NeuroNews issue 42 – EU

July 2021 | Issue 42

Featured in this issue:

www.neuronewsinternational.com

Profile William Mack page 14

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Waleed Brinjikji Novel therapy for CSF hypotension

Benefits of EVT for basilar artery occlusion “cannot be excluded” following another inconclusive study A randomised controlled trial (RCT) involving 300 patients found that functional outcomes among basilar artery occlusion stroke patients “did not differ significantly” with endovascular therapy (EVT) compared to standard medical care. Nevertheless, writing in the New England Journal of Medicine (NEJM), the study’s authors state that “the results of this trial may not exclude a substantial benefit of EVT”—with larger trials now being needed to determine the efficacy and safety of EVT for basilar artery occlusion.

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his trial was based on information acquired from the that “true equipoise remains regarding the efficacy of prospective BASICS (Basilar artery international EVT in patients with a minor deficit”. He added: “The cooperation study) registry, which collected data on BASICS registry and trial both suggest that patients with EVT versus intravenous (IV) thrombolysis between 2002 a minor deficit do better with IV thrombolysis alone and 2007, and also follows the 2020 BEST (Endovascular while, in clinical practice, treating physicians still feel treatment versus standard medical treatment for uncomfortable withholding EVT. If anything, this trial vertebrobasilar artery occlusion) trial—a randomised shows that EVT is less effective in basilar artery occlusion trial assessing endovascular treatment of basilar compared to anterior circulation occlusion—so, we artery occlusion that was discontinued before do have to improve our treatment approach in its intended enrolment basilar artery occlusion.” due to poor recruitment The BASICS trial was a multicentre, and a high rate of open-label, international RCT conducted crossover between the across 23 centres in seven countries, medical care and EVT from October 2011 through December EVT + best therapy groups. Both of these 2019, involving patients with strokes due studies also failed to to basilar artery occlusion. The study’s fully demonstrate the superiority of EVT researchers compared the efficacy and safety over standard medical therapy. of EVT—initiated within six hours after the The latest major study in this space, the estimated time of basilar artery occlusion—with those BASICS trial, was conducted by Wouter J of standard medical therapy.

Schonewille (stroke neurologist, Department The primary outcome was a favourable of Neurology, St Antonius Hospital, functional result, defined as a score of Nieuwegein, The Netherlands) and zero-to-three on the modified Rankin colleagues, who—writing in NEJM— scale at 90 days, with the primary safety state: “Few patients with basilar artery outcomes being symptomatic intracranial Best therapy alone occlusion have been included in major haemorrhage detected via neuroimaging trials of EVT, which have mainly enrolled within three days after the initiation patients with strokes in the anterior cerebral of treatment, and mortality at 90 days. circulation. The vascular anatomy, clinical Secondary clinical outcomes were an excellent presentation, and severity of neurologic deficit, functional result, defined as a modified Rankin in patients with basilar artery occlusion scale score of zero-to-two; National Institutes differ from those in patients with anterior of Health Stroke Scale (NIHSS) score at 24 circulation strokes. These differences suggest hours; distribution of modified Rankin scale that trials of endovascular treatment should scores; and health-related quality of life at be conducted independently for patients with 90 days. strokes in the basilar artery territory.”

Some 300 of 424 eligible patients were However, after the results of this trial randomly assigned to a trial group, with 154 showed no significant benefit of EVT patients (age=66.8±13.1 years; 35.1% female versus standard medical therapy—which [n=54]) assigned to the endovascular group to involved close to 80% of patients receive EVT plus standard medical therapy, receiving IV thrombolysis and 146 (age=67.2±11.9 years; 34.2% Wouter J in both treatment arms— female [n=50]) assigned to the medical Schonewille Schonewille told NeuroNews Continued on page 4

Favourable functional outcome:

44.2% 37.7%

Flow Neuroscience Changing mental health treatment with tDCS page 23

Long-term effectiveness of STN-DBS for Parkinson’s confirmed with 15-year follow-up study New findings published in Neurology, the medical journal of the American Academy of Neurology (AAN), have confirmed the longterm effectiveness of deep brain stimulation of the subthalamic nucleus (STN-DBS) in treating Parkinson’s disease—with a “significant improvement” in motor complications and a stable reduction of dopaminergic drugs being observed more than 15 years after surgery. The study’s researchers state that this is, to the best of their knowledge, “the longest and largest follow-up described in patients with DBS”.

SPEAKING TO NEURONEWS, THE study’s lead author Elena Moro (professor of neurology, Movement Disorders Unit, Grenoble Alpes University Hospital Center, Grenoble, France) said: “We recognise that, in the very long term, it can be difficult to predict the improvement in QoL [quality of life] after DBS. However, considering that these people with Parkinson’s disease undertaking DBS have been living with the condition for at least 10 years, for them to not have a decreased QoL after a total of 25 years of Parkinson’s is quite an achievement from my point of view.”

In their report, Moro et al write that—in people with advanced Parkinson’s disease— STN-DBS is a well-recognised and effective treatment in both short- and long-term follow-up. Despite this, the few available data regarding motor response from STN-DBS after more than 10 years focus on small populations, and do not allow solid conclusions about the treatment’s effects “in the very long term” to be drawn. This lack of direct evidence on its sustained benefits means it is challenging to decide whether to replace the stimulator device Continued on page 2

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July 2021 | Issue 42

Deep brain stimulation

Long-term effectiveness of STN-DBS for Parkinson’s confirmed with 15-year follow-up study

reductions were sustained—despite the inevitable progression of levodopa-resistant motor and non-motor symptoms in the disease’s late stages—providing Class IV evidence that, for Parkinson’s, STN-DBS remains effective in treating motor complications at least 15 years after surgery. “This information about the long-term outcomes after DBS surgery can be useful to patients, caregivers and treating physicians when counselling about surgery,” the authors state.

Continued from page 1 at the end of its lifespan, they add.

“So far, the clinical evidence that both STN The researchers embarked on a study to and pallidal DBS are effective in advanced evaluate the effects of STN-DBS beyond Parkinson’s disease is very strong,” Moro 15 years after surgery—mainly focusing added. “No other invasive treatments or on changes in Parkinson’s disease-related new neuromodulation techniques can be motor complications. For this, data on motor compared in terms of the number of people complications, QoL, activities of daily treated, number of published studies, and living, Unified Parkinson’s Disease Rating follow-up. However, even for DBS, data at Elena Moro Scale (UPDRS) motor scores, dopaminergic more than 10 years after surgery is lacking, treatment, stimulation parameters, and side and—although retrospective—this study reports effects of STN-DBS, were retrospectively retrieved from on the oldest cohort in the world with STN-DBS. Within all consecutive Parkinson’s patients operated on with 30 years, patients belonging to this cohort show that bilateral STN-DBS at the Grenoble Alpes University DBS significantly impacted their life. While Parkinson’s Hospital from 1993 to 2004, and compared before disease did progress, surgery reduced their disease surgery, and at one year and beyond 15 years post surgery. disability to a great extent for more than 15 years. No Some 51 patients, with a median follow-up time of 16 other invasive treatment has shown these results to date.” years (range=15–24 years), were ultimately recruited, and Moro et al allude to several potential limitations of the STN-DBS was found to be effective in improving motor study, including the high percentage of patients (40.6%) fluctuations and dyskinesia in 39 of these patients (76%). lost at long-term follow-up creating a risk of bias, and a Compared to baseline, the time spent with dyskinesia lack of long-term follow-up data for some patients. (item 32, UPDRS) was reduced by 75%, and the time On the subject of future research directions, Moro spent in the “off state” (item 39, UPDRS) diminished by added: “Ideally, one would compare a control group with 58.7%. In addition, dopaminergic drugs were reduced a surgical group in the long term. However, these studies by 50.6% at long-term follow-up. Parkinson’s Disease are very difficult, since it has been demonstrated already QoL (PDQL) total scores improved by 13.8%, and the that DBS is superior to the best medical treatment, and it emotional and social function domains in the patient would therefore not be ethical to deny DBS to people who cohort also improved by 13.6% and 29.9%, respectively. want to have it. Because of this, observational long-term “Few and mostly manageable” device-related adverse cohorts are important to add further knowledge about events were observed during long-term follow-up, the long-term DBS effects. Our study also did not focus on authors write. On these adverse events, Moro stated: several non-motor aspects of Parkinson’s disease. Further “Device-related side effects are obviously expected in studies might investigate these important areas.” any study. Compared to the available literature, we did not find any unexpected issues. However, over the past 30 years, DBS technology has made several advances, and I expect to have fewer adverse events in the future with the new devices.” She added that, in advanced Parkinson’s, medications used to treat the disease often induce sideeffects like dyskinesia, motor and non-motor fluctuations, impulse control disorders, and psychosis, but that this study demonstrates the benefits STN-DBS holds as “the only therapy” capable of minimising these side effects through the reduction of dopaminergic drugs.

Overall, this retrospective, single-centre study showed STN-DBS is effective in improving motor complications in the very-long-term follow-up of advanced Parkinson’s patients. Short-term QoL improvements and medication

This information about the longterm outcomes after DBS surgery can be useful to patients, caregivers and treating physicians when counselling about surgery.”

The latest stories from the neuro world

News in brief

n LATEST AHA/ASA STROKE GUIDELINE REPRESENTS “PARADIGM SHIFT”: Following updates to the American Heart Association (AHA)/American Stroke Association (ASA)’s secondary prevention of stroke guideline—which placed increased emphasis on identifying the cause of a stroke or transient ischaemic attack (TIA) to inform prevention strategies for additional strokes—Dawn O Kleindorfer discusses more holistic approaches, and other key features of the update, with NeuroNews.

For more on this story visit page 5. n FLOW DIVERTER STUDY WITH VIRTUAL PARTICIPANTS SEES SIMILAR RESULTS TO TRADITIONAL TRIALS: A study involving virtual participants—rather than real patients—was “as effective as traditional clinical trials” in evaluating the treatment of brain aneurysms using a flow diverter, according to new research published in Nature Communications, and has been described as a proof of concept for in-silico trials.

For more on this story visit page 10. n RTMS IS “WELL-ACCEPTED” FOR THERAPEUTIC USE IN PSYCHIATRIC POPULATIONS: A systematic review published in Neuromodulation: Technology at the Neural Interface by Georgia Stillianesis and colleagues found that psychiatric populations perceive the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) for mental health conditions to be beneficial, safe, and no more dangerous than conventional therapy options, with participants showing low levels of fear and a willingness to recommend the intervention to others.

For more on this story go to page 22.

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July 2021 | Issue 42

Basilar artery occlusion

Benefits of EVT for basilar artery occlusion “cannot be excluded” following another inconclusive study Continued from page 1

treatment group to receive standard medical therapy alone. Crossover from one treatment group to the other occurred in three of 154 patients assigned to the endovascular group (1.9%) and seven of 146 patients assigned to the medical treatment group (4.8%). No patients had been lost to follow-up at 90 days.

Schonewille and colleagues report that, in the intention-to-treat analysis, 68 of 154 patients (44.2%) in the endovascular group had a favourable functional outcome, compared to 55 of 146 patients (37.7%) in the medical treatment group. Regarding secondary outcomes, a total of 54 patients (35.1%) in the endovascular group and 44 patients (30.1%) in the medical treatment group demonstrated an excellent modified Rankin scale score.

Patency of the basilar artery at 24 hours, assessed by means of computed tomography angiography (CTA), was 84.5% in the endovascular group and 56.3% in the medical group—although Schonewille stated that, “as the trial did not show a significant benefit of EVT over best medical therapy, this higher patency rate is not clinically significant”, adding that this finding simply suggests “EVT more often leads to futile recanalisation”.

Subgroup analysis also indicated median NIHSS scores at 24 hours of 11 and 15 in the endovascular and medical treatment groups, respectively.

In terms of the trial’s safety endpoints, mortality at 90 days was 38.3% in the endovascular group and 43.2% in the medical treatment group, and the risk of

symptomatic intracranial haemorrhage within three days after the initiation of treatment was 4.5% in the endovascular group and 0.7% in the medical care group.

Schonewille et al also note that malignant brain oedema occurred in 17 patients (11%) in the EVT group and in seven patients (4.8%) in the medical treatment group.

Despite there being “no statistically significant difference” in primary outcomes between the two groups assessed in the trial, the authors conclude that the upper limit of the 95% confidence interval in the risk ratio of 1.50 “cannot exclude the possibility” of benefit from EVT. “The trial therefore did not show an advantage of EVT over medical therapy, but these findings may be inconclusive” they add. “These results may inform the design of future trials in this field, for which recruitment and implementation have been difficult.” In their report, Schonewille and colleagues also allude to the ongoing BAOCHE (Basilar artery occlusion Chinese endovascular) trial, which is assessing the efficacy of EVT more than six hours after symptom onset in patients with basilar artery occlusion, stating that it “may inform the results of the

The BASICS registry and trial both suggest that patients with a minor deficit do better with IV thrombolysis alone while, in clinical practice, treating physicians still feel uncomfortable withholding EVT.”

current [BASICS] trial” as well.

Speaking to NeuroNews, Schonewille said: “Besides the time window, the main difference between the BAOCHE and BASICS trials is that, in BASICS, 80% of patients in both treatment arms were treated with IV thrombolysis, while patients in BAOCHE are either ineligible for IV thrombolysis or have received IV thrombolysis alteplase therapy without recanalisation.

This trial will therefore not be able to show if EVT is superior to IV thrombolysis beyond six hours after symptom onset—but, a positive result, showing efficacy of EVT, should lead to a new trial testing the efficacy of EVT versus IV thrombolysis in the late time window.”

Regarding further research directions, Schonewille also proposed that future studies “should focus on improving patient selection and treatment approaches”, adding that large, multicentre international registries ought to look for imaging profiles that could identify patients with a minor deficit, at a heightened risk of subsequent deterioration, and those with a severe deficit and a fair chance of a favourable outcome, as these patients are more likely to benefit from endovascular therapy.

“Patients with basilar artery occlusion may benefit from IV thrombolysis, EVT, or both,” Schonewille stated. “The main benefit of IV thrombolysis is that it is easy to use and available in all primary stroke hospitals, with a low complication rate. Unless contraindicated, patients with basilar artery occlusion should therefore be treated with IV thrombolysis. There is no doubt that EVT leads to higher recanalisation rates, but with a higher risk of haemorrhagic complications and the potential risk of occluding perforating arteries with mechanical manipulation of the clot. EVT should be reserved for patients with a low likelihood of a favourable outcome without EVT—whereby EVT is worth the risk. Hopefully, future research will help us to identify these patients.”

CX DEBATE

Thrombolysis versus thrombectomy: Parity indicated between basilar occlusion treatments Thrombolysis is considered as effective as mechanical thrombectomy for the treatment of basilar artery occlusion (BAO)—despite existing evidence on both intervention options being limited. This is according to an audience poll conducted during the final day of the Charing Cross (CX) 2021 Digital Edition (19–22 April, online).

A DEBATE ENTITLED “Thrombolysis is as effective as thrombectomy for basilar thrombosis” saw Wouter J Schonewille (St Antonius Hospital, Nieuwegein, The Netherlands) argue in favour of the motion, while Shelley Renowden (North Bristol NHS Trust, Bristol, UK) argued against. the motion.

Despite Renowden’s assertions that the degree and speed of recanalisation for BAO is “undoubtedly superior” with mechanical thrombectomy— particularly when using newer thrombectomy devices—the majority of the CX audience (58%) ultimately sided with Schonewille, following his suggestion that intravenous (IV) thrombolysis is more appropriate in treating the majority of BAO patients, and thrombectomy should be reserved only for certain, more severe cases.

Schonewille kicked off the debate by claiming that, while numerous clinical trials have demonstrated the efficacy of endovascular thrombectomy (EVT) in treating acute ischaemic stroke patients with large vessel occlusion, most of these trials have excluded BAO patients, meaning the results “cannot be extrapolated to these patients”. He also referenced the BASICS (Basilar artery international cooperation study) trial—which involved using EVT combined with best medical management (BMM) versus BMM alone, and found “no significant difference” in outcomes between the two treatment arms.

Schonewille stated that IV thrombolysis was found to be the best treatment option in patients with lower scores (<10) on the National Institutes of Health Stroke Scale (NIHSS), and concluded his presentation by adding that patients with BAO should be treated with IV thrombolysis, while EVT should

Pictured clockwise from top left: Sophie Renton (London, UK), Barbara Rantner (Munich, Germany), Hugh Markus (Cambridge, UK), Shelley Renowden (Bristol, UK) and Wouter J Schonewille (Nieuwegein, The Netherlands)

be limited to certain patients with a moderate or severe NIHSS score (≥10).

Renowden countered these points by arguing that, despite the problems some trials, including BASICS, have experienced with recruitment, “there is enough information to conclude that thrombectomy and the standard medical treatment is more effective than the standard medical treatment alone for BAO—for those with an NIHSS score of 10 or higher within 6–8 hours of stroke onset”. In addition, Renowden also referenced the BEST (Endovascular treatment versus standard medical treatment for vertebrobasilar artery occlusion) trial, and data from the BASILAR (Endovascular treatment for acute basilar artery occlusion) study,

in which she claimed the outcomes for BAO patients who received EVT were “significantly better” than those seen in patients who did not receive EVT. And, when questioned by Hugh Markus (University of Cambridge, Cambridge, UK)—one of the session’s moderators—about which BAO patients she would deem suitable for thrombectomy, Renowden said it is important to consider various factors relating to the individual patient, including their age, NIHSS and Glasgow Coma Scale (GCS) scores, and ultimately what chance they have of achieving a “good, independent outcome”. However, despite these suggestions, Renowden’s argument only garnered 42% of the CX audience’s vote.

Issue 42 | July 2021

Stroke prevention

Behavioural interventions and more holistic approach signal “paradigm shift” in latest AHA/ASA stroke guideline In May, the American Heart Association (AHA)/American Stroke Association (ASA) updated one of its flagship guidelines—the secondary prevention of stroke guideline—for the first time since 2014, with the key takeaway being an emphasis on identifying the cause of a stroke or transient ischaemic attack (TIA) to inform specific prevention strategies for reducing the risk of additional strokes. Dawn O Kleindorfer, chair of the guideline writing group, and professor and chair of the Department of Neurology at the University of Michigan School of Medicine (Ann Arbor, USA), spoke to NeuroNews to discuss this “critically important” strategy in stroke prevention, as well as an increased focus on thinking about “the whole person” when treating stroke.

H

aving a stroke or TIA increases the risk of having a stroke in the future—this is something that is widely accepted by the stroke community. However, new and more granular data on this phenomenon are emerging all the time. As such, the AHA/ ASA saw fit to introduce the “2021 guideline for the prevention of stroke in patients with stroke and transient ischaemic attack” this year, publishing it in the journal Stroke. One of the most important new recommendations in this guideline is for clinicians to perform diagnostic evaluations on patients to determine the cause of their first stroke or

TIA within 48 hours of symptom onset.

“We are recommending that this diagnostic workup is done early, and the reason for that is because there are a few causes of stroke that have a high risk immediately after the event,” Kleindorfer said. She cited the fact that patients who have even a mild TIA due to a blocked artery in the neck, for example, may have an elevated risk of a far more severe stroke that can cause permanent damage within the following week—but this risk can be addressed if the blocked artery is detected early on. “My hope is that this will help change the care approach, and help people recognise that the diagnostic

For patients who have survived a stroke or TIA, the secondary prevention guidelines recommend: ● Managing their vascular risk factors, especially high blood pressure, as well as Type 2 diabetes, cholesterol, and not smoking. ● Limiting salt intake and/or following a Mediterranean diet—typically with emphasis on monounsaturated fat, plant-based foods, and fish consumption, with either high extra virgin olive oil or nut supplementation. ● If they are capable of physical activity, engaging in moderate-intensity aerobic activity for at least 10 minutes, four times per week, or vigorousintensity aerobic activity for at least 20 minutes, twice per week.

For healthcare professionals, the updated treatment recommendations highlighted in the guideline include: ● Using multidisciplinary care teams to personalise care for patients, and employing shared decision-making with the patient to develop care plans that incorporate a patient’s wishes, goals and concerns. ● Screening for and diagnosing atrial fibrillation, and starting bloodthinning medications to reduce recurrent events if needed. ● Prescribing antithrombotic therapy, including antiplatelet medications, or anticoagulant medications to prevent blood clotting, for nearly all patients who do not have contraindications. ● Carotid endarterectomy, surgical removal of a blockage or, in select cases, the use of a stent in the carotid artery, should be considered for patients with narrowing arteries in the neck. ● Aggressive medical management of risk factors and short-term dual antiplatelet therapy are preferred for patients with severe intracranial stenosis thought to have caused a stroke or TIA. ● In some patients, it is now reasonable to consider percutaneously closing a patent foramen ovale via a less invasive, catheter-based surgical procedure.

workup really is something that is urgent and needs to be done, so that we can then direct the right treatments to prevent the next event from happening.”

Prevention based on cause

The structure of the guideline’s latest form differs from the previous document, with “pages and pages of text” giving way to more manageable “knowledge chunks”, as well as tables and algorithms to help clinicians “find the topic or disease that [they] are really interested in”. This “user-friendly” format begins by outlining the different causes of a stroke or TIA under different sections, before moving on to various treatment recommendations based on this.

Kleindorfer hopes the updated structure “will make it easier for the busy clinician to be able to scan and find what they need within the document for the particular patient they are seeing that day”.

However, this restructuring is driven by more than just convenience. As the AHA/ASA outlined in a press release, “many risk factors for a second stroke remain poorly managed among stroke survivors” and, as such, the new guideline emphasises the need for clinicians to investigate the cause of a stroke or TIA—whether it is blockages in the large arteries in the neck or brain, small arteries in the brain being damaged from high blood pressure or diabetes, irregular heart rhythms, or something else—when deciding how to treat a given patient. “We recommend that—if you come into the hospital—somebody should look at your heart, the arteries in your neck, bloodwork, and other diagnostic tests as needed,” Kleindorfer added. “Those things were never really laid out specifically before.”

A more holistic approach

As well as this reshuffling of priorities in recurrent stroke management, the concept of behavioural interventions now features more prominently in the guideline too.

“One of our top 10 messages—which was actually slightly controversial when we first introduced it—was that, if you want to change people’s behaviour, handing them a brochure is not enough,” Kleindorfer said. “I think educating our patients is really important, but just handing them a pamphlet and nothing else is not going to work. That is something of a paradigm shift, because a lot of doctors want to talk about the benefits of aspirin versus clopidogrel, versus anticoagulation, and my first question is always: do you know that they are taking it? And, do you know that they can afford it? These kinds of questions are much more important than whether the patient should be on 50mg or 81mg of aspirin.”

“We are really asking people to consider the whole person, and to think about ways to prevent stroke beyond just the latest technology and the dosing of medications,” she added.

Compliance, social determinants of health, and the patient’s overall motivations and understanding of their own disease, were all factors highlighted by Kleindorfer here. She

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went on to state that an infrastructure setup within existing health systems— including social workers, psychologists and physical therapists—is what will be required in order to truly influence patient behaviour. “The doctor can start the process, but it really needs to be followed up with a system to support the patient, and their family, so that they understand what the patient is going through as well,” Kleindorfer noted.

The importance of up-to-date guidelines

Kleindorfer described updates like this as “critical”, also asserting that “an outdated guideline is no use—in fact, it can be harmful”. “These big topic-type guidelines like secondary prevention of stroke […] are what we call the flagship guidelines, and they need to be reviewed and revised every few years,” she added.

While Kleindorfer said the secondary stroke guideline has typically been updated every five years in the past, a handful of advisory statements put out between 2014 and this year meant the guideline was still able to keep pace with the most important pieces of research and new information throughout this period.

Regarding what may be subject to change over the course of the coming five-year timeframe—prior to the next potential guideline update—Kleindorfer stated that several currently ongoing studies are likely to have been completed by then, including research into stenosis in the neck and managing carotid artery narrowing, as well as those looking at cryptogenic strokes—in light of recent evidence that anticoagulation may not be the best way to treat these patients.

We are really asking people to consider the whole person, and to think about ways to prevent stroke beyond just the latest technology and the dosing of medications.”

Dawn O Kleindorfer

Dawn O Kleindorfer

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Issue 42 | July 2021

Diagnostic imaging

Researchers propose optimisation of duplex velocity criteria for diagnosing ICA stenosis Writing in an online Vascular Medicine article, researchers from the Intersocietal Accreditation Commission (IAC) Vascular Testing division report findings from a multicentre study of duplex ultrasound for diagnosis of internal carotid artery (ICA) stenosis.

THE STUDY WAS DEVELOPED IN RESPONSE to wide variability in the diagnostic criteria used to classify severity of ICA stenosis across vascular laboratories nationwide and following a survey of members of IAC-accredited facilities supporting efforts toward standardisation. The primary objective of the study was to evaluate the widely-used SRU Consensus Criteria (SRUCC) and, if needed, to propose further optimisation to these criteria.

Researchers found that carotid duplex interpretation using SRUCC produced significant overestimation of stenosis for both moderate (50–69%) and severe (>70%) ICA lesions as determined by catheter angiography.

The authors conclude that laboratories currently using

SRUCC should consider modification of existing criteria to incorporate more stringent and accurate parameters for ICA stenosis greater than 50% by increasing the peak systolic velocity (PSV) threshold to >180cm/sec or requiring the ICA/CCA PSV ratio >2 in addition to PSV of >125cm/sec.

“This study reflects more than six years of work of a team of IAC staff and multispecialty volunteers with case study materials collected from 11 centres [in the USA]. While the SRUCC are broadly used, they had never been formally compared to the gold standard of catheter angiography. We have shown that use of SRUCC overestimated degree of ICA stenosis and identify potential opportunities for modifications that can ultimately enable greater accuracy and consistency in ICA interpretation across vascular laboratories,” said lead investigator, Heather L Gornik (University Hospitals Harrington Heart and Vascular Institute, Cleveland, USA), IAC Vascular Testing immediate pastpresident.

“Through its use of real-world data from IACaccredited vascular laboratories, this paper highlights

Through its use of real-world data from IAC-accredited vascular laboratories, this paper highlights the opportunity to improve the quality of care for patients with carotid disease.”

the opportunity to improve the quality of care for patients with carotid disease,” said Tatjana Rundek (University of Miami Miller School of Medicine, Miami, USA), IAC Vascular Testing president. “By modifying existing criteria to incorporate more accurate parameters and implementing these criteria broadly, the accuracy of diagnostic ultrasound testing can be improved across our vascular community.”

As a next step, IAC Vascular Testing will disseminate a white paper document summarising the study results and providing guidance to vascular laboratories for implementation of criteria and further steps toward standardisation across the vascular testing community.

Heather L Gornik

Tatjana Rundek

Case report indicates 3D black blood vessel wall imaging can predict reperfusion therapy outcomes for DVO The early findings from a case report have highlighted the potential held by 3D black blood vessel wall post-contrast imaging to predict the outcomes of reperfusion therapy for distal vessel occlusion (DVO)—although the report’s authors also state that a larger study will now be required to verify these findings.

THE REPORT IS PUBLISHED in the Journal of Cardiovascular, Neurovascular and Stroke by Mohd Fandi Al Khafiz Kamis (University Putra Malaysia [UPM] Teaching Hospital, Selangor, Malaysia) and UPM Department of Radiology colleagues.

In discussing these early findings, Kamis et al write: “Detection of intraarterial thrombus in DVO is becoming increasingly important in acute stroke imaging. The evolution of medical devices for mechanical thrombectomy has allowed the smaller distal vessels to be treated via an endovascular approach. It is also useful to reassess vascular patency after the administration of thrombolysis agents. Large vessel occlusion [LVO] is undisputedly a

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known cause for disability in acute stroke, but DVO in an eloquent area of a specific branch can potentially lead to a significant neurological deficit.

“Advances in magnetic resonance imaging [MRI] allow detection of intra-arterial thrombus via 3D black blood vessel wall imaging. Our case demonstrates reperfusion of the affected vessel at five days after thrombolysis—evidenced by resolution of the previously noted peri-thrombus vascular hyperintensity sign [PVHS] and intraluminal enhancement. Restoration of arterial flow suppression on 3D black blood imaging supports these findings.”

According to the report, direct visualisation of intra-arterial thrombus in acute ischaemic stroke is widely

assessed, in LVO, through a hyperdense the stroke, secondary to undiagnosed middle cerebral artery (MCA) sign on a AF. A time-of-flight magnetic resonance computed tomography (CT) scan, or via angiography (MRA) also revealed an a blooming artifact on a gradient echo absent flow signal in the affected cortical MRI sequence. And, while the sensitivity artery. The report details how a 3D of these signs is not as reliable in smaller black blood post-contrast MRI showed DVO, the emergence of 3D black blood interface between PVHS and intraluminal contrast-enhanced MRI enables clinicians enhancement of the affected cortical to visualise the distal vessel wall and branch of the left MCA. intraluminal features, and subsequently Thrombolysis with 0.9mg of alteplase narrow down the differential cause of per kilogram total of bolus, and oneischaemia and possible biomarkers to hour infusion, was then conducted in monitor reperfusion therapy responses. the patient. The report details that their The case reported by Kamis et immediate, post-thrombolysis NIHSS al involved a 37-year-old male score was static, but that an smoker who had developed improvement in this score, dysarthria and receptive from six to two, was noted aphasia. The patient’s eight hours after the procedure. premorbid modified Rankin Dual antiplatelet therapy was Score (mRS) was zero, with started on day five from the no known underlying diseases. patient’s symptom onset and, Their National Institutes of prior to discharge, their NIHSS Mohd Fandi Al Health Stroke Scale (NIHSS) score further improved to Khafiz Kamis score was six, with language one. Repeated 3D black blood and speech the most affected MRI five days after the acute components. An electrocardiogram also event also showed a luminal patency revealed atrial fibrillation (AF). in the affected cortical vessel that was An MRI scan performed within two “indicative of a good response towards hours of symptom onset in the patient reperfusion therapy”. showed restricted diffusion at the left In conclusion, Kamis et al state parietal lobe and diffusion-weighted that the vessel wall imaging features imaging with mismatch on fluid observed here, followed by a “vast attenuation inversion recovery (FLAIR). clinical improvement” after thrombolysis, Cortical enhancement was also noted at highlight the potential of 3D black blood the MCA-PCA (posterior cerebral artery) post-contrast imaging to predict the watershed region, which the report states outcome of reperfusion therapy for DVO, was suggestive of subacute infarct— but that a larger study “is needed to explaining the cardioembolic origin of verify these early findings”.

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July 2021 | Issue 42

Carotid stenting

CAROTID

TCAR associated with “promising early and late outcomes”, pooled data suggest A systematic review and meta-analysis has found that transcarotid artery revascularisation (TCAR) is associated with “promising early and late outcomes” in patients with internal carotid artery stenosis, although symptomatic patients still carry a higher risk of early cerebrovascular events. This is the conclusion of George C Galyfos (Hippocration Hospital, Athens, Greece) and colleagues, whose work was published as an Editor’s Choice paper in the European Journal of Vascular and Endovascular Surgery (EJVES).

THE AUTHORS STATE THAT EITHER CAROTID endarterectomy (CEA) or transfemoral carotid stenting (tfCAS) are usually recommended for the treatment of significant carotid stenosis. However, they note that both techniques have certain limitations. “Open surgery is associated with higher surgical stress, and could be the cause of the higher cardiac risk compared with stenting,” they elaborate, while tfCAS, on the other hand, carries the risk of intraoperative embolisation and chronic renal insufficiency, among others. “[TCAR] offers an alternative strategy in patients where CEA or transfemoral stenting face difficulties,” Galyfos et al write. This review aimed to evaluate pooled data on patients undergoing TCAR and—in contrast to other similar reviews— evaluates both early and late outcomes as well as the effect of preoperative symptoms on early stroke/transient ischaemic attack (TIA), the authors detail.

The investigators searched the Medline, Embase, Scopus, and Cochrane Library databases for eligible studies. For a study to be included in the review, it

had to have been published online by September 2020 and to have reported 30-day mortality and stroke/TIA rates in patients undergoing TCAR. Data were pooled in a random effects model and the weight of effect for each study was also reported.

Writing in EJVES, the authors relay that they included eighteen studies in their analysis, comprising a total of 4,852 patients or 4,867 procedures. In terms of the quality of the included studies, the research team specify that eight were of a high standard, with seven meeting the criteria for a medium-quality study, and the remaining three a low-quality study.

Galyfos and colleagues report that the pooled 30-day mortality rate was 0.7% (n=32; 95% confidence interval [CI], 0.5–1), the 30-day stroke rate 1.4% (n=62; 95% CI, 1–1.7), and the 30-day stroke/TIA rate 2% (n=92; 95% CI, 1.4–2.7). They add that pooled technical success was 97.6% (95% CI, 95.9–98.8).

In terms of other outcomes, the investigators communicate that the cranial nerve injury rate was 1.2% (n=14; 95% CI, 0.7–1.9) while the early myocardial infarction rate was 0.4% (n=16; 95% CI, 0.2–0.6). The haematoma/bleeding rate was 3.4% (n=135; 95% CI, 1.7–5.8), they convey, noting that one-third of these cases needing drainage or intervention. They also reveal that, within a follow-up of three to 40 months, the restenosis rate was 4% (n=64/530; 95% CI, 0.1–13.1) and death/stroke rate 4.5% (n=184/3,742; 95% CI, 1.8–8.4).

Considering symptomatic patients specifically, Galyfos et al found that this subgroup had a higher risk of early stroke/TIA than asymptomatic patients (2.5% vs. 1.2%; odds ratio, 1.99; 95% CI, 1.01–3.92); p=0.046).

The authors acknowledge some limitations of this review, including the retrospective nature of the majority of included studies—despite most being of medium to high quality—almost three-quarters of the patients originating from the Vascular Quality Initiative (VQI), and there being insufficient data to conduct certain subgroup analyses, such as for diabetic patients.

Galyfos and colleagues conclude that TCAR is a “promising method” for treating internal carotid artery disease as it is associated with a low rate of early death, stroke, and other complications. However, they stress that symptomatic patients have a higher risk of early cerebrovascular events when this technique is used.

In closing, the authors consider the direction of future research: “Prospectively-designed studies comparing outcomes between TCAR and CEA in symptomatic patients are needed to further evaluate the benefit of this technique”.

Issue 42 | July 2021

Carotid stenting

Treatment of asymptomatic carotid bifurcation occlusive disease and the potential role of stent placement Peter A Schneider Comment & Analysis Peter A Schneider (San Francisco, USA) discusses the role stenting can play, alongside the existing best medical therapy, in treating asymptomatic carotid disease patients.

B

est medical therapy (BMT) is mandatory in all patients with carotid occlusive disease. In addition, asymptomatic patients with a carotid stenosis greater than 80% and a reasonable long-term life expectancy should be considered for carotid bifurcation repair.

There is current conventional wisdom frequently being repeated suggesting that medical management of atherosclerotic occlusive disease has improved so much that repair of carotid bifurcation disease is no longer necessary. BMT has improved.

However, it has not been evaluated as the sole treatment for patients with the severity of carotid occlusive disease that we would currently consider for repair.

Here are some features of the evolution of carotid disease management: Medical management has improved— but we do not know how much.

Repeating frequently that BMT alone is adequate treatment for >80% asymptomatic stenosis does not make it so.

No matter how effective medical management becomes, we will continue to face issues of compliance, side-effects and complications that prevent the reality of BMT in a substantial percentage of the patients.

We can identify factors that put patients at increased risk for neurologic events from asymptomatic carotid bifurcation occlusive disease, including plaque progression, large plaque volume, intraplaque haemorrhage, silent cerebral infarcts, embolisation on transcranial Doppler, and other factors. These findings are associated with a 5–14% annual stroke risk.1–9 Almost all the data we have evaluating the efficacy of medical management of carotid bifurcation plaque comes from patients with mild-to-moderate lesions, which would not currently be considered for repair. This is true of several

marquee studies that are routinely used to support a “medical management alone” advocacy (e.g. SMART, Oxford Vascular, ASED).

In the few studies that have evaluated the results of medical management of significant carotid plaques—those which we would currently consider for repair— the finding was in favour of repair plus best medical management.10, 11 One of the best examples is the Oxford Vascular study.

This has been held for years as “evidence” that repair is not of value in addition to BMT. The study has a preponderance of patients with moderate

There are

9,435 patients in the VQI database

periprocedural medical management and new technology. The periprocedural stroke and death risk for carotid endarterectomy (CEA) in asymptomatic patients in CREST was 1.4% and in ACT I was 1.7%.13, 14 Some of this improvement may be due to improved periprocedural medical management with antiplatelet agents and statins.

In addition, patients that qualify for repair, but who may have unfavourable anatomic characteristics for CEA, may be treated with transcarotid artery revascularisation (TCAR), which appears to be just as safe as CEA. Carotid stenting can now be performed using TCAR, which includes direct sheath access to the common carotid artery with proximal clamping and carotid flow reversal.

The combination of avoiding the aortic arch, initiating cerebral protection prior to crossing the lesion, and instituting flow reversal to prevent particulates from reaching the brain, has provided outstanding results for carotid stent placement using TCAR. Periprocedural stroke and death rates in the Roadster trials were 1.3% in Roadster 1 and 0.9% in Roadster 2.15, 16 Among 9,435 patients analysed from the Vascular Quality Initiative (VQI) database, stroke or death occurred after CEA in 1.3% and after TCAR in 1.4% (p=0.49).17 Since TCAR is a relatively new procedure, there is the likelihood for continued improvement in results as various patient selection and technical aspects are refined.

TCAR has provided a less invasive alternative to CEA that appears to

1.3%

Stroke/death occurred in 1.3% after CEA

1.4%

Stroke/death occurred in 1.4% after TCAR

carotid stenosis and the threshold for study entry was a peak systolic velocity of 150cm/seconds—a threshold that would be too low to ever be considered for repair in an asymptomatic patient.

When the smaller cohort of patients with >80% carotid stenosis were evaluated, the rate of neurologic events on BMT was >20% at one year and nearly 30% at two years.12 The results of carotid bifurcation repair have also improved, probably due to a combination of improved

provide similar very low stroke and death rates, with a lower risk of myocardial infarction and a dramatically lower risk of cranial nerve injury. There are currently more than 20,000 TCAR cases in the VQI database sponsored by the Society for Vascular Surgery (SVS).

As these are being analysed, we can see that excellent results can be achieved early in one’s experience, and that adding TCAR to a programme provides a net benefit with the availability of an additional option for repair. Currently, in

9

the USA, asymptomatic carotid stenosis patients with >80% stenosis who have a minimum of a three-to-five-year life expectancy and a factor placing them at high risk for CEA can be eligible for TCAR. The idea that low annual stroke risks with BMT can be inferred by evaluating patients with mild or moderate carotid occlusive disease—which we would not currently consider for carotid bifurcation repair—does not make any sense. In addition, repair of asymptomatic carotid disease in addition to BMT in wellselected patients can be performed with either CEA or TCAR with very low rates of stroke or death.

References: 1. Kakkos SK, Sabetai M, Tegos T, et al. Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis. J Vasc Surg 2009;49(4): 902–9.

2. Spence JD, Tamayo A, Lownie SP, et al. Absence of microemboli on transcranial Doppler identifies low-risk patients with asymptomatic carotid stenosis. Stroke 2005;36(11): 2373–8.

3. Topakian R, King A, Kwon SU, et al. Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis. Neurology 2011;77(8): 751–8.

4. Conrad MF, Boulom V, Mukhopadhyay S, et al.

Progression of asymptomatic carotid stenosis despite optimal medical therapy. J Vasc Surg 2013;58(1): 128–35.

5. Shah Z, Masoomi R, Thapa R, et al. Optimal medical management reduces risk of disease progression and ischemic events in asymptomatic carotid stenosis patients: a long-term follow-up study. Cerebrovasc Dis 2017;44(3–4): 150–9.

6. Kakkos SK, Griffin MB, Nicolaides AN, et al. The size of juxtaluminal hypoechoic area in ultrasound images of asymptomatic carotid plaques predicts the occurrence of stroke. J Vasc Surg 2013;57(3): 609–18.

7. Naylor AR, Schroeder TV, Sillesen H, et al. Clinical and imaging features associated with an increased risk of late stroke in patients with asymptomatic carotid disease. Eur J Vasc Endovasc Surg 2014;48(6): 633–40.

8. Hellings WE, Peeters W, Moll FL, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study.

Circulation 2010;121(17): 1941–50.

9. Garoff M, Ahlqvist J, Edin LT, et al. Bilateral vesseloutlining carotid artery calcifications in panoramic radiographs: an independent risk marker for vascular events. BMC Cardiovasc Disord 2019;19: 225.

10. Conrad MF, Michalczyk MJ, Opalacz A, et al. The natural history of asymptomatic severe carotid artery stenosis. J Vasc Surg 2014;60(5): 1218–26.

11. Kolos I, Troitskiy A, Balakhonova T, et al. Modern medical treatment with or without carotid endarterectomy for severe asymptomatic carotid atherosclerosis. J Vasc Surg 2015;62: 914–22.

12. Howard DPJ, Gaziano L, Rothwell PM, et al. Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Lancet 2021;20(3): 193–202.

13. Silver FL, Mackey A, Clark WM, et al. Safety of stenting and endarterectomy by symptomatic status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke 2011;42(3): 675–80.

14. Rosenfield K, Matsumura JS, Chaturvedi S, et al. Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis. N Engl J Med 2016;374: 1011–20.

15. Kwolek CJ, Jaff MR, Leal JI, et al. Results of the ROADSTER multicenter trial of transcarotid stenting with dynamic flow reversal. J Vasc Surg 2015;62: 1227–35.

16. Kashyap VS, Schneider PA, Foteh M, et al. Early Outcomes in the ROADSTER 2 Study of Transcarotid Artery Revascularization in Patients With Significant Carotid Artery Disease. Stroke 2020;51(9): 2620–9.

17. Malas MB, Dakour-Aridi H, Kashyap VS, et al.

TransCarotid Revascularization with Dynamic Flow reversal versus Carotid Endarterectomy in the Vascular Quality Initiative Surveillance Project. Ann Vasc Surg 2020.

Peter A Schneider is a professor of surgery in the Division of Vascular and Endovascular Surgery at the University of California San Francisco in San Francisco, USA. Disclosures: The author discloses that they are a consultant for Silk Road Medical, Boston Scientific, and Medtronic.

July 2021 | Issue 42

10 The virtual era

Livestreamed procedures close distance between clinicians and trainees during pandemic

Philipp Taussky Comment & Analysis Philipp Taussky (Salt Lake City, USA) outlines a simple yet effective livestreaming platform that he believes holds benefits for neurosurgeons during the ongoing COVID-19 crisis, and beyond.

O

ne of the challenges faced by the medical community during the COVID-19 pandemic has been how to continue training students, physicians, and medical device representatives, despite restrictions on travel and hospital capacity.

Those precautions have significantly affected our ability to teach by diminishing opportunities for inperson observation in operating rooms.

Fortunately, an emerging strategy is poised to improve the accessibility of procedural education, both during the pandemic and after it has abated.

Using a simple and effective livestreaming platform, our team at the

University of Utah has exponentially expanded its educational reach. Having had no previous strategy for reliably broadcasting cases, we have been amazed to watch this technology close the distance between our clinicians and their trainees, allowing them to collaborate efficiently in real time, regardless of where they are in the world.

With the click of a button that connects the procedure room to the tablets or laptops of viewers, the pioneering platform by Avail Medsystems has also enabled another instructional breakthrough: our ability, for the first time ever, to broadcast emergent procedures at a moment’s notice.

Flow diverter study with virtual participants “as effective as traditional clinical trials” A study involving virtual participants— rather than real patients—was “as effective as traditional clinical trials” in evaluating the treatment of brain aneurysms using a flow diverter, according to new research.

These findings, which are published in the journal Nature Communications, have been described as a proof of concept for “in-silico trials” where, instead of recruiting people to a real-life clinical trial, researchers build digital simulations of patient groups.

IN-SILICO TRIALS MAY “REVOLUTIONISE the way clinical trials are conducted”, a University of Leeds press release states, by decreasing the time and costs of getting new medical devices and medicines developed, while also reducing human and animal harm in testing.

The virtual patient populations are developed from clinical databases to reflect age, sex and ethnicity, but they also simulate the way disease affects the human body—for example, the interactions between anatomy, physics, physiology, and blood biochemistry—before those simulations are then used to model the impact of therapies and interventions.

In its most obvious application, this compact, high-tech mobile workstation allows us to broadcast live from our operating room or angio suite to medical students, residents, fellows, physicians, sales representatives, and device engineers. Conversely, the platform can support physicians who want a more experienced colleague “looking over their shoulder” as they conduct a procedure— without having to fly in an expert.

Our team has found the technology especially helpful in swiftly and effectively teaching field representatives from Medtronic and other medical device companies how the tools they provide are used in practice. While observing procedures, the representatives learn about anatomy, equipment, and procedure-room setup, becoming better prepared to develop new devices and support physicians in their use.

But perhaps the platform’s most transformative implementation has been the livestreaming of stroke treatments.

Through the use of novel devices, stroke thrombectomy has become one of modern medicine’s greatest advancements, yet many in the field have never seen one performed. Until recently, inviting them to observe the procedure was nearly impossible, as these cases are emergent, and time is of the essence.

Today, we can effortlessly loop them in through the Avail system.

The simple-to-use, subscriptionbased platform includes high-definition cameras, a screen, and plug-ins for imaging sources, offering views of the

This international research, led by the University of Leeds, investigated whether an in-silico trial could replicate the results of three real-life clinical trials that assessed the effectiveness of a flow diverter device, which is used to treat brain aneurysms by redirecting blood and reducing flow into the aneurysm.

Participants in the virtual trial

They built a virtual population using real patient data drawn from clinical databases, ensuring that the anonymised virtual patients closely resembled the patients used in real flow diverter clinical trials in terms of age, sex and aneurysm characteristics.

The researchers then built a computational model that analysed how the implanted device would affect blood flow in each of the virtual patients. They were able to study different physiological conditions for each patient, such as normal and high blood pressure, and perform analyses on patient subgroups too. The in-silico trial had 82 virtual patients, while the selected traditional clinical trials—PUFS, PREMIER and ASPIRe—featured 109, 141 and 207 patients, respectively. About half of the patients across the three traditional trials had high blood pressure.

The results of the in-silico trial predicted that 82.9% of the virtual patients with normal blood pressure would be successfully treated with a flow diverter. In the traditional clinical trials, the number of people who were successfully treated was 86.8%, 74.8% and 76.8%, respectively, indicating that the in-silico trial replicated the traditional clinical trials’ results.

In-silico trials hold “huge potential”

Alex Frangi, Diamond Jubilee chair in Computational Medicine and Royal Academy of Engineering chair in Emerging Technologies at the University of Leeds (Leeds, UK), who supervised the study, said: “The results demonstrate the huge potential of in-silico trials.

surgical field, the physician’s hands, the inside of the patient’s body, the team members conducting the procedure, and the back table holding surgical equipment. Users can remotely control the angle and zoom function of the cameras while monitoring imaging, such as intravascular ultrasound (IVUS), fluoroscopy or biplane fluoroscopy. Audience members can even communicate in real time with the broadcasting practitioner via two-way audio and an annotation system.

When I conduct procedures using this system, I feel as if learners are with me in the room. The important difference is how many of them can attend. Once they are connected, participants can use apps like Zoom or Microsoft Teams to share the livestream with hundreds of others—a capability we find extremely exciting.

We also appreciate the fact that viewers can be engaged in other activities until the moment they tune in, whether in their homes, at work, or even, in one recent case, at a ski lodge. That flexibility, coupled with the ability to far surpass the limits on in-person procedure-room attendance, means that Avail’s technology will remain a valuable teaching tool long after pandemic restrictions have ended.

Philipp Taussky is a neurointerventional surgeon, and section chief and chief value officer of the Department of Neurosurgery at University of Utah Health in Salt Lake City, USA. The author has no disclosures.

We have shown that the approach can replicate the findings of traditional clinical trials—and they do that in a fraction of the time it normally takes, and at a fraction of the cost.”

In the in-silico trial, the researchers were also able to adapt their model to investigate new hunches or emerging scientific findings. And, by modelling the physics of blood flow and the biochemistry of blood clotting in aneurysms under different physiological conditions, they were able to identify patient subgroups at higher risk of different types of stroke. Being able to analyse medical device performance in this way could allow biomedical engineers to optimise device design and reduce the risks associated with treatment.

“In-silico trials offer an opportunity to do virtual experiments that could explain concepts that are difficult to study in conventional clinical trials,” Frangi added.

“The current approach to improve our understanding of new medical devices is slow, as conventional trials can easily take five-to-eight years from their design to completion. In-silico trials could reduce this period to less than six months in some circumstances, making knowledge and therapeutic technologies safer, and more promptly available to clinicians and patients.”

In-silico trials offer an opportunity to do virtual experiments that could explain concepts that are difficult to study in conventional clinical trials.”

Alex Frangi

Issue 42 | July 2021

Data from 1,000 aneurysms indicate Pipeline Embolization Device is safe and effective The endovascular treatment of intracranial aneurysms using the Pipeline Embolization Device (PED; Medtronic) has been deemed safe and effective following a study involving data on 1,000 aneurysms from a single-centre registry. The study, the findings of which are published in the research journal Neurosurgery, found high rates of long-term complete aneurysm occlusion, stable or improved functional outcomes, and low rates of both complications and mortality.

“THE PED IS THE MOST EXTENSIVELY investigated FD [flow diverter] available on the market,” the study’s researchers, Ivan Lylyk (Department of Interventional Neuroradiology and Neurosurgery, Instituto Médico ENERI-Clínica La Sagrada Familia, Buenos Aires, Argentina) and colleagues, write.

“Initially, treatment with the PED was aimed principally at wide-necked and uncoilable aneurysms located in the anterior circulation below the internal carotid artery (ICA) bifurcation.

“As experience with PED grew and the technology matured, its use has expanded to include less complex and posterior circulation aneurysms, along with a greater understanding of associated complications; however, long-term follow-up data on these new

Flow diverters 11 indications are limited. Here, we report the results of the PEDESTRIAN [PEDs for the treatment of intracranial aneurysms] registry. We report the clinical and radiographic results from 1,000 aneurysms of various size and morphology treated with the PED, including those patients with long-term follow-up (≥5 years).”

In their retrospective review of data from the PEDESTRIAN registry, Lylyk et al included patients with complex intracranial aneurysms treated using the PED between March 2006 and July 2019. These criteria saw a total of 835 patients (mean age=55.9±14.7 years; 80.4% female) with 1,000 aneurysms included in the review, who were assessed via the primary angiographic endpoint of complete occlusion and long-term stability.

Clinical and radiological follow-up was performed at three-to-six months, 12 months, and yearly thereafter.

In total, 1,214 PEDs were deployed, Lylyk et al report, with a single device being used in 84.2% and two or fewer devices being used in 95.8% of aneurysms.

Adjunctive coiling was performed in 9.3% of aneurysms and intraoperative technical complications occurred in 4.8% of treated aneurysms, with incomplete wall apposition of the device requiring balloon angioplasty representing the majority of technical complications (3.3%) seen across the patient cohort.

Follow-up catheter angiography was available for 87.4% of patients—with 861 aneurysms—at a mean of 24.6±25 months. Twelve-month angiography using Raymond Roy Classification (RRC) revealed complete occlusion (RRC I) of 75.8% of aneurysms, while 4.4% had a residual neck (RRC II) and 19.8% showed residual filling (RRC III). For the 323 patients with available intermediate angiographic follow-up data (from two-to-four years), complete occlusion was observed in 92.9%, and this improved further to 96.4% of patients in delayed angiography (beyond five years).

Retreatment was required in 4% of aneurysms, of which 92.5% involved

implanting another FD device. Meanwhile, regarding clinical results, modified Rankin Scale (mRS) scores remained stable or improved in 96.2% of patients in the periprocedural period (≤30 days), increasing to 99.1% in the longer term (≤5 years), Because of this, Lylyk et al conclude: “Clinical and angiographic outcomes progressively improved over long-term followup, demonstrating intracranial aneurysm treatment with PED is safe and effective in a large cohort of aneurysms.”

Stroke-related complications occurred in 3.6% of patients—with the majority of these cases being caused by in-stent thrombosis (2.5%)—and nine deaths occurred due to stroke. “We found a trend towards lower rates of thromboembolic complications since the implementation of prasugrel,” Lylyk et al add, reporting that 26 (4.4%) patients on the antiplatelet medication clopidogrel developed stroke compared with four (1.6%) patients on prasugrel. Haemorrhagic complications occurred in 1.8% of patients, resulting in 11 deaths. The overall morbidity rate, including from subarachnoid haemorrhage, was 2.7% and the all-cause mortality rate was 4.6% across the entire patient cohort.

Only aneurysm size was found to be a significant predictor of neurological death when assessed via Cox logistic regression.

“Our study has several limitations inherent to the retrospective, singlecentre design of data analysis, which may limit generalisability of the data, as well as the lack of core lab adjudication,” the authors also state.

Even so, Lylyk told NeuroNews that, with up to 13 years of follow-up for the first cases in the PEDESTRIAN registry, this series does demonstrate “for the first time” that PEDs are safe and effective “in the very Ivan long run”.

Lylyk

July 2021 | Issue 42

12 Endovascular stroke treatments CX DEBATE

Stenting should be reserved for extracranial vertebral arteries only

Stenting is something that, for now at least, should be considered in the extracranial vertebral arteries only—and not the intracranial arteries—for symptomatic atherosclerotic stenosis, as indicated by a majority vote from attendees at the Charing Cross (CX) 2021 Digital Edition (19–22 April, online).

AFTER HEARING ARGUMENTS from either side of this controversial topic, mainly regarding the potential safety risks and clinical benefits associated with intracranial artery stenting in stroke patients, 64% of the CX audience voted in favour of the motion that ‘Only extracranial, Andrew Clifton not intracranial, vertebral arteries should be considered for stenting’, while 36% voted against.

The debate saw Andrew Clifton (St George’s University Hospitals NHS Foundation Trust, London, UK) start by presenting in favour. He chose to focus on VIST (Vertebral artery ischaemic stenting trial)—a study that compared vertebral angioplasty and stenting plus best medical treatment (BMT) with BMT alone, and concluded that stenting may be effective in reducing stroke risks, predominantly in extracranial vertebral artery stenosis patients. VIST also found no strokes or major complications in 48 patients who underwent stenting for extracranial stenosis, while two strokes—one of which was fatal—were observed in 13 intracranial stenosis patients.

Clifton expanded his argument to include two further clinical trials, VAST (Vertebral artery stenting trial) and SAMMPRIS (Stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis), pooling data from 354 patients across all three studies to assert that “some benefit” in stroke prevention was observed for extracranial, but

not intracranial, stenting, with a “marked” periprocedural risk of stroke and death seen in the latter.

Clifton finished his presentation by claiming neither extracranial nor intracranial stenting strategies have been shown to provide a statistically significant benefit in stopping Thomas Liebig recurrent stroke, adding that—while larger trials may reveal a more tangible benefit in extracranial stenting—he “can only advocate stenting of symptomatic, extracranial vertebral stenosis within 14 days of a transient ischaemic attack or posterior circulation stroke, and only in the context of a randomised trial”, but “cannot advocate” stenting for intracranial stenosis.

The riposte to Clifton’s argument was then provided

by Thomas Liebig (Ludwig Maximilian University of Munich, Munich, Germany), who began his argument against the motion by stating that extracranial versus intracranial stenting “should not be the question”, but that treatment choices should depend on the individual patient’s anatomy. And, while he conceded there is little existing evidence on rescue stenting, Liebig referenced a study published in the Journal of NeuroInterventional Surgery last year that found the survival rate in acute stroke patients receiving rescue stenting was “almost double” that of patients who did not.

Liebig went on to argue that advances in medical imaging technologies have meant patients who require stenting can be identified more effectively—allowing

Noninferiority of thrombectomy alone further demonstrated in acute ischaemic stroke treatment The noninferiority of mechanical thrombectomy alone—compared to mechanical thrombectomy plus intravenous tissue plasminogen activator (IV-tPA)—for the treatment of acute ischaemic stroke has been demonstrated across more than 109,000 patients within a national US database. These results were presented at the International Symposium on Endovascular Therapy (ISET; 9–11 May, Miami, USA).

“O

ur results indicate that mechanical thrombectomy alone was used more frequently than mechanical thrombectomy plus IV-tPA among patients with acute ischaemic stroke,” Waseem Wahood (Nova Southeastern University, Fort Lauderdale, USA) said.

“Both treatment groups had similar odds of mortality, but the mechanical thrombectomy alone group had higher odds of 90-day poor functional outcome compared with the mechanical thrombectomy plus IV-tPA group. These results support the findings in the three recent clinical trials.”

According to Wahood, the results from three clinical trials also investigating the efficacy of various

endovascular treatments for patients with acute ischaemic stroke—the DEVT, DIRECT-MT and SKIP studies—were published in 2020 and 2021, with DEVT and DIRECT-MT both demonstrating mechanical thrombectomy’s noninferiority when compared to mechanical thrombectomy plus IV-tPA. Wahood and colleagues therefore queried a national inpatient database, the Healthcare Cost and Utilization ProjectNational Inpatient Sample (HCUP-NIS), for patients undergoing mechanical thrombectomy for acute ischaemic stroke between 2006 and 2018. Across a total of 109,385 admissions, some 68,940 (62%) patients’ admission involved thrombectomy alone, and the investigators compared these patients

clinicians to tailor their treatment strategies accordingly.

When questioned by one of the session’s moderators, Hugh Markus (University of Cambridge, Cambridge, UK), over wider trials being needed to prove the benefits held by intracranial stenting, Liebig said he agreed “absolutely”, but added: “The point I was trying to make with my presentation is that it is generally not doing all patients a good service if you are very dogmatic about something, and are saying you should never do it.”

Later in the discussion, when asked whether new stenting technologies may shed more light on intracranial, and indeed extracranial, stenting, Clifton said: “Intracranially, yes, technology will make a big difference—and patient selection will make a big difference—but I think we have got to prove that extracranial works first, because the complication rates in the intracranial arms of all those previous trials were so high”. Regarding future trials, Liebig added that, with the help of improved technology and better patient selection, “we might find patients that actually have more benefit than risk from doing these treatments”.

Intracranially, yes, technology will make a big difference— and patient selection will make a big difference— but I think we have got to prove that extracranial works first, because the complication rates in the intracranial arms of all those previous trials were so high.”

Andrew Clifton

to those who underwent thrombectomy plus IV-tPA regarding 90-day poor functional outcome, inpatient mortality rate, and patient profile for tPA usage.

Regarding mortality rate, those who received mechanical thrombectomy alone had “similar odds” of death compared with those receiving thrombectomy plus IV-tPA (odds ratio=1.01; p=0.80). This led Wahood and colleagues to conclude that their own findings were broadly aligned with those of previous trials like DEVT and DIRECT-MT regarding the noninferiority of mechanical thrombectomy alone—in spite of the thrombectomy-alone group seen in their own investigations also having higher odds of poor functional outcome compared with the thrombectomy plus IV-tPA group (odds ratio=1.14; p=0.002).

They found an increase in the trend of mechanical thrombectomy being used without IV-tPA among patients with acute ischaemic stroke (trend=3.27%; p<0.001) over time, with a 72% rate of thrombectomy alone being seen in 2018 compared to just 52% in 2006. Multivariable regression analysis regarding patient profiles indicated that

patients who identified as Black (odds ratio=0.83; p<0.001) or Hispanic (odds ratio=0.83; p=0.002) were more likely to undergo mechanical thrombectomy alone compared with those who identified as white.

Additionally, Wahood reported that those in the top quartile of household income had lower odds of undergoing mechanical thrombectomy alone compared with those in the lowest quartile (odds ratio=0.90; p=0.040), while admissions in urban teaching hospitals were more likely to receive thrombectomy alone compared with those in urban nonteaching hospitals (odds ratio=1.61; p<0.001). One key limitation of the study that Wahood also highlighted was the fact he and his colleagues were not able to control for the time of administration of the different treatment types. “The clinical trials were capped at 4.5–6.5 hours, while the national database we used does not record hour of administration,” he added.

Waseem Wahood

July 2021 | Issue 42

14 Interview

Profile

William Mack

William Mack is a professor of neurosurgery and vice-chair of academic affairs in the Department of Neurological Surgery at the University of Southern California (USC) Keck Medical Center, and the principal investigator and director of the Cerebrovascular Laboratory in the Keck School of Medicine’s Zilkha Neurogenetic Institute (Los Angeles, USA). He is also the current president of the Society of NeuroInterventional Surgery (SNIS).

Mack discusses his career in neurointervention with NeuroNews.

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

I have always had an interest in science and medicine.

My uncle is a paediatric cardiac surgeon and I have been fascinated by his work since I was a child. I became interested in neuroscience during college and medical school. I was very intrigued by how the brain works.

Helping people during difficult times has always been appealing to me and I have a great sense of fulfilment knowing that the work I do has a profound impact on my patients’ lives. I was attracted to neurointerventional surgery because it gave me the opportunity to participate in a rapidly evolving, cutting-edge field of medicine that focuses on helping people during critical times. Being able to perform minimally invasive brain surgery is also something I find incredible.

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

I have been fortunate to have a number of fantastic mentors that have helped shape my career, and there are several outstanding individuals that have been directly responsible for my training at various stages.

My parents, Bill and Deena Mack, taught me the value of hard work, respect, and the importance of pursuing a job that I love. As a medical student and resident at Columbia University, I had the privilege of working in Sander Connolly’s laboratory. He is the epitome of a surgeon-scientist and a true inspiration. During residency, I had the opportunity to learn cerebrovascular and neuroendovascular surgery form Robert Solomon, Sander Connolly, Philip Meyers and Sean Lavine. They were each exceptional surgeons and caring doctors who taught me the importance of preparation, surgical discipline, and working in a collaborative team. During my fellowship, I learned from Fernando Vinuela, Gary Duckwiler and the University of California, Los Angeles (UCLA) team—true pioneers in the neurointerventional field who taught me the importance of innovation, biotechnology, and the need to constantly evaluate our treatments in a scientific manner. As a faculty member at USC, I have had the opportunity to learn every day from a master cerebrovascular surgeon, Steven Giannotta, and I have gained an appreciation for the amount of learning that can be done long after the formal training of residency and fellowship. I am also grateful to be able to learn each day from my partners Arun Amar, Jon Russin, Matt Tenser and Ashkan Mowla.

What has your experience been as the president of the Society of NeuroInterventional Surgery?

It has been a fantastic experience; both inspiring and humbling. I have had the chance to work with such an impressive group of people who are devoted to advancing the field of neurointerventional surgery. It is truly a great time to be involved with this specialty. The field is growing through multidisciplinary collaborations and innovation is occurring at a rapid pace. We have become large enough to have a voice that is heard across medical and leadership communities, and we have used

this voice to advocate for our patients. Although we have accomplished so much as a group over the course of the year, it feels as if there is so much more that can be done—and the society must pick which important issues to focus its time and efforts on.

How has COVID-19 affected your work at SNIS over the past year?

COVID-19 has limited the ability of our teams to meet in person. We had to convert our annual conferences, board meetings and practical courses to virtual platforms. Our physicians were also unable to proctor new procedures in person for a period of time. Nonetheless, we carried out each of these events successfully in the “new normal”. This took a lot of planning from the organisers and administrative team, but it also showed us how adaptive we could be when we needed to. In some ways, we have become more connected with people who live greater distances away, and these advances will not go away after the pandemic.

However, we have all missed the personal interactions and camaraderie of face-to-face meetings, and are very excited to congregate at the annual meeting in Colorado Springs this year.

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

The success of the randomised controlled mechanical thrombectomy trials in 2015 and beyond was the most important development in the field of neurointervention during my career. I think that neurointerventional surgeons believed stroke to be a surgical disease early

If you want an exciting and expanding field of medicine, neurointervention is the place to be.” on. We had all seen up close the successes of the early mechanical thrombectomy procedures. It took some time to optimise device development and systems of care, but the resounding success of the 2015 trials convinced the rest of the medical profession. This is a procedure that has a “number needed to treat” that is far fewer than many of the most successfully treated diseases in all of medicine, and those trials demonstrated the power of collaboration and well-designed clinical trials around an innovative procedure with great benefit to our patients.

What is the most significant unsolved problem in the field right now?

Designing and implementing proper stroke systems of care is very important in our field right now. Getting our stroke patients to the right place the first time around is critical. We have the personnel, devices, and techniques, to effectively treat large-vessel ischaemic stroke and, while practitioners involved in acute stroke care have

worked effectively in multidisciplinary teams, we now need to implement standardised transport and routing measures that ensure efficiency within the system. This is also the focus of the SNIS Get Ahead of Stroke effort.

What is your proudest achievement in the field of neurointervention?

Among my proudest achievements in neurointervention has been my participation in the collaborative and inclusive efforts that have been initiated and implemented by the SNIS board of directors over the past year. I take great pride in being a part of something that I feel will move our entire field forward on behalf of our membership and our patients. SNIS has worked with the Joint Cerebrovascular section of the American Association of Neurological Surgeons/Congress of Neurological Surgeons (AANS/CNS) and the Society of Vascular and Interventional Neurology (SVIN) to help establish objective and responsible fellowship

Issue 42 | July 2021

Interview 15 guidelines, and is working towards implementing an organised fellowship match. In addition, the SNIS board of directors unanimously voted to create a new voting board position, the Diversity, Equity & Inclusion Chair, which will lead engagement with the SNIS membership in all aspects of diversity, and promote equity and inclusion within the society.

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

The brain-computer interface work being done by Thomas Oxley and the team at Synchron is absolutely fascinating to me. The ability to help a person control motor function through their thoughts is incredible.

Equally impressive is the ability to do so in a minimally invasive fashion via the blood vessels. The Stentrode device represents a move towards restorative neuroendovascular surgery as, rather than removing or treating existing pathologies, this technology will allow patients to recover function that was previously lost.

This could be the beginning of a whole new field for neuroendovascular surgery and medicine.

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

It is an unbelievable field. Progress is more rapid than in any other area of medicine. You can access the entire body, including the brain and spine, through the vascular tree, in a minimally invasive fashion—that is the basis of our specialty. The innovative tools that we use today will be replaced by newer, more effective devices that the members of our group help design and develop. We are treating diseases like subdural haematomas, and performing procedures like venous sinus stenting, that did not even exist several years ago. Neurointervention is an expanding field, our society membership is growing rapidly, and the impact factor of our Journal of NeuroInterventional Surgery is increasing substantially each year. If you want to work in an exciting and expanding field of medicine, neurointervention is the place to be.

alisonlang.com

What are your interests outside of the field of medicine?

Fact file

Education:

1992–1996: BA, Neurobiology and Behaviour, Cornell University, Current appointments: Ithaca, USA 2018–present: Professor of 1996–2001: MD, Medicine, Columbia Neurosurgery and vice-chair of University College of Physicians and Academic Affairs, Department of Surgeons, New York, USA Neurological Surgery, Keck Medical 2011–2013: MS, Clinical and Biomedical Center, University of Southern California Investigation, University of Southern (USC), Los Angeles, USA California, Los Angeles, USA Principal investigator and director, 2019–2022: MBA, Marshall School Cerebrovascular Laboratory, Zilkha of Business, University of Southern Neurogenetic Institute, Keck School California, Los Angeles, USA of Medicine, University of Southern California (USC), Los Angeles, USA

I enjoy spending time with my wife, Courtney, and my five children—Jacob, 11; Daniella, 9; Charlie, 7; Lexi, 5; and Emma, 2. It is very busy in our household. We play sports, travel, and enjoy spending time with our extended family. Over the course of the past year, we have cooked themed dinners every Friday night that we eat together as a family. We have gotten creative in order to avoid any duplicates over the course of 50 weeks. We also have movie nights every Saturday and try to spend time outdoors together. In my free time, I like to ski, hike, swim and play golf too.

Honours (selected):

Fellow, American College of Surgeons (ACS), 2018 USC Neurosurgery Teaching/ Mentorship Award, USC Department of Neurosurgery, 2019 President, Society of NeuroInterventional Surgery (SNIS), 2020–2021 Chair-elect, Cerebrovascular Section, American Association of Neurological Surgeons/ Congress of Neurological Surgeons (AANS/CNS), 2021–2022

July 2021 | Issue 42

18 Novel interventions

Clinical improvements seen following transvenous paraspinal vein embolisation for CSF hypotension A case series to assess transvenous paraspinal vein embolisation of cerebrospinal fluid (CSF)-venous fistulas—a novel treatment approach for spontaneous intracranial hypotension (SIH)—has resulted in a “clinical and radiographic improvement” across all the patients involved. The findings of this case series are published in the American Journal of Neuroradiology (AJNR).

IN ADDITION TO STATING that no technical or permanent neurologic complications were seen in any of the five patients, the report’s authors, Waleed Brinjikji (Mayo Clinic, Rochester, USA) et al, conclude that “our findings are important because they suggest that CSF-venous fistulas may be amenable to obliteration via transvenous embolisation and may not require surgical intervention”.

According to the authors, a number of treatment options have previously been proposed for CSF-venous fistulas— which are increasingly being recognised as a cause of SIH—including “extremely effective” surgical ligation, nerve root skeletonisation, and blood/fibrin patching. Despite this, they also note that a recent series involving 42 patients saw an 80% improvement, or resolution, in magnetic resonance imaging (MRI)

findings of CSF hypotension, while other minimally invasive treatment options like epidural blood patches and fibrin glue injections “have been shown to be effective in a minority of patients”.

They therefore set out to report the “first ever” cases of transvenous paraspinal vein embolisation being used to treat CSF-venous fistulas, which involved retrospectively reviewing five patients diagnosed with a CSF-venous fistula on digital subtraction myelography (DSM). For this novel procedure, they opted to occlude the venous outflow of the CSF-venous fistula using a liquid embolic material (Onyx, Covidien).

The transfemoral route was used to gain access in four patients, while a transjugular approach was used in one.

Four of the patients were male and one was female (mean age=60 years).

Brinjikji et al report that all patients

had position- and Valsalvawith transvenous paraspinal dependent headaches, two vein embolisation for CSFhad hearing loss, four had venous fistulas, they add that tinnitus, and three had cognitive limitations of their case series disturbances or “brain fog”. include the relatively short Regarding the results of follow-up duration of two-tothe case series, the authors four months, a lack of uniform write: “At last follow-up pretreatment MRI protocols due Waleed Brinjikji [median=three months; to the patients being referred range=two-to-four months), from multiple different centres, all patients had documented clinical and the fact that measures—such as the improvement. Three patients had Headache Impact Test-6, quality of life, complete resolution of SIH-related and other standardised questionnaires— symptoms. One patient had complete were not collected. As such, they resolution of headaches and hearing loss conclude that “further studies are needed but had persistent tinnitus. However, this to confirm our technique and to study the patient was found to have a semicircular durability of this treatment effect”. canal dehiscence, which confounded the evaluation of the tinnitus. One patient, [who had] mild residual pachymeningeal enhancement, had a 50% improvement in headache and hearing loss, but persistent tinnitus.

“In all cases, the fistulas were localised using DSM and, in all cases, embolisation resulted in significant improvement in both imaging findings and clinical symptoms. Pain localised to the site of the embolisation was a common minor complication, but in no cases did this require narcotics, and in all cases the pain subsided in a matter of weeks. All procedures were performed on an outpatient basis and there were no permanent neurologic deficits.”

Brinjikji et al also note that all five patients were discharged home on the day of the procedure. Despite the Waleed Brinjikji et al reported positive findings associated

Our findings are important because they suggest that CSFvenous fistulas may be amenable to obliteration via transvenous embolisation and may not require surgical intervention.”

Issue 42 | July 2021

Revolution in neurotherapy?

Spotlight on focused ultrasound at 2021 EAN Congress While focused ultrasound is by no means a brand-new innovation in the field of neurotherapy—having first been deployed in the 1950s, if not earlier, for therapeutic, non-invasive purposes—the emergence of magnetic resonance imaging (MRI) guidance and other novel technologies have increased its applications markedly since the turn of the century, and the potential, unrealised uses it has in interventional neurology today are perhaps even greater still. This theme, and the possibility of a “revolution in neurotherapy”, were explored at the 7th Congress of the European Academy of Neurology (EAN; 19–22 June 2021, virtual) in a session where transcranial, ultrasound-based surgery for tremors, blood brain barrier opening, and focal neuromodulation with ultrasound, all featured.

ANDRES M LOZANO, CHAIRMAN OF neurosurgery at Toronto Western Hospital (Toronto, Canada), began the session by outlining the use of focused ultrasound in neurosurgery, as it can be used to penetrate the skull non-invasively and create therapeutic lesions—a technique that can be further optimised with MRI guidance. Lozano reported examples of this approach’s deployment to treat tremors via a thalamotomy, with sound energy being administered to an awake patient for about 13 seconds at a time. “We usually start making small lesions at low temperatures, and we gradually increase the temperature by subsequent sonications until the tremor disappears—and the effects, of course, are immediate,” he added.

Lozano stated that, following evidence on the effectiveness of this technique from a randomised clinical trial published in the New England Journal of Medicine (NEJM) in 2016, MRI-guided focused ultrasound (MRgFUS) has joined a group including three other major treatment options that Toronto Western Hospital offers outpatients with Parkinson’s disease and other movement disorders who have failed medication—the first line of therapy. These surgeries are radiofrequency (RF) lesioning, deep brain stimulation (DBS) and radiosurgery with a gamma knife. Lozano reported that about 90% of patients at the centre are currently opting for MRgFUS when given the choice between these four treatments.

“Focused ultrasound has overtaken DBS, which ranks as number two in patients with tremor, and so this has really revolutionised our treatment of tremor because patients are now coming in and asking for focused ultrasound—and many patients do not want an invasive therapy like RF or DBS,” he added. Lozano claimed there is a “general trend” towards minimally invasive, low-maintenance therapies like MRgFUS right now, and that patients and physicians alike who have previously shunned surgery will accept focused ultrasound as a viable option, in his experience.

Novel interventions 19 In addition to expanding the use of focused ultrasound to bilateral staged thalamotomies for essential tremor, which has been performed in a handful of patients to date, as well as other movement disorders like dystonia, Lozano emphasised the possibility of targeting other areas of the brain with focused ultrasound beyond the ventral intermediate (VIM) nucleus—including the globus pallidus internus (GPi), subthalamic nucleus (STN), and pallidothalamic tract (PTT).

In concluding his presentation, Lozano alluded to numerous other, broader areas within neurotherapy that focused ultrasound could be used for, ranging from brain tumour ablation to psychiatric indications like depression, anxiety and pain—many of which are currently being investigated through Phase I or preclinical trials. He also highlighted the treatment of epilepsy and hydrocephalus, and the idea of dissolving blood clots, as especially “exciting” therapeutic possibilities, but tempered this by stating there is still “work to be done” to investigate these concepts further.

Opening the blood brain barrier

The session’s second talk saw Jean-François Aubry, research director at the French National Centre for Scientific Research (Physics for Medicine Paris, Paris, France), discuss efforts to transiently, and safely, open the blood brain barrier using ultrasound—something that he claimed is a clinical need, as roughly 95% of therapeutic drugs currently are unable to penetrate this barrier and enter the brain. As is also the case with the

Andres M Lozano

Jean-François Aubry

Focused ultrasound has overtaken DBS, which ranks as number two in patients with tremor, and so this has really revolutionised our treatment of tremor because patients are now coming in and asking for focused ultrasound.”

Andres M Lozano

neurosurgical applications Lozano discussed previously, the history of focal blood brain barrier opening with ultrasound dates back as far as the mid-20th century, according to Aubry, although these early efforts induced damage to the barrier, and their effect was irreversible.

He stated, however, that a “game-changer” was uncovered in the early-2000s, with the use of contrast agents being the principle on which safely opening the blood brain barrier is based today. And, while the majority of examples of this being done have involved animal subjects, certain applications have been completed in humans. Aubry alluded to a 2019 report of a clinical safety and feasibility study, published in Scientific Reports, that demonstrated the use of blood brain barrier opening, followed by administration of chemotherapy to treat brain tumours, in five patients.

In addition, he referenced a 2018 study in Nature Communications that achieved its primary outcome

of safely opening the barrier in five early-to-moderate Alzheimer’s disease patients.

According to Aubry, the initial findings of both of these studies are now being expanded and investigated further. “So, this is very important work in paving the way for many treatments—but, actually, it is also very interesting in the development of new devices that may be smaller and easier to use on patients,” he added. A team from Columbia University in the USA has developed its own novel, neuronavigation-guided, single-element focused ultrasound transducer, Aubry told the EAN audience, and—as recently as December 2020—used it to treat its first patient via blood brain barrier opening within the context of a clinical trial.

Aubry went on to highlight a handful of alternative methods for ultrasound-based blood brain barrier opening, including his own team’s work to develop a cheaper, yet still high-quality and precise, focused ultrasound technique using a 3D-printed acoustic lens that costs “a couple of euros” and a single-element transducer. Finally, he referenced the potential held by another technique, developed by French start-up company CarThera, which involves implanting a transducer device at the surface of the brain before using a generator-powered transdermal needle to apply ultrasound. This approach has been assessed in a safety and feasibility study involving 21 patients with recurrent glioblastoma, according to Aubry, the findings of which were published in Clinical Cancer Research last year.

Neurostimulation with ultrasound

Before concluding, Aubry briefly touched on ultrasonic neurostimulation—adding that, while many of the principles this technique is based on are similar to those seen in ultrasound-based blood brain barrier opening, a key distinction is that the former does not require a contrast agent. He added that more than 250 articles on ultrasound stimulation have been published since 2000—with the number of new articles in this space increasing significantly each year since 2015, leading Aubry to assert that “the field is growing exponentially”.

These closing remarks provided an appropriate introduction to the session’s final presentation—which saw Roland Beisteiner, associate professor in the Department of Neurology at the Medical University of Vienna (Vienna, Austria), take a closer look at ultrasound-based focal neuromodulation for clinical therapy. While he asserted that, over the past few years, several different technologies have come to the fore in this space, he chose to focus on the latest of these breakthroughs: transcranial pulse stimulation (TPS).

Beisteiner outlined the various advantages TPS has over previous focused ultrasound techniques, including the fact its pulse generation is based on an already widely and clinically established technology, its “very short pulses” enabling the avoidance of secondary stimulation maxima, and the risks associated with brain heating also not being present during the process. He went on to specify particular benefits of TPS compared to approaches like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)—most notably an “unprecedented precision” in targeting brain tissue with pathological conductivities, which may open up new possibilities in treating movement disorders, stroke, and multiple sclerosis (MS), and the fact TPS can be seen to offer a clinical option akin to non-invasive DBS. Beisteiner described the latter as a “really fantastic” novel option, relaying that numerous psychiatric and neurological diseases, from addiction, depression, and obsessive compulsive disorder (OCD) to Alzheimer’s, epilepsy, and pain, could benefit from a non-invasive form of DBS such as this. On Alzheimer’s disease specifically, he referred to data from a 2019 study published in Advanced Science, which showed “significant long-term improvement of memory” at three months following TPS, before alluding to a separate study from 2021 that built on this research by showing TPS can reduce cortical atrophy in Alzheimer’s patients.

Issue 42 | July 2021

21

Study shows “major energy savings” can be achieved in spinal cord stimulation for chronic pain The results of the HALO (High and low frequency options) study, which are published online in the scientific journal Neuromodulation: Technology at the Neural Interface, indicate that “major energy savings” are possible in the administration of subperception spinal cord stimulation (SCS) to treat chronic pain.

I

n the study, a number of different frequencies, from 1kHz down to 10Hz, were used to deliver subperception relief for back, leg, and overall pain—with all tested frequencies providing effective and sustained pain reduction out to one year, and 85% of patients reporting a preference for SCS delivered at lower frequencies of 400Hz or less.

“Effective subperception pain relief was achieved in SCS at sub-kHz frequencies, down to 10Hz, using a novel electric field shaped to preferentially modulate the dorsal horn,” Simon Thomson (Basildon and Thurrock University Hospitals, Basildon, UK) et al write in their report. “Following the neural dosing curves reported in our study, our field configuration enabled effective targeting and a significant increase in efficiency.

“These findings will enable effective and energyefficient therapy, as well as personalised stimulation dosing across patients and over time. Finally, these results provide insights useful in the search for mechanisms of action, and guidance on requirements for useful comparison of subperception settings in clinical and preclinical experiments.”

Despite the use of subperception SCS most commonly being associated with waveforms that require high energy, the necessity of these waveforms for effective subperception pain relief has not been established, according to Thomson et al. The researchers therefore intended to explore whether effective subperception pain relief can be achieved using frequencies of less than 1kHz. They enrolled 30 chronic pain patients diagnosed with failed back surgery syndrome (n=29), or chronic radiculopathy (n=1), causing chronic neuropathic pain of the low back and lower limbs, who had subsequently been implanted with an SCS system (Precision Spectra/ Spectra WaveWriter, Boston Scientific), in a multicentre, consecutive, observational case series. The mean age in this patient cohort was 54 years (range=35–74 years), and 22 of the 30 participants (73%) were female.

An effective stimulation location, or ‘sweet spot’, was determined using a novel electric field shape designed to preferentially modulate dorsal horn elements at a frequency of 1kHz. Following this search, the patients were provided with a set of programmes with select sub-kHz frequencies—600, 400, 200, 100, 50, and 10Hz—over three-to-four consecutive visits, in order to improve power usage and explore the role of frequency in subperception. All of these programmes used the same field identified in the sweet spot search at 1kHz, and each frequency was amplitude adjusted and provided with titration to enable optimisation of the neural dose.

All 30 patients underwent frequency titration for a mean period of six months. The mean numerical rating scale (NRS) scores for back pain decreased from a baseline of 8.2±0.2 to 3.1±0.2 with 1kHz, 2.5±0.3 with 200Hz, and 3.1±0.2 with 10Hz, yielding a mean of 67% back pain relief across all frequencies. And,

while 200Hz provided the largest back pain reduction (71%), Thomson et al note that “importantly, the null hypothesis that pain scores were different at the different frequencies was rejected, indicating that all frequencies provided equivalent back pain relief”. The authors add that similar results were seen for leg and overall pain relief, with 200Hz providing the largest pain reduction of any frequency—but not to a statistically-significant extent.

Thomson et al also state that, regarding optimisation of the neural dose, adjustment of the pulse-width was required to be able to achieve effective and equivalent pain relief across the different frequencies. “It was observed that, as frequency was decreased, increasing the pulse-width in a nonlinear fashion enabled the pain relief to be maintained,” they add. Therapeutic amplitude, on the other hand, was observed to be “relatively constant” across frequencies following the described pulse-width adjustments, and as such no significant association was found between subperception

These findings will enable effective and energy‐efficient therapy, as well as personalised stimulation dosing across patients and over time.” therapeutic amplitude and frequency.

Charge-per-second was found to significantly decrease as frequency was decreased, dropping from 326±145μC/s at 1kHz to 108±42μC/s at 200Hz, and 9±3μC/s at 10Hz—thus providing the potential for a “large energy saving” by decreasing frequency.

Compared to 1kHz, efficiency increased by 74% at 200Hz and by 97% at 10Hz in the trial. According to the study’s authors, patients generally reported preferences for a range of different frequency options, indicating that no particular frequency was best for all patients, and effective pain relief was sustained at long-term follow-up (mean of one year from the beginning of frequency titration, and two years from SCS implantation), with a mean pain reduction of 62% in overall (NRS=3.10), 60% in back (NRS=3.18), and 73% in leg (NRS=2.82) pain compared to baseline.

“These data support the idea that effective subperception therapy is not achieved by the optimisation of any single parameter—for example, a single outperforming frequency or waveform—but rather that there is a family of effective parameter combinations, and Simon Thomson any given frequency can be effective

if targeting is appropriate and the other stimulation parameters are adequately adjusted,” Thomson et al write. “Furthermore, the present observations at low frequency challenge our current mechanistic thinking and the notion that high frequency and/or high energy stimulation is required for effective subperception SCS.” In addition, they assert that the HALO study’s present results, combined with those of the PROCO randomised controlled trial (RCT), which assessed the effects of rate on analgesia in kHz-frequency SCS and was also subsequently published in Neuromodulation: Technology at the Neural Interface in January 2018, “have enabled us to derive a set of parameter combinations that result in effective subperception therapy across a broad range of frequency in SCS, from 10–10,000Hz”.

“These derived rules of neural dosing can be considered a first step in a unified framework for dosing stimulation in SCS,” Thomson et al add. “In support of this notion is the fact that parameter settings that others have shown to be effective could be represented as single points on the neural dosing curves of the present model. Having the understanding and ability to use multiple effective stimulation doses, instead of working with a single modality, may help practitioners manage the large variability that exists in SCS—both

Compared to 1kHz, efficiency increased by 74% at 200Hz and by 97% at 10Hz in the trial.

97 % 74%

0% 1kHz

200Hz 10Hz

between subjects due to differences in physiology, disease aetiology, lead type and placement, and within subjects due to disease progression and accommodation to chronic stimuli. In contrast, committing to a single waveform, despite being simpler, does not allow patients to reduce charging, explore their response with other doses, or change dose over time, and may increase the likelihood of explantation.”

The study’s authors also conclude that future work may include expanding the present neural dosing model to include other dimensions that potentially impact electrical dosing in SCS, such as cycling and other temporal parameters, stimulation location and field shape, and wash-in/wash-out time. In addition, Thomson et al note that the replication of these observations in further samples, as well as the longerterm follow-up of these patients to evaluate whether there is potential to prevent habituation effects using these lower doses, and to explore the use of modulation of frequency and neural dosing over time, may be of interest too.

July 2021 | Issue 42

22

New algorithm could enable nextgeneration deep brain stimulation devices By delivering small electrical pulses directly to the brain, deep brain stimulation (DBS) can ease tremors associated with Parkinson’s disease or help relieve chronic pain. The technique works well for many patients, but researchers would like to make “next-generation” DBS devices that are a little smarter by adding the capability to sense activity in the brain and adapt stimulation accordingly—and a new algorithm developed by Brown University bioengineers could enable progress on this front by removing a key hurdle that makes it difficult for DBS systems to sense brain signals while simultaneously delivering stimulation.

“WE KNOW THAT THERE ARE ELECTRICAL signals in the brain associated with disease states, and we would like to be able to record those signals and use them to adjust neuromodulation therapy automatically,” said David Borton (Brown University, Providence, USA), corresponding author of the study describing the algorithm. “The problem is that stimulation creates

electrical artifacts that corrupt the signals we are trying to record. So, we have developed a means of identifying and removing those artifacts, so all that is left is the signal of interest from the brain.”

The research, which is published in Cell Reports Methods, was co-led by Nicole Provenza, also of Brown University, and Evan Dastin-van Rijn (University of Minnesota, Minneapolis, USA), who also worked on the project while he was an undergraduate at Brown.

There are several factors that make it difficult to sense and stimulate via an implantable DBS system at the same time, their report notes. The frequency signature of the stimulation artifact can sometimes overlap with that of the brain signal researchers want to detect. To eliminate the artifact and leave other data intact, the

I think one big advantage to our method is that even when the signal of interest closely resembles the simulation artifact, our method can still tell the difference between the two.”

Nicole Provenza

rTMS found to be “wellaccepted” for therapeutic use in psychiatric populations Psychiatric populations perceive the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) for mental health conditions to be beneficial, safe, and no more dangerous than conventional therapy options like medication—as indicated by a systematic review published in the journal Neuromodulation: Technology at the Neural Interface.

THE REVIEW ALSO CONCLUDES that, while the positive participant attitudes and experiences observed support the clinical implementation of rTMS, future work is now needed to determine perceptions of this therapy across a range of conditions, such as chronic pain, and to assess perceptions of transcranial direct current stimulation (tDCS), and other non-invasive devices.

“This systematic review indicated that participants with psychiatric conditions who engaged in rTMS were wellinformed and educated regarding the procedure, perceiving it to be safe and beneficial,” Georgia Stillianesis (Western Sydney University, Sydney, Australia) et al write. “Participant attitudes and experiences were positive, reflected by low levels of fear and their willingness to recommend the intervention to others.”

Non-invasive brain stimulation techniques like rTMS are currently considered the gold-standard therapy for pharmacologically resistant depression, and this success has led to its uptake in other disorders including chronic pain, stroke and Parkinson’s disease.

The report’s authors state, however,

that—despite an emerging body of evidence demonstrating the safety and effectiveness of non-invasive brain stimulation—the clinical application of this intervention remains “relatively limited to research settings and psychiatric conditions”, with their systematic review being “the first to synthesise data exploring patient perceptions regarding the therapeutic use of non-invasive brain stimulation”.

In the report, Stillianesis et al detail how an online search of the Cumulative Index to Nursing and Allied Health Literature (CINHAL), PubMed, Web of Science, and Medline, was performed, in addition to screening the reference lists of relevant articles, to build up data for the review. Studies exploring participant perceptions—including knowledge, experience, and attitudes—regarding non-invasive brain stimulation therapy Georgia Stillianesis

exact waveform of the artifact needs to be identified, which presents another problem. Implanted brain sensors are generally designed to run on minimal power, so the rate at which sensors sample electrical signals makes for fairly low-resolution data, and accurately identifying the artifact waveform with such lowresolution data is a challenge.

To get around that problem, Brown’s researchers came up with a way to turn low-resolution data into a high-resolution picture of the waveform—by cobbling bits of data together into a high-resolution picture of the artifact waveform using mathematics.

In a series of laboratory experiments and computer simulations, the team showed that their algorithm outperforms other techniques in separating signal from artifact. They also used the algorithm on previous data from humans and animal models to show they could accurately identify artifacts and remove them. “I think one big advantage to our method is that, even when the signal of interest closely resembles the simulation artifact, our method can still tell the difference between the two,” Provenza said. “So, that way, we are able to get rid of the artifact while leaving the signal intact.”

Another advantage, the researchers add, is that the algorithm is not computationally expensive and could run in real time on current DBS devices—opening the door to real-time artifact-filtering, which would enable simultaneous recording and stimulation. “That is the key to an adaptive system,” Borton stated. “Being able to get rid of the stimulation artifact while still recording important biomarkers is what will ultimately enable a closed-loop therapeutic system.”

were considered eligible.

Four full-text studies comprising data from 163 participants met the authors’ inclusion criteria. The participants across these studies had received rTMS to treat a range of conditions—most commonly for treatment-resistant major depression (79.9%), but also obsessive-compulsive disorder (OCD), somatoform disorders and schizophrenia in some cases. Overall, 58% of the participants were female. The mean age across the three studies that reported ages ranged from 20–49 years.

Regarding knowledge of rTMS, the review found participants held generally high levels of knowledge of the treatment, and its safety and potential indications for administration, with the majority (91%) of participants across three of the four eligible studies being able to correctly define rTMS, and most of the participants in one study being aware of the time (97.5%) and frequency (90%) associated with the procedure—as well as the fact it must be administered by a trained health professional (95%).

The systematic review found the majority of participants in three of the four studies held positive attitudes toward rTMS, reporting it to be humane (98%), not cruel (97%), sophisticated (100%) and modern (92%). The report also notes that a minority of participants believed rTMS should be outlawed (6%), although no additional information was provided as to why this should be.

Furthermore, most of the participants in one study stated they would recommend rTMS to a close relative or friend (72.5%),

and similar findings were seen in two of the other studies—with the majority adding that they would only endorse the treatment if it was recommended by a physician (86%).

All four studies gathered participant experiences of rTMS after it was administered, with three assessing the application of the same rTMS device (Magstim), and the other comparing experiences of three different rTMS devices (Magstim, NeuroStar and Brainway Deep TMS H-Coil System).

While two of these studies demonstrated lower levels of fear after rTMS when compared to pretreatment fear levels, one reported no changes in fearfulness among participants before and after treatment.

In terms of treatment effectiveness, one study reported that the majority of participants (63%) considered rTMS to be effective, with slightly more than half (56%) of the participants in two of the other studies saying they were undecided, or unsure. Stillianesis et al note: “Interestingly, participants who reported higher levels of improvements were more willing to receive subsequent treatment.”

As well as concluding that most of the participants in their review perceived rTMS to be safe and beneficial, Stillianesis et al state that future work is needed to determine perceptions of rTMS in other conditions, including non-psychiatric populations. “Emerging evidence suggests rTMS is welltolerated in these populations,” they write. “A recent study published after the completion of our advanced search supports this notion, demonstrating that stroke patients have positive experiences with rTMS—they reported no unpleasant aspects and attributed their improvement in function to the treatment.”

Issue 42 | July 2021

23

Brains, currents and depression: How stimulation is changing the future of mental health treatment Daniel Månsson (Malmö, Sweden) of Flow Neuroscience outlines the benefits held by transcranial direct-current stimulation (tDCS) in the treatment of depression—and how clinical evidence supporting its use can be expanded even further in the future.

Daniel Månsson Comment & Analysis

E

lectricity has had a recurrent role throughout the history of medicine, ever since patients experiencing headache pain in ancient Rome were treated with the remedy of a live fish placed on their forehead.

Whilst the black torpedo fish—which produced electricity—has long since been removed from the recommended list of treatments, the research and use of electricity for a diverse range of conditions has prevailed. Spurring on centuries of research, during the 1950s, 60s and 70s, the first controlled experiments indicating that stimulation via electrical currents could increase cortical activity in the brain were published.

Fast forward past the rise of psychopharmacology, which overshadowed the progression of brain stimulation research during the 1980s and 90s, and the last 20 years have seen the study and application of weak direct-current stimulation delivered transcranially being implicated in the treatment of mental health disorders.

In terms of depression, scientists have since validated across randomised controlled trials that tDCS is as effective as other treatments, is safe to use, and is less expensive than other options, indicating its accessibility.

Current landscape in tDCS

tDCS is now a used and effective practice across a range of disorders including depression, anxiety and chronic pain. So, what exactly is it we are doing? tDCS is a non-invasive, gentle brain stimulation technique that uses direct electrical currents to stimulate specific brain areas.

A constant low current (0.5–2mA) passes through two electrodes placed on your head, and this stimulates neural activity in the brain.

There are two types of stimulation with tDCS; anodal and cathodal. The former excites neural activity whilst the latter reduces neural activity. When used to treat depression, tDCS solutions, such as Flow, target the dorsolateral

prefrontal cortex—an area involved in higher executive functioning that, when impaired, has been indicated in depression. Alongside this, studies have shown that the positive effects of tDCS last beyond the acute stimulation session and may influence the modulation of serotonergic and dopaminergic systems.

Current research and applications are taking advantage of these findings, with different protocols being developed to dive deeper into the technique, opening up a world of exciting possibilities outside of clinic-only settings. For mental health disorders, we see tDCS used most often in the study and treatment of depression, followed by schizophrenia and addiction. There is also preliminary evidence for the use of tDCS in the treatment of anxiety, post-traumatic stress disorder (PTSD) and anorexia nervosa.

A tDCS session is usually 30 minutes, and the recommended protocol follows five tDCS sessions per week during the first three weeks, then two sessions per week as needed. According to the studies, most people notice a reduction of their depressive symptoms within three weeks, which is also what we have seen in the patients who use Flow.

In the long-term, we have seen some patients requiring continued stimulation at one or two sessions per week to maintain the reduction in their depressive symptoms, whilst for others, the acute treatment programme suffices. The difference we see with our patients at Flow is furthering our research into alternative treatment protocols to cater to further patient specificity. As we know with mental health, individual expressions play a crucial role in treatment response.

Moving into the home setting

Interestingly, tDCS as a therapeutic option for home use has grown both from clinical demand and the accepted safety of the treatment itself. Within clinical settings, tDCS has shown no serious side-effects or adverse events. Coupled with the fact that the electrical current is

very gentle, it seemed to be a no-brainer for the field to optimise this technique as an at-home therapy. In healthcare and mental health, we have seen a rise in patient demand for more accessible and affordable options, which naturally calls for us as clinicians and researchers to innovate traditional methods that have shown efficacy into more autonomous treatments.

Similarly, there is also a healthcareled demand to have more alternatives to offer patients, which has sparked the development of many digitally-led remote solutions in recent years. This was no different for my co-founder, Erik Rehn, and I when we were embarking on Flow Neuroscience, as we could see an excellent therapeutic option to treat depression with tDCS and take this outside of clinic-only settings by implementing the technology into a remote, compact device.

In terms of benefits, at-home mental health therapies can address many of the pain points we see for patients, clinicians and researchers alike. For clinicians and researchers, having a remote, self-administered depression treatment allows for easier-to-administer clinical trials, reduced costs, and increased participation, as people are no longer bound to in-clinic visits. For patients, tDCS provides a non-pharmaceutical option proven to reduce symptoms and accessing this technique via a personal device further enables them to manage their mental health across their lifetime.

As a collective, we need to keep pushing towards providing more solutions that can optimise long-term management of mental health disorders—an area where current standard care is underachieving.

Competition in neuromodulation

Compared to other neuromodulation techniques, tDCS is the most malleable for scaling across general populations. If we zoom out to invasive neuromodulation treatments, such as deep brain stimulation (DBS), these produce highly effective results at a patientspecific level but are limited as they are specialised, clinic-based treatments.

Despite the positive results with invasive neuromodulation techniques, they are not widely accessible and, due to the insertion of an electrode into specific brain areas, the effects are not necessarily replicable from patient to patient.

An alternative non-invasive stimulation technique is electroconvulsive therapy (ECT). This treatment is used in cases of severe or treatment-resistant depression but, again, is administered in the clinic whilst the patient is under anaesthetic.

This type of treatment—whilst noninvasive—uses a current that is 400 times stronger than tDCS and elicits a general seizure of the brain, targeting the temporal cortex at the side of the brain.

ECT can, in addition, elicit strong side-effects like memory loss, confusion and pain. These techniques whilst more widely known are not as beneficial as tDCS when it comes to patient access, recovery and side-effects. The option of a

weaker current that is safe to use at home, and provides an effective treatment whilst having little-to-no side-effects, gives a huge advantage to this type of technique both for patients and clinicians.

Future research in tDCS

However, tDCS has not been without its critics, and there is still progress to be made for it to be a widely prescribed treatment. Firstly, we need to continue research using diverse patient groups and larger sample sizes. Secondly, we need to expand our research into stimulation protocol possibilities to open up further flexibility for clinicians to prescribe and use tDCS safely. Thirdly, there needs to be an increase in the inclusion of remote devices delivering tDCS, such as Flow, in clinical research.

Progress in these areas will develop tDCS into one of the only personalised, accessible and empowering mental health treatments on the market. To further the adoption of at-home tDCS treatments, we also need to place more emphasis on clinicians to use pioneering solutions to support the growing body of research in real-life settings.

As we look towards the future, I am excited, because tDCS, and brain stimulation in general, will push the boundaries for how we treat mental health both in terms of personalisation and accessibility. Despite incredible advances, we still see a heavy focus on pharmaceutical development, with one new antidepressant costing around US$5 billion to produce. And, this just is not good enough. Medication has about a 30–50% efficacy rate, and that is just for those receiving treatment; for many, this is not an option due to side effects, treatment resistance, or personal reasons. If the only other option we have to offer people is therapy, which, again, has around a 50% efficacy rate for those able to access it—and can take years to produce effects—then we have reached a plateau.

With several decades of solid research into non-invasive brain stimulation, we know that tDCS has the proven effects in altering the activity in the brain to bring symptom relief for patients. At little cost to produce, the ability for the patient to self-administer, and no reliance on medication, tDCS will change how we can scale and treat populations at large. Further personalisation is a much stronger possibility with neuromodulation than either pharmaceuticals or therapy, since it is the modulation of clearly defined structures involved in depression.

Daniel Månsson is a clinical psychologist, and the CEO and cofounder of Flow Neuroscience—a Swedish medical technology company using its tDCS headset device and an artificial intelligence (AI)-powered smartphone app to treat mental health conditions.

Disclosures: The author discloses that they are the CEO and co-founder of Flow Neuroscience.

July 2021 | Issue 42

24

Michael J Fox Foundation launches new resource to educate Parkinson’s patients on DBS The Michael J Fox Foundation has launched “Deep Brain Stimulation and Parkinson’s— From Decision-making to Daily Life with the Device”, an online resource designed to educate patients and care partners about deep brain stimulation (DBS) surgery as a treatment option to help manage symptoms.

The resource also provides practical tips for thinking about, undergoing and living with DBS, includes perspectives and voices from the patient and family community, and shares information on the latest research and available DBS devices.

THE NEW RESOURCE ON DBS AND Parkinson’s disease was written by Michael J Fox Foundation senior vice-president of Medical Communications and movement disorder specialist

Rachel Dolhun (New York, USA). The guide, which has been medically reviewed by leading Parkinson’s physicians and DBS experts, includes personal reflections and anecdotes from families who experienced DBS. In addition, the foundation says it sourced common questions, themes and tips on DBS through its social media channels, and its diverse community of people and families living with Parkinson’s disease.

“Some of the most common questions from patients and families—whether they have been recently diagnosed or have lived with Parkinson’s for many years—are around DBS,” said Dolhun. “The goal of this guide is to provide information about the DBS journey, everything from thinking about the treatment option to having the procedure and beyond. And, ultimately, to empower people and families to learn more, ask questions, or start conversations about this treatment option.”

According to a press release from the foundation, patients and their families can use this 22-page guide to: ● Begin learning about DBS as a treatment option and whether it is right for them, and the symptoms it may or may not help ● Prepare practical questions to discuss with doctors and loved ones before DBS surgery, during surgery, and life after ● Assess general guidelines and tips for practicing regular activities while living with DBS

Men and women respond equally well to spinal cord and DRG stimulation despite contrasting baseline pain scores

In a study intended to explore gender differences in patients with failed back surgery syndrome (FBSS) or chronic visceral pain, men and women have been shown to respond equally well to spinal cord stimulation and dorsal root ganglion (DRG) stimulation at followup—although some disparities, including “significantly lower” baseline average pain scores in male patients, were observed.

“FEMALE GENDER AND OLDER age were associated with greater likelihood of having an explant compared to male gender and younger age, highlighting the potential utility of demographic information to identify patients who may encounter challenges with spinal cord stimulation,” Beatrice Bretherton (Pain Management Department, Leeds Teaching Hospitals NHS Trust, Leeds, UK) and colleagues add. “The influence of gender and age on outcomes should be further scrutinised and systematically reported in future prospective and retrospective research that measure psychosocial, biological, and clinical parameters.”

In spite of this, there were no significant differences at follow-up between men and women regarding their responses to various forms of neurostimulation for pain relief. Writing in Neuromodulation: Technology at the Neural Interface, Bretherton et al state that this suggests gender may have “marginal effects” on spinal cord and DRG stimulation responses “despite playing an influential role at baseline”.

According to the study’s authors, the findings of multiple previous investigations have indicated that pain treatments may benefit one gender over the other and, as such, it is important

to evaluate gender differences because they may affect a clinician’s perception of the severity of the pain condition, and, in turn, influence treatment choices.

However, even with this “accumulating evidence” pointing to differences between men and women in responses to pain treatment, they note that there is limited evidence exploring gender differences in patient responses to spinal cord and DRG stimulation.

The researchers investigated this phenomenon via a retrospective, singlesite study involving all patients with FBSS or chronic visceral pain who had received a fully implanted 10-kHz spinal cord stimulation, BurstDR (Abbott) or DRG system in the Leeds Teaching Hospitals NHS Trust between March 2012 and March 2020. They report that differences between men and women in baseline and follow-up average pain, worst pain, and quality of life (QoL) were ascertained, with the influence of gender on the occurrence and reasons for revision and explants also being assessed.

The study was exploratory and not hypothesis driven.

The final sample comprised 387 patients (54.5% female), Bretherton et al state, and men were significantly older compared to women (mean difference=2.33 years, p=0.044) while

● Provide information on the latest devices available and ongoing research “Deep Brain Stimulation and Parkinson’s—From Decision-making to Daily Life with the Device” was made possible through support from Abbott Laboratories, the foundation states. “By partnering with the Michael J Fox Foundation, we are able to help provide people living with Parkinson’s disease and their families the educational resources they need to make informed treatment decisions to help them live their lives to the fullest,” said Binith Cheeran, director of Medical Affairs for Neuromodulation at Abbott.

In addition to introducing this free guide, which is available to download at michaeljfox.org/DBSguide, the Michael J Fox Foundation claims it is involved in further efforts to improve existing DBS therapies for Parkinson’s disease—including via the Registry for the Advancement of Deep Brain Stimulation Therapy in Parkinson’s Disease (RAD-PD).

This study is funded by the foundation and aims to guide DBS care decisions by gathering clinicianmeasured and patient-reported data on the experience, methods and outcomes of DBS. Findings from the RADPD could also improve existing understanding of best DBS settings for symptom control, potential side effects, and gaps in access to DBS therapy. Since its inception in 2000, the foundation claims to have invested more than US$9 million into researching DBS for Parkinson’s.

baseline average pain was significantly lower in men than women. Men and women responded equally well to 10kHz spinal cord stimulation, burst spinal cord stimulation, and DRG stimulation, and there were no significant differences between the genders in average pain, worst pain and QoL at follow-up—both before and after controlling for age. The mean follow-up duration was 24 months.

In addition to this, rates of revision were similar across the final sample (16%) and between the different study subgroups (FBSS=15%; visceral pain=18%; 10-kHz spinal cord stimulation=13%; burst spinal cord stimulation=17%)—the only exception being that the percentage of patients undergoing a surgical revision seemed to be higher for DRG stimulation (54%), although Bretherton et al note that this may have been due to the smaller DRG sample size. Gender was “significantly associated with lead fracture revisions”, as a greater percentage of men (5%) had revisions due to lead fractures compared to women (1%). Bretherton et al propose that this final distinction may have been due to differences in physical activity levels between men and women, and requires further investigation.

In total, 54 of 441 patients (12%)

This is a key finding considering the importance of tailoring treatments to the needs of individual patients.”

underwent a full-system explantation, with insufficient pain relief found to be the most common reason for explant across genders in the subgroups, followed by infection and requiring a magnetic resonance imaging (MRI) scan.

The authors also highlight that more women (13%) than men (6%) had an explant due to insufficient pain relief.

The female gender and older age were “intriguingly” associated with a greater likelihood of having an explant compared to male gender, and younger age, as well.

In their report, Bretherton et al note that they observed differences in baseline measures emerging between different spinal cord stimulation systems within each gender group. For instance, QoL was significantly lower in females with 10-kHz spinal cord stimulation compared to those with burst spinal cord stimulation, and males with 10-kHz stimulation had significantly higher average pain at baseline than males with BurstDR alternatives.

“Although these differences disappeared at follow-up, the profiles of patients undergoing 10-kHz spinal cord stimulation may be distinct from those with burst spinal cord stimulation,” the authors add. “This is a key finding considering the importance of tailoring treatments to the needs of individual patients.” They also allude to several limitations of their study, including psychological variables and challenges in measuring physical activity levels, as well as the differences in biology between men and women.

Beatrice Bretherton

Issue 42 | July 2021

Market watch 25

Product News Philips enrols first patient in WE-TRUST stroke study to assess new workflow approach

Philips has announced the first patient has been enrolled in the WE-TRUST (Workflow optimisation to reduce time to endovascular reperfusion for ultra-fast stroke treatment) study at Vall d’Hebron University Hospital in Barcelona, Spain.

This marks the start of the first global multicentre randomised controlled trial (RCT) to assess if the company’s Direct to Angio Suite workflow approach— which combines stroke diagnosis and treatment in the same angiosuite—can improve patient outcomes less than six hours after stroke onset.

“After suffering a stroke, fast time to treatment is paramount to giving patients the best possible outcomes,” said Raul Nogueira, director, Neuroendovascular Service Marcus Stroke and Neuroscience Center at Grady Health (Atlanta, USA) and WE-TRUST principal investigator.

“What we will learn about improving time to treatment in the WE-TRUST trial has the potential to significantly improve how acute stroke patients are diagnosed and treated. With the help of an advanced brain scan technology in the angiosuite, for example, we intend

to eliminate the need for conventional CT [computed tomography] or MRI [magnetic resonance imaging] scans for stroke triage in select patients to save valuable time.”

The multicentre, prospective, openlabel, blinded WE-TRUST RCT will take place at 15 leading stroke sites, and aims to enrol more than 560 patients across the USA, South America and Europe. The primary endpoint of the WE-TRUST trial, which is anticipated to be completed by 2023, is clinical outcome measured by the patients’ functional status on the modified Rankin Scale (mRS) three months after the procedure.

Chordate Medical receives CE mark to treat chronic migraine with neuromodulation product

Chordate Medical has received a CE marking that permits its Kinetic Oscillation Stimulation (KOS) technology to be marketed, sold and used for the treatment of chronic migraine within the European Union.

The company’s KOS neuromodulation treatment method is already CE marked for the treatment of chronic nasal congestion, or rhinitis, but that clearance has now been extended to include its

use as a preventive treatment for chronic migraine in adults over the age of 18.

Treatment with KOS uses vibrations to stimulate the nerves in the mucous membranes of the nose, which is believed to balance the autonomic nervous system. This can help people with migraine who are believed to have an imbalance or irritation of the autonomic nervous system. KOS also has few or no side effects, especially in comparison to botox and other treatments for migraine.

Despite already gaining a CE mark, Chordate will continue with its ongoing migraine study until it is completed— which is expected to be after the summer of 2021. And, while the final results of the study are now “not as decisive” due to the company having already gained approval for its KOS technology, they will nevertheless be published in a scientific journal, and serve as academic evidence of the clinical efficacy and safety of the treatment.

of radiology at Pauls Stradiņš Clinical University Hospital (Riga, Latvia).

“We recently brought the Stream family of products into our institution, and I have been very pleased with the additional physician control and positive outcomes when using this nextgeneration stentriever in my practice,” said Kupčs. “With the Stream17, I appreciate the ability to navigate through a small .017-inch microcatheter to effectively remove thrombus in more distal vessels. Moreover, the device was easy to use and resulted in efficient, full recanalisation of the vessel.”

This builds on an announcement from March 2021 of the first clinical use of Perflow’s Cascade17 non-occlusive remodelling net, which maintains vessel patency during coil embolisation treatment of intracranial aneurysms.

The company’s Cascade and Stream net product families are both commercially available in Europe, but are yet to be cleared for clinical use in the USA.

Perflow Medical announces first clinical use of Stream17 dynamic neurothrombectomy net

Perflow Medical has announced the first successful clinical use of its Stream17 dynamic neurothrombectomy net—a lower-profile device designed to effectively treat haemorrhagic and ischaemic stroke patients with more tortuous anatomies. The first clinical procedures using the device were completed by Kārlis Kupčs, head

SNIS 18th Annual Meeting & Fellows Course

Stream17

Register Now

July 26-30, 2021 The Broadmoor Colorado Springs, CO

Programming in conjunction with: European Society of Minimally Invasive Neurological Therapy

https://www.snisonline.org/meetings/snis-18th-annual-meeting/

July 2021 | Issue 42

26 Market watch

Product News Medtronic, Surgical Theater to provide first real-time AR platform for complex cranial procedures

Medtronic will partner with Surgical Theater to provide the first augmented reality (AR) platform for use in real time during complex cranial procedures.

The partnership will see Medtronic’s StealthStation S8 surgical navigation system interfaced with Surgical Theater’s SyncAR technology.

The collaboration will enable neurosurgeons to use AR technology in real time to enhance visualisation during complex cranial procedures—harnessing the SyncAR platform’s fighter-jet simulation technology to allow surgeons to visualise structures in the brain, test virtual surgical tools and plan surgeries before entering the operating room.

By integrating this technology with the StealthStation S8 cranial solution, surgeons can expand the benefits of AR and, “for the first time”, see a 360-degree AR rendering overlaid onto the live surgical site during brain surgeries. This is intended to improve precision and efficiency during these complicated procedures.

“SyncAR offers important benefits in planning and practicing how to approach complex cases, and now being able to actually use AR during procedures to see where instruments are in relation to critical structures, while never losing focus on the patient, is a significant advance,” said Thomas Steineke, boardcertified neurosurgeon and chairman of the JFK Neurosciences Institute (Edison, USA). “In neurosurgery, it is paramount to correctly identify and navigate critical brain structures. AR-enhanced visualisation interfacing with the StealthStation will help me achieve the best possible outcomes for my patients.”

Neuromodulation device for treating MS-related gait deficit receives FDA authorisation

Cambridge Consultants and Helius Medical Technologies have confirmed their “groundbreaking” Portable Neuromodulation Stimulator (PoNS) device—developed for the short-term treatment of gait deficit due to mildto-moderate symptoms from multiple sclerosis (MS)—has received marketing authorisation from the US Food and

PoNS device

Drug Administration (FDA).

The two companies collaborated to develop this technology in order to treat patients suffering from neurological disease. The device is the first commercial product from Helius and is designed to provide potentially lifechanging therapy for MS patients.

The PoNS device is a non-invasive, body-worn medical device that delivers controlled neurostimulation to two cranial nerves via the tongue, making it the “first and only tongue-delivered neuromodulation therapy” approved in the USA. When used in conjunction with physical therapy, PoNS treatment is believed to enhance a patient’s neuroplasticity, improving their ability to learn, train, and rehabilitate.

The interactive PoNS controller, designed for user-centric patient and clinician workflow, is coupled with a mouthpiece electrode system that delivers precise neurostimulation during therapeutic exercise. In addition, a clinician interface with cloud-based data management software provides doctors with a digital ecosystem to enable efficient patient care.

Penumbra receives FDA clearance for Red 62 reperfusion catheter

Penumbra has announced US Food and Drug Administration (FDA) 510(k) clearance and commercial availability of the Red 62 reperfusion catheter— the latest addition to the company’s comprehensive Penumbra system. Red 62 is designed to navigate complex distal vessel anatomy and deliver powerful aspiration, alongside the Penumbra Engine, for the removal of blood clots in acute ischaemic stroke patients with large vessel occlusions.

“In my initial experience with Red 62, I am impressed by how responsive the catheter is as I navigate through the intricate vessels of the brain,” said Kurt Reuland, interventional neuroradiologist at Christus Trinity Mother Frances Health System (Tyler, USA). “The performance and length of Red 62 enable me to address a broader group of patients using aspiration thrombectomy to remove blood clots, and improve my patients’ health outcomes.”

The Red 62 is engineered with the latest innovations in tracking and aspiration technology to address large

vessel occlusions located in more challenging distal vessel anatomies while maximising powerful aspiration to remove blood clots. It has a low diameter profile and extended length to reach the target vessel.

Perfuze announces CE mark and treats first patients with Millipede 088 catheter

Perfuze has announced that the first five acute ischaemic stroke patients have been treated with its Millipede 088 clot aspiration catheter—having received CE mark approval for the device in February 2021.

“Our initial experience with the device has been very positive,” said interventional neuroradiologist John Thornton (Beaumont Hospital, Dublin, Ireland), who performed the first case.

“I believe the large bore and distal flow control capability offers unique safety and efficacy advantages over existing devices.”

The Millipede 088 is a clot aspiration catheter that has a 0.088-inch inner diameter. This feature provides two unique advantages: an increase in distal tip surface area of up to 50% compared to existing devices, providing an equivalent increase in aspiration power, and distal flow control that may prevent distal emboli.

“I am extremely pleased with the device,” added interventional neuroradiologist Matt Crockett (Beaumont Hospital, Dublin, Ireland).

“In the thrombectomy case that I performed, the Millipede 088 was used as primary therapy for the patient. It ingested a large occlusive M1 clot in a single pass, resulting in an mTICI 3 reperfusion [complete vessel re-opening] in less than 15 minutes.”

FDA approves “first-of-itskind” SenSight directional lead system for DBS therapy

Medtronic has announced US Food and Drug Administration (FDA) approval and first US implants of the SenSight directional lead system, which is used for deep brain stimulation (DBS) therapy. SenSight is a first-of-its-kind DBS directional lead that combines the benefits of directionality with the power of sensing, allowing physicians to deliver precise, patient-specific DBS therapy for the treatment of some symptoms associated with movement disorders like Parkinson’s disease, dystonia and essential tremor, and medically refractory epilepsy.

“Until now, sensing capability and directional leads have not been available in the same DBS system, so we have had to choose one technology or the other, based on the predicted needs of each patient,” said Kelly D Foote, professor of neurosurgery at the University of Florida (Gainesville, USA). “Now, by coupling this new directional lead with a pulse generator capable of brain sensing, we are excited to be able to offer our patients the synergistic benefits of both technologies. Furthermore, the ability to continuously record brain activity while affected patients go about their daily

lives is a powerful research tool that is rapidly improving our understanding of these brain circuitry disorders that diminish the lives of so many people.”

For the SenSight directional lead system, Medtronic claims to have reimagined how a lead system for DBS therapy is designed, with the patient, neurosurgeon, and programming neurologist in mind. Deliberate choices related to materials and design were made to enhance comfort for patients, allow for more precise stimulation, and streamline the surgical procedure—all while being able to capture objective data for more efficient, informed programming.

SenSight directional lead systems were first implanted at the University of Florida by multidisciplinary teams in June 2021, and also previously received a CE mark and fully launched in Western Europe in March.

CINA ASPECTS

Avicenna.AI gains CE mark for AI tool to assess stroke severity

Avicenna.AI has received CE mark certification for its CINA ASPECTS AI tool for stroke severity assessment.

CINA ASPECTS automatically processes non-contrast computed tomography (CT) scans and calculates an Alberta Stroke Program Early CT (ASPECT) score in order to assist radiologists within their existing systems and workflow.

ASPECTS is a topographic scoring system used to quantify the severity of a stroke from a CT scan of the brain.

It divides the brain territory affected by a stroke into 10 areas of interest, and provides a score between zero and 10, where 10 is normal and zero indicates widespread ischaemic damage throughout the affected area.

CINA ASPECTS—which is part of Avicenna.AI’s CINA Head family of artificial intelligence (AI) tools for the treatment of stroke and neurovascular emergencies—computes a heat map indicating the probability of hypodensity and/or sulcal effacement in the brain, and displays a list of infarcted regions. It provides tilted and resliced CT images to allow easy comparison of the right and left hemisphere. In addition to assisting clinicians with evaluating the ASPECT score from CT scans, CINA ASPECTS also helps improve the reproducibility of the score, which often varies depending on the radiologist reading the scan.

Issue 42 | July 2021

Market watch 27

Industry News UK charity funds “worldfirst” study into long-term COVID-19 impact on stroke

The Stroke Association is funding what it claims will be the world’s first study to determine the long-term impact of COVID-19 on stroke survivors. The study will attempt to establish how differences in patients with and without the virus may influence their treatment and care needs—including how they can avoid the risk of having further strokes.

In the study, researchers at University College London Hospitals (UCLH) NHS Foundation Trust will follow up to 4,000 stroke survivors, with and without COVID-19, from 13 emergency stroke units, tracking recovery, rehabilitation and health for up to 18 months after they have experienced a stroke. Comprehensive, specialist medical information from these patients, including brain scans, blood samples and measures of disability, will be collected and assessed to build an understanding of how the virus impacts stroke recovery, as well as which treatments could best support survivors’

recoveries and prevent recurrent strokes.

“Research that compares stroke in patients with and without COVID-19 is essential to understand if COVID-19 results in more severe strokes, where survivors will need more support to recover from its devastating effects,” said Richard Perry, lead researcher at UCLH (London, UK). “While redeployed to stroke wards at the start of the pandemic, I would see patients admitted with unusual strokes, who would then go on to have a positive COVID-19 test.

New Medical Device Regulation comes into effect across EU The new European Union (EU) Medical Devices Regulation (MDR) came into effect on 26 May 2021—replacing the Medical Device Directive (MDD).

The Regulation revises quality and safety standards, as well as the range of regulated devices, and was first initiated in May 2017 with an initial three-year transition period applied.

Implementation was, however, delayed

by 12 months due to the COVID-19 pandemic. Separate regulations governing in vitro diagnostics (IVDs) are set to come into effect in May 2022.

According to the European Commission, the MDR creates a “robust, transparent, and sustainable” regulatory framework, that will improve clinical safety and create fair market access conditions for manufacturers.

First annual World Stroke Thrombectomy Day announced

The Society of Vascular and Interventional Neurology (SVIN)’s Mission Thrombectomy 2020+ Initiative (MT2020+) announced the first annual World Stroke Thrombectomy Day at the Global MT Revolution Regional Conference in May 2021.

By designating this official day, MT2020+ intends to raise public awareness about thrombectomy surgery for the treatment of severe stroke, and instil new global calls to action. “We are very pleased to announce this annual global day that allows us to call on various stakeholders around the world to rapidly, equitably and sustainably continue to improve access to thrombectomy for stroke in their regions,” said Dileep Yavagal, MT2020+ global chair and past president of SVIN.

Stroke and heart condition patients want virtual healthcare to continue post pandemic

The Heart and Stroke Foundation of Canada has revealed data from online and telephone surveys indicating there is “great promise, and a continued desire” for virtual healthcare opportunities beyond the COVID-19 pandemic.

“Virtual care is meant to complement, not replace, in-person visits,” said Patrice Lindsay, director of Health Systems Change at the foundation.

“But, virtual healthcare has enormous potential to provide quality care for people living with stroke or heart conditions, and reduce the burden on the healthcare system from prevention to acute care, disease management, rehabilitation and end-of-life care.”

An online survey of more than 3,000 people living with stroke, heart disease or vascular cognitive impairment, and caregivers, found over half of these populations wanted the option for virtual appointments beyond COVID-19—an increase from a similar survey carried out a year prior—while a Sentis Research telephone poll from April 2021 showed more than 70% of respondents wanted their provincial government to provide funding to improve access to virtual care.

Calendar of events

Event details correct at time of publication.

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

26–30 July 2021 SNIS (Society of NeuroInterventional Surgery) 18th Annual Meeting and Fellows Course Colorado Springs, USA

8–10 September 2021 ESMINT (European Society of Minimally Invasive Neurological Therapy) Congress Nice, France

www.snisonline.org/meetings/snis-

www.esmint.eu/esmint-congress

18th-annual-meeting

1–3 September 2021 7th ESOC (European Stroke Organisation Conference) Virtual

14–16 September 2021 LINNC (Live Interventional Neuroradiology, Neurology & Neurosurgery Course) Paris Paris, France

www.eso-conference.org

www.linnc.com/Course-information/

15–16 September 2021 Neuro Convention Birmingham, UK www.neuroconvention.com

26–28 September 2021 World AVM (ArterioVenous Malformations) Congress New York City, USA www.avm2021.org

28–29 October 2021 13th WSC (World Stroke Congress) Virtual https://worldstrokecongress.org

17–20 November 2021 SVIN (Society of Vascular and Interventional Neurology) Annual Meeting Phoenix, USA www.svin.org

LINNC-Paris-2021

September

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