NeuroNews 30 – June US edition

June

Issue

18 30

App

Dylan N Wolman

Profile

and Jeremy J Heit

Neuroimaging for EVT

Mayank Goyal

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WAKE-UP trial shows that thrombolysis can benefit certain stroke patients with unknown time of onset In patients with unknown symptom onset stroke with magnetic resonance imaging (MRI) pattern of diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch, treatment with alteplase resulted in better functional outcome than placebo. These benefits were consistent across all categories of outcome and major clinical secondary endpoints.

T

he effect size of MRI-guided thrombolysis in unknown symptom onset stroke is comparable to the effect size of thrombolysis <4.5 hours.

The study set out to prove efficacy and safety of MRI-based thrombolysis on patients with unknown time of onset. This is common, with around 25% of stroke patients having an unknown time of onset.

Patients often wake-up with stroke, making it impossible to say when onset was.

As a result of the WAKE-UP trial these patients can now benefit from intravenous thrombolysis.

The WAKE-UP trial results were presented at European Stroke Organisation Conference (ESOC; 16–18 May 2018, Gothenburg, Sweden) by lead investigator Götz Thomalla, University Medical Centre, Hamburg, Germany.

The European Union–funded study was also published online simultaneously in the New England Journal of Medicine.

“This is the first positive trial of IV thrombolysis in stroke with unknown time of onset and will lead to a paradigm change,” Thomalla said. “It will make a big impact on clinical practice as about 25%

of stroke patients have undetermined time of onset, and approximately one third to one half of these will now qualify for the treatment based on these imaging criteria.”

To see whether treatment with alteplase would improve functional outcomes in patients with an unknown time of stroke onset and a mismatch between diffusionweighted imaging and fluidattenuated inversion recovery (FLAIR) findings on MRI, the researchers conducted a randomised controlled trial.

The patients enrolled had an ischaemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on FLAIR, suggesting that the stroke had occurred within the previous 4.5 hours.

Patients who had planned thrombectomies were excluded.

For the study, researchers screened 1,362 patients ischaemic stroke of unknown time of onset to identify those with an ischaemic lesion visible on diffusion-weighted MRI but no parenchymal hyperintensity on fluid-

attenuated inversion recovery (FLAIR).

Of these patients, 503 had suitable imaging results and were randomly assigned to alteplase or placebo. Most patients had mild to moderate strokes.

The primary endpoint was favourable outcome, as defined by a score of 0 or 1 on the mRS, at 90 days. This occurred in 53.3% of the alteplase group and 41.8% of the placebo group (adjusted odds ratio, 1.61; 95% CI, 1.09–2.36; p=0.02).

The secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale compared with placebo.

The shift analysis also showed benefit with alteplase: the median mRS score at 90 days was one in the alteplase group and two in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 – 2.23; p=0.003).

There was a trend toward increased mortality in the alteplase group, with 10 deaths (4.1%) in patients receiving alteplase vs. 3 (1.2%) in the placebo group (odds

ratio, 3.38; 95% CI, 0.92–2.52; p=0.07).

In the alteplase group, four deaths were attributed to symptomatic intracranial haemorrhage and one to recurrent ischaemic stroke. The other five deaths were attributed to noncerebral causes unrelated to the initial stroke or treatment.

The rate of symptomatic intracranial haemorrhage was 2% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57–42.87; p=0.15).

Addressing the risk-benefit ratio, senior author, Christian Gerloff, University Medical Center, Hamburg, pointed out that results from the shift analysis suggested that the benefits of treatment outweighed the harms.

“The shift analysis was even more significant than the primary endpoint.

This includes all categories, including death—so the mortality data do not weaken the overall benefit,” he commented.

The researchers hope that the results of WAKE-UP will have an immediate impact on clinical practice and guidelines of stroke treatment and that MRI-based thrombolysis will become the standard of care.

ReActiv8 results: Neurostimulation safe and effective treatment for chronic low back pain

Following implantation of a restorative neurostimulation system significant improvements were observed in pain, disability and quality of life compared to baseline in patients with chronic refectory low back pain.

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he ReActiv8-A trial was a prospective single arm clinical trial that collected performance and safety data on a new implantable restorative neurostimulation system for patients with chronic refractory low back pain. The results were presented

by Vivek Mehta, St Bartholomew’s Hospital, London, UK, at the World Congress of the World Institute of Pain (WIP; 9–12 May 2018, Dublin, Ireland).

Bilateral stimulation of the medial branch of the L2 dorsal ramus elicits episodic contractions of the lumbar multifidus and reactivation of lumbar multifidus motor control and restoration of dynamic stability has been a hypothesised mechanism of action facilitating recovery.

The trial enrolled 53 patients (age 44±10 years, pain duration 14±11 years) who were implanted at nine centres in Europe and Aus-

tralia. Selection criteria included disabling chronic refractory low back pain despite 90-days of medical management, no indications for spine surgery and no prior surgery. Patients administered 30 minute stimulation sessions twice daily for a minimum of 90 days.

Measures recorded were numerical rating scale (NRS) for pain, Oswestry Disability Index (ODI) for disability, EQ-5D for quality of life and treatment satisfaction.

Utilising matched data, significant improvements (p<0.001) were observed in pain, disability, and quality of life compared to baseline. NRS (6.8±0.2 at baseline) improved 35%±5% at 90-days (n=52), 32%±5% at six months (n=51) and 33%±6% at one year (n=47). The proportion of patients with a clinically important improvement one or more of the numerical rating scale, the Oswestry Disability Index and

EQ-5D were 94%, 86% and 87% respectively. Similarly, 89%, 84% and 81% reported being satisfied or very satisfied with the treatment. There were no unanticipated adverse events and no serious therapy related adverse events.

The study concluded that neurostimulation to contract the lumbar multifidus appears to be a safe and effective treatment option for these patients with chronic refractory low back pain.

June

International study suggests combination therapy may prevent second stroke in certain people Results from POINT, an international clinical trial of more than 4,880 participants, simultaneously published in the New England Journal of Medicine, show that combining clopidogrel and aspirin following a small stroke or experiencing minor stroke symptoms decreases risk of a new stroke, heart attack or other ischaemic event within 90 days. The combination therapy was also associated with an increase in major bleeding, although many of those episodes were non-fatal and did not occur in the brain.

“T

hese findings are likely to have a global effect on clinical practice, as these drugs are easily available in many hospitals and clinics,” said Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke. “As the benefit of the combination was concentrated in the first two weeks while risk of bleeding was constant over 90 days, it may be especially valuable in acute management of a minor ischaemic stroke or transient ischaemic attack (TIA).”

The Platelet-Oriented Inhibition in New TIA and minor ischaemic stroke (POINT) clinical trial follows an earlier study, which showed benefits of this drug combination in a Chinese population.

POINT was conducted to see whether the benefits could be expanded to a more diverse group of patients.

The study, led by S. Claiborne Johnston, dean and professor of neurology at Dell Medical School at The University of Texas at Austin, USA, included patients who had experienced either a minor stroke or a transient ischaemic attack (TIA), in which blood supply to a part of the brain is briefly stopped and can be a risk factor for a larger stroke. Study participants were given clopidogrel and aspirin or aspirin alone to see whether the combination therapy could prevent a larger stroke within three months.

Johnston’s team found that the combination of clopidogrel and aspirin prevented more ischaemic events, such as stroke and heart attack, compared to aspirin alone. The results showed that 5% of

patients in the combination therapy group and 6.5% of patients taking only aspirin experienced such an event within 90 days. However, the combination therapy was associated with a greater risk of major bleeding, or haemorrhage, than aspirin alone. In the aspirin-only group, 0.4% of patients suffered a major haemorrhage but 0.9% of patients taking clopidogrel and aspirin had severe bleeding.

The findings suggest that for 1000 patients, clopidogrel plus aspirin would prevent 15 ischaemic attacks but may cause five instances of major haemorrhage. The majority of these haemorrhages occurred outside of the brain and were not fatal.

“We saw a real benefit with the combination therapy, but that treatment does come with a risk,” said Johnston.

“Overall, the risk of severe bleeding was very small, but it was not zero.”

The study was stopped early because the combination therapy was found to be more effective than aspirin alone in preventing severe strokes but also due to the risk of severe haemorrhage.

Clopidogrel and aspirin prevent platelets from sticking together and forming clots in blood vessels, although they work in different ways. Aspirin blocks molecules that activate the clotting process while clopidogrel prevents a specific chemical from attaching to a receptor.

“Each year, strokes cause millions of disabilities around the world and preventing many of those would lead to not only tremendous health savings, but improved quality of life for many individuals and their families,” said Johnston.

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Randomised controlled trial needed to determine safety of direct mechanical thrombectomy as compared with intravenous thrombolysis prior to mechanical thrombectomy The meta-analysis trial showed no evdence that rates of successful reperfusion differed in direct mechanical thombectomy and intraveous thrombolysis prior to mechanical thrombectomy.

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n contrast to previous synopses and when analysis is confined to studies with a low risk of selection bias (i.e., comparable IVT (intravenous thrombolysis) -eligible patients in both treatment strategy groups), data published in the Journal of NeuroInterventional Surgery suggest that for patients who finally undergo mechanical thrombectomy, direct mechanical thrombectomy may offer comparable safety and efficacy as compared with intravenous thrombolysis prior to mechanical thrombectomy. The analysis showed that outcome comparisons yield mixed results when less comparable patients are considered (direct mechanical thrombectomy in IVT-ineligible patents vs. intravenous thrombolysis prior to mechanical thrombectomy in IVT-eligible patients). These findings are the rationale of randomised controlled trials, comparing both treatment approaches.

The authors, Kaesmacher et al, write: “Available data do provide substantial indications of clinical non-inferiority, suggesting that the conduct of randomised clinical trials evaluating direct mechanical thrombectomy versus intravenous thrombolysis prior to mechanical thrombectomy in large vessel occlusion (LVO) patients is appropriate when including only major vessel occlusions and when rapid access to endovascular treatment can be assured. The value of pre-interventional recanalisation in intravenous thrombolysis prior to mechanical thrombectomy needs further evaluation and should be reported more consistently.”

To look at whether there is a benefit the group performed a meta-analysis in accord with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

The pooled effect sizes were calculated using the inverse variance heterogeneity model and displayed as summary odds ratio (sOR) and corresponding 95% confidence interval (95% CI). Sensitivity analysis was performed

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by distinguishing between studies including direct mechanical thrombectomy patients eligible for IVT (IVT-E) or ineligible for IVT (IVT-IN).

The primary outcome measures were functional independence (modified Rankin Scale ≤2) and mortality at day 90, successful reperfusion, and symptomatic intracerebral haemorrhage.

The analysis looked at 20 studies, incorporating 5,279 patients. They found that there was no evidence that rates of successful reperfusion differed in direct mechanical thrombectomy and intravenous thrombolysis prior to mechanical thrombectomy patients (sOR 0.93, 95% CI 0.68 to 1.28). In studies including IVT-IN direct mechanical thrombectomy patients, they found that patients undergoing direct mechanical thrombectomy tended to have lower rates of functional independence and had higher odds for a fatal outcome as compared with intravenous thrombolysis prior to mechanical thrombectomy patients (sOR 0.78, 95% CI 0.61 to 1.01 and sOR 1.45, 95% CI 1.22 to 1.73). Importantly however, they also highlight that “No such treatment group effect was found when analyses were confined to cohorts with a lower risk of selection bias (including IVT-E direct mechanical thrombectomy patients).”

The authors conclude: “The quality of evidence regarding the relative merits of intravenous thrombolysis prior to mechanical thrombectomy versus direct mechanical thrombectomy is low. When considering studies with lower selection bias, the data suggest that direct mechanical thrombectomy may offer comparable safety and efficacy as compared with intravenous thrombolysis prior to mechanical thrombectomy. The conduct of randomised-controlled clinical trials seems justified.”

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June

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MR CLEAN

Time to treatment may be more strongly associated with good functional outcomes than previously thought The link between time to endovascular treatment for acute ischaemic stroke and good functional outcomes may be stronger than previously thought. This may be due to more selected patients who were treated in randomised control trials.

T

he study, published in Circulation, found that for every hour delay in time from stroke onset to endovascular treatment start resulted in a 5.3% decrease in the probability of functional independence and a 2.2% increase in mortality. It also found that for every hour delay from stroke onset to successful reperfusion resulted in a 7.7% decrease in the probability of the functional independence.

These findings highlight the need for patients to undergo endovascular treatment as quickly as possible, as this greatly improves the functional outcomes.

The study states that, “Reducing delays in the delivery of endovascular thrombectomy should be a primary objective of all stroke centres that refer or treat patients with acute ischaemic stroke”.

It has previously been reported that

every hour delay in time from onset to start of endovascular treatment resulted in a 3.4% decreased probability of functional independence and for every hour delay from time of onset to successful reperfusion there is a 5.2% decreased probability of functional independence.1 However these findings may not be generalisable due to the strict inclusions and exclusion criteria that many trials used.

Data from the MR CLEAN Registry was used to assess the association of time to endovascular treatment with functional outcome in current, everyday clinical practice. The MR CLEAN Registry is an ongoing, prospective, observational study in all centres that perform endovascular treatment in the Netherlands.

Registration started directly after the final randomisation in March 2014 in the Multicentre Randomised Clinical Trial

of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN trial).

Overall, 1,488 patients were included in the analysis and all of them had a known stroke onset time. For 1,117 patients (75%) the actual time of stroke onset was known and for the other 371 patients (25%) the time last seen well was known. The inclusion criteria were groin puncture within 6.5 hours of stroke onset, being 18 years old or over, being treated at a MR CLEAN trial centre, intracranial proximal arterial occlusion in the anterior circulation as demonstrated by CT angiography, magnetic resonance angiography or digital subtraction angiography.

An increased time to start of endovascular thrombectomy was associated with worse functional outcome (adjusted common odds ratio = 0.83 per hour, 95% confidence interval: 0.77– 0.89) and a 2.2% increase in mortality.

Every hour increase from stroke onset to endovascular thrombectomy start

resulted in a 5.3% decreased probability of functional independence (mRS 0–2).

In the 742 patients with successful reperfusion, every hour increase from stroke onset showed an even stronger association with poor functional outcome (adjusted common odds ratio = 0.79 per hour, 95% confidence interval: 0.71– 0.88). This results in a 7.7% decreased probability of functional independence.

The data from the trial suggest that the association between time to endovascular thrombectomy for acute ischaemic stroke might be even stronger than previously suggested in studies on more selected patient populations from randomised controlled trials.

The authors conclude: “These findings emphasise that functional outcome of endovascular thrombectomy patients can be greatly improved by shortening onset to treatment times.”

References 1. Savers et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischemic Stroke: A Meta-analysis. JAMA. 2016;316:1279-1288.

MR CLEAN Registry shows that endovascular treatment for acute ischaemic stroke is as effective and safe as in the setting of a randomised controlled trial The results of the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry show that in routine clinical practice, endovascular treatment for patients with acute ischaemic stroke due to proximal intracranial vessel occlusion in the anterior circulation is at least as effective and safe as in the setting of a randomised controlled trial.

The findings confirm that endovascular treatment should be the standard of care for patients with acute ischaemic stroke due to proximal intracranial vessel occlusion in the anterior circulation and were published in the British Medical Journal.

E

ndovascular treatment consisted of arterial catheterisation with a microcatheter to the level of occlusion, followed by mechanical thrombectomy or thrombus aspiration, or both, with or without delivery of a thrombolytic agent. The method of endovascular treatment for each patient was left to the discretion of the treating doctors.

Several randomised trials and meta-analyses have shown efficacy and safety of endovascular treatment for acute ischaemic stroke due to proximal intracranial vessel occlusion in the anterior circulation, within six hours from symptom onset.

Whether outcomes and safety in routine clinical practice are comparable to previous randomised clinical trials of endovascular treatment for acute ischaemic stroke is unknown and current information about outcomes and safety of endovascular treatment is derived from patients treated in the setting of a randomised controlled trial.

Overall, 1,628 patients were registered in the MR CLEAN Registry between 16 March 2014 and 15 June 2016. For the current analysis 140 patients were excluded, mostly because of occlusion in the posterior circulation or treatment starting after 6.5 hours from the onset of symptoms. This meant that there were 1,488 patients were available for final analysis.

“Despite consistent proportions of patients who experienced successful reperfusion in the MR CLEAN Registry and the MR CLEAN trial, the improved functional outcome in patients in the MR CLEAN Registry can be explained by a shorter time from onset

Ivo Jansen

of symptoms to successful reperfusion or last contrast bolus of more than one hour”, write the papers authors.

After additional adjustment for this variable, the difference in benefit of endovascular treatment between the MR CLEAN Registry and the MR CLEAN trial intervention arm decreased and was no longer statistically significant. This again emphasises the importance of decreasing time from symptom onset to start of endovascular treatment as well

as procedure times. Faster successful reperfusion might also have contributed to the lower rates of haemicraniectomy and stroke progression patients in the MR CLEAN Registry. Increased experience of the interventionists could also have contributed to the rate of good functional outcome in routine clinical practice.

Finally, the proportion of patients who died within 90 days of onset of symptoms was higher than those in the MR CLEAN trial. This could be explained by a broader population being considered for endovascular treatment in routine clinical practice, including patients of greater age and prestroke morbidity.

The primary outcome was the modified Rankin Scale (mRS) score, ranging from 0 (no symptoms) to 6 (death) at 90 days after the onset of symptoms.

Secondary outcomes were excellent functional outcome (mRS score 0–1), good functional outcome (mRS score 0–2), and favourable functional outcome (mRS score 0–3) at 90 days; score on the extended thrombolysis in cerebral infarction scale at the end of the intervention procedure; National Institutes of Health Stroke Scale score 24–48 hours after intervention; and complications that occurred during intervention, hospital admission, or three months’ follow up period. Outcomes and safety variables in the MR CLEAN Registry were compared with the MR CLEAN trial intervention and control arms.

The authors conclude: “In routine clinical practice, endovascular treatment for patients with acute ischaemic stroke is at least as effective and safe as in the setting of a randomised controlled trial.”

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Large vessel occlusion detection

ACT-FAST algorithm shows higher specificity and reliability than existing scales for clinical LVO recognition The three-step ambulance clinical triage for acute stroke treatment (ACT-FAST) algorithm shows higher specificity and reliability than existing scales for clinical large vessel occlusion (LVO) recognition, despite requiring just two examination steps. The inclusion of an eligibility step allowed recognition of endovascular-eligible patients with high accuracy and using a sequential algorithmic approach eliminates scoring confusion and reduces assessment time.

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study published in Stroke looked at clinical triage scales for prehospital recognition of large vessel occlusion and found that they are limited by low specificity when applied by paramedics. The authors created the three-step ambulance clinical triage for acute stroke treatment (ACT-FAST) as the first algorithmic LVO identification tool, designed to improve specificity by recognising only severe clinical syndromes and optimising paramedic usability and reliability.

The study reports the three steps of the algorithm: “The ACT-FAST algorithm consists of unilateral arm drift to stretcher <10 seconds, severe language deficit (if right arm is weak) or gaze deviation/hemineglect assessed by simple shoulder tap test (if left arm is weak), and eligibility and stroke mimic screen.”

The ACT-FAST examination steps were retrospectively validated, and then

prospectively validated by paramedics transporting patients with suspected stroke in the emergency department, for the identification of internal carotid or proximal middle cerebral artery occlusion. The diagnostic performance of the full ACT-FAST algorithm was then validated for patients accepted for thrombectomy.

Lead author Henry Zhao comments: “I tried to design a practical yet accurate LVO identification tool appropriate for multicultural populations in order to improve outcomes for patients in reducing time to endovascular thrombectomy and reduce the healthcare inequality for patients who do not live near an endovascular centre.”

The study found that in retrospective (n=565) and prospective paramedic (n=104) validation, ACT-FAST displayed higher overall accuracy and specificity, when compared with existing LVO triage

Henry Zhao

scales. Agreement of ACT-FAST between paramedics and doctors was excellent (κ=0.91; 95% confidence interval, 0.79–1.0). The full ACTFAST algorithm (n=60) assessed by paramedics showed high overall accuracy (91.7%), sensitivity (85.7%), specificity (93.5%), and positive predictive value (80%) for recognition of endovascular-eligible LVO. The finalised ACT-FAST algorithm was designed with two examination

steps, followed by a final eligibility and stroke mimic screen step.

“The first step of ACT-FAST assesses for unilateral arm weakness using the NIHSS method of arm drift and is fulfilled when one arm drifts to the stretcher within 10 seconds. If the patient does not quickly turn their head and eyes to focus on the assessor in response to calling their first name and tapping them on the shoulder, they are assessed as having severe hemi-neglect,” write the authors.

“This test was chosen in preference to the NIHSS method of extinction assessment, which paramedics reported to be difficult to assess in uncooperative patients. The last step of ACT-FAST is designed to determine that deficits are not pre-existing, that time of onset is <6 hours, to determine premorbid functional level, and to rule out common stroke mimics.”

The ACT-FAST examination steps were validated, as was the full ACT-FAST algorithm. The algorithm was designed in steps.

The authors write: “Future studies will test whether field application of ACT-FAST by paramedics to bypass suspected patients with LVO directly to endovascularcapable centres can reduce delays to endovascular thrombectomy.”

Portable device detects severe stroke with 93% sensitivity The volumetric impedance phase shift spectroscopy (VIPS) device is a portable, noninvasive way of detecting severe stroke, including emergent large vessel occlusion (ELVO), with a sensitivity of 93% and a specificity of 92%, making it a promising tool for the triage of severe stroke patients. In contrast, a standard physical examination achieves an accuracy of 40–89% in identifying patients with large vessel occlusion who could benefit from endovascular therapy. The results of the VITAL study were published in the Journal of NeuroInterventional Surgery.

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urrent triage efforts consist mainly of neurological assessment that use physical examinations but these are highly user dependent and can fall short of sufficient diagnostic accuracy. Commonly used tests are the three-item Stroke Scale (3ISS), Los Angeles Motor Score (LAMS), Rapid Arterial Occlusion Evaluation Scale (RACE), the Cincinnati Prehospital Stroke Severity Scale (CinPSS), Field Assessment Stroke Triage for Emergency Destination (FAST-ED), and PASS. These scales focus on different elements of the neurological examination. Some put accuracy first while others focus on reproducibility and ease of use. Their diagnostic accuracy remains low, with reported sensitivities ranging from 55% to 85%, specificity from 40% to 89%, and area under the curve from 0.73 to 0.78.

The authors write, “Given the complexity of presentations associated with neurologic disease and the high rate of severe stroke mimics, scales that rely entirely on the neurologic examination are inherently error prone and incapable of sufficiently diagnosing severe stroke patients.”

VIPS (Cerebrotech Medical Systems) is a non-invasive technology capable of detecting a bioimpedance signature across body tissue. The device functions by transmitting an array of varying frequencies of low energy radio waves from each side of the back of the head to a receiver in the

forehead portion of the visor. Radio waves of different frequencies are modified differently as they pass through the tissue, depending on the type and fluid properties of the tissue, producing a unique signature for varied brain pathologies and the VIPS device exploits the alterations in tissue electrical properties that occur as a result of fluid and electrolyte changes. In a region of the brain that is ischeamic due to an ELVO, arterial blood content is diminished and the distribution of fluids and electrolytes between the intracellular, extracellular, and intravascular spaces may be substantially shifted. These alterations result in a change in the tissue bioimpedance. Because acute stroke typically affects the hemispheres unequally, ELVO induces an asymmetry in the bioimpedance of the brain. The larger the fluid and electrolyte changes in the affected cerebral region (i.e., the larger the stroke), the greater the bioimpedance asymmetry.

The study showed that a novel non-invasive device can rapidly acquire physiological data that may yield high sensitivity and specificity for detection of severe stroke.

Stroke treatment systems of care have been designed for the past 20 years around rapid administration of tissue plasminogen activator. Now with level 1a evidence in support of thrombectomy for ELVO, it is important to be

able to triage ELVO patients to thrombectomy capable centres as accurately and quickly as possible. Data suggest that approximately 75% of ELVO patients are denied a chance at thrombectomy due to delays in triage. The VIPS device is quick and easy to use, meaning it could significantly reduce triage times. Patients who are transferred from one hospital to another have longer revascularisation times, worse Alberta Stroke Program Early CT (ASPECT) scores at the time of treatment, and suffer worse outcomes.

The ideal diagnostic test to improve patient triage would be portable, fast, require minimal specialised training, pose no additional risks to the patient, perform in a reproducible and accurate manner, and be low cost such that it could be widely adopted in all ambulances to integrate into our current triage system. This is the first formal study evaluating a device with the potential to satisfy all of these characteristics.

VIPS device

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Neuroimaging

Highly efficient neuroimaging for endovascular mechanical thrombectomy patient triage DYLAN N WOLMAN JEREMY J HEIT COMMENT & ANALYSIS Dylan N Wolman and Jeremy J Heit write in NeuroNews about the importance of neuroimaging and the role it plays in patient evaluation.

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cute ischaemic stroke secondary to large vessel occlusion (LVO) of the anterior circulation is a devastating condition, with an approximately 70% risk of death or serious disability if untreated or treated by medical therapy alone.1,2 Recent unprecedented advances in acute ischaemic stroke treatment by endovascular mechanical thrombectomy have been shown to reduce significantly the morbidity and mortality of these severe strokes.3-5 Following the success of these endovascular trials, the stroke neurology and neurointerventional communities are treating many more patients with acute ischaemic stroke due to LVO, and their attention is increasingly turning toward effective systems of care and the most expeditious neuroimaging evaluation of endovascular mechanical thrombectomy candidates. Rapid and accurate identification of endovascular mechanical thrombectomy candidates both at comprehensive stroke centres and in smaller referring hospitals is essential to providing timely and appropriate care to acute ischaemic stroke patients.

The neuroimaging evaluation of acute ischaemic stroke patients has advanced in parallel to endovascular mechanical thrombectomy. Patients most likely to benefit from endovascular mechanical thrombectomy have a small core infarction, salvageable tissue at risk of infarction (penumbra), and an LVO.1-8 These patient characteristics should be identified on non-invasive computerised tomography (CT) and magnetic resonance imaging (MRI) studies prior to performing endovascular mechanical thrombectomy to ensure that acute ischaemic stroke patients are being treated appropriately..9 There is wide variation in imaging protocols designed to answer these questions, but more comprehensive protocols with perfusion imaging have shown a larger treatment effect when compared to protocols that do not incorporate perfusion imaging.5-13 In these more comprehensive imaging protocols, the size of the core infarction is identified based upon diffusion-weighted imaging (DWI) MRI or CT perfusion estimates of core infarction, the presence and size of salvageable tissue is determined

by CT or MRI perfusion imaging, and the presence of an LVO is determined by CT or MR angiography.9 However, the large amount of information provided by these comprehensive imaging protocols must be balanced with a several minute time delay that is required to perform perfusion imaging.

The ideal non-invasive imaging protocol to determine endovascular mechanical

thrombectomy candidacy would be fast, accurately identify the presence of a small core infarction, salvageable tissue at risk of infarction and LVO presence, and easily performed at both comprehensive and referring hospitals. At Stanford University Medical Center, USA, we most commonly use MRI for endovascular mechanical thrombectomy triage. Our simplest and most rapid acute ischaemic stroke protocol includes: DWI, gradient-echo imaging (to exclude cerebral haemorrhage), time-of-flight MR angiography, and MR perfusion imaging.

This protocol has a total imaging time of five minutes and 10 seconds and answers all questions necessary for appropriate endovascular mechanical thrombectomy triage.14 However, we thought that this short protocol could be further streamlined.

Perfusion imaging provides excellent delineation of salvageable tissue, but it also provides important information regarding the presence and location of an LVO. Neurointerventionalists can leverage their detailed knowledge of cerebral vascular anatomy to infer the location of an LVO based upon the pattern of a perfusion deficit.

We hypothesised that perfusion imaging would provide the same information as CT or MR angiography regarding the presence of an LVO, and we leveraged this concept in a recent publication.14 We retrospectively determined whether patients with acute ischaemic stroke symptoms could be accurately triaged toendovascular mechanical thrombectomy based only on DWI and MR perfusion imaging alone.14 Three readers reviewed DWI and MR perfusion images from 219 patients with acute ischaemic stroke symptoms, 73 of whom underwent endovascular mechanical thrombectomy for acute ischaemic stroke due to LVO. The readers identified the presence of a small core infarction on DWI, the presence of salvageable tissue on MR perfusion imaging, and LVO presence and location on MR perfusion imaging. Patients with these three characteristics were deemed endovascular mechanical thrombectomy candidates by the readers, and results were compared to those made at the time of patient presentation. We found DWI and MR perfusion alone to have a remarkable 96% sensitivity and 98% specificity for accurate endovascular mechanical thrombectomy triage. Additionally, readers accurately localised LVOs to the ICA/ M1 segment in 96% of cases and the M2 segment in 88% of cases, while correctly identifying patients with an LVO in 99%

of cases. We concluded that DWI and MR perfusion alone is highly accurate, sensitive, and specific for appropriate endovascular mechanical thrombectomy triage, LVO identification, and LVO localisation.

Our results strongly suggest that conventional vessel imaging with MR or CT angiography may be confidently replaced with perfusion imaging in nearly all patients.

The omission of non-invasive angiography offers a modest time savings of approximately 2.5 minutes, which may be beneficial in the care of acute ischaemic stroke patients. More importantly, however, is the applicability of our results to acute ischaemic stroke patient triage from transferring hospitals to comprehensive stroke centres, which has important implications for stroke systems of care. Our study was performed with the gold standard MRI, but it logically follows that similarly accurate patient triage to endovascular mechanical thrombectomy and LVO detection and localisation may be performed with CT perfusion techniques.

Consider the following example, which is based upon the system we have instituted at Stanford with several of our referring hospitals. A community hospital performs CT perfusion in an acute ischaemic stroke patient with symptoms that are suspicious for anLVO. These images are processed automatically using RAPID (iSchemaView), and the summary images from the CT perfusion study are automatically forwarded to the comprehensive stroke team members as an email. These summary images provide a volumetric estimation of core infarction and of the salvageable tissue at risk as well as the identification of an LVO, as shown in our study. Furthermore, these images can be easily interpreted on a mobile phone.

The community hospital physician can then call the stroke team to discuss transfer of the patient, and the comprehensive stroke team members can determine endovascular mechanical thrombectomy eligibility with a high degree of accuracy. Moreover, futile patient transfers due to the absence of an LVO, a large core infarction (>70 ml), or a volumetric match between the core infarction and salvageable penumbra are avoided.

Currently, up to 72% of acute ischaemic stroke patients transferred for possible endovascular mechanical thrombectomy do not undergo treatment secondary to futile transfer, which underscores the need to simplify and improveacute ischaemic stroke patient triage. Our early experience with this stroke system of triage has been very successful, and we are working to expand our programme to additional community hospitals to optimise the care of acute ischaemic stroke patients.

Many comprehensive stroke centres are currently struggling with a sudden and marked increase in the volume of acute ischaemic stroke patients requiring evaluation for possible endovascular mechanical thrombectomy following the positive results of the DAWN and DEFUSE 3 trials, which have extended the endovascular mechanical thrombectomy treatment window to 16-24 hours.4, 5 Both of these studies used CT

perfusion to estimate the core infarction in the majority of patients (the other patients underwent evaluation with MRI), and it is likely that perfusion imaging will become increasingly used in the evaluation of acute ischaemic stroke patients, particularly in late time windows. The results of our study provide a helpful roadmap to comprehensive centres as they evaluate their own systems of care following the successful DAWN and DEFUSE 3 trials.

The remarkable advancements in acute ischaemic stroke treatment by endovascular mechanical thrombectomy now require pre-endovascular mechanical thrombectomy imaging triage to evolve toward protocols that are efficient and provide the best information for safe, accurate, and expeditious patient treatment. Our study is the first to test the hypothesis that perfusion weighted imaging contains adequate angiographic data for endovascular mechanical thrombectomy triage. Although additional prospective studies are necessary to confirm our findings that endovascular mechanical thrombectomy triage may be safely and accurately performed in the absence of CT or MR angiography, we are confident that our results will be helpful to other stroke healthcare systems as they work to provide endovascular mechanical thrombectomy to many more eligible patients.

Dylan N Wolman, Department of Radiology, and Jeremy J. Heit, University Medical School, Stanford, USA Corresponding Author: Jeremy J. Heit Clinical Assistant Professor of Radiology 300 Pasteur Drive, Room S047 Stanford, CA 94305 650-723-6767 (office) 650-498-5374 (fax) jheit@stanford.edu References: 1. Lima FO et al. Prognosis of untreated strokes due to anterior circulation proximal intracranial arterial occlusions detected by use of computed tomography angiography. JAMA Neurol.

2014;71(2):151-7.

2. Bhatia R, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischaemic stroke: real-world experience and a call for action. Stroke.

2010;41(10):2254-8. .

3. Saver JL et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From Ischaemic Stroke: A Metaanalysis. JAMA. 2016;316(12):1279-88.

4. Nogueira RG et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. NEJM. 2018;378(1):11-21.

5. Albers GW et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. NEJM. 2018;378(8):70818. Epub 2018/01/25.

6. Saver JL et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. NEJM. 2015;372(24):2285-95.

7. Campbell BC et al. Endovascular therapy for ischaemic stroke with perfusion-imaging selection. NEJM. 2015;372(11):1009-18.

8. Albers GW. Late Window Paradox. Stroke. 2018;49(3):76871.

9. Heit JJ, Wintermark M. Imaging selection for reperfusion therapy in acute ischaemic stroke. Curr Treat Options Neurol.

2015;17(2):332.

10. Patel VP, Heit JJ. Ischaemic Stroke Treatment Trials: Neuroimaging Advancements and Implications. Top Magn Reson Imaging. 2017;26(3):133-9.

11. Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischaemic stroke. NEJM. 2015;372(1):11-20.

12. Jovin TG et al. Thrombectomy within 8 hours after symptom onset in ischaemic stroke. NEJM. 2015;372(24):2296-306.

13. Goyal M et al. Randomized assessment of rapid endovascular treatment of ischaemic stroke. NEJM. 2015;372(11):101930.

14. Wolman DN et al. Can diffusion- and perfusion-weighted imaging alone accurately triage anterior circulation acute ischaemic stroke patients to endovascular therapy? Journal of Neurointerventional Surgery. 2018. Epub 2018/03/21.

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Smoking and stroke

Smoking increases the risk of ischaemic stroke in young men There is a strong dose–response relationship between the number of cigarettes smoked daily and ischaemic stroke among young men. The authors recommend that, although complete smoking cessation is the goal, even smoking fewer cigarettes may reduce the risk of ischaemic stroke in young men.

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he study, published in Stroke, also found evidence for a dose-response relationship between cigarette smoking and risk of stroke in middle-aged and older adults as well but the association was not as strong.

The more cigarettes men under 50 years smoked, the more likely they were to have a stroke.

Men under 50 who smoked were more likely to have a stroke, and their risk increased with the number of cigarettes they smoked, according to the new research.

An increasing number of young adults are suffering ischaemic stroke, which is the most common stroke type. Tobacco use is on the rise among young adults. It is already established that the more young women smoke the greater their stroke risk; however, little is known about young men’s stroke risk from smoking.

Among the participants, 615 of 625 cases and 530 of 537 controls had complete data for all covariates, leaving a final study population of 1,145 subjects. Cases were less educated and were more likely to have hypertension, diabetes mellitus, myocardial

infarction, angina, and obesity (body mass index >30; all p<0.05). Among controls, current smokers were less educated and were more likely to be black than their non-smoking counterparts (all p<0.05).

The age-adjusted model and the odds ratio for the current smoking group compared with “never smokers” was 1.88 (95% CI, 1.44–2.44). Furthermore, when the current smoking group was stratified by number of cigarettes smoked, there was a dose– response relationship for the odds ratio, ranging from 1.46 (95% CI, 1.04–2.06) for those smoking <11 cigarettes per day to 566 (95% CI, 2.14–14.95) for those smoking <40 cigarettes per day. In the fully-adjusted model, there is a similar dose response observed but with slightly lower odds ratios.

In the age-adjusted model, the odds ratio for the former smoking group compared with never smokers was 1.42 (95% CI, 1.01–1.99), with similar results for the fullyadjusted model.

“The key takeaway from our study on men younger than 50 is ‘the more you smoke, the more you stroke,’” said lead study author Janina Markidan, University of

Maryland School of Medicine in Baltimore, USA. Researchers studied 615 young men (age 15–49) who had a stroke in the prior three years. Researchers compared the men with stroke to 530 healthy men in the same age range. They also categorised participants as never smokers, former smokers and current smokers. Current smokers were divided into groups based on the number of cigarettes smoked daily, one to 10, 11 to 20, 21 to 39 or 40 or more.

Men who smoked were 88% more likely to have a stroke than men who never smoked.

Among current smokers, men who smoked fewer than 11 cigarettes daily were 46% more likely to have a stroke than those

who never smoked.

But the heavier smokers, smoking at least two packs a day, were nearly five times more likely to have a stroke than those who never smoked.

“The goal is to get these young men to stop smoking, however if they can smoke fewer cigarettes it could help reduce their stroke risk,” Markidan said.

Researchers did not record the concurrent use of other tobacco products which could have affected results. They also did not control for factors such as alcohol consumption, physical activity or recall bias. However, similar findings in a Swedish study, suggested that there was not a major effect from recall bias.

Study finds that smoking may improve recanalisation after stroke A study published in Stroke showed that good outcome in smokers is mainly related to differences in baseline characteristics and not to biological effects of smoking, but that smoking still independently predicted recanalisation of middle cerebral artery in multivariable analyses.

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he data indicated that smoking had no beneficial effect on stroke outcome after intravenous thrombolysis and contradicted the study hypothesis of a smoking paradox in stroke. The apparently good outcome in smokers were largely related to younger age and other differences in baseline characteristics. Although the odds for arterial recanalisation after intravenous thromboloysis might be higher in smokers because of different pathophysiologic mechanisms, the earlier occurrence of stroke in the lifetime of smokers offsets a potential benefit in recanalisation. However, the authors suggest that further study is needed to understand why smokers have higher recanalisation rates.

The impact of smoking on the outcome of patients after stroke is controversial and the study aimed to address the relationship between smoking and stroke outcome in those patients that had undergone intravenous thrombolysis with a large cohort study and adjusting for potential confounders and incorporating recanalisaion rate.

The prospective multicentre study looked at 1,865 patients with acute ischaemic stroke who were treated with intravenous thrombolysis (IVT). Using uni- and multivariable modeling, it was assessed whether smoking was associated with favourable outcome (modified Rankin Scale score of 0–1) and mortality. In addition, the occurrence of symptomatic

intracranial haemorrhage and recanalisation of middle cerebral artery was measured.

Patients needed to meet the following criteria for study inclusion: treatment with IVT (alteplase) for acute ischaemic stroke according to the current guidelines of the European Stroke Organisation, obtainable information about smoking status of the patient, and availability of outcome data at three months. Patients were classified as smokers when they reported active cigarette use.

Of the 1,865 patients, 19.8% were smokers (n=369). They were younger (mean 63.5 vs. 71.3 years), less often women (56% vs. 72.1%), and suffered less often from hypertension (61.3% vs.

70.1%) and atrial fibrillation (22.7% vs. 35.6%) when compared with non-smokers.

Favourable outcome and three-month mortality were in favour of smokers in unadjusted analyses (45.8% vs. 39.5% and 9.3% vs. 15.8%, respectively), whereas symptomatic intracranial haemorrhage was comparable in both cohorts. Smoking was not associated with clinical outcome and mortality after adjusting for confounders (odds ratio, 1.20; 95% confidence interval, 0.91–1.61; p=0.197 and odds ratio, 1.08; 95% confidence interval, 0.68–1.71; p=0.755, respectively). However, smoking still independently predicted recanalisation of middle cerebral artery in multivariable analyses (odds ratio, 2.68; 95% confidence interval, 1.11–6.43; p=0.028).

The conclusion of the study suggests that good outcome in smokers is mainly related to differences in baseline characteristics and not to biological effects of smoking. The higher recanalisation rates in smokers, however, call for further studies.

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Aneurysm

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LUNA aneurysm embolisation system similar in safety and efficacy to coiling for treatment of intracranial aneurysms The LUNA aneurysms embolisation system (Medtronic) has been found to be safe and effective for the treatment of bifurcation and sidewall aneurysms results, published in the Journal of NeuroInterventional Surgery suggest.

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ndovascular aneurysm coiling is a valid therapeutic option for treating cerebral aneurysms and endovascular treatment can be considered first for the treatment of ruptured and unruptured aneurysms. However, coiling, either as a standalone procedure or with the use of the balloon-enhanced (or balloon-remodelling) coiling technique, can be limited by the filling of only a limited percentage of the aneurysm volume, introducing the possibility of coil compaction and recanalisation over time.

The authors write: “Difficulty of coiling widenecked aneurysms can be addressed with the use of adjunctive microstents and stent-assisted coiling is also a valid alternative for treating wide-necked aneurysms. This treatment method is associated with lower aneurysm recurrence rates compared with coiling alone. However, this method has an increased periprocedural rate of haemorrhagic complications related to antiplatelet treatment.”

The LUNA aneurysm embolisation system is a flow disruption device intended to treat a broader array of aneurysms. The aneurysm embolisation system is a self-expanding intrasaccular flow disruption device that is placed inside the aneurysm cavity, providing a mesh of metal across the neck of the aneurysm that isolates it from the parentartery blood flow. The shape allows the device to treat either bifurcation or sidewall aneurysms. The purpose of this study was to evaluate the procedural, short-term, and long-term safety and effectiveness of the LUNA aneurysm embolisation system when used in accordance with the manufacturer’s instructions for use.

The LUNA aneurysm embolisation system Post-Market Clinical Follow-Up study was a prospective, multicentre, single-arm study that was designed to evaluate device safety and efficacy.

Bifurcation and sidewall aneurysms were included. Aneurysm occlusion was assessed using the Raymond-Roy classification scale and disability was assessed using the modified Rankin Scale (mRS). Morbidity was defined as mRS >2 if baseline mRS ≤2, increase in mRS of 1 or more if baseline mRS >2, or mRS >2 if aneurysm was ruptured at baseline. Clinical and angiographic follow-up was conducted at six, 12 and 36 months.

Sixty-three subjects with 64 aneurysms were enrolled. Most aneurysms were unruptured (60/63 [95.2%]); 49 were bifurcation or terminal (49/64 [76.6%]).

Mean aneurysm size was 5.6±1.8mm (range, 3.6–14.9mm), and mean neck size was 3.8±1.0mm (range, 1.9–8.7mm).

Though immediate postoperative adequate occlusion was low (11/63,

18%), adequate occlusion was achieved in 78.0% (46/59) and 79.2% (42/53) of the aneurysms at 12 months and 36 months, respectively. Four patients were retreated by the 12-month follow-up (4/63 [6.3%]) and three patients were retreated by the 36-month follow-up (3/63 [4.8%]). There were two major strokes (2/63 [3.2%]),

one minor stroke (1/63 [1.6%]) and three incidents of intracranial haemorrhage in two subjects (2/63 [3.2%]) prior to the 12-month follow-up. There was one instance of mortality (1/63, 1.6%).

Morbidity was 0% (0/63) and 1.8% (1/63) at the 12-month and 36-month follow-ups, respectively.

The authors report: “Our study’s results support the safety and efficacy of the LUNA AES for the treatment of unruptured bifurcation and sidewall intracranial aneurysms of a wide range

of sizes. This series represents the first cohort of subjects ever treated with the LUNA AES device. Analysis of the treated population showed excellent LUNA AES implantation success, with implantation in 61/64 aneurysms (95.3%) and limited use of adjunctive implant devices (7/61, 11.5%). Both sidewall and bifurcation aneurysms were successfully treated. Treatment was most effective for small aneurysms and least effective for large aneurysms, though our sample size of large aneurysms was small.”

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Interview

Profile

Mayank Goyal

Mayank Goyal is a professor in the Department of Radiology and Clinical Neurosciences at the University of Calgary, Canada. He is the Director of Imaging and Endovascular treatment at the Calgary Stroke Program. Goyal’s passion and main research interest is acute stroke imaging, workflow and intervention. In his spare time he likes traveling, playing racket sports, golfing, and reading.

What drew you to medicine and interventional neuroradiology in particular?

I was a more of a physics, math and logic kind of kid and grew up playing sports. I do not really know how I ended up in medicine. However, once I got into medicine, I was clear I was interested in neuro….for me it was like the ‘the last frontier’ in the understanding of functioning of the human body.

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

I did my medical training and residency at the All India Institute of Medical Sciences in New Delhi, India. During my training there the people who had the greatest impact on my career were Raju Sharma and N K Mishra. During those formative years, they taught me the importance of a patient-centric approach to practice of medicine, the value of old-fashioned hard work and the power of collaboration. Subsequently, I moved to Toronto, where I did a fellowship at the University of Toronto under the supervision of K terBrugge and R Willinsky. Working under these legends of Neurointervention, helped me understand the value of good data, evidence based medicine and how necessary it is to focus on an issue or problem and stick to it.

You have been practising for a number of years. How have you seen the field of interventional neuroradiology change and develop over that time?

I remember as a resident spending time tying detachable balloons to microcatheters. Practically there were very few conditions one could treat (brain and spine arteriovenous malformations, carotico-cavernous fistulas) and there was also limited tools. Then the megaadvancement was: coiling of aneurysms. As expected, we were initially treating only those aneurysms that could not be surgically treated e.g. basilar tip aneurysms. The ISAT trial changed all that and led to a major jump in neurointervention volumes. Of course, clearly the biggest advancement by far for the field is the recent change in the treatment of acute ischaemic stroke. I do not think there has been a similar precedence in the whole of medicine where five randomised controlled trials show the same result.

In your opinion, what has been the most practice-changing advance in terms of treatment options and devices?

The answer is obvious: endovascular thrombectomy for acute stroke. One has to remember that there are few opportunities in the practice of medicine where one is curative (as opposed to preventive). When we treat an unruptured aneurysm or AVM: we are trying to prevent risk of future rupture. Even when we treat a ruptured aneurysm, there is no immediate impact on the patient.

This is totally different in an acute ischaemic stroke due to large vessel occlusion (LVO). It is like magic; pull the clot out and the patient becomes better….the Lazarus effect!

However, in terms of technology, technique and training, we have scope for improvement. I had proposed the use of TICI 2c many years ago and now it is being

used in mainstream. I think we should be looking at both time to and the quality of reperfusion: groin to first past TICI 2c/3, not TICI 2b/3. This will take into account not only the devices and technique but also individual skill in getting to the clot and successfully removing it.

What is on your wish list in terms of the future development of stroke therapy?

The single biggest problem we collectively face right now is getting the correct patient to the correct hospital quickly. We have the obligation to make endovascular thrombectomy (EVT) available to everyone as early as possible after stroke onset. Besides the need for better tools in the field to detect patients likely to have an LVO, we also need sensible, practical policy and organisation to have an appropriate distribution of EVT capable stroke centres and corresponding triage capabilites.

You are the principle investigator of the ESCAPE and SWIFT-PRIME trials, which looked at the use of stent retrievers and showed that their use improved outcomes. What was the impact of these studies, and what further advancements do you see on the horizon?

These two studies were among the five that made EVT the standard of care. As I have mentioned before, this is a revolution in stroke care with worldwide impact and gives significant hope for an otherwise dismal disease.

As we analyse data from these studies and from the HERMES collaboration, it is becoming hard to find a sub-group in which EVT does not work. We have been able to show benefit in patients at any age, either sex, irrespective of time of onset, severity of stroke, site of occlusion. There is benefit in patients with moderate to good ASPECTS and/ or collaterals. And we have been able to confirm the importance of time and speed. Onset to imaging decides the likelihood of favourable imaging and in those with favourable imaging, imaging to reperfusion decides the likelihood of favourable outcome.

Patient selection had a big role to play in the success of those trials. How was the protocol defined and do you believe that this should be used to select all thrombectomy-eligible patients going forward?

Are other selection criteria/ modes still viable?

Most of recent trials were designed to choose patients that had the highest likelihood of showing effect of treatment. This made sense at the time given the ‘failure’ of previous trials to show benefit of

EVT. Even the trials that did not have very conservative inclusion criteria (like MR CLEAN) was also ultimately enrolling patients with good ASPECTS. The final result was an overwhelming effect size (including in the recent late window trials). Clearly there are patients who were not enrolled in the trials that were at the margins of the inclusion criteria that will also benefit from treatment. We have to keep that in mind as we move forward. Also, one thing that cannot be argued against is: time is brain. Thus, imaging protocols and patient selection should be simple, widely implementable and not

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Interview

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Fact File

time consuming. Given ease of access of CT and no contraindications, in most situations CT should be the preferred modality and the protocol should include a CT head (to exclude haemorrhage) and a CT angiogram (to detect LVO; there is the collateral benefit of providing the vascular anatomy to plan the EVT). In addition, one has to think of the fastest and most robust way to exclude patients who have a large core. This is why we have made a modification to our CTA protocol

to multiphase CTA that allows evaluation of collaterals, making it easier to detect LVO and helping to confirm the ASPECTS reading. I believe that this CT, mCTA protocol is sufficient, efficient and widely implementable.

What are your other current research interests?

We are currently running a worldwide trial called ESCAPE NA1 trial testing the added benefit of neuroprotection (we are testing the compound NA1) in patients undergoing EVT. At the moment we have 282 patients enrolled. I have just finished the UNMASK EVT study aimed at trying to understand the variance of physician decision making in acute stroke. It is the first study of its kind and is based on the principles set forth by Nobel Laureate Dan Kahneman.

Additionally, I continue to push for evidence based, data-driven practice of medicine and we are planning additional RCTs and registries. I am building a web-based platform for increasing the efficiency of stroke research through crowdreview and crowdfunding. The site is called letsgetproof.com.

What was your most memorable case and what did you learn from it?

I remember clearly the first stroke case I treated using Solitaire in 2009. At that time it was not close to being approved and we had just got it on the shelf for stent-assisted coiling. This young 45 year old woman had come in with dense left hemiplegia.

She was an immigrant who was doing three jobs to make ends meet. She had an ICA-M1 occlusion. I finished the entire case, skin to skin in under 15 minutes using the stent retriever. At that time it felt like magic. She fully recovered on the table and said: Can I go back to work? The case was memorable for many different reasons: the ‘magic’ of opening the vessel, the tenacity of the human spirit and of course, the procedural efficiency with better technology.

What are your interests and hobbies outside of medicine?

I love to travel with my family, see new cultures and places and meet new people.

As a family we also love racket sports, and board games. I play golf once in a while with my sons (although I never keep score).

I love to read all kinds of books including mystery, science fiction, history, non-fiction and philosophy. Some of the books I have recently read and liked are by Michener, Asimov, Gawande, Malcolm Gladwell and Taleb. I also love to write; I write opinion pieces and editorials in flights. I do love recent TV shows: Breaking Bad, Homeland etc. My wife and I love to socialise; we have a big friend circle and have a rule about always having Saturday dinner with friends.

Academic appointments

Professor of Radiology and Clinical Neurosciences, University of Calgary, Diagnostic and Interventional Neuroradiology Director, Imaging and Endovascular treatment, Calgary Stroke Program

Awards (recent)

2018 CAR – Distinguished Career

Achievement Award 2017 ASTECH (Alberta Science and Technology) Innovation Award 2016 President’s Excellence Award: Research. Alberta Health Services 2015 Researcher of the year: Clinical faculty. Cumming School of Medicine 2015 Contributions to Innovation in the field of Neurointervention. Society of Vascular and Intervention Neurology

Research

ESCAPE Worldwide randomised controlled trial carried out at 22 sites.

SWIFT PRIME 39 sites across North America and Europe.

SEER Patient level meta-analysis of trials that used the Solitaire device.

HERMES Collaboration of seven randomised controlled trials testing endovascular thrombectomy.

One of the unique aspects of the collaboration is that we re-evaluated all the images centrally. It is the largest patient level database of its kind and it has allowed us to evaluate many of the sub-groups.

ESCAPE NA1 Ongoing worldwide trial tested the added benefit of neuroprotection in patients undergoing endovascular thrombectomy UNMASK EVT First study of its kind assessing factors contributing to physician decision making in taking patients for endovascular thrombectomy based on the principles of neuroeconomics

Experience

2000–06 Associate Professor Department of Radiology Ottawa Hospital, Ottawa 2000 Clinical Fellow, Neuroradiology Ottawa Hospital-Civic Campus, Ottawa, Canada 1998 –2000 Clinical Fellow, University of Toronto, Toronto, Canada 1996–98 Assistant Professor, Neuroradiology, All India Institute of Medical Sciences, New Delhi, India

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Medical therapy

Stroke prevention drugs may help reduce dementia risk for atrial fibrillation patients Patients with atrial fibrillation could reduce the risk of dementia by taking stroke prevention medications, according to recommendations published online in EP Europace1, a European Society of Cardiology journal, and presented at European Heart Rhythm Associatin Congress (EHRA; 18 –20 March 2018, Barcelona, Spain).2 The international consensus document was also published in HeartRhythm, the official journal of the Heart Rhythm Society (HRS), and Journal of Arrhythmia, the official journal of the Japanese Heart Rhythm Society (JHRS) and the Asia Pacific Heart Rhythm Society (APHRS).

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he expert consensus statement on arrhythmias and cognitive function was developed by the EHRA, a branch of the European Society of Cardiology (ESC); the HRS; the APHRS; and the Latin American Heart Rhythm Society (LAHRS).

Heart rhythm disorders (arrhythmias), as well as some procedures undertaken to treat them, can increase the risk of cognitive decline and dementia. The international consensus document was written for doctors specialising in arrhythmias and aims to raise awareness of the risks of cognitive impairment and dementia and how to reduce them.

The document states that atrial fibrillation is associated with a higher risk for cognitive impairment and dementia, even in the absence of apparent stroke. This may be because atrial fibrillation is linked with a more than two-fold risk of silent strokes. The accumulation of silent strokes and the

associated brain injuries over time may contribute to cognitive impairment.

Stroke prevention with oral anticoagulant drugs is the main priority in the management of patients with atrial fibrillation. The consensus document says that oral anticoagulation may reduce the risk of dementia.

Adopting a healthy lifestyle may also reduce the risk of cognitive decline in patients with atrial fibrillation. This includes not smoking and preventing or controlling hypertension, obesity, diabetes, and sleep apnaea.

“Patients with atrial fibrillation may be able to reduce their risk of cognitive impairment and dementia by taking their oral anticoagulation medication and having a healthy lifestyle,” said Nikolaos Dagres, lead author and consultant, Department of Electrophysiology, Heart Centre Leipzig, Germany.

The document also reviews the association between other arrhythmias and cognitive dysfunction, including post-cardiac arrest, in patients with cardiac implantable devices such as implantable cardioverter defibrillators (ICDs) and pacemakers, and ablation procedures.

Treatment of atrial fibrillation with catheter ablation can itself lead to silent strokes and cognitive impairment.

To reduce the risk, physicians should follow recommendations

for performing ablation and for the management of patients before and after the procedure.3,4 The consensus document notes that physicians may suspect cognitive impairment if a patient’s appearance or behaviour changes—for example, if appointments are missed. Family members should be asked for collateral information. If suspicions are confirmed, the consensus document recommends tools to conduct an objective assessment of cognitive function.

The paper highlights gaps in knowledge and areas for further research. These include, for instance, how to identify atrial fibrillation patients at increased risk of cognitive impairment and dementia, the effect of rhythm control on cognitive function, and the impact of cardiac resynchronisation therapy (CRT) on cognitive function.

References 1. Dagres N, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice? Europace. 2018. doi: 10.1093/europace/euy046.

2. EHRA 2018 session: Arrhythmias and cognitive impairment on 19 March from 14:00 to 15:30 in the His lecture room 3. Kirchhof P, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893–2962. doi:10.1093/eurheartj/ ehw210 4. Calkins H, et al. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: Executive summary. Europace.

2018;20(1):157–208. doi: 10.1093/europace/eux275.

Drug reduces inflammation in stroke patients An anti-inflammatory drug given to patients in the early stages of a stroke has been shown to reduce harmful inflammation. The drug, anakinra (brand name Kineret), is currently licenced for treating rheumatoid arthritis and was given as a small injection just under the skin.

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he researchers, from The University of Manchester, UK, had previously shown that IL-1 increases inflammation and brain injury following a stroke. Anakinra works by blocking the actions of IL-1 which is released into the body following injury caused by a stroke.

The findings, published in Stroke, don not say how the reduction in inflammation will impact on clinical outcomes.

The study, funded by the Stroke Association, follows earlier research that shows the drug given as an intravenous therapy reduces inflammation in stroke and sub arachnoid haemorrhage patients.

Eighty participants were given six doses of the drug or placebo over three days. The first dose was given within six hours after the onset of the stroke symptoms.

Inflammatory markers were measured in the blood before treatment began and during study treatment.

Craig Smith (The University of Manchester, UK) said, “Though strokes affect different people in different ways, for many people they have a devastating effect on their long-term health and wellbeing. Excessive inflammation after a stroke is known to be harmful and predicts a worse outcome in

patients. We have shown that Kineret injections, started within six hours of stroke onset significantly reduces levels of inflammation in patients.”

IL-1Ra reduced plasma inflammatory markers which are known to be associated with worse clinical outcome in ischaemic stroke. Subcutaneous IL-1Ra is safe and well tolerated. Further research is needed to see whether anakinra is an effective treatment for ischaemic stroke and whether it can be given alongside current treatments such as thrombolysis.

The study shows that treatment with subcutaneous IL-1Ra in hyperacute ischaemic stroke significantly reduces plasma concentrations of IL-6 and CRP for the first three days. These findings are consistent with reduced concentrations of these plasma inflammatory markers observed in the groups previous studies of subcutaneous IL-1Ra in aSAH10 and intravenous IL-1Ra in acute stroke and aSAH. The authors write that as far as they are aware, such robust and consistent reduction of downstream peripheral inflammatory markers has not been demonstrated with other candidate anti-inflammatory drugs for acute stroke.

The study was designed in line the Stroke Therapy Academic Industry Roundtable II&II (STAIR-I&II) consensus recommendations for phase 2 clinical trials

of candidate drugs for acute ischaemic stroke and the dosing regimen was based on robust pharmacokinetic modeling and known preclinical therapeutic concentrations. A relevant surrogate outcome measure was selected for the primary outcome, measured using well-established methods and confirming proof of concept. The study design allowed the researchers to test IL-1Ra alongside thrombolysis with intravenous alteplase to explore combination therapy. The planned sample size for the primary analyses was reached and used ordinal analysis of the mRS secondary outcome.

Mediation analysis enabled hypothesis generation to inform future experimental and clinical studies.

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New research

Flow-redirection intraluminal device system safe and effective in the treatment of intracranial aneurysms A European multicentre study for the evaluation of a dual-layer flow-diverting stent for the treatment of wide neck intracranial aneurysms found that the flow-redirection intraluminal device system (FRED) performed favourably when used to treat aneurysm obliteration and, in most cases, resulted in complete angiographic occlusion in one year.

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he research, published in the American Journal of Neuroradiology, looked at consecutive patients with intracranial aneurysms treated with the FRED between February 2012 and March 2015 were retrospectively reviewed. Complications and adverse events, transient and permanent morbidity, mortality, and occlusion rates were evaluated.

During the study, 579 aneurysms in 531 patients (median age, 54 years; range, 13–86 years) were treated with the FRED. Seven per cent of patients were treated in the acute phase (≤3 days) of aneurysm rupture. The median aneurysm size was 7.6 mm (range, 1–36.6mm), and the median neck size 4.5 mm (range, 1–30mm). Angiographic follow-up of three months was available for 516 (89.1%) aneurysms. There was progressive occlusion witnessed with time, with complete occlusion in 18 (20%) aneurysms followed for up to 90±14 days, 141 (82.5%) for 180±20 days, 116 (91.3%) for 1 year±24 days, and 122 (95.3%) aneurysms followed for >1 year. Transient and permanent morbidity occurred in 3.2% and 0.8% of procedures, respectively. The overall mortality rate was 1.5%.

The European FRED study (EuFRED) is the largest

study to date to evaluate the safety and efficacy of the dual-layer flow-diverting stent, FRED. Fifteen European neurovascular centres contributed 531 patients with 579 aneurysms treated in 534 procedures during three years. Any aneurysm deemed suitable for FRED by the treating neurointerventionalist was eligible. The study included a wide variety of aneurysms as encountered in the real-world patient population. Transient and permanent morbidity occurred in 3.2% and 0.8%, respectively, of procedures. The overall mortality rate was 1.5%.

Complete occlusion was achieved in 95.3% of aneurysms followed for >1 year.

In the EuFRED, 12.2% of aneurysms treated were in the anterior circulation distal to the internal carotid artery, and 13.3%, in the posterior circulation.

Thus, more than one-quarter of aneurysms were located outside traditional locations, which, the authors write, “mirrors a trend in the literature on flow diversion that advocates its use further distal in the cerebrovascular tree at or beyond the circle of Willis.” While approximately one-quarter of aneurysms in the EuFRED were classified as large and giant and deemed too difficult to treat using

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traditional endovascular techniques, the median aneurysm diameter of 7.6 mm suggests that flow diversion may be suitable for aneurysms traditionally managed with coil embolisation with or without assist devices such as stents or balloons.

Follow-up infarct volume is a strong independent predictor of functional outcome after acute ischaemic stroke due to proximal intracranial occlusion

Analysis of Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES), published in The Journal of NeuroInterventional Surgery, confirms that follow-up infract volume is a strong independent predictor of functional outcome at 90 days in patients with acute ischaemic stroke due to proximal intracranial occlusion of the anterior circulation presenting within six hours of onset.

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he study examined the association of follow-up infarct volume with 90-day modified Rankin Scale (mRS) score and investigated its dependency on acquisition time and modality.

Data from the ESCAPE, EXTENDIA, SWIFT PRIME, REVASCAT, MR CLEAN, PISTE, and THRACE trials was pulled together to form the HERMES database. These trials looked at the benefits of endovascular thrombectomy in patients with anterior circulation ischaemic stroke. According to the original trial imaging protocols, all participating sites were required to perform 24-hour follow-up imaging and were free to choose between computed tomography (CT) and magnetic resonance imaging (MRI). Participating centres from MR CLEAN and THRACE were

additionally requested to perform followup imaging at five days, or at hospital discharge. In EXTEND-IA, ESCAPE, SWIFT PRIME, REVASCAT, and PISTE, five-day follow-up imaging was at the discretion of the intervention site. All patients with follow-up non-contrast CT (NCCT) or MRI carried out at least 12 hours and up to two weeks (336 hours) after stroke symptom onset were included.

Of 1665 included patients, 83% were imaged with CT. Median follow-up volume was 41ml (IQR 14–120) and large follow-up volume was associated with worse functional outcome (OR=0.88 [95% CI 0.87 to 0.89] per 10ml) in adjusted analysis. A model including follow-up volume, location, and haemorrhage type best predicted mRS score. A follow-up volume of ≥133mL was highly specific for unfavourable outcome and follow-up

volume was equally strongly associated with mRS score for assessment on CT and MRI, even though large differences in volume were present (48ml [IQR 15–131] vs. 22ml [IQR 8–71], respectively).

Associations of both early and late followup volume assessments with outcome were similar in strength (p=0.60[95% CI 0.56 to 0.64] and ρ=0.55[95% CI 0.50 to 0.60], respectively).

The study found that the relationship between follow-up volume and functional outcome was consistent across all models and follow-up volume proved to be an independent predictor and the addition of lesion location and haemorrhage type increased the predictive value of the models. The negative effect of outcome ASPECTS involvement on functional outcome was mainly driven by the influence of the internal capsule and the

M5 region. These regions may include the corticospinal tract and the motor cortex, which emphasises the pivotal role of damage to these areas in determining functional independence of patients Writing in the article the authors say, “Our study confirms these results in the largest patient-level dataset on endovascular thrombectomy to date.

This unique dataset also allowed us to answer questions about how different imaging approaches affected the interaction of follow-up volume and functional outcome. Of note, once follow-up volume and baseline NIHSS score were included in our models, infarct laterality was not an independent predictor of outcome, suggesting that the baseline NIHSS score captures most of the stroke lateralisation effect.”

June 2018

The addition of subcutaneous nerve stimulation to optimised medical management is more effective than optical medical management alone in relieving low back pain at up to nine months Despite the study terminating early due to recruitment difficulties, the results suggest that the addition of subcutaneous nerve stimulation to optimised medical management is clinically and statistically more effective than optimised medical management alone in relieving low back pain at up to nine months. These findings support the results of a number of earlier uncontrolled case series.

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he SubQStim study was the largest multicentre randomised control trial comparing optimised medical management and subcutaneous nerve stimulation to optimised medical management in patients with back pain due to failed back surgery syndrome. Failed back surgery syndrome was defined as persistent low back and/or leg pain after technically and anatomically successful lumbar spine surgery.

The study aimed to compare the effectiveness of peripheral nerve stimulation using a subcutaneous lead implant technique—subcutaneous nerve stimulation plus optimised medical management vs. optimised medical management alone in patients with back pain due to failed back surgery syndrome.

Patients were recruited from 21 centres, in Europe, Israel, and Australia. Eligible patients were randomised in a 1:1 basis to subcutaneous nerve stimulation and optimised medical management or optimised medical management arms. Those in the subcutaneous nerve stimulation arm were implanted with a neurostimulator and up to two subcutaneous percutaneous cylindrical leads in the area of pain.

Patients were evaluated pre-randomisation and at one, three, six, and nine months post-randomisation. The primary endpoint was the proportion of subjects with a ≥50% reduction in back pain intensity (“responder”) from baseline to nine months. Secondary outcomes included proportion of responders with a ≥50% reduction in back pain intensity at six months and ≥30% reduction at nine months, and the mean change from baseline in back pain intensity at six and nine months between the two arms.

Those recruited to the study need to demonstrate predominant back pain and be aged 18 or older and were excluded if they had or were being treated with a neurostimulator or intrathecal drug delivery system.

There was a slow rate of recruitment which led to the study being terminated early with 116 patients randomised. A total of 33.9% (19/56, missing: n=20 [36%]) of subjects in the optimised medical management and subcutaneous nerve stimulation arm and 1.7% (1/60, missing: n=24 [40%]) in the optimised medical management arm were responders at month nine (p<0.0001). Secondary objectives showed a

significant difference in favour of optimised medical management and subcutaneous nerve stimulation arm.

The results of the trial indicate that the addition of subcutaneous nerve stimulation to optimised medical management is more effective than optimised medical management alone in relieving low back pain at up to nine months.

Transcranial direct current stimulation for upper limb neuropathic pain: A double-blind randomised controlled trial A double-blinded, randomised control trial found no evidence that 1mA transcranial direct current stimulation is beneficial to people with upper limb neuropathic pain, but it may provide lasting relief for some people.

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he goal of the study was to evaluate the effect of anodal transcranial direct current stimulation on pain and function in people with upper limb neuropathic pain. Thirty patients were randomly allocated into active- and shamtranscranial direct current stimulation groups. Baseline assessments of pain and function, as well as quantitative sensory testing (QST) to probe the function of the nociceptive system, were undertaken prior to participants receiving five days of active or sham anodal transcranial direct current stimulation (1 mA) over the primary motor cortex. The outcome measures were reassessed at one, three and eight week’s post-intervention.

The researchers found that group analyses revealed no significant improvement in pain, function, or quantitative sensory testing measures

over time in either group. They did find that there were significantly more individual responders (≥30% change in pain) in the active compared to the sham transcranial direct current stimulation group at the final followup. In the active group, there was a significant correlation indicating those with higher baseline pain had greater pain relief.

The authors write: “Overall, we found no evidence that five days of active transcranial direct stimulation is effective for people with upper limb neuropathic pain. However, there were more individual responders in the active transcranial direct current stimulation group. It appears that those individuals who have higher baseline pain and who respond to active stimulation early after treatment are more likely to experience sustained pain relief. We were not able to detect

Gwyn Lewis

any changes in nociceptive processing following active transcranial direct current stimulation, but this may relate to the low overall effect on pain.

Future studies should aim to identify characteristics of those who are more

likely to respond to transcranial direct current stimulation.”

Transcranial direct current stimulation is a non-invasive method of brain stimulation that because of its painless and relatively simple application, has been used as a therapeutic intervention in many neurological and psychiatric conditions, including chronic pain.

However, findings across trials designed to look at its effectiveness have not always been consistent, with reviews and meta-analyses on the efficacy of transcranial direct current stimulation for chronic pain present conflicting conclusions.

Lead Author Gwyn Lewis, (Auckland University of Technology, New Zealand), said: “We need to work out why transcranial direct current stimulation works for some people with chronic pain and not others. Determining in more detail how it impacts the pain system will be key to this.”

The study was published in the European Journal of Pain.

June

Final results from PROCO randomised control trial: Level I evidence for equivalent pain relief from 1 kHz to 10 kHz with appropriate neural dosing The PROCO randomised controlled trial is a multicentre, double-blind, crossover study that investigated effects of spinal cord stimulation frequency (1 to 10 kHz) on analgesia (Clinicaltrials.gov identifier: NCT02549183). It showed that patients received equivalent pain relief from 1 kHz to 10 kHz with appropriate neural dosing while requiring significantly less charge than higher frequencies.

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atients were implanted with spinal cord stimulation systems and underwent an eight week search during which up to 14 stimulation locations were tested to identify the best location (“sweet spot”) of stimulation at 10 kHz within the searched region (T8–T11). An electronic diary (e-diary) prompted patients for pain scores three times per day.

Those patients that responded to 10 kHz (≥ 30% back pain relief per e-diary) proceeded to rate randomisation during which 1 kHz, 4 kHz, 7 kHz, and 10 kHz were assigned in randomised order for blinded evaluation and used for four weeks each while stimulating at the same sweet spot. Pulse width

and amplitude were adjusted to optimise therapy.

Twenty patients completed rate randomisation. Pain scores for each patient were averaged over the five day evaluation period for each rate, yielding 80 data points for statistical analyses. All rates provided equivalent back pain relief. 1OnekHz was around three times more efficient than higher frequencies and pain relief was sustained using the rate selected for three month follow-up after rate randomisation (1 kHz: n = 10; 4 kHz: n = 2; 7 kHz: n = 5; 10 kHz: n = 3).

The study provides Level I evidence for equivalent pain relief from 1 kHz to 10 kHz with appropriate neural dosing.

Using 1 kHz required significantly less charge than higher frequencies.

Spinal cord stimulation helps gait dysfunction in advanced Parkinson's disease patients Pilot study demonstrates significant therapeutic outcome of spinal cord stimulation in advanced Parkinson’s disease (PD) patients

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he findings were published in Movement Disorders. This exploratory, open-label pilot study investigated the therapeutic efficacy of midthoracic epidural SCS at different stimulation parameter combinations in 5 PD participants with significant gait dysfunction and freezing of gait.

This is the first study to use objective gait technology to assess the efficacy of SCS for gait in advanced PD patients.

Benefits of dopaminergic therapy and deep brain stimulation are limited and unpredictable for axial symptoms in Parkinson's disease. Dorsal spinal cord stimulation may be a new therapeutic approach. The objective of this study was to investigate the therapeutic effect of spinal cord stimulation on gait including freezing of gait in advanced PD patients.

Preliminary results of the CRISP study suggest that intraoperative paresthesia mapping may not be required for BurstDR trials The CRISP study is looking at patients with chronic back pain.

They were implanted with two leads; one using paraesthesia mapping (PM) and the other using the anatomic midline-based (AM) procedure. Stimulation contacts were programmed using the standard mapping procedure for the PM lead, and contacts overlapping the T9-T10 junction were utilised for the AM lead.

During the trial patients evaluated the AM and PM leads in a random order.

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he need for intraoperative mapping in paraesthesiafree spinal cord stimulation (SCS) is unknown. In this study, the therapeutic efficacy of BurstDR SCS delivered using leads implanted with the conventional paraesthesia mapping approach to leads implanted with the anatomic midline-based approach was compared.

The result were presented by Adnan Al-Kaisy, Guy’s & St. Thomas’ NHS Foundation Trust, London, United Kingdom at the World Congress of the World Institute of Pain (WIP; 9–12 May 2018, Dublin, Ireland).

Twenty-eight patients (mean age = 50.8±10.2 years) successfully completed the trial so far (total 33 planned enrolment = 60). Pain relief at trial was 67% in the AM and 64%

in the PM arms (p<0.0001) with no significant differences between the two approaches (p=0.69). Pain relief at three months was sustained at 63% for the AM and 68% for the PM. Quality of life was significantly improved and disability reduced with both AM and PM leads (p<0.0001) with no difference between the two approaches (p=0.32 and p=0.64 respectively). At the end of the trial preference between leads was divided evenly between AM (13) and PM (15) leads.

Preliminary results of the CRISP study suggest that intraoperative paraesthesia mapping may not be required for BurstDR trials, and anatomical midline-based placements have the potential to provide similar clinical outcomes.

Neuromodulation therapy gives relief from hand tremor Non-invasive neuromodulation therapy using a custom stimulation pattern provides symptomatic relief from hand tremor in essential tremor, according to a study presented at the annual meeting of the American Academy of Neurology, held from April 21 to 27 in Los Angeles, USA.

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ajesh Pahwa, from the University of Kansas Medical Center in Kansas City, USA and colleagues randomised 77 subjects to receive peripheral nerve treatment or sham stimulation of the tremordominant hand in an acute, in-clinic, study. In a chronic, at-home, study, 61 patients were randomised to treatment, sham, or standard of care; participants underwent two or more sessions each day during the study.

The treatment, a wrist-worn neuromodulation device, stimulates the median and radial nerves in the wrist and delivers a stimulation pattern that is tuned to interrupt a person's tremor.

For the in-clinic study, participants received one session of either the treatment stimulation or sham stimulation to the wrist of the hand with the more severe tremor. The tremor was evaluated before and after the session.

Physicians assessed the severity of tremor in the entire arm and the assessments showed a 65%

improvement in the treatment group compared to 32% in those who received sham stimulation.

Participants performed certain activities of daily living in the clinic and were asked to rate their performance before and after stimulation. Those who received treatment stimulation showed a 27% improvement compared to 16% for sham stimulation. Overall, 88% of those receiving the treatment reported improvement in their tremor after receiving treatment stimulation.

"The study conducted in the clinic showed that treatment stimulation was safe and produced significant improvements in both physician-rated and patient-rated measures of tremor severity compared to sham stimulation," said study author Rajesh Pahwa.

For the at-home study, 61 participants received either treatment stimulation, sham stimulation or their usual treatment. Those who received treatment stimulation had a minimum of two sessions

a day for up to one month.

Tremor severity was measured using sensors on the device before and after each therapy session. People receiving treatment stimulation showed a reduction in their tremor severity after 89.5% of the treatment stimulation sessions as measured by the sensors.

The researchers found that the therapy was safe and produced significant improvements compared to sham in the physician-rated Tremor Research Group Essential Tremor Rating Assessment Scale dominant upper limb scores and in patientrated Bain & Findley activities of daily living scores in the acute study.

There were no significant adverse events. Mild adverse events were reported by 3% of participants and they resolved spontaneously without intervention. Baseline tremor characteristics, including frequency, were identified in the kinematic data in the chronic study, as were tremor characteristics and response over the course of the study.

"Our research suggests that this noninvasive therapy may offer meaningful relief from the symptoms of hand tremor for people with essential tremor," Pahwa said in a statement.

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Product News CE mark for overactive bladder neuromodulation device

StimGuard has received a CE mark for a wireless neuromodulation device to treat chronic symptoms of an overactive bladder.

“A wireless system that enables urologists to inject such a clinically proven therapy represents a shift in the field where there has only been one option for over 15 years,” Karl-Dietrich Sievert, professor and co-chairman of urology, University of Rocstock, Germany, and co-founder of StimGuard, said in a release. “The ability of the CE Marked StimGuard sacral nerve stimulator (SNS) System to offer the same level of stimulation at the micro-wireless level will give patients an alternative to a bulky battery or excessive invasive surgeries, but still provide the same control.”

The company said the major advantage of the StimGuard SNS system is the elimination of the implanted battery source (a pacemaker-like device), called an implantable pulse generator (IPG), required by the other SNS device on the market. With the StimGuard technology, only a small device, 5% of the size of the other option, with electrode contacts and an embedded chip is placed within the body through a needle mated with a wire receiver, enabling a potentially lower-cost option. With other systems, the patient undergoes an invasive surgery to have a battery pack surgically implanted under their skin.

The battery pack would have to be replaced every three to five years, which is eliminated with the StimGuard SNS System.

Medtronic receives FDA approval for deep brain stimulation therapy for medically refractory epilepsy

The US Food and Drug Administration (FDA) has granted premarket approval for Medtronic’s deep brain stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures, in individuals 18 years of age or older who are refractory, or drug-resistant, to three or more antiepileptic medications. DBS therapy for epilepsy delivers controlled electrical pulses to a target in the brain called the anterior nucleus of the thalamus (ANT), which is part of a network involved in seizures.

According to the Epilepsy Foundation, 3.4 million individuals in the United States have epilepsy.

Antiepileptic drug (AED) medication is the primary treatment to control seizures; however, up to one third of individuals with epilepsy have seizures that do not successfully respond to AEDs. “Many patients in the United States with severe epilepsy are not able to control their seizures with currently-available drugs and are not candidates for potentially curative surgery,” said Robert Fisher, director of the Stanford Epilepsy Center, Stanford University, USA, and lead principal investigator of the SANTE trial. “Epilepsy that is refractory to AED treatment is an unsolved problem, and DBS therapy will now serve as an important new treatment option, including for people with poorly localised or multiple regions of seizure origin.”

The FDA approval is based on both the blinded phase and the 7-year follow-up data collected in Medtronic’s clinical trial called SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy).

The SANTE trial was a prospective, randomised, double-blind pivotal study to evaluate the use of DBS therapy for patients with medically refractory epilepsy with partial-onset seizures, with or without secondary generalisation, that were drug-resistant to three or more antiepileptic medications. The trial

collected data from 110 patients who were implanted with a Medtronic DBS system at 17 centres located in the USA Results include: The median total seizure frequency reduction from baseline was 40.4% vs. 14.5% for the placebo group at three months, and 75% at seven-years, with open-label ongoing therapy.

Twenty subjects (18%) experienced at least one six-month seizure-free period between implant and year seven, including eight subjects (7%) who were seizure-free for the preceding two years.

Seizure severity and quality of life scales both showed statistically significant improvements from baseline at year seven.

No significant cognitive declines or worsening of depression scores were observed through the blinded phase or at year seven. Improved scores were observed at seven-years on measures of executive functions and attention.

security researcher of a potential vulnerability related to the Medtronic N’Vision 8840 Physician Programmer, a small, handheld device used solely by healthcare professionals to program certain Medtronic neuromodulation devices. The researcher’s report details that the compact flash application card used in the physician programmer may contain unencrypted patient personal health information if that information is not deleted following individual patient device programming,” the company said.

Positive late-breaking data from the INTREPID study announced

The US Department for Homeland Security warns of cybersecurity weakness of neurostimulator programmer

The US Department of Homeland Security (DHS) has flagged a weakness in the security of a device for programming Medtronic’s neurostimulator implants.

Exploiting the vulnerability would give a hacker access to personal health information.

After being alerted to the vulnerability by security company WhiteScope, the DHS put out a notice alerting users to the risk that N’Vision clinician programmer could leak personal information.

Physical access to an N’Vision flash card is needed to access the information. Once that barrier is overcome, an attacker would need little skill to access the information, which is not encrypted by the device at rest. The issue was given a score of 4.6, classing it as a medium-severity vulnerability.

Medtronic is yet to develop a product update to address the vulnerability but has highlighted steps users can take to minimise the risk. These centre on ensuring the flash cards do not fall into the wrong hands.

The risks posed by the vulnerabilities vary from product to product, both because of differences in the ease of exploiting them and the likely fallout from doing so. But the National Cybersecurity and Communications Integration Centre is advising users to take mitigating steps even when the chances of a breach are slim.

Medtronic issued a statement about the DHS notification: “Medtronic was notified by an external

Vercise DBS System (Boston Scientific)

The one-year data from the INTREPID study, the first and only prospective, double-blind, randomised, sham-controlled, multi-centre study of deep brain stimulation (DBS) for advanced, levodopa-responsive Parkinson’s disease (PD) in the United States has been announced.

The INTREPID study evaluated 292 patients at 23 sites in the USA and successfully met its primary and secondary endpoints. The data, which supported the recent US FDA approval of the Vercise DBS System (Boston Scientific) for the control of symptoms of PD, demonstrated the safety and effectiveness of one of the most innovative additions to the field of DBS in 30 years. DBS is used to treat the symptoms of Parkinson’s disease, a degenerative condition that affects more than one million people in the USA and 10 million worldwide.

Highlights of the one-year results include: A 49.2% improvement in motor symptoms as measured by clinicians in Unified Parkinson’s Disease Rating Scale III scores compared to pre-surgery screening; A six-hour improvement in time without troublesome dyskinesias as measured by a patient-completed three-day Parkinson’s disease diary (motor diary); More than 40% of stimulation programs used current that was fractionalised over two or more contacts; and An overall sustained improvement in quality of life as measured by the Parkinson’s Disease Questionnaire 39.

“This study meets a new level of rigor in evaluating the effectiveness of a DBS system,” said Jerrold Vitek, McKnight professor and chair, Department of Neurology, University of Minnesota Medical School, USA, and coordinating principal investigator for the INTREPID study. “The double-blind design gives us confidence that the improvements in patients on time with good symptom control, as evaluated by the diary data, are an objective measure of the outcomes and suggests patients will benefit from the Vercise System.”

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says Raul Nogueira (Grady Memorial Hospital and Emory University, Atlanta, USA). “These patients now have a much better chance for an independent life without disability.”

Product News Cerenovus receives US FDA clearance for next generation stent retriever device used to treat ischaemic stroke

Cerenovus has announced it has received 510(k) clearance from the US Food and Drug Administration (FDA) for its EMBOTRAP II revascularisation device, EmboTrap II a next generation stent retriever used to capture and remove life-threatening blood clots from the brain following an ischaemic stroke.

The EMBOTRAP II device is designed to rapidly restore blood flow by gripping and retrieving clots within the neurovasculature, with minimal compression, protecting against further complications.

In the ARISE II study, which was submitted as part of the 510(k) application to the FDA, neurointerventional stroke physicians were able to restore blood flow in 80% of patients treated within three passes and in about half of patients within a single pass. At the 90-day follow-up, more than two-thirds were functionally independent. The study included 228 patients with large vessel occlusions and moderate to severe neurological deficits.

State-of-the-art imaging solution provides automated scoring to assess early signs of brain ischaemia

At the European Stroke Organisation Conference (ESOC; 16–18 May 2018, Gothenberg, Sweden), iSchemaView publicly launched RAPID ASPECTS, a digital imaging solution that assists clinicians in assessing early signs of brain

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ischaemia in stroke.

RAPID ASPECTS automatically generates a standardised score—based on clinically validated machine learning algorithms—that enables physicians to easily communicate about the extent of a patient’s ischaemic changes and to determine eligibility for thrombectomy (clot removal). In addition, RAPID ASPECTS provides clear visualisation of the brain so that clinicians can better scrutinise each region and confirm the automated score. RAPID ASPECTS is CEmarked for use in Europe.

The original Alberta Stroke Program Early CT Score (ASPECTS) is a manual 10-point scoring system that relies on determining subtle changes in non-contrast CT examinations. This has traditionally required the expertise of an experienced neuroradiologist or stroke neurologist.

Yet even stroke imaging experts have been shown to display significant scoring variability in most studies using ASPECTS. RAPID ASPECTS automates and standardises the scoring process to help clinicians more accurately assess early signs of brain ischaemia.

Trevo retriever becomes first and only device indicated for acute ischaemic stroke treatment up to 24 hours in Europe

Following the expanded indication in the USA by the Food and Drug Administration (FDA) in February, the Trevo retriever (Stryker) has received CE marking as a front-line treatment for patients experiencing acute ischaemic stroke up to 24 hours from symptom onset, increasing the treatment window by 18 hours.

“The 24-hour indication opens the treatment window to patients whose stroke would previously have progressed until all the brain tissue surrounding the affected arteries was dead, leaving them with a life of significant disabilities,”

Trevo retriever

FDA cautions about risks of coiling for brain aneurysms

After reports of periprocedural stroke and death with the use of neurovascular stents for stent-assisted coiling (SAC), the US FDA issued a safety alert with recommendations for safe use of these devices in the treatment of unruptured brain aneurysms.

Reports received of periprocedural stroke and death may have been related to procedural risks or poor patient selection, the FDA determined.

“Neurovascular stents for SAC provide important options for the treatment of wide-neck brain aneurysms, and their technology continues to evolve. However, these procedures are not without risks, and careful patient selection and proper device use are critical to ensure that the benefits to the patient outweigh the risk of treatment. Many patients with unruptured brain aneurysms can be managed conservatively with routine monitoring and follow-up depending on their individual risk factors for aneurysm rupture,” wrote the FDA’s William Maisel in the letter to healthcare providers.

In smaller brain aneurysms or in patients with reduced life expectancy, the risks of endovascular coiling may outweigh their benefits, the agency noted. Operators should also be aware that neurovascular stents are only approved for certain brain aneurysms, and that they should avoid use of these devices in patients who cannot take systemic anticoagulant or antiplatelet drugs.

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Clinical News patient’s brain to gather data and map brain activity. By doing this, leading neurosurgeons Jothy Kandasamy and Drahoslav Sokol were able to identify the region responsible for generating the surges in the electrical signals which cause epileptic seizures.

The neuromate stereotactic robot’s role in the procedure was to support the instrumentation and aid the neurosurgeons to align the electrodes according to pre-planned trajectories. Carrying out this type of procedure with the assistance of a robot can significantly reduce operating time compared with traditional methods.

Vesalio reports positive results in early NeVa human thrombectomy procedures and recently published pre-clinical data Neuromate stereotactic robot

First neuromate stereotactic robotassisted procedure in Scotland has taken place

The first Renishaw neuromate stereotactic robot-assisted procedure in Scotland has taken place at The Royal Hospital for Sick Children, Edinburgh.

The Royal Hospital for Sick Children, Edinburgh, has carried out the first neuromate stereotactic robotassisted neurosurgery procedure in Scotland. The case was a paediatric stereoelectroencephalography (SEEG) carried out on an eight-year-old female patient suffering from severe epilepsy.

SEEG uses intracerebral electrodes to measure electrical signals in the brain. During the procedure in Edinburgh, 15 electrodes were inserted into the

Vesalio has announced that it has completed European enrolment of the first twenty-five human cases in a post-market registry of the proprietary NeVa neurothrombectomy platform for the treatment of stroke.

Procedures have been performed at six centres in four countries to date, early results demonstrate superior first pass clot removal and TICI 2b–3 recanalisation. These results are consistent with improved efficacy revealed in published pre-clinical data and pending in vitro study publications.

On February 13, 2018 Interventional Neurology published “Preclinical Evaluation of the NeVa Stent Retriever: Safety and Efficacy in the Swine Thrombectomy Model.” The data summary highlights a 97% success rate of mTICI 2b–3 scores with an average of 1.2 passes.

Vesalio will be initiating a prospective 100 patient study that will be inclusive of patients up to 24 hours of

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stroke onset and with broad real-world inclusion criteria in Q2 of this year. In addition, the data for the first 50 patient registry will be submitted for publication.

With the improving global infrastructure for stroke treatment and the influence of the recently published data from the DAWN and DEFUSE 3 Trials on expanded stroke treatment windows, the NeVa neurothrombectomy platform is well positioned to impact the high growth mechanicalthrombectomy market expected to exceed US$500 million globally by 2020.

First patient enrolled in TIGER pivotal clinical study

The first patients have been enrolled in the TIGER (Treatment with Intent to Generate Reperfusion) study.

This is a multicentre study of the performance of TIGERTRIEVER (Rapid Medical), a thrombectomy device for the acute treatment of ischaemic stroke.

The TIGER study is an investigative device exemption (IDE) clinical study for the purpose of supporting Rapid Medical’s 510(k) submission to the US Food and Drug Administration to obtain clearance to market the device in the USA. The study will take place in up to 25 stroke centres throughout the USA. Neurologists, Jeffrey Saver, UCLA Medical Center, Los Angeles, and Rishi Gupta, director, Neurocritical Care at WellStar Health System, Georgia, USA, are the principal investigators of the study.

The initial cases in the IDE study were performed

by Gupta and Ahmad Khaldi, the director of Cerebrovascular Neurosurgery at Wellstar Medical. “We are pleased to have enrolled the first patients and to have a leadership role in the TIGER study. Stent retrievers are now the gold standard for treating ischaemic stroke, and TIGERTRIEVER is a new generation stent retriever. Its unique design will hopefully show that it addresses the limitations of current devices and will improve patient outcomes,” states Gupta.

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Calendar of events 18–22 January

ISET—26th Annual International Symposium on Endovascular Therapy

23–27 July

Miami, USA

SNIS: Society of NeuroInterventional Surgery 15th Annual Meeting & Fellows Course

Fontainebleau Miami Beach

San Francisco, USA

T +1 305 279 2263

E questions@ccmcme.com W www.iset.org

11–13 June

LINNC: Live Interventional Neuroradiology & Neurosurgery Course Paris, France

W: www.linnc.com

W: www.snisonline.org

6–8 September

ESMINT: European Society of Minimally Invasive Neurological Therapy Annual Meeting Nice, France

W: www.esmint.eu

19–23 September

14–17 November

17–20 January

Rotterdam, Netherlands

San Diego, USA

Las Vegas, USA

14–16 October

4–6 December

6–8 February

Montreal, Canada

Telford, UK

ESNR: European Society of Neuroradiology Annual Meeting W: www.esnr.org

4th World AVM Congress W: www.avm2018.org

17–20 October

World Stroke Congress

SVIN: Society of Vascular and Interventional Neurology annual meeting W: https://www.svin.org

UK Stroke Forum Conference W: https://www.stroke.org.uk/

NANS: North American Neuromodulation Society 22nd Annual Meeting W: http://www.neuromodulation.org/

ISC: International Stroke Conference Honolulu, USA

W: https://exhibitatsessions.org/ international-stroke/

Montreal, Canada

W: www.world-stroke.org

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