NeuroNews Issue 33 EU

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MISTIE III endpoint is missed, but experts agree on implications for clinical practice

Mark McDonald:

AI in stroke detection

Profile

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Novel technique outperforms conventional spinal cord stimulation

Daniel Hanley

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Bart van der Worp:

MISTIE III may have missed the primary endpoint, but Daniel Hanley (Johns Hopkins University, Baltimore, USA) maintained throughout his presentation at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA) that the minimally invasive surgery plus recombinant tPA for intracerebral haemorrhage (ICH) evacuation phase III trial “produced new scientific understanding in each of the three areas investigated: mortality and functional change, effect of surgical performance on outcome, and the safety of the MISTIE procedure.”

t one year, the minimally invasive technique attained no further superiority, with an estimated 45% of patients in the MISTIE group achieving a modified Rankin Scale (mRS) score of 0–3; comparable to the 41% of those that received standard medical care (p=0.33).

“The results convey that the MISTIE procedure did not improve function at the hypothesised 11–12% effect size, but it did increase survival by 6%, [and] it was safety adopted by a large number of surgeons new to the technique,” concluded Hanley. Addressing the 58% of patients who had their haematoma reduced to 15ml or less, achieving the surgical goal, Hanley reported that “MISTIE did produce a significant improvement of 10.5%.”

The trial’s surgical co-chair, Issam Awad (University of Chicago, USA), commented on the latter finding as he presented more detailed surgical results at the ISC: “While less stringent evacuation could suffice for survival benefit, reduction of ICH to below 15ml [at the end of treatment] or above 70% evacuation was required for good functional outcome at one year.

This is the first description of specific thresholds of

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haematoma evacuation to impact functional outcome in ICH surgery trials.”

Offering a rationale to MISTIE III, Hanley alluded to the fact that current evidence and guidelines do not support surgical intervention on a routine basis to improve outcome after supratentorial ICH, in comparison with conservative management.

Acknowledging that meta-analyses of prior multisite MISTIE trials indicated a significant potential for image-guided minimally invasive surgery with alteplase, Hanley outlined the three goals of the current study aimed at expanding the promise of this technique.

First, the study investigators aimed to define

We produced new scientific understanding in each of the three areas investigated.”

Continued on page 2

Continuous differential-target multiplexed (DTM) spinal cord stimulation (SCS) provides better thermal and mechanically induced pain relief compared to highrate and low-rate SCS, concluded Ricardo Vallejo (Millennium Pain Center, Bloomington, USA), lead author and winner of the best basic science abstract presented at the North American Neuromodulation Society annual meeting (NANS; 17–20 January, Las Vegas, USA).

Congruent with these results, Michael Fishman (Center for Interventional Pain and Spine, Exton, USA) later presented data confirming better results with DTMSCS in a difficult-to-treat population of patients with intractable low back pain.

“WE HAD A difficult patient population; they were older than landmark studies; they had a longer duration of chronic back pain, and we have targeted the holy grail because all of the subjects had primary back pain,” said Fishman. Addressing the NANS audience, he highlighted that the back pain responder rate for DTM-SCS was 80%, yet only 50% for conventional SCS, while the leg pain responder rate was 100% for DTM-SCS and 40% for conventional SCS. Referring to the conventional SCS outcomes, he said “they were surprising to me, I thought they [the leg pain responder rates] would be higher”, as he postulated that, “maybe we have been overlooking certain interactions and biological processes. Maybe we need to start looking at pain as a process rather than as a paraesthesia.”

The rationale behind the differential-target multiplexed approach to SCS was first brought to light by Vallejo and colleagues’ research on the measurement of glia-to-neuron ratio in spinal cords at vertebral levels relevant to SCS (T8–T11). According to the authors, the study provided anatomical support on the effects of electrical stimulation on neuroglia Continued on page 19

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MISTIE III

MISTIE III endpoint is missed, but experts agree on implications for clinical practice functional and/or mortality change. They subsequently set out to assess the safety of the surgery-drug combination, and later, due to the novelty of the procedure, to assess the impact of procedural performance on outcome. “Because MISTIE was a new procedure, and the surgeons and teams were new to MISTIE, there was a strong emphasis on safety in this large generalisable trial,” noted Hanley.

MISTIE III, the open-label, blinded endpoint phase 3 trial, was carried out at 78 hospitals in the USA, Canada, Europe, Australia and Asia. In total, 506 patients presenting with a supratentorial ICH with a volume of at least 30ml free from vascular malformations on CT that could be randomised 12 to 72 hours after onset were enrolled in the trial. A computergenerated number sequence with a block size of four or six was used to centrally randomise patients to image-guided MISTIE treatment (1mg alteplase every eight hours for up to nine doses), or standard medical care.

“There was an overall balance in demographic factors with only a slight imbalance between the assigned groups in only two categories: prior use of anticoagulants, and prior use of antiplatelet agents,” said Hanley.

Acknowledging that baseline characteristics “may affect prognosis”, he commented that the investigators “achieved [an] excellent balance of all these important factors predicative of outcomes such as Glasgow Coma Scale scores, National Institutes of Health Stroke Scale (NIHSS) scores, ICH size and blood pressure.” Yet, he said, this balance was “less perfect” for the location of the clot—deep versus lumbar—as there was a 7% difference between the MISTIE group and controls.

Speaking to the ISC audience, Hanley said: “While 90% of the surgeons had never performed the procedure, all had substantial experience with the

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components of each step.” The MISTIE III procedure begins with CT-based neuronavigation, either real-time in the CT scanner or virtually to target the clot. Then, according to Hanley, a rigid cannula is placed into the middle of the clot, followed by a catheter—facilitating up to nine injections of alteplase and passive clot removal. Evacuation was terminated when the haematoma was 15ml or less, confirmed by daily CT scans.

MISTIE III: The findings

MISTIE III failed to demonstrate that minimally invasive surgery plus recombinant tPA improves functional outcome in the trial cohort as a whole, per intention-to-treat analysis, as the proportion of patients in the experimental arm and the control had a comparable mRS score of 0–3 at 365 days, 45% and 41%, respectively.

Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models that adjusted for baseline variables conveyed that the estimated odds ratio comparing MISTIE with standard medical care for mRS scores >5, vs. ≤5, was 0.60 (p=0.03).

Additional odds ratios for mRS scores >4 vs. ≤4, >3 vs. ≤3, and >2 vs. ≤2, incurred values of 0.84 (p=0.42), 0.87 (p=0.49), and 0.82 (p=0.44), respectively.

Regarding safety outcomes, Hanley reported that at seven days, two (1%) of 255 patients in the MISTIE group and 10 (4%) of the 251 patients in the standard medical group had died, while at 30 days, 24 (9%) and 37 (15%) in the respective groups had died (p=0.07).

Additionally, the number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups. Six (2%) patients in the MISTIE group versus three (1%) controls had symptomatic bleeding (p=0.33), while

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MISTIE III failed to demonstrate that minimally invasive surgery plus recombinant tPA improves functional outcome.” benefit in mRS 0–3 (adjusted odds ratio [aOR]: 1.75; p=0.03).

However, Awad reported that when this goal was unmet—at >15ml—mRS was no different from medical therapy (aOR: 0.76; p=0.238). Further, as endof-treatment size increased, adjusted odds ratios decreased (range: 1.8–1.53) for the incremental threshold groups (≤15 vs. >15, p=0.011; ≤20 vs. >20, p=0.02; ≤30 vs. >30, p=0.068).

Of importance, the likelihood of mRS 0–3 correlated robustly with the efficiency of clot removal (aOR: 0.63/10ml time-averaged ICH, p<0.001).

The MISTIE III investigators observed that more efficient ICH evacuation was more likely accomplished in deep ICH,

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Issam Awad

two MISTIE patients compared to zero controls (p=0.16) had brain bacterial infections.

Further, at 30 days, 76 (30%) patients in the MISTIE arm and 84 (33%) patients receiving standard medical care had one or more serious adverse event, a difference which was statistically significant (p=0.012), according to Hanley.

The MISTIE III surgical results were subsequently presented by Awad. With the effect of MISTIE on clot resolution quantified as: volume remaining at the end of treatment and volume remaining averaged over the time-course of treatment, Awad acknowledged that the planned analysis of surgical performance indicated that ICH removal to the endof-treatment goal of <15ml demonstrated

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and by surgeons and site with the greatest experience (p<0.0001). Awad noted that prior anticoagulant use was associated with less efficient ICH evacuation (OR: 7.73; CI: 2.78, 21.5, p<0.0001).

An expert’s discussion

Despite the study investigators highlighting that: “Pragmatic use of MISTIE cannot be recommended”, Christopher Kellner (Cerebrovascular Center at Mount Sinai, New York, USA) said—according to an ISC press release— “The information that they have presented suggests that a procedure that was more effective in removing the blood clot might be more effective in improving the patients functional outcome.”

Pointing to the surgical results presented by Awad, Kellner postulated: “We now know that to improve functional outcome, we have to leave no more than 15ml. That is something that has not been shown in any intracerebral haemorrhage surgical trial in the past, and it gives us a marker to look for as we are doing surgical procedures.”

According to the same press release, Bruce Ovbiagele (University of California, San Francisco, USA), speaking on behalf of the American Heart Association/ American Stroke Association, commented that the lessons obtained from this evolving technique are “supremely important in helping us to better understand what is going on” in patients with ICH. “It is important to do another trial,” said Ovbiagele, “to help define how aggressive surgeons should be

in haematoma evacuation to balance the functional benefits with risks of mortality.” However, he emphasised: “In the meantime, it is premature to make any changes to clinical practice on the basis of MISTIE III. Other than within a clinical trial, I would not encourage surgeons […] to be more aggressive with clot removal… because we have been in these situations before where a signal from one trial is tested in a subsequent trial and [it] does not pan out.”

Alluding to the three ongoing studies—ENRICH, MIND and INVEST—that are currently evaluating minimally invasive surgical techniques in patients with ICH, Kellner theorised that “these procedures seem to be more effective at removing the clot and therefore might be more successful at improving functional outcomes than MISTIE.” But Awad cautions: “Novel techniques should

The ultimate treatment that we need [...] is a surgical treatment that treats all ICH patients, especially patients who are at risk for expansion.”

be subjected to the same standards of rigor and generalisability as MISTIE. And trial readiness mandates heightened experience with the surgical task, to deliver the outcome in every case, and not just on average.”

“I think the ultimate treatment that we need to figure out—and I think people will continue looking for other surgical options here—is a surgical treatment that treats all ICH patients, especially patients who are at risk for expansion,” Kellner added.

Yet, furthering discussion on the lessons acquired from MISTIE, Awad commented during his presentation: “Generalisation of best performance with this procedure, and other techniques of this kind, will require strict articulation of the goals of the surgical task and pursuit thereof, focused surgeon education emphasising technical nuances, and better demonstrate experience.”

The equity research division of the international investment banking company Goldman Sachs has also paid this trial particular attention, initially theorising— based on the murmurings of guideline writers—that MISTIE III could contribute to future guidelines. Now, post-presentation, the company stated in a recent report: “We view these results as a positive indicator for the interventional treatment of ICH in the long run, but not definitive enough to meaningfully sway clinical practice in the near term. More data and likely more refined techniques—to improve on the success rate—are needed to establish the field”.

CT perfusion core volume and time found strongly associated with thrombectomy outcomes The likelihood of good clinical and safety outcomes after endovascular thrombectomy (EVT) in patients with large core on CT ASPECTS (Alberta stroke programme early CT score) declined substantially based on CT perfusion core volume and time. This conclusion was presented during a late-breaking session by Amrou Sarraj, associate professor at the Department of Neurology, UT McGovern Medical School, Houston, USA, at the International Stroke Conference (ISC; 6–8 February, Honolulu, USA).

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lthough Sarraj acknowledged that CT ASPECTS detects hypodense tissue, CTP identifies regions of very low blood flow or volume, meaning that large core definition may differ between CT and CTP. As the majority of upcoming large core randomised controlled trials (RCT’s) use only CT for patient inclusion, Sarraj and colleagues set out to evaluate the variability of endovascular thrombectomy outcomes in patients with large core on CT in relation to CT perfusion core volume and time.

In order to identify anterior circulation occlusions (internal carotid artery, middle cerebral artery, M1/ M2) with no baseline disability and treated up to 24 hours, Sarraj and colleagues combined the cohort of

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a prospective multicentre study of imaging selection (SELECT) with the prospective multicentre registry— TREVO. CT perfusion core volume was determined by automate software, while independent core labs adjudicated ASPECTS. According to Sarraj, the primary outcome was defined as a good 90day modified Rankin Scale (mRS; of 0–2), while symptomatic intracerebral haemorrhage, neurological worsening,

Amrou Sarraj

and mortality were secondary outcomes; all of which were stratified by perfusion volume (<50cc, 50–100cc, and >100cc) and time.

Of the 2,453 patient combined cohort, 221 had ASPECTS ≤5, while Sarraj reported that the baseline characteristics were similar between the two SELECT and TREVO cohorts. In the current study, good outcome rate was 35% in ASPECT ≤5. Of importance, Sarraj remarked that outcome rates decreased

As the volume increased and time to reperfusion progressed, the rates of functional independence declined.”

as CTP core volume increased (<50cc: 48%, 50-100cc: 20%, >100cc: 0%; p trend=0.03). Further, Sarraj and his colleagues observed that for every 10cc increase in CT perfusion core volume, the probability of a good outcome decreased by 27%. Moreover, a substantial reduction in good outcome was witnessed for patients with longer times from onset.

In terms of safety outcomes, both neurological worsening (4%, 22%, 100%, p trend<0.001) and mortality (4%, 30%, 50%, p trend=0.006) significantly increased with increasing CT perfusion core volume. Similarly, rates of symptomatic intracerebral haemorrhage also significantly increased from 4% to 75% for volumes ≤100 compared to those >100cc.

Despite the contribution of this data in relation to its implications for future trials, Sarraj alluded to particular caveats present in the current study. He acknowledged that unlike the initial SELECT trial, there were no medical management controls present in the combined cohort, meaning that no conclusions about benefit can be made.

Furthermore, imaging selection in the TREVO registry was carried out at investigators’ discretion.

Regardless of the limitations, Sarraj maintained that in terms of patients with large core on CT, as the volume increased and time to reperfusion progressed, the rates of functional independence declined, while both mortality and symptomatic haemorrhage rates increased. Acknowledging the current study’s contribution to optimising the stroke patient pathway, Sarraj also highlighted the scope of this data in relation to helping inform the design of future large core RCT’s.

Image courtesy of the American Heart Association

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Efficacy of endovascular stroke therapy outside of specialised centres needs further examination Real-world data investigating patient outcome after endovascular stroke therapy in high versus low volume centres finds a 30% increase in the likelihood of a good outcome for every 10 additional thrombectomy procedures performed at a particular hospital per year. The findings were presented by Sunil Sheth, McGovern Medical School at UTHealth, Houston, USA, at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA), while the study was simultaneously published in Stroke.

“WITH THE WAVE of clinical trials published in the last few years, endovascular therapy has dramatically changed the way we approach ischaemic stroke care,” began Sheth.

He acknowledged that one of the key challenges burdening stroke systems currently is patient access to thrombectomy, as well as the appropriate screening and testing beforehand.

Sheth alluded to the fact that the data emerging from trials published in 2015 were from procedures performed at high volume tertiary care referral centres; centres with advanced neuroimaging, surgery and neuro-trained nurses. For this reason, he questioned whether the results could be translated to other clinical settings.

Addressing the ISC audience, Sheth argued: “There is a push to disseminate these treatments out in the community into local hospitals where patients may get treated faster because it is closer to where they live, and can be evaluated by the emergency medical services.

However, the efficacy of this treatment in these settings is unknown.”

The current study aimed to gain a better understand of real-world practice and outcomes of endovascular stroke therapy. In order to do so, Sheth and colleagues looked into practice patterns of thrombectomy over a 10-year period (2006–2016) in a large cohort, and subsequently evaluated the association between clinical outcomes and hospital treatment in higher versus lower volume settings.

Sheth and his team performed a retrospective cross-sectional study, utilising both the Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID), as well as the State Emergency Department Database (SEDD) on all discharges from nonfederal acute care hospitals in Florida, from 2006–2016. Sheth noted that these datasets allowed the investigators to track individual patients through inpatient and emergency room visits.

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As Sheth et al also used the Nationwide Inpatient Sample (NIS) dataset from 2012–2016, they were able to assess the generalisability of the findings for the Florida cohort in a larger national sample.

The primary endpoint was good neurological outcome, defined as discharge to home or acute rehabilitation.

Sheth and his colleagues included patients if they had endovascular stroke therapy, yet excluded those that had any diagnosis or treatment of arteriovenous

volume centres, there was a lower volume of patients that received IV tPA; 35% compared with 50% in the lower volume centres.

Pointing to a series of graphs, Sheth described the annual trends that were observed over the 10-year period.

The total number of thrombectomy procedures that were performed increased continuously, with a jump in the amount carried out in 2015, which, according to Sheth, coincided with the release of prominent endovascular stroke therapy trials. Further, the investigators observed a similar trend in the number of patients that were transferred for thrombectomy, while a continuous increase in the number of hospitals that were performing at least one thrombectomy procedure per year was also found.

In terms of the distribution of the thrombectomy procedures performed in this time period, Sheth et al found that in 2008, the top three performing hospitals carried out almost 50% of the procedures, while the top eight carried out nearly 90%. However, in 2016 a dramatic shift in the distribution of procedures took place: the top three only carried out 20%, and the top eight almost 40%. “By then, there were far more hospitals doing the procedure and the number of cases was distributed across a much larger number of hospitals,” remarked Sheth.

When validating these findings using their Nationwide cohort—hospitals across the USA—Sheth said: “Again, we saw a similar increase in the number of

There is a push to disseminate these treatments out in the community into local hospitals where patients may get treated faster. ” malformation or fistula, prior intracerebral haemorrhage, or trauma.

In total, 3,890 patients from the Florida cohort were treated with thrombectomy, the median age being 73 (range: 61–82), while 51% were female and 44% received IV tPA. Sheth reported that the characteristics and past medical history of the patients treated at relatively lower volume centres (n=1,974) and those treated at relatively higher volume centres (n=1,916) were similar. One difference that Sheth mentioned was that in the higher

procedures that were being performed annually, with a similar jump in 2015.”

The authors subsequently looked at the number of procedures that were being performed in centres with a relatively lower volume—fewer than 20 procedures per year—and found that this pattern throughout the 10-year time period echoed the increase in the total annual thrombectomy procedures carried out at all hospitals, indicating that a substantial amount of procedures were performed in lower volume centres.

After adjusting the analysis for

Sunil Sheth

age, sex, and comorbidities, Sheth found that a continuously increasing likelihood of good outcome was found to be associated with an increase in the number of annual thrombectomy procedures performed in a Florida cohort, a finding which was validated through the nationwide cohort (OR: 1.3; 95% CI: 1.2, 1.4).

Following this, Sheth said that the study investigators looked into whether they could account for the fact that these larger thrombectomy volume centres may also be more sophisticated.

Thus, they investigated the likelihood of good discharge outcome for patients that had acute ischaemic stroke but did not receive thrombectomy in hospitals.

However, for these particular patients, no relationship was observed between outcome and thrombectomy volume of the hospital. This finding argued against the fact that higher endovascular volume centres were simply better at caring for patients with acute ischaemic stroke, and that outcome differences may be directly related to endovascular treatment volumes.

Discussing the findings, Sheth maintained that: “The challenge that is facing these stroke systems is: How to ensure that every patient can have rapid access to high quality thrombectomy.”

He acknowledged the current solutions to this particular challenge: traditional hub-and-spoke models, tip-and-treat models (where the physician and team travels to the patient), thrombectomycapable models (smaller hospitals that perform thrombectomy with fewer requirements), and mobile stroke units— that help with the prehospital triage.

“Through these real-world data, we observed a significant effect of hospital volume on discharge outcomes, with the odds ratio indicating a 30% increase in the likelihood of good outcomes for every 10 additional annual endovascular stroke treatments per year,” said Sheth.

Of importance, he highlighted that these findings also support the idea that the results of the recent endovascular stroke trials may not be generalisable to every clinical setting.

However, Sheth noted particular limitations, the main one being that beyond thrombectomy volume, there are numerous hospital-specific factors that can determine outcome, such as time of onset, occlusion location, recanalisation grade and infarct volume.

Yet, in summary, Sheth said that

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three important take-aways of the current findings still stand. In the large population-level study of patients treated with thrombectomy between 2006 and 2016, Sheth and colleagues observed a continuous increase in the annual treatment rates and the number of thrombectomy performing hospitals. Further, they witnessed a shift in procedural volume across a “substantially greater number of hospitals”, while the patients treated with thrombectomy in hospitals with greater annual procedural volume had better discharge outcomes. Sheth reported that, in conclusion, these findings support the need for further study on the efficacy of endovascular stroke therapy outside of specialised centres.

Speaking to NeuroNews, Sheth contextualises the importance of this treatment: “There is no country in the world where the absolute number of people living with or died from stroke has declined between 1990 and 2013.

In the USA, approximately 795,000 people experience a stroke each year with nearly 90% being acute ischaemic stroke, which remains the leading cause of adult disability in the USA. In 2015 landmark clinical trials demonstrated that endovascular stroke treatments for patients with large vessel occlusion

leads to dramatic improvements in patient outcomes.

“However, in the wake of these results, stroke systems of care around the globe are now faced with the daunting task of ensuring that patients with acute ischaemic stroke have access to appropriate screening and therapy.

“The evidence of benefit for endovascular stroke therapy that emerged from these trials was derived from treatments rendered almost exclusively at high volume stroke centres, with specialised neuro-imaging, neurointensive care, neuro-rehabilitation

and neuro-nursing. However, since the publication and adoption of these findings into guidelines, it has become wellestablished that the likelihood of good neurologic outcome for these patients remains dependent on minimising delays in treatment. Even 15-minute delays in endovascular reperfusion have been associated with quantifiable decrements in clinical outcomes.

As such, there has been an increase in demand for the procedure, as well as calls for the dissemination of the treatment away from tertiary-care referral centres into the community, to avoid the costly

Inferior outcomes for cerebral aneurysms treated at lowvolume centres Despite an increase in the number of cerebral aneurysms treated at lower volume centres, the finding that high-volume centres are associated with improved patient outcomes persists. Mehmet Enes Inam (University of Texas Health Science Center at Houston, USA) presented data from a large cohort study to support this association at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA).

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lthough no statistically significant difference in mortality was observed between high- and low-volume centres, Inam and colleagues found that the likelihood of discharge to home was seen to increase with a higher volume, defined as more than 10 total treatments, of unruptured cerebral aneurysms treated at the performing hospital per year.

Addressing the ISC audience, Inam said “Prior studies suggest that the treatment of unruptured cerebral aneurysms have spread from high-volume centres into lower-volume centres in the past decade, coinciding with the increase of endovascular coiling relative to surgical clipping.” Yet, regardless of this trend, Inam highlighted that the fields’ understanding of outcomes from cerebral aneurysm treatments by hospital volume is lacking.

In light of the advancements in endovascular therapies, Inam and colleagues set out to investigate three areas of uncertainty. Firstly, they examined whether there has been a trend in unruptured cerebral aneurysm treatment rates over time. Secondly, they studied whether there has been a shift in treatments away from higher volume to Mehmet Enes Inam

lower volume centres at the population level, and lastly, they investigated whether there is an observable difference in outcomes between patients treated in lowversus high-volume centres.

The authors carried out a retrospective cross-sectional study. They utilised the HCUP State Inpatient Databases (SID) from Florida, between 2005 and 2016, as well as a Nationwide Inpatient Sample (NIS) from 2012–2016,” Inam stated. International Classification of Disease codes—ICD-9-CM and ICD-10-CM were used, which, according to Inam, had been established in other studies.

Patients were excluded if they had any primary or secondary diagnosis of subarachnoid haemorrhage, due to the complicated nature of treatment and management. “We have only included unruptured cerebral aneurysms that underwent a clipping or coiling treatment,” remarked Inam. The primary endpoint was discharge disposition. While good outcome was defined as discharge to home, poor

The finding that high-volume centres are associated with improved patient outcomes persists.”

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delays associated with inter-hospital transfer.

“On the other hand, transferring endovascular stroke therapy patients to higher volume centres has also been associated with reduced mortality. In the absence of clear data on the relative efficacy of treatment in lower volume centres, this lack of clarity on the optimal distribution of endovascular stroke therapy resources had led to considerable confusion, with stroke centre certifying agencies such as The Joint Commission initially requiring physician and hospital minimal endovascular stroke therapy volume requirements for certification, and then very recently revoking and then reinstating that criterion.

“Given the need to structure stroke systems of care in the modern treatment era, as well as the poorly characterised effect on endovascular stroke therapy outcomes away from tertiary-care referral centres, understanding the trends in treatment patterns, as well as outcomes in relation to treatment volumes and inter-hospital transfer, is of vital importance. The study described here provides for the first time large-scale data on the utilisation of the procedure, as well as the finding that its outcomes are directly tied to annual volumes.”

outcome was defined as in-hospital mortality or discharge to a skilled nursing facility.

From the Florida cohort, the study investigators identified 6,204 patients (mean age: 59 [50–67]; 75% female). Inam reported that—with the exception of sex—the characteristics of the population at low volume and high volume centres were “almost identical”. This similarity was also observed in the nationwide sample, in which they identified 49,965 patients (mean age: 58 [50–66]; 74% female).

Reporting on the initial results of the study, Inam stated that the total number of aneurysm treatments per year in the NIS had steadily increased between 2012 and 2016. In accordance, the number of hospitals treating aneurysms per year increased sizeably in the same time period, Inam said; a finding which also applied to lower volume centres.

In terms of patient outcomes, mortality in the Florida sample was comparable between high and low volume centres. However, according to Inam, there was a greater proportion of patients discharged home from high volume centres compared to the number discharged from low volume centres. “This was not as significant in the NIS, but we still observed a 4% difference in likelihood of a patient being discharged to home; 80% in low volume centres and 84% in high,” commented Inam.

Additionally, he said: “When we carried out the logistic regression, the Florida cohort showed significant likelihood of discharge to home with increased number of hospital treatments per year.” In relation to the NIS, Inam and colleagues also observed statistically significant results, as the likelihood of discharge to home was again seen to increase with a high volume of hospital unruptured cerebral aneurysm treatments annually.

Alluding to limitations of the study, Inam explained that due to the population-level data, the investigators were unable to assess patient selection factors or provide aneurysm location, shape and size. However, Inam concluded that in this large cohort study, while higher-volume centres were associated with improved outcomes, the number of aneurysms treated at lower volume centres continues to rise.

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Artificial intelligence in prehospital stroke detection: Automation in motion Mark McDonald Comment & Analysis Acknowledging the current limitations that hinder optimal stroke screening in the prehospital setting, Mark McDonald (University of Virginia, Charlottesville, USA), one of the co-founders of NeuroView Diagnostics—a medical technology start-up company—outlines the efforts that are underway to overcome such shortcomings. With an emphasis on artificial intelligence (AI), he details the current development of new technologies, and what the future holds for them.

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troke is the second leading cause of death and third most common cause of disability worldwide, with approximately 15 million people suffering a stroke every year.1,2 Reduction in time to treatment by as little as 15 minutes significantly decreases death and disability in stroke patients.3 Unfortunately, identifying stroke in the field is challenging. Without the use of a diagnostic aid or specialised protocol, emergency medical service (EMS) providers fail to detect stroke in as many as 40% of patients.4 Although exam-based screening tools have been shown to improve stroke detection and remain the current standard of care,5 EMS providers fail to recognise roughly 15% of strokes.6,7 This figure equates to over 100,000 missed strokes in the USA if all incident strokes were screened by EMS providers.8 Many of these patients are inappropriately triaged, have a delay in treatment, or may miss the treatment window altogether. This is particularly problematic for patients with large vessel occlusion, who require urgent transport to highly specialised stroke centres for endovascular therapy.

The major limitation with exam-based screening tools is that they depend on accurate interpretation of the neurological exam, which can be challenging for nonneurologists.

Efforts are currently underway to develop and implement new technologies to overcome the limitations in traditional prehospital stroke screening. One such alternative approach is to not rely on the neurological examination at all. New portable technologies that use spectroscopy or

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ultrasound show promise in their ability to directly detect stroke with large vessel occlusion by assessing features of brain tissue composition or blood flow.9,10 However, it is unclear how well these devices work for detecting small lacunar or brainstem strokes. Another alternative to traditional stroke screening is the use of telemedicine. Instead of the EMS provider making the final decision about

the presence of stroke, they can engage a tele-neurologist to evaluate the patient.

One limitation to this approach is that it still requires the EMS provider to make a decision about the likelihood of stroke, in order to know when to engage the tele-neurologist. NeuroView seeks to improve the recognition of stroke in the prehospital setting without imaging the brain or engaging a tele-neurologist.

Using artificial intelligence, we aim to automate the detection of stroke deficits in order to make better predictions about stroke in the field.

Facial weakness is a core component of the most commonly used prehospital screening instruments.11 One study demonstrated that EMS providers failed to identify weakness in 15% of stroke patients and interpreted facial weakness as being present when it was absent in 33% of patients.12 Researchers recently showed that a 3D depth camera was able to identify abnormal orofacial movements and detect stroke with 87% accuracy.13 In light of this, our team set out to automate the detection of pathological facial weakness using standard video— video that does not require the use of specialised equipment. Using computer vision and machine learning, two types of AI, our team developed an algorithm that can recognise facial weakness in standard video with 89% accuracy.14 However, our algorithm’s accuracy did not significantly differ from the average accuracy of EMS providers in our study.14 We are continually working to improve our algorithm’s performance by adding more training data, refining feature extraction, and exploring the use of different machine learning classifiers.

Automating the identification of facial weakness is an important first step in the detection of stroke in the field. In order to further refine this algorithm and develop other deficit detecting algorithms, we

We plan to integrate these individual deficit detection algorithms into a stroke prediction model that we will train using video data.”

The NeuroView founders: (L to R) Andrew Southerland, Omar Uribe, and Mark McDonald

are currently building a video library of healthy controls and stroke patients with deficits, including facial weakness, abnormal eyes movements such as gaze deviation and nystagmus, limb weakness, and limb incoordination or ataxia. We then plan to integrate these individual deficit detecting algorithms into a stroke prediction model that we will train using video data of patients being evaluated for acute stroke. Some of these patients will have stroke; others will not. Our goal is to create AI-based software that can analyse video of a patient recorded on a mobile device and screen for stroke.

Better recognition of stroke in the prehospital setting will lead to earlier and more frequent treatment with acute stroke therapy, reducing disability for thousands of stroke patients in the USA and abroad.

Beyond stroke, our mission at NeuroView is to empower nonneurologists to deliver better care when neurological expertise is unavailable.

Demand for neurology in the USA exceeds supply by 11%, with a projected shortfall of 19% by 2025.15 This disparity is more pronounced worldwide with 71 of the 84 countries surveyed reporting either no neurologist or less than one neurologist per million people.16 We are starting with the misdiagnosis of stroke in the prehospital setting, but the potential impact of AI based assessment tools for neurological disease is much greater.

Mark McDonald is a fourth year neurology resident physician at the University of Virginia and Chief Scientific Officer of NeuroView Diagnostics.

References 1. Feigin, V. L., et al. Global burden of stroke. Circulation research, 120(3) (2007), 439-448.

2. “Stroke statistics”, The internet stroke center, http:// www.strokecenter.org/patients/about-stroke/strokestatistics/ 3. Saver, Jeffrey L., et al. “Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke.” Jama 309.23 (2013): 2480-2488.

4. Smith, W. S., Isaacs, M., & Corry, M. D. (1998).

Accuracy of paramedic identification of stroke and transient ischemic attack in the field. Prehospital Emergency Care, 2(3), 170-175.

5. Adams, H. P., et al. . Guidelines for the early management of adults with ischemic stroke.

Circulation, 115(20) (2007), e478-e534.

6. Purrucker, J. C., Hametner, C., Engelbrecht, A., Bruckner, T., Popp, E., & Poli, S. (2015). Comparison of stroke recognition and stroke severity scores for stroke detection in a single cohort. J Neurol Neurosurg Psychiatry, 86(9), 1021-1028.

7. Wojner-Alexandrov, A. W., Alexandrov, A. V., Rodriguez, D., Persse, D., & Grotta, J. C. (2005). Houston paramedic and emergency stroke treatment and outcomes study (HoPSTO). Stroke, 36(7), 1512-1518.

8. Stroke Facts. Center for Disease Control https://www. cdc.gov/stroke/facts.htm Accessed Jul 2017.

9. Kellner, C. P., Sauvageau, E., Snyder, K. V., Fargen, K. M., Arthur, A. S., Turner, R. D., & Alexandrov, A. V. (2018). The VITAL study and overall pooled analysis with the VIPS non-invasive stroke detection device. Journal of neurointerventional surgery, 10(11), 1079-1084.

10. 43 European Stroke Conference. 26th Conference, Berlin, Germany, 24-26 May 2017: Abstract e-Book.

Cerebrovasc Dis 2017;43.

11. Brandler, E. S., Sharma, M., Sinert, R. H., & Levine, S. R. (2014). Prehospital stroke scales in urban environments: a systematic review. Neurology, 82(24), 2241-2249.

12. Nor, A. M., McAllister, C., Louw, S. J., Dyker, A. G., Davis, M., Jenkinson, D., & Ford, G. A. (2004).

Agreement between ambulance paramedic-and physician-recorded neurological signs.

13. Bandini, A., Green, J., Richburg, B., & Yunusova, Y. (2018). Automatic Detection of Orofacial Impairment in Stroke. Proc. Interspeech 2018, 1711-1715.

14. McDonald, M., Uribe, O., Zhuang, Y. et al (2019).

Comparison of human and machine learning based facial weakness detection. Poster presented at the International Stroke Conference. Honolulu, HI. 15. Dall, T. M., Storm, M. V., Chakrabarti, R., Drogan, O., Keran, C. M., Donofrio, P. D., ... & Vidic, T. R. (2013).

Supply and demand analysis of the current and future US neurology workforce. Neurology, 81(5), 470-478.

16. Bergen, D. C., & World Federation of Neurology Task Force on Neurological Services. (2002). Training and distribution of neurologists worldwide. Journal of the neurological sciences, 198(1), 3-7.

April

Issue

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Research

9

Intensive neurorehabilitation may provide benefit for chronic stroke patients

A new study indicates that when provided at much higher doses than is typical, neurorehabilitation provides clinically important differences in upper limb mobility for chronic stroke patients (median time post-stroke 18 months). On the basis of these findings, the study authors claim “post-stroke rehabilitation must adopt the same aspirational approach” that has been used for the management for acute stroke.

WRITING IN THE Journal of Neurology, Neurosurgery & Psychiatry, Nick S Ward (Department of Clinical and Motor Neuroscience, UCL Institute of Neurology, London, UK) and others state that, at present, “the general consensus remains that most spontaneous recovery of the upper limb occurs after the first three months after stroke and current level of rehabilitation results in little improvement after that, particularly at the levels of impairment”. While they note that improving outcomes through higher doses of rehabilitation “is an attractive option”, studies assessing intensive rehabilitation therapies have not “produced the magnitude of improvement that will change clinical practice”. Furthermore, Ward et al comment that the dose level of the rehabilitation in these studies “remained relatively low” (18–36 hours) and there is “scepticism” that patients could tolerate “much higher doses” of rehabilitation than that already studied.

However, the authors report that the Queen Square Upper Limb Neurorehabilitation programme provides 90 hours of treatment— focussing on the upper limb—for chronic stroke patients (more than six months post-stroke). Therefore, the aim of the present study was to review the outcomes of the patients in this programme, identify any predictors of response, and the relationship between

changes in impairment and activity.

Of 224 patients in the programme who completed six-months’ follow-up, the median time since stroke was 18 months (ranging from 12 months to 51 months). Ward et al report: “By six months after the programme, 68.3% of the patients had achieved greater than the minimum clinically important difference (MCID) of 5.25 points on the Fugl-Meyer score. For the Action Research Arm Test (ARAT), this figure was 61.6%.” They also reviewed improvements in the Chedoke Arm and Hand Activity Inventory (CAHAI), Arm Activity Measure (ArmA-A) and the Arm Activity Measure B (ArmA-B) but comment that there is no published MCID for these scores. “MCID is often quoted at 10% of the maximum score. If this were the case, then by six months, MCID would have been reached by 59.4% of patients for CAHAI, 53.8% for ArmA-A, and 72.3% for ArmA-B,” the authors state. They did not identify predictors of treatment response beyond admission scores.

Looking to the future, Ward et al say that the “next wave of upper limb rehabilitation must investigate much higher doses of the treatment than is currently attempted”. Although they acknowledge that some may believe that delivering such high doses in current healthcare settings “is not possible”, they counter this “pragmatic view” with their “aspirational view”.

The next wave of upper limb rehabilitation must investigate much higher doses of treatment than is currently attempted. ” Nick Ward

They claim: “It is in fact precisely the role of clinical research to challenge what we currently do in order to reshape and improve our clinical services to make them better”. The authors add that the introduction of thrombolysis made acute stroke management better and “post-stroke rehabilitation must adopt the same aspirational approach”.

Ward et al conclude: “Our experience suggests that much higher

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Opioid epidemic triggers sharp incline in hospitalisation rates for stroke associated with infective endocarditis Hospitalisation rates for stroke associated with infective endocarditis and opioid use were stable for around two decades before sharply increasing. The study authors, Setareh Salehi Omran (Weill Cornell Medicine, New York, USA) and colleagues have attributed the sharp incline observed in 2008 to the emergence of the opioid epidemic.

INTRAVENOUS OPIOID USE can lead to infective endocarditis, which can result in stroke.

Acknowledging the insufficient data surrounding this neurological complication of opioid abuse, the authors set out to investigate whether an increase in opioid abuse has led to a higher incidence of stroke associated with infective endocarditis and opioid use.

Utilising the National Inpatient Sample from 1993–2015 and the validated International Classification of Diseases (ICD-9-CD) codes, Omran and colleagues identified 5,283 hospitalisations for stroke associated with infective

doses and intensity of upper limb neurorehabilitation can be delivered and our results should inform future clinical trial design.”

According to Ward, all patients can benefit at some level from phyiotherapy regardless of months/years since they had a stroke. He adds: “The scientific question is whether giving high dose rehab early (0–3 months) has more of an effect than the same dose later on— we do not know the answer to this.”

endocarditis and opioid use. Interestingly, the rate increased from 2.4 (95% CI: 0.5, 4.3) to 18.8 (95% CI: 14.4, 23.3) per 10 million US residents per year.

Joinpoint regression—which was used to assess trends—detected two segments. Between the time period of 1993–2008, no significant change in the hospitalisation rate was observed. In contrast, rates significantly increased from 2008 to 2015, the annual percentage change standing at 20.3% (95% CI: 10.5%, 30.9%). The latter trend was most dramatically observed in the non-Hispanic white patients in north-eastern and southern USA.

Furthermore, Omran et al reported that while stroke hospitalisations increased across ages and genders, the greatest increase in the past decade occurred in women and those less than 45 years old.

“Our study provides new information on the neurological consequences of the opioid epidemic.

These novel findings indicate that increasing opioid abuse in the USA is not only causing more social/ occupation dysfunction, cardiac complications, and premature mortality, but may also be increasing the population burden of permanent functional disability as a result of stroke,” write the study authors.

Also addressing the increase in heroin use, Omran and colleagues postulated that “the rise in heroin use combined with high-risk injection practices may help explain why opioid-related infective endocarditis is becoming more prevalent and leading to complications, such as stroke and death.”

“These findings add to the urgency of addressing the underlying opioid epidemic in the USA,” concluded the authors, as they further highlighted that these findings shed light on the need for improved awareness of the cerebrovascular complications of opioid use.

10

April

Cost analysis concludes that the direct cost of stroke, at US$35 billion annually, represents only the tip of the iceberg The direct cost of stroke that currently stands at around US$35 billion annually represents only the tip of the iceberg. Unemployment, missed work days, and premature mortality extend this figure, as costs attributed to these indirect expenditures equate to a further US$68.5 billion. The cost analysis that connoted this conclusion was presented by Tarun Girotra (University of New Mexico, Albuquerque, USA) at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA).

R

eporting that nearly two thirds of the total cost associated with stroke, at US$103.50 billion per year—when analysed using noninstitutionalised US civilian populations—were found to be indirect costs, Girotra highlighted that the strokes occurring in the 35–64 age range were to blame for the bulk of this economic loss. Furthermore, patients at 45-64 years of age incurred more annual direct costs than those aged 65–79 years, despite having a lower prevalence of stroke.

“The cost of illness analysis primary consists of two costs”, said Girotra, addressing the ISC audience, “direct costs consist of expenditures relate to hospitalisation, nursing home care, healthcare provider visits, medications and medical durables. But equally important are the indirect costs; the loss of productivity from unemployment, underemployment and premature mortality”.

Pointing to previous limitations of prior stroke cost of illness analyses, Girotra put forward that many solely focused on direct costs and were not inclusive of all age groups, while others used older databases without national reach. In light of this gap in the literature, Girotra and colleagues decided to perform a comprehensive cost of illness analysis for stroke in the US, incorporating all age groups.

Data for the current analysis was sourced from the Medical Expenditure Panel Survey (MEPS) from 2003 to 2014. “For those of you who are unfamiliar with the database, it is a multistage sample representative of the noninstitutionalised US civilian population,” Girotra explained. He also noted that the subjects’ insurance provider and medical provider was available, which was used to corroborate the information obtained from the subjects.

For the direct costs—defined as the sum of the indirect out-of-pocket payments and payments issued by insurance—Girotra and colleagues looked at expenditures from the database pertaining to inpatient hospital stay, outpatient care, prescription medications and more. Indirect cost components were obtained through the US National Vitals Statistics database, where employment status, the number of missed work days and premature mortality was calculated.

According to Girotra, a chi-square test to compare baseline characteristics between stroke and non-stroke patients was initially implemented. Next, a two-part econometric model was used to ascertain the adjusted incremental expenditure for patients with stroke versus non-stroke patients. “For this, we implemented a probit model to test the probability of observing a zero versus positive expenditures”, noted Girotra. A generalised linear model with gamma distribution and log link was carried out, while Girotra said that all incremental expenditures were controlled for gender, ethnicity, education, insurance status, census region, income, marital status and CCI. Addressing the indirect costs, Girotra said that a negative binomial regression model was used in the adjusted model to estimate the difference between missed work days. While a logistic regression model

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Health economics

was used to estimate the probability of full year employment, an economic model first proposed

by Grosse et al—known as the Present Value of “one life”—calculated indirect costs resulting from premature mortality. According to Girotra, this model includes market and non-market (household) lifetime productivity for different age groups in both genders, and utilises the American Time Use Survey (ATUS).

Finally, Girotra also highlighted the fact that the US dollar values were inflated to the 2016-dollar value using the Consumer Price Index obtained from the US Bureau of Labor Statistics.

Findings

Of the 253,235,052 civilian noninstitutionalised US population that were identified, just over 8 million (8,101,159; 32%) had stroke. Weighted samples of 10,175 stroke patients and 314,694 non-stroke patients were compared.

Girotra acknowledged that as far as baseline variables were concerned, the overall stroke prevalence was higher in patients 65 years or older, females, white and non-hispanic black, non-married, high school graduate, publically insured participants, Midwest and South rew well as poor and low-income categories.

Two thirds of the total cost associated with stroke were found to be indirect costs.”

Age Groups

Cost per Person ($)

Prevalence (in %)

Stroke population

Total cost (in billion $)

≤44 years

5,243

0.4

547,507

2.8

45-64 years

5,915

3.6

2,457,354

14.5

65-79 years

4,322

10.4

2,918,405

12.3

≥80 years

3,746

18.0

1,843,244

6.9

of 45–64 years—although had a lower stroke prevalence and a lower stroke population, incurred a greater direct cost of US$14.5 billion, compared to the 65–79 group, which incurred US$12.3 billion”.

After indirect costs were adjusted for variables, Girotra said that the annual wage difference between stroke survivors and non-stroke patients was -US$14,254 (95% CI: -US$16,023, -US$12, 485); a difference of which they attributed to unemployment or underemployment. “When we looked at the annual wage difference and expanded it to the number of stroke patients we had in the country, the annual loss was US$38.1 billion”, commented Girotra.

In addition, stroke survivors had 4.2 more missed work days (per year) compared to the non-stroke patients, while their risk of unemployment was 60% higher compared to non-stroke patients. Subsequent study into premature mortality, through utilising Grosse et al’s Present Value of one life econometric model, yielded a total loss of US$30.4 billion. “The interesting finding here is that the age group of 35–65 incurred an economic loss of US$14.6 billion—roughly half of the total US$30.4 billion dollars”, Girotra exclaimed.

Through aggregating the total annual costs spent on stroke patients compared to non-stroke patients in the USA, Girotra reported that the total incremental direct cost (US$35 billion), plus the total indirect cost from underemployment (US$38.1 billion) and premature mortality (US$30.4 billion) equates to $103.5 billion.

“There are certain limitations of these kinds of studies,” noted Girotra, “the MEPS database includes noninstitutionalised citizens only, meaning the population living primarily in nursing homes are not surveyed. This is a large chunk of stroke survivors which have a lot of economic impact on society in general”. Furthermore, according to Girotra, the authors were unable to calculate indirect costs associated with loss of productivity from unemployment and absenteeism of family members acting as caregivers. Paediatric strokes are also not routinely picked up as adult strokes are, noted Girotra, which may also underestimate the total annual cost of stroke.

Age group (years)

Total death 2014

Present value of one life

Present value of mortality (in billion)

<1

93

1,357,715

0.126

1-4

33

1,357,715

0.045

5-14

88

1,579,220

0.139

15-24

177

1,845,536

0.327

25-34

579

1,808,639

1.047

35-44

1,745

1,472,032

2.568

45-54

5,349

1,020,564

5.459

55-64

11,727

562,298

6.594

65-74

19,663

269,317

2.295

75-84

36,353

139,338

5.065

≥85

57,292

116,753

6.689

Total

133,099

30.4

Number of deaths and cost of mortality due to stroke by age group

Annual adjusted incremental direct cost of stroke per patient stratified by age

“We were able to get a total incremental direct cost [of stroke] per single patient; of US$4,317”, remarked Girotra. Of this average figure, which ranged from US$3,828 to US$4,807, Girotra noted that just under 50%, US$1,920, were related to inpatient costs.

However, through looking at the overall annual incremental direct cost of stroke, Girotra reported that the total was US$35 billion. He acknowledged this himself and his colleagues observed an interesting finding when they stratified cost by age: “The age group

wDespite these shortcomings, Girotra maintained that through this nationally representative database, the direct cost of stroke represented only the tip of the iceberg, with two thirds of the total cost attributed to indirect costs. Addressing the fact that stroke still remains a highly preventable disease, Girotra said: “There is a significant financial incentive to increase community outreach programmes to control stroke risk factors and improve stroke care delivery models to increase acute stroke treatment”.

12

April

Intensive blood pressure lowering beyond recommendations safely reduces the risk of bleeding, but fails to limit post-stroke disability

Although intensive blood pressure lowering with intravenous thrombolysis is safe in patients with acute ischaemic stroke, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with current guideline treatment, according to late-breaking science presented at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA). Simultaneously published in Stroke, this large international clinical trial was presented by Craig Anderson (University of New South Wales, Sydney, Australia) and Thompson G Robinson (University of Leicester, Leicester, UK).

S

peaking to the ISC audience, Anderson alluded to the long standing uncertainty in relation to optimal blood pressure control: “We do not know whether any benefits from a more intensive treatment, particularly in regards to reducing the risk of intracerebral haemorrhage, may be offset by harms of promoting cerebral ischaemia in the vulnerable ischaemic penumbra.”

The international, randomised, open-label blindedendpoint phase 3 trial: Enhanced control of hypertension and thrombolysis stroke (ENCHANTED), aimed to examine the superiority of a more intensive regime to a <140mmHg systolic target, against the long-standing guideline criterion of <180mmHg systolic target after recombinant tPA (alteplase). The study included tPAeligible acute ischaemic stroke (<4.5 hours of onset) whose blood pressure remained elevated beyond 150 and who could receive randomised blood pressure treatment within six hours of stroke onset.

“The intensive treatment had the goal of getting the blood pressure range of <140mmHg within an hour, and to sustain that to up to 72 hours using local agents,” noted Anderson. “This was tested against local interpretation

of the guideline criteria in the control group.” Ten subgroups were pre-defined to examine any interaction of the treatment effect (interaction with the rtPA dose), while the ENCHANTED investigators used both central and site monitoring of the accumulated data for quality control purposes.

The primary outcome was an ordinal shift analysis of the full range of scores on the modified Rankin scale (mRS) at 90 days, while the primary safety measure was any intracranial haemorrhage. “We estimated that a sample size 2,100 patients would provide 90% power to determine a 14% relative shift in the primary outcome, and a 40% reduction in the primary safety measure”, said Anderson.

In total, 2,227 patients were recruited between 2013 and 2018. Due to data irregularity, 31 patients were excluded, leaving 1,081 patients in the intensive arm (mean age: 67 [50–75]; 37% female), and a further 1,115 in the control group (mean age: 67 [59¬76]; 39% female). According to Anderson, the baseline characteristics of the two groups were well balanced; “the median NIHSS score was 7 (4–12) in the intensive arm, and 8 (4–12) in the controls; more than two thirds of patients had either large artery

The blood pressure paradox in acute ischaemic stroke “lies in the modifying effect of reperfusion” The relationship between blood pressure and outcomes is highly dependent on reperfusion, conclude Lang Hong (Fudan University, Shanghai, China) and colleagues on behalf of the INSPIRE group.

Recently published in Annals of Neurology, the study denotes that “active blood pressure-lowering treatment may be inappropriate in acute ischaemic stroke patients prior to reperfusion treatment”.

Through these findings, the authors shed light on why rapidly lowering blood pressure beyond recommendations—outlined in the ENCHANTED trial (see above)—failed to limit post-stroke disability.

THE AUTHORS NOTED that thus far, positive, negative, and even U-shaped correlations between blood pressure and outcome have all been described.

“Especially [in patients] with large vessel occlusion or a proximal stenosis, higher blood pressure may help sustain collateral perfusion [...], yet high blood pressure may also increase the risk of complications”, write the authors.

Aiming to depolarise expert opinion on the matter, Hong et al set out to investigate the association between post-stroke baseline blood pressure, collateral flow, infarct growth, and clinical outcomes in

Issue

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Blood pressure

acute ischaemic stroke patients with large vessel occlusion or stenosis, using baseline CT perfusion to measure collateral flow.

Patients presenting within 12 hours of symptom onset from seven medical centres based in China, Australia, and Canada between 2011 and 2017 were prospectively recruited for the International Stroke Perfusion Imaging Registry (INSPIRE). In total, 306 patients (mean age: 69.5 [60–79]; median baseline NIHSS: 12 [7–16]; 59.8% male) that identified with large vessel occlusion/stenosis with baseline multimodal CT, follow-up imaging and complete clinical profiles were included.

atheroma or small vessel cerebrovascular disease”.

Robinson proceeding to present the main results of ENCHANTED, and acknowledged the lack of superiority for the primary functional outcome: “There was no difference in the mRS shift at 90 days between arms with an adjusted odds ratio of 1.01 [95% CI: 0.87, 1.17; p=0.87]”. He noted that this neutral result was confirmed in both the adjusted and the per protocol analysis: “There was no significant heterogeneity of the primary outcome— with respect to age, ethnicity, baseline systolic blood pressure, ischaemic stroke subtype and dose of tPA”.

Addressing the “long standing concerns” regarding the effect of intensive blood pressure reduction in severe stroke, Robinson said: “We undertook a post hoc analysis by grades of neurological severity (quartiles of NIHSS scores), and this did not affect the primary outcome”.

However, intracranial haemorrhage was statistically significantly lower in the intensive arm, while across a range of definitions of symptomatic intracerebral haemorrhage, these rates were also lower. “Of importance, there was no increased adverse events with the intensive blood pressure lowering arm,” Robinson added.

Addressing the ISC audience, he questioned the clinical implications of these results. “There is perhaps no evidence to support a major change in the guidelines, but it appears that clinicians are to some extent already more comfortable about control of blood pressure more intensively in this patient group, and it is important to state that the treatment is clearly safe and reduces the risk of intracranial and intracerebral haemorrhage”.

Although Robinson said that “ENCHANTED has not fully resolved the uncertainty for the optimal level of blood pressure control, [or] the approach which one should use in terms of promoting recovery”, he postulated that in terms of moving this intensive approach forward: “We need to do further research on our extensive brain imaging databases to understand why this reduction in haemorrhage did not overall translate into better recovery”.

Through a multivariate analysis, the authors observed that with every increase of 10mmHg in baseline systolic blood pressure, the odds of achieving an excellent functional outcome decreased by 12% (OR= 0.88; 95% CI: 0.78, 0.995; p=0.048). In contrast, increased baseline blood pressure was associated with better collateral flow, where every 10mmHg increase was associated with an increase in the delay time ratio.

Lastly, the paper detailed a subgroup analysis carried out on patients with major reperfusion, where Hong et al report that in such patients: “Higher baseline blood pressure was associated with decreased infarct growth and a better clinical outcome”.

Providing an explanation for the “paradox”—high blood pressure leading to smaller infarct core in acute ischaemic stroke, the authors write that it “lies in the modifying effect of reperfusion”.

They add: “Initially, higher baseline blood pressure may improve collateral

We need a randomised trial which must include pretreatment perfusion imaging of reperfusion status.”

flow to sustain penumbra and prevent the core from expanding. Patients with good collaterals are likely to be ‘slow infarct core growers’”. Yet, Hong and colleagues acknowledge that in patients with good collateral flow, “if there is subsequent reperfusion, there may be smaller infarct volume, and hence better clinical outcomes.

However, if the occlusion persists and reperfusion does not occur, eventually the infarct core will grow [...], leading to a worse clinical outcome”.

With these findings in mind, cocorresponding author Xin Cheng (Fudan University, Shanghai, China) provided an explanation for why the recent ENCHANTED trial failed to demonstrate superiority to guideline-recommended blood pressure-lowering: “In ENCHANTED, intensive blood pressure lowering was initiated a median 20 minutes after the administration of intravenous thrombolysis, where tissue perfusion status was unknown and, indeed, presence of vessel occlusion was only documented in 9%”.

Speaking to NeuroNews, Cheng commented: “ENCHANTED and our recent study raised the intriguing hypothesis that in patients with acute large vessel occlusion, maintaining higher blood pressure to sustain collateral flow before reperfusion therapy, but then aggressively lowering blood pressure to prevent haemorrhagic transformation may be beneficial. To test this hypothesis, we need a well-designed randomised trial, which must include pre-treatment perfusion imaging of reperfusion status.”

April

Issue

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Standard treatment of hyperglycaemia in acute ischaemic stroke outperforms an intensive approach Intensive glucose control (80–130mg/dL) does not improve 90-day functional outcome and increases the risk of severe hypoglycaemia. This is the conclusion presented by Karen C Johnston, professor of neurology at the University of Virginia School of Medicine, Charlottesville, USA, during the International Stroke Conference (ISC; 6–8 February, Honolulu, USA).

GIVEN THAT HYPERGLYCAEMIA is common in acute stroke patients and is associated with worse functional outcomes when compared to stroke patients maintaining a normal blood sugar level, Johnston and colleagues set out to assess the efficacy and safety of up to 72 hours of glucose control using continuous intravenous insulin infusion, compared to standard subcutaneous sliding scale insulin.

Although the study’s findings suggested otherwise, Johnston and her team initially hypothesised that intensive glucose control (target range: 80–130mg/dl) with intravenous insulin infusion in hyperglycaemic acute ischaemic stroke patients within 12 hours of symptom onset would elicit favourable outcomes, observed through an absolute 7% improvement measured by the modified Rankin Scale (mRS) at 90 days following stroke. In terms of safety, they theorised that such intensive control will be safe, measured by a <4% increase in severe hypoglycaemia (<40mg/dl) compared to the standard control in acute ischaemic stroke patients treated up to 72 hours.

The SHINE study was a multicentre, randomised controlled trial carried out at 63 sites across the USA, inclusive of 1,151 hyperglycaemic patients enrolled within 12 hours of stroke symptom onset, between April 2012 and August 2018. The trial also implemented a blinded outcomes assessment, while the randomisation algorithm prevented serious imbalance by NIHSS score, intravenous thrombolysis and clinical centre. Johnston reported that the main exclusion criteria deeming patients ineligible included those with: type I diabetes, pre-existing confounding conditions, renal dialysis, as well as patients that were unable to follow the protocol.

Johnston noted that the data safety and monitoring board recommended stopping enrolment after the fourth interim analysis as the necessary enrolment had been reached. The primary efficacy outcome—90-day mRS (baseline severity adjusted)—was achieved by 20.5% of patients in the intensive group, and 21.6% of those in the standard group. However, Johnston reported that the adjusted relative risk was 0.97 (95% CI: 0.87, 1.08), indicating no difference between the two groups.

Hyperglycaemia Regarding the primary safety outcome, severe hypoglycaemia (<40mg/dl) occurred in 2.6% of the intensive group and did not occur in the standard group. Statistically speaking, the risk difference was 2.58 (95% CI: 1.29, 3.87), indicative of an increased risk of severe hypoglycaemia in the intensive group. Further efficacy outcomes included a favourable NIHSS (0 or 1) score that was achieved by 43.7% and 44.7% of patients in the intensive and standard group, respectively. Furthermore, a favourable Barthel Index (95–100) was reached by 55.2% and 54.7%, while median stroke specific quality of life (SSQOL) scores were 3.8 and 3.7 for patients

13

in the intensive and standard group, respectively. None of these secondary outcomes were statistically or clinically different.

Concluding the findings, Johnston stressed that the successful and efficient completion of the SHINE trial has enabled questions to be answered regarding the best glucose control for hyperglycaemic patients that have undergone an acute ischaemic stroke.

Despite this, she maintained that intensive glucose control (80–130mg/ dl) does not improve 90-day functional outcomes and increases the risk of severe hypoglycaemia. Thus, subcutaneous insulin with target <180mg/dl remains the preferred approach.

14

April

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Interview

Profile

Bart van der Worp

President of the European Stroke Organisation (ESO) Bart van der Worp emphasises the need for additional treatment options for patients with acute ischaemic stroke, next to reperfusion strategies. Still hoping that these options could come from the field of neuroprotection, he tells NeuroNews about the important trial results he is awaiting this year, as well as his plans for the future of the society and his interests outside of medicine.

What drew you to neurology and stroke therapy in particular?

Alongside a long-standing interest in the functioning of the brain, two professors of neurology at my university had excellent teaching skills and convincingly conveyed the importance of carefully taking the patient’s history and performing a detailed but focused neurological examination. Professor Jan van Gijn, who was also a renowned clinical investigator in the field of stroke, served as a role model to me; later convincing me to choose neurology early in the 1990’s. I had a strong interest in the pathophysiology of ischaemic stroke and was impressed by the impact of stroke on the lives of the patients and their families, and by the lack of treatment options at that time. I decided to commit myself to improving treatment options, which proved to be more difficult than I expected when I was young.

Did anyone else influence your career?

In addition to Jan van Gijn, I quietly admired frontrunners in the field of experimental stroke, including Bo Siesjö and Uli Dirnagl, as well as Werner Hacke, who specialised in acute stroke treatment. They (and others) managed to persuade the medical field that stroke could be a treatable condition.

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

It will come as no surprise that I am extremely happy with major therapeutic developments in the past 20 years, not only in the field of stroke, but also for multiple sclerosis, for example. These really have a great impact on the lives of many patients with diseases that often had a very poor prognosis at the time I started working in neurology.

You are a member of CAMARADES. Why has this group been established and what does it set out to achieve?

CAMARADES has been founded because of the observed huge and unacceptable failure of most animal experiments to translate to the clinic. CAMARADES has identified sources of bias in animal work; developed recommendations for improvements in the design and reporting of animal studies, and improved meta-analysis methodology to be able to apply this better to animal studies. We hope this will lead to more methodological rigour in animal experiments, fewer animals that are “wasted”, and ultimately a better translation of animal experiments to the clinic.

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

In the 1990s, neuroprotection for patients with acute stroke was really hot—based on new insights in the pathophysiology of stroke and the positive results of thousands of animal studies. I was among many who strongly believed that this was the way forward.

Unfortunately, the very large majority of findings in

animal studies could not be reproduced in clinical trials, and only reperfusion therapies have convincingly shown to improve outcomes in selected patients with acute ischaemic stroke. Furthermore, only a minority of the patients with acute stroke are eligible for intravenous thrombolysis or endovascular treatment, and the risk of a poor outcome is still considerable even when treated.

Additional treatment options are therefore strongly needed.

My biggest disappointment so far is the lack of evidence of benefit for hypothermia in patients with acute stroke. Hypothermia (or cooling) has an unchallenged benefit in animal models of acute ischaemic stroke, and has therefore been coined as the “gold standard” for neuroprotection. Unfortunately, results of animal studies have not yet been replicated in clinical trials despite major efforts, including one American and one European phase III clinical trial.

These trials seriously failed to recruit to target and at least the European trial was severely hampered by regulatory hurdles and practical problems to achieve a modest temperature reduction in patients. I hope that the ongoing PRECIOUS trial, which assesses the effect of the prevention of infections and fever with simple, safe, and inexpensive drugs, will show that even a modest temperature reduction can be of benefit in patients with acute stroke.

I hope that the ongoing PRECIOUS trial [...] will show that even a modest temperature reduction can be of benefit in patients with acute stroke.”

What are your current research interests?

I still have not left the field of neuroprotection, and next to exploring the effects of temperature reduction in PRECIOUS, I co-lead the MR ASAP trial, which assesses whether glyceryl trinitrate started within three hours of stroke onset will preserve brain tissue better before reperfusion therapies (IVT or EVT) are started.

I also co-chair the phase II secondary prevention trial APACHE-AF, which assesses the optimal antithrombotic strategy in patients with atrial fibrillation who had an intracerebral haemorrhage during treatment with an anticoagulant. Finally, I carry out research in the field of end-of-life decisions and palliative care.

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

One of several large stroke trials that will be presented at ESOC 2019 is RESTART, a randomised trial for adults surviving spontaneous intracerebral haemorrhage who had taken an antithrombotic drug before the haemorrhage. This trial has tested whether a policy of starting antiplatelet drugs results in a net reduction of

all serious vascular events during follow-up, compared with a policy of avoiding antiplatelet drugs. The results of this trial will hopefully inform difficult decisions in these patients in daily clinical practice.

As president of the ESO since 2018, what have you achieved, and what are your hopes for the future?

The work in ESO is obviously performed in collaboration with colleagues from all over Europe and even from elsewhere. The organisation has grown considerably over the past five years, in part thanks to the start of our own conference (ESOC) in 2015.

The conference has become a huge success, with the

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Fact File

Professional experience

2000–present: Neurologist, Department of Neurology, UMC Utrecht Brain Center, The Netherlands 2004–2005: Six-month fellowship at the National Stroke Research Institute, Melbourne, Australia

Education and certificates

1999: PhD degree, Faculty of Medicine, Utrecht University. Thesis: Treatment of acute ischaemic stroke with antioxidants. The gap between laboratory and clinic.

1992–2000: Speciality training in neurology, University Medical Center Utrecht, Department of Neurology 1983–1991: Medical education, Utrecht University

Chief investigator of multicentre randomised clinical trials (selected)

2017–present: MR ASAP: Multicentre randomised trial of acute stroke treatment in the ambulance with a nitroglycerin patch 2015–present PRECIOUS: Prevention of complications to improve outcome in elderly patients with acute stroke. A randomised, open, phase III clinical trial with blinded outcome assessment

Awards What are the highlights of the 2019 annual meeting?

To be honest, highlights are difficult to select because of the wealth of research data from all over the world that will be presented, alongside high-quality state-of-the-art lectures by renowned experts. However, many people may consider the presentation of the results of at least seven major stroke trials among the highlights. presentation of results of ground-breaking trials in the field of stroke, and numbers of participants increasing each year (4,500 in 2018). In addition, ESO now has its own successful journal, which will hopefully be indexed in PubMed shortly, and an increasing number of guidelines, among many other activities.

My primary aim is to consolidate these successes and to make these even greater where possible. However, we are also working on getting stroke higher on the political agenda in Europe; implementing the recently published Stroke Action Plan for Europe in all European countries, and on making the society “greener”.

What is your key message to young neurologists?

For their own careers: follow your passion, and believe that everything is possible until the opposite is proven.

For patient care: the truth is at the bedside!

What are your interests and hobbies outside of medicine?

I love good food and do my best to improve my own cooking skills through membership of a cooking club, but my main hobby since a left the city for a house in a village a few years ago is gardening. This might also be my greatest talent, so perhaps I took the wrong turn many years ago…

2010: Clinical Established Investigator, The Netherlands Heart Foundation 2001: Award for Excellency in Stroke Research, the European Stroke Council 1991: Talma-Eijkman Prize for Medicine, for excellent research as a medical student

Other activities (selected)

2018–present: President European Stroke Organisation 2016–2018: President Elect ESO 2014–2018: Member of the writing committee of the Dutch Stroke Guideline 2013–2017: Member of the Guideline Committee of ESO 2008–2011: Member of the committee on quality of The Netherlands Neurological Association

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Reperfusion promotes favourable outcomes in ischaemic stroke patients with ASPECTS 0–5 treated with mechanical thrombectomy In a subgroup of acute ischaemic stroke patients presenting with Alberta stroke program early CT score (ASPECTS) 0–5, who were treated with mechanical thrombectomy, successful reperfusion was found to be beneficial without increasing the risk of intracerebral haemorrhage. The corresponding study, recently published in Stroke, was carried out by Johannes Kaesmacher (Institute of Diagnostic and Interventional Neuroradiology) and Urs Fischer (Department of Neurology), University Hospital Bern, Switzerland, and colleagues from a large consortium.

KAESMACHER AND colleagues remark: “The COLLEAGUES put forward proportion of patients treated that the issue of whether with low ASPECTS scores ischaemic stroke patients differed significantly between presenting with low ASPECTS participating centres.” Primary should be treated with outcome was defined as mechanical thrombectomy modified Rankin Scale (mRS) remains “one of the most 0–2 at 90 days, while secondary relevant unanswered questions outcome included rates of in acute stroke treatment”. They Johannes Kaesmacher and Urs Fischer 90-day mRS 0–2, 90-day set out to analyse the effect of mortality and the occurrence of successful reperfusion on functional outcome, mortality symptomatic intracerebral haemorrhage. and symptomatic intracerebral haemorrhage. Through Overall rates of favourable outcome and mortality utilising the BEYOND-SWIFT registry (Berneseat 90 days in the low ASPECTS subgroup were 40.1% European registry for ischaemic stroke patients treated (95/237) and 40.9% (97/237), respectively, while outside current guidelines with neurothrombectomy successful reperfusion was achieved in 69.9% of devices using the Solitaire Fr with the intention for patients in this cohort. The authors report that successful thrombectomy), the study investigators also aimed to reperfusion was associated with favourable clinical assess the safety and efficacy of endovascular treated outcome (mRS 0–3; adjusted odds ratio [aOR] 5.534; patients in this subgroup as compared to a group of 95% CI: 2.363–12.961), functional independence (mRS patients presenting with ASPECTS 6–10.

0–2; aOR 5.583; 95% CI: 1.964–15.873), major early Of the 1,532 patients included from the retrospective, neurological improvement (aOR 11.635; 95% CI: international, multicentre observational registry, 237 3.980–34.011), and reduced mortality (aOR 0.180; 95% patients were ASPECTS 0–5 (mean age: 67.1±14.4 CI: 0.083–0.390). Kaesmacher and colleagues ascertain years), while 1,295 were ASPECTS 6 or over. Further that these effects remained significant after adjusting for supporting the notion that treatment decisions regarding imaging modality-associated variance, but were “less the former subgroup vary greatly, Kaesmacher and marked in patients presenting with ASPECTS 0–4”,

Reversal agent andexanet alfa decreases acute major bleeding The blood thinner reversal agent, andexanet alfa, was effective at stopping acute major bleeding in patients taking factor Xa inhibitor blood thinners, concluded late-breaking science presented by the study’s senior author, Truman J Milling Jr (Seton Dell Medical School Stroke Institute, Austin, USA) at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA).

S

imultaneously published in the New England Journal of Medicine, the data indicated that treatment with andexanet markedly reduced antifactor Xa activity, while 82% of patients were reported to have excellent or good haemostatic efficacy at 12 hours.

According to an ISC press release, Milling Jr highlighted: “The study supported the May 2018 FDA approval of andexanet et al alfa, now the only approved agent for patients taking rivaroxaban and apixaban [factor Xa inhibitors]

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when urgent reversal is needed for lifethreatening or uncontrolled bleeding”.

In total, 352 patients (mean age: 77; 53% male) who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor were enrolled from

as they say that only the effect on mortality remained significant here.

Furthermore, rates of symptomatic intracerebral haemorrhage were lower in successfully reperfused patients (aOR 0.235; 95% CI: 0.062–0.887).

According to the authors, although interventions led to less successful reperfusion and tended to be more complicated in patients with ASPECTS 0–5 compared to those with ASPECTS 6–10, rates of symptomatic intracerebral haemorrhage remained comparable.

With regards to imaging modalities, Kaesmacher and colleagues note that the present analysis included both patients with CT (n=78) and with diffusionweighted (n=154) ASPECTS. They recognised that “although diffusion-weighted ASPECTS is thought to be more sensitive in terms of detecting early ischaemic changes, it may also overestimate the final infarct core”. However, the study investigators did not find a significant interaction between the effect of successful reperfusion and the imaging modality that determined the ASPECTS score.

Alluding to particular limitations of the study, Kaesmacher et al say that, most importantly, ASPECT scores were rated at each centre, hence were not core-lab adjudicated—meaning the validity may be compromised. Further, the low ASPECTS group was primarily supplied by three centres, “limiting the generalisability of the findings”. In summary, the study authors say: “Because of the retrospective, nonrandomised nature of the data and the lack of an untreated control group, our results should be viewed as hypothesis generating”.

Yet, Kaesmacher and colleagues maintain that the findings support the notion that rapid and complete reperfusion in large vessel occlusion acute ischaemic stroke patients is beneficial. “The data stress the need for a randomised controlled trial comparing the benefits of endovascular therapy versus best medical treatment in this subgroup of patients”. Moreover, as the study sheds light on the potential impact of the imaging modality used for ASPECTS and the associated outcomes, the authors further postulate that cut-offs for treatment are likely to be not directly comparable among centres using CT or MRI.

86 sites worldwide. Prior to a two-hour infusion, all patients received a bolus of andexan et etal alfa—designed to rapidly neutralise the anticoagulant effects of blood thinners in the event of acute bleeding. “Andexanet et al alfa acts as a factor Xa decoy to bind molecules that target and inhibit factor Xa,” stated Milling Jr. Bleeding was predominantly intracranial in 227 patients (64%) and gastrointestinal in 90 patients (26%). “In patients who had received apixaban, the median anti-factor Xa activity decreased from 149/7ng per millilitre at baseline to 11.1ng after the andexanet bolus,” Milling Jr reported. This equated to a 92% reduction overall (95% CI: 91, 93). Further, in patients who had received rivaroxaban, the median value decreased from 211.8ng per millilitre to 14.2ng; 92% reduction (95% CI: 88, 94).

Milling Jr and colleagues also investigated the percentage of patients with excellent or good haemostatic efficacy at 12 hours after the end of the infusion, with haemostatic efficacy adjudicated on the basis of prespecified

82% of patients were reported to have excellent or good haemostatic efficacy at 12 hours.”

Truman J Milling Jr

criteria. This outcome was achieved in 204 of the 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event occurred in a further 34 (10%), “which are some pretty impressive numbers in a population of anticoagulated major bleeding patients”, said Milling Jr. Lastly, he added that these thrombotic events were “greatly mitigated” by restarting anticoagulation.

Addressing the ISC audience, Milling Jr concluded that a reduction in antifactor Xa activity was not predictive of haemostatic efficacy overall, but was modestly predictive in patients with intracranial haemorrhage.

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At-home rehabilitation is comparable to clinicbased therapy to improve mobility in stroke patients Home-based telerehabilitation is just as effective as clinic-based therapy at restoring arm function among stroke survivors, according to late-breaking data presented at the American Stroke Association’s International Stroke Conference 2019 (ISC; 5–8 February, Honolulu, USA).

“M

any patients receive suboptimal rehabilitation therapy doses after stroke due to limited access to therapists and difficulty with transportation,” said the study’s lead author Steven C Cramer (University of California, Irvine, USA).

“This can be addressed by telehealth, which enables patients to access high doses of rehabilitation therapy in their home.”

Researchers conducted a randomised, assessor-blinded, non-inferiority trial with 124 stroke survivors (average age 61) at 11 US StrokeNet Clinical Trial Network sites.

Survivors underwent six weeks of intensive rehabilitation therapy targeting arm weakness. Each was randomised to receive therapy either in the clinic, with a therapist in person, using traditional methods or in their home using a telerehabilitation system, with a remote therapist accessed using videoconferencing.

For both groups, treatment was 36

sessions, 18 supervised, 18 unsupervised, and every session was 70 minutes: at least 15 minutes of arm exercises, at least 15 minutes of functional training, and five minutes a day of stroke education. The intensity, duration, and frequency of the therapy was matched across both arms of the study.

“We really strived to give the same therapy, either traditional in-clinic or at home via the telehealth clinic,” Cramer said.

The in-clinic group’s supervised treatment sessions were held at the research centre, with a therapist in person, whilst their unsupervised sessions were held at home using an individualised booklet. The telerehabilitation cohort had a 30-minute videoconference at the start of each of their supervised treatment sessions, conducted at home. The unsupervised treatment sessions in the telerehabilitation group also took place at home, using the telerehabilitation system—and no therapist contact.

Compliance was high and similar

between both groups: 98.3% (58/62) in the telerehabilitation group, and 93.4% (57/62) in the in-clinic group. Arm function improved substantially and equivalently in both groups.

“A computer-based telerehabilitation system delivered to patient’s homes uses ‘game-ified’ therapy activities, exercises and educational sessions (such as ‘Stroke Jeopardy’). Therapists can assess progress via videoconference,” Cramer explained.

“We demonstrated that home-based telehealth methods provide comparable benefits to traditional in-clinic methods,” Cramer said. “In the future, telehealth approaches to post-stroke rehabilitation might help patients reduce disability by increasing access to very large doses of therapy.”

The primary outcome measure used was the change in the arm motor FuglMeyer score, a 66-point impairment scale that informs physicians on arm mobility, assessed from baseline to 30 days posttherapy. At baseline, the Fugl-Meyer score was 42.7±8.7 in the in-clinic group, and this improved to 8.36±7 at 30 days posttreatment. For the telerehabilitation group, this improvement was very similar: from 42.8±7.8 at baseline to 7.86±6.7 30 days after treatment. Interpreting these results for the audience, Cramer said: “We can say that telerehabilitation is not inferior [to traditional treatment].” In both treatment types, the difference in Fugl-Meyer score seen over the course of the therapy sessions was clinically important.

Secondary outcome measures were the gains in stroke knowledge (Cramer

Alteplase administered nine hours after stroke achieves better functional outcomes, reperfusion and early neurological improvement The use of thrombolysis with alteplase beyond 4.5 hours in patients with acute ischaemic stroke who were carefully selected using automated CT perfusion imaging was found to elicit “excellent functional outcome”. Henry Ma from Monash University in Melbourne, Australia, who presented the results of the EXTEND (Extending the time for thrombolysis in emergency neurological deficits) trial in a late-breaking session at the International Stroke Conference (ISC; 5–8 February, Honolulu, USA) explained that “EXTEND is the first positive thrombolysis trial in an extended time window using automated CT imaging”.

CURRENT THINKING IS that thrombolysis must be given less than 4.5 hours from stroke onset in patients with acute ischaemic stroke. However, Ma put forward that some studies have shown that the ischaemic penumbra can exist up to 24 hours after stroke onset and intervention after 4.5 hours can lead to improved clinical outcomes.

The EXTEND study sought to investigate whether patients with significant penumbral mismatch at 4.5 to 9 hours after stroke onset or after “wake up stroke” have improved clinical outcomes when given thrombolysis with intravenous alteplase compared with placebo.

The EXTEND trial was a phase 3 multicentre, randomised, double-blind, placebo-controlled trial of alteplase versus placebo. Patients were stratified into three groups according to time after stroke: 4.5–6 hours, 6–9 hours and wake up stroke when time from stroke onset is not known.

Patients were selected for the trial using automated CT perfusion or MRI perfusion imaging, which identified salvageable brain tissue. Penumbral mismatch criteria were hypoperfusion to core volume ratio >1.2, perfusion lesion to core absolute difference >10ml and ischaemic core

This is the first positive thrombolysis trial in an extended time window using automated CT.” lesion volume ≤70ml.

The primary outcome was excellent functional outcome (modified Rankin Score, mRS 0–1) at three months. Other prespecified outcomes included independent functional outcome (mRS 0–2), early reperfusion, clinical improvement with National Institutes of Health Stroke Scale (NIHSS) reduction of eight points or reaching 0–1 at 24 hours, death and symptomatic intracerebral haemorrhage. Intention to treat and per-protocol analyses were both performed.

The study was terminated after publication of the WAKE UP trial, which demonstrated that thrombolysis treatment of patients with wake up stroke who were selected using MRI

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informed the ISC audience that previous work evidenced that stroke patients exhibited a “remarkable lack of knowledge about their disease, and its risk factors, and its prevention”) and changes in motivation.

Following treatment, Cramer noted that both groups showed significant gains in stroke knowledge, with a non-significant advantage to using the telerehabilitation system (p=0.2). He said: “This is the part of the telehealth promise: it is holistic medicine, it is not only rehabilitation, but it is also education, and more.”

“These are games that have been designed specifically to expand on knowledge about motor control”, Cramer continued. “The different games and different settings therapists could select for a patient had varying movement speeds, timings, planning, range of motion, target sizes, cognitive demand, hemifield bias— so if the patient had a right hemisphere stroke, the therapist could choose to have more of the game targets appear in the left visual hemifield.”

In future work, Cramer hypothesised that telerehabilitation might be paired with a drug: “In a new, ongoing trial, we are looking at people taking their pills while they are doing their telerehabilitation.”

Cramer also told audience members: “We could also use it to get detailed remote measurements between discharge and day 90. We might also treat other neurological deficits beside the arm, such as language, legor, dysphagia. And lastly, we can study telehealth to improve access, and see if we can lower the cost of post-stroke rehabilitation care.”

brain imaging led to significantly better outcomes. In total, 225 patients were recruited: 112 received placebo and 113 received thrombolysis.

For intention-to-treat analysis, patients who received alteplase achieved better functional outcomes than those given placebo (35% vs. 29%; adjusted risk ratio [aRR] 1.44; p=0.04). Per-protocol analysis included 204 patients: 99 who were treated with alteplase and 105 with placebo; 10% had a stroke onset of 4.5–6 hours; 25% had a stroke onset of 6–9 hours; and 65% had wake up stroke. A large vessel occlusion was found in 70% of patients given thrombolysis and 72% of those given placebo.

Results of per-protocol analysis also showed better functional outcomes in patients given alteplase (mRS 0–1; 37% vs. 29%; aRR 1.45; p=0.045). Other improved outcomes were independent functional outcome (mRS 0–2; 51% vs. 43%; aRR 1.30; p=0.049) at three months, increased early reperfusion (51% vs. 28%; aRR 1.78; p=0.001) and neurological improvement (NIHSS reduction ≥8 points or 0–1; 25% vs. 10%; aRR 2.67; p=0.006) at 24 hours. Mortality was similar in both groups at three months (11.1% vs. 9.5%; aRR 1.03; p=0.77), while symptomatic intracerebral haemorrhage was 6% vs. 1%, respectively (aRR 6.48; p=0.066).

Ma concluded: “Alteplase-treated patients presenting within nine hours or with wake up stroke selected by automated perfusion imaging achieved a significantly higher rate of excellent functional outcome compared to placebo.” The per-protocol analysis showed “a similar primary outcome as the positive intention to treat analysis result.” Superior rates of reperfusion, recanalisation and early neurological improvement were all found in those treated with alteplase compared with placebo.

Ma also noted: “There was an increase in the rate of symptomatic intracerebral haemorrhage consistent with other thrombolytic trials, but this was not associated with increased mortality and did not negate the positive result of improved rate of excellence functional outcome.”

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Novel technique outperforms conventional spinal cord stimulation Continued from page 1

interaction, as glia make up a majority (92–95%) of the posterior spinal cord structures at these relevant levels whereas neurones are relatively sparse (5–8% in this region. This conclusion paved the way for a pre-clinical comparison of DTM-SCS with low- and high-rate SCS, as Vallejo surmised: “It is plausible to enhance the neuro-glial interaction and provide pain relief with SCS using a DTM approach”.

Speaking to the NANS audience as to whether SCS should be optimised for glial cells, Fishman stated: “We think so.” He acknowledged that in the T8– T11, glial cells outnumber neurons 12:1, meaning that most of the stimulation applied to the cord is actually being applied to glial cells. “Glial cells also respond to electrical pulses but they do so more differently than neurone cells do”, explained Fishman. Providing context to the terminology, he said “differential targeting” refers to multiple cell types being targeted, and “multiplexed” means that multiple signals are combined with the delivered stimulation.

The preclinical comparison of SCS approaches was carried out by inducing the spared nerve injury (SNI) neuropathic pain model in rats (n=10–13 per group).

According to Vallejo, through implanting the rats with a quadrupole cylindrical lead, DTM-SCS, low- or high-rate SCS was applied continuously for 48 hours using an external neurostimulator.

While DTM-SCS used multiplexed signals between 20 and 1,200Hz (below 200µs, pulse width), low-rate used signals at 50Hz (150µs) and high-rate at 1,200 (50µs). Intensity was set to 70% of the motor threshold and pain

Ricardo Vallejo

Michael Fishman

behaviour—both mechanical and thermal hypersensitivity—was tested before SNI, as well as before and after SCS. Vallejo reported that DTM-SCS relieved mechanical hypersensitivity significantly better than high-rate SCS and low-rate SCS (60.7±8.4% vs. 34.9±5.5% and 35.0±6.0%).

Accordingly, this technique also relieved hypersensitivity to thermal stimuli, whereas neither high-rate or low-rate SCS reduced it significantly.

Interestingly, Vallejo said that further analyses conveyed that the spared nerve injury “significantly modulates genes involved in the immune and inflammatory processes […], highlighting the role of glial cells”. In light of the better outcomes for this novel technique, he proposed: “DTM-SCS modulated significantly more biological processes associated with the neuro-glia interactions such as regulation of cell communication, regulation of signal transduction, trans-

synaptic signalling, regulation of protein phosphorylation, and regulation of ion transport than what high-rate SCS and low-rate SCS modulated”.

Reiterating the importance of studying these modulatory processes, Fishman and colleagues hypothesised that multiplexing electric signals—with signals differentially targeting glia (astrocytes, microglia, oligodendrocytes) and neurones—may produce a beneficial impact in relieving chronic pain.

Fishman and his team carried out a prospective, multicentre, openlabel, crossover study in order to compare the pain relief from DTMSCS with conventional SCS. An investigational device was used for DTM-SCS, programmed by the sponsor’s (Stimgenics) representatives to ensure that multiplexed signals were maintained between 20 and 1,200Hz, and under 1ms.

In total, 25 subjects with chronic intractable back pain were enrolled (mean

age 64.2; 60% male). The mean duration of chronic pain in this sample was 18 years, while the mean baseline back pain numerical rating score (NRS) was 7.

Fishman reported that in terms of conventional SCS outcomes, the mean back pain NRS had reduced to 4.1, while DTM-SCS achieved a score of 2.4; a difference of 1.7 points between the two therapies (p<0.0001). Back pain responder rates for DTM-SCS was 80% and 50% for conventional SCS. For chronic leg pain, conventional SCS elicited a mean leg pain NRS of 3.7, while DTM-SCS achieved 1.4; equating to a difference of 2.3 points (p=0.0003). Leg pain responder rates for DTM-SCS was 100%, indicating a statistically significant improvement over conventional SCS which achieved 40%.

Furthermore, Fishman highlighted that 85% of the subjects preferred DTM-SCS. The authors were able to conclude that DTM-SCS can achieve significantly greater back pain relief and back pain responder rates when compared with conventional SCS. Moving forward with these results, Fishman suggested that “a larger, longer-term randomised clinical study is needed to confirm the potential advantages of DTM-SCS for chronic back pain”. However, in relation to these positive outcomes, he said that it “makes us very excited to present to you— hopefully—the results of an RCT next year. We are actively enrolling plenty of patients.” Speaking to NeuroNews, Fishman commented, “The randomised controlled trial compares DTM-SCS as the test arm with conventional SCS as the control arm in a 1:1 randomisation.

The test arm is programmed by the sponsor (Stimgenics) and the control arm is programmed by Medtronic representatives. The study will compare the test and control groups in a number of endpoints, including a statistical test of superiority”.

Review shows inaccuracies of deep brain stimulation data for minimally conscious patients following traumatic brain injury Results from a systematic review reveal that evidence for the use of deep brain stimulation (DBS) of various targets to promote recovery in patients with disorders of consciousness is based on a “small population of heterogeneous patients”. Ali Rezaei Haddad and colleagues from the University of Oxford, UK, report that in the eight studies analysed, time from injury to stimulation was “significantly variable and problematic”, while evidence supporting the use of DBS in minimally conscious patients following traumatic brain injury is lacking.

RECENTLY PUBLISHED IN Neuromodulation: Technology at the Neural Interface, the review was carried out using an array of electronic bibliographic databases to identify the relevant literature. “We included all studies describing applications of DBS on patients in minimally conscious state following traumatic brain injury,” write Haddad and colleagues.

Of the eight studies that were identified, the experience of DBS in 10 patients aged 15–58 was analysed.

Acknowledging the variability, Haddad et al write: “The time from injury to simulation ranged from three to 252 months, with the duration of follow-up post-DBS ranging from 10 to 120 months.” While seven patients improved their post-surgical outcome score measures, a descriptive favourable outcome was reported in one patient. A further two patients were reported not to have shown any improvements following the intervention.

Providing an explanation for the variable time until stimulation, the authors highlighted that spontaneous recovery can occur within the first year of injury. However,

Haddad and colleagues allude to the fact that spontaneous recovery presents as a “considerable issue” when examining the use of DBS in disorders of consciousness. “It has been reported that over four-fifths of patients who are in a minimally conscious state up to six months’ post-injury achieve spontaneous recovery by ten months. Furthermore, the recovery rates of traumatic brain injury patients are significantly higher when compared to other aetiologies,” write the authors, later acknowledging that while interpreting the results from DBS studies, “it is crucial to take into account the natural progression of this condition, especially at one-year post injury.”

In light of the findings, Haddad et al write: “This review suggests that future studies should attempt to adopt a patient-specific selection criterion rather than conditionspecific due to inaccuracies associated with the clinical diagnosis and different behavioural profiles of patients in minimally conscious state.” In addition, they put forward that patients should be randomised into stimulation and non-stimulation groups, and subsequently followed up for

two to four years.

“Although some patients showed promising results in validated outcome measures, we conclude that the evidence supporting the use of DBS in minimally conscious state patients following traumatic brain injury is not sufficient as there is a lack of well-designed trials due to the challenges associated with this condition,” surmise Haddad and the team. Furthermore, they allude to the fact that despite the decreasing mortality rate associated with traumatic brain injury, the number of patients enduring long-term consequences of this injury, such as poor functional survival outcomes—including disordered consciousness—is on the rise. And, according to the authors, advances in neurosurgery and cute critical care only aids the acceleration of this figure.

Thus, referring to traumatic brain injury as a “silent epidemic” on a global scale, Haddad and colleagues maintain the importance of the need for interventions to reduce its incidence alongside improving the associated mortalities.

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Evoke: The first RCT to measure spinal cord activations in response to SCS The protocol design for a multicentre, prospective, randomised, double-blind study comparing ECAP- (evoked compound action potential) controlled closed-looped with open-loop, fixed output spinal cord stimulation (SCS) was presented by Robert Levy, Institute of Neuromodulation and Pain Relief, Boca Raton, USA, at the North American Neuromodulation Society (NANS) annual meeting (17–20 January, Las Vegas, USA).

“I

f this study shows superiority in the study arm, it will be a major breakthrough for future studies of paraesthesia independent systems”, commented co-author Timothy Deer, president and CEO of The Spine & Nerve Centers, Charleston, USA. The Evoke study seeks to improve outcomes of SCS for chronic pain by eliciting and analysing real-time objective measurements of spinal cord activation alongside other neurophysiological properties.

Levy explained that all approved SCS therapies— regardless of whether the stimulation induces paraesthesia—are open-loop in that they produce fixedoutput stimuli. Yet, fixed-output SCS systems do not take into account the broad range of electrical field strengths

emitted to the spinal cord due to changes in distance between the electrode and the spinal cord resulting from normal physiological activity, such as breathing, and movement.

In contrast, closed-loop stimulation can modulate the current delivered in real-time to maintain consistent spinal cord activation. Levy argued that such objective measures of spinal cord activation may lead to improvements in diagnosis, assessment and the subsequent treatment of chronic pain. Further, they provide the foundation for an “individualised mechanism-based treatment approach”, enabling more effective neuromodulation therapies that align with IMMPACT (Initiatives on Methods, Measurement and Pain Assessment) recommendations.

Is neurophysiology required for optimal deep brain stimulation targeting?

Kim Burchiel Comment & Analysis Addressing the lack of randomised data comparing the outcomes of “awake” versus “asleep” deep brain stimulation (DBS), Kim Burchiel (Oregon Health and Science University, Portland, USA) discusses the evolving evidence-base regarding the implantation of deep brain stimulation electrodes under general anaesthesia, in turn highlighting an array of cognitive improvements found to be superior in the “asleep” DBS group.

IMPLANTATION OF DEEP brain stimulation (DBS) electrodes has traditionally been accomplished in awake patients, under local anaesthesia, using microelectrode recording to physiologically verify target acquisition.

Evidence is now mounting that imageguided implantation of DBS electrodes can be accomplished under general anaesthesia in patients with Parkinson’s disease, and that post-operative outcomes under general anaesthetic can be equivalent to those achieved using physiologic guidance, including motor (tested using the Unified Parkinson’s Disease Rating Scale; UPDRS II-III), levodopa equivalent daily dose, complications and adverse events, as well as target accuracy, inpatient length of stay and 30-day readmission rates. Compared to awake DBS, asleep DBS also results in less intracranial air, which is a potential source of brain shift and the malposition

of electrodes. Results with asleep DBS for essential tremor indicate that there is comparable improvement in tremor when compared to “awake” DBS. Implant costs of awake and asleep DBS are comparable.

Presently, no prospective randomised and controlled study has been completed comparing DBS under local anaesthetic versus general, but a prospective trial is underway.

At Oregon Health and Science University, we have studied the issue of DBS implantation, and compared our latest results in awake patients with microelectrode recording, to a more recent cohort of patients in which asleep DBS was performed. The results showed that there was no significant difference observed in improvement of UPDRS III between awake and asleep patients.

Interestingly, improvement in ON time without dyskinesia, quality of life scores

The primary objective of Evoke is to demonstrate noninferiority of ECAP-controlled closed-loop SCS compared to open-loop, fixed-output SCS in the proportion of subjects with ≥50% reduction in average overall trunk and limb pain and no increase in pain medication at three-months. “If noninferiority is met, superiority will be tested,” Levy surmised.

Confirming that enrolment of the Evoke study has now been completed, Levy described the characteristics of the two treatment cohorts. In total, 134 SCS candidates from up to 20 US sites were randomised 1:1, either to closedloop or open-loop SCS. Patients were required to have a diagnosis of chronic, intractable pain which had been refractory for ≥6 months, as well as VAS overall, back and leg pain scores of ≥6cm.

Regarding the current state of Evoke, data collection and analyses are underway, said Levy, as he maintained that this study is the first randomised, double-blind pivotal study in the field of neuromodulation to measure SC activation in response to SCS. Speaking to NeuroNews about progressing in the field, Deer theorised: “The next steps will be an evolution to either artificial intelligence in spinal stimulation, or the advent of new lower energy requiring waveforms. The best solutions for the patient will be determined in real world experiences”.

for cognition and communication, and speech outcomes—notably category and phonemic fluency—were all superior in the asleep DBS group.1,2 There is an on-going discussion regarding what these findings portend for the future of DBS surgery. At the very least, image-guided DBS electrode implantation may be one option in the selection of appropriate surgical techniques for patients with Parkinson’s disease, essential tremor, and other disorders, who require DBS. Under this scenario, intraoperative imaging will likely be a requirement for imageguided DBS electrode placement.

Considerable work has already been accomplished using intraoperative MRI and CT guidance for DBS surgery. It is likely that one of these imaging systems will emerge as the dominant technology for image-guided DBS surgery. Where MRI has the advantages of no radiation and the potential for “live” updates of electrode position; cost, alongside accessibility and a compromised surgical environment, remain its shortcomings.

CT has the advantage of being a less expensive and more accessible without the concerns of ferromagnetic instrumentation in the surgical field. Yet, it requires a radiation dose to the patient, which would only be increased by successive “live” updates, requiring repeated imaging.

There may be other technologies that could reduce, or even obviate the need for intraoperative imaging—but these are yet to be developed.

The question at hand is whether awake DBS surgery, with microelectrode recording guidance, is the best way to conduct routine (non-research) implantation of DBS electrode for movement disorder therapy. Microelectrode recording is certainly the biggest challenge of awake surgery, in that it requires dedicated equipment, neurophysiologic expertise, an awake patient, and potentially more time in the operating room.

The main issue with microelectrode recording is that it also appears to have a linkage to intracerebral haemorrhage and stroke.3 Without a clear advantage

of microelectrode recording mapping, this additional risk may not be justified. Further, 28,000 cases of DBS implantation procedures (2004–2013) from the Centers for Medicare & Medicaid Services registry and National Surgical Quality Improvement Program have been examined, showing revision/ removal rates of 15.2–34%, for the two registries, respectively. The authors of this study4 concluded that 48.5% of these replacements were due to improper targeting or lack of therapeutic effects. This is a concerning statistic given that virtually all of these procedures were performed on awake patients with microelectrode recording guidance. Thus, using the “goldstandard” approach, roughly 10–15% of all initial DBS implants in the USA appear to be mispositioned.

Without question, awake DBS with microelectrode recording is a valuable research approach to improve our understanding of Parkinson’s disease, essential tremor, and many other conditions. Although there is no prospective randomised trial data comparing the outcomes of awake and asleep DBS, the evidence is growing that routine awake DBS with microelectrode recording may be supplanted by asleep DBS utilising image-guidance, and intraoperative imaging.

Kim Burchiel is the John Raaf professor and the Head of the Division of Functional Neurosurgery at Oregon Health and Science University.

References 1. Brodsky MA, Anderson A, Murchison C, Seier M, Wilhelm J, Vederman A, Burchiel KJ. Clinical Outcomes of Asleep vs Awake Deep Brain Stimulation for Parkinson Disease. Neurology Nov 2017, 89 (19) 19441950; DOI:10.1212/WNL.0000000000004630.

2. Aziz TZ, Hariz M. To Sleep or Not to Sleep During Deep Brain Stimulation Surgery for Parkinson Disease.

Neurology Nov 2017, 89 (19) 1938-1939; DOI:10.1212/ WNL.0000000000004635 3. Zrinzo L, Foltynie T, Limousin P, Hariz MI: Reducing hemorrhagic complications in functional neurosurgery: a large case series and systematic review. J Neurosurg Sept 2011. [DOI: 10.3171/2011.8.JNS10147] 4. Rolston JD, Englot DJ, Starr PA Larson PS. An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: Analysis of multiple databases. Parkinsonism Relat Disord 2016 Dec;33:7277. doi: 10.1016/j.parkreldis.2016.09.014. Epub 2016 Sep 12.w

April

Real-world review reports significant reduction in pain with high-frequency 10kHz SCS A multicentre real-world review of 10kHz of spinal cord stimulation (SCS) for the treatment of chronic back and leg pain has elicited positive results, complementing the findings of a previously published randomised controlled trial (RCT). Thomas Stauss (Advanced Pain Management, Greenfield, USA), and colleagues report that at least 70% of the 1,660 patients reviewed responded to therapy; a figure of which was sustained through 12 months.

THE RESEARCH, RECENTLY published in Annuals of Clinical and Translational Neurology, aimed to reduce the gap in the literature regarding the lack of large observational studies on this type of therapy. Stauss and colleagues performed a real-world, multicentre, retrospective review in order to investigate the efficacy of 10kHz SCS in a large number of patients (1,660) with chronic trunk and/or limb pain.

The data, retrospectively sourced from a global database, were inclusive of patients that were trialed and/or permanently implanted with a Senza system (Nevro), delivering high frequency SCS at 10kHz between April 2014 and January 2018.

Both academic and non-academic centres (n=8) across three countries participated in the review, with each site having experienced at least 100 implanted patients over a two-year period.

The authors evaluated responder rates at three, six, and 12 months postimplantation. Patient response was defined as ≥50% pain relief compared with initial baseline findings. During last visit analyses, Stauss and colleagues

investigated overall change in function, sleep, quality of life and medication intake—and also compared these to baseline. They reported that the mean time between implantation and the last visit was 8.9 months (range: 0.1­–33.2).

Of the 1,660 patients treated with high frequency SCS, 84% had both chronic back and leg pain. At least 70% of patients were found to respond to therapy throughout 12 months of follow-up.

Of importance, Stauss and colleagues reported that this sustained responder rate

was corroborated by the last visit value (74.1%).

Furthermore, the majority of patients reported concomitant improvements in function (72.3%), sleep (68%), and quality of life (90.3%) at their last visit compared to baseline. Additionally, 32.1% (n=1,070) of patients reported a decrease in medication intake at their last visit (40% of European patients and 28.9% of American patients).

Safety data—available from 1,290 patients—indicated that 48 patients

Intrathecal drug delivery implants shown to reduce or eliminate systemic opioid use Data displaying a meaningful proportion of patients eliminating or decreasing systemic opioid following the implantation of intrathecal drug delivery systems were recently presented by John Hatheway, Northwest Pain Care, Spokane, USA, at the North American Neuromodulation Society’s 2019 annual meeting (NANS; 17–20 January, Las Vegas, USA).

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atheway began his presentation by acknowledging that presently, around 11.5 million Americans are misusing opioids, with 62% of these people using them to relieve physical pain. According to Hatheway, previous research using insurance claims data found that 51% of patients eliminated systemic opioids at one-year following intrathecal drug delivery system implantation.

Hatheway and colleagues aimed to further prior retrospective claims research to evaluate systemic opioid dosing patterns via the morphine milligram equivalents before and after implantation of the intrathecal drug delivery system. They also aimed to assess the correlation between systemic opioid dosing and the probability of discontinuation following the start of the intrathecal delivery system.

“We utilised the Truven marketscan database; a database encompassing around a third of all commercial claims in the USA,” Hatheway said. This retrospective database analysis included both de-identified data and patient-level healthcare claims information on over 135 million patients. However, Hatheway noted that patients with the following were excluded: spasticity, cancer, no opioid prescription in the six months prior to the intrathecal drug delivery system, pump explant or no refill

within one year, as well as patients with non-continuous plan enrolment.

The team were also able to determine daily morphine equivalent doses through the Truven database. In order to carry out the analysis, all prescriptions were converted to morphine milligram equivalents, with patients’ average daily intake categorised either as low (1–50mg/day), moderate (51–90), or high (≥90).

Hatheway and his colleagues defined the opioid discontinuation date as the patient’s last systemic opioid prescription days’ supply during baseline, 30-day washout following implantation, or 365-day follow-up. “There was one exception to this rule”, Hatheway said, “if a patient received one prescription of opioids with a less than 30-day supply during the 365–395 day period—that was considered an acute prescription, and we would still consider those patients as discontinued.”

In total, 631 patients met the inclusion criteria, with 43% (mean age 59.3 years) discontinuing systemic opioid therapy immediately prior to, or in the year following the intrathecal drug delivery system implantation. In light of this finding, Hatheway said: “Two factors associated with discontinuation stand out in this case: if patients were 80 years or over [they were more likely to discontinue], or if they were in the low dose group, they were twice as likely

(3.7%) had their devices explanted.

Twenty-two (1.7%) were removed following infection, 15 (1.2%) due to loss of efficacy, and a further 11 (0.8%) were removed for other reasons. On discussion of this finding, Stauss and colleagues put forward that this overall explant rate was “far less than historical norms for traditional spinal cord stimulation, such as those utilising low frequencies.”

Interpreting the data, Stauss and colleagues state that the real-world results are consistent with the findings of a previously published RCT. However, they allude to limitations of the review, all of which they stated were related to the real-world setting as well as the study’s retrospective nature, lack of control and use of non-standardised measures for particular outcomes, such as sleep.

Additionally, as the data were not entered systematically across all centres, Stauss et al acknowledge that the dataset may have been nonhomogenous. Furthermore, the authors point to a methodological shortcoming as they write: “The study evaluated overall pain relief rather than separate back and leg pain relief as measured in the SENZA-RCT.” Despite the caveats, Stauss and colleagues conclude that the current retrospective analysis revealed that the therapy provided sustained an effective pain relief in >70% of patients at all follow-up time points. Thus, the review provides complementary evidence to support the treatment of chronic back and leg pain with high frequency SCS at 10kHz.

to discontinue than patients in the high dose group.”

Overall, 84% of patients reduced their daily morphine milligram equivalents in the year following implantation, relative to one-year baseline levels (excluding washout).

Further, among the patients who continued opioid therapy (mean age 55.5 years), 77% reduced their morphine milligram equivalents following implantation. However, Hatheway reported that for the patients who did not eliminate systemic opioids, the average daily morphine milligram equivalents increased from 12 months to one month prior to implantation.

Concluding the findings, Hatheway posited that the data displayed a meaningful proportion of patients eliminating or decreasing systemic opioid therapy following the implantation of intrathecal drug delivery systems. Further, he maintained that the percentage or patients eliminating therapy is highly correlated to baseline morphine milligram equivalent level prior to the start of intrathecal drug delivery.

Interestingly, he said that despite heightened awareness of weaning protocols in recent years, the investigators observed minimal to no implementation of weaning protocols over the study period (2011-2016), with relatively steady morphine milligram equivalent levels prior to implantation. Providing a reason for this, Hatheway postulated: “The CDC guidelines went into effect in 2016, so we thought that possibly, this weaning could be more extensive down the line. It will be interesting to look at this data again in a few years to see if that changes.”

Despite the findings, Hatheway acknowledged that a significant opportunity remains to assist more patients in completely eliminating their reliance on opioid therapy.

Moving forward with these results, he remarked: “We are now involved in a prospective study looking into best practices for opioid weaning prior to intrathecal drug delivery system implantation, to maximise the percentage of patients able to discontinue systemic opioid therapy.”

April

Product News Medtronic announces FDA clearance and US launch of the Accurian RF system for nerve tissue ablation

Medtronic has announced US Food and Drug Administration (FDA) 510(k) clearance of the Accurian RF ablation platform, which conducts radio frequency (RF) ablation of nerve tissues.

RF ablation is a minimally invasive procedure in which current produced by radio waves heats up a small area of nerve tissue to stop it from sending pain signals, thereby reducing pain. The Accurian system combines proprietary hardware and quad core processing with advanced software for power and temperature control resulting in consistent and predictable lesion formation. It also offers independent channel management and advanced smart features that may support procedural efficiency.

“The Accurian RF ablation platform is a significant addition in my practice because I know I will get the same lesion every time in every channel due to how responsive the generator is in managing power and temperature,” said Leo Kapural, a pain physician at Carolinas Pain Institute and Center for Clinical Research in Winston-Salem, USA. “RF ablation requires both precision and flexibility. Accurian is intuitive and easy to use and enables me to easily upgrade the system and perform enhanced lesions with cooled RF probes.”

The Accurian RF ablation platform can perform standard, pulsed, and enhanced procedures using internally-cooled probes to create a comprehensive range of lesion shapes, sizes, and volumes.

It has independent channel control and chip-enhanced probes for easy on-screen identification, as well as smart features, such as downloadable procedure reports to support ease of use and efficiency. The Accurian system has been extensively tested for lasting reliability and is upgrade-ready as technology advances.

Positive results for the treatment of medicationresistant epilepsy using Neuroelectrics’ Starstim

At the recent American Epilepsy Society Annual Meeting in New Orleans, USA, Neuroelectrics presented positive results from its clinical trial treating

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patients with drug resistant epilepsy with Starstim, a device that uses transcranial current stimulation to deliver mild electric currents to the scalp to calm abnormal activity of the brain.

Of the 17 patients that completed the study, treatment with Neuroelectrics’ Starstim device resulted in a reduction in seizure frequency of at least 40% from baseline in 75% of the patients, measured eight weeks after treatment. Also, no device-related adverse events were reported during the study.

Neuroelectrics sponsored the FDAapproved investigational device study of its Starstim product at Boston Children’s Hospital, with adult patients being referred from nearby Beth Israel Deaconess Medical Center (Boston, USA). A parallel study following the same protocol was conducted at the National Institute of Neurology and Neurosurgery in Mexico City, Mexico.

All patients enrolled in the study had not responded to at least two antiepileptic medications, and for many the next step would be brain surgery to resect the region of the brain where the seizures originate. The treatment protocol used 20 minutes of daily stimulation applied for 10 times over two weeks, followed by an eight-week monitoring period to measure seizure frequency.

The Starstim device employs a form of non-invasive neuromodulation known as transcranial current stimulation (tCS) to deliver mild electrical currents to the brain. Neuroelectrics’ proprietary Precision-tCS technology develops a personalised stimulation protocol to target the specific areas of the patient’s brain where the seizures originate, as identified by the treating neurologist. The Starstim device is worn for 20 minutes per day, and there is no penetration of the brain or skin.

CMS trial clearance for LivaNova’s vagus nerve stimulation therapy for treatment-resistant depression

LivaNova has recognised that the US Centers for Medicare & Medicaid Services (CMS) finalised its National Coverage Determination (NCD) for the LivaNova vagus nerve stimulation therapy (VNS therapy) system for treatment-resistant depression.

Per its final decision, CMS has modified the NCD for VNS therapy for treatment-resistant depression to include feedback received during the comment period in a manner that aligns the coverage with evidence development framework with current indications and standard of practice for clinical study design in this disease state.

This final decision initiates coverage for Medicare beneficiaries through Coverage with Evidence Development when offered in a CMS-approved, double-blind, randomised, placebo-

controlled trial with a follow-up duration of at least one year, as well as the coverage of VNS Therapy device replacement. The Coverage with Evidence Development also includes the possibility to extend the study to a prospective longitudinal study.

Axonics

Axonics granted full-body MR-conditional CE mark for its sacral neuromodulation system

Axonics has announced that it has received CE mark approval for 1.5T and 3T full-body magnetic resonance imaging conditional labelling for the Axonics r-SNM (sacral neuromodulation) system; a device used for the treatment of urinary and bowel dysfunction.

The Axonics r-SNM system is the only implantable SNM system that has received full-body MRI conditional labelling for sale in Europe.

Raymond W Cohen, CEO of Axonics, said, “Without this labelling, any patient requiring an MRI scan on any body part below the head must have their neurostimulator surgically explanted prior to the MRI scan, resulting in an additional surgery for the patient and additional costs to patients and the healthcare system.

The Axonics r-SNM product also incorporates a miniaturised and longlived implantable neurostimulator that is one-third the size of the only competitor and is qualified to last at least 15 years in the body. The system also features a fast and safe charging capability with an infrequent charging interval, and a patient-friendly wireless remote control.

Karen L Noblett, chief medical officer of Axonics, reiterated: “Full-body MRI labelling is critical to patients who need, or may anticipate needing, magnetic resonance imaging. This new expanded labelling eliminates a major concern for both groups of patients and will allow more patients to choose SNM to treat their urinary and bowel dysfunction without compromising their quality of life.”

Medtronic’s deep brain stimulation for medicallyrefractory epilepsy launches in the USA Medtronic has announced both the US launch of deep brain stimulation (DBS)

for medically-refractory epilepsy and the first commercially implanted patient at Emory University in Atlanta, USA. According to the Epilepsy Foundation, as many as 3.4 million Americans have epilepsy, with one-third estimated to be drug-resistant.

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

The approval was based on results from the SANTE (Stimulation of the anterior nucleus of the thalamus in epilepsy) trial, wherein patients had a median seizure frequency reduction of 75% at seven years’ post-implant.

“The commercial availability of DBS provides an important surgical treatment option for patients who suffer from epilepsy and do not respond to medication,” said Robert E Gross, MBNA Bowman chair and professor, Emory University Department of Neurosurgery, neurosurgical primary investigator for the SANTE trial. “ANT DBS has been shown to significantly reduce the frequency and severity of seizures and improve quality of life out to seven years. The first patient implanted since commercialisation is doing very well. While it has only been two months since the system was turned on, his frequency of seizures has declined by more than 50%, and we expect improvement to increase further with additional programming sessions.”

“With the FDA approval, commercial launch, and policy updates from several health insurers, we are positioned to help more people than ever before. We are also initiating a 140 subject postapproval study where we will evaluate three-year safety and effectiveness outcomes at centres in the USA and Europe,” said Mike Daly, vice president and general manager of the Brain Modulation business, which is part of the Restorative Therapies Group at Medtronic.

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Market watch

Product News

Laboratory evaluation of a robotic operative microscope: A visualisation platform for neurosurgery

Operative microscopes have become fundamental to the success of modern neurosurgical and other surgical specialty procedures. They have become active platforms for the development of improved user-control interfaces and robotic systems. Latest developments provide significantly more functions than previous operative microscopes.

A one-year study was recently conducted by Evgenii G Belykh (St Joseph’s Hospital and Medical Center, Phoenix, USA) and colleagues in order to perform a comprehensive assessment of the new, cutting-edge ZEISS KINEVO 900, a first-ever robotic visualisation system. The study compares its performance to the previous model of ZEISS surgical microscope. Carried out

in a neurosurgery research laboratory, the assessment covered robotic, exoscopic, endoscopic and fluorescence functionalities.

The study found that the KINEVO 900 provides a number of improvements over the previous surgical microscope.

For example, novel robotic functions including the “PositionMemory” and “PointLock” functions of the KINEVO 900 were found to be helpful in procedures requiring small bone windows.

Additionally, the 3D 4K digital hybrid visualisation of ZEISS KINEVO 900 was found to be a significant improvement over prior technology. With the exoscopic visualisation mode and long working distance, the entire operative room team can appreciate the detailed structures in the depth of surgical corridor.

The KINEVO 900 also provides better discrimination between the fluorescent signal and the surrounding area by means of a significantly improved perception of brain and blood colours. Non-fluorescent tissues appeared much brighter and more natural in colour with the KINEVO 900 digital display and slightly brighter through oculars compared to the previous system.

Lastly, endoscope assistance in microscope-operated intracranial

25

surgeries offers an additional visualisation of the deep structures.

However, endoscope assistance is limited by a decrease or at least significant impediments in manoeuvrability when compared with using the operative microscope.

to deliver the right balance of atraumatic navigation and proximal support.

Balt announces receiving CE marks for Ballast .088 Long Sheath

At the European Congress of Radiology (ECR; 27 February–3 March, Vienna, Austria) Siemens Healthineers will introduce the Artis icono biplane, an angiography system with special functions for neuroradiology.

An integral feature of this new system is its significantly improved 2D and 3D imaging, improving image quality and reducing the radiation dose required.

As the C-arm can now perform new movement patterns, the areas of the cranial base and skull cap can now be represented with practically no artifacts in a 3D visualisation. The fast and flexible axial movements are the result of new, high-precision industrial drives from Siemens. Interventions can be highly efficient thanks to the intelligent system control. For example, it is

Balt International has announced receiving the CE mark for the Ballast .088 Long Sheath. The Ballast .088 Long sheath is indicated for the introduction of interventional devices into peripheral, coronary and neurovasculature. It is

a class III medical device which is described as a guiding catheter and as an introducer sheath.

The Ballast .088 will be commercially available in different lengths, from 80cm, via 90cm and up to a 100cm long. This new generation sheath is designed with a braided reinforced proximal segment, an optimised progressively softer distal coil segment and a low-profile outer diameter

Artis icono from Siemens Healthineers expands precision with improved visualisation in neuroradiology

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possible to switch seamlessly between 2D and 3D imaging during an intervention, which makes intra-procedural progress checks much easier. Artis icono biplane is expected to be available in the summer of 2019.

“Improving the visualisation of bleedings that occur anywhere in the cranial area can make it possible to skip prior conventional imaging for certain patients with a suspected stroke—which means that these patients can be taken directly to the angio lab for diagnosis and treatment, shortening the lead time before the vascular occlusion is removed.

Any time saved in treating strokes can mean the difference between living independently and living in a wheelchair,” says Michael Scheuering, head of interventional radiology at Siemens Healthineers.

A number of studies now show that treatment in the form of thrombectomy can be extended to a broader range of patients than previously assumed. This lets neurointerventionalists treat ischaemic stroke patients who were previously not eligible for this highly effective treatment.

Artis icono was developed to help physicians in stroke centres deal with the challenge of treating more patients faster and with greater accuracy.

Corindus announces FDA submission for neurovascular intervention indication for CorPath GRX

Corindus Vascular Robotics announces that it is seeking premarket clearance from the US Food and Drug Administration (FDA) to use the CorPath GRX System in neurovascular intervention.

“We will leverage our recent achievements in telerobotics and strong focus on technology development to build a remote stroke solution to tackle the challenge of access to care. This would extend the reach of highlyskilled specialists across the globe by granting remote access to patients suffering from life-altering diseases where access to care is limited and time to treatment is paramount,” said Mark Toland, president and CEO of Corindus.

This news comes on the heels of Corindus’ announcement that its technology was successfully used to conduct the first-in-human telerobotic intervention study. The study was the world’s first-in-human percutaneous coronary intervention conducted from a remote location approximately 20 miles outside of the catheterisation lab.

Industry News Scott Gottlieb resigns as head of US FDA

Physicians’ Education Resource to host first annual International Congress on the future of neurology

Physicians’ Education Resource (PER), a worldwide leading resource for continuing medical education (CME), will host the first annual International Congress on the Future of Neurology conference from September 27–28 at the Intercontinental New York Times Square in New York City. The educational programme will be chaired by Stephen D Silberstein, professor of neurology, director, Jefferson Headache Center at Thomas Jefferson University, Philadelphia, USA. This meeting will have 25 faculty across all core areas of neurology highlighting new data and sharing best practices in an interactive learning environment,” said Phil Talamo, president of PER.

The commissioner of the US Food and Drug Administration (FDA), Scott Gottlieb, has unexpectedly resigned after serving just shy of two years in the post.

Gottlieb announced his intention to stand down in a letter to Alex Azar II, the secretary of the Department of Health and Human Services, the FDA’s parent agency, on 5 March.

He took up the position in May 2017, and has presided over a number of important initiatives, including the development of the new 510(k) pathway for device clearances.

Scott Gottlieb

Calendar of events 19–21 May 7th World Intracranial Hemorrhage Conference Granada, Spain www.worldich.org/2019

22–24 May 5th European Stroke Organisation Conference Milan, Italy www.eso-conference.org

25–30 May INS: International Neuromodulation Society 14th World Congress Sydney, Australia

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

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

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

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

www.linnc.com

www.esmint-2019

www.1st-international-congress-on-

www.svin.org

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

19–22 September ESNR: European Society of Neuroradiology Annual Meeting Oslo, Norway www.esnr.org

the-future-of-neurology

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

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

www.slice-online.com

www.neuromodulation.com

September

Profile: Istvan Szikora

Issue 19

ious Brain Is consc safe?

Brainto sedation

NeuroNews is a trusted, independent source of news and opinion in the neurointerventional and neurosurgical world.

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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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