NeuroNews Issue 34 US

June

Issue

19 34 Padma Gulur:

Cybersecurity Page 20

Adam Arthur:

Profile

Page 19

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Big data set to increase the efficiency of stroke outcomes research A topical review published in Stroke investigates new approaches for the collection of outcomes data after stroke. In the context of global technological growth, the authors, David Ung, Monique F Kilkenny (senior author), Monash University colleagues (Melbourne, Australia) and international colleagues from the USA and Canada, propose: “Continued advancements in streamlining data linkage, without compromising privacy, will not only lead to an explosive increase in the use of data linkage for stroke outcomes research, but will also fill research gaps as we work towards understanding other patient groups.” They further conclude: “These real-world data offer a promising opportunity for evaluations to improve evidence-based practice and policy decision-making.”

T

he authors acknowledge that currently “the quality of outcomes data such as mortality, adverse events, and disability can vary by type and timing of the collected data, such as the inhospital, short-term and long-term periods”. Proposing that there are three primary strategies for collecting outcomes data after stroke: clinical studies, clinical stroke registries, and administrative data, the authors weigh up their advantages and shortcomings against the utility of linking datasets.

For example, while Ung et al suggest that administrative databases were not designed for research or clinical purposes, they propose that such databases “reflect real-world practice, are large and comprehensive, population-based, have potentially indefinite follow-up, and are less expensive and resource intensive than clinical studies”.

However, the authors also allude to their limitations, the primary one concerning selection biases. “Selection biases can make it difficult to appropriately define the population, [as] patients with better access to healthcare or who present with more severe and non-fatal symptoms may be more likely to be captured.”

Furthermore, Ung and colleagues speculate that these databases may include inaccurate or incomplete data that may not encompass the entire population. They also add: “Another limitation arises when codes that lead to greater reimbursement of funds to hospitals are favoured over the principal

Continued advancements [...] will also fill research gaps as we work towards understanding other patient groups.”

Continued on page 2

Latest FDA caution for the use of off-label drugs in intrathecal drug delivery systems deemed “inconsistent with current practice”

While the US Food and Drug Administration (FDA) has called for caution regarding the use of off-label medications administered intrathecally, pain management experts have come together and, in a letter to the editor of Neuromodulation, call for an addendum to the communication due to its “inconsistency with current practice”.

“USE CAUTION WITH implanted pumps for intrathecal administration of medicines for pain management,” reported the recent FDA safety communication. With the action aiming to improve safety, it was intended for patients who have an implanted pump, as well as caregivers and healthcare providers. Several physician leaders feel this caution needs more clarification, including Timothy Deer (The Spine and Nerve Center of the Virginias, Charleston,

USA) and Philip Kim (Center for Interventional Pain Spine, Bryn Mawr, USA), among an array of pain treatment experts. “We are concerned that this FDA alert may have the unintentional action of inappropriately limiting our ability to offer treatments within the standard of care for our chronic intractable pain patients,” write principal authors Deer and Kim. While Deer and colleagues say they agree with the FDA’s goal of improving safety and reducing risks, they put forward that general use of off-label medications has been an ongoing practice standard for many years and suggest that the safety communication “will have a detrimental impact on many patients and on the practice of medicine in the USA and potentially abroad”.

According to manufacturer registry data highlighted in the letter, over 80% of patients treated for chronic pain of a noncancerous origin receive drugs that Continued on page 19

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June

Big data set to increase the efficiency of stroke outcomes research Continued from page 1

reason a patient is hospitalised.”

According to the authors, the latter phenomenon is termed “code creep”, and has been estimated in an American study to increase payments for physician visits by 2.2% every year. In light of the aforementioned factors, Ung et al surmise: “The combination of these factors not only impacts the ability to identify stroke cases, but also affects the ability to adjust outcomes by stroke severity and compare performance across health centres or hospitals.”

are discharged from hospital, validate the diagnosis of the index stroke, and enable capture of comorbidities.”

Additionally, the use of data linkage in prospective studies can minimise the effect of patients lost to follow-up, say the authors.

Lastly, they posit that a further area where this technological asset may

serve to be useful is in evaluating the translation of research knowledge, or an evidence-based treatment, into routine practice by enabling the observation of trends in treatment overtime.

Yet, limitations of data linkages exist, while its application poses an array of challenges. “The availability and quality of databases for linkage are country-dependent and can be inconsistent,” say Ung and his team.

They also highlight the issue of public approval and governance, claiming that they are “impediments to linking data in some countries, such as Taiwan and Australia”.

For instance, they allude to a study published last year by Cheng-Yang

The expansion of data linkage

In the context of patient records, the process of data linkage can be defined as the merger of administrative databases with registries or clinical studies. “It can be particularly valuable in stroke research,” say the authors, “as, in developing countries at least, most people attend healthcare-related services before, during and after their stroke event.”

Ung and colleagues further put forward that as excessive resources are required to track outcomes after discharge, linkages with administrative data can provide “an adjunct approach to cost-effectively and longitudinally capture longer-term outcomes in both clinical studies and registries”.

Referring to the key benefits of data linkage, the authors postulate that cost-effectiveness and efficiency comes out on top. “Not only does it reduce the overall time and financial cost associated with collecting these data, but it also reduces responder burden.”

Moreover, alluding to examples of successful linkage between prospective stroke research cohorts and registries, and administrative data, Ung and colleagues acknowledge: “These linkages have provided the opportunity to determine outcomes after patients

Editor-in-chief:

Prof Philip M Meyers

Publisher:

Stephen Greenhalgh

Head of Publishing: Sadaf Kazi

Editor:

Jessica Thompson jessica@bibamedical.com

Editorial contribution:

Jocelyn Hudson, Sonia Davies, Angela O’Neill, Suzie Marshall

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Big data

Hsieh (Department of Neurology, Tainan Sin Lau Hospital, Tainan, Taiwan) and colleagues, in Epidemiol Health, confirming that researchers in Taiwan are prevented from linking clinical registry databases with administrative databases due to the public’s concern for privacy, protests from human rights organisation, and the amount of red tape necessary to get permission to link data.

In accordance, Ung and colleagues agree that, in this increasingly digitalised world, patients have increasing rights to control their own digital fingerprint. Yet, they write: “By understanding the nature, historic context and limitations of individual administration databases, researchers can unpack these large data and use these to enrich comprehensive assessments in clinical studies for outcomes of stroke.”

The future

David Ung

Monique F Kilkenny

Unlocking this wealth of data could help generate new hypotheses in stroke, minimise data waste and justify future comprehensive research.”

Not only does [data linkage] reduce the overall time and financial cost associated with collecting these data, but it also reduces responder burden.”

Throughout the past two decades, the authors recognise that only a handful of countries, such as Sweden, Denmark, Finland, Scotland, New Zealand, Canada, and Australia, claim to realise the utility of such “high-quality, complete, and linked heath data”.

The use of data linkage in the context of stroke-related outcomes remains in its infancy, state the authors, as currently many populationbased studies only link with a national death registry to ascertain mortality.

Yet, Ung et al argue that after successful examples of data linkage in the research of stroke, “there is a renewed impetus to use this approach around the world”.

Ultimately, Ung and his team propose: “Many countries that do not currently use linked data in stroke research already possess systems capable of collecting routine health information at local and national levels, especially with the increasing adoption of electronic medical records.

Unlocking this wealth of data could help generate new hypotheses in stroke, minimise data waste, and justify future comprehensive research into important and untested outcomes.”

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2019

4

June

Ambulance administration of transdermal glyceryl trinitrate does not improve outcomes in patients with acute stroke

A study in which ambulance paramedics treated patients suspected of having an acute stroke with transdermal glyceryl trinitrate (GTN) to lower their blood pressure found that “there was a strong tendency for GTN to be associated with a worse outcome” than placebo. Philip Bath from the University of Nottingham in the UK, who presented the results of RIGHT-2 (Rapid intervention with glyceryl trinitrate in hypertensive stroke trial-2) in a late-breaking session at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA), concluded: “We cannot recommend the use of GTN in the ambulance.”

ACCORDING TO BATH, while high blood pressure predicts poor outcome in acute stroke, the best way to lower blood pressure and improve outcome in acute stroke is not yet known. GTN, a nitric oxide donor, was found to be safe when given to patients with acute stroke in the ENOS (Efficacy of nitric oxide in stroke) trial. Accordingly, in the RIGHT pilot trial and in an early subgroup in the ENOS trial, transdermal GTN given in ultra-acute/hyper-acute stroke improved functional outcomes in both ischaemic and intracerebral stroke. Thus, RIGHT-2 sought to investigate whether administering GTN earlier after stroke onset would improve outcomes.

Bath described RIGHT-2, which was a multicentre, parallel-group, prospective, randomised, blindedendpoint controlled trial, carried out from May 2015 to April 2018 in adults who presented to paramedics in the context of a 999 ambulance call for “stroke”. Patients were included in the trial if they had a face-arm-speechtime (FAST) score of ≥2, presented within 4 hours of stroke onset and had a systolic blood pressure greater than 120mmHg. Patients were randomised in the ambulance, with a paramedic applying either a GTN or sham transdermal patch, with three more patches applied in hospital on successive days. The trial was planned for 850 patients from more than five ambulance services and over 30

associated acute hospital stroke centres across the UK. The primary outcome was the seven-level modified Rankin Scale (mRS) at 90 days, of which the study investigators assessed by central telephone follow-up with masking to treatment.

The trial was planned Philip Bath as a standard intention-totreat analysis but the rate of stroke mimics (non-stroke/non-transient ischaemic attack [TIA]) was higher than predicted at 26% vs. 12%, meaning that more than a third of patients were not the target for treatment. This required an increase in the sample size to 1,050, while the protocol was changed to a hierarchical analysis, with primary analysis in the target population (stroke or TIA patients). If the latter was found to be positive, a pragmatic analysis with intention-to-treat was subsequently carried out.

The RIGHT-2 results

Of the 1,149 patients in the trial, 568 received GTN and 581 received sham patches. Adherence with the first patch was >99%, and with the first two patches was only

Novel thrombectomy system aims to remove the clot with a single first pass

Acknowledging that current methods used to remove clots to treat stroke can leave up to 20% of targeted material, Vasotorq, a medical device company based in Clyde Hill, USA, has developed a solution, having recently patented a nitinol stent with distal protection designed to remove distal emboli from vasculature with greater efficacy. Speaking to NeuroNews, co-founder and CEO of Vasotorq, Joseph M Eskridge, outlines how Vasotorq’s thrombectomy system differs from those currently used, and discusses the company’s plans for the future.

What was your rationale behind developing Vasotorq’s thrombectomy system?

Current stent retrievers can require up to seven to 10 passes through the clot to remove all of the clots. Many physicians give up after three attempts. We aim to remove the clot with a single first pass.

Many stent retrievers used in current practice today leave behind distal emboli in 10–20% of cases according to the operating surgeon. One study indicated that surgeons are missing

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Stroke treatment

even more distal emboli when the case was reviewed by an independent third party physician.

How does the Vasotorq thrombectomy system improve on previous generations of stent retrievers?

Vasotorq’s next-generation stent adds an expandable distal protection umbrella that keeps the clot intact in one piece and catches emboli before they can

57%, mainly because many patients were discharged once they got to hospital with a TIA or mimic; 96% of patients had primary outcome and 98% vital status.

The average age of patients was 72 years (52% male), with an onset to randomisation of 71 minutes with a patch applied two minutes later. Patients were later diagnosed with ischaemic stroke (52%), intracerebral haemorrhage (13%), TIA (9%) and mimic (26%). Additionally, the authors reported that systolic blood pressure was approximately 162mmHg in 25% of patients, while the FAST score was a maximum of three in 60% of patients.

According to Bath, the reduction in blood pressure with GTN was lower than expected, with systolic blood pressure reducing by 5.7mmHg and diastolic blood pressure by 2.6mmHg at hospital admission. On day two, systolic blood pressure reduced by 5.3mmHg, while diastolic blood pressure reduced by 2.1mmHg in patients in the GTN group compared with the sham group.

However, the difference in blood pressure between the groups then disappeared by days three and four.

In terms of the primary outcome in stroke/TIA, Bath said it “was poor for GTN”. According to the time of randomisation, the effect of GTN on mRS was negative in patients treated within one hour, neutral with a negative tendency in those treated within one to two hours, and neutral with a positive tendency in those treated beyond two hours.

Moreover, Bath concluded that in the stroke/TIA target population: “There was a neutral effect on the mRS, but there was a strong tendency for GTN to be associated with a worse outcome”. He further put forward that “the difference between the results of the RIGHT pilot study and RIGHT-2 trial is due to time before treatment, with a reduction from 264 minutes to 71 minutes”.

Addressing the ISC audience, Bath discussed this discrepancy: “The problem largely lies with intracerebral haemorrhage. In that very first hour [of time before treatment] we are of course breaking the law we learnt at medical school, which is the first part of haemostasis is spasm… and we gave an antispasmodic—a vasodilator.

“But this is just speculation,” Bath added, as he ultimately concluded: “There is no indication for the use of GTN in the ambulance.”

break away and travel downstream.

Other than stroke, does the system have any further indications?

Outside of stroke, Vasotorq’s nextgeneration stent can be used in the coronary arteries during myocardial infarctions, the pulmonary arteries during pulmonary embolic showers and in the peripheral arteries in chronic total occlusions.

Are you currently working on any other projects at Vasotorq?

We are also working on the software for a mobile app that uses artificial intelligence to diagnose distal embolic

The stent adds an expandable distal protection umbrella that keeps the clot intact in one piece and catches emboli.”

Joseph Eskridge

occlusions in the left brain dominant hemisphere for expressive speech, receptive language, right arm and leg motor and sensory functions. This helps the surgeon determine if pursuing distal breakaway emboli justifies the additional risk to the patient.

What are the next steps moving forward?

We are currently seeking National Institute of Health grants and accredited investor funding and plan to seek additional indications once we achieve brain and stroke approval.

6

June

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Research

Survey indicates nearly 40% of procedures involve a combined thrombectomy technique

BIBA MedTech polled 39 acute stroke centres—most of which were interventional neuroradiology centres—about the types of thrombectomy procedures they perform for the management of acute ischaemic stroke. They found that, on average, 38% of the thrombectomy procedures that each centre performs involves both direct aspiration and stent retrieval.

Source: BIBA MedTech Insights

IN THE SURVEY, 39 centres in Western Europe were asked to say how many of the thrombectomy procedures they performed in Q1 of 2019 (1 January–30 March 2019) involved direct aspiration only, a combination of direct aspiration and stent retrieval, and stent retrieval only. On average, they reported that 47% of procedures involved direct aspiration only, 38% involved both direct aspiration and stent retrieval thrombectomy, and 15% involved a stent retriever only. Each

centre performed approximately 37 thrombectomy procedures in Q1. See Figure 1.

At present, the optimal first-line mechanical thrombectomy treatment is not clear. Writing in the American Journal of Neuroradiology, Chun On Anderson Tsang (Department of Neurosurgery, Queen Mary Hospital, Hong Kong) and others note that a direct aspiration, first pass technique for the endovascular treatment of stroke (ADAPT) is now an established alternative to stent

retrieval thrombectomy and has become “the standard of care at many centres” [as suggested by the BIBA MedTech survey]. However, they add that randomised controlled trials— such as ASTER (Contact aspiration vs. stent retrieval for successful revascularisation)—have not shown superiority of ADAPT over stent retrieval thrombectomy. Therefore, the authors performed a meta-analysis of studies that had comparative data for the thrombectomy techniques to provide further insight into this issue.

Tsang et al found that stent retrieverfirst thrombectomy and aspirationfirst thrombectomy were associated with comparable final reperfusion rates and functional outcomes. While stent retriever therapy was superior in achieving reperfusion as a stand-alone first-line with a lower use of rescue devices, it had a longer groin-to-

BIBA Briefings

BIBA Briefings provide in-depth analysis of the latest market intelligence from BIBA MedTech Insights, which provides consulting and market analysis services to medical professionals and organisations in the medical device industry in Europe and North America. The platform also reviews data and news.

For more information about BIBA Briefings or BIBA MedTech Insights, please contact Merveille Anderson merveille@bibamedical.com

Coagulation markers found associated with functional outcome in acute stroke A study has found that intensive blood glucose control of acute ischaemic stroke patients with hyperglycaemia has a critical impact on important markers of blood coagulation in those who are not treated with IV tissue plasminogen activator (tPA). These patients were found to have a greater reduction in the tissue factor pathway markers of blood coagulation tissue factor procoagulant activity and FVIII, and a greater elevation in FVII, than patients treated with standard blood glucose control.

THE PRIMARY RESULTS of the iSPOT trial (Insights on selected procoagulation markers and outcomes in stroke trial), a sub-study of the SHINE trial, which found that intensive blood glucose control did not improve functional outcomes after an acute ischaemic stroke compared with standard blood glucose control, were presented by Nina Gentile (Temple University School of Medicine, Philadelphia, USA) at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA).

The reason the iSPOT study was needed, explained Gentile, “was to try and help explain why acute stroke with hyperglycaemia is associated with worse functional outcomes. Previous studies have shown that tissue factor pathway markers of blood coagulation are elevated in acute ischaemic stroke and these markers are considerably higher in patients with hyperglycaemia, so there was a need for a study into the effects of blood glucose control

reperfusion time. Thus, they conclude: “The optimal first-line thrombectomy approach for specific location or stroke aetiology remains unclear.”

The ASTER investigators have decided to take a different approach to explore this issue. In the ongoing ASTER 2 trial, they are comparing first-line combined stent retrieval thrombectomy and ADAPT with first-line stent retrieval therapy.

Speaking to NeuroNews earlier this year, investigator Bernard Lapergue (Department of Stroke Center and Diagnostic and Interventional Neuroradiology, University of Versailles and Saint Quentin en Yvelines, Foch Hospital, Suresnes, France) said: “If our trial is positive, we will have strong evidence to support the combined use of stent retrieval thrombectomy plus contact aspiration [ADAPT] to obtain the best rate of recanalisation.”

on blood coagulation markers and their relationship to stroke outcomes.”

The study was carried out with a subset of patients enrolled in the SHINE trial. The SHINE trial had two treatment arms—one group was given intensive control with a target blood glucose of 80–130mg/dl while the other received standard treatment with a target blood glucose <180mg/dl. The SHINE functional outcome was NIH stroke scale (NIHSS)-adjusted modified Rankin Scale (mRS) score at 90 days. The iSPOT trial sought to compare markers of blood coagulation by treatment, functional outcome and the interaction between treatment and outcome.

Eight markers of tissue factor pathway of blood coagulation were measured across 48 hours in the study.

A total of 270 patients were enrolled in the trial. With the exception of an expected difference between intensive

and standard arm 48-hour blood glucose levels, Gentile reported that patients had similar characteristics.

According to Gentile, Biomarkers were extremely elevated at baseline and fell over 48 hours. “There was a significant increase in FVIIa levels in patients not treated with IV tPA,” she added.

When analysing the change in factor levels by functional outcome, in non-tPA treated patients there was a significant increase in FVIIa with favourable outcome as compared with unfavourable outcome (p<0.01). There were also significant reductions in tissue factor procoagulant activity and FVII—both strong markers of coagulation—as well as a significant increase in FVII with favourable outcome compared with unfavourable outcome.

When analysing the relationship of change in factor levels and functional outcome for the intensive blood glucose control group, Gentile noted that the trends only become significant in non-IV tPA treated patients, in terms of both greater reductions in tissue factor procoagulant activity and FVIII, and an elevation in FVII. However, for the relationship of change in factor levels and functional outcome for the standard blood control group, there was only a small increase in FVII, but no appreciable differences in any other markers.

“Further studies will be required to understand these findings fully, particularly in context of the SHINE study’s overall primary results, and to consider targeted therapy for patients with hyperglycaemia after stroke,” concluded Gentile.

June

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New research

Societal benefit after SWIFT Prime and DAWN trials “vastly surpasses” clinical equipoise Even for a “highly promising treatment” such as mechanical thrombectomy, the ethical dilemma of depriving control patients of the active treatment during the execution of well-designed randomised controlled trials (RCTs) is dramatically offset by the proven benefit to the larger group of patients who are subsequently treated based on its results. This conclusion was presented by Gabriel Rodrigues (Grady Memorial Hospital, Atlanta, USA) at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA) earlier this year.

R

odrigues and his team carried out a retrospective analysis of a database for consecutive cases of acute ischaemic stroke treated with thrombectomy at a comprehensive stroke centre between March 2012 and October 2018. They mathematically estimated the social value of the SWIFT Prime and DAWN RCTs—both of which found mechanical thrombectomy to be a safe and effective treatment for acute ischaemic stroke. Through these calculations, the investigators were able to compare the clinical data, as well as the monthly rate of thrombectomy performed in the stroke centre before and after the trial results were presented.

“While RCTs are the best source of evidence for safety and efficacy of interventions in medical practice,” Rodrigues explained, “the requirement for a control group may raise ethical concerns regarding clinical equipoise. Patients should not be disadvantaged by enrolling in a trial. And studies with no potential to generate social value [the expected benefit

for society as a whole] are generally considered unethical, especially if they impose risks on subjects.”

In the current study, Rodrigues said that social value was estimated by comparing the number of patients deprived from benefit by acting as controls, versus the number of patients who subsequently benefited from the new treatment after the trial.

In the SWIFT Prime trial, 13 patients (six controls and seven treated) were enrolled during the course of 11 months in a comprehensive stroke centre. Rodrigues reported that: “For a less disabled outcome in 90 days with an NNT [number needed to treat] of 2.6, if all 13 patients enrolled had been treated, five patients would have benefited. However, with the RCT (six controls, seven treated), 2.7 out of 13 patients would have benefited, therefore retrospectively depriving 2.3 patients from a ≥1-point modified Rankin Scale (mRS) shift in this period.”

Additionally, he added that for a good outcome (mRS 0–2) in 90 days with NNT

Perfusion-weighted parameter is “outstanding” at detecting penumbral flow in acute stroke The performance of the best perfusionweighted measure—time-to-maximum—to detect the upper penumbral flow threshold in ischaemic stroke has been deemed “outstanding” by the study investigators.

The results, published in Annals of Neurology, led the authors, Olivier ZaroWeber from Max Planck Institute for Neurological Research, Cologne, Germany, to conclude: “Time-to-maximum >5.6 seconds-based penumbra detection is reliable to guide treatment decisions up to 48 hours after stroke onset and might help to expand reperfusion treatment beyond the current time windows.”

FROM AN ARRAY of perfusion-weighted imaging parameters, Zaro-Weber and colleagues found that time-to-maximum outperformed the rest in detecting penumbral tissue. Moreover, they reported: “The optimal threshold to discriminate penumbra from oligaemia was

of four, without an RCT, 3.25 of the 13 patients would have benefited; but with the RCT (six controls, seven treated) 1.75 patients out of 13 would have benefited, therefore depriving 1.5 patients from a good outcome in 11 months.

However, despite initially depriving a number of patients from a good outcome, Rodrigues pointed to the long-term advantages. “The monthly rate of mechanical thrombectomy in the comprehensive stroke centre increased from 13.9 patients treated per month before SWIFT Prime, to 23.5 patients treated per month after the trial’s results were presented (March 2015 to October 2018), equating to an additional 9.6 patients treated per month. Rodrigues explained: “We provided a less disabled outcome

It took less than one month to overcome the difference and compensate for the ‘harmed’ patients.”

[NNT 2.6] to 3.7 additional patients per month and a good outcome [NNT 4] to 2.4 additional patients per month, therefore it took less than one month to overcome the difference and compensate for the retrospectively ‘harmed’ patients in the SWIFT Prime study.”

A similar calculation was carried out for the DAWN trial, in which 38 patients (16 controls and 22 treated) were enrolled during the course of 26 months in the comprehensive stroke centre. For a less disabled outcome in 90 days for an NNT of 2.0, without an RCT 19 of the 38

time-to-maximum >5.6 seconds with a sensitivity and specificity of >80%.”

The authors put forward that, in the clinical setting, the choice of the best perfusion-weighted map and its optimal penumbral flow threshold is still a matter of debate. In light of this, as well as the stroke studies that have shown the clinical benefit of mismatch-based thrombectomy six to 24 hours after stroke onset (such as DEFUSE 3 and DAWN), Zaro-Weber set out to prospectively validate perfusion-weighted parameters with full quantitative O-PET (positron-emission tomography), to ensure this imaging procedure is a reliable tool to detect salvageable tissue in acute stroke.

In the current study, 10 patients (group A; six female, four male) with acute and subacute ischaemic stroke underwent perfusion-weighted/diffusion-weighted MRI and consecutive full quantitative O-PET within 48 hours of stroke onset.

“Penumbra as defined by O-PET cerebral blood flow, oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established perfusion-weighted measures, to optimise penumbral tissue detection,” write the study investigators. Further, they note that the same validation based on penumbra as defined by quantitative O-PET cerebral blood flow was carried out for comparative analyses in 23 patients.

On discussion of the results, Zaro-Weber and colleagues say: “The current study has new important implications for mismatch detection in acute stroke.” While maintaining that the threshold-independent performance of perfusionweighted time-to-maximum was excellent, with an AUC (area under the curve) of 0.88, they reported that the bigger PET cerebral blood flow group validation (group

9

patients would have benefitted, while with an RCT (16 controls, 22 treated), 11 of the 38 patients benefitted, therefore retrospectively depriving eight patients from a ≥1-point mRS shift in this period.

Likewise, for a good functional outcome in 90 days (mRS 0–2) with an NNT of 2.8, without an RCT, 13.6 patients out of 38 would have benefited, while with an RCT (16 controls, 22 treated) the benefit was provided to 7.9 patients out of 38, therefore retrospectively depriving 5.7 patients from a good outcome in this period.

The monthly rate of mechanical thrombectomy increased in 6–24-hour patients: before DAWN (June 2014 to May 2017) 8.1 patients were treated per month, while after DAWN (June 2017 to

October 2018) 11.9 patients were treated per month. This equates to an additional 3.8 patients in the 6–24-hour treatment window per month. Rodrigues reiterated the importance of this: “We provided a less disabled outcome (NNT 2) to an additional 1.9 patients per month and a good outcome (NNT 2.8) to an additional 1.4 patients a month, therefore it took less than five months to benefit more patients than we allegedly harmed.

In light of these findings, he concluded that: “The local and societal benefit after a scientific breakthrough as defined in an RCT vastly surpasses the potential burden to the relatively few control patients left untreated in the face of prior equipoise.”

B) provided evidence that time-to-maximum, time-to-peak and first movement without delay correction are the best perfusion-weighted imaging parameters to detect the upper penumbral flow threshold.

Additionally, based on the study’s findings, the authors advise: “If no selection of an arterial input function is feasible, nondeconvolved time to peak >3.8 seconds is a very good alternative to time-to-maximum.”

The current study has new important implications for mismatch detection in acute stroke.”

While Zaro-Weber and colleagues acknowledge the small patient cohort in the current study, they recognise that it is due to the challenging logistics to perform these measures in acute stroke. However, they emphasise that this is the biggest patient sample of full quantitative O-PET with consecutive perfusion-weighted magnetic resonance in acute stroke.

In conclusion, the study investigators state: “From a clinical point of view, these results are important because the optimal perfusion-weighted maps and penumbra thresholds validated against full quantitative PET up to 48 hours of stroke onset are pivotal to detect penumbral tissue and can help the clinician to decide on revascularisation or other options of treatment in acute stroke beyond the established time windows.”

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June

CX audience votes against neurointerventionists exclusively performing intracranial thrombectomy In the closest debate of the Acute Stroke Challenges session that took place on the first day of the Charing Cross (CX) Symposium (15–18 April, London, UK), Jan Kovac (Leicester, UK) and Andrew Clifton (London, UK) discussed whether intracranial thrombectomy should be limited to neurointerventionists.

KOVAC, A CARDIOLOGIST, whose proposition was that it should not be limited to neurointerventionists, won the debate with 57% of the vote, but a

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Acute stroke challenges

substantial minority (43%) supported Andrew Clifton’s arguments that the procedure should be limited to neurointerventionists.

While Clifton argued that experience and proper training leads to “appropriate patient selection [and] faster, safer procedures with fewer complications”, Kovac said that, given the magnitude of the potential clinical and economic benefits of mechanical thrombectomy, a “collaboration of various interventional specialists is desirable to deliver this therapy to a wider population”.

Kovac argued that “Mechanical thrombectomy is the best evidencebased therapy for acute ischaemic stroke if provided in a timely manner by an experienced, multidisciplinary team.” He went on to say that “There is currently a hiatus between evidence and its implementation into practice

across the world, with practice varying significantly within and between countries. For several logistical, practical and economic reasons, collaboration of various interventional specialists is desirable to deliver this therapy to a wider population.”

Indeed, he concluded that, “Given the magnitude of the potential clinical and wider economic benefits from mechanical thrombectomy, it should now be a key priority to address the substantial infrastructure and workforce obstacles impeding rapid and widespread implementation in the UK, Europe and beyond.”

Intracranial thrombectomy

The debate on intracranial thrombectomy was part of a whole session dedicated to the procedure.

Hugh Markus (Cambridge, UK), who was chairing the session, called intracranial thrombectomy “one of the huge advances in stroke care at the moment”. Outlining its significance, he said “for every three patients we treat, we can cure one, so it is a massive treatment effect. It has transformed stroke care.”

In a keynote lecture, David Hargroves (Kent, UK) reviewed what thrombectomy trials “really tell us”, and how the findings can be implemented into routine clinical practice.

In light of the DAWN and DIFFUSE-3 trials, he said that there is a strong evidence basis for thrombectomy and that this treatment should be available to all patients.

Additionally, Hargroves posited that regional and countrywide networks are required to deliver and achieve its 10% potential reach. However, he said, caution is needed when reorganising stroke services, so as not to destabilise the ‘core’ business and therapeutic benefit of organised care, closest to home.

The session was moderated by Barbara Rantner (Innsbruck, Austria).

Virtual reality for training purposes may elucidate “who can do the procedure”

Thomas Liebig (Munich, Germany) looked at the use of virtual reality in thrombectomy training. He described his own training as similar to that of learning to drive a car, and contrasted it with the simulator experiences of pilots who must demonstrate their competencies in a virtual environment. Liebig pointed out that skilled performance is difficult to characterise, and then outlined his work with University College Cork (Republic of Ireland) to develop surrogate parameters for performance metrics that can be used in a simulator.

The findings, he said, “have the potential not only for training purposes” but, in a nod to the earlier debate on intracranial thrombectomy, could also allow us to “discriminate between a person who can do the procedure and those who should be doing something else”.

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Perioperative stroke

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STEP Study

Multicentre dataset reveals the added value of diffusionweighted imaging to reduce perioperative stroke Novel data from the Stroke from Thoracic Endovascular Repair (STEP) collaborators have provided insight into current practice of thoracic endovascular aortic repair (TEVAR), and the future role of diffusion-weighted magnetic resonance imaging (DW-MRI) in reducing stroke from endovascular repair. The multicentre dataset was presented at a Charing Cross (CX) Highlight Session, chaired by study investigator Roger Greenhalgh, and featuring a panel of moderators involved with the study­—including Tilo Kölbel (Hamburg, Germany), Stéphan Haulon (Le Plessis Robinson, France), Fiona Rohlffs (Hamburg, Germany), Hugh Markus (Cambridge, UK), Heinz Jakob (Essen, Germany) and Gustavo Oderich (Rochester, USA).

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aking a collaborative approach to investigating stroke risks associated with thoracic aortic repair, STEP is an independent, allencompassing, open and interdisciplinary study aiming to provide best practice for endovascular procedures, ultimately lowering the risk of cerebral embolism.

The STEP collaborators have reported that “currently, better evaluation is needed” in terms of cerebral infarction and cognitive function after performing thoracic endovascular procedures. “There should be a better way to quantify what happens to the brain from cerebral infarction, embolism, haemorrhage and even thrombus,” Rohlffs said in an introduction of the session at CX. For this reason, she explained, the STEP collaborators worked to pool experience from participating centres in the USA and Europe.

Summarising the major conclusions presented last year at CX, Rohlffs stated that with the pooled experience and multidisciplinary guidance from specialists in neurology, interventional cardiology, cardiothoracic surgery and neuroradiology, “we learned that imaging is a crucial tool for us to evaluate stroke after the procedure, as well as silent brain lesions that can occur after TEVAR”. The main aim of STEP, noted Greenhalgh, is to investigate “what infarctions there are, the type of infarctions after the procedure, and whether surgical technique can improve”. It was highlighted that, as surgeons trying to recognise clinical stroke may underdiagnose this condition, the potential value of introducing DW-MRI was evaluated in phase 2 of the STEP collaboration.

This potential value, the panel explained, lies in the ability of DW-MRI to recognise whether a lesion appearing in follow-up imaging is associated with the procedure itself, while also providing a means to monitor the outcome and improvement in the longterm. From the panel, Markus noted that what is “really exciting” about DW-MRI in this area is clear “when looking at it for improving surgical endovascular technique”.

Among the STEP operators, three centres (Hamburg, Germany; Paris, France, and the MayoClinic, USA) were able to provide new data on the use of DW-MRI post-TEVAR procedures, involving zone 0, 1, 2 and 3 of the aortic arch. The total series of 37 cases combined from these centres presents the “largest global experience” to date, Greenhalgh noted.

According to Kölbel, “the biggest difference to what is already known is that these cases include a large number of very proximal landings—with a significant zone 0 and zone 1 percentage. It is important that MRI

is done within a certain post-procedural time frame, and we were able to keep to the range of two to eight days, with the exception of only one patient.” He added, this suggested time frame of up to eight days was established with advice from Markus. Haulon expanded on the finding that a high proportion of cases were performed in the most proximal landing zones: “What was interesting about this dataset was that in less than three months, we managed to gather over 20 cases with proximal landing in zone 0 and 1, equating to almost 60% of the entire cohort.”

DW-MRI should be a standard of care [...] whether open or endovascular, we should press upon the funding bodies of our hospitals.”

The panel of STEP moderators

A second unanticipated result was the key finding that while new lesions were seen on DW-MRI in 80% of zone 0 cases, “63% of zone 3 patients were found to have new lesions on DW-MRI”, Haulon highlighted. These new lesions were seen despite the investigators use of preventative measures, including carotid clamping and, notably, CO2 flushing of the device systems before the standard saline flush. The latter technique was introduced by Kölbel and Rohlffs, whose work suggests the CO2 flush of stent-grafts may help reduce air embolisation during TEVAR. However, through a survey of collaborators regarding current practice, the limitation for DWMRI funding was brought to light, as the majority of centres were unable to make use of the imaging modality. “We found that in US centres where STEP collaborators operate, they cannot get funding for DW-MRI,” Greenhalgh explained. “However, perhaps the institutions could be persuaded, that if they perform this scan in the postoperative period, it can be recognised whether infarcts seen on imaging were present prior to the procedure.” As a result, an argument for funding could be made, as centres could distinguish between procedurally associated harm and pre-existing lesions.

Nevertheless, Markus warned that despite the “interesting findings” of the study and potential for DW-MRI to improve endovascular practice, “it remains important to have cognitive testing, to determine the impact thoracic endovascular repair may have on the patient”. This was elaborated on by Greenhalgh, who pointed to the fact that “some cognitive symptoms of neural damage may appear, even without visible DWMRI lesions.”

Both Markus and Greenhalgh remarked that future investigation will require a larger number of patients—both for improved understanding of the value of DW-MRI and current TEVAR practice, as well as to ensure adequate power in the analysis of cognitive testing data.

Concluding the session, Greenhalgh argued: “DW-MRI should be a standard of care—by which I mean that whether open or endovascular, we should press upon the funding bodies of our hospitals and institutions that the procedures should include funded DW-MRI.”

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Interview

Profile

Adam Arthur

Adam Arthur was one of few neurosurgeons in the USA to develop a busy practice in both open cerebrovascular surgery and endovascular neurosurgery. As is so often the case, he has had an array of influential mentors that helped guide him as he paved his career.

Now, as the current president of the Society of NeuroInterventional Surgery (SNIS), he tells NeuroNews about the important trial results he is awaiting this year, the highlights of the 2019 meeting, and the specific technology he is looking foward to seeing evolve.

What drew you to medicine and neurosurgery in particular?

paper is easy to read and thought-provoking.

Have you had any important mentors throughout your career? What have they taught you?

I have been frustrated that, despite multiple attempts, we have failed to demonstrate the benefit of cerebral bypass surgery in clinical trials.

Outside of neurosurgery, I am irritated that we still do not have flying cars. I watched the Jetsons as a kid and it is completely unacceptable that we are all still bumbling around, driving on roads and waiting at the airport.

I love working in a team with smart, motivated people.

I love getting to work with my hands, doing real things that have measureable results. I love getting to help patients, and being able to work with new technology.

It is unbelievable that I get to do all of those things as a “job”.

I have been lucky to have several outstanding mentors.

During residency I particularly benefited from working under Dick Schmidt and Bill Couldwell at the University of Utah (Salt Lake City, USA). Both are fantastic surgeons who emphasised dedication, meticulous microsurgical technique and the importance of thoughtful surgical judgment.

My most influential endovascular mentor is John Barr. I came to Memphis because of his endovascular skills and his abilities as a teacher. I got to stay on as his partner, so it was a seven-year fellowship, which I am sure John would say was needed! As a bonus I got to work with two neurosurgeons on the open surgical side: Clarence Watridge and Morris Ray. There is a Persian proverb that roughly translates to “the branches with the most fruit bend lowest to the ground”. Clarence Watridge is a superb surgeon and an incredible doctor, but comports himself as a humble servant. Morris Ray is an amazing surgeon, but never sought to promote himself.

Since becoming an attending I have been influenced by several mentors. Dan Barrow, Jacques Dion, Alex Berenstein and Chuck Kerber have all gone out of their way to be kind to me. It is a strange and wonderful thing to have a role model become a friend.

The majority of your research sets out to improve the treatment of patients with cerebrovascular diseases, such as aneurysms and stroke. What sparked your interest in these areas?

Cerebrovascular anatomy is beautiful and fascinating.

The brain is the most amazing thing we have yet encountered. My interest started with becoming entranced by cerebrovascular microsurgery and then I learned to love endovascular neurosurgery. Stroke— both haemorrhagic and ischaemic—is the most vicious enemy we face because it maims so many more than it kills, taking away vital capabilities from people, often with no warning.

Your Masters degree focused on the methodology of clinical trials. What do you think makes a good research paper?

It starts with a question. The question must be well articulated and the answer must matter. The trial must be planned so that it can answer the question and then it must be executed well. Finally, there is no substitute for clear, well-organised writing. A good

What has been the biggest disappointment, i.e. something that you thought would be practice-changing but was not?

What are the most important trial results that you are awaiting in the near-future?

CREST-2 (Carotid revascularisation and medical management for asymptomatic carotid stenosis trial) will be important. In the USA we are much more aggressive about intervening on patients with asymptomatic carotid stenosis than in most other countries. CREST-2 should tell us whether that is advisable or not.

What technology are you keeping an eye on?

I am very interested in technologies for early identification of patients with emergency large vessel occlusions (ELVO) and for those with intracerebral haemorrhage. CT is an awfully big and expensive

The field is grounded in a passion for putting patients first, and I hope that never changes.” tool to use for screening and is a choke point for the treatment of stroke patients. I also look forward to the continued evolution of angiography systems. I think that interactive three-dimensional artificial intelligence assisted endovascular intervention should be possible in my lifetime.

As the current president of SNIS, what have you achieved, and what are your hopes for the future?

Neuroendovascular surgery is maturing into its own specialty despite the fact that most of us began training as radiologists, neurologists or neurosurgeons. I have been lucky to lead SNIS at a time when there is a lot happening to improve the field and what we have to offer for patients. The field is grounded in a passion for putting patients first and I hope that never changes.

What are the highlights of the 2019 meeting?

It is a phenomenal programme filled with diverse

speakers and topics. There is, however, one thing that I am looking forward to above all the others.

This is the first year that we will be addressed by a stroke patient. Amy Walters is one of the most brilliant and kind people I have ever met and she suffered a stroke at the SNIS meeting two years ago.

We have established a lectureship in her honour and she is coming to give the first lecture. She is working through a significant aphasia and it will be an incredible moment when she gets up in front of the neurointerventional community to share her experience. There is so much happening in our field with technology, technique and policy. It is good for us to be reminded of the patients’ experience.

What advice do you hope your mentees/students will always follow?

I hope they remember to enjoy their lives and help others to do the same.

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Fact File

Clinical appointments:

Professor of Neurosurgery, University of Tennesee Health Sciences Center and Semmes-Murphey Neurologic and Spine Clinic 2018–Present: Chairman, Department of Neurosurgery, Methodist University Hospital, Memphis, USA 2010–Present: Director, Vascular and Endovascular Neurosurgery, Methodist University Hospital, Memphis, USA 2010–Present: Chief, Interventional Neuroradiology, Baptist Memorial Hospital, Memphis, USA 2009–Present: Director, Cerebrovascular and Endovascular Neurosurgery, Semmes-Murphey Clinic and University of Tennessee (Knoxville, USA), Department of Neurosurgery 2008–Present: Director, Neurointensive Care Unit, Baptist Memorial Hospital, Memphis, USA

Current society positions:

2019–Present: Chair, NREF/AANS Education Committee 2019–Present: Treasurer, AANS/CNS Joint Cerebrovascular Section 2019–25: Member, Neuroendovascular Surgery Advisory Council, Committee on Advanced Specialty Training, The Society of Neurological Surgeons 2018–19: President, Society of NeuroInterventional Surgery

Current research (selected):

What has been your most memorable case?

There are many that I will never forget but I can tell you about one. I cared for a young woman who had been dealt a really tough hand. Her parents had both died in an accident. She had had several heart surgeries and was dependent on an external pump while she awaited a heart transplant. She had lost all of her toes as a complication of vasopressor medications. The external pump became infected and she ruptured first one, then a second mycotic brain aneurysm.

She was suffering terribly and was despondent when I met her. We were able to treat her aneurysms without giving her a stroke, which was a minor miracle. But it was hard to convince her that there was any chance of joy or future for her. The musician Ben Harper came to town and I reached out and asked him to come and see her. He was absolutely amazing. He serenaded her and charmed her and was late to his show because of it.

She lit up for quite a while and became an expert on Ben Harper’s music, expounding on it to anyone who would listen. Eventually they had to operate on her heart to replace the infected pump and she bled to death around the time that my first son was born. The moments of happiness that she had before her death still burn in my memory. I wish we could have done more for her.

What are your interests outside of medicine?

Most of my family are artists and academics so I grew up with a love for art, theater and literature. I enjoy playing soccer and snowboarding. I am always up for sharing good food and wine with friends and family.

I suppose I am most interested in my wife, who is brilliant, funny and beautiful, and in the three strange short people who live in our house with us (Merrick is 10, and Gus and Violet are eight).

WEB-IT – International principal investigator MIND – International co-principal investigator RAGE – International co-principal investigator STEM – International co-principal investigator EVOLVE – International co-principal investigator BRAVO – International co-principal investigator

Professional education:

2004–2006 Fellowship (Open Cerebrovascular and Endovascular Neurosurgery) University of TN Health Sciences Center 2002 Masters in Public Health, University of Utah 1998–2004 Residency in Neurosurgery, University of Utah 1994–1998 Medical Degree, University of Virginia

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Improving treatment time

Interdisciplinary approach to in-hospital stroke improves detection and treatment time A recent study found that revision of an existing in-hospital stroke (IHS) protocol was associated with a lower rate of stroke mimics, and shorter time to intravenous and intra-arterial intervention.

The paper, authored by Jody Manners (University of Pittsburgh Medical Center, Pittsburgh, USA), Ashutosh Jadhav (senior author) and colleagues, was recently published in the Journal of NeuroInterventional Surgery.

Ashutosh Jadhav

THE INVESTIGATORS NOTE that IHS is associated with high morbidity and mortality, including delayed time to recognition, associated comorbidities, and initial care from non-stroke trained providers. They hypothesised that guided revision of a formalised “stroke code” system can improve diagnosis and time to thrombolysis and thrombectomy.

In this study, Manners and colleagues sought to understand sources of delay in IHS within an established inpatient stroke protocol at a large academic campus. They implemented guided protocol modifications to include parallel processing to improve IHS recognition, assessment, and treatment, and compared data points of interest with a preimplementation cohort.

The investigators write that a preimplementation group contained 136 cases and a post-implementation group, 69 cases. They report that a reduction in stroke mimics (52% vs. 33%, p=0.01) occurred after protocol initiation and that the mean time to imaging after a stroke code call was 7.6 minutes shorter (p=0.05) in the pre- versus postimplementation group.

Manners and colleagues

mimics and time metrics.

The authors mention that overcoming unique obstacles to diagnosis and treatment of IHS is an area of ongoing research, and that prior work has demonstrated the benefits of an established inpatient stroke team, protocols for stroke code response, and bundled evaluations to reduce in-hospital stays.

They also note that little is known regarding specific sources of delay and how to target workflow to deliver faster treatment and reduce morbidity. “One potential strategy to improve efficiency is implantation of parallel workflow”, which they suggest “has been shown to reduce door-to-groin times in the emergency room setting.”

The authors report “significant reductions in time to neurological assessment, imaging, and in reperfusion therapy” after implementation, with the greatest reduction occurring in time from imaging to treatment, with an average reduction of 25 minutes.

Manners and colleagues write that prior estimates suggest an average time to treatment of 100 minutes or more.

They note that this is “well beyond the accepted goal of 60 minutes, which is

retrospectively analysed IHS activations occurring at a comprehensive stroke centre between 2013 and 2016 to guide revisions of an established stroke protocol to improve provider communication and time to imaging, reduce stroke mimic rate, and improve the use of parallel processing.

Nursing staf were responsible for almost two thirds of symptom recognition.”

After protocol implementation, the investigators prospectively collected data between 2016 and 2017 for comparison with the preimplantation group, including diagnostic accuracy and relevant time points, such as code call to examination, examination to imaging, and imaging to intervention. Finally, they performed a multivariable regression analysis to identify independent predictors of stroke

The value of timely endovascular therapy necessitates the launch of Target: Stroke Phase III The time to alteplase administration in Get With the Guidelines (GWTG)-Stroke hospitals has “substantially improved” following implementation of Target: Stroke Phase II. The results of the study, which found that the median door-to-needle time decreased from 66 minutes to 51 minutes, were presented at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA) by Gregg C Fonarow, professor of cardiovascular medicine at UCLA (Los Angeles, USA) and lead author of the study.

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pecifically, the implementation of Target: Stroke Phase II—a national quality improvement initiative focused on improving stroke care and outcomes—led to a reduction in door-to-needle times within 60 minutes for 75% or more of acute ischaemic stroke patients, fulfilling the primary goal of what the initiation set out to achieve. According to Fonarow, the initiative was also associated with improvements in clinical outcomes for such patients.

The secondary goal aimed to achieve 45 minutes or less door-to-needle time in 50% or more in acute ischaemic stroke patients. Fonarow explained that, when patients treated in Phase I of the initiative were compared with those treated in Phase II, the median door-to-needle time reduced from 66 to 51 minutes, while the percentage of patients with door-to-needle times of less than or equal to 60 minutes increased from 42% to 67%.

As quoted in an ISC press release, Fonarow highlighted the importance of these results: “Every minute a stroke goes untreated, a typical patient loses 1.9 million neurons— so a faster response time is critical to improve patient outcomes.”

The success of the Gregg Fonarow Phase II initiative has led the American Heart Association/American Stroke Association to announce the outline of its Phase III Target: Stroke programme.

The programme acknowledges the changing landscape of stroke treatment in terms of the recently proved value of endovascular therapy, as it primarily sets out

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achieved in only one in five patients with IHS”. In comparison, time to treatment in the post-implementation cohort from code call was less than the benchmark of 60 minutes in all three cases of tPA administration and in five of the six cases of thrombectomy. The remaining case occurred in 66 minutes.

Similar to previous studies, the investigators found a pattern of limited recognition of symptom onset in many cases due to “confounding polypharmacy and postoperative status”.

They suggest that the expansion of stroke education to additional providers “could improve recognition and reduce the time between last seen well and activation of the stroke code”.

They continue: “Nursing staff were responsible for almost two thirds of symptom recognition in a prior evaluation of IHS, highlighting the need to expand education beyond those involved in the rapid response teams to include all levels of care providers.”

The investigators note a few limitations of the study, including the singlecentre protocol implementation being a potential hindrance to feasibility in other institutions. However, they note that the concepts within the model: dedicated training providers, parallel processing, and improved communication, “could be applied for future encounters across institutions of practice”.

Additionally, the data were limited to clinical outcome measures, including discharge disposition or death as a primary marker. The authors write: “We acknowledge that a functional status marker like the modified Rankin Scale score would be further beneficial to evaluate potential improvement in the post-implementation cohort as a result of improved treatment times.”

to achieve “initial use of a thrombectomy device within 90 minutes for direct-arriving patients (60 minutes for transfer patients) in 50% or more of eligible acute ischaemic stroke patients”.

“Phase III of this initiative further raises the bar by setting more aggressive targets for timely treatment with IV alteplase,” commented Fonarow. “But now the aim goes beyond faster door-to-needle times. Phase III introduces a second type of intervention into the mix, setting the first ever targets for prompt treatment with endovascular therapy.”

In terms of the primary goals of Target: Stroke Phase III, door-to-needle times remain a focus, with the new initiative aiming to achieve this time within 60 minutes for 85% or more of stroke patients, with a secondary goal of getting down to 45- and 30-minute timelines as well.

“We see these goals as aggressive, but also completely attainable,” remarked Fonarow. “More importantly, we believe that it will continue to improve outcomes and save the lives of additional acute ischaemic stroke patients,” he added.

Phase III of this initiative further raises the bar by setting more aggressive targets for timely treatment.”

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Latest FDA caution for the use of off-label drugs in intrathecal drug delivery systems deemed “inconsistent with current practice” Continued from page 1

currently remain unapproved in the USA for chronic intrathecal use. For patients treated for cancer pain syndromes, this figure rises to greater than 90%. Although Deer and colleagues write that reasons for these current practice standards are “multidimensional”, they say many include those patients who failed on-label medications due to side-effects or a poor response to treatment with a lack of efficacy at reasonable dosing. Further, a “lack of commercially available concentrations and national drug availability” has also contributed to current practices carried out today.

Acknowledging the issues raised within the FDA communication, the authors conclude that many of these were “inaccurately linked to only non-FDA approved medications”. Specifically, pump failure with rotor malfunction and corrosion related to off-label use was referenced in the FDA safety communication. However, Deer and colleagues point to an array of evidence revoking this association. For instance, a registry specific to targeted drug delivery that enrolled 60 centres and included data from 7,459 patients from 2003–2016 (2,330 on-label programmable pumps; 5,189 off-label) found no statistically significant difference in risk of failure between the on-label and off-label pumps implanted for the treatment of pain (p=0.31). The authors posit that such findings supporting the use of off-label medications have been maintained in post-market studies, where the majority of patients continued on intrathecal therapy received off-label medications.

Additionally, dosing errors—which can occur when there is inadequate vigilance regarding drug ordering, dosage entry and device programming—have also been linked to only non-FDA approved drugs. Although Deer and colleagues propose that device malfunction can be directly related to intrathecal catheter granuloma from morphine, even if used in the labelled fashion, they

Key findings from a review of the indications, complications, and incidence of subsequent spine surgery A retrospective database review of 12,297 spinal cord stimulator (SCS) patients outlines key findings concerning the indications, incidence of minor and major complications, and rate of subsequent spinal surgery following SCS placement for degenerative spine disease. The study, published in Neuromodulation, found that the most common indication for SCS implantation was post-laminectomy syndrome.

argue that publications highlighted by the polyanalgesic consensus conference (PACC)—formed of an international multidisciplinary body of pain treatment experts—aim to address the need for protocols to alleviate these dosing errors.

The PACC was formed in 2000, as the panel of experts set out to review evidence pertaining to the efficacy and safety of intrathecal therapy in view to providing guidelines and recommendations for use. In the letter, Deer and colleagues write that both continued innovations and PACC reassessments shed light on the importance of a

The [FDA’s statement] places physicians at potential increased liability despite practicing within the standard of care.” strong patient-physicians-industry-regulatory partnership.

Thus, the authors argue that the FDA alert needs to be clarified in order to achieve protecting patients and for FDA oversight to improve care. “In this era of opioid misuse, overdose, and death, it is even more important that the option of intrathecal drug delivery remains viable and continued communication be ongoing with the physicians who treat these intractable pain patients, the manufacturers of the devices, and the FDA.” Thus, the authors concluded their letter to the editor with an array of recommendations. First, they maintain that off-label medications have been used safely for over 20 years, with no substantive data suggesting that off-label

Lawal Labaran from the Department of Orthopaedic Surgery, University of Virginia (Charlottesville, USA) and colleagues write that common postoperative complications included wound infection and removal of SCS electrodes at one year postoperatively.

They also concluded: “About 17% of patients had an emergency department visit for spine-related symptoms within one year of device implantation and 15.5% underwent subsequent spine decompression and/or fusion within three years after primary SCS placement.”

According to the authors, studies have shown SCS to be more effective in the treatment of chronic pain in spine patients compared to conservative medical management and reoperation. Despite this, Labaran et al express uncertainty about the long-term efficacy of SCS implants and their necessity in degenerative spine disease treatment, as they add: “The current literature lacks a long-term outlook on the complications, indications, and insight on the proportion of patients who undergo a subsequent spine surgery as a measure of the long-term efficacy of SCS.” The study investigators set out to retrospectively examine these factors through a commercially available database: the PearlDiver Patient Records Database. The authors extracted information from all Medicare

targeted drug delivery is unsafe as long as the PACC guidelines are followed. Regardless, they write: “When medically appropriate, physicians should consider the use of on-label drugs in the treatment of chronic pain with intrathecal drug delivery devices. This is true in both the noncancer and cancer-pain populations.”

They further suggest that where off-label agents or adjuvants are used to alleviate any side effects or loss of efficacy in patients receiving intrathecal drug delivery, this should be approached based on “proper animal data, human studies of safety, or an established track record of safety and efficacy in the medical literature”.

Moreover, the authors recommend that ongoing patient evaluation with careful monitoring of side effects should occur. If any adverse events are to occur, Deer and colleagues emphasise, “patient care should be immediately reassessed, and treatment modification should be carried out”, while they call for any reporting of such events to be “transparent, timely […], fully categorised and made available to physicians to assist in risk to benefit discussions and decision-making”.

Reiterating the practicality of physicians, manufacturers, and the FDA all working together to assess additional labelling for drugs that are commonly used, the authors also highlight that the presence or large device registries should allow for safety analyses, further assisting in improved guidance. Importantly, Deer and colleagues recommend that the FDA considers funding a prospective intrathecal drug delivery registry to track the safety and dosing with various intrathecal medications.

Ultimately, they write: “Our recommendation is to create a collaboration of physicians, medical societies, manufacturers, pharmacies, and the FDA to focus on this important issue.” Subsequently, they stress the need for the FDA to provide an addendum to their recent safety communication, as it remains “inconsistent with current practice”.

“The [FDA’s statement] places physicians at potential increased liability despite practicing within the standard of care”, claim Deer et al, as they conclude by calling for collaborative discussions with the FDA to develop additional guidance for patients receiving intrathecal drug delivery systems in the USA.

patients who underwent a primary SCS implantation through a laminectomy between 2005 and 2014, with each patient studied within 90 days, one year, two years, and three years postoperatively.

Using ICD-9 (International Classification of Disease, Ninth Revision) codes, Labaran et al excluded patients with a history of spine infection, trauma, and primary malignancy.

A total of 12,297 SCS patients were included. Through an analysis of patient demographics, a higher incidence of SCS implantation in patients less than 65 years old (43.4%) was found, with the lowest incidence seen to occur in patients greater than 85 years (2.4%). All patients had a mean Charlson Comorbidities Index (CCI) of 4.63±2.34, while 60.6% of the patient cohort were female.

Although the most common indication for open SCS placement was postlaminectomy syndrome (25.2%), chronic pain syndrome followed closely behind (20.2%), while other indications include lumbago or backache (14%) and thoracic or lumbosacral neuritis or radiculitis (9.1%).

In terms of SCS complications, the authors reported a 4.2% and 17.2% incidence of postoperative emergency department visits at 90 days and one-year, retrospectively.

Moreover, the incidence of SCS removal or reimplantation was 0.3% and 3.4% at 90 days and one-year. According to Labaran,

further notable complications included surgical site infection, haematoma, seroma and intraspinal abscess.

Lastly, the review indicated that within 90 days of SCS, 0.9% (110 out of 12,297), of patients had a subsequent spinal surgery, with the rate increasing to 7.1%, 11.7% and 15.5% at one, two, and three years, respectively.

The authors put forward that “this information will be useful for preoperative planning and patient education, while contemplating revision spine surgery versus SCS, especially for physicians who have adopted or plan to adopt this technique for failed spine surgery.”

Nonetheless, they say that as the results are limited to open SCS placement with laminectomy, the findings cannot be extended to percutaneous implantation.

Additionally, the authors allude to the possibility of inaccuracies due to nonuniform coding practices, including instances of miscoding and noncoding of diagnoses, given that such errors have been identified previously in national databases.

Despite these limitations, the study investigators maintain that this retrospective review is “one of the largest studies investigating the indications and complications of SCS implantation”, with its primary advantage being the large sample size and ability to track healthcare use following surgery.

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Cybersecurity: Providers and patients beware Padma Gulur Comment & Analysis Within the context of evolving technologies that continue to expand healthcare connectivity, Padma Gulur warns of the “immense vulnerability of current systems”. Arguing that stolen medical records supersede the value of credit card information on the black market, she outlines the cybersecurity threats to current medical devices, and the measures that are being taken to tackle these dangers.

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ybersecurity is a top priority in healthcare and involves many facets. Safeguarding healthcare information networks from penetration to damage or disruption is critical. The era of electronic medical records and the reliance on computerised lab reports and electronic patient communications have exposed healthcare to new vulnerabilities.

In addition, medical devices increasingly pose unique risks when they are used for monitoring or administrating therapies to patients, or when they are implanted in the body. The risk may stem from manipulation of software applications hacked to perform malicious operations or corruption of the hardware itself through infected firmware.

Recent malware and ransomware attacks on healthcare systems—including pacemaker hacks in 2011 and the more recent ‘Wannacry’ attack that shut down the National Health System in the UK along with others across Europe and Asia—highlight the immense vulnerability of current systems.

As we strive for greater connectivity in healthcare, the flip side of the coin is increasing vulnerability. From the comfort of their couch, experienced hackers could launch a malicious attack on millions, striking people when they are most vulnerable as they seek healthcare.

Medical Information: More valuable than other forms of identity theft

Stolen medical records tend to have a higher value on the black market than stolen credit card information. Access to medical information can allow for changed lab values, altered results and fraudulent communications; the risks are endless and the consequences severe.

The medical records of children are particularly valuable. It is not uncommon to find a vendor in the USA selling kids’ social security numbers and dates of birth (known on the dark web as “fullz”), that were hacked from a paediatrician’s database.

Risk to medical devices

The cybersecurity of medical devices has increasingly become a concern to healthcare providers and patients.

These devices tend to have significant vulnerabilities and susceptibilities to security threats that arise from the use of commercial, off-the-shelf software components such as operating systems,

spinal cord stimulators, intrathecal or insulin pumps.

Although there has never been a documented case of a medical device being hacked, numerous researchers have proven that such a hack is not only possible, but could be fatal. As early as 2008, a group of researchers at Beth Israel Deaconess Hospital (Boston, USA) showed that they could hack a heart defibrillator/pacemaker and reprogramme it to shut down or deliver a fatal jolt of electricity to the heart. Recently, a hacker demonstrated that he/she was able to override the radio signal on an insulin pump and have it dump a lethal dose of insulin to the patient.

The US Food and Drug Administration (FDA) issued a safety alert regarding cybersecurity vulnerabilities in two models of Medtronic programmers, which are used with cardiac implantable electrophysiology devices. This cybersecurity vulnerability is associated with using an internet connection to connect the programmers to Medtronic’s software distribution network, which allows providers to download software updates. The FDA confirmed that when the programmers are linked to an internet connection, the Medtronic network could be exploited, enabling an unauthorised user to alter the programmer to change its functionality during the device implantation procedure or during follow-up visits. To remediate these vulnerabilities and enhance cybersecurity

necessarily to wreak havoc but to do a public service. Some of these people are using this avenue to advocate for political or social causes using actions referred to as hacktivism.

Grey hat hackers are a blend of both black hat and white hat activities, but they are less skilled compared to the black hat or white hat. Grey hat hackers look for vulnerabilities in the system without permission. If issues are found, they report it to the owner; sometimes they request a small fee for discovering and fixing the problem. If the owner does not respond, they may post the vulnerability in the public forum for the world to see.

Regulatory oversight

The FDA, Homeland Security (through ICS-CERT), the research hacking community and product makers are working together by participating in cyber advisories to improve the security of health care information systems and medical devices.

The FDA originally issued a guidance on this topic in 2014 followed by a draft update in 2018. The draft guidance incorporates new recommendations, including a “cybersecurity bill of materials,” which is a list of commercial and/or off-the-shelf software and hardware components of a device that could be susceptible to vulnerabilities.

It also introduces two tiers of devices based on potential harm to patients from cybersecurity threats: those with higher risk, including implanted devices such as pacemakers or neurostimulation devices; and those with standard risk, which includes devices that contain software.

Intrusion detection systems

Stolen medical records have a higher value on the black market than stolen credit card information.” which inherit the related vulnerabilities.

Further, hospitals, clinics and physician practices are often slow to deploy upgrades and patches, compounding the issue of outdated software components that lead to security and privacy vulnerabilities.

Monitoring devices, anaesthesia machines and medication barcode systems are among the tools that can be corrupted and lead to significant patient safety issues. Drug infusion systems and diagnostic devices can lead to more direct patient harm if their functions are maliciously altered.

Perhaps most concerning of all is the risk to implanted medical devices, such as implanted pacemakers, defibrillators,

of device programmers,Medtronic disabled access to the wireless connectivity. When software updates are needed, a Medtronic representative manually updates, via a secured USB,

Hackers: Black, white and grey

The traditional hacker is a person with the ability to penetrate existing computer infrastructure without permission and with a malicious intent. These are known as black hat hackers.

Not all hackers seek to damage and destroy. White hat hackers are those individuals who break into systems to point out security flaws or bring attention to a cause. Their intentions are not

Computer scientists continue to develop systems that can help detect and/or counter cyberattacks on healthcare systems.

An example is a system for detecting malware on medical devices, called WattsUpDoc. This was developed by researchers Benjamin Ransford and Denis Foo Kune, who first unveiled the platform in 2013 before forming the commercial outfit Virta Labs. This intrusion detection system attempts to detect malware on implanted medical devices by monitoring tiny changes in power consumption.

Be aware, be prepared

The possible consequences resulting from a cybersecurity incident could be monumental, with broad implications for patient health, care delivery, and provider litigation risk.

As a provider or a patient, the key is to be aware of the risk. Providers should work to safeguard patients by establishing security protocols and securing each practice. Patients should be informed as needed of issues and educated on potential risks.

Padma Gulur is a professor of anaethesiology and the executive vice chair for operations and performance at Duke Anaethesiology, Duke University (Durham, USA).

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Burst stimulation of the spinal cord leads to greater pain modulation than tonic stimulation

Data from a substudy of SUNBURST suggest that burst stimulation of the spinal cord regulates the medial pain pathway to a greater extent than tonic stimulation, through selective modulation of the dorsal anterior cingulate cortex. Writing in Neuromodulation, Thomas Yearwood, Sven Vanneste (senior author) and colleagues postulate the existance of “an inherent difference in the central neural mechanisms during burst and tonic stimulation, which could potentially alter the patient’s perception of pain”.

BURST SPINAL CORD stimulation (SCS) delivers groups of pulses at a higher frequency and at amplitudes much lower than tonic stimulation. The authors hypothesised that a comparison of the central neural activation patterns during tonic and burst stimulation has the potential to investigate differences in neural processing and the underlying mechanisms involved in modulating the perception of pain.

Because there is not an SCS burst system that is compatible with functional magnetic resonance imaging (fMRI), the authors used fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate differences in neural activity during tonic and burst stimulation, and to assess any corresponding correlation with patient reported pain scores. FDGPET uses an analogue of glucose as the biologically active molecule.

The SUNBURST trial was a prospective, multicentre, randomised open-label crossover study; this sub-study collected seven patients in one study site at an extra visit during SUNBURST, adding the FGD-PET and the pain

vigilance and awareness questionnaire (PVAQ). Participants were randomised 1:1 to receive either tonic or burst stimulation for 12 weeks; at the end of this time they crossed over to the other treatment. A PET scan was taken at baseline and after 12 weeks of tonic stimulation and after 12 weeks of burst stimulation.

Among the inclusion criteria were age ≥22 years, and presence of chronic intractable pain of the trunk and/or limbs, with an average score of ≥60 on the visual analogue score (VAS) seven-day pain diary. Outcome parameters for the efficiency of treatment were measured with the VAS and the PVAQ, which assessed the overall impact of pain intensity and the emotional component related to pain, and were conducted at baseline, prior to implantation, and at the end (after 12 weeks) of each of the two study arms of tonic or burst stimulation.

Compared to baseline, the VAS score for pain reduced by an average of 41.5% (standard deviation [SD] 34.3) among those receiving tonic stimulation, and by 36.2% (SD 21.8) among those receiving burst stimulation. A suppression of 14.4%

Burst spinal cord stimulation affects the processing of cognitivemotivational aspects of pain more than tonic stimulation The behavioural findings of a recent study “strongly suggest” that burst spinal cord stimulation (SCS) outperforms tonic stimulation in terms of its affect on the processing of cognitive-motivational aspects of pain. Koen PV Meuwissen and colleagues from the Pain Management and Research Centre, Maastricht University (Maastricht, The Netherlands) reported these results, published in the journal of Neuromodulation.

G

Tonic vs Burst stim

(SD 34.3%) was observed for tonic stimulation compared to burst stimulation.

On the PVAQ scale, tonic stimulation demonstrated an increase of 9.3% versus a reduction of 17.8% for burst stimulation, when compared against baseline. Direct comparison of tonic and burst stimulation showed a reduction of 26.3% (SD 21.7) for burst stimulation.

Imaging data showed a significant increase in metabolic rate in the premotor cortex from baseline with both tonic and burst activity stimulation. There was also a significant increase in metabolic rate compared to baseline in the dorsal anterior cingulate cortex during burst stimulation.

A regression analysis of the VAS for pain and the metabolic changes between burst and tonic stimulation demonstrated a significant effect. A VAS for pain reduction was shown to correspond to an increased metabolic rate in the dorsal anterior cingulate cortex, the precuneus and the dorsal

iven that recent electroencephalography findings suggest that both burst and tonic SCS may have different supraspinal working mechanisms, the authors propose that a valid method to assess the cognitive-motivational aspects of pain is becoming increasingly important. Although they acknowledged that the majority of preclinical SCS studies rely on reflexmediated Von Frey analysis, Meuwissen and colleagues argue that the latter technique is unable to assess supraspinal cognitive-motivational aspects of pain.

However, they allude to a recent operant testing method that has been introduced, known as the mechanical conflict-avoidance system. According to the study investigators, when the animal is “placed in a brightly lit compartment which leads to a passage with a heightadjustable array of nociceptive probes,” the animal applies a “cost-benefit” analysis, weighing up the level of on-going pain, as well as the height of the probes and the averseness of the light. Meuwissen and colleagues write: “In general, as ongoing pain intensity or probe height increases, animals require more time to exit the light chamber.” Therefore, the stimulus-dependent measure analysed was latency to exit the light chamber—defined as time from light being turned on to having all four paws on the probe bed.

First, the authors set out to determine the effect of the partial sciatic nerve ligation rat model for chronic neuropathic pain on exit latency. Secondly, they aimed to assess the cognitive-motivational aspects of both tonic and burst SCS-induced pain relief—again using exit latency as a measure of this novel operant testing system.

lateral prefrontal cortex. According to the researchers: “This suggests that the higher the pain suppression with burst stimulation, the larger the increase will be in the metabolic rate of the dorsal anterior cingulate cortex, the precuneus and the dorsal lateral prefrontal cortex in comparison to tonic stimulation.”

A small number of patients were included in this sub-study, with only one round of data acquisition.

Despite this, said Yearwood et al, the findings “seem to confirm the previous electrophysiological findings that support burst stimulation having a larger impact on the medial pain pathway than tonic stimulation, as demonstrated by its selective modulation of the dorsal anterior cingulate cortex”.

The researchers called for larger studies, and add: “Studies using fMRI with an MRI compatible SCS burst device could further help to explain the underlying mechanism.”

In total, 38 male rats (five weeks of age) were used. In terms of their exit latencies, Meuwissen and colleagues reported that burst and tonic SCS differed significantly at 4mm probe height, at 3.8 vs. 5.8 seconds, respectively (p<0.01). Accordingly, at 5mm probe height, exit latencies were 3.2 for burst and 5.4 seconds for tonic SCS (p<0.05). Of note, the authors found that when reflex-based Von Frey testing was applied, this difference was not detected (tonic vs. burst SCS at 30 minutes of stimulation: p=0.73; 60-minute stimulation: p=0.42).

In light of this significant difference in 4mm probe height between neuropathic animals and sham-animals, Meuwissen and colleagues write: “The mechanical cognitive-avoidance system of pain is a valid operant testing method for the assessment of aspects of pain in neuropathic partial sciatic nerve ligation rats.” Further, they explain that the results also revealed that “Burst SCS seems to specifically modulate, much more than Tonic SCS, cognitive-motivational aspects of pain behaviour”.

Alluding to future directions of preclinical SCS, Meuwissen and colleagues suggest the inclusion of operant testing methods in preclinical assessment could provide a valid measurement for the cognitivemotivational aspects of pain, which in turn may present as a solution to the lack of translational progress in the pain field. Maintaining the importance of the mechanical cognitive-avoidance system as a tool to examine supraspinal aspects of pain, the study authors surmise: “A better understanding of the supraspinal aspects will allow further analysing and optimising of the emotional/ motivational properties of the burst SCS protocol.”

June

“Pain insensitive patient” may pave the way for new treatments of chronic pain A recent study investigating a rare genetic mutation in a patient who “feels no pain” has suggested new routes to developing gene-therapy based analgesics for the treatment of chronic pain. Alongside the rise of neuromodulation techniques, new analgesics that target the genes responsible for the sensation of pain provide non-opioid pain relief, further assisting in the alleviation of the opioid crisis seen today.

WHEN A 66-YEAR-OLD female patient requested no painkillers after undergoing surgery on her hand, her anaesthetist decided to look further into her medical history. Seeing that she had little need for pain relief, even after having suffered from broken limbs and childbirth, the patient was referred to geneticists at University College London (UCL) and Oxford University (both in the UK).

Now, speaking to NeuroNews, lead author of the study, James Cox (Wolfson Institute for Biomedical Research, UCL, London, UK) details exactly what the genetic mutation has revealed as well as how the findings of the study contribute to the treatment of chronic pain, and the next steps moving forward.

pain insensitive, also presents with additional symptoms including a happy, non-anxious disposition, enhanced wound healing, reduced stress and fear symptoms and mild memory deficits. The genetic mutations highlight the importance of the endocannabinoid system to pain perception and in particular FAAH as an analgesic and anxiolytic drug target.

How may your findings contribute to the treatment of chronic pain?

What exactly has this genetic mutation uncovered?

We have studied a female patient who carries both a change in the fatty-acid amide hydrolase (FAAH) gene that makes the enzyme less active and also a microdeletion downstream of FAAH, in a novel gene called FAAH-OUT. This patient, in addition to being

James Cox

The “neurosurgical robot” facilitates further research in deep brain stimulation The application of robot-assisted lead implantation in nonhuman primate neuromodulation research has been deemed feasible, accurate, safe and efficient in a recent study published in Neuromodulation. With multiple methods validating the accuracy and safety of the technique, the authors, Guan-Yu Zhu and Ying-Chuan Chen from Beijing Tiantan Hospital, Capital Medical University (Beijing, China), further postulate that these findings can prospectively be beneficial to neurological studies.

W

hilst the therapeutic effects of deep brain stimulation (DBS) have been displayed throughout an array of diseases, including Parkinson’s disease, dystonia and epilepsy, the study investigators claim that the underlying mechanisms remain unclear; an issue they attribute to the lack of primate DBS models.

In comparison to traditional methods of drug administration and electrode implantation, the authors write that the “neurological robot” has many unique advantages in nonhuman primate stereotactic surgery. For instance, they put forward that anatomic registration can be achieved based on selftapped screws, ensuring both accuracy and safety, while the six-freedom robotic arm ensures that the electrode can be implanted without a restricted entry angle and entry point.

According to Zhu, Chen, and colleagues, the multi-freedom robotic arm can—to

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an extent—solve the challenge of the discrepancy in head size between humans and monkeys. Thus, to investigate these proposed advantages, Zhu, Chen and colleagues selected 12 adult male rhesus monkeys (mean age: 6.1 years) for the study. They were randomly assigned, with six receiving DBS to the subthalamic nucleus, and six receiving DBS to the anterior nucleus of the thalamus. In addition, the authors note that three monkeys were randomly selected from the anterior nucleus group to undergo stereoelectroencephalography (SEEG) electrode implantation in the hippocampus, as they theorised that SEEG may be necessary to evaluate the outcome and mechanism of DBS in controlling seizures.

Zhu, Chen and colleagues highlight that the design of the surgical plan was based on the preoperative MRI images, using the robotic system. “The trajectories

Millions of people world-wide are living in chronic pain. This pain is often poorly treated and the over-prescription of opioid-based drugs has contributed to an opioid epidemic that is causing significant morbidity and mortality. New painkilling and non-opioid based medications are

urgently needed. We hope that these findings will lead to the development of new analgesics that target FAAH/ FAAH-OUT and provide better non-opioid based pain relief for chronic pain patients.

Do the findings expand the opportunities for personalised therapy for chronic pain?

“Chronic pain” should be thought of as lots of different diseases—just like ‘cancer’ can be subdivided into, for example, bowel, liver, prostate, or pancreatic cancer.

If we can stratify chronic pain patients correctly with in-depth phenotyping and molecular genetic analyses, we will be able to make headway in treating distinct patient populations with the most appropriate analgesic drugs.

If and when new FAAH-based analgesics come to the clinic, we can then determine which subgroups of chronic pain patients would benefit from those types of painkillers.

Since the story was broken, has anyone else who does not experience pain come forward?

Yes, we have been delighted with the response, with over 80 pain insensitive patients getting in contact.

What are the next steps in terms of research?

We are looking forward to working with the new patients and begin sequencing their DNA—some of these patients may have mutations in known pain genes whilst others may have mutations in completely new ones. We are also keen to understand how the FAAH-OUT gene functions and are currently carrying out gene editing experiments in human cells to learn more about how it regulates FAAH expression. We are also excited at the prospect of using gene therapy as an approach to treat chronic pain and have several ongoing studies in this area.

of the DBS electrode were designed according to the implantation trajectories in humans, multimodal image was used, and consideration was given to avoid their passage through sulci, blood vessels, vascular structures and screws”.

Mean Euclidean errors (those pertaining to distance) of the entrance and target points were calculated by postoperative image fusion in order for the authors to statistically observe the accuracy of the robotic system.

Additionally, the correlation between entrance and target error, as well as the difference among various manipulations, were analysed.

Time consumption was also recorded.

The mean Euclidean errors of the target point and entry point of DBS of the subthalamic nucleus were 1.05±0.54mm and 0.52±0.17mm, respectively, while DBS of the anterior nuclei of the thalamus elicited errors of 1.12±0.74mm (for the target point) and 0.58±0.24mm (for the entry point). Regarding the SEEG group, target and entry point errors were 2.68±1.03 and 1.47±0.63mm, respectively.

Interestingly, while significant differences were observed in both target and entry point errors between the DBS and the SEEG groups, the DBS group displayed superior accuracy. Moreover, the data suggest that entrance errors had a significantly positive correlation with the target errors in the subthalamic nuclei DBS group and the SEEG group. Lastly, the authors report that time consumption in robotic surgery was much shorter compared with traditional techniques, with no major complications occurring.

On discussion of the findings, Zhu,

Chen, and colleagues write: “Owing to their high similarity to humans, experiments on nonhuman primates are ideal for neurological research, especially those relating to DBS and SEEG implantation.”

Although they propose that robotic stereotaxy is a novel technique in nonhuman primate studies, they suggest that a steep learning curve may exist. Yet, they add that as investigators become more familiar with the procedures of robotic surgery, “the new approach became an increasingly timesaving technique”.

Furthermore, in terms of future applications in nonhuman experiments, the study investigators write: “The ‘neurosurgical robot’ can definitely facilitate further research in DBS, SEEG, or even some newly emerging methods, such as ultrasound stimulation.” They add: “We can also use this method to implant a substance or quickly and accurately remove tissues from the target area. Additionally, nonhuman primate experiments could be applied to explore the potential new DBS targets, such as the pedunculopontine nucleus.”

Despite the fact that the authors reported favourable results, they note that the number of monkeys and subsequent targets was small, given the ethical limitations. Further, the robotic system is expensive, which inevitably might limit its use in animal research. Yet, Zhu, Chen and colleagues reiterate that in comparison to traditional techniques, robotic-assisted methods can facilitate more accurate lead positioning, while the use of more flexible adaptors for unique research purposes could reduce complications and save time.

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Specific spinal cord stimulation waveforms modulate gene expression of neuropathic pain Distinct spinal cord stimulation (SCS) waveforms have been found to differentially modulate several key transcriptional pathways that are associated with chronic pain conditions. These results, published in Neuromodulation, carry important implications for SCS, as the authors—Ricardo Vallejo from Millennium Pain Center (Bloomington, USA) and colleagues—suggest moving beyond the traditional paradigm of neuronal activation to focus also on modulating immune-driven processes.

V

allejo and colleagues set out to study the mechanism by which different waveforms may result in analgesic effects through induced gene expression. “We hypothesised that waveforms with varying phase polarities and charge balance result in diverse behavioural patterns and expression of genes due to unique mechanisms of action.”

Providing a rationale to the study, they write: “An important aspect to consider is that the stimulated tissue contains glial cells in addition to neurons.” Referring to the essential role that glial cells play in establishing and maintaining a chronic pain state, Vallejo et al emphasise the significance of neuroglia interactions, as they inevitably promote neuroinflammation when they become unbalanced.

“Considering that glial cells respond to electrical stimuli, albeit different than neurons, it is conceivable to design new therapeutic waveforms that may improve current clinically observed results,” claim the authors. They further allude to the array of controllable waveform parameters that are applied to the spinal cord, acknowledging that they consist of frequency, pulse width (duration), amplitude, and phase polarity, as well as interphase delay and duty cycling.

The authors point to a previously published study that listed the main biological processes regulated by SCS after Chronic Constriction Injury model. Immune response, synaptic signalling, cell-cell signalling, transsynaptic signalling and chemical synaptic transmission were among these regulatory factors. The previous work of Vallejo et al—which won the best science abstract presented at the last North American Neuromodulation Society’s annual meeting (NANS; 17–20 January, Las Vegas, USA)— provided congruent results, while it further emphasised the role of SCS on glial modulation.

In the current study, Vallejo and his team utilised a neuropathic pain rat model in order to examine the effects

of monophasic, as well as chargeunbalanced and charge-balanced biphasic SCS waveforms on pain behaviour and gene expression.

“Rats [84 in total] were implanted with a four-contact cylindrical minilead and randomly assigned to two control [no-pain and pain model] and five test groups [n=14 in each] featuring monophasic, as well as charge-unbalanced and charge-balanced biphasic SCS waveforms,” report the authors. In order to measure efficacy, mechanical and cold allodynia (pain) was assessed. The ipsilateral dorsal quadrant of spinal cord adjacent to the lead was harvested following stimulation and processed to determine gene expression via real-time reversetranscriptase polymerase chain reaction.

In terms of subsequent analyses, the authors note that gene expression, SCS intensity and behavioural score as percent of baseline were all statistically analysed and used to generate correlograms.

Vallejo and colleagues found, “as expected,” that the behavioural score as percent of baseline was significantly lower for the pain model group compared to the no-pain group. This

the correlograms revealed a linear correlation between regulation of expression of a given gene in relation to SCS intensity, the behavioural score as a percent of baseline, or other genes.

On discussion of these findings, the study investigators put forward that “the behavioural analysis confirmed the success of the pain model, as shown by the significant difference in the behavioural scores for sham and the spared nerve injury groups.” SCS was found to ameliorate mechanical sensitivity within an array of waveforms (cathodic, anodic, symmetric biphasic and asymmetric biphasic with twice anodic content) when comparing prestimulation to post-stimulation. Vallejo et al note that “interestingly”, only one waveform— asymmetric biphasic with half anodic content—failed to significantly reduce mechanical sensitivity.

Yet, the authors write that “there were no differences between the different waveforms on their effect on mechanical sensitivity,” which led them to acknowledge that “the hypothesis that the experimental waveforms would cause different behavioural responses

A better understanding of this activity opens the opportunity to develop waveforms to better control pain conditions.” behavioural score was also observed to have significantly improved poststimulation compared to pre-stimulation (using waveforms with different anodic content). However, the authors acknowledged that this behavioural score was not restored to sham levels.

Furthermore, the authors explained that the analysis regarding the reversetranscriptase polymerase chain reaction “showed that eight genes demonstrated a significant difference between the pain model and SCS waveforms, and between waveforms.” Moreover,

was not validated”.

In contrast, the investigators report: “Consistent with our hypothesis, we observed significant differential modulation in the expression of genes involved in immune related biological processes by different waveforms.”

They highlight that the most balanced waveform (symmetrical biphasic) had the most effect on the expression of genes related to the immune system, relative to spared nerve injury cohort.

Further, they write: “There are strong correlations between fold changes [of

gene expression] and the content of anodic component of the waveform for the unbalanced waveforms particularly in the genes involved with the immune function modulated by glial cells.”

Alluding to a critical consideration in evaluating the modulation of gene expression, the authors acknowledge that there is limited overlap between different pain models. Yet, pointing to a study that utilised three neuropathic pain models—Spared Nerve Injury, Spinal Nerve Ligation, and Chronic Constriction Injury—they reiterate the finding that “the largest group of commonly modulated transcripts is involved in the immune function.”

In terms of the current study’s limitations, the Vallejo and colleagues recognise that the lack of a sham group without implantation presents as a particular caveat. However, they argue that “given the previously published results showing the efficacy of the spared nerve injury model, [they] feel its validation is not necessary to meet the goals set forth in this study”.

In summary, the current study focused on the impact of phase polarity regarding the modulation of gene expression in the spinal cord of nerve injured rodents following 24 hours of continuous SCS. Concluding the investigation, Vallejo and his team propose: “Our results support that specific waveforms differentially modulate several key transcriptional pathways relevant in chronic pain conditions including the immune response, synaptic signalling, and oxidation-reduction process. This work implies that the composition of the waveform is an important factor in driving the modulation expression of genes involved in such processes, particularly the effect of anodal stimulation.”

Moving forward with these findings, the study investigators postulate: “A better understanding of this activity opens the opportunity to develop waveforms to better control pain conditions.”

June

Product News

Abbott partners with NIH on BRAIN initiative to advance research for neurological disorders

Abbott have announced that it has partnered with the National Institutes of Health (NIH) on the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) initiative to accelerate advancements in neuroscience research. As part of the agreement, Abbott will provide the company’s neuromodulation technologies—including directional deep brain stimulation (DBS), spinal cord stimulation (SCS), and dorsal root ganglion (DRG) therapy—for research related to these NIH initiatives to explore their application for chronic pain and progressive movement disorders, such as Parkinson’s disease.

“The NIH is investigating the application of these devices for the treatment of a wide range of neurological and neuropsychiatric conditions and chronic pain,” said Nick B Langhals, programme director for neural engineering within the Division of Translational Research at the National Institute of Neurological Disorders and Stroke. “The neuromodulation technologies provided by Abbott will help us determine the inner workings of the nervous system to help fill gaps in our current knowledge of the brain and provide opportunities for exploring how the brain interacts with the human body in patients with neurological conditions.”

Launched in 2013, the BRAIN Initiative looks to understand the functions of the human brain by researching and developing new uses for innovative technologies. Recently, the BRAIN Initiative assembled participants from contributing federal agencies, nonfederal organisations, as well as members of the media, public, and Congress at its 5th Annual Investigators Meeting in Washington, DC, USA. The meeting provided a forum for discussing recent scientific developments and potential new directions in brain research, while it identified areas for collaboration and research coordination.

NeuroPace present positive data from studies of the RNS System

NeuroPace has presented long-term clinical results demonstrating that the RNS System for refractory epilepsy significantly reduces seizure frequency in patients, with one in three people achieving 90% or greater reduction in seizure frequency at nine years. Data from new research illustrating potential for the RNS System to identify objective biomarkers in the brain were also

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Clinical News presented. Both developments were shared at the American Academy of Neurology (AAN) 2019 Annual Meeting in Philadelphia (USA).

The company’s long-term treatment study of the RNS System is the largest and longest prospective neuromodulation study in the field of epilepsy, with 256 patients across 33 epilepsy centres prospectively analysed for nine years.

The study showed that treatment with the RNS System resulted in significant

Prospective data demonstrates effective pain relief and improved function using Medtronic’s Evolve workflow with spinal cord stimulation

Medtronic has announced primary endpoint (three-month) results of the Vectors post-market clinical study that demonstrated effective pain relief and improved function in patients with chronic intractable back and leg pain treated with spinal cord stimulation (SCS) utilising the Evolve workflow.

Medtronic offers the Evolve workflow

nerve stimulation (PNS) system in the treatment of post-amputation pain.

The study demonstrated that shortterm PNS therapy may provide enduring clinically significant pain relief, reduce opioid use and improve quality of life in patients with post-amputation pain, a type of neuropathic pain. This is the first study of an FDA-cleared PNS system to demonstrate statistically significant and clinically meaningful improvements in pain relief for both residual limb pain and phantom limb pain. The study has been published in Regional Anesthesia and Pain Medicine, the official peer-

RNS system

seizure reduction and improved quality of life for patients, including improved memory and cognition. Median seizure reduction across all patients in the study (who had drug-resistant epilepsy and a median of 10 seizures per month) was 75% at nine years. Results of the study were previously shared at the American Epilepsy Society Annual Meeting in December 2018.

“These nine-year results demonstrate compelling long-term seizure reduction in patients treated with the RNS System,” said Dileep Nair, a consultant to NeuroPace, principal investigator of the study and section head of adult epilepsy at the Neurological Institute at Cleveland Clinic.

Neuromod prepares for global commercialisation of Lenire tinnitus treatment

Neuromod Deviceshas provided an update on organisational and leadership growth in preparation for European commercialisation and US regulatory clearance application.

Following the completion of two of the largest clinical trials ever conducted in tinnitus; including 517 participants, the company is now advancing towards initial commercialisation of its CEmarked product in Ireland and Germany, which will be marketed under the brand name Lenire.

To support commercialisation activities, Neuromod is investing in establishing the appropriate quality, regulatory and supply chain infrastructure to support near term European plans and lay the foundation for the company’s US strategy.

SPR Microlead

to help physicians balance high-dose and low-dose therapy settings on Medtronic SCS systems, including the Intellis platform. Results were presented at the American Society of Interventional Pain Physicians (ASIPP) annual meeting and found that patients experienced a statistically significant and clinically meaningful improvement, with 69% of patients experiencing ≥50% improvement in overall pain and 70% achieving a personal activity goal at three months.

Ninety per cent of study subjects had a successful screening trial. One-hundred and three were then implanted with the device, and 98 patients completed the primary endpoint (three-month) visit. Data from the study demonstrated sustained pain relief, improved quality of life and decreased disability after device implant, shown through the following statistics: 69% of patients had at least a 50% improvement in overall pain 70% of patients achieved a personal activity goal 81% of patients were satisfied with their therapy 65% improved at least one disability category in the Oswestry Disability Index (ODI).

Study of SPR Therapeutics’ peripheral nerve stimulation system demonstrates sustained relief of postamputation pain SPR Therapeutics have announced the study results of its SPRINT peripheral

reviewed publication of the American Society of Regional Anesthesia and Pain Medicine (ASRA).

Study participants had experienced post-amputation pain for periods ranging from four months to more than 30 years. All participants underwent the minimally-invasive ultrasound-guided placement of SPR’s Microleads which are constructed using a 100-micron wire.

Participants were randomised to receive SPRINT PNS therapy or placebo for four weeks. The placebo group then crossed over and all study participants received PNS for four subsequent weeks.

Specifically, a significantly greater proportion of the participants who received SPRINT PNS experienced significant pain relief (58%) compared to 14% of those who received placebo. The delivery of therapy for four additional weeks in the SPRINT PNS group resulted in 67% of the participants reporting significant pain relief.

While prospective follow-up is ongoing, of those participants who completed follow-up at 12 months, 80% reported continued relief with an average pain reduction of 76%. Furthermore, opioid use among moderate to high users (which represented about a quarter of the participants) decreased by more than 70% in the SPRINT PNS group compared to less than 1% in the placebo group. The most common side effect was skin irritation or redness at the lead exit site or related to the use of adhesive patches or bandages. There were no serious side-effects.

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Market watch

Medtronic launches Solitaire X revascularisation device in the USA

Product News

Vesalio secures US$5 million investment capital funding

Vesalio announces it has recently raised US$5 million in funding. The capital will support the continued global expansion of the NeVa neurothrombectomy system, finance key clinical studies and launch new product introductions.

This announcement follows the company’s report regarding its expansion of international distributor network and Stroke Congress Exhibition presence, claiming that it now has market coverage in 39 countries for the NeVa neurothrombectomy system.

“We are very pleased to secure the additional capital funding. We are in the process of initiating several prospective clinical studies for regulatory clearance requirements. In addition to the key studies, we will continue to expand our product offering and geographic sales coverage,” remarked Steve Rybka, CEO of Vesalio.

Balt USA announces CE mark obtained for Titan aspiration catheter Balt USA has announced that it has obtained CE mark for the Titan aspiration catheter. The Titan catheter line consists of a highly navigable, large bore (0.070”) aspiration catheter and a smaller bore (0.036”) catheter for navigation and support.

Obtaining the CE mark for Titan enhances the Balt stroke portfolio as it will be available alongside the CatchView revascularisation stent, Vasco catheters, Ballast long sheath and Hybrid guidewires to provide a complete stroke solution to the marketplace.

Pascal Girin, CEO at Balt, said: “Titan marks the sixth significant product approval obtained by Balt within the last year and contributes to Balt’s rapid succession of products to the neurovascular community.”

Medtronic has announced the US launch of the Solitaire X revascularisation device, and its first use in patients for the treatment of acute ischaemic stroke.

For 10 years, the Solitaire revascularisation device has enabled physicians to help patients have a better chance at recovering from stroke. Solitaire X is a fourthgeneration device featuring an optimised delivery system for improved efficiency—while retaining the technical features that have made the Solitaire family of revascularisation devices clinically proven and highly effective.

In addition, Medtronic introduces

Phenom 21 Catheter, a 160cm length microcatheter for the delivery of all sizes of Solitaire X. The Solitaire X device mechanically removes blood clots from blocked vessels in the brain to restore blood flow in patients suffering an acute ischaemic stroke with large vessel occlusion. When combined with Phenom 21, Solitaire X provides a low clot crossing profile, with smooth delivery to occlusions in distal vessels as small as 2mm.

25

Imperative Care announce US clearance of its ZOOM aspiration system

Imperative Care has announced US Food and Drug Administration (FDA) 510(k) clearance of the company’s ZOOM aspiration system—a family of products designed to facilitate clot removal during ischaemic stroke.

The ZOOM aspiration system includes the ZOOM reperfusion catheters, ZOOM aspiration pump, ZOOM canister, and the ZOOM aspiration tubing. The reperfusion catheters are designed with the TRX tip to navigate complex anatomy and optimally engage blood clots.

They come in four sizes (0.071”, 0.055”, 0.045”, and 0.035” internal diameter) and are designed to enable smooth tracking through challenging vasculature.

“For any ischaemic stroke procedure, getting to the brain quickly with the right tools to remove clots is paramount.

Imperative Care has developed a portfolio of access and aspiration catheters that work together to facilitate fast and effective clot removal,” said Ariel Sutton, executive vice president of marketing at Imperative Care.

“The ZOOM aspiration system is for use in the revascularisation of patients with acute ischaemic stroke secondary to intracranial large vessel occlusive disease (within the internal carotid, middle cerebral—M1 and M2 segments, basilar, and vertebral arteries) within eight hours of symptom onset.”

26

June

Issue

19 34

Events

Clinical News

Positive safety and effectiveness results in WEBIT pivotal trial

MicroVention has announced the publication of the WEB-IT pivotal trial results in the online edition of the Journal of NeuroInterventional Surgery.

The WEB aneurysm embolisation system met its primary safety and effectiveness endpoints in this prospective, single-arm study of 150 patients

conducted at 21 US and six international centres. The results of the study led to the premarket approval of the WEB system late last year by the US Food and Drug Administration (US FDA) in the USA for treatment of wide neck bifurcation aneurysms in the brain.

“The WEB-IT pivotal trial shows that the WEB system is an effective and extremely safe treatment for a subset of aneurysms that are challenging to treat with standard embolisation coils and assist devices. None of the aneurysms treated with the WEB system in the trial had follow-up bleeding events,” stated Adam Arthur, director of cerebrovascular and endovascular neurosurgery at Semmes Murphey Neurologic and Spine Institute (Memphis, USA), associate professor of neurosurgery at University of Tennessee (Knoxville, USA), and a principal investigator of the WEB-IT trial.

The WEB system provides a clinicallyproven, single device treatment option that advances the treatment of up to 35% of all

brain aneurysms. The system’s proprietary microbraid technology bridges the aneurysm neck to disrupt blood flow and creates a scaffold for a long-lasting effect.

The WEB system has been CE marked since 2010 with more than 6,000 cases performed throughout the world.

“The results of the WEB-IT trial match the patient outcomes we have seen in the six other good clinical practice studies completed in Europe,” said David Fiorella, director of neurointerventional radiology, Stony Brook University Cerebrovascular and Stroke Center and a principal investigator of the WEB-IT trial.

Many stroke patients not screened for osteoporosis, despite known risks

The majority of stroke survivors are not screened or treated for osteoporosis, broken bones, or fall risk—despite stroke being a risk factor for these conditions.

The risk is up to four times greater than in healthy people, according to new research in the American Heart Association’s journal Stroke.

Stroke survivors often face reduced mobility—a trait that decreases bone mineral density and increases risk for bone breaks. Less than one-third of older

women living in the USA are screened for osteoporosis and the treatment rate for some high-risk patients tops out at 30%.

“Our study adds to previous research that found despite an increased risk, only a small number of people who have recently had a stroke are tested and treated for osteoporosis,” said Moira Kapral, lead author of the study and professor of medicine and director of the division of general internal medicine at the University of Toronto, Canada.

Researchers identified stroke survivors age 65 and older who either had visited the emergency department or had been hospitalised for stroke between July, 2003 and March, 2013 at 11 regional stroke centres throughout Ontario (Canada), from the Ontario Stroke Registry. According to the journal report, using administrative databases allowed researchers to link the registry with information about bone mineral density testing, prescription medications and deaths.

Of the 16,581 stroke survivors included in the study, only: 5.1% had bone mineral density testing; 15.5% were prescribed medications for osteoporosis within one year after stroke; and a small percentage of stroke survivors were prescribed medications for osteoporosis for the first time.

Calendar of events 03–05 June LINNC: Live Interventional Neuroradiology & Neurosurgery Course Paris, France

22–25 July SNIS: Society of NeuroInterventional Surgery 16th Annual Meeting Miami, USA

www.linnc.com

www.snisonline.org

04–07 June 5th World Parkinson Congress Kyoto, Japan

04–06 September ESMINT: European Society of Minimally Invasive Neurology Therapy Annual Meeting Nice, France

https://wpc2019.org

www.esmint-2019

September

Profile: Istvan Szikora

Issue 19

ious Brain Is consc safe?

Brainto sedation

e to or less: Tim 60 minutes in acute stroke reperfusion st be reduced therapy mu Page 6

has now ic stroke sed, ischaem nt of acute the brain is reperfu of sity faster for the treatme that the Tudor Jovin (Univerof the terial therapy w observed of intra-ar also been e. Therefore, says cy and workflo the The efficacy hed, but it has outcom the efficien around how of a good gravitate s to move the rgh, USA), been establis e, Pittsbu must now the chance minute be to reduce the higher School of Medicin stroke patientthat a time of 90 acute goal should ins Pittsburgh caring for the He mainta too long and the is still entire teamcan be made faster. puncture ure -groin proced door-to less. patient from 60 minutes or to iolthat time

finds US study erior DRG sup tional to conven across stimulation ts all endpoin odulation

tional Neurom ss (INS; Congre al At the Interna ) princip 12th World Society’s Montreal, Canadapresented 6–11 June, Timothy Deer, FDA-defined investigator,onth data (the and for safety trial for the the three-m endpoint ATE primary dorsal root of the ACCUR efficacy) He reported that showed not first time. (DRG) stimulation superiority but also ganglion eriority, cord only non-inf tional spinal endpoint all primary over conven

across ional Neurorad stimulation the Live Intervent (LINNC; 22–24 peaking at analyses. gery Course that it has been said ogy & Neurosur France) Jovin minutes delay from lthough DRG June, Paris, every 30 to about 10% stimulation d that roughly n translates discovere “It is clear is approved outcome. onset to reperfusio of a good time of symptoms in use in ip between the likelihood and has been for decrease in very strong relationsh we need to get Australia is a n and Europe and the United that there reperfusio as fast as in onset and e to reperfuse some time, symptoms stimulation to the angiosuit States DRG investitreatthe these patients in steps he said. ty remains under are critical possible,” that there the opportuni US-based teams have gation. The study is Jovin explained TE first medical in which stroke ACCURA ment process times, stemming from le, room arrival; these emergency the first large-sca n. to shorten on arrival; randomised reperfusio the hospital prospective and finally, contact at to develop of dorsal groin puncture; we have to start Axium clinical trial stimula. steps first image; critical efficiency our root ganglion nal “Around these we use to measure or picture-to roin conventio that ence The door-to-g tion versus some metrics picture-to-puncture They reflect stimulaIII was ongoing. median, which metrics are (Marcus NeurosciRaton ical metrics. spinal cord time IMS that the Very useful physiolog Boca with 2.7 hours were at the explains you establish Institute at n. These are , Registry was Boca tion for patients pain and largely from when reperfusio Hospital, in the Merci has mismatch were you spend to time RESCUE) is “very sobering” l Regional complex regional that the patient explained the time that treatment (IMS III, MR and periphera Jovin maintains 10% chance a small infarct, e physiology for Raton, USA) root syndrome metric previous trials lost represents a patient has has favourabl The other important why all the hours to that the dorsal 30 minutes causalgia. to take three that the patient a simple backthe brain. of a system negative. “Every therefore, if we ganglion is reperfuse there is no Giving some is that is the efficiency outcome, when you roin, then He the premise of a good that captures fast as possible, which roin spinal structure on page 16 from door-to-g Jovin said. ground into ganglion is the metric Continued through as and door-to-g ” move the patient trials were negative,” to stroke teams to root patient -puncture of dorsal these call Levy move the n, Robert Both picture-to correlated with outcome, surprise that as a wakeup stimulatio those results door-to-groin. strongly to described shown to be he said, is together. recordhave been 2 task now, on page that were get their act tal side, the Continued roin times most Jovin said.

On the pre-hospi the door-to-g he believes is the He presented in terms Registry, which how efficient ed in the Mercidataset that captures ular stroke endovasc tive treating representa US hospitals of treatment

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30 September–02 October SLiCE: Stroke Live Course Nice, France

www.esnr.org

www.slice-online.com

27–28 September 1st Annual International Congress on the Future of Neurology New York, USA www.1st-international-

21–24 October WFITN: World Federation of Interventional and Therapeutic Neuroradiology Naples, Italy

congress-on-the-future-of-

www.wfitn2019.com

20–23 November SVIN: Society of Vascular and Interventional Neurology annual meeting Atlanta, USA www.svin.org

02 December Encephalitis Conference 2019 London, UK

03–05 December UK Stroke Forum Conference Telford, UK www.stroke.org.uk

23–26 January NANS: North American Neuromodulation Society 23nd Annual Meeting Las Vegas, USA https://neuromodulation.org

www.encephalitis.info/ conference

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2015

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19–22 September ESNR: European Society of Neuroradiology Annual Meeting Oslo, Norway

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