implanted SCS patients and considered MRI-conditional.

With a conditional classification, MRI scans can be safely administered under certain conditions, such as the type of MRI scanner, implant configuration and anatomical location. The MRI safety labelling also includes 1.5T and 3T scans of the head and extremities for SCS and peripheral nerve stimulation (PNS) systems.

According to a press release, in today’s medical practice, MRI scans are necessary and routinely performed for diagnosis and clinical care. It is very likely that a patient with chronic pain will require a future full-body MRI scan. The clearance for full-body MRI labeling removes a potential barrier for eligible patients to select the Nalu neurostimulation system as a means to help manage their chronic pain.

“Expanding our MRI label from head and extremity only to full-body is a significant factor for extending our reach across the USA,” said Earl Fender, Nalu’s president and CEO. “With this clearance, clinicians can now recommend our life-changing therapy to eligible patients with fewer concerns about future imaging. It also underscores Nalu’s ongoing commitment to advance medical devices with miniaturised technology to provide meaningful differences in patients’ lives.”

“When evaluating neurostimulation systems best suited for my patients, I always consider their immediate and long term needs with regards to disease progression and imaging,” said Dawood Sayed, associate professor, University of Kansas School of Medicine and division chief of Pain Medicine, Kansas City, USA. “The small size and broad capabilities of the Nalu implant is something that is especially important to many of my patients. Adding full-body conditional MRI allows me to offer this effective therapy to an even greater number of patients with chronic pain, while maintaining more of my patients’ available imaging options.”

IRRAS expands IRRAflow device to Latin America

IRRAS AB has announced it has reached

Issue 40 | December 2020

Market watch 31 and our team is actively working with leading physicians to plan an effective product launch.”

Product News an exclusive distribution agreement for commented, “We are pleased to their IRRAflow device, with Anade SA, partner with Anade SA to expand a distributor of neurosurgical medical the commercial availability of our devices and technologies through Latin IRRAflow product line to physicians America. and patients throughout According to their press multiple markets in Latin release, IRRAflow is the America,” he continued. company’s initial commercial “Currently, IRRAflow has product. IRRAS claims it received regulatory clearance is a transformative medical in Costa Rica and Argentina, device system that combines and regulatory clearance is controlled irrigation with being pursued in five additional ongoing fluid drainage to markets. This partnership better manage patients with allows us to accelerate intracranial bleedings. The commercial launches in these system’s automated use of IRRAflow markets with the capable sales irrigation addresses challenges professionals of Anade and its associated with traditional passive fluid sub-distribution partners identifying and drainage, such as catheter blockages and training customers in each of these new infection. markets.”

Additionally, IRRAS claims that Miguel Ferro, vice president of IRRAflow’s irrigating fluid helps to Anade SA, added, “We are excited to dilute toxic material, such as blood or bring a product, such as IRRAflow, to bacteria, that is collected within the these initial markets in Latin America. intracranial space and makes it easier to IRRAflow clearly complements our remove. existing neurosurgery portfolio by Coenraad Tamse, vice president providing a next-generation solution for of international sales for IRRAS the treatment of intracranial bleeding,

Medtronic recieves Health Canada license for Percept PC DBS system

Medtronic Canada has received a Health Canada licence for the Percept PC deep brain stimulation (DBS) system with BrainSense technology.

According to Medtronic’s press release, BrainSense technology makes Percept the first and only licensed DBS neurostimulation system with the ability to chronically capture and record brain signals while delivering therapy to patients with neurologic disorders associated with Parkinson’s disease, essential tremor, dystonia, or epilepsy.

The company claims this technology allows physicians to track patient brain signals and correlate these with patientrecorded actions or experiences, such as symptoms, side-effects, or medication intake, enabling more personalised, data-driven neurostimulation treatment.

Medtronic stated the first implant of the newly-licensed device in Canada will occur at Toronto Western Hospital.

Alfonso Fasanso, professor of neurology at the University of Toronto, Toronto, Canada, commented, “Percept

is the first commercially available implantable pulse generator with the ability to record and store the day-to-day brain activity of patients with implanted electrodes for deep brain stimulation.”

He continued, “Neurologists will have, for the first time, the opportunity to monitor their patients’ condition well beyond the relatively short time devoted to the doctor-patient interaction in the clinic. Percept will also expand our understanding of brain functioning during physiological and pathological states and set the stage for the development of closed-loop (i.e. adaptive) deep brain stimulation.”

Medtronic’s press release stated DBS is an individualised therapy delivered from a small pacemaker-like device, placed under the skin of the chest or abdomen, to send electrical signals through very thin wires (leads) to a targeted area in the brain related to the symptoms of a neurological disorder, such as Parkinson’s disease.

Mike Daly, vice president and general manager of the brain modulation business at Medtronic, Dublin, Ireland, stated, “There is nothing currently available that can replace clinical judgement in treating patients. For the first time, this technology gives clinicians feedback directly from the DBS patient’s brain.”

Calendar of events

Event details correct at time of publication.

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

15–16 January NANS: North American Neuromodulation Society Virtual Meeting Virtual www.conference.neuromodulation. org

30–31 January WIP Taipei Interventional Pain Workshop Taipei City, Taiwan (also offered virtually) www.wiptaipei.tw

1–2 February 29th Israel Society for NeuroScience Annual Meeting Virtual

12 March 1st European Life After Stroke Forum Virtual

www.isfn.org.il

www.safestroke.eu/elasf/

2–4 Februray 8th ESO-ESMINT-ESNR Stroke Winter School Virtual

17–19 March ISC: International Stroke Conference 2021 Virtual

www.strokewinterschool.com

www.professional.heart.org/es/

9–10 March European Neuro Convention Birmingham, England

meetings/international-strokeconference

19–22 April CX 2021 Vascular and Endovascular Controversies Digital Edition Virtual www.cxsymposium.com

22–26 May ASNR: American Society of Neuroradiology Annual Meeting San Francisco, USA (also offered virtually) www.asnr.org/annualmeeting/

www.neuroconvention.com

September

2019 | Issue

Georgios

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