NeuroNews 32 January 2019

Jan

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19 32 Michael Chen:

Telemedicine in stroke

Todd Sitzman: Page 10

Profile

Page 19

Page 16

Going beyond DAWN and DEFUSE 3: New studies point to need for expanded selection criteria in real-world application A series of studies published in the Journal of NeuroInterventional Surgery is bringing attention to potential constraints in the practice-changing DAWN and DEFUSE 3 trials, when applied to a real-world population, in terms of patient selection, the representability of the 24-hour time window, and the lack of consideration for patients considered to be “slow progressors”.

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he findings of the DAWN and DEFUSE 3 trials have had a profound effect on the acute ischaemic stroke field; providing the basis for new American Heart Association/American Stroke Association guidelines; the UK now following suit, with NICE guidelines soon to extend the eligibility window for treatment of thrombectomy to up to 24 hours for selected acute ischaemic stroke (AIS) patients. “New evidence shows that extending the eligibility period of thrombectomy to up to 24 hours can be very cost-effective. There is also a potential benefit for improved quality of life by reducing the level of disability people can experience as a result of a stroke,” said Paul Chrisp, the director for the Centre for Guidelines at NICE. Now, two studies consecutively carried out by Shashvat M Desai, Ashutosh P Jadhav (senior author) and colleagues, University of Pittsburgh, Pittsburgh, USA, investigated endovascular thrombectomy (EVT) outside of DAWN and DEFUSE 3. The first study

looked at trial ineligible patients who presented in the six to 24-hour time window. The second identified patients who received thrombectomy beyond 24 hours, but otherwise met DAWN criteria.

In this initial trial, Jadhav and colleagues carried out a retrospective review of patients admitted for acute ischaemic stroke to a single comprehensive stroke centre during the DAWN trial enrolment period, identifying all patients presenting in the six to 24-hour time window, and subsequently investigated this sample for trial eligibility, baseline characteristics, treatment, and outcomes.

The team found that approximately 70% (n=142) of the 204 patients presenting six to 24 hours after time last known well (TLKW), with a National Institutes of Health Stroke Scale (NIHSS) score of ≥6 and AIS due to anterior circulation large vessel occlusion, were DAWN and/or DEFUSE 3 ineligible. Jadhav et al reported that previous exclusion from these trials occurred most commonly due to large infarct

Ashutosh P Jadhav

core (>70mL), pre-modified Rankin Scale (mRS) >2, absence of trial eligible salvageable issue, and/or middle cerebral artery occlusion (segment 2, M2).

In terms of treatment, 26% (n=37) of trial ineligible patients with large vessel occlusion strokes received off-label EVT and 30% of them achieved functional independence (mRS 0–2) at 90-days, with an acceptable safety profile. Additionally, rates of symptomatic intracranial haemorrhage and mortality were 8% and 24%, respectively.

Although the authors acknowledged that the current study was limited by its retrospective nature, small sample size and a clinical judgement-based patient selection process, they maintained that it suggests that further liberalisation of indications for EVT in late time windows is achievable.

Jadhav and colleagues were able to conclude that strict adherence to DAWN and DEFUSE 3 criteria would have denied EVT to 18% (n=37) of the 204 Continued on page 2

Study finds significant reduction in pain with high-frequency 10kHz peripheral nerve stimulation

A randomised controlled trial (RCT) of peripheral nerve stimulation (PNS) at 10kHz frequency demonstrates a significant reduction in pain scores for patients suffering from chronic pain. While the authors—Philip Finch and colleagues from Perth Pain Management Centre (Perth, Australia)—reported that the decrease in pain and disability after stimulator implantation were maintained in both groups at three to six months, they found that these decreases were greater in PNS implants as opposed to spinal cord stimulator implants.

These data were recently published in the journal Neuromodulation.

REGARDING THE CURRENT study, Finch and colleagues carried out an initial one-year clinical audit of patients undergoing permanent implantation of 10kHz frequency stimulators, for both spinal cord stimulation (SCS) for low back and lower limb pain, and for PNS for peripherally located chronic neuropathic pain. Following the positive results of this audit, the authors set

out to design a double-blind RCT inclusive of PNS patients of whom were already implanted with 10kHz devices (Nevro)—with the device switched either ON or OFF in a randomised fashion. The double-blind approach was possible because 10kHz stimulation cannot be felt.

Through both the clinical audit and the subsequent RCT, Finch and his

colleagues aimed to determine the effect of high-frequency stimulation on pain treated with a PNS system, including the time to commencement of analgesia once the device was switched ON, as well as time for pain to return once the device was switched OFF. Additionally, in the PNS group, sensory perception was examined for evidence of a sensory nerve conduction block appearing during

stimulation.

The clinical audit assessed pain, disability and medication status for 12 months after stimulator implantation in 58 SCS patients (mean age: 55.8±13.4, 59% male), and in 11 PNS patients (mean age: 59.4±17.1 years, 46% female), between January 2013 and February 2017. Specifically, the PNS Continued on page 19

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Acute ischaemic stroke

Going beyond DAWN and DEFUSE 3: New studies point to need for expanded selection criteria in real-world application Continued from page 1

patients who harbored an anterior circulation large vessel occlusion presenting to a comprehensive stroke centre within six to 24 hours of TLKW, and with an NIHSS score of ≥6.

Strict adherence to DAWN and DEFUSE 3 criteria would have denied EVT to 18% of the 204 patients who harbored an anterior circulation large vessel occlusion.

- Jadhav et al In their second investigation, the same authors acknowledged the proportion of patients in the DAWN trial with large vessel occlusion strokes who had “enough collateral support to sustain a penumbra and harbour small ischaemic core”—also known as “slow progressors”. In light of this, Jadhav and colleagues set out to examine patients who met the DAWN criteria but underwent thrombectomy beyond 24 hours of TLKW. Jadhav et al carried out a retrospective review of endovascular thrombectomy databases at three comprehensive stroke centres in order to compare baseline characteristics, efficacy, and safety outcomes with patients in the DAWN trial intervention arm.

Of the 21 patients that met inclusion criteria, rates of successful reperfusion (modified thrombolysis in cerebral infarction [mTICI] 2b–3, 81% vs. 84%, p=0.72), 90-day functional independence (mRS 0–2, 43% vs. 48%, p=0.68), as well as symptomatic intracranial haemorrhage (5% vs. 6%, p=0.87), were comparable across the two groups.

Despite its technical success, the study was again limited by its retrospective nature and small sample size. The authors also reported that a lower proportion of patients in the current case series had atrial fibrillation compared with patients in the DAWN trial intervention arm, which may have impacted the outcomes.

However, Jadhav and colleagues concluded that the findings of the study—“the largest case series for anterior circulation thrombectomy beyond 24 hours of

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In light of the good functional outcomes and acceptable safety parameters that were observed, the authors reported that their institutional experience of EVT performed more than 12 hours from onset is reflective of previous trials outlining the benefits of EVT in selected patients, despite using alternative neuroimaging techniques to inform patient selection.

Moving forward, Motyer and colleagues postulated that although EVT is rapidly establishing itself as best practice beyond conventional time limits, uncertainty still remains regarding the assessment of late presenting AIS patients—particularly the role of advanced neuroimaging in this context. In conclusion, Motyer and colleagues write: “It is essential that optimal neuroimaging and associated inclusion criteria be correctly defined so as to ensure maximum benefit and minimum harm to these patients”.

Furthermore, in accordance with Motyer and colleagues, Jadhav et al maintain that both multicentre analyses and randomised controlled trials are necessary to validate these late window findings, and to further define thresholds for EVT, in order to maximise indications and prevent long-term disability.

Additional interpretation

Commenting on these findings, Joseph Broderick (University of Cincinnati, Cincinnati, USA) told NeuroNews that they should be interpreted with caution, and not used to expand current practice.

“These smaller case series in later time windows and outside of the criteria for DAWN and DEFUSE 3 are intriguing and supportive of randomised trials of EVT for these subgroups (larger cores and longer time windows). Identifying more patients who can benefit from EVT is needed. However, these data should not be used to expand current clinical practice and indications for EVT since the true efficacy and safety in these patients as compared to best medical therapy has yet to be determined.”

These data should not be used to expand current clinical practice and indications for EVT since the true efficacy and safety in these patients as compared to best medical therapy has yet to be determined.

- Joseph Broderick

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last known well”—support the fact that EVT appears to be safe and feasible in patients with acute ischaemic stroke due to large vessel occlusion meeting all DAWN trial criteria but treated beyond 24 hours of TLKW. Furthermore, the authors stressed their support for directing patient selection on a tissue-based paradigm without any clear time cut-off.

A further study conducted by Ronan Motyer (Beaumont Hospital, Dublin, Ireland) and colleagues, who also advocate for a tissue-based approach to patient selection, investigated EVT in a late intervention cohort (beyond 12 hours of stroke onset).

Maintaining the likes of recent trials, the authors write: “both clinical and neuroimaging findings are considered a better determinant of individual pathophysiology than symptom duration alone”.

However, in contrast to DAWN and DEFUSE 3, Moyter and colleagues calculated the Alberta Stroke Program Early CT Score (ASPECTS) and collateral grade in order to guide their patient selection.

Motyer and colleagues carried out a retrospective review of all EVT cases performed at their affiliated institution for proximal anterior circulation acute ischaemic stroke with symptom onset over 12 hours.

Patients were assessed with non-contrast CT brain and multiphase CT angiography.

In total, of the 542 patients with AIS who underwent EVT from June 2010 to July 2017, only 4.6% (25 patients) were >12 hours from stroke onset. The median age of these patients was 69 years, with median NIHSS on presentation at 14, ranging from 5–26.

Additionally, median ASPECTS was 8 (IQR 8–9), while the rate of moderate-good collateral status was 96% (in 24 patients).

Furthermore, the authors reported that the rate of successful recanalisation (TICI 2b–3) was 88% in 22 patients. Additionally, in 13 patients, the rate of functional independence was 52%, demonstrated by a 90-day modified Rankin Scale score of 0–2.

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2019

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Stroke

Pooled analysis of EVT trials: Promising safety profiles continue alongside the late window paradox

Endovascular treatment (EVT) for acute ischaemic stroke patients with large vessel occlusion initiated beyond six hours from time last seen well is a highly effective therapy. This finding was maintained across all subgroups in the AURORA pooled analysis of endovascular stroke trials, including those defined by time, age, mode of presentation and Alberta stroke program early CT score (ASPECTS). The data were presented by Raul G Nogueira (Grady Memorial Hospital, Atlanta, USA) at the Stroke Live Course (SLICE; 1–3 October, Nice, France).

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ccording to Nogueira, the impact of time regarding the effectiveness of EVT has not been previously reported on, yet he emphasised the current findings indicate that “Time does not matter, as long as you have a mismatch.” In the current context, a mismatch is defined as a clinical deficit that is disproportionately severe relative to the infarct volume.

The idea of AURORA was to combine multiple late window trials into a pooled analysis. These include DAWN and DEFUSE 3 data, as well as the ESCAPE trial patient cohort (enrolled between six and 12 hours), and the REVASCAT patients (enrolled between six and eight hours). Nogueira reported that the baseline characteristics of the patients that fulfilled the criteria for the AURORA trial (EVT within the six to 24-hour window) were balanced between the thrombectomy cohort (n=241) and the control cohort (n=216) in terms of physiological characteristics, as well as ASPECTS scores and occlusion location. Only the National Institutes of Health Stroke Scale (NIHSS) scores were found to differ significantly at baseline, at 16.3±5.4 for the thrombectomy cohort and 17.4±5.9 for the controls. Importantly, Nogueria also noted that the majority of the patient population of AURORA had a strong mismatch.

Through comparing the safety profile of AURORA to an early window intervention trial such as HERMES (zero to six hour treatment window), Nogueira

acknowledged that the outcomes regarding rates of symptomatic intracranial haemorrhage were found to be very similar for the endovascular treatment groups in both trials (5% for AURORA and 4.4% for HERMES): “What this shows is that you can treat patients at the late window with similar safety as the early window as long as they have a mismatch.”

Furthermore, as the modified Rankin Scale (mRS) scores of 0–2 at 90-days were 47% for EVT compared with 17% for controls, Nogueira reported that the number needed to treat for a favourable outcome was only 3.3. Additionally, the utility-weighted mRS scores were 5.5±3.6 for EVT compared to 3.5±3.4 for controls, which Nogueira noted was “similar to the DAWN population, which is not surprising”.

A finding of particular interest, according to Nogueira, includes that time had little effect regarding the onset of randomisation for treated patients (odds ratio [OR] per 60 minutes: 0.98 [0.92, 1.05]; p=0.558).

In contrast, the controls tended to get worse over time (OR per 60 minutes: 0.83 [0.74, 0.94]; p=0.004).

Therefore, the treatment effect size is higher at the tail end; a finding that encompasses the late window paradox. “We do not know why this occurs, it could be due to the late benefit of some of the intravenous tPA patients, or maybe the late patients are more prone to collateral failure”, postulated Nogueira, “But this was seen in both DAWN and DEFUSE 3; and now again in the current pooled analysis.”

Moreover, he reported that no interaction was found between treatment and mortality rates; indicative of the fact that treatment is not more dangerous as time goes on. This lack of interaction was also observed between treatment and rates of symptomatic intracranial haemorrhage.

Nogueira noted that even with an extended treatment window, “time is still brain”, as he stated that the chances of having a clinical-core mismatch drops over time. Speaking to the SLiCE audience, he said: “The important question is: what is the proportion of patients that will qualify for treatment, that will have a mismatch?” In light of a recent statistic that suggested the use of EVT was likely to increase by roughly 40% following the results of DAWN and DEFUSE 3, Nogueira noted that it is imperative that one understands that regardless of the expanded time window, time is still very essential.

In conclusion, Nogueira said that endovascular treatment initiated beyond six hours from last seen well is a highly effective therapy and no less effective than treatment initiated within six hours (among patients with a core mismatch); a finding that was maintained across all subgroups. Furthermore, the safety profile is acceptable; no different than that observed with treatment administered within six hours.

Moving forward with the current findings, Nogueira stated: “It is time to analyse trial data, but incorporate physiology and clinical judgement.”

RACECAT trial: 715 patients enrolled, with interim analysis expected soon

The preliminary results of the RACECAT trial—a study comparing transfer of acute stroke patients with suspected large vessel occlusion (LVO) to the closest local stroke centre versus direct transfer to an endovascular stroke centre in the Catalan Territory—were presented at the Stroke Live Course (SLICE; 1–3 October, Nice, France) by Marc Ribo, University Hospital Vall d’Hebron, Barcelona, Spain.

CURRENTLY, THERE ARE 715 patients enrolled in the trial. By the time 701 patients have reached three months of enrolment, safety and efficacy interim analyses will take place—which Ribo predicted will be by the end of 2018.

The authors have collected population and demographic details of the patients, and know for each geographical area of Catalonia how many patients are included, screening failures, as well as how many should have been included but were not.

Ribo noted that the interim analysis will determine the future of the trial, explaining that if no significant difference between groups is observed, the probability of stopping the trial is 64%.

It was the approval of endovascular treatment for acute stroke that led Ribo and colleagues to conduct the RACECAT trial. Ribo noted that when a patient is suspected to suffer an acute stroke in the pre-hospital setting, there are no solid data to recommend transfer to the closest primary stroke centre (PSC) or to by-pass the PSC in order to reach a comprehensive stroke centre (CSC).

While the first option will prioritise

IV t-PA, the latter option will delay IV t-PA in order to advance eventual endovascular treatment. The RACECAT trial aims to generate evidence to answer this important question. If the results suggest that the patient’s outcome would be better if they lived closer to a stroke centre, Ribo claimed that new stroke centres may have to be built to accommodate this.

Secondary endpoints that are being examined include the safety and efficacy of the treatments—in terms of distance travelled and time from onset, in both ischaemic and haemorrhagic stroke.

Further, the percentage of patients receiving IV t-PA or endovascular treatment is being analysed.

Ribo noted that the investigators used the pre-hospital RACE scale (rapid arterial occlusion evaluation), in order for the paramedics to assess the stroke patients before they were admitted to hospital. Subsequent improvement or worsening of symptoms can be detected using this parameter; while allowing for a clear distribution of scores.

Ribo noted that if only patients with a

If no significant difference is observed, the probability of stopping the trial is 64%.

- Marc Ribo RACE score higher than 4 are selected, then 30% of this patient population will undergo endovascular treatment.

However, if better selection through a quick NIHSS (National Institutes of Health Stroke Scale) score on admission occurred, alongside verifying the Rankin score and performing a Dyna-CT— then 60% of the patients will end up benefitting from endovascular treatment.

Interim data for the RACECAT study was collected from the administrative and safety analysis—inclusive of 400 matched patients, with each group

exhibiting a median NIHSS score of 17 at the first hospital admission.

The distribution of diagnoses at hospital arrival included patients with a RACE score higher than 4. Ribo stated that the authors expected to see 43% of patients with a large vessel occlusion, while the actual figure that was found was 40.5%.

Ribo et al had estimated an overall endovascular treatment rate of 23.5%; group A (prioritising IV t-PA) was expected to have a 12% rate of endovascular treatment, and group B (prioritising endovascular treatment) was expected to have a rate of 35%. Ribo stated: “Although I do not have data about the findings [as] it is blinded; we think that this is a reasonable difference in terms of access to endovascular treatments […] when keeping in mind that we are talking about patients that are being transferred sometimes more than two hours to the comprehensive stroke centre.”

If only RACE scores of 9 were taken into consideration, Ribo said, around 60% of patients would have a large vessel occlusion. However, the authors also included patients with a RACE score of 5; a score presenting with a 31.5% rate of large vessel occlusion.

Through completion of the RACECAT study, important questions will be answered: where should these patients be primarily transferred, what is the safety of long pre-hospital transfers, and in which geographical areas should be considered for creating a new CSC.

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New devices

Favourable revascularisation rates for first-in-man results of the Versi retriever in acute ischaemic stroke

First-in-man results of the Versi retriever (NeuroVasc Technologies) in acute ischaemic stroke patients with large vessel occlusions demonstrate a promising safety profile and efficacious revascularisation rates. The study—recently published in the Journal of NeuroInterventional Surgery—was carried out by senior author Satoshi Tateshima, UCLA Medical Center, Los Angeles, USA, and colleagues.

TATESHIMA AND COLLEAGUES acknowledged that thrombectomy using existing stent retriever devices has been recognised as a first-line therapy for acute ischaemic stroke due to large vessel occlusions in the anterior circulation. However, they noted that in vitro studies (also authored by Tateshima) shed light on certain caveats of conventional stent retrievers.

According to the authors, tortuous anatomy can force them to collapse or become stretched—losing capture of the thrombus, while an acute angle in the internal carotid artery or the middle cerebral artery has been found to correlate with lower success rates in mechanical thrombectomy.

Given these findings, the authors aimed to report on the first-in-man experience with the Versi retriever in patients with acute ischaemic stroke. The stent of the Versi retriever is made of nitinol and possesses 2–4 staggered articulating segments, helping to prevent its collapse by facilitating opening instead of narrowing during retrieval.

The investigators carried out a single-centre, singlearm, first-in-man registry under institutional review board control. All patients with acute ischaemic stroke due to large vessel occlusion were consecutively enrolled between September and November 2017. The inclusion criteria required intravenous tPA to have been previously ineffective. The clinical and procedural data were retrospectively analysed, including: National Institutes of Health Stroke Scale (NIHSS) scores at both admission and discharge; modified Rankin Scale (mRS)

Versi retriever

The results from this first-in-man consecutive case series demonstrate the safety and efficacy of the Versi retriever.

prior to onset, at discharge and at 90 days, angiographic data and adverse events, with angiographic results after the procedure—self-graded based on the thrombolysis in cerebral infarction (TICI) scale by each operator.

In total, 11 patients with a mean age of 69.4 years were treated with the Versi retriever. The median NIHSS score on admission was 16 (IQR: 10–34), while the occluded vessel was located in the anterior circulation in 81.8% of patients. Revascularisation rates of TICI 2b–3 and TICI 3 at final angiogram were achieved in 100% and 63.6%, respectively. Additionally, a favourable functional outcome (modified Rankin Scale 0–2) at 90 days was obtained in 72.7%. Moreover, the authors reported that no symptomatic intracranial haemorrhage occurred and no procedure-related complication was observed.

Irrespective of these positive findings, Tateshima et al acknowledged a shortcoming of the study, in that it was a retrospectively reviewed single-centre case series with a small sample size. Given this, the authors noted that the results may not prove the clinical value of the unique design of the Versi stent.

Regardless, Tateshima and colleagues were able to conclude that the results from this first-in-man consecutive case series demonstrate the safety and efficacy of the Versi retriever in acute ischaemic stroke patients with large vessel occlusions. Yet, taking into the account its unproved clinical value, they acknowledged that further in vitro and large clinical studies are necessary in order to confirm the true performance of the device compared with the current existing stent retrievers.

Pivotal US LVIS trial demonstrates safe and effective coil embolisation for the treatment of wide-necked aneurysms

The final results of the pivotal US LVIS trial confirms that the LVIS stent system allows safe and highly effective coil embolisation of wide-necked aneurysms. The findings of what the authors refer to as the “third generation of aneurysm-bridging microstents,” have recently been published in the Journal of NeuroInterventional Surgery—with the study conducted by David Fiorella, State University of New York, USA, and colleagues, on behalf of the LVIS investigators.

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he LVIS devices (MicroVention) are self-expanding, retrievable, microstents indicated for the treatment of wide-necked aneurysms.

Previously, both prospective and retrospective studies have demonstrated

favourable safety and efficacious profiles.

Hence, Fiorella and colleagues aimed to conduct an investigational device exemption (IDE) study designed to determine the safety and effectiveness of the LVIS devicesupported coil embolisation of wide-necked aneurysms that were located either in the anterior or posterior intracranial circulations.

The data from this pivotal US LVIS study were used to support a US regulatory submission for premarket approval, thus, the primary purpose of the paper serves to summarise the safety and effectiveness of the LVIS devices.

The pivotal trial was a prospective, multicentre, single-arm interventional study that was conducted at 21 US centres. A total of 153 patients with wide-necked aneurysms of the anterior and posterior intracranial circulations were enrolled between July 2013 and October 2014. The primary effectiveness endpoint was successful aneurysm treatment with the LVIS system, defined as complete (100%) aneurysm

occlusion at 12 months on conventional angiography, without retreatment and without significant (≥50%) stenosis of the treated artery at 12 months—determined by an independent core laboratory. With regards to the safety profile, the primary safety endpoint was the rate of stroke or death within 30 days, or ipsilateral stroke or neurological death within 12 months.

According to the authors, the study was conducted under good clinical practices with independent adjudication of all adverse events that occurred.

Of the 153 patients enrolled, the mean age was 58.3±10.5 years—the majority of whom were female (71.9%) and had a history of hypertension. The authors noted that despite the frequency of previous neurological events, the average National Institutes of Health Stroke Scale (NIHSS) score at baseline was 0.6 (±2.6), and most participants (82.4%) had scores of zero.

In terms of aneurysm characteristics, the mean aneurysm dome height was 6±2.2mm

and the mean width was 5.5±2.3mm—with the mean neck width at 4.2±1.4mm. In total, 22 patients presented for retreatment of a previously ruptured aneurysm target aneurysm. The primary effectiveness endpoint was observed in 70.6% (108/153) in the intent to treat population. Of the patients that were eligible for follow-up 12-month angiography, 79.1% (110/139) demonstrated complete occlusion, with ≥95% occlusion observed in 92.1% (128/139) of this population. Regarding the safety profile, eight patients (5.2%) had at least one primary safety endpoint in the intent to treat population.

In light of these findings, Fiorella and colleagues noted that the pivotal US LVIS trial demonstrated that the LVIS devices—when used in conjunction with coils—for the treatment of wide-necked aneurysms can achieve both durable and adequate occlusion at one year in almost all patients (>95%).

“The braided structure allows for the device to be resheathed after deployment is initiated, and at the same time optimises vessel wall apposition in tortuous anatomy,” discussed the authors, stating that such properties are likely to account for the high levels of adequate or complete aneurysm occlusion observed in the present study. Finally, Fiorella and colleagues concluded that these data are concordant with other studies of the LVIS devices, and they maintained that this pivotal trial indicates that the LVIS devices are both safe and effective for the treatment of wide-necked aneurysms.

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New devices

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New Pipeline Flex embolisation device with shield technology demonstrates promising angiographic and safety outcomes at one year The first prospective, multicentre evaluation of the Pipeline embolisation device with shield technology for the treatment of intracranial aneurysms elicits a promising safety profile and efficacious angiographic outcomes. The current study was conducted by Mario Martínez-Galdámez, Hospital Universitario Fundación Jiménez Diaz (Madrid, Spain), and colleagues, with the data now published in the Journal of NeuroInterventional Surgery.

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he Pipeline embolisation device (PED; Medtronic) was the first neuroendovascular device used for flow diversion, and has since become a routine treatment option for intracranial aneurysms. While the safety and efficacy of the first-generation PED has been proved repeatedly, the recent modification of the Pipeline Flex embolisation device that incorporates shield technology had yet to be reported on.

The Pipeline Shield has the same design and configuration as its predecessor, but holds a surface modification where a synthetic phosphorylcholine biocompatible polymer is bonded to the strands that comprise the Pipeline braid, aiming to reduce thrombogenicity.

The authors acknowledged that previous in vitro studies have found the Pipeline Shield to be less thrombogenic that other flow diverters. Thereafter, through investigating the periprocedural outcomes and early safety results of

using the Pipeline Shield in the treatment of unruptured intracranial aneurysms, Martínez-Galdámez and colleagues found that the device demonstrated high technical success, while no major shortterm complications within 30 days of the procedure occurred. In light of this, the authors aimed to report on the long-term safety and efficacy with the Pipeline Shield at one-year follow-up.

Martínez-Galdámez and colleagues carried out a prospective, multicentre, single-arm study for the treatment of unruptured intracranial aneurysms using Pipeline Shield. In total, 50 patients (mean age, 53 years; 82% female) with 50 target aneurysms were enrolled between March and October 2015, and treated at seven neurovascular centres in six European countries.

The primary endpoint was a major stroke in the territory supplied by the treated artery, or neurological death at one-year post-procedure. The secondary endpoint was the rate device-related neurologic adverse events within one-

year of the procedure. Additionally, angiographic outcomes were assessed by an independent radiology laboratory at six-months and one-year; subsequently analysed by an independent core radiology laboratory.

Regarding the 50 target aneurysms, the mean diameter was 8.82±6.15mm, while 38/50 (76%) were small (<10mm), 11/50 (22%) were large (≥10 and<25mm), and 1/50 (2%) was giant (≥25mm). Forty-seven (94%) were located in the internal carotid artery and three (6%) in the vertebral artery.

In relation to the primary endpoint, no major strokes or neurologic deaths were reported at one-year following the procedure, while complete occlusion was achieved in 27/33 (81.8%). The authors also reported no instances of aneurysm recurrence or retreatment.

However, Martínez-Galdámez and colleagues acknowledged that there were a total of seven device-related neurologic adverse events: six cases of in-stent stenosis which were non-serious, and one case of internal carotid artery thrombosis which was a serious adverse event.

Despite this, the authors write that the Pipeline Shield may have a “more benign” pattern of significant in-stent stenosis compared to the previous generation of the device, given the

finding that only 9.4% of the cases with angiographic data were reported to have >25–50% in-stent stenosis in the current study.

Yet, in terms of the study’s shortcomings, the authors reported missing angiographic data on several patients, and acknowledged that this may have led to a misrepresentation of occlusion rates observed at one-year.

Further, the target aneurysms in the current study were small in size, which may have additionally biased the safety outcomes.

Nonetheless, Martínez-Galdámez and colleagues noted that the current study is the first prospective study to evaluate the use of the Pipeline Shield device.

They concluded that as observed rates of aneurysm occlusion and in-stent stenosis in the current study were comparable to previously published results with the earlier generation devices, the Pipeline Shield device is safe and effective for the treatment of intracranial aneurysms.

Of note, they also reported that there were no cases without antiagregation in the current cohort, and each institution applied their daily basis antiplatelet protocol. Thus, in concordance with the results of this clinical study, MartínezGaldámez and colleagues accentuated the fact that standard antiplatelet regimens should still be recommended.

New flow direction endoluminal device found to exhibit an “excellent safety profile” and efficacious occlusion rates New data confirm the safety and efficacy of the flow directional endoluminal device (FRED; MicroVention), given its high rate of complete aneurysm occlusion and low rate of retreatment at one-year. The SAFE study (Safety and efficacy of FRED embolic device in aneurysm treatment) was carried out by Laurent Pierot (Hôpital Maison-Blanche, Reims, France) and colleagues, and has been recently published in the Journal of NeuroInterventional Surgery.

THE MAIN FINDINGS of this single-arm, multicentre, prospective, good clinical practice study, include the impressive safety profile of the device, given that the oneyear morbidity rate was 2.9%, with mortality at 1.9%.

Further, a high degree of efficacy was observed in relation to the device, with six-month and one-year complete occlusion in 61.1% and 73.3%, respectively, and a low retreatment rate at one year: 2.2% The FRED embolic device is a double-layer flow diverter with a stent-like outer layer and a flow diverter part inside the stent. The authors note that the specific design of the FRED embolic device enhances its navigability; an advantageous element in terms of tortuous anatomy.

In total, 103 patients (85.5% female, mean age: 52.4±11 years) with unruptured and recanalised aneurysms located in the anterior circulation treated with FRED and FRED Jr were prospectively included. The trial was carried out at 13 interventional neuroradiology centres in France. Patients were excluded if they had an intracranial haemorrhage within 30 days of the procedure, or had already had an aneurysm treated, located on the same vessel, or if the aneurysm was located in the posterior circulation. A Clinical Event Committee and Core Laboratory independently evaluated clinical outcome and anatomical results.

While previous systematic evaluations exclusively covered internal carotid artery (ICA) aneurysms, the authors note that the SAFE study is more comprehensive. Aneurysm locations in the SAFE study included: supraclinoid internal artery in 71 (68.9%), cavernous ICA in 15 (14.6%), anterior cerebral or anterior communicating artery in nine (8.7%), and middle cerebral artery in eight (7.8%). Additionally, most aneurysms were small (<10mm) in 71 patients (68.9%). Specific anatomical results include complete occlusion in 66/90 patients (73.3%), neck remnant in 7/90 patients (7.8%), and aneurysm remnant in 17/90 patients (18.9%).

Pierot et al acknowledge that the study has some limitations. First, SAFE is not a randomised trial and safety and efficacy cannot be directly compared with a control group. Second, most aneurysms were small,

which is not the typical indication for flow diversion.

In 71 patients (68.9%), the aneurysms were less than 10mm wide. However, the authors believe it was “reasonably pragmatic to evaluate the FRED device in real-life practice.”

Pierot and colleagues recognise that the problem of safety is a “potentially limiting factor” in the use of flow diversion and attribute the high safety observed SAFE to the following factors: the design of the study, patient selection, and the fact that the study was carried out in centres experienced with flow diversion.

In conclusion, the authors write that one-year clinical data analysis in the SAFE study confirms the high degree of safety of the FRED device. Furthermore, anatomical results demonstrate a high rate of complete occlusion at six months, of which the authors note, “is still increasing at one year.”

Anatomical results demonstrate a high rate of complete occlusion at six months, of which the authors note is still increasing at one-year.

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Stroke interventions

ADVERTORIAL

From a primary to a comprehensive stroke centre: Steps to success at St. Mary’s Medical Center and the Palm Beach Children’s Hospital In 2008, St. Mary’s Medical Center and the Palm Beach Children’s Hospital in West Palm Beach, Florida USA, initiated an ambitious transition from a primary to a comprehensive stroke centre, sparked by their insight into the undeniably increasing incidence of stroke based on changing demographics, and their understanding that: “If treatment is started in time, stroke does not have to lead to a poor prognosis.”

THE HOSPITAL BEGAN by purchasing their first biplane system;1 the first edition to their array of stateof-the-art GE Healthcare equipment that remains the workhorse. Following this, Ali Malek, M.D., a boardcertified neuro-interventionalist, was brought in as medical director to help lead the program; his medical expertise and extensive training aiding the teams’ development and dedication to prioritising stroke care.

All in all, St. Mary’s Medical Center and the Palm Beach Children’s Hospital noted that very few new hires were necessary. Instead, an on-going education process was implemented, with nurses, respiratory therapists, emergency services personnel educated through lectures, observation and hands-on training.

Additionally, GE helped train staff on the use of new equipment, while Dr. Malek trained them on protocols and procedures.

Strict stroke protocols and care pathways were implemented, following an “If X, then Y” standardised structure. Stroke treatment requires a consistent, accurate and precise process to do the best for the patient. The hospital also acknowledged that response time is crucial for stroke, and each of these departments needs to have staff trained in stroke care, so when a “stroke alert” is called, the staff are ready to handle it accordingly.

The technology used from the initiation of the program remains an important factor to its success, with the major equipment purchased to support the program coming from GE Healthcare. “We purchased two biplane machines,1 along with CT and MRI products from GE,” said Dr. Malek. In addition to this, AngioViz2—an application designed to help physicians visualise characteristics related to blood flow, displays the result of increased perfusion pre- and posttreatment. Dr. Malek uses AngioViz on every stroke case, stating that: “AngioViz caters to the sensitivity of the human eye allowing us to see subtle defects in perfusion even after an embolectomy, which helps

guide us to know when to stop.”

However, with some of the major advances that coincide with a comprehensive stroke program, new obstacles need to be overcome to ensure that new therapies are consistently translated into clinical practice. Close collaboration alongside a shared protocol should replace the previously fragmented approach to ensure best practice.

In order to execute this, the physicians at St. Mary’s Medical Center and the Palm Beach Children’s Hospital reached out to local emergency medical services (EMS) providers to include them as part of their stroke team. For example, the first responders are continuously brought in to observe the beneficial nature and notable difference that the comprehensive stroke program provides; both within the walls of the hospital and throughout the community that the hospital serves.

Therefore, St. Mary’s Medical Center and the Palm Beach Children’s Hospital also acknowledged that when setting up a comprehensive stroke centre, communication with the surrounding community should not be undervalued, with the assumption that an informed public will know the signs of stroke and call for emergency services quickly. Moreover, the surrounding hospitals need to establish a relationship of trust for the best patient outcomes, irrespective of the fact that they are essentially competitors.

The factors described above essentially consist of the four “steps to success” implemented by St. Mary’s Medical Center and the Palm Beach Children’s Hospital: people, processes, technology and EMS communication. Yet, whether this transition from a primary to a comprehensive stroke centre may be an end in itself or pave the way for an even brighter future for stroke patients; the stroke team must remain aware of the new equipment, processes, procedures and research in order to provide the best care possible.

Nonetheless, Dr. Malek and the stroke team are

striving to improve: “Our goal was that 100% of all patients that are eligible for tPA, get tPA, and 100% of all patients that are eligible for intervention, get intervention. That is what we have now, 100%,” stated Dr. Malek.

St. Mary’s Medical Dr. Ali Malek Center and the Palm Beach Children’s Hospital currently maintains a stroke database and works with The Joint Commission to ensure the hospital adheres to the American Stroke Association’s “Get With The Guidelines” parameters.

The team also holds weekly meetings, where specific stroke cases are discussed, while a monthly CME (Continuing Medical Education) meeting is held for the entire hospital. In terms of the wider community, lectures and screening events are held regarding how to recognise the signs of stroke and when to call 911.

Thus, having a comprehensive stroke centre with an extensive level of treatment present in the community offers immeasurable benefits to everyone living there.

In addition, the benefits of the same transition are evident to the hospital itself, as expanded services provide additional traffic. In the case of St. Mary’s Medical Center and the Palm Beach Children’s Hospital, the institution expanded the entire service line for neurology, offering paediatric neurology and epilepsy treatment—resulting in the development of the Palm Beach Neuroscience Institute.

1. Biplane system here refers to Innova 3131-IQ upgraded to be equivalent to Innova IGS 630 2. Statements reflect users opinion. AngioViz is an option that requires AWworkstation

Combining contact aspiration and stent retriever techniques for treating large vessel occlusion stroke: The ASTER2 trial Last year saw the first ASTER trial confirm no difference between ADAPT (a direct aspiration first pass technique) and stent retriever as frontline mechanical thrombectomy strategies in the treatment of large vessel occlusion stroke. However, at the European Society of Minimally Invasive Neurological Therapy (ESMINT; 6–8 September, Nice, France), Bertrand Lapergue, French National Institute of Health and Medical Research (Paris, France), presented the beginnings of ASTER2, a trial combining stent-aspiration techniques. Here, he talks to NeuroNews about the trial so far, and states that the final results will be presented at the International Stroke Conference later this year.

What was the rationale behind the ASTER2 trial?

Revascularisation is a major issue given that disability after acute ischaemic stroke (AIS) is strongly correlated with recanalisation grades and time. The European and American recommendations

propose that clinical trials should be conducted to determine the best thrombectomy device to increase the rate of successful recanalisation.

In the ASTER randomised controlled trial (RCT), which aimed to compare the use of contact aspiration (CA) versus

stent retriever (SR) techniques as first-line endovascular treatments, no difference was observed in successful reperfusion rate (CA, 85.4% vs. 83.1% for SR). The concomitant use of the CA technique during SR mechanical thrombectomy has been described in some retrospective case series. The advantages of the combined stent-aspiration technique include the potential synergistic effect of the technique when used simultaneously, as well as the use of a flexible large-bore catheter in a triaxial system—which provides stability for the stent-retriever. Clinical experience has shown that the combination of contact aspiration, and stent retriever techniques provides rapid, effective, and safe recanalisation. The potential synergistic

effect of CA and SR devices in first-line endovascular treatment remains to be evaluated in an RCT, as does the potential cost effectiveness of this strategy.

Why did you want to investigate the combined therapy approach?

The ASTER2 trial aims to provide further evidence of the benefit of synergistic effect of CA and SR devices among patients with ischaemic stroke secondary to large vessel occlusion of the anterior circulation.

This prospective trial will be the first RCT with a PROBE design, intended to compare combined CA and SR in first-line strategy with the standard firstline SR strategy on perfect reperfusion

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Recommendations

9

New international recommendations provide the minimum requirements for ischaemic stroke interventions

Following the outcomes of five randomised controlled trials demonstrating the benefit of mechanical thrombectomy in the management of acute ischaemic stroke (AIS) with emergent large vessel occlusion (ELVO), a multisociety meeting was implemented, dedicated to the training of physicians performing AIS intervention. The recommendations that arose from the meeting—the World Federation of Interventional and Therapeutic Neuroradiology Congress—were subsequently published in multiple scientific journals.

A

recent paper published in the Journal of NeuroInterventional Surgery—written by Laurent Pierot, Université Reims-ChampagneArdenne, Reims, France, and a multitude of colleagues representing neuroradiological and stroke societies worldwide—provides recommendations that outline the minimum requirements to provide an AIS intervention.

Pierot and colleagues write that the following recommendations are based on expert opinion and best available evidence, in relation to the optimal conditions for the safe practice of AIS intervention. Furthermore, they noted that only by ensuring that patients are treated in a centre capable of handling the procedural technicalities as well as the management of the patient prior to, during, and following thrombectomy, can the chance of replicating the results of major randomised trials be accomplished.

Pierot and colleagues acknowledged the benefits—in terms of lower mortality rates—of thrombectomy performed in a high-volume as opposed to a low-volume centre. According to the recommendations, the global consensus group advocate for a minimum of 50 intracranial thrombectomy procedures for ELVO per year, as well a minimum of 120 neuroendovascular procedures, whether diagnostic or interventional, per year, for each level 2 centre. Additionally, each individual neurointerventionalist should perform at least 15 acute intracranial procedures and 50 neuroendovascular procedures a year. However, the authors noted that these thresholds should be considered as the minimum caseload, as the recommendations are international and

therefore have to be compatible with the development of new activity in this area. They write: “With the increased implementation of AIS intervention in the world, it may be desirable to revise these thresholds in the future.”

With regards to medical personnel, the authors emphasised that outstanding stroke care can only be accomplished alongside a successful multidisciplinary team, with a minimum of three clinicians with training and qualifications in acute ischaemic stroke interventions.

Moreover, a 24/7 in-hospital anaesthesia team with experience in caring for patients undergoing AIS intervention should be present, while further occupational therapy service should be available for rehabilitation.

Furthermore, to ensure that quality improvement processes are optimal, Pierot and colleagues recommended that all technical and clinical data of AIS intervention procedures, including patient outcomes and follow-up, must be entered into an electronic database. At a minimum, process metrics such as time from arrival to intravenous tPA, to the start of angiography, and to the beginning of recanalisation, as well as overall recanalisation rates, should be reviewed and subsequently compared against published benchmarks. Additionally, the authors proposed that standardised care pathways should be implemented with clinical practice guidelines to ensure consistent care delivery, while the centre should provide continuing education related to cerebrovascular disease and stroke for all core members of the centre.

The authors acknowledged that the practice of AIS intervention should ideally take place in a level 1 centre— an institution that routinely provides

rate; the trial’s primary outcome. We hypothesised that first-line combined CA and SR strategy would increase successful thrombolysis in cerebral infarction (TICI) grade 2c/3 recanalisation rate. Perfect reperfusion defined as modified thrombolysis in cerebral infarction (mTICI) 2c/3 at the end of the endovascular procedure was chosen as the primary outcome because it is a strong early indicator of treatment success and has been correlated with good clinical outcome with lower disability than patients with mTICI 2b. Thus, achieving mTICI 2c/3 reperfusion is the interventionalist’s goal in endovascular stroke treatment.

remains low (below 50%) whatever SR or CA used first.

Growing evidence showed that the rate of TICI 2c/3 or the rate of first pass effect strongly impact the clinical outcome.

The choice of the first-line endovascular procedure is a critical issue given that the number of passes is correlated with higher per procedure complications and lower favourable outcome. If our trial is positive, we will have strong evidence to support the use of combined SR+CA strategies to obtain the best rate of recanalisation.

What are the clinical implications if the combined CA+SR is found to be superior?

Whatever the first-line strategy chosen by the interventionalists, the rate of TICI 2c/3

What are the next steps moving forward?

Our goal is to obtain a perfect recanalisation after the endovascular therapy. Concerning the best endovascular strategy, two major issues remain to be investigated: the impact of the balloon guide catheter and the combined/adjuvant pharmacological therapy.

services for neurological disorders and neurointerventional treatments to patients with different neurovascular disorders. However, if a level 1 centre is regionally unavailable, a centre treating only ischaemic stroke (level 2) can be established if the following conditions apply: no level 1 centre is available within two hours of interfacility transport time; the level 2 centre must care for at least 100 AIS treatments per year (including intravenous thrombolysis) and have an incorporated stroke centre or unit with trained stroke physicians. Additionally, the authors recommended that the level 2 centre should be organised in a cooperative and collaborative manner alongside a level 1 centre.

That being said, Pierot and colleagues write that for level 2 centres that were established under the aforementioned conditions, the practice should adhere to a particular standard in terms of the facilities and treatment available, as well as procedural volume, quality improvement processes including the medical personnel, and community outreach involving the emergency medical services.

In relation to facilities, the authors recommended that stroke unit beds, an intensive care unit, a neuroradiology services with a suitable angiography room, as well as a team of acute stroke neurointerventionalists, a dedicated stroke team and a neurosurgery department—ideally in-house or in a nearby hospital—should all be available on site. Additionally, a suitable interventional angiographic suite allows for the ability to routinely accommodate general anaesthesia, while the authors also write that “at a minimum, each

suite should include a single plane high resolution digital subtraction angiography unit with road mapping capabilities.”

Lastly, the authors noted the importance of the collaboration between level 2 centres and local emergency medical services (EMS) in order to coordinate prehospital care; “Outstanding stroke care starts not in the hospital but in the field”, write Pierot and colleagues.

Of importance, if patients present to a level 3 centre due to proximity, the level 2 centre should assist in the identification of the suspected or confirmed ELVO patients and should work alongside EMS to facilitate rapid transfer to a level 2 (or level 1, if available) centre. Therefore, it was recommended that representatives of the centre should work with local and regional EMS to ensure they are aware of the system’s capabilities, while feedback to the EMS was also advocated for, in view to identifying which aspects of care need improving upon.

Although the prevalence of stroke is increasing alongside changing demographics, the authors referred to the fact that a series of randomised trials published in 2015 initiated a “major revolution in acute stroke intervention.”

Thus, with such profound benefits of rapid mechanical thrombectomy observed, Pierot and colleagues documented the list of aforementioned recommendations. They maintained that: “In order to replicate the dramatic results of the major randomised trials, we must ensure patients throughout the world are treated in a centre with the capabilities necessary to handle not just the procedural aspects, but also the medical management of the patient prior to, during, and post-thrombectomy.”

Inclusion and exclusion criteria Inclusion

Exclusion

• Age 18 and older • Clinical diagnosis of AIS in the anterior circulation • Neuroimaging demonstrates large vessel proximal occlusion (distal ICA through MCA bifurcation, M1 or M2) • With or without IV thrombolysis • Groin puncture carried out within 8 hours of first symptoms • Consenting requirements met according to French laws

• Acute ischemic stroke involving posterior circulation (vertebrobasilar occlusion) • Known or suspected pre-existing (chronic) large vessel occlusion in the symptomatic territory • Angiographic evidence of carotid dissection or tandem cervical occlusion or stenosis requiring treatment • Allergy to radiographic contrast agents.

• Disability prior to the stroke (mRS >3) • Pregnant or breastfeeding women • Severe or fatal comorbidities that will likely prevent improvement or follow-up or that will render the procedure unlikely to benefit the patient • Under legal protection • No affiliation to a social security scheme • Opposition of the patient or their family

Abbreviations: ICA=internal carotid artery, IV=intravenous; MCA=middle cerebral artery; mRS=modified Rankin scale.

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Innovation

The evolving role of telemedicine in acute stroke treatment Michael Chen Comment & Analysis Amid the current modernisation of ischaemic stroke treatment, Michael Chen discusses how telemedicine not only has tremendous value, but should become a more standard part of any future stroke network.

M

odern treatment of acute ischaemic stroke is characterised by a number of unique access challenges. The initial diagnosis is primarily based on clearly visible clinical findings that rely on a specialist who understands how to administer and interpret the neurologic exam. Current treatments including pharmacologic or mechanical thrombolysis are not only proven, but time sensitive. However, the specialists who can provide accurate diagnoses as well as the therapies are limited. In fact, there are thought to be just over

1,100 neurologists who specialise in stroke in the USA, while half of the hospitals have no neurologists on staff.

Only 55% of Americans live within 60 miles of a primary stroke centre. As a result, the diagnosis and management of a patient with an acute ischaemic stroke is often led by the local emergency room physician. Furthermore, access for patients with large vessel occlusions to thrombectomy is limited because of the entrenched design of stroke care over the last 20 years being focused exclusively on delivering intravenous lytics. The accreditation priorities of the 1,100 primary stroke centres in the USAâ&#x20AC;&#x201D;with only 10% of them being able to delivery thrombectomyâ&#x20AC;&#x201D;have focused exclusively on shortening door to needle times, with the early and accurate diagnosis of a large vessel occlusion (LVO) often considered an afterthought.

One classic example of how complicated the access challenges to appropriate stroke care are is in the determination of a patient with a LVO at the spoke hospital; what may seem intuitive is challenging to implement.

Non-neurological physicians may have difficulty reliably discerning cortical symptoms such as aphasia and neglect. Using National Institutes of Health Stroke Scale (NIHSS) cut-offs may not be reliable when the person administering the NIHSS does not regularly perform the exam. Erring on the side of taking any patient with the suspicion of a large vessel occlusion, over time, may incur certain costs that may be hidden, but remain significant.

In particular, if the patient does not have an actual large vessel occlusion, then unnecessary transfers would lead to wasted transportation costs, sometimes including the use of a helicopter, as well as family transportations costs and opportunity costs for future patients with higher acuity.

With these concerns in mind, it becomes increasingly obvious why telestroke not only has tremendous value, but should become a more standard part of any future stroke network. At its essence, it allows a specialist, who understands not only how to perform, but also interpret a neurologic exam, to make the clinical diagnosis of a stroke and determine if

There are thought to be just over 1,100 neurologists who specialise in stroke in the USA, while half of the hospitals have no neurologists on staff.

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Innovation

11

Aneurysm coiling is the main endovascular approach for managing intracranial aneurysms A panel report (January–June 2018) from the BIBA MedTech Neurovascular Monitor indicates that aneurysm coiling is the predominant endovascular approach for managing intracranial aneurysms in Western Europe. The monitor surveys physicians from five countries in Western Europe (France, Germany, Italy, Spain, and the UK) and found that 12,200 (73%) of 16,764 endovascular procedures performed for the management of intracranial aneurysms were with aneurysm coiling. Use

of an intrasaccular device was the least used endovascular approach: 760 (5%) of 16,764. See Figure 1.

However, of all cases of intracranial aneurysms in Western Europe between January and June 2018, only 20% were with an endovascular approach (16,764 of 82,698 overall). Conservative therapy was actually the most common approach (61,992; 75%) and surgery was the least common (3,942; 5%).

Researchers look at developing a minimally invasive device for recording neurons

Mehdi Kiani and Susan Trolier-McKinstry (both Penn State University, State College, USA) are working on a two-year project to develop a minimally invasive device for recording and modulating neurons. According to a report in Penn State News, the device will be designed to be a fully wireless implant that rests on the surface of the brain (instead in the tissue) and ultrasonically stimulates regions of the brain via an external wearable unit.

The report states that the proposed “short-term” applications of the device include being able to study the brain of animals who are genetically similar to humans (such as rodents) with greater accuracy to better understand them and, by extension, understand human brains better. However, in the longer-term, the plan is for the device to be used for deep brain stimulation for neurological conditions such a Parkinson’s disease, dystonia and even obsessive compulsive disorder.

BIBA Briefings

Source: BIBA MedTech Neurovascular Monitor Panel Report Q1–Q2 2018

there are cortical signs to suggest a large vessel occlusion. This is much more powerful than a NIHSS threshold which has its inherent imperfections and is administered by someone not familiar with it. Telemedicine has the potential to reduce unnecessary transfers, and gives confidence to the spoke hospital to admit the patient for further management. It might also be an opportunity, particularly if a LVO is suspected and transfer is planned, to obtain informed consent ahead of time, which is preferable that obtaining consent over the phone.

Busy stroke centres can now have up to 15 telestroke hospitals in their network, seeing over 100 consultations per month. The large majority of these consultations lead to the patient remaining at the spoke hospitals, and the rates of alteplase treatment are closer to where they should be. The best long-term value that telestroke creates is responsive, improved diagnostic accuracy in helping spoke hospitals manage their patients, while maintaining

a relationship whereby patients who might benefit from thrombectomy can have rapid access to higher levels of care.

There are still significant challenges in the implementation of any telestroke network, and significant resources and time are certainly needed to build it. There are potentially medicolegal ambiguity and financial sustainability concerns—particular in lower volume spoke hospitals—as well as adequate technological infrastructure concerns including support when there are technical difficulties as well as issues of reimbursement to those who are available 24/7 to answer the calls.

Multiple technologies that are currently being evaluated range from mobile stroke units and artificial intelligence, to interpret imaging studies and helmet devices; aiming to provide information similar to what the portable electrocardiogram provides, all to frontload the ability to determine stroke severity. Since such an essential component of the diagnosis of an acute

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

The aim of each report is to give an overview of the key information affecting the medical device industry, enabling those working in the industry to keep abreast of the latest developments and make knowledgeable decisions.

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

ischaemic stroke lies in the clinical exam, the live video that is the basis for telestroke will likely remain an essential component of future stroke networks.

Michael Chen is an associate professor in the department of Neurological Surgery at Rush University Medical, Chicago, USA

Telestroke not only has tremendous value, but should become a more standard part of any future stroke network.

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Stroke certification

The current state of ESO Stroke Unit and ESO Stroke Centre certification and future directions

members of the SU-Committee. There may be national differences, for example concerning outpatient clinics, and in such cases, the national auditor should give explanatory information in the report to the ESO head office.

Following the introduction of possible ESO certification 1.5 years ago, the first hospitals in Europe were ESO certified for high-quality stroke care: First certified ESO Stroke Units (SU) and Stroke Centres (SC) in Europe

Ulrike Waje-Andreassen Comment & Analysis Based on a presentation by Stefan Engelter (Universitätsspital Basel, Switzerland) at the European Society of Minimally Invasive Neurological Therapy (ESMINT; 6–8 September, Nice, France) Congress, Ulrike Waje-Andreassen, who has chaired the European Stroke Unit Committee since 2016, discusses the current state of institutional stroke care, the development of the national certification process, and the committee’s aims for the future.

E

fficient organisation of hospital care is one of the cornerstones of stroke treatment. Treatment in stroke units has been shown to be very effective in reducing death and disability; demonstrated by both systematic reviews across randomised controlled trials and observational, “real life” studies.1,2 More importantly, as the beneficial effect was shown before intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) became acute key treatment elements, treatment in stroke units is effective per se; independent of IVT or EVT. Moreover, it is applicable to all stroke patents, irrespective of the type of stroke, its severity, the patients age, or the use of acute revascularisation therapy.

Nevertheless, a survey in 2005—inclusive of 886 randomly selected hospitals in 25 European countries— showed that 51% of hospitals provided stroke care below a minimum level.3 In light of this, the European Stroke Organisation (ESO) executive committee provided a mandate in 2007 for developing stroke unit certification, leading to the first ESO recommendations on how to establish a stroke unit (SU) and a stroke centre (SC).4 These recommendations were transformed to ESO SU and SC application forms, published in May at the ESO conference 2016 in Barcelona. Online application at this certification platform has since been possible.

ESO SU and ESO SC are now two well-defined levels of institutional stroke care. The SC is a fully equipped institution providing the same service as a SU, and in addition offering thrombectomy and other neuroradiological and surgical interventions at given frequencies. Seven main criteria are addressed for SU and SC care, concerning: lead, personnel, general infrastructure, investigations, interventions and monitoring, teaching, meetings and research, as well as numbers and quality indicators. In total, these main criteria contain 44 benchmarks for a stroke unit and 49 for a stroke centre. Application forms together with guidelines for pre-work have been published by ESO.5 The most decisive criteria are defined as must criteria that have to be fulfilled. Additional criteria are rated and graded from zero to three points: zero points indicating that the item is not present at all; one point meaning that there is some fulfilment; two indicating that there are still some deficiencies, while three points indicates complete fulfilment of the requested documentation. The sum of all points provides a rating in adherence with the optimal standard that will be set by members of the Stroke Unit Committee.

There may be hospitals with neuroradiology, endovascular intervention, vessel surgery, neurosurgery within their own walls and may in many ways qualify for an ESO SC, but when actual hospital statistics do not meet the minimal volume criteria that are must criteria for an ESO SC, then these hospitals will be certified as ESO

SU. There may also be hospitals that would qualify for an ESO SC according to possibilities of a broad spectre of diagnostics and intervention.

However, there seems to be a clear discrepancy between the number of patients and the number of doctors, nurses and other stroke team personnel, which can inhibit their ability to follow patient’s day by day and provide outpatient clinic follow-up at three-months for continuous registration of clinical outcome, it would also lead to certification as ESO SU. Further building of the stroke team is needed in order to provide the high quality that is expected for an ESO SC. The paradox is that there are often dedicated colleagues at these sites, who have had little support by their national health authorities.

Working with patients with acute stroke needs maintenance, including updated research and knowledge, alongside the associated skills among experienced and regularly trained staff, in order to provide continuous high quality stroke care. Therefore, re-certification is mandatory, and has arbitrarily been chosen to be done every fifth year. Certified ESO SU and SC will get a reminder from the ESO head office, when time for re-certification is approaching, and we expect that some of the primarily certified ESO SU will be re-certified as ESO SC. Many hospitals and nations now focus on acute intervention during the first hours after stroke onset.

Though this part of stroke care is addressed in the certification process, ESO application addresses the entire chain of stroke care, from acute management to rehabilitation and re-stroke prevention strategies.

In addition, stroke unit care undeniably requires a multidisciplinary team, where maintenance of knowledge and skills is necessary for all members in the stroke team.

High quality stroke care means good collaboration within the stroke team, other departments and other colleagues in clinical and rehabilitation medicine for treatment and follow-up of physical-, cognitive-, language-speech- and swallowing functions and of anxiety and depression.

For nations without national certification processes, national auditing performed by an ESO commissioned auditor is the first step towards certification.

Collaboration between the applying hospital and the national auditor is required, and remains a necessary stimulation process in order to create better understanding and working for increased quality in national stroke care.

National auditors cannot audit their own hospital, but they are supposed to understand and help the applicant present their hospital by providing important core information.

Auditors should be members of the ESO with good clinical knowledge and access to all links in the chain of stroke care as active clinicians and preferably also with experience in research. Only approval of the application form by the national auditor enables auditing by the

Name of the hospital

SU/ SC

City

Country

Metropolitan Hospital

SU

Pireus

Greece

Centro Hospitalar de Vila Nova de Gaia

SC

Espinho

Portugal

AZ Sint-Jan Brugge-Oostende AV

SU

Brugge

Belgium

Europe Hospitals

SU

Brussels

Belgium

Mater University Hospital

SU

Dublin

Ireland

Erasmus MC University Medical Center

SC

Rotterdam

The Netherlands

University Hospital St Luc

SU

Brussels

Belgium

University Hospital

SC

Basel

Switzerland

ESO stroke unit and stroke centre certifications are not meant as substitutes for well-established national certification work; national certification work is highly appreciated. Early support by national health authorities has contributed for some nations to a great extent to establish national certification programmes already years and decades ago. The national certification programmes of Germany, Switzerland and the Czech Republic have been the first ones that have been endorsed by the ESO. Endorsement criteria were continuously running national certification programs for at least five years, fulfilling ESO’s SU and SC certification criteria, as well as on-site visits and re-certification for any certified hospital. The ESO’s certification system will provide a lean—webbased—auditing tool for ESO certification interested hospitals from these countries.

The Stroke Unit Committee are very happy that other nations, with support of their governments, are following the important and necessary work regarding the development of national certification processes, adapted to those in the ESO with the aim to improve national stroke care.

The Stroke Unit Committee has 10 members, consisting of neurologists or stroke physicians from 10 European countries—well experienced in clinical work, teaching and research, all contributing to this article. The SUCommittee members are: Ulrike Waje-Andreassen, Stefan T Engelter, Diederik WJ Dippel, Darius G Nabavi, Damian Jenkinson, Ondrej Skoda, Andrea Zini, Dilek N Orken, Laurent Derex and Ivan Staikov.

Ulrike Waje-Andreassen is a neurologist at Haukeland University Hospital, and is professor of neurology at the Institute of Biological and Medical Psychology (IBMP), University of Bergen, Norway. In 2012, Waje-Andreassen became member of the ESO Stroke Unit Committee.

References 1. Stroke Unit Trialists C. Organised inpatient (stroke unit) care for stroke.

Cochrane Database Syst Rev. 2002: CD000197.

2. Candelise L, Gattinoni M, Bersano A, et al. Stroke-unit care for acute stroke patients: an observational follow-up study. Lancet. 2007; 369: 299-305.

3. Leys D, Ringelstein EB, Kaste M, et al. Facilities available in European hospitals treating stroke patients. Stroke. 2007; 38: 2985-2991.

4. Ringelstein EB, Chamorro A, Kaste M, et al. European Stroke Organisation recommendations to establish a stroke unit and stroke center. Stroke. 2013; 44: 828-840.

5. Waje-Andreassen U, Nabavi DG, Engelter ST, et al. European Stroke Organisation certification of stroke units and stroke centres. Eur Stroke J. 2018; 3: 220-226.

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Awareness

Hospitals participating in GWTG - Stroke offer higher quality healthcare to ischaemic stroke patients

A recent study reports data indicative of higher quality health care for hospitalised patients with ischaemic stroke at hospitals participating in the Get With The Guidelines - Stroke (GWTG-Stroke) programme. The study, conducted by George Howard (University of Alabama, Birmingham, USA) and colleagues, published in JAMA Neurology, advocates for additional efforts to be made in order to enhance hospital participation in GWTG-Stroke, given the important clinical benefits the programme delivers.

THE GWTG-STROKE programme was developed by the American Heart Association/American Stroke Association (AHA/ASA) as a stroke-care qualityimprovement programme, and has so far been implemented in over 2000 hospitals—treating approximately half of the patients discharged with stroke in the USA. The programme’s success in terms of guideline adherence as well as the proportion of patients discharged to home, 30-day mortality and one-year mortality for patients admitted to GWTG-Stroke hospitals have been acknowledged by the implementation of similar programmes in other countries.

However, the authors noted that what remains unclear is whether the improvement in guideline adherence seen amongst the GWTG-Stroke hospitals

result directly from programme itself, or whether there is a national upturn of acceptance for guidelines—improving care at all hospitals.

Moreover, Howard and colleagues noted that data collected as part of the GWTG-Stroke programme cannot be used in isolation to document better care compared with non-GWTG-Stroke hospitals. Taking this into account, Howard and colleagues aimed to use national data describing hospital care quality that were collected independently of the programme in order to assess the association of the GWTG-Stroke programme with the quality of care of patients with stroke.

A subpopulation of 546 participants from the Reasons for geographical and racial differences in stroke (REGARDS)

study was used; inclusive of patients with ischaemic stroke occurring during a nine-year follow-up, who were previously randomly selected; recruited between 2003–2007. Within this sample, 207 (36%) were treated in a hospital participating in GWGTStroke, while 339 (64%) were treated in a nonparticipating hospital. Data from these patients were analysed between July 2017 and April 2018.

Quality of care measures that were contrasted between the two cohorts included: use of tissue plasminogen activator, performance of swallowing evaluation, antithrombotic use in the first 48 hours, lipid profile assessment, discharge receiving antithrombotic therapy, discharge receiving a statin, neurologist evaluation, providing weight loss and exercise counselling, education on stroke risk factors and warning signs, and assessment for rehabilitation.

Participants treated at participating hospitals (mean age: 74, 48% male) were more likely to receive five of 10 evidencebased interventions recommended for patients hospitalised with ischaemic stroke, compared with patients seen at nonparticipating hospitals (mean age: 73, 48% male). Specifically, patients treated in the GWTG-Stroke hospitals were more likely to receive tissue plasminogen activator, education on risk factors, lipid and swallowing evaluation, as well as an evaluation by a neurologist. In summary, those seen in participating hospitals received a mean of 5.4 (95% CI, 5.2–5.6) interventions compared with 4.8 (95%

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CI, 4.6–5.0) in nonparticipating hospitals (p<0.001).

On a relative basis, Howard et al noted that the most dramatic difference associated with admission to a GWTGStroke hospital was for t-PA use—where the relative risk of use was nearly four times higher for patients treated at a participating GWTG-Stroke hospital.

However, the authors acknowledged that their reliance on medical records to assess whether the participants had received the intervention was perhaps the study’s largest shortcoming. For example, the authors noted that patients who were not administered t-PA may have simply been ineligible for its use; a factor that was challenging to assess from medical records.

In conclusion, Howard and colleagues maintained that the current study has revealed that patients cared for at a GWTG-Stoke participating hospital receive better care and have better outcomes. They stressed the clinical implications of these findings, as currently, only approximately 50% of patients with stroke are treated at participating GWTG-Stroke hospitals; leaving a sizeable proportion of stroke patients in the USA treated with sub-optimal care and compromised outcomes.

In light of this, they suggested that additional efforts should be made in order to enhance hospital participation in GWTG-Stroke, as the programme presents with meaningful benefits for both patients and hospitals, in terms of stroke care and outcomes.

Medical attention seeking for TIAs and minor stroke after the ‘Act FAST’ public education campaign remains unchanged

Standing in stark contrast to the public’s response to major stroke, the extensive FAST-based public education campaign has not improved the response to transient ischaemic attack (TIA) or minor stroke in the UK, concluded a recent study published in JAMA Neurology. The authors, Frank J Wolters and colleagues, University of Oxford, Oxford, UK, stressed that this data highlights the need for future campaigns to become tailored specifically to transient and less severe symptoms.

W

olters and colleagues acknowledged that the Among 2243 consecutive patients with first TIA or risk of major stroke is high in the hours, and stroke, 1656 had a minor stroke or TIA. With regards to even days, following a TIA or minor stroke, but response behaviour to major stroke following the FAST can be drastically reduced by urgent medical treatment. The campaign, patients more often sought medical attention Face, Arm, Speech, Time (FAST) test was adopted as a tool within three hours, compared to before the campaign. to improve symptom recognition after stroke and has since In contrast, for TIA and minor stroke, there was no formed the basis of public education in many countries. improvement in use of emergency medical services The campaign was presented as an ongoing television (OR: 0.79; 95% CI: 0.50, 1.23; p for interaction=0.03 vs. public awareness campaign in the UK, subsequently major stroke) or time to first seeking medical attention improving the public’s response to major stroke. However, within 24 hours (OR: 0.75; 95% CI: 0.48, 1.19; p for what remained unclear was the association of the campaign interaction=0.006 vs. major stroke). Moreover, patient with response behaviour after TIA or minor stroke, perception of symptoms after TIA and minor stroke was especially considering the differences in the presentation of found to be associated with more urgent behaviour, but symptoms, including event duration, severity and coverage correct perception declined after the FAST campaign (from by the FAST acronym.

37.3% [289 of 774] to 27.6% [178 of 645]; OR: 0.64; 95% In light of this, Wolters and the team CI: 0.51, 0.80; p<0.001). Furthermore, 188 prospectively studied patient perception had a stroke within 90 days of their initial and behaviour after TIA and stroke in a TIA or stroke, of whom 93 (49.5%) followed population-based study before and after the unattended TIAs for which no medical ongoing FAST campaign. Additionally, they attention was sought; similar before and after investigated the number of early strokes after the FAST campaign (43 of 538 [8.0%] before a TIA for which no medical attention was vs 50 of 615 [8.1%] after, p=0.93). sought. The sample includes all consecutive In discussion of these findings, Wolters incident TIA and stroke cases, with the and colleagues noted that as the percentage exception of subarachnoid haemorrhage, that of strokes that followed shortly after an initial occurred outside the hospital between April TIA remained unchanged after the FAST 2002 and March 2014. Data analysis was campaign, approximately 100 strokes per carried out from July 2013 to March 2015.

The ‘Act FAST’ campaign one million people a year could have been

prevented. “These ignored events are an important target for stroke prevention,” stated the authors. They further alluded to the high effectiveness of preventive strategies within the first hours and days after TIA and noted that the influence of public education will largely depend on a campaign’s ability to convince patients to take action within this crucial window of time.

With regards to the decline in correct symptom perception that was observed following the FAST campaign for TIA and minor stroke, the authors attributed this finding to the fact that patients may be falsely reassured when their symptoms do not match the severe symptoms presented via the campaign.

Although Wolters et al maintained that the findings are valid and hold the ability to guide future public education campaigns, they noted a couple of caveats present in the current study. For instance, the retrospective diagnosis of unattended TIAs preceding stroke is subjective, and hence may be prone to recall bias. The authors also acknowledged that they did not ask about individual exposure to and awareness of the campaign that was being investigated.

Concluding the study, Wolters et al noted that in contrast to major stroke, the extensive FAST-based public education has not improved the response to TIA and minor stroke in the UK, highlighting the need for campaigns to become tailored specifically to transient and less severe symptoms, in view to encouraging urgent patient response to imminent stroke warning signs.

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Haemorrhagic stroke

ADVERTORIAL

IRRAflow: A new innovative fluid management system to treat intracranial bleeding A conversation with neurosurgeon, Dr Christos Panotopoulos Globally, strokes claim a life every 10 seconds, and it is estimated that, every two seconds, someone somewhere in the world has a stroke (Global status report on noncummunicable diseases, 2011).1 Every year, approximately 25 million strokes occur globally, making stroke the second leading cause of death for people above the age of 60 (Benjamin, 2018).2

T

hese strokes can be broken down into two basic categories, ischaemic stroke and haemorrhagic stroke. Ischaemic stroke, or obstructions that disrupt blood flow to the brain, account for approximately 85% of all strokes (Benjamin, 2018).

Haemorrhagic strokes, the second category of stroke, occur when a weakened vessel ruptures and bleeds into the brain. While these haemorrhagic bleeds occur less frequently and only account for 15% of all strokes, they do have higher morbidity and mortality, resulting in 40% of all stroke deaths (Mracsko & Veltkamp, 2014).3 Over the past decades, significant innovations have been introduced to treat ischaemic stroke. For example, clot removing devices (thrombectomy) have become the standard of care in acute brain ischemia.

For the majority of haemorrhagic stroke cases, though, innovation has been more limited. Apart from coils and flow diverters used for intracranial aneurysms, non-surgical treatment, combined usually with invasive intracranial pressure (ICP) monitoring and passive cerebrospinal fluid (CSF) drainage, remains the standard of care. Despite being the typical treatment option for most intracranial bleedings, these passive techniques are associated with a list of well-documented complications, including occlusions, infections, excessive drainage, and secondary haemorrhage (Lele AV, 2017).4 Recently, new research and product development have started to focus on advancing the care of neurocritical patients with haemorrhagic bleeds. The MISTIE and CLEAR clinical trials have attempted to substantiate whether more rapid blood removal, after intracerebral or intraventricular haemorrhage, can improve patient outcomes (Hanley, 2016), (Hanley, 2017).5,6 New technologies are now also bringing a proactive, therapeutic mentality to treating these patients.

IRRAS is an example of a cutting-edge company that is focused on bringing innovative technology to therapeutically treat haemorrhagic stroke. The company’s first product, IRRAflow®, is an intracranial fluid management system that was recently FDAcleared for use in the United States. IRRAflow provides an active, controlled fluid exchange system to therapeutically treat haemorrhagic events and is indicated for ICP monitoring and drainage of any intracranial fluid.

Dr Christos Panotopoulos

NeuroNews recently spoke with Dr Christos Panotopoulos, the inventor of IRRAflow, about this exciting new treatment option, the need for such advancement, and his experience to date with the system. Dr Panotopoulos currently serves as a Special Advisor to IRRAS in addition to his duties as a Senior Consultant Neurosurgeon and Head of Neurosurgical Research at Mediterraneo Hospital in Athens, Greece, BRAINS-Sparsh Hospital and BRAINS Advanced Institute of Neurosciences in Bangalore, India.

Why did you invent the IRRAflow system?

The IRRAflow system was built around the concept of active, controlled fluid exchange, based on the fact that it is faster to wash out any pathological extracellular fluid collection, as we do during open surgery, than expect it to be evacuated by gravity alone.

IRRAflow combines periodic, controlled irrigation and aspiration of the catheter probe in order to exchange any pathological fluid collection with neutral physiological fluids. This system’s fluid exchange, by design, cleans the entire inner catheter probe’s surface while the fluid movement helps to disrupt potential clot or bacteria colony formation on the catheter probe’s intracranial external surface, thereby eliminating the underlying reasons for the problems associated with passive drainage: blockage and infection.

Moreover, when this fluid irrigation is combined

Active fluid exchange

with efficient drainage and continuous, reliable ICP monitoring that includes safety alarms, a process of active controlled fluid exchange occurs. This fluid exchange offers several advantages over historic treatments for evacuation of extravasated intracranial blood. Extravasated blood follows the intracranial path of least resistance and adheres firmly to the brain parenchyma and meninges, away from the neurosurgeon’s optical field, thus resisting surgical efforts to remove it efficiently without further damaging brain tissue during an operation. Passive drainage, such as today’s standard of care, the external ventricular drain (EVD), is inherently inefficient because of its inability to overcome this clot adhesion. Active irrigation of the catheter helps to enhance the ability to dilute and remove this collected blood for a much longer period than can be performed during an open craniotomy.

When collected blood is not removed sufficiently, it can have other debilitating effects as well. In patients with subarachnoid haemorrhage due to a ruptured intracranial aneurysm, vasospasm is a major contributor to morbidity and mortality and has been reported to occur up to 30% of the time (Ota, et al, 2017).7 The cause of this vasospasm is irritating by-products of the extravasated intracranial blood, which, as discussed, resists all surgical evacuation efforts. The fluid exchange principle has been shown in early clinical experience to have excellent efficiency in the most severe of these cases, which can result in optimal clinical outcomes (Venkataramana, et al., 2012).8

What are some of the issues that you referenced earlier with historic treatment approaches?

Drainage efficiency, blockage, infection and safety.

As previously mentioned, during an open craniotomy and associated clot removal, the neurosurgeon cannot access all of the places that extravasated blood migrates intracranially. When he or she does have direct vision, there is an obvious need not to further damage the brain structures during the blood removal, which compromises the effort. EVDs, on the other hand, rely only on gravity and intracranial pressure. As a result, EVD’s generally need a lot of treatment time for the evacuation of a clinically significant blood volume and often leave enough volume of residual blood to create secondary adverse effects, like hydrocephalus. It is also well established in bibliography that the treatment duration of haemorrhagic stroke patients is inversely related to their clinical outcome (Sam, Lim, Sharda, & Wahab, 2018).9 Extravasated blood is highly viscous and sticky even when diluted with cerebrospinal fluid, resulting in occlusive material forming at the EVD catheter’s tip. These occlusions have been shown to occur up to 40% of the time (Fargen KM, 2015).10 When these catheter occlusions do occur, needed drainage is compromised, preventing fluid and debris from being removed. If an EVD cannot provide an adequate relief of pressure, rising ICP can lead to further severe neurological damage or death.

Therefore, in any neuro ICU, we inject either saline or a thrombolytic medication to unblock the catheter.

This manual flushing increases the risk of infection by opening the closed, sterile system and potentially

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Haemorrhagic stroke

introducing external bacteria. EVD-associated infections are a well-documented risk and have been shown to impact up to 20% of all placed EVDs (Lele AV, 2017). If this flushing process does not work, then the catheter must be removed, and a new one must be introduced. Studies have demonstrated that, when an EVD is replaced, the risk of secondary haemorrhage increases by 66% (Fargen KM, 2015). Hence, with existing technology, we are subjecting the patient to multiple interventions, increased risk of infection, and unsuitably poor outcomes.

Lastly, a major problem with EVDs is that we do not have any safety control on pathological fluid outflow rate other than periodically having somebody manually check the patient’s ICP, visually check the amount of drained fluid, and make the needed changes to the height of the drainage collection bag. As a result, underdrainage, where therapy is compromised and prolonged, overdrainage, which can cause problems such as ventricular collapse or secondary intracranial bleeding, and catheter blockage, with the abovementioned deleterious patient effects, might be detected with a harmful or even fatal delay for the patient.

How does the IRRAflow system address these issues?

IRRAflow Control Unit

The efficiency of the fluid exchange concept for the evacuation of intracranial extravasated blood has been

Case Review: Intraventricular haemorrhage Pathology treated

Male, 18 years old

■ Intraparenchymal and intraventricular haemorrhage due to hypertension

Treatment description

■ IRRAflow catheter probe inserted ■ Active fluid exchange performed for 27 total hours

Treatment result

■ Patient stabilised, returned to regular ward, discharged to rehab ■ No drainage occlusions seen ■ No infection seen

Pre-IRRAflow treatment

Post-IRRAflow treatment

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demonstrated with the IRRAflow system and its previous embodiments in more than 100 patients in Greece, India, Sweden, Germany, and Finland with subarachnoid, intraventricular, intraparenchymal, and subdural haemorrhages. In these cases’ experience to date, treatment times were much shorter and post-treatment residual blood volumes were less than expected by the treating neurosurgeons (Venkataramana, et al 2012), (Data on File at IRRAS).11 This increased drainage efficiency can most likely be attributed to the gradual and continuous dilution of the pathological intracranial fluids by irrigating the catheter with physiological fluids as well as the continuous pressure fluctuations inside the pathological collection, which are created by the appropriate irrigation patterns. Both these factors are well known to everybody who has ever tried to wash anything.

By design, the IRRAflow catheter probe is irrigated regularly in a way that essentially guarantees its patency.

Catheter blockages are theoretically impossible since any material build-up at the catheter’s tip is washed away during the next irrigation phase, which will occur in, at most, a couple of minutes. Additionally, the volume and flow rate of each irrigation is such that the length of the IRRAflow catheter probe’s outer surface is washed by backflow, thus potentially eliminating the chance for any bacterial colonisation (Data on File at IRRAS). On top of this, the skin’s point of catheter entry is isolated from the environment by a special “dome” filled with antiseptic cream and sutured securely in place.

To date, in the early European clinical experience, probably because of these underlying design elements, there have not been any documented blockages or probeassociated infections detected in any IRRAflow treatment.

This was also the case in the previous embodiments during the development of our fluid exchange principle (Venkataramana et al 2012). The growing problem of bacterial resistance in Neurosurgical Intensive Care Units and the above characteristics and clinical performance of IRRAflow, are the reasons for the absence of antibiotics inside the construction material of the IRRAflow catheters.

As for safety, IRRAflow also automatically, reliably, and continuously monitors ICP and alerts hospital personnel with visual and sound alarms immediately when the patient’s ICP is out of the pressure range set by the treating neurosurgeon, which eliminates any delay in detecting under or over drainage and any treatment’s compromise.

References 1. (2011). Global status report on noncummunicable diseases. Geneva: World Health Organization.

2. Benjamin, L. E. (2018). Heart Disease and Stroke Statistics - 2018 Update.

Circulation, 1–426.

3. Mracsko, E, & Veltkamp, R. (2014). Neuroinflammation after Intracerebral hemorrhage. Frontiers in Cellular Science, 1–13.

4. Lele AV, e. a. (2017). Perioperative Management of Adult Patients With External Ventricular and Lumbar Drains: Guidelines From the Society for Neuroscience in Anesthesiology and Critical Care. J Neurosurg Anesthesiology, 191–210.

5. Hanley, D. F. (2016). Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial. Lancet Neurology, 1228–37.

6. Hanley, D. F. (2017). Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet, 603–11.

7. Ota, N, Matsukawa, H, Kamiyama, H, Tsuboi, T, Noda, K, Hashimoto, A, . . . Tanikawa, R. (2017). Preventing Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage with Aggressive Cisternal Clot Removal and Nicardipine. World Neurosurgery, 630–40.

8. Venkataramana, N, Rao, S, Naik, A, Shetty, K, Murthy, P, Bansal, A, & Panotopoulos, C. (2012). Innovative approach for prevention and treatment of post subarachnoid hemmorhage vasospasm: A preliminary report. Asian Journal of Neurosurgery, 77–80.

9. Sam, J E, Lim, C L, Sharda, P, & Wahab, N A. (2018). The Organisms and Factors Affecting Outcomes of External Ventricular Drainage Catheter-Related Ventriculitis: A Penang Experience. Asian Journal of Neurosrugery, 250–7.

10. Fargen KM, H. B.-Z. (2015). The burden and risk factors of ventriculostomy occlusion in a high-volume cerebrovascular practice: results of an ongoing prospective database. Journal of Neurosurgery, 1–8.

11. (n.d.). Data on File at IRRAS.

Dr Christos Panotopoulos, MD, Ph.D., has been a practicing neurosurgeon and clinical researcher for the last 25 years in Greece, France, Sweden and India and has created several inventions and patents including IRRAflow. Dr Panotopoulos founded IRRAS AB in 2012, served as its Chief Medical Officer and Director until May 31, 2018 and as a Special Advisor & Member of Clinical Advisory Board since June 1, 2018. Furthermore, he is the Founder and Director of INDERES Ltd, a company which is active in brain cancer and brain trauma research since June 2018.

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Interview

Profile

Todd Sitzman

Todd Sitzman is the medical director of Advanced Pain Therapy at a comprehensive pain clinic in Hattiesburg, USA. As president of the North American Neuromodulation Society (NANS), he reflects on the society’s success, growth, and expanding influence over the past 12 months. Here, he talks to NeuroNews about how he has seen the field change, his hopes for the future, and his interests outside of medicine.

What drew you to medicine, and to neuromodulation and pain management in particular?

I was fortunate to be drawn to medicine at an early age, and never seriously considered any other profession.

No immediate family or relatives presented themselves as physician role models, but instead my interest stemmed from a life-long passion to help people. For me, a career in pain management was a natural fit. I was introduced to pain medicine as a specialty during my anaesthesiology training. There is no other specialty that allows a physician to care for patients utilising his or her knowledge of anatomy, physiology, pharmacology, radiology and interventional procedures on a daily basis.

Who have been your career mentors, and how have they inspired you?

Over the years I have been influenced by many individuals, and the list continues to grow. Without identifying specific individuals, I most admire those who exhibit compassion, calmness and respect for others—be it physician, nurse or receptionist. My professional growth has been influenced by several of my North American Neuromodulation Society (NANS) colleagues, often by challenging me and opening my eyes to different clinical perspectives. I firmly believe that the acquisition of knowledge is never ending.

As physicians, we gain knowledge through didactic education and skills through hands-on training. But, to become a physician in the truest sense, you need selfless compassion.

How have you seen the field of neuromodulation change and develop over your years practising medicine?

Over the past twenty years I have seen spinal cord stimulation and intrathecal drug delivery undergo continuous innovation, and I am certain that the therapies I utilise now will evolve over the next twenty years. Regarding electrical neuromodulation, I have practised in an era during which technology has evolved from a two-contact single trial lead to dual sixteen contact percutaneous leads; from single lead bipole arrays to multi-lead, multichannel guarded arrays; from metronomic tonic frequencies to those with registered trademark surnames. Innovation takes time and is a long-term process and must involve patient improvement over existing therapies. Fortunately, many technologic advances in neuromodulation have resulted in significant improvement in patient outcomes. Whether it be decrease in pain, improvement in spasticity or movement disorder or an improvement in incontinence, without significant improvement in therapeutic outcome these advances are merely marketing efforts. We have all benefits from true innovation in the field of neuromodulation.

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

My mind does not store and recall “cases” per se.

I have so many memorable individual patients and their families. Although I treat between 125 and 150 individual patients weekly, and have done so for more

than 15 years, nearly all are memorable. It may sound cliché, but I strongly feel that I have learned as much, if not more, from my clinical failures as from my clinical successes. An early career pain specialist may not have the knowledge to recognise an adverse event or assumes that it will resolve with time, whereas an experienced pain clinician intuitively looks for early signs of untoward events and treats immediately.

Outside of your own research, what has been the most the most interesting paper or presentation that you have seen in the last 12 months?

I have been to several regional and national meetings over the past year. In particular, I enjoy attending young clinician/investigator presentations. The one that stands out to me was a poster presentation at last year’s NANS meeting. A high school student, working in the lab at a well-respected university, presented on molecular changes in neural tissue exposed to varying electrical fields.

She was knowledgeable, well-spoken and poised. I was beyond impressed. She reminded me of a classmate that broke into our high school computer lab on weekends to write code because it was the only time that he could work for 12 to 18 hours without interruption. Back then, there was no such thing as a home PC. Needless to say, he went on to Harvard…I didn’t.

What are any major questions in the field of neuromodulation that remain unanswered?

I believe that the major questions in the field of neuromodulation may not be answered in my lifetime; most involve mechanisms of action. I am okay with this, but would like for us to answer why certain therapies work for some patients and not others? Perhaps a prospective, long-term outcomes registry will give us the answers. NANS is in the early stages of funding and building a cloud-based neuromodulation registry looking prospectively at the many outcome measures including pain relief, implantable pulse generator life, complications and healthcare utilisation.

My expectations for neuromodulation as a clinical therapy are quite realistic. These are therapies and not cures, and patients should be made clearly aware of this prior to permanent implantation. At best, neuromodulation may serve as the cornerstone of an ongoing treatment regimen, but is rarely monotherapy.

Despite unrealistic hype, at present, patients with chronic pain will continue to require longitudinal care using multiple therapies.

Spinal cord stimulation has recently been in the news for its remarkable ability to restore walking in patients with paralysis, how do you see this area of neuromodulation developing in the future?

It is fantastic, and offers hope to millions of individuals with plegic and paretic neuromuscular disorders. NANS has taken a strong role in bringing together scientists, engineers and clinicians with the goal of fostering collaboration in the research and development of

implantable medical devices that will eventually be part of clinical practice. In addition to our annual meetings, NANS has sponsored joint meetings with the Neural Interfaces Conference, the Congress of Neurological Surgeons and New York City Neuromodulation Conference. The relationships developed by these collaborative efforts are creating excellent opportunities for sharing new ideas and developing neuromodulation research leading to tomorrow’s therapies.

Should neuromodulation be part of the solution to the opioid crisis in the USA? If so, what are the current barriers and what can be done to change this?

The opioid crisis in the USA is a complex problem requiring an equally complex solution. As a therapeutic modality to treat pain, of course neuromodulation can be part of the solution to avoid long-term exposure to opioids and to minimise the risk for opioid addiction.

Opioid addiction and overdose-related deaths are worldwide health concerns. However, while minimally invasive neuromodulation therapies may offer one solution to avoid long-term opioid therapy, it is naïve to believe that their use will make a dent in the number of opioid-related deaths; the majority of which are from

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Interview sponsored clinical research, paid and unpaid, for the two years of my presidency. This allows me to maintain an unbiased, conflict-free perspective when making NANS Board decisions.

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Fact File

You have been a member of the North American Neuromodulation Society (NANS) for 16 years, how have you seen it grow and what has it accomplished?

I have seen the annual meetings grow from a few hundred to several thousand; from single track meeting agendas to those with three parallel tracks; from venues seating a few hundred to multiscreen auditoriums seating a thousand; from a handful of corporate sponsors to scores of industry sponsors. I believe that NANS’ growth is directly reflective of ongoing science in the neuromodulation field: basic science and clinical research.

In your role as president for the North American Neuromodulation Society what have you achieved, and what are your hopes for the future of the society?

This year marks the 25th anniversary of NANS. We are planning on several events to celebrate this milestone starting with our January 2019 annual meeting and continuing throughout the year. In addition to our annual meeting, we will present at the national Consumer Electronics Show with our industry partners in order to showcase neuromodulation as a growing therapeutic field among other rapidly-growing medical technologies.

In addition, this year we developed a patientfocused website: AskAboutPain.com. This website provides brand neutral information to patients about neuromodulation therapies, and is a valuable resource for our members and their patients.

As I reflect on 2018 NANS activities, I can succinctly say it has been an “organisational success”. Through my years on the NANS Board, I can attest that our success is truly a team effort. Our team of dedicated NANS professional staff, board members, committee members and physician members have devoted countless hours of personal time and are responsible for NANS’ accomplishments. I have every confidence that we will continue to celebrate our success and growth into the future.

What are the highlights of the 2019 annual meeting?

illicit use of opioids.

Current barriers to neuromodulation therapy patient access include restrictive insurance policies and falling clinician reimbursement. NANS has worked hard to advocate for patient access to neuromodulation therapy by partnering with other medical specialties, medical societies, industry and media. The NANS Policy and Advocacy Committee has lead the charge for maintaining and enhancing patient access by directly challenging restrictive worker’s compensation, commercial insurance and governmental policies that restrict the use of these valuable therapies. We now have a seat with the American Medical Association House of Delegates and visibility at the AMA’s RUC and CPT committees. Our influence has never been greater, and will continue to expand thanks to NANS’ growing membership and individual member efforts.

What are your current research interests?

My focus in clinical research is the treatment of chronic pain, regardless of the source. The NANS bylaws specifically prohibit the president from serving in a consulting relationship with industry during the term of his or her office. As such, I have divested from industry-

Last year over 2900 total attendees joined us for our annual meeting in Las Vegas, USA. This year is NANS 25th anniversary and we anticipate even greater attendance. This year’s annual meeting theme is “The Science Behind Successful Outcomes”. With the dedicated efforts of NANS’ scientific programme chair, David Provenzano, the content of our annual meeting will offer current, engaging and innovative neuromodulation educational content. We will once again offer our pre-meeting hands-on cadaver course to over 150 pain fellows and neurosurgery residents, in addition to hands-on courses for neurology residents and engineers designed for them. We will expand this offering to include certification of attendance for peripheral nerve stimulation. I would like to acknowledge and commend the efforts of the NANS’ pre-meeting workshop co-chairs Michael Fishman, Michael Hanes, Bryan Hoelzer, and Jonathan Riley.

What are your interests and hobbies outside of medicine?

I am fortunate to enjoy my leisure time outside of medicine on a weekly basis. My “hobby” outside of medicine is music, specifically jazz. Growing up in New Orleans I was exposed to wonderful sounds of jazz, brass band and funk. There is music playing continuously in my fluoroscopic suite and in the operating room. On weekends I travel to my small studio flat in the French Quarter, a 90-minute drive from my home and office.

With a dozen music venues within five blocks, I rarely pass up an opportunity to enjoy live music.

Professional appointments 2010–Present: Director, Bellevue Surgery Center, Hattiesburg, USA 2005–Present: Medical Director, Advanced Pain Therapy, Hattiesburg, USA 2003–2005: Medical Director, The Center for Pain Medicine Wesley Medical Center; Hattiesburg, USA 1998–2003: Assistant Professor of Anaesthesiology Mayo Medical School, Rochester, USA 1997–2003: Consultant, Anaesthesiology and Pain Management, Mayo Clinic; Jacksonville, USA Society memberships 2003–Present: American Society of Interventional Pain Physicians 2002–Present: North American Neuromodulation Society 2003–Present: Mississippi Pain Society (Past president) 2001–Present: Southern Pain Society (Past president) 1998–Present: Spine Intervention Society 1998–Present: A merican Academy of Pain Medicine (Past president) 1993–Present: A merican Society of Anesthesiologists 1987–Present: American Medical Association Honours and awards (selected) 2013: Patient Advocacy Award, American Society of Interventional Pain Physicians 2012: Hubert L. and Renee S. Rosomoff Award for Excellence in Pain, Southern Pain Society 2012: Distinguished Service Award, American Academy of Pain Medicine 2011: P resident’s Distinguished Service Award, Southern Pain Society 2008: Patient Access Advocacy Hero Award, Medtronic Neuromodulation.

North American Neuromodulation Society Meeting 2005: Ambassador of the Year Award, National Pain Awareness Campaign 2003: Scientific Merit Award (clinical poster presentation), 19th Annual Meeting of the American Academy of Pain Medicine

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Study finds significant reduction in pain with high-frequency 10kHz peripheral nerve stimulation Continued from page 1

population was comprised of patients with an electrode positioned either along a branch of the occipital or trigeminal nerve (four), a limb nerve trunk (four), the S1 nerve root (one), the genitofemoral nerve (one) or the ileo-inguinal (one patient).

In this PNS cohort, a double-blind design was implemented to assess pain and other sensory modalities, before and after the stimulator was switched either ON or OFF for either two hours (protocol one) or four hours (protocol two).

The study investigators reported that decreases in pain and disability after stimulator implantation were maintained in both groups across the 12-month follow-up period. These decreases, however, were significantly greater in patients implanted with a PNS than SCS device (p=0.040). More precisely, in the PNS trial patients, pain increased after the system had been turned OFF overnight for at least 12 hours before

testing. Furthermore, pain did not change following two hours of PNS, yet decreased significantly after four hours.

The authors also noted that analgesic use remained unchanged after spinal stimulator implantation, but significantly decreased for those implanted with the PNS device. Additionally, patients with a PNS implant reported higher satisfaction and less physical disability, compared to the SCS cohort. That being said, complication rates were similar for SCS and PNS implants (21 of 58 patients [36.2%], and 5 of 11 [45.5%], respectively). Similar problems were encountered regardless of the implant, including: wound infection, haematoma, lead migration, and a need to reposition the implantable pulse generator. Lastly, other sensory modalities were found to have been minimally affected by stimulation, regardless of its duration.

On discussion of the aforementioned findings, Finch and colleagues write: “The clinical audit confirmed the utility

The audit confirmed the utility of treating both spinal and peripheral pain with 10kHz stimulation. of treating both pain of spinal origin and peripheral sources with 10kHz stimulation.” Taking into account the fact that pain reduction was greater in the PNS group, they suggested that “this reflects the more specific single nerve anatomical targets for neuromodulation”, yet, alternatively “might indicate differing mechanisms of peripheral neuromodulation to spinal stimulation”.

The study investigators acknowledged certain limitations to their study; primarily the small sample size and the uneven distribution between cohorts.

Further, Finch and colleagues reported difficulty comparing the effect of SCS on pain of peripheral origin, with pain of peripheral origin treated with PNS, as

Good news for gamblers: Transcranial direct current stimulation found to enhance decision making and cognitive flexibility Transcranial direct current stimulation (tDCS) offers a novel intervention for individuals with gambling disorder, concluded a recent study that found that its use enhanced both decision making and cognitive flexibility in a population of gambling individuals.

The study was conducted by Ahmet Zihni Soyata and colleagues (Istanbul University, Istanbul, Turkey) and recently published in European Archives of Psychiatry and Clinical Neuroscience.

ACCORDING TO SOYATA et al, gambling disorder refers to a progressive and chronic maladaptive disorder characterised by the failure to control gambling activities despite various aversive outcomes. The authors suggested that two components of cognitive control that play a critical role in the emergence, persistence and relapse of gambling behaviour include decision making and cognitive flexibility. A previous paper—published in the journal of Drug and Alcohol Dependence— even concluded that such deficits in decision making were found to be more common in gambling disorder compared with alcohol use disorder.

Therefore, Soyata and colleagues set out to investigate whether tDCS over the dorsolateral prefrontal cortex (DLPFC; implicated in executive functioning) would modulate decision making and cognitive flexibility in individuals with gambling disorder.

In total, 20 participants (all male) that met the criteria for gambling disorder were randomised 1:1 to either the treatment condition; receiving three every-otherday 20-minute mA sessions, consisting of active tDCS, or the control condition; receiving sham-stimulation.

Neurocognitive tests such as the Iowa Gambling Task and the Wisconsin Card Sorting Task were used to assess decision making and cognitive flexibility, respectively. The tasks were administered to each participant prior to stimulation and following the last session. In this triple-blinded design, the participants, interventionists and the assessors were blinded to the

condition during experimentation.

A repeated measures analysis of variance (RMANOVA) was employed in order to measure the effect of tDCS on the difference in pre- and post-scores on the two neurocognitive tasks. The primary outcome measures were pre-tDCS and post-tDCS Iowa Gambling Task net scores and the number of perseverative errors

the numbers were too low for statistical analysis. This being so, they stressed the need for this shortcoming to be addressed in future studies.

Finch and colleagues concluded that this is the first RCT that demonstrates a significant clinical effect on pain reduction using high frequency (10kHz) peripheral neuromodulation; specifically, a significant reduction in pain scores when stimulation was conducted for at least four hours. In addition, the authors maintained that the effects on peripheral sensory modalities were minimal— indicating that conduction block may not be an important mechanism in achieving adequate analgesia. This study was conducted without industry or outside funding support.

(the repetition of responses) in the Wisconsin Card Sorting Task.

Baseline clinical severity, depression, impulsivity levels and cognitive performance were found to be similar between groups. In terms of the post-stimulation findings, tDCS over the DLPFC resulted in more advantageous decision making, as the ANOVA indicated a main effect of time (pre- versus post-tDCS) on Iowa Gambling Task net scores (F1,16=13.571, p=0.002), as well as a significant tDCS intervention x time interaction (F1,16=8.128, p=0.01, ɳp=0.330). Regarding the effect of tDCS on cognitive flexibility, no main effect of time on the number of perseverative errors was found.

However, a significant intervention x time interaction was observed (F1,16=8.782, p<0.001, ɳp2=0.350).

Through these results, Soyata and colleagues were able to conclude that tDCS as a neuromodulatory technique enhanced the cognitive functioning of gambling individuals. They wrote: “For the first time […] three sessions of 20-minute tDCS over the bilateral DLPFC might be a novel intervention to enhance decision making and cognitive flexibility in individuals with gambling disorder”.

Of importance, the authors noted that the current findings are consistent with the majority of studies conducted in healthy populations, as well as a previously studied population of clinically impulsive veterans and individuals with addictive disorders.

Furthermore, Soyata et al acknowledged that the results extend the literature by suggesting that the DLPFC presents as a potential target for tDCS in conditions associated with deficits of cognitive control.

However, the authors said that the results should not be interpreted as DLPFC specific due to the broad pattern of stimulation delivered by tDCS, which may have resulted in either direct or indirect stimulation to surrounding areas, such as the right orbitofrontal cortex—an area also highly implicated in decision making.

Moving forward, Soyata and colleagues suggested that future research efforts are needed to carefully examine the precise molecular mechanisms involved in the effect of tDCS, including short- and long-term effects of different electrode montages, as well as the dosing of tDCS in relation to the clinical variables and cognitive functions in gambling disorder.

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20 ADVERTORIAL

The Importance of Consistent and Replicable Outcomes in Choosing a Neurostimulation Therapy

by Timothy Deer

Timothy Deer

We are all familiar with the Level 1 multicentre randomised controlled studies required for regulatory approval of medical devices throughout the world, and rely on them for evaluating and—once approved—incorporating therapy advances into clinical practice.

The clinical evidence obtained from these trials is essential to establishing safety and efficacy before devices become commercially available. Equally important, but perhaps less appreciated, is the ability to reproduce those initial results post approval in an uncontrolled environment.

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his is especially vital in pain management: when choosing a therapy, it is critical for physicians to have confidence that an approved device will perform as well in the real-world setting as it did in controlled clinical studies.

With innovative neurostimulation devices, we can offer our patients a chronic pain management alternative to opioids and palliative prescription drugs.

While a compelling promise, the reality is that there are many devices that look great on paper based on their registrational trial results but oftentimes may not replicate in everyday practice. Device performance may slip for many reasons, including lack of physician engagement and control, physician bias or issues related to patient selection.

When choosing a neurostimulation therapy, strong real-world evidence and consistent, replicable results are key.

To gauge consistency and replicability of outcomes, I encourage pain specialists, interventional

patient outcomes. Of course, we need to see consistent improvement in pain scores—but a patient is so much more than a pain score. Taking a more holistic view requires that we look for consistency in functional and emotional improvement as well. We must be attuned to the impact of the therapy on a patient’s quality of life.

To do so, employing catastrophising, the most accurate predictor of quality of life in people with chronic pain, is essential for evaluation of this very important data point.

One therapy I have worked with extensively is Abbott’s BurstDRTM stimulation. In the large randomised SUNBURST trial, BurstDR stimulation was proven to have superior outcomes over tonic stimulation. In addition, and importantly, these outcomes were consistently replicated in extensive post-SUNBURST testing, across diverse clinical settings over the last eight years.2 It is these types of data that add to my confidence in a specific therapy, and in this case, in BurstDR stimulation.

data at the annual North American Neurological Society earlier this year. Data showed that a majority of subjects selected BurstDR therapy when they were allowed to choose tonic or BurstDR stimulation during the long-term follow-up period.1 BurstDR stimulation provided pain reduction through two years of therapy. Each patient was exposed to both therapies and preference for BurstDR stimulation improved over time. This is very unique in this category as 68% showed preference at 12 months and it increased to 81% at 24 months.1 My takeaway: 24-month data shows that Abbott’s waveform is durable and sustainable showing strong consistent real-world outcomes, which is critical when physicians are making decisions for their patients.

Further analyses of seven studies encompassing more than 250 patients across three continents demonstrated 87% patient preference for BurstDR stimulation over tonic stimulation.7 The quality of these data and their replicability across geographies over years of testing represents a gold standard for the level of evidence we should require when making therapy choices.

As clinicians, we have the benefit of access to large amounts of data to inform our treatment decisions. To best serve our patients, we must look for consistency from long-term studies beyond commercial trials. We also must always discuss the risks of these innovations in the setting of the patient’s history and experience.

This would include the risks of infection, bleeding, nerve injury and other potential complications. To be complete in that discussion, we must always frame it in a setting of alternatives, which in many cases have been opioid medications or larger and more invasive surgeries. Considering the risk of those options, we feel that neuromodulation is a very viable option in the correctly selected patient.

Timothy Deer is an interventional pain specialist. He is president and CEO of the Spine & Nerve Center of the Virginias in Charleston, West Virginia, USA, and Clinical Professor of Anesthesiology and Pain at West Virginia University School of Medicine in Morgantown, West Virginia, USA.

neurologists and neurosurgeons to take a close look at data collected in the period three or four years following a device’s approval. Before choosing a therapy for your patients, I urge you to keep an eye out for pooled analyses of studies being done by independent investigators to assess whether those studies have the same outcomes as the commercial studies.

Furthermore, it is important that we are assessing the most meaningful data points to ensure optimal

But as mentioned earlier, pain reduction just is not enough. BurstDR stimulation is unique in that it emulates natural firing patterns in the brain and is believed to modulate both the sensory and emotional pathways—therefore addressing both pain and the perception of pain.3,4,5 In fact, in one study, BurstDR stimulation decreased pain catastrophising by almost 50% compared to tonic stimulation, resulting in higher levels of patient satisfaction.6 We presented results from SUNBURST two-year

References 1. Abbott. New Data Demonstrates Burst Stimulation From St. Jude Medical Provides Superior Pain Relief Over Traditional Tonic Spinal Cord Stimulation For the Treatment of Chronic Pain. Press Release. December 11, 2015.

2. Deer, T, Slavin, KV, Amirdelfan, K. et al, Success Using Neuromodulation With BURST (SUNBURST) Study: Results From a Prospective, Randomized Controlled Trial Using a Novel Burst Waveform. Neuromodulation. 2018 Jan;21(1):56-66. doi: 10.1111/ner.12698. Epub 2017 Sep 29.

3. St. Jude Medical. (2016). St. Jude Medical™ Prodigy™ Neurostimulation System Programming and Reference Manual. Plano, TX. 4. St. Jude Medical. (2016). St. Jude Medical™ Proclaim™ Neurostimulation System Clinician’s Manual. Plano, TX. 5. De Ridder, D, Vanneste, S, Plazier, M and Vancamp, T. (2015). Mimicking the brain: Evaluation of St. Jude Medical’s Prodigy Chronic Pain System with Burst Technology. Expert Review of Medical Devices, 12(2), 143–150. http:// dx.doi.org/10.1586/17434440.2015.985652 6. Bocci, T, De Carolis, G, Paroli, M, Barloscio, D, Parenti, L,Tollapi, L, Valeriani, M and Sartucci, F. 2018. Neurophysiological Comparison Among Tonic, High Frequency, and Burst Spinal Cord Stimulation: Novel Insights Into Spinal and Brain Mechanisms of Action. Neuromodulation 2018; E-pub ahead of print. DOI:10.1111/ner.1274 7. Abbott Data on File

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ADVERTORIAL

Q & A with Steven Falowski: BurstDR Novel Waveform and Advances in Neuromonitoring for Chronic Pain Management While commonly used to treat unmanageable chronic pain and even movement disorders since the 1980s, neuromodulation therapy has continuously evolved over the years, resulting in advances that can truly be considered cutting edge. Often perceived as science fiction given the use of chips in the brain or sensors on the spinal cord, we are now at a crossroads of innovation in the space, which could ultimately result in an important and much needed paradigm shift in chronic pain treatment options.

Tell us about your area of focus as it relates to chronic pain management.

I am highly involved in neurologic research and perform functional neurosurgery at St Luke’s University Health Network in Bethlehem, Pennsylvania, USA. Simply put, my role is largely focused on quality of life.

My goal is always to restore people to functioning quality lifestyles with neuromodulation.

How has neuromodulation evolved in the last several years when it comes to treating chronic pain?

Technology is improving at a quick pace as we combine our knowledge of neuroscience and computer software.

Over the past five years, the approach has shifted to waveforms—the way we stimulate the nerves on the spinal cord. Historically, patients would experience paraesthesia as a result of nerve stimulation, which indicated that the therapy was working. Abbott has since developed BurstDRTM stimulation that achieves the same result without causing the tingling sensation that many patients found to be an uncomfortable side effect of the treatment.

How are waveforms used in spinal cord stimulation and what do they do to the brain?

There are two primary pathways that bring pain information to the brain.

Pain perception is a combination of pain intensity and attention to pain. The lateral thalamic pathway is associated with pain intensity; the medial thalamic pathway with attention to pain. BurstDR

stimulation, a novel waveform from Abbott, affects both pathways.1

How does spinal cord stimulation with BurstDR work?

With BurstDR stimulation, we are able to modulate the affective component of pain for the first time.1 This is a significant advancement, allowing us to stimulate the nerves that go into the spinal cord and reach the deepest tissues in the back fibres. I have conducted extensive research using all the waveforms for available stimulation technologies. The largest difference in efficacy, as measured by signal strength and energy efficiency, was seen with Abbott’s BurstDR stimulation.2

What types of tools do you use to measure how a neurostimulation therapy is working?

I use neuromonitoring in my operating room (OR) to aid in implanting neuromodulation devices. This affords us an objective method for monitoring the nervous system and, more importantly, to observe and record its responses to various forms of neurostimulation.3,4 Interoperative neuromonitoring, or IONM, was introduced in the 1970s when radical new spinal correction procedures were being developed. The aim was to monitor the flow of sensory and motor information up and down the spinal cord in order to minimise surgical complications and make sure we were targeting the right location.3,4

What do you see when you

Steven Falowski

perform IONM for tonic stimulation?

With tonic stimulation, EMG responses are activated proximally and spread distally. There is a linear 1:1 relationship of stimulus to response. Typically, to see responses spread further down the leg to the foot, we need to continue to increase the amplitude.5

And when you measure BurstDR stimulation?

BurstDR stimulation has a unique effect on the nervous system. The BurstDR waveform provides five pulses of energy.5,6 When it reaches the spinal level, it turns into one big response and is interpreted as such.5 As shown in Figure 1, there is not a 1:1, or linear, response for each of the five spikes in the burst train. Instead, propagation and subsequent temporal summation into a non-linear response occurs. Deep fibres, such as those in the foot, respond selectively to low amplitudes, in the range of 0.5–2mA.5

How do you see neuromodulation therapy evolving in the future?

This is an exciting time in functional neuroscience, more specifically in pain management, as we continue to make significant strides in advancing non-opioid alternatives for patients. We now have Level 1 data, the highest-level quality of data, available to us. We are looking more and more at waveforms, and how we are measuring these will influence future technology. I see future innovation focusing on manipulating the waveforms to be energy efficient, meaning longer battery life. It is worth noting that BurstDR stimulation is a non-rechargeable device that appears to be the most energy efficient, generating signals at the lowest thresholds with a propagating effect that leads to a hyperexcitable or primed stimulation state.

In addition, as we look to the future of neuromodulation, there is a consensus and excitement around leveraging this technology to treat new diseases and conditions, such as depression and chronic pain from post-orthopedic procedures. Ultimately, we are looking to open the door for more patients to benefit from neurotechnology.

References 1. De Ridder, D, Vanneste S. Burst and Tonic Spinal Cord Stimulation: Different and Common Brain Mechanisms.

Neuromodulation: Journal of the International Neuromodulation Society. 2016;19(1):47-59.

2. Courtney, P, Espinet, A, Mitchell, B, et al. Improved Pain Relief with Burst Spinal Cord Stimulation for Two Weeks in Patients Using Tonic Stimulation: Results from a Small Clinical Study. Neuromodulation. 2015;18(5):361-366.

3. Harrington, PR. Treatment of scoliosis: correction and internal fixation by spine instrumentation. June 1962. J Bone Joint Surg Am. 2002;84-A(2):316.

4. Tamaki, T, Kubota, S. History of the development of intraoperative spinal cord monitoring. European Spine Journal. 2007;16(S2):140–146. doi:10.1007/s00586-0070416-9.

5. Falowski, S. An Observational Case Series of Spinal Cord Stimulation Waveforms Visualized on Intraoperative Neuromonitoring. Neuromodulation: Technology at the Neural Interface. 2018. doi:10.1111/ner.1278 6. Abbott. Proclaim™ Implantable Pulse Generator Clinician’s Manual.

Neuromonitoring proves uniqueness of BurstDR stimulation

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Majority of radiculopathy patients prefer burst to conventional tonic stimulation

BurstDR stimulation confers a greater reduction in leg and back pain intensity in patients with failed back surgery syndrome than spinal cord stimulation (SCS) does, a recent study published in Neuromodulation: Technology at the Neural Interface concludes.

TWENTY-ONE PATIENTS were analysed in this observational, multicentre study. Laura Demartini (Pain Unit, Clinical Scientific Institutes Maugeri, Pavia, Italy) and colleagues set out to compare conventional tonic stimulation with the BurstDR stimulation modality in patients with lower limb radiculopathy or failed back surgery syndrome. They found that nearly three-quarters (74%) of this small cohort preferred the use of BurstDR stimulation over tonic. Demartini et al attribute this preference to “the greater improvement in physical and psychological aspects of pain and to the absence of unpleasant perceptions and paraesthesia on SCS with the BurstDR modality.”

BurstDR stimulation is a recently developed neurostimulation modality, which uses bursts of high frequency, low amplitude waves that mimics naturally occurring neuronal firing of thalamic cells in the central nervous system.

Since use of the burst waveform in SCS for the treatment of chronic pain was first reported in 2010, its superiority to traditional, tonic stimulation has been evidenced in patients previously treated with SCS. The present study is the first to compare tonic and BurstDR stimulation during SCS trial phases in SCS-naïve patients.

The study investigators report that in 38% of cases (eight of 21), patients responded successfully to the tonic stimulation trial with regard to global and leg pain; comparatively, 43% (nine of 21) responded to BurstDR with regard to leg pain and axial pain. Only one patient responded to tonic stimulation exclusively, while four

Graph depicting greater improvement in leg pain with BurstDR stimulation

patients only responded well to BurstDR stimulation.

However, the authors note that both tonic and BurstDR stimulation modalities “displayed scant efficacy in controlling axial pain, which still constitutes a difficult target.” This is in contrast to previous studies, which did elucidate a statistically significant improvement in axial pain following SCS. Additionally, both SCS modalities did significantly reduce global pain scores. Following tonic stimulation, there was a reduction in pain score from 7.76 to 5.85 (p<0.05). There was an even greater pain score reduction following BurstDR stimulation, down to a rating of 4.71 (p<0.0001).

Additionally, treatment with both tonic and BurstDR

SCS lowered the pain catastrophising scale (PCS) results but there is a trend for patients with higher PCS scores to choose BurstDR stimulation. The authors explain that “This preference is in line with recent theories to the effect that BurstDR stimulation acts on the lateral and medial pain pathways (emotional-perceptive component of pain) through distinct mechanisms, which possibly involve both GAB(a)ergic and glutamatergic networks at an intracortical level. Therefore, patients with a high PCS would benefit more from the BurstDR modality.”

The study authors also show a significant improvement in quality of life, as assessed by the EQ-5D and EQ-VAS questionnaires. This improvement in quality of life was greater for BurstDR stimulation than it was for tonic stimulation (p<0.0001). Demartini and team write that as their data “suggest that BurstDR stimulation more effectively reduces pain on movement (dynamic pain)”, this “surely contributed to the improvement in quality of life observed.”

Speaking of the clinical ramifications of this research, Demartini says: “Testing different stimulation modalities is a useful way to determine whether patients who do not respond to conventional tonic stimulation can benefit from stimulation with different wave forms.” However, she noted that “The preference of a particular waveform during the trial does not preclude the possibility of changing the stimulation modality once the therapy loses effectiveness over time.”

Similar findings indicating the possible superiority of BurstDR stimulation for treating patients affected by failed back surgery syndrome have also been reported.

A recent meta-analysis published in Neuromodulation by researchers from the Baylor College of Medicine in Houston, USA in 2016 found that BurstDR SCS “possibly causes more pain reduction for short-term duration than tonic SCS without eliciting paraesthesia.” However, this particular review noted that further research was needed exploiting a larger sample size and utilising a standardised study design to confirm this finding.

FDA safety statement calls for caution in the use of implanted pumps for intrathecal drug administration for pain management The growing awareness of patients undergoing pain management and given pain medicines administered intrathecally that are not US Food and Drug Administration (FDA) approved for use with the implanted pump, has led the FDA to release a safety communications statement detailing recommendations regarding the appropriate use of implanted pumps for intrathecal drug administration.

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he release was sparked by the FDA having received numerous Medical Device Reports (MDRs) describing adverse events with implanted pumps, including pump failures, dose errors and other potential safety issues. The MDRs described a variety of patient symptoms including pain, opioid withdrawal, fever, vomiting, muscle spasm, cognitive changes, weakness, and cardiac and respiratory distress. Thus, the FDA decided to review available data from a multitude of sources; premarket device applications, mandated FDA post-approval studies, as well as current device labelling and information from health care providers were all analysed in view to the FDA releasing safety information and recommendations allowing both patients and providers to make informed treatment decisions.

According to the safety statement, pump failure is not always associated with the type of medication used. However, the data reviewed by the FDA indicated that the implanted pump failure rate may more than double when medicines not approved for intrathecal administration with the pump are infused.

Furthermore, not all medicines are

evaluated for compatibility with the components of the pump, as some medicines or fluids (that are not FDA approved) may contain preservatives or characteristics that can damage the pump tubing, or lead to corrosion. If this occurs, the implanted pump may undergo motor stalls—preventing medication delivery which could lead to potential drug withdrawal symptoms.

The FDA statement also acknowledged that the accuracy of the dose calculation software is dependent on using the approved medicine, as well as the medicine concentration and medicine characteristics.

Therefore, if there is more than one medicine in the pump reservoir, the pump software can only calculate the dose based on a single infusion rate. Moreover, the technological limitations of the pumps mean that the lower the infusion rate, the greater the risk of flow rate inaccuracy.

Thus, the patient may not receive the intended dose at very low flow rates, which could potentially lead to symptoms associated with under- or over-dosing.

Finally, the FDA Safety Communication acknowledged that the spinal cord and brain tissue are highly susceptible to

the effects of medicines administered intrathecally, meaning these drugs must meet additional safety standards. For instance, both the medicine itself (if infectious agents are present) or the interaction of the materials between the pump and medicines may be toxic to the spinal cord and brain tissue.

In light of these issues associated with administering medicine that is not approved for use by the FDA, the safety statement concluded that intrathecal delivery of medication using an implanted pump for pain management should remain reserved for patients who fail other treatment options. Even when selecting patients eligible for its use, several clinical factors should be considered, including severity, type and location of the pain as well as individual patient factors: diagnosis, projected lifespan, comorbidities and individual response to different medicine.

Given the findings, the statement noted some recommendations for patients, caregivers, pharmacists and health care providers for when considering a medicine for use in an implanted pump.

Firstly, they recommended reviewing the implanted pump labelling in order to

identify the medicines and concentrations approved for use with that specific pump.

Furthermore, they emphasised awareness that the following medicines are not currently approved for use, including: hydromorphone, bupivacaine, fentanyl and clonidine—as well as any mixture of two or more different kind of medicines, or any compounded medicine.

Although the safety statement acknowledged that patients may experience some relief from using medicines not approved for intrathecal administration in their implanted pumps, such use may pose subsequent risks, such as the aforementioned pump failures, dosing errors and/or further safety issues.

The FDA statement also encouraged that health care providers, patients, and caregivers should consider and discuss both the benefits and risks of using implanted pumps for the intrathecal infusion of medications for pain management, in order to make informed treatment decisions. Lastly, in relation to the patients undergoing pain management, the FDA recommended that they report adverse events to the FDA if they suspect an implanted pump is problematic.

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The top ten takeaways from “The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation” Timothy Deer Comment & Analysis In 2018, the International Neuromodulation Society (INS) project on Consensus Conferences published “The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation”. This paper, published in the journal Neuromodulation, has a goal of improving safety and efficacy for those implanting dorsal root ganglion (DRG) stimulation devices. Lead author, Timothy Deer, past president of INS and chairman of the American Society of Pain and Neuroscience, now provides the top ten takeaways of the publication.

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he INS has a long history of creating consensus statements and best practice recommendations based on a careful analysis of the peer reviewed literature, expert opinion, and ongoing research. These guidelines began in 2000 with the first analysis of the field of intrathecal drug delivery and evolved into recommendations for neurostimulation for the treatment of pain. In the many years of creating this practice guidance the consensus conference has evolved with increasing vigour and careful scoring of information including data analysis and scoring tables.

The creation of a new guidance is prompted by the interval need to update the field, or new therapies that are in need of guidance. In 2018 the INS sponsored a best practice evaluation of dorsal root ganglion stimulation. Several key points were presented in these findings. Ten important points are summarised here:

1.

2.

The NACC (Neuromodulation

Appropriateness Consensus Committee) was created to bring key opinion leaders across the globe to provide direction for the safe and effective application for neuromodulation therapies for the larger global medical community.

This publication is the first time this detailed process has been applied to DRG stimulation. This project was funded by the INS and overseen by the INS consensus committee.

Best practice guidelines were

created for DRG stimulation using extensive literature review of current research, clinical experience of neuromodulation experts, and majority consensus on key procedural and clinical applications.

3.

SCS, the operator will place one to two leads at or around the T8 to T12 level. In DRG stimulation, the operator can use up to four leads which can theoretically be placed at any level in the spine that contains a DRG. The manuscript defined which levels are optimal for different body parts or pain syndromes to help demystify how to best utilise DRG stimulation.

6.

The manuscript illustrated the high

level of evidence available in the literature that supports the use of DRG stimulation. The ACCURATE study alone had 152 patients with Level 1 evidence supporting DRG stimulation. This US IDE study was funded by the manufacturer and overseen by the US Food and Drug Administration (FDA). When one takes into account all of the available publications on DRG stimulation, there are several hundred patients with the majority of these publications being completed without industry funding. The real-world experience has largely matched the original investigational device exemption pivotal study.

Spinal cord stimulation (SCS) is a

well-established treatment modality for chronic neuropathic pain. DRG stimulation is a form of spinal stimulation in which targeted nerves are stimulated to treat various focal neuropathic pain states. Being a significant modification of the existing SCS technique, physicians incorporating this therapy have had to seek additional training and guidance to incorporate DRG stimulation safely and effectively. This publication is a way to set current best practices for this relatively new and advanced therapy.

4.

There is a great deal more variability

in the way DRG stimulation can be performed from a procedural standpoint as compared to traditional SCS. This manuscript makes graded recommendations on the various technical aspects of the procedure in an attempt to standardise the treatment and improve efficacy and safety.

5. Another significant difference

between DRG stimulation and traditional SCS is the variability of stimulation targets. In traditional

7.

The indications for which DRG

stimulation has been reported in the literature varies considerably (i.e. pain after total knee arthroplasty and pelvic pain to post-surgical chest wall pain and phantom limb pain). This manuscript also evaluated all of the currently available evidence and graded it in an effort to help implanting physicians improve their outcomes by knowing which indications have the most/best evidence.

8. The manuscript highlighted a number of physician-initiated studies like the DRG FOCUS study that showed

the “real-world” efficacy of DRG stimulation and was completed without any industry funding.

These physician led studies are important for evaluating how patients potentially will respond in a clinical setting.

9.

New publications have been

important to show how effective DRG stimulation is compared to traditional SCS, and also presents statistics on safety and the overall lower incidence of adverse events like loss of efficacy and lead migration. The safety profile of DRG is statistically the same as conventional SCS but the overall efficacy in most studies are showing improved efficacy.

10. The manuscript called for additional

evolution in the therapy including new product development for leads, sheaths, and battery technology. The need for a DRG paddle lead to treat complex patients is highlighted with recommendations of possible therapy growth for those who currently are not appropriately treated with modern technology. In addition, the authors felt new options for hybrid systems that could allow for both spinal cord and DRG stimulation could be important for future advances. The need for continued updates in the area of implantable devices is very important. The Consensus process will continue going forward with a focus on patient safety and efficacy.

Readers should continue to survey the journal Neuromodulation for upcoming peer reviewed updates in this important manuscript series.

Timothy Deer is the president and CEO of the Spine and Nerve Center of the Virginias in Charleston, USA and chairman of the American Society of Pain and Neuroscience.

These guidelines began in 2000 with the first analysis of the field of intrathecal drug delivery and evolved into recommendations for neurostimulation for the treatment of pain. In the many years of creating this practice guidance the consensus conference has evolved with increasing vigour.

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The future of neurostimulation: Smart neuromodulation Dirk De Ridder Comment & Analysis Better understanding of the brain alongside the integration of artificial intelligence may represent the future of neuromodulation. From machine learning and novel technology to non-invasive brain-computer interfaces that may hold the potential to repair brain damage; Dirk De Ridder (University of Otago, Dunedin, New Zealand) speculates what the development of this field permits, as well as what has been holding it back.

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he treatment of neurological and psychiatric disease is compromised by the recent (+/- 2011) disengagement of the big pharma in developing novel medications for brain disorders. The reason is that designing drugs for central nervous system disorders has 50% less chance of making it to market and takes 30% longer than for other indications, such as cancer and heart disease.1,2 Thus, a novel

non-pharmacological way of treating brain related pathologies is of crucial importance if progress is to be made in treating these most debilitating disorders.

Interestingly, this methodology is already available, albeit in an immature fashion.

More than 60 years ago, in 1952, Delgado described implantation of intracranial electrodes for recording electrical brain activity as a diagnostic tool, and deep

Figure 1: the brain is characterised by a small world topology, intermediate between two extremes, a completely regular fully predictive system, and an entirely random, completely unpredictable system

Figure 2: Any symptom of a brain disorder is the emergent property of a reorganised network. Neuromodulation can be used to normalise the symptom-generating reorganised brain networks associated with a brain disorder

Figure 3: Closed-loop neuromodulation uses positive and negative feedback to control the output of the internal pulse stimulator (IPG). In a smart system, the loop learns through AI; adjusting to the context and intention in order to predict what output is required

brain stimulation via the same electrodes as a possible treatment for mental disorders.3 This concept was based on the clinically beneficial effects of destructive psychosurgery through lesioning and the then recent (1947) development of stereotaxy for better targeting.4 The described technique became adapted for movement disorders in 1963 by Bechtereva in Russia5 and later in 1987 by Benabid in the Western world.6 The last 30 years has however been characterised by a stagnation in novel technology for brain stimulation, in sharp contrast to the exponential technological advancement in consumer devices such as smart phones, personal computers, etc.

If neuromodulation is to fill in the gap left by the big pharma’s withdrawal from neuroscience it must mature to a sophistication that goes beyond technology from the last millennium. But what are the essential ingredients for this evolutionary jump in neuromodulation technology to occur for the benefit of desperate patients with unaided brain disorders, whether neurological or psychiatric?

The future of neuromodulation fundamentally depends on three pillars: first; better understanding of the brain, second; better technology, and lastly; integration of artificial intelligence (AI) for the development of smart neuromodulation.

Largely due to the impetus given by the ‘decade of the brain (1990-2000)’, the understanding of the brain morphology, physiology and pathophysiology has increased dramatically, but this has not yet been implemented in brain stimulation for clinical purposes. The brain is currently seen as a complex adaptive system, defined by the presence of a small world topology and embedded noise.7 Small world topology means that the structure and function of the brain is intermediate between two extremes, a fully deterministic regular or lattice network on the one hand, and a completely chaotic unpredictable8 random topology on the other hand. A small world topology permits adaptive flexibility, which neither of the two extremes exhibit (figure 1).

All complex adaptive systems, whether economy, internet, ant colony or brain, exhibit the same characteristics, in that they are complex, and adaptive—they have the capacity to change and learn from experience. They also show self-organisation, in that their complexity increases without an external organiser, as well as self-similarity, meaning that the whole has the same shape as one or more of the parts. But most importantly they are characterised by emergence. Emergence arises when an entity has properties its parts do not have, due to interactions between the parts. As such any symptom or brain disorder can be seen as an emergent property of a reorganised small world network.9 Neuromodulation can therefore be seen as a way to normalise symptomgenerating reorganised networks (figure 2).

This implies that the future of neuromodulation will have to incorporate the neurophilosophy of network science if it is to mature to a treatment worthy of the third millennium, analogous to what is seen in the development of self-driving cars and so forth.

This better understanding of the brain as a complex adaptive small world system requires better technology, not just for the deployment of novel stimulation designs10 such as burst stimulation,11 but also by incorporating sensing technology, which permits to record brain activity and connectivity measures, analogous to and extending from what is already available in pacemaker technology. The first initial steps are being taken by the industry for feedbackbased, closed-loop spinal cord stimulation in the treatment of pain,12 and responsive brain stimulation for epilepsy,13 demonstrating the potential of this technology. Yet, these closed-loop and responsive stimulations are not smart in that they do not learn (figure 3 left).

These systems behave like a servo-system in a car, without prediction, and cannot be applied beyond what

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they are programmed for. A smart system can learn to better detect the neural activity and connectivity signatures of the presence of a symptom as well as the intensity of a symptom, whether sensory, motor, cognitive, emotional or social. A smart system can learn to select an optimal stimulation design to better normalise the symptom by increasing or decreasing connectivity and thus changing the network structure.

And optimally, a smart system can predict symptoms as to prevent their re-occurence in chronic disease states.

Furthermore, a smart system improves itself, and learns to respond differentially depending on the context and intention (figure 3 right).

In order for neuromodulation to become smart, it needs to embed AI in its design, which controls both the sensing and execution of the neuromodulation device. In essence, the device needs a little brain to control itself, in order to become flexible and adaptive, in order to learn from the past to predict how it should behave in the future in a similar context depending on a specific goal. This tends to frighten many people, who fear computers will take over control from humans, once AI supersedes human intelligence, in a moment coined the singularity, predicted to occur around 2045.14 So, how far are we? What is the current state of affairs? Is there novel technology that could be useful for the development of smart neuromodulation? And, is there interest from the industry in the development of flexible adaptive brain-computer interfaces?

A first step in adaptive flexible neuromodulation is the decoding of symptoms, thoughts, memories, actions, perceptions, and so on. Recently, AI using machine learning has been capable of finding an objective signature for symptoms such as pain, tinnitus, tremor, depression,15 but also for memories,16,17 which can even be used for restoring memories and transplanting them in other animals.18 But once sensory, emotional, cognitive or social stimuli are detected they need to lead to a percept, i.e. the interpretation of a stimulus.19 Electrical microstimulation of the somatosensory cortex for example with high resolution high density electrodes permits to induce different sensory percepts that feel fairly natural.20 It is clear that neuroscientific knowledge is currently only at the initial stage of cognitive, emotional and social decoding and of artificial sensory, thought or memory perception generation, but with the very rapid growth of machine

learning, decoding will be rapidly improving. Yet, at present, high resolution stimulation is required and is still running behind.

In order to sense and stimulate novel, less invasive electrode designs with improved integration in the brain is also required. This could be aided by novel technologies such as syringe injectable mesh electronics,21 which in animals are shown to integrate seamlessly with the brain in contrast to thin film electronics22 and result in stable chronic recording of brain activity.23 Neural dust, 1mm sized individual electrodes use ultrasonic power and communication to enable a scalable, wireless, and battery-less system for interfacing with the nervous system.24 These new technologies combined with greatly improved artificial intelligence will permit in the future to construct invasive and non-invasive brain-computer interfaces, that could integrate with brain tissue and thus repair brain damage, normalise pathological activity and connectivity or even enhance normal brain functioning. This has led to a race between nonneuromodulation companies such as Google, Facebook, DARPA, Kernel, Neuralink, Softbank vision fund to develop an ultra-fast high bandwidth brain-computer interface. Visionaries such as Elon Musk (Neuralink) dream to extend Paul MacLean’s triune brain25 with electronics. The underlying idea is that Paul MacLean’s vision of the brain as a structure with three evolutionary layers (the brainstem being the reptilian brain, the cingulate cortex defined as the emotional brain, and the cortex dedicated to cognition) will be extended with a fourth layer of electronics that will permit for each individual brain to become linked to the cloud.

Whereas for now this is clearly impossible, visions such as these combined with the singularity idea of AI surpassing all of human intelligence pave the way for futurologists and science fictionists to envision a future in which the boundaries between humanity and computers become progressively more blurred.

Whether we want this or not, this avenue is the way neuroscience currently moves, and the medical neuromodulation field can only benefit from these evolutions. The industry has understood this and large companies such as Abbott are hiring people from Google and other companies who push the limits of AI to drive innovation in neuromodulation.

In conclusion, the future of neurostimulation is smart neuromodulation.

Percutaneous PNS may hold the potential to shift the chronic pain management paradigm A recent study demonstrates the potential value of percutaneous peripheral nerve stimulation (PNS) for chronic low back pain (LBP). Data reported by Christopher A Gilmore and colleagues, Center for Clinical Research, Carolinas Pain Institute, Winston Salem, USA, published in the journal of Neuromodulation, found that improvements in pain, medication, as well as patient-centric outcomes, lasted beyond the removal of percutaneous PNS leads.

ALTHOUGH A PRESCRIBING physician may find it difficult to escape the press surrounding the opioid epidemic, Gilmore and colleagues shed light on the current crisis, writing: “Neuromodulation may provide an opportunity to reduce the need for opioids for chronic LBP”, and acknowledged that so far, “the cost and invasiveness of existing systems have limited its adoption”.

Initially designed to enable percutaneous delivery of therapy without surgery while reducing complications, the authors put forward that “percutaneous PNS also provides a less-invasive and less costly treatment option to reduce pain and disability”.

The PNS system features a lead with a coiled, fine-wire design intended to reduce lead migration that has previously shown a low risk of

Dirk De Ridder is a Belgian neurosurgeon. He is currently the Neurological Foundation Professor of Neurosurgery at the University of Otago in Dunedin, New Zealand.

References 1. Gribkoff VK & Kaczmarek LK (2017) The need for new approaches in CNS drug discovery: Why drugs have failed, and what can be done to improve outcomes. Neuropharmacology 120:11-19.

2. Kesselheim AS, Hwang TJ, & Franklin JM (2015) Two decades of new drug development for central nervous system disorders. Nat Rev Drug Discov 14(12):815-816.

3. Delgado JM, Hamlin H, & Chapman WP (1952) Technique of intracranial electrode implacement for recording and stimulation and its possible therapeutic value in psychotic patients. Confinia neurologica 12(5-6):315319.

4. De Ridder D (2013) A short history of neurosurgical localization. World Neurosurg 80(5):479-481.

5. Bechtereva NP, Bondartchuk AN, Smirnov VM, Meliutcheva LA, & Shandurina AN (1975) Method of electrostimulation of the deep brain structures in treatment of some chronic diseases. Confinia neurologica 37(1-3):136-140.

6. Benabid AL, Pollak P, Louveau A, Henry S, & de Rougemont J (1987) Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Applied neurophysiology 50(1-6):344-346.

7. Amaral LA, Diaz-Guilera A, Moreira AA, Goldberger AL, & Lipsitz LA (2004) Emergence of complex dynamics in a simple model of signaling networks.

Proc Natl Acad Sci U S A 101(44):15551-15555.

8. Bullmore E & Sporns O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 10(3):186198.

9. Barabasi AL, Gulbahce N, & Loscalzo J (2011) Network medicine: a network-based approach to human disease. Nat Rev Genet 12(1):56-68.

10. De Ridder D, Perera S, & Vanneste S (2017) State of the Art: Novel Applications for Cortical Stimulation. Neuromodulation 20(3):206-214.

11. De Ridder D, Vanneste S, Plazier M, & Vancamp T (2015) Mimicking the brain: evaluation of St Jude Medical’s Prodigy Chronic Pain System with Burst Technology. Expert Rev Med Devices 12(2):143-150.

12. Russo M, et al. (2018) Effective Relief of Pain and Associated Symptoms With Closed-Loop Spinal Cord Stimulation System: Preliminary Results of the Avalon Study. Neuromodulation 21(1):38-47.

13. Geller EB (2018) Responsive neurostimulation: Review of clinical trials and insights into focal epilepsy. Epilepsy Behav.

14. Kurzweil R (2005) The Singularity is Near (Penguin, New York).

15. Vanneste S, Song JJ, & De Ridder D (2018) Thalamocortical dysrhythmia detected by machine learning. Nature communications 9(1):1103.

16. Berger TW, et al. (2012) A hippocampal cognitive prosthesis: multi-input, multi-output nonlinear modeling and VLSI implementation. IEEE Trans Neural Syst Rehabil Eng 20(2):198-211.

17. Song D, et al. (2018) Sparse Large-Scale Nonlinear Dynamical Modeling of Human Hippocampus for Memory Prostheses. IEEE Trans Neural Syst Rehabil Eng 26(2):272-280.

18. Deadwyler SA, et al. (2013) Donor/recipient enhancement of memory in rat hippocampus. Front Syst Neurosci 7:120.

19. De Ridder D, Elgoyhen AB, Romo R, & Langguth B (2011) Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc Natl Acad Sci U S A 108(20):8075-8080.

20. Flesher SN, et al. (2016) Intracortical microstimulation of human somatosensory cortex. Science translational medicine 8(361):361ra141.

21. Liu J, et al. (2015) Syringe-injectable electronics. Nat Nanotechnol 10(7):629-636.

22. Zhou T, et al. (2017) Syringe-injectable mesh electronics integrate seamlessly with minimal chronic immune response in the brain. Proc Natl Acad Sci U S A 114(23):5894-5899.

23. Schuhmann TG, Jr, et al. (2018) Syringe-injectable Mesh Electronics for Stable Chronic Rodent Electrophysiology. J Vis Exp (137).

24. Neely RM, Piech DK, Santacruz SR, Maharbiz MM, & Carmena JM (2018) Recent advances in neural dust: towards a neural interface platform. Curr Opin Neurobiol 50:64-71.

25. MacLean P (1990) The triune brain in evolution (Plenum Press, New York).

infection. “If successful, this approach has the potential to provide effective neuromodulation therapy earlier in the treatment continuum,” Gilmore et al write.

To evaluate the use of percutaneous PNS for the treatment of chronic low back pain (LBP), patients with chronic LBP were enrolled in an FDA investigational device exemption case series. Specifically, subjects with chronic axial LBP—pain confined to the lumbar region, lasting at least 12 weeks—were eligible for participation. Percutaneous PNS leads targeted the medial branch of the dorsal ramus in the region of the LBP. These fine-wire leads were guided using ultrasound and known anatomical landmarks, and remained placed for the 30-day therapeutic window.

In total, nine subjects (mean age: 53.5 years) met the criteria. Subjects reported an average pain intensity (BPI-5) of 5.7 and a worst pain intensity (BPI3) of 7.7 at baseline. Following PNS treatment, the majority of these subjects reported statistically and clinically significant reductions in both average pain intensity (BPI-5; average reduction

of 3.4) and worst pain intensity (BPI3; average reduction of 4.4) scores, which continued through to the fourmonth follow-up. In addition, subjectreported reductions in pain intensity were demonstrated by concomitant and sustained reductions in analgesic medication use, while clinically significant reductions in patient-centric outcomes of disability, pain interference and patient global impression of change were also reported by subjects.

Thus, these improvements in pain, medication, and patient-centric outcomes led Gilmore and colleagues to conclude that the current study demonstrates the potential value of percutaneous PNS for the treatment of chronic LBP. On further discussion of the findings, the authors maintain that the therapy outlined in the current study holds the potential to shift the paradigm surrounding chronic pain management.

“Along with providing the benefits of neuromodulation therapy to patients early in the treatment continuum [...], the present work highlights the value and safety profile of this approach.”

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Product News

Nuvectra receives full-body MR-conditional CE mark approval for Algovita

Nuvectra has announced that it has received full-body MR-conditional approval for the company’s Algovita spinal cord stimulation (SCS) system from its European Notified Body, TÜV SÜD. The approval closely follows the company’s announcement regarding its receipt of head-only MR-conditional approval for Algovita from the US Food and Drug Administration (FDA).

Scott Drees, chief executive officer, commented, “Full-body MR-conditional approval in Europe further validates the safety of our Algovita system and follows our recent announcement of FDA head-only MR-conditional approval in the US. We look forward to the continued advancement of the system with submission for full-body MR-conditional approval to the FDA in early 2019.”

The Algovita SCS system utilises internal pulse generators used for spinal cord stimulation alongside patentprotected stretchable lead technology to deliver four unique stimulation modes to patients seeking non-pharmaceutical relief from chronic pain. Algovita’s SCS system has already been implanted in over 2,000 patients in the USA.

Stimwave receives FDA clearance for first Wireless SCS System with iPhone and Apple Watch patient controllers for opioid free pain management

Stimwave Technologies has announced that it has received US Food and Drug Administration (FDA) clearance for the WaveCrest Mobile iOS platform patient controllers for opioid free pain management. This new system now gives patients iPhone and Apple Watch mobile control over WaveMaster multi-waveform automated programming for the Wireless Freedom spinal cord stimulator (SCS) system for relief of chronic pain.

The Freedom SCS System is the first wireless, fullyprogrammable SCS neuromodulation device providing a life-changing technological breakthrough for the more than 90 million people in the USA who endure daily chronic back and leg pain.

WaveCrest Mobile allows a patient to use an iPhone, iPod

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Touch, or an Apple Watch to adjust their pain relief therapy. This is the first FDAcleared software that allows the Apple Watch to control a neuromodulation device implanted inside the body. The software is designed to be easy to use and secure. WaveCrest Mobile enables pain sufferers to fine-tune the power level, visualise battery life, and modify programmes that were pre-programmed by their clinician to control pain without opioids.

“Pain suffers are rapidly migrating to the Stimwave Freedom wireless pain relief system as an opioid free option to control their pain and now they can adjust their therapy with the swipe of their finger through their Apple Watch or iPhone/iPod Touch discretely any time as needed,” said Stimwave chairman and CEO Laura Tyler Perryman. “Transformation of pain treatment moving from opioids and pills to interventional solutions like Stimwave can only happen as a result of empowering the masses to take control of their pain.”

Stimwave’s Freedom stimulators are implanted in an outpatient procedure with no need for general anaesthesia, a large surgical incision or a bulky internal battery known to lead to numerous complications from other older technologies. These products are expected to significantly reduce the lifetime cost of care for chronic pain patients and offer a safe, viable and effective alternative to opioids.

“Patients’ needs in pain management are unique and customised programming is a must. The Freedom System not only is the smallest option available for patients— eliminating the complexities of an implanted lithium ion battery—but offers a wide variety of advanced programming features that the patient can choose through their mobile device,” said Ellen Lin, medical director of San Antonio’s Advanced Spine and Pain Center.

Utilising the Stimwave Freedom

System, clinicians utilise an iPad application to easily program the system using WaveMaster advanced therapy waveforms offering the ability to easily and quickly provide patients with an array of programming waveforms, frequencies and combinations of options to ensure long term pain relief, all available on the Apple Watch or iPhone controller.

FDA approves new SynchroMed II myPTM Personal Therapy Manager that enables patients to alleviate unpredictable pain

SynchoMed II device

Medtronic has announced US Food and Drug Administration (FDA) approval of the new SynchroMed II myPTM personal therapy manager for patients with chronic pain. This device enables patients to alleviate their unpredictable pain by delivering on-demand boluses, or drug doses, within therapeutic limits set by their physician. myPTM works with the SynchroMed II Intrathecal Drug Delivery system, also known as a Medtronic pain pump, which delivers medication directly to the fluid around the spinal cord to relieve chronic pain in appropriate patients. The Medtronic pain pump, an implantable drug pump, provides long-term pain relief at lower doses and with fewer side effects compared to oral pain medications and may allow some patients to eliminate the use of systemic opioids. Personalisation of the therapy gives patients the ability to alleviate unpredictable pain and may further reduce the need for oral opioids.

“The Medtronic pain pump and myPTM are powerful tools to safely treat chronic pain including intractable cancer pain,” said John A Hatheway, owner and provider at Northwest Pain Care in Spokane, USA. myPTM is an easy-to-use application on a touchscreen Samsung J3 smart device that is customised to help patients to manage their pain. Healthcare providers can set daily therapeutic doses and allow for on-demand bolusing, or drug delivery, within pre-established limits. myPTM features clear bolus delivery, access to therapy details, and lockout alerts if patient demand exceeds prescribed limits. Physicians also have access to reports that provide insights needed to track progress and collaborate on therapy goals with their patients.

“Samsung and Medtronic have partnered to offer an innovative solution for patients with chronic pain,” said David Rhew, chief medical officer,

vice president and general manager for Enterprise Healthcare, Samsung Electronics America. “The ability to directly manage one’s medical condition from a smartphone device is groundbreaking and changes the way we think about the personalisation of care.”

“We are striving to simplify targeted drug delivery therapy to make it more accessible. The Control Workflow and Clinician Programmer provide physicians with tools to effectively administer the therapy, and the myPTM provides customised pain relief options for patients,” said Charlie Covert, vice president and general manager of the Targeted Drug Delivery business, part of the Restorative Therapies Group at Medtronic. “As the opioid crisis continues, we are inspired by Medtronic’s mission to continue to innovate and expand access to care for patients who may benefit from our therapies, which have the potential to eliminate the need for oral opioids.”

First use of SPRINT endura PNS system to treat complex regional pain syndrome SPR Therapeutics has announced that Marc Huntoon, director of pain management at the Neuroscience, Orthopaedic and Wellness Center, VCU Medical Center, Richmond, USA, was the first to use the recently FDA-cleared SPRINT endura single-lead peripheral nerve stimulation (PNS) system, for the treatment of complex regional pain syndrome.

Complex regional pain syndrome is a debilitating, chronic pain condition affecting the limbs that can be induced by surgery, trauma or injury. While it can be very difficult to treat, earlier intervention has been shown to improve outcomes, and PNS can be an effective option.

Historically, PNS involved an invasive neurosurgical procedure, and as a result it was not often considered as an early treatment option. The SPRINT system is a minimally invasive PNS option that is conducive to use early in the treatment continuum.

“In my experience, patients suffering from chronic pain benefit from early intervention with peripheral nerve stimulation. Now that there is a less invasive percutaneous option, PNS can more easily be deployed sooner in the care continuum,” said Huntoon of VCU Medical Center. “This new method of peripheral nerve stimulation is generally safe, effective and minimally invasive.”

In addition to treating complex regional pain syndrome, it has also been helpful in treating other pain conditions such as back pain, shoulder pain, post-amputation pain, and pain following surgery, such as total knee replacement.

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Market watch

Clinical News New results demonstrate ability to automatically detect suspected large-vessel occlusion stroke in noncontrast CT head scans

Viz.ai has further advanced the field of strxoke imaging and workflow by developing a novel method for the detection of signs of large vessel occlusion (LVO) stroke in noncontrast CT head scans (NCCT).

Researchers from Emory University who independently assessed the new technology, will present a research study comparing the algorithm’s read of a NCCT with CT angiogram-based ground truth at the Society of Vascular and Interventional Neurology (SVIN) 2018 Annual Meeting.

Neuroimaging has expanded beyond its traditional diagnostic role and has become a critical tool in the evaluation and management of stroke. The objectives of imaging include prompt accurate diagnosis, treatment triage, prognosis prediction, and secondary preventative precautions. While capitalising on the latest treatment options and expanding upon the “time is brain” doctrine, the ultimate goal of Viz. ai is to maximise the number of treated patients, minimise the time to treatment and improve the outcome of patients suffering stroke, one the most costly and morbid diseases.

“Earlier detection and notification of suspected LVO stroke patients using a regular CT scan will open up the opportunities for treatment,” said Raul Nogueira, professor of neurology at Emory University and director of Grady’s Neuroendovascular Service.

“This ground-breaking research further demonstrates the opportunities that artificial intelligence can offer in helping physicians make fast stroke triage decisions thereby broadening patient access to life-changing therapies.”

Non-contrast computed tomography (NCCT) is the ubiquitous first imaging study for patients with suspected stroke.

Signs like the Hyperdense Vessel Sign (HDVS) are one of the earliest identifiable findings in patients with acute ischemic stroke. Recognition of specific signs in the NCCT can aid the earlier diagnosis of large vessel occlusions (LVOs) and faster triage to endovascular reperfusion.

“Viz.ai is committed to developing novel technology to assist physicians in making faster decisions, and speed access to life saving treatment,” said Chris Mansi, neurosurgeon and CEO of Viz. ai. “AI based NCCT analysis has shown great potential in detecting potential LVO stroke patients earlier and could create a new paradigm of proactive stroke workflow based on the most commonly available imaging modality.”

First patients enrolled in CERUS study to treat

intracranial aneurysms using Contour Neurovascular System to reduce the risk of rupture

Cerus Endovascular has announced enrolment of the first patients in the CERUS study (Contour Neurovascular System European Pre-Market Unruptured Aneurysm Study). The CERUS study aims to assess the safety of the company’s Contour Neurovascular System, which is designed to reduce the risk of rupture when treating patients with intracranial aneurysms.

CERUS is a prospective, 30-patient, single-arm, multicentre, pre-market trial. The study is expected to complete enrolment within the next four months and is being conducted at 10 leading European neurological centres in Germany, France, Austria and Denmark.

Co-principal investigator, Professor Thomas Liebig, of Ludwig Maximillian’s University Hospital, Munich, has performed three of the first four cases with the fourth performed at University Hospital Schleswig-Hostein, Kiel, in Germany.

When asked about his impression, Liebig said, “The Contour System combines the benefits of flow disruption and redefinition of the aneurysm-toparent vessel-border without any material in the parent artery. Thus, it doesn´t mandate long-term antiplatelet therapy.

Sizing was straightforward in these first cases and was done with regard to the neck only since the Contour does not aim for bulk replacement of the aneurysmal cavity. Angulation and irregularity of the aneurysm dome seemed to play a lesser role, as well. We are aware of the need for a more valid database with more cases to support these impressions but at the moment we are quite content with our initial experience and look forward to the co-investigators experiences and to the first control visit of the patients we have treated so far.”

The Contour Neurovascular System is a next generation intra-saccular flow diverter and flow disruptor which targets the neck of the aneurysm. Intra-saccular flow diverters divert blood flow from the aneurysm and promotes healing, thereby reducing the risk of aneurysm rupture, a main cause of haemorrhagic stroke. The device is easily positioned and can be repositioned should more optimal device positioning be warranted.

Accurate positioning of the device and effective delivery and deployment

are important factors in the successful treatment of intracranial aneurysms.

After deployment, the device conforms to the wall of the lower hemisphere of the aneurysm and across the neck sealing the neck opening.

New data shows positive outcomes for the NeuroBlate laser system for patients with brain metastasis

Monteris Medical, a company specialising in minimally invasive, image-guided laser ablation systems, has announced that the favourable results of its Laser ablation after stereotactic radiosurgery (LAASR) clinical study have been published in the Journal of Neurosurgery.

A prospective, multicentre clinical study conducted by leading academic medical centres, LAASR confirmed the beneficial outcomes of laser interstitial thermal therapy (LITT) in a group of 42 patients with brain lesions that recurred follow-

ing stereotactic radiosurgery (SRS) for metastatic brain tumours.

The LAASR clinical study enrolled patients with brain lesions that recurred following stereotactic radiosurgery for metastatic brain cancer. The recurring lesions—which ranged in size from 0.4cm3 to 38.6cm3—were ablated with the Monteris Medical NeuroBlate System. This patient population often has complex progressive medical issues and limited options, often leading to debilitating neurologic symptoms and deteriorating cognitive function causing progressive decline in their quality of life.

The options for these patients, including open surgery and steroid drug therapy, may be limited and are often associated with high levels of morbidity.

The LAASR study results demonstrated that the potential benefits of LITT for this patient population include stabilising the quality of life and cognitive function of this challenging patient population. Additional benefits included reduced or eliminated steroid usage and short length of hospital stay.

The study confirmed that LITT can be effective in controlling both recurrent brain metastases and radiation necrosis, as shown by the primary outcome results of the trial on progression-free survival (PFS) of 74% at last follow-up (12-26 weeks) and overall survival (OS) of 72% at 26 weeks. No unanticipated adverse events related to the device/procedure were seen. Neurological complications related to the LITT procedure were shown in 12% of the patients and included intracerebral haemorrhage, headache, and new or worsened neurological deficits such as motor

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weakness.

Veronica L Chiang, co-principal investigator, Department of Neurosurgery, Yale University, commented, “Given the side effect profile of alternative options for this patient population, the stabilisation in the Karnofsky Performance Scale, preservation of quality of life, and reduction in steroid usage all represent positive outcomes of the LAASR study.”

Furthermore, Manmeet Ahluwalia, co-principal investigator of the Cleveland Clinic’s Brain Tumor and NeuroOncology Center, added, “SRS is an effective first-line treatment for patients with metastatic brain cancer. However, for patients with recurrent disease that may not be appropriate for additional SRS or surgical resection, the LAASR study results indicate that LITT can be an effective option.”

Monteris is exclusively focused on advancing both LITT technology and clinical research to serve the unmet needs of neurosurgeons and their patients.

The company’s NeuroBlate System is a minimally invasive, MRI-guided laser ablation tool for brain lesions, including brain tumours and epileptic foci. In addition to its recently published LAASR study, the Monteris commitment to high quality clinical data is continuing with its LAANTERN2 prospective, multicentre registry that has enrolled over 300 patients.

Canadian-led international study shows huge costs of delayed access to stroke care

It has been known for years that it is important to get stroke patient’s treatment as soon as possible to increase their chances of recovery. A Canadian-led international study that was presented at the 11th World Stroke Congress (17–20 October, Montreal, Canada) quantifies how important every hour can be—both for patients and for costs to society and the healthcare system.

The study, led by clinicians at the University of Calgary (Calgary, Canada), found that every hour of delay resulted in shortened or diminished quality of life as well as substantially higher healthcare and societal costs.

“Faster treatment results in better outcomes and better quality of life,” said Michael Hill of the Department of Clinical Neurosciences at the University of Calgary, one of the study authors.

“The speed of treatment is one of the modifiable factors that will improve outcomes and reduce cost at both the system and the hospital level.”

Study collaborators from the USA, UK, France, Spain, Netherlands and Australia joined the Canadian researchers in examining outcome records and treatment costs for patients who had an ischaemic stroke and were eligible for endovascular thrombectomy (EVT). With EVT, a person with an ischaemic stroke has the clot physically removed as soon as possible after symptoms start. The process involves threading a thin tube through an artery and guiding it with X-ray imaging through blood vessels

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to the brain. A retrievable stent is used to remove the clot. The procedure has shown remarkable results in studies, reducing the overall death rate by 50% and greatly diminishing the lasting effects of stroke in many patients.

The study concluded that within the first six hours, every hour of delay in starting the EVT procedure resulted in an average loss for the patient of nine months at full quality of life (known as a quality-adjusted life year or QALY), or 18 months less at 50% quality of life due to disabilities.

As for cost, the study found every hour of delay within the first six hours resulted in increased healthcare costs of US$6,173 per QALY and society costs of US$7,597 per QALY. The losses are even greater during the very first hours after a stroke occurs. Within the first three hours, the study found, treatment delay of two hours—that are typically spent getting a patient to a stroke centre, evaluated, and brain imaged, even in relatively good

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Market watch circumstances—would result in average losses for the patient of close to two QALYs (two years) and extra healthcare and societal costs of US$11,000 and US$15,000 per QALY (year), respectively.

A further ‘hot topic’ presentation at the World Stroke Congress outlined a study—led by Patrice Lindsay of Heart & Stroke—that looked at pre-hospital behaviour of young stroke patients compared to older ones. The study found that young adults (ages 18–44), especially women, were less likely to take an ambulance to the hospital when they had a stroke.

Researchers studied 2003–2016 data from the Canadian Institute for Health Information to compare hospital arrival times after stroke based on gender and age. At the same time, they looked at public polling data to analyse stroke awareness among different groups.

Hospital arrival time was an average seven hours for older adults and younger men, but nine hours in younger women.

Yet, polling showed that more women knew at least one FAST sign of stroke compared to men.

“Young adults, especially women, are less likely to use ambulance services and more likely to arrive to hospital late, even though they have more knowledge of stroke,” Lindsay says. “Targeted public health messaging is required to ensure younger adults seek timely stroke care.” Every hour of delay causes poorer outcomes after stroke and diminished quality of life.

Product News

Acandis receives European CE mark approval for its ACCERO stent

Acandis has announced that it has received European CE mark approval for its ACCERO stent, which is now available for sale in Europe. The ACCERO stent is intended for use with embolisation materials in the treatment of intracranial aneurysms.

ACCERO, the new self-expanding braided stent from Acandis is characterised by an excellent opening behaviour, superior wall apposition and a very smooth implant surface. “Our engineers designed a dedicated radial resistive force of the stent to ensure reliable coil retention. In addition, ACCERO offers ease-of-use and an improved radiopacity concept; the

platinum-nitinol composite wire allows the visibility of the entire contour of the stent.” said Andreas Schuessler, CEO of Acandis.The ACCERO can be delivered through 0.0165–0.0170“ microcatheters and double lumen balloon guide catheters and can be re-sheathed more than 95% of its length.

The Acandis proprietary BlueXide surface finishing aims to optimise haemocompatibility and facilitates stent delivery by using a corrosion-protective BlueXide surface, ensuring an extremely low nickel ion release. Furthermore, high oxygen and nitrogen intensities of the protective titanium oxide/oxynitride film will work to reduce platelet adhesion, favouring endothelialisation as opposed to native oxide; ultimately aiming to improved vessel healing.

First intracranial aneurysm patients treated with BRAVO Flow Diverter

Cerenovus has announced that the first patients have been treated with the BRAVO Flow Diverter, following recent CE mark approval for the device to be used in the treatment of intracranial aneurysms.

“The BRAVO Flow Diverter is a welcome addition to the existing treatment options for intracranial

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Bravo flow diverter

aneurysms” said Patrick Brouwer, senior consultant neurointerventionalist at Karolinska University Hospital, Stockholm, Sweden, and evaluator for the BRAVO Flow Diverter. “I am impressed with the overall handling of the device, in particular the ease of use, opening functionality and stability of the device placement.”

Accurate positioning of the flow diverter and effective delivery and deployment are important factors in the successful treatment of intracranial aneurysms. The design of the BRAVO Flow Diverter reflects these requirements and aims to provide surgeons with confidence when positioning and deploying the device, contributing to complete diversion effect.

The device is currently not approved for use in the USA.

Penumbra launches JET 7 and Penumbra JET D in the USA

Penumbra has announced US commercial availability of the Penumbra JET 7 and Penumbra JET D reperfusion catheters

Market watch powered by the Penumbra ENGINE aspiration source. The Penumbra JET 7 and JET D reperfusion catheters deliver deep vacuum aspiration power of the Penumbra ENGINE to enable physicians to extract thrombus effectively and safely in acute ischaemic stroke patients.

The Penumbra JET 7 is the Penumbra System’s seventh generation reperfusion catheter for proximal large vessel occlusions, and JET D reperfusion ratheter is designed specifically for distal occlusions. JET 7 reperfusion catheter has a large 0.072” lumen for deep vacuum aspiration and is designed for trackability and navigation, featuring 20 transitions from the proximal shaft to distal tip, a progressive distal coil wind for flexibility and Quad-Wire technology in the proximal shaft for enhanced pushability. JET D brings deep vacuum aspiration power to distal occlusions with a smaller profile.

“The JET 7 reperfusion catheter with its advanced tracking technology and large 0.072” aspiration lumen is the most advanced device for stroke. In my clinical experience, I was able to easily and quickly navigate the JET 7 through tortuous anatomy to the face of the clot and achieve full revascularisation after a single pass,” said Alejandro M Spiotta, Medical University of South Carolina, Charleston, USA. “We know from our own published experience that increases in aspiration lumen size have led to faster recanalisation times and higher likelihood of success at first pass without compromising safety.”

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Industry News

iSchemaView RAPID integrates with Join, Allm’s medical communications platform

iSchemaView has announced that the RAPID platform is now compatible with Join, a medical communication app developed by Allm, a multinational developer of mobile communications platforms for the healthcare industry.

The integration of RAPID imaging results into the Join platform allows for time-critical brain scans to be quickly and securely shared among the members of the acute stroke care team, to accelerate key diagnostic decision making for the patient and facilitate the care team’s communication.

RAPID is the de facto standard for the automated analysis of brain images

used for the diagnosis and treatment of stroke, including CT angiography, CT perfusion, MR diffusion and perfusion and CT ASPECT scoring, which can now be accessed through the Join app. This integration enables another channel for streamlined connections with physicians, EMS and healthcare imaging communication systems such as PACS, allowing medical professionals to share clinical information broadly and quickly.

James Conners, associate professor of neurology, Rush University Medical Center, Chicago, USA, said: “Our personal user experience with the combined platform has been nothing less than positive. The integration allows for swift and seamless communication with the stroke care stakeholders from the ambulance to the angiosuite.”

Developed by stroke experts, RAPID combines unmatched expert feature extraction and other proprietary machine learning algorithms to deliver the best-inclass platform that has quickly become the standard in three quarters of USA comprehensive stroke centres.

“By integrating with Join, we are utilising another critical mobile channel to bring RAPID’s unmatched imaging results to medical professionals around the globe,” said Anil Singhal, iSchemaView SVP World Wide

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Operations. “Together we are facilitating communication about critical patient information, in context, right from mobile devices. We are also excited to have Allm join our mission to successfully diagnose and treat more stroke patients than ever before.”

“Allm’s goal is to create nextgeneration mobile technologies and communications platforms for the healthcare industry that truly benefit medical professionals and improve patient care,” said Harry Reddy, president of Allm North America, and GM of Global Strategy Division of Allm Group.

“Creating integration between our Join app and RAPID’s imaging helps advance Allm’s goal. We look forward to expanding RAPID’s reach and the integration with the Join app worldwide.”

“Diagnosis of acute stroke is a high pressure, time sensitive situation,” said Marc Ribo from the University of Barcelona, Spain. “The combination of the RAPID and Join platforms is a powerful tool to enable our team to confidently get the stroke patient to the right clinical treatment in this lifethreatening environment.”

Viz.ai designated as American Heart Association/ American Stroke Association

Get With the Guidelines compatible vendor

Viz.ai has been designated as a compatible vendor for the American Heart Association/American Stroke Association Get With The Guidelines (GWTG) registry, a programme for assisting hospitals in measuring and improving cardiovascular disease and stroke care through researchbased guidelines.

The Association’s Get With The Guidelines–Stroke programme currently

supports healthcare professionals in over 2,000 hospitals and is designed to improve stroke care by promoting consistent adherence to the most up-todate research and scientific publications, clinical tools and resources, quality improvement field staff support, patient education resources, and continuous quality improvement performance feedback reporting. Since the programme’s inception in 2003, over five

million stroke patient records have been recorded into the GWTG database.

As a compatible vendor, Viz.ai aims to improve quality metrics in the stroke workflow by facilitating fast and accurate detection and referral of large vessel occlusion strokes and enabling better collaboration between the stroke teams at comprehensive and referral hospitals.

“The inclusion of Viz.ai as an American Heart Association Get With the Guidelines Compatible Vendor demonstrates the potential role that applied artificial intelligence and workflow software has in providing consistent quality care,” said Raul Nogueira, professor of neurology at Emory University and director of Grady’s Neuroendovascular Service. “Viz LVO serves as a fully automated stroke alert system that identifies suspected LVO patients who may be eligible for lifechanging mechanical thrombectomy.”

Viz.ai’s comprehensive suite of deep learning applied artificial intelligence and workflow software automatically detects and directly alerts on-call stroke specialists about suspected large vessel occlusions (LVOs) across their entire stroke network in just minutes. When combined with insights from Viz CTP automated perfusion software and the convenience of Viz VIEW’s mobile

viewing and Viz HUB’s HIPAAcompliant messaging software. Viz LVO significantly augments stroke teams’ capability to proactively identify and triage a potential stroke. It aims to enable the right decision to be made by the right specialist at the right time.

Penumbra announces acquisition of controlling interest in MVI Health

Penumbra has announced it has closed on the acquisition of a controlling interest in its joint venture, MVI Health Inc. After closing the transaction, Penumbra increased its ownership to 90% of the equity of MVI Health for US$20 million in upfront cash consideration.

MVI Health, originally formed in May 2017, is a joint venture between Penumbra and Sixense Enterprises, a leader in virtual reality software and tracking solutions for enterprise. Since its founding, MVI Health has been developing virtual reality technology for healthcare applications.

MVI Health, headquartered in Alameda, USA, is supported by investments from Penumbra and licensed intellectual property and other resource contributions from Sixense Enterprises.

Calendar of events 17–20 January NANS: North American Neuromodulation Society 22nd Annual Meeting Las Vegas, USA

15 April Acute Stroke Controversies @ CX London, UK

22–24 May 5th European Stroke Organisation Conference Milan, Italy

www.cxsymposium.com

www.eso-conference.org

6–8 February ISC: International Stroke Conference Honolulu, USA

18–23 May ASNR: American Society of Neuroradiology Annual Meeting Boston, USA

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

www.exhibitatsessions.org

www.2019.asnr.org

www.neuromodulation.com

22–23 March LINNC Americas Miami, USA

19–21 May 7th World Intracranial Hemorrhage Conference Granada, Spain

www.neuromodulation.org

www.linnc.com

www.worldich.org/2019

September

Profile: Istvan Szikora

Issue 19

ious Brain Is consc safe?

Brainto sedation

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

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

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

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

ional Neurorad the Live Intervent (LINNC; 22–24 peaking at 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 investitreatthese patients steps in the 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 hospital the prospective and finally, contact at to develop of dorsal groin puncture; we have to start Axium clinical trial stimula. first image; critical steps our efficiency 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 as is the metric Continued and door-to-g ” move the patient trials were negative,” to stroke teams to patient through -puncture of dorsal root these call Levy move the n, Robert Both picture-to correlated with outcome, surprise that as a wakeup roin. results stimulatio those door-to-g 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 presented terms He in Registry, which how efficient ed in the Mercidataset that captures ular stroke tive treating endovasc representa US hospitals of treatment

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3–5 June LINNC: Live Interventional Neuroradiology & Neurosurgery Course Paris, France

4–6 September ESMINT: European Society of Minimally Invasive Neurology Therapy Annual Meeting Nice, France

www.linnc.com

www.esmint-2019

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

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

www.snisonline.org

www.esnr.org

30 September–2 October SLiCE: Stroke Live Course Nice, France www.slice-online.co

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

2015

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