NeuroNews 41 US

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April 2021 | Issue 41

Featured in this issue: 90-day functional outcomes were similar between patients who achieved mTICI 2c and those who achieved mTICI 3 reperfusion 42.4% vs. 45.1%


Ching-Jen Chen Complete reperfusion vs near-complete reperfusion

Profile Mitchell Elkind

Dylan J Edwards

page 14

page 20

New thrombectomy device offers promising results In a late-breaking presentation given on the final day of the International Stroke Conference (ISC) virtual meeting (17–19 March), researchers presented a “promising” new thrombectomy device that is reported to achieve a successful reperfusion in 84.6% of patients.

Jeffrey Saver


effrey Saver (University of California, Los Angeles, Los Angeles, USA) and Rishi Gupta (Wellstar Health System, Marietta, USA) presented their findings from the TIGER (Treatment with the intent to generate endovascular reperfusion) trial. “The trial confirmed that the Tigertriever (Rapid Medical) is not only safe and effective, but demonstrably improved outcomes over similar trials testing previous technology,” observed Saver. “Tigertriever is an important advance in stroke treatment devices and a win for patients.”

Tigertriever achieved superiority when compared to historical controls

In relation to their primary endpoints, Gupta reported that “superiority was achieved” when compared to historical control studies. This study saw 84.6% of patients achieve a modified treatment in cerebral ischaemia (mTICI) 2b–3 within three passes of the Tigertriever, compared to 73.4% with historical stent retrievers. For efficacy, the primary outcome was successful revascularisation (mTICI 2b–3) within three passes with the Tigertriever. Secondary outcomes included good functional outcome—defined as a modified Rankin Score (mRS) between 0–2—at 90 days, first-pass successful revascularisation (mTICI 2b–3), and patient-reported outcome (PRO) scores. For safety, the primary outcome was a composite of symptomatic haemorrhage at 24 hours (12–36 hours), and all-cause mortality by 90 days. Secondary outcomes

Stroke neuromodulation Robotic therapy in stroke recovery

Rishi Gupta

included asymptomatic intracranial haemorrhage within 24 hours (1–36 hours), neurological deterioration (≥4-point increase on the National Institutes of Health Stroke Scale [NIHSS]) within the first 24 hours, and embolisations in previously uninvolved vascular territories (ENT). In their serial revascularisation outcomes, researchers saw that, at the first pass with the Tigertriever, 57.8% of patients had an mTICI 2b–3. At the end of up to three Tigertriever passes, this was 84.6%, and after rescue devices were used at the end of procedure, it was 95.7%. Regarding secondary endpoints, 58% of patients achieved an mRS of 0–2 at 90 days; this is compared to historical control where this outcome was 43%. When comparing the primary safety endpoint, researchers compared 90-day mortality and/or intracranial

The trial confirmed that the Tigertriever is not only safe and effective, but demonstrably improved outcomes over similar trials testing previous technology.” Continued on page 4

Greater outreach needed for women and minority pain patients During a presentation at the North American Neuromodulation Society (NANS) virtual meeting (15–16 January) entitled “Outcomes and Access to Neuromodulation for Women and Underrepresented Minorities: A Call to Action”, speakers discussed a range of factors that may contribute to a reported disparity in the access to and outcomes after neuromodulation-based procedures for women and minorities. Factors discussed included implicit bias, cultural differences, and lack of representation of women and minorities in neuromodulation-related specialties, medical societies, and academic leadership. NeuroNews conducted exclusive interviews with two speakers from this presentation—Myrdalis Diaz-Ramirez (Sarasota Pain Relief Centers, Sarasota, USA), who discussed disparities in neuromodulation access and outcomes, and Stephanie Vanterpool (University of Tennessee Medical Center Department of Anaesthesiology, Knoxville, USA), who detailed how outreach can improve access. “THE TENDENCY IS FOR neuromodulation therapies to be offered or more accessible to Caucasian men, with private insurance, fewer comorbidities, seen at higher volume hospitals, and with higher income households,” comments Diaz-Ramirez regarding her research into the disparities in access to pain treatment. “For deep brain stimulation (DBS), the access is over 90% to those able to reach a large academic centre in metropolitan areas. Despite this, African American patients who met characteristics for DBS received the procedure much less frequently than non-African Americans. DBS seems to be also received more frequently by Caucasian men. The racial disparities are amplified when adjusting for physician and Continued on page 2


April 2021 | Issue 41

Neuromodulation access

Greater outreach needed for women and minority pain patients Continued from page 1

clinic characteristics.” Diaz-Ramirez and colleagues conducted a search across a number of academic libraries, including PubMed and the Florida State University library, and were only able to find eight articles relating to disparities in access to neuromodulation. Diaz-Ramirez says, “The data we have available from specific research about disparities in neuromodulation, including access and outcomes, are very limited.” She continues: “Most of the articles are retrospective, with data over 10 years old. They do not take into account the shift of using a great part of the technology, mainly for pain management, into the outpatient setting. The data also focuses on only three examples of neuromodulation: spinal cord Stephanie stimulation for pain, deep brain stimulation for Parkinson’s disease, Vanterpool and vagal nerve stimulation for pain.” Vanterpool details: “In one of the largest national surveys of disparities in neuromodulation, Mark Jones [Weil Cornell Medical College, Department of Anaesthesiology, New York, USA] and colleagues reviewed the Center for Medicare services database of over 1.2 million patients who had the diagnosis of post-laminectomy pain syndrome or chronic pain syndrome, two of the primary diagnoses that we use for neuromodulation. In that study, only 4.8% of those patients received spinal cord stimulation (SCS) as a treatment option, and of those, we found that Black, Hispanic, Asian, and North American Native patients were significantly less likely to receive SCS compared to patients who were white. This also held true when adjusted for socio-economic status, and for other clinical factors. Additionally, it was also found in that paper patients of lower socio-economic status across the board had less access to SCS.” When asked about differences in outcome for minority group patients, Diaz-Ramirez notes: “In a study where they compared Medicaid patients to patients with private insurance, they found no difference in complications, nor two-year re-operation for spinal cord stimulator surgery.” However, these findings were not the same for women, as she further comments, “They found women would have more subsequent examinations in a particular clinic with less pain relief and more findings of depression after permanent implants had been implanted.”

Vanterpool explains what the aim of outreach can be for these patients: “To inform patients that the treatment option is available to them is really one of the main goals of patient outreach.” Vanterpool goes on to explain how clinicians can play a role in improving these disparities: “When it comes to engaging with patients from other backgrounds, I think it really starts with a conscious intention to do that, and then also setting an example. As a senior clinician, you want to ensure that any unconscious biases or conscious biases that you have are appropriately addressed and not interfering with your patient interactions. The best way to do this is to make sure that you are making an accurate diagnosis for any patient that comes in front of you, regardless of their race, ethnicity, or socioeconomic status.” Vanterpool advises: “Different diagnoses or causes of pain have evidence-based treatments. We need to focus on making sure that we have accurately identified the diagnosis as clearly and closely as possible, and then equally and across the board apply evidence-based treatments. In that Myrdalis Diazone way we would ensure that we Ramirez are not allowing race and ethnicity to cloud our treatment options for these patients. It sounds a little bit easier than it is to just focus on the diagnosis, but that really is one of the foundations of it.” Diaz-Ramirez notes limitations in her research due to the data available: “Hispanics and Asian/Pacific Islanders are mentioned without a significant specific conclusion drawn. They do not mention North American Native patients, for example, nor other groups. There are no studies that mention [the] LGBTQ+ [community].” She ultimately concludes: “We are at the beginnings of studying disparities in neuromodulation.” In concluding, Vanterpool states: “Outreach is really a combination of three things: awareness, advocacy, and application. By applying those three things, to ensure that socio-economic disparities or racial disparities do not factor into evidence-based treatment options for patients, we can increase awareness and access to our patients for these life-saving and life-changing neuromodulation therapies.”

Outreach is really a combination of three things: awareness, advocacy, and application.”

News in brief

The latest stories from the neuro world

n IMMEDIATE ANGIOGRAPHY COULD REDUCE STROKE TREATMENT TIME: A late-breaking abstract presented at the International Stroke Conference (ISC) (17–19 March, virtual) by Manuel Requena reports that immediate angiography, rather than the standard computed tomography (CT) scan, reduced stroke treatment time and was linked to improved recovery.

For more on this story visit page 5. n WOMEN IN NEUROSURGERY: WHY IS THE FIELD STILL MALE DOMINATED? Despite the increasing numbers of women across all medical fields, neurosurgery still lags behind. A recent study in The Journal of Neurosurgery found eight main factors which contribute to this shortfall, as well as looked at some country-specific statistics.

For more on this story visit page 8. n CLOSED-LOOP NEUROMODULATION COULD RESTORE MEMORY AFTER TRAUMATIC BRAIN INJURY A presentation by Robert E Gross at the North American Neuromodulation Society (NANS) virtual (15–16 January) meeting presented evidence on the successful use of closed-loop stimulation on the lateral temporal cortex for patients with traumatic brain injury.

For more on this story visit page 21. Editor-in-chief:




Prof Philip M Meyers Roger Greenhalgh

Content director: Urmila Kerslake


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April 2021 | Issue 41

ISC late-breakers

haemorrhage at 24 hours. For the Tigertriever it was 18.1%, and for the historical control, this figure was at 20.4%. The ISC audience was also given other safety endpoints: asymptomatic intracranial haemorrhage at 24 hours was 30.7% (in 36 patients), neurologic deterioration (≥4 NIHSS increase) was seen in 7.7% (9) of patients, and ENT in 2.6% (three) patients. In the historical control, the weighted average for ENT was 7.4%. The median time from puncture to revascularisation was 24 minutes, which Gupta commented is a “very rapid reperfusion”. The median time from last known normal to puncture was 172 minutes, and last known normal to revascularisation was a median of 208 minutes. Gupta concluded: “The Tigertriever is a highly-effective and safe device to remove thrombus in LVO stroke patients eligible for mechanical thrombectomy.”

84.6% 73.4%

“The physician controls the radial expansion and force according to visual and tactile feedback. This allows the device to be aligned with the target vessel diameter, and adjustment of the radial forces needed to penetrate the clot, while minimising vessel tension. Being fully visible, the device provides visual feedback and better operator control.”

Study design

Researchers state that the study objective was to evaluate the safety and effectiveness of the device in restoring blood flow by removing clots in patients with acute ischaemic stroke due to large vessel occlusion (AISLVO). This was a multicentre, single-arm, prospective, objective performance criterion, investigational device exemption (IDE) study. There were a total of 17 sites, the device was compared with a performance goal derived from six pivotal trials of marketed stent retrievers (Solitaire, Medtronic and Trevo, Stryker). Researchers screened 1,712 patients. Although 183 were eligible for angiography, 23 patients were excluded after due to the target clot being too distal. Enrolment took place across two phases: a lead-in and the main phase. Enrolment for the lead-in phase of the study began in May 2018, and 43 patients were included. At this stage, sites enrolled up to four patients. Enrolment was completed when they either achieved two successful reperfusions or performed four cases following case review and approval by the central neurointerventionalist principal investigator. In the main phase, 117 patients were enrolled. The data presented at ISC focused on this cohort. Enrolment ended in March 2020.

84.6% of patients achieved an mTICI 2b–3, compared to 73.4% in the historical control

Other devices

According to Saver, current devices failed to achieve successful reperfusion—defined as an mTICI score of 2b–3—in one-quarter of patients included in the HERMES (Endovascular thrombectomy after largevessel ischaemic stroke) five-trial pooled analysis. They also failed to achieve excellent reperfusion (mTICI 2c–3) in two-thirds of patients. In addition, many of the pivotal thrombectomy trials showed that current devices were associated with complications such as ENT in a small number of patients, and symptomatic intracranial haemorrhage in a low number of intracranial haemorrhages, Saver communicated. Saver stated that the Tigertriever is a novel, radially adjustable, fully visible, stent retriever. He continued,

No significant difference between IVT plus EVT compared with EVT alone A late-breaking abstract presented at the International Stroke Conference (ISC) 2021 (17–19 March, virtual) reports results from the MR CLEAN-NO IV (Multicenter randomised clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands) trial, which is assessing the efficacy and safety of direct endovascular thrombectomy (EVT) compared with intravenous thrombolysis (IVT) followed by EVT in patients with acute ischaemic stroke caused by an occlusion of the anterior circulation. Researchers found no statistically significant difference in outcomes between these groups. THIS STUDY’S ORIGINS WERE in the first MR CLEAN trial in 2015. According to researchers, this was the

first trial to demonstrate the benefit of endovascular treatment in addition to standard treatment. Researchers report a further inspiration for this study were those trials carried out in Asia, especially DIRECT-MT (Endovascular thrombectomy with or without intravenous alteplase in acute stroke). DIRECT-MT was carried out in China and is the sister trial of MR CLEAN-NO IV. Yvo Roos, co-principal investigator (PI) of MR CLEAN-NO IV (Amsterdam University Medical Center, Amsterdam, the Netherlands), commented that the DIRECT-MT trial “Showed significant non-inferiority of direct endovascular treatment on functional outcome, and showed a tendency towards less haemorrhages with direct EVT treatment.” The hypothesis for MR CLEAN-NO IV was that “direct EVT for patients with acute ischaemic stroke caused by an intracranial proximal large vessel occlusion in the anterior circulation is superior to IV alteplase followed by EVT in terms of functional outcome.” The MR CLEAN-NO IV trial is a randomised, controlled, open-label, blinded-endpoint trial that included patients with acute ischaemic stroke caused by an occlusion of the anterior circulation. The first patient was enrolled in the trial in January 2018, and the last October 2020. A total of 539 patients were included across 20 stroke centres. Of these, 273 were allocated to direct

Yvo Roos

An independent core lab adjudicated angiogram images taken after each pass/attempt, including the first-pass effect, for three Tigertreiver passes, and at the end of the procedure after use of rescue devices in initial non-responders.

Group demographics

The mean age in this cohort was 65 years, 61.5% (72) of patients were male, the median NIHSS was 17, nearly two-thirds of patients received intravenous tissue plasminogen activator (t-PA) prior to treatment, the mean time to t-PA treatment was 95 minutes, and the mean ASPECTS (Alberta stroke programme early computed tomography score) was 8.9. Comorbidies included hypertension in 76.9% (89) of patients, dyslipidaemia in 48.7% (57) of the cohort, atrial fibrillation in 40.2% (47), diabetes mellitus in 30.8% (36), and prior stroke/TIA in 13.7% (16). The majority of patients’ target occlusions (57.3%; 67 individuals) were located in the middle cerebral artery (MCA) in the M1. Other locations included the intracranial internal carotid artery (20.5%; 24 patients), MCA in the M2 (19.7%; 23 patients), and the basilar artery (2.6%; three patients). Disclosures: Jeffrey L Saver: Serves as a principal investigator (PI) for the TIGER study (Rapid Medical) and acts as a consultant or is on the advisory board for Medtronic, Stryker, Cerenovos, and Rapid Medical. There is an institutional conflict of interest from the University of California, which has patent rights over stent retrieval devices for stroke. Rishi Gupta: Serves as PI for the TIGER study (Rapid Medical), PI for the ASSIST registry (Stryker Neurovascular), and PI for the RECCLAIM II study (Zoll). He is on the Clinical Events Committee (CEC) for the MIND trial (Penumbra) and is a consultant for Cerenovos.

Charles Majoie

We propose to continue standard care, so IV alteplase followed by EVT for patients who are eligible for both and admitted directly to thrombectomycapable centres.” EVT and 266 to the IVT and EVT group. No patients were lost to follow-up. The primary outcome was the subjects’ modified Rankin Scale (mRS) at 90 days. Secondary outcomes included mRS dichotomisations, National Institutes of Health Stroke Scale (NIHSS) score, reperfusion (on Expanded treatment in cerebral ischaemia [eTICI] score), final infarct volume, and safety outcomes such

as mortality. Researchers found no statistically significant difference between the two groups. Primary outcomes were similar, with 51.1% of patients recording a modified Rankin Score (mRS) of 0–2 in the IVT plus EVT group; this figure 49.1% in the direct EVT group. At the other end of the scale, researchers also noted no large difference between groups for patients with an mRS of 4–5, with the IVT plus EVT group having 23.7% and the direct EVT group having 20.5%. In secondary outcomes, investigators observed one statistically significant difference in the beta of the NIHSS score, with a finding of 0.21 five to seven days after discharge in the direct EVT group. Roos concluded: “We did not show superiority nor non-inferiority of direct EVT over IV alteplase followed by EVT, and we found similar haemorrhage rates with or without IV alteplase before EVT.” Charles Majoie, (Amsterdam University Medical Centre, Amsterdam, the Netherlands) and co-PI for the study, commented: “For now, we propose to continue standard care, so IV alteplase followed by EVT for patients who are eligible for both and admitted directly to thrombectomy-capable centres, but the trial also allows for more individualised treatment in certain subgroups, for instance omitting IV alteplase in patients with carotid-T occlusions in whom EVT can start promptly. When in doubt, leave it out.”

Issue 41 | April 2021

ISC late-breakers

Immediate angiography could reduce stroke treatment time A late-breaking abstract at ISC presented by lead study author Manuel Requena, a neurologist and neurointerventionalist fellow at Vall d’Hebron Hospital (Barcelona, Spain), reports that immediate angiography, rather than the standard care of computed tomography (CT scan), reduced stroke treatment time and was linked to improved recovery. ACCORDING TO RESEARCHERS, standard emergency department treatment for stroke patients involves a CT scan, which uses X-rays to pinpoint the presence and location of a blood clot. Angiography is an advanced X-ray imaging method that uses a catheter inserted into the blood vessel to find the location and size of the blockage. This study focused on determining if immediate angiography improved treatment time and recovery, compared to standard CT scans. “Our study is the first clinical trial that shows the superiority of direct transfer to an angiography suite,” said Requena. “Our findings were close to what we expected, and we were surprised that they

occurred so early in the study. We trust that they will be confirmed in ongoing, multicentre, international trials.” Beginning in October 2018, stroke patients who were admitted to Vall d’Hebron Hospital within six hours of stroke symptom onset with a suspected blocked blood vessel were randomly assigned to receive angiography or a cardiac CT scan. There were a total of 150 stroke patients by November 2020; the average age of the patients was 73 years, and more than half were men. In this interim analysis, stroke patients assigned to angiography underwent testing within 19 minutes of entering the hospital—less than half of the 43 minutes

Ischaemic stroke and TIA risk in COVID-19 patients lower than previously believed, study finds The elevated risk of ischaemic stroke and transient ischaemic attack (TIA) in hospitalised COVID-19 patients may be lower than previously reported—although it is still higher than the risks associated with influenza and other infections, a latebreaking presentation at ISC reports. SAATE SHAKIL—LEAD AUTHOR OF THE study and a fellow in the Division of Cardiology at the University of Washington’s School of Medicine (Seattle, USA)—stated that, across a sample of 21,073 hospitalised COVID-19 patients, the risk of death was also more than twice as high in those who experienced ischaemic stroke or TIA compared to those who did not. According to Shakil, the potential for increased ischaemic stroke risk in COVID-19 patients was first noted in spring 2020, as the pandemic began to affect the USA more severely—with multiple studies published last year finding the occurrence of ischaemic strokes to be between 0.9% and 2.8%, compared to about 0.2% in influenza patients. A further American multicentre study published in early 2021 found an ischaemic stroke incidence of 1.3% among 8,163 COVID-19 patients. Shakil and her co-authors used the American Heart Association (AHA) COVID-19 registry to further this existing research, and identified a subset of 21,073 patients hospitalised with an active COVID-19 infection, across 160 US hospitals, between March and November 2020, giving them a sample size that


help improve outcomes for our stroke patients.” A limitation of this study is that the hospital already had extensive experience with immediate angiography, so findings may differ at hospitals or care centres with less angiography expertise or experience. Another limitation is that the results of the study were not monitored by an external review group.

Manuel Requena

for the patients who received a CT scan. Similarly, stroke patients assigned to angiography received endovascular treatment to restore blood flow 54 minutes faster, on average, compared to CT scan recipients. At 90 days post-stroke, angiography patients were more likely than CT scan patients to show a one-point improvement on the six-point scale that measures stroke disability. “Stroke patients transferred directly to an angiography suite were less likely to be dependent on assistance with daily activities compared to the stroke patients who received the current standard of care—CT scan,” Requena said. “More frequent and more rapid treatment can

Stroke patients transferred directly to an angiography suite were less likely to be dependent on assistance with daily activities compared to the stroke patients who received the current standard of care—CT scan.”

among people hospitalised with COVID-19, the study was “much larger” than any of those used in previous initially intended to find out if there were any racial studies of ischaemic stroke risk among COVID-19 disparities within this group of patients. patients. It found that disparities based on race and ethnicity The study found that, in this cohort, there was a did exist to some extent, as non-Hispanic Black total number of 289 strokes, representing 1.4% of the patients accounted 31% of all ischaemic stroke patients sampled patients. Of these 289 strokes, 152 (52.6%) in the sample—compared to their overall representation were ischaemic strokes, and eight (2.8%) were TIAs— in the AHA registry, which was 27%—while this resulting in a total of 160 ischaemic cerebrovascular trend was reversed among Hispanic patients, as the events. percentage of ischaemic stroke patients in this group The researchers therefore calculated an overall was far lower than the overall percentage of Hispanic ischaemic stroke or TIA incidence of about 0.75% COVID-19 patients in the registry. Researchers also within their sample of 21,073 hospitalised COVID-19 found that ischaemic stroke risk in the sample was patients. As Shakil said, while this percentage is highest among non-Hispanic Black patients, with an lower than the 0.9–2.8% range previously suggested above-average incidence of 0.91%, followed by nonby other, smaller-scale investigations, it is higher Hispanic white patients and Hispanic patients, who than the 0.2% incidence of ischaemic stroke among had ischaemic stroke incidences of 0.75% and 0.52% influenza patients. In addition, the study found that respectively. This was in spite of non-Hispanic several comorbidities—including hypertension, white patients being, on average, the oldest cerebrovascular disease, coronary artery racial or ethnic group in the sample, with disease (CAD), diabetes and atrial a mean age of 67.7 years, compared to fibrillation—had a “significantly higher mean ages of 63.5 years and 63.1 years prevalence” among COVID-19 patients strokes respectively in the Hispanic and nonwho experienced an ischaemic stroke or representing Hispanic Black patient groups. TIA, compared to patients who did not. The study concluded that hospitalised According to Shakil, there was also a % COVID-19 patients who experienced an higher prevalence of critical illness features ischaemic stroke or TIA were more likely to be and poor in-hospital outcomes among those older, male, and with a higher prevalence of COVID-19 patients who did experience an comorbidities like atrial fibrillation, diabetes ischaemic stroke or TIA, as they had to stay in and hypertension than those without stroke hospital for roughly twice as long, on average. or TIA. Hospitalised COVID-19 patients who Regarding future research, Shakil stated experienced an ischaemic cerebrovascular that there is a need to evaluate the temporal event were found to have more than double and geographical changes in ischaemic the percentage of in-hospital mortality rates stroke and TIA risk among COVID-19 compared to those who did not, while increased patients—and that an adjusted analysis of rates of intensive care unit (ICU) admission, the study’s outcomes by race, comorbidities mechanical ventilation and renal replacement and illness severity, and an assessment therapy were also observed within the of the longer-term impact of sample. COVID-19 on cardiovascular Shakil also stated that, alongside and stroke risks,should also be its goal of assessing the conducted. prevalence of ischaemic stroke Saate Shakil

289 1.4


April 2021 | Issue 41

Stroke care access

Despite some advances, women still face disparities when it comes to global burden of stroke The continued global burden of stroke and how it disproportionately affects women are highlighted in the February issue of Stroke, according to a press release from the American Heart Association (AHA). STROKE EDITORS SELECTED NINE manuscripts focused on stroke disparities in women in this collaboration with Go Red for Women, the association’s global movement to end heart disease and stroke in women. Stroke editor-in-chief, Ralph L Sacco, (McKnight Brain Institute, Miami, USA), says: “Stroke continues to be a leading cause of death and disability worldwide, with women being more adversely affected by the global burden of stroke. “As our population ages, the number of stroke survivors will continue to rise, especially among

women. We must include more women in stroke research so we can enhance the critical evidence necessary to provide the appropriate stroke treatments needed to save and improve lives.” Two of the studies addressed concerns about the lack of women in stroke clinical trials, thus limiting information to ensure appropriate stroke treatment for women. The full nine manuscripts were as follows: Why are women less represented in intracerebral haemorrhage trials?–Tatiana Greige et al The under-enrolment of women in stroke clinical trials: What are the causes and what should be done about it?–Cheryl Carcel; Matthew Reeves Sex, age, and socioeconomic differences in nonfatal stroke incidence and subsequent major adverse outcomes–Ralph K Akyea et al Advances in stroke: stroke in women–Moira K Kapral et al The female stroke–sex differences in acute treatment and early outcomes of acute ischemic stroke–Anna Bonkhoff et al Absence of consistent sex differences in outcomes from symptomatic carotid endarterectomy and stenting trials–Virginia Howard et al Influence of pregnancy on haemorrhage risk in women with cerebral and spinal cavernous malformations–Nycole Joseph et al Sex-related differences in clinical features, neuroimaging and long-term prognosis after transient ischemic attack–Francisco Purroy et al Stroke incidence by sex across the lifespan–Manav Vyas et al

Study finds people in rural areas less likely to receive specialty care for neurologic conditions According to a press release from the American Academy of Neurology (AAN), a new study has found that while the prevalence of neurologic conditions like dementia, stroke, Parkinson’s disease and multiple sclerosis (MS) is consistent across the USA, the distribution of neurologists is not, and people in more rural areas may be less likely to receive specialty care for certain neurologic conditions. The study was published in the online issue of Neurology, and was funded by the AAN.


rian C Callaghan (University of Michigan, Ann Arbor, USA), study author and fellow of the AAN commented, “Neurologists in the USA are not evenly spread out, which affects whether patients can see a neurologist for certain conditions like dementia and stroke.” He continued: “Our research found that some areas of the country have up to four times as many neurologists as the lowest served areas, and these differences mean that some people do not have access to neurologists who are specially trained in treating brain diseases.” However, according to the AAN, Callaghan noted that the proportion of people receiving specialty care from a neurologist in more rural areas varied by condition. People with specific, less common conditions such as Parkinson’s disease and MS were just as likely to see a neurologist in more rural areas as in more urban areas, while people with less specific neurologic symptoms that are

more common, suchas dementia, pain, dizziness, vertigo, or sleep disorders, were more likely to see a neurologist in more urban areas than in more rural areas. The press release reports that for the study, researchers reviewed one year of data for 20% of people enrolled in Medicare and identified over two million people with at least one office visit for a neurologic condition. Researchers recorded the number of times people had an office visit with a neurologist during that year and compared that to how many times people had office visits with other health-care providers for a neurologic condition. Researchers identified a total of 13,627 neurologists practicing in the regions where study participants lived. Researchers also found the areas with the fewest neurologists had an average of 10 neurologists for every 100,000 people, while the areas with the most neurologists had an average of 43 neurologists for every 100,000 people.

According to the AHA, stroke is the second leading cause of death worldwide. More than 101 million people have a stroke each year, and more than 6.6 million people die of a stroke annually. About one in four stroke survivors will experience another stroke within five years. Sacco added: “The papers highlighted in this issue feature international research and perspective from more than half a dozen countries. This collective work from some of the most renowned scientists in the field offers important insight, recommendations, and guidance for addressing this critical topic. “We are pleased to publish this important research to enhance our understanding of the unique differences in the diagnosis, treatment, and prevention of stroke in women. Our essential goal is to prevent stroke, reduce disability and ultimately save lives; education and awareness are critical first steps.”

Stroke continues to be a leading cause of death and disability worldwide, with women being more adversely affected by the global burden of stroke.”

Ralph L Sacco

The association reports that overall, 24% of people with a neurologic condition were seen by a neurologist. In more rural areas, this number was 21%, compared to 27% in the areas with the most neurologists. Most of that difference was made up of people with dementia, back pain, and stroke. For dementia, 38% of people in more rural areas saw a neurologist, compared to 47% in more urban areas. For stroke, 21% of people in more rural areas saw a neurologist, compared to 31% in more urban areas. On the other hand, more than 80% of people with Parkinson’s disease received care from a neurologist, no matter where they lived. The numbers were similar for multiple sclerosis. “It is important that all people have access to the best neurologic care,” said James C Stevens (Fort Wayne Neurological Center, Fort Wayne, USA), president of the AAN. “Not surprisingly, more neurologists tend to work and live in metropolitan

One way to give people more access to neurologic care is with telemedicine, which has been used successfully during the COVID-19 pandemic.” James C Stevens

24% of people with a neurologic condition were seen by a neurologist.

In more rural areas, this number was


compared to


in the areas with the most neurologists areas, but this study underlines the need to ensure that rural areas also have a supply of neurologists to meet demand. One way to give people more access to neurologic care is with telemedicine, which has been used successfully during the COVID-19 pandemic.” A limitation of the study is that researchers looked at neurologic visits only for people with Medicare coverage, so results may not be applicable to younger people with private insurance.


April 2021 | Issue 41

Representation in neurosurgery

Women in neurosurgery: Why is the field still maledominated?

Factors including representation, a lack of mentoring, and discrimination have been among the issues cited by female neurosurgeons as contributing to gender disparity in the field. This is according to a study published in the Journal of Neurosurgery by Tina Lulla (Rutgers New Jersey Medical School, Newark, USA) et al, who conducted a systematic literature review of studies pertaining to women in neurosurgery.


he authors note in their introduction, “An increase in the neurosurgical workforce is necessary to meet the growing burden of neurosurgical diseases, such as cerebrovascular accidents and traumatic brain injury.” They further comment that despite 50.7% of medical students in the USA being women, according to the Association of American Medical Colleges (AAMC) in 2017, only 8.4% of neurosurgeons in the USA are women. Researchers looked at 39 studies describing the density of women neurosurgeons in particular regions, 18 of which documented the proportion of practising female neurosurgeons in a single or in multiple countries. The majority of these studies were from the past five years.

Factors in lack of representation

The paper identified eight factors that the authors report were contributing to the gender disparity in the field. These included: conference representation, the proverbial glass ceiling, lifestyle, mentoring, discrimination, interest, salary, and physical burden. Through their analysis, investigators saw 55 countries represented, with North America being the most researched region. They note that Asia and Europe were also well represented, but they could not find any analysis of Africa or Australia. According to the authors, the most frequently cited factor was mentorship, with 22 (56.4%) of studies finding it impactful. They also note that mentorship was mentioned as a factor even from the earliest study, in 2004, and was mentioned across multiple continents. Researchers comment, “Female medical students are more likely to enter programmes with a higher proportion of female residents. Mentorship has also been shown to improve recruitment as well as retention of women into neurosurgery.” The second most cited factor—mentioned across 19 (48.7%) studies—was lifestyle, such as work, family goals, and personal goals. Similar to mentorship, this factor was mentioned consistently and across multiple continents, which, according to researchers, indicated this is not a culture-specific concern. Authors cite a number of studies, including one from Japan, in which women had reported leaving their neurosurgery careers due to difficulty balancing their career and motherhood, and a study that reported that both male and female residents were leaving surgery due to lifestyle reasons. The authors comment that “In conjunction with our analysis, these data suggest that work-life balance is of increasing importance to incoming surgical trainees regardless of gender.” Other consistently cited factors were unequal opportunities and discrimination. Researchers report

that a questionnaire assessing the barriers faced by Indian women in 2017 saw 74.5% of respondents claim they felt supported by their male colleagues, yet, 40% reported they faced discrimination for their gender. On this factor investigators comment, “It is vital to encourage men in the field to mentor women at every stage of their careers. Having both genders actively involved in nurturing and encouraging women as they progress in their neurosurgical careers can propel women forward professionally.”

efforts to achieve gender equity in neurosurgery; expanding mentorship opportunities within the field and mitigating barriers to entering the field may benefit individuals of many backgrounds.”

Percentage of women in neurosurgery






For the authors, a limitation of their study was the lack of information on 140 countries. However, they also note that they were limited by the “inherent dichotomous use of gender characterisation” within the studies they used. For researchers, this means that they did not have the distinction between surgeon-identified sex and surgeon-ascribed gender. They further note that they only included two genders, and had no information on nonbinary or transgender neurosurgeons. Investigators found that while there are women performing neurosurgery across the world, “there is a great benefit to fostering global connections for neurosurgeons of all genders.” Authors further comment that they “firmly believe the pursuit of gender equity in neurosurgery need not conflict with broader efforts to increase the global neurosurgical workforce.” Lulla commented, “Our goal with this study was to determine the current gender distribution of neurosurgeons around the world and the possible factors contributing to country-specific gender disparities. In order to make strides towards gender equity in the field, it is essential to understand what has led to our current distribution. Our analysis revealed eight factors across multiple continents that contributed to gender disparities in neurosurgery. Addressing these factors will enable us to grow the global neurosurgical workforce while simultaneously moving towards gender equity.”



Global representation of women

Overall, it was found that Italy had the highest proportion of female neurosurgeons, at 36%. Countries with similarly high proportions include El DENMARK Salvador (29.33%), Denmark (26%), Uruguay (25.81%), and Finland (25%). It should be noted that these countries all vary in their number of neurosurgeons; Italy has 1,320, whereas Uruguay only has 31. The authors also found URUGUAY some indications of a growing enrolment of women in neurosurgery. For example, they found that in Italy, 55% of neurosurgery residents were women, while in Denmark, this was 40%. The countries with FINLAND the lowest proportion of female neurosurgeons were Kosovo (0%), Cyprus (0%), South Korea (1.7%), and Kazakhstan (2%). Authors note that Kosovo and Cyprus report overall fewer neurosurgeons: 20 and 22, respectively. However, South Korea reported 3,169 neurosurgeons and Kazakhstan over 300, which investigators observe is “on par” with countries with






Addressing these factors will enable us to grow the global neurosurgical workforce while simultaneously moving towards gender equity.” higher representation. Further to this point, the authors report that the number of female neurosurgery residents was lower in these countries also. In South Korea, of the 335 neurosurgery residents in 2018, 21 (6.3%) were female. The authors return to the factor of mentorship with regard to this point, commenting, “Fostering a large network of women neurosurgeons across the globe may help to create a strong network of mentorship and learning opportunities. “Efforts to increase the global neurosurgical workforce can be made in conjunction with


Tina Lulla

Issue 41 | April 2021

Mobile stroke units

Mobile stroke units may “result in lower rates of disability” A late-breaking abstract presented at the International Stroke Conference (ISC) 2021 (17–19 March, online) has presented evidence that patients who received care from a mobile stroke unit (MSU) were less likely to have a disability three months after their stroke than those taken to the emergency department by a standard ambulance. of the ongoing BEST-MSU (Benefits “OUR GOAL IN THIS STUDY WAS of stroke treatment delivered using a to treat patients on the mobile stroke unit within an hour of the onset of their stroke mobile stroke unit) study. Due to local limitations, researchers were not able to symptoms, and we were gratified that randomise patients so instead alternated one-third of the patients were actually weeks the MSU was in service; in the off treated within that time frame,” said week, there would be standard medical James C Grotta, lead study author and management. Across both weeks, patients director of stroke research at the Clinical were adjudicated for tPA treatment Institute for Research and Innovation by a blinded adjudicator, a vascular at Memorial Hermann—Texas Medical neurologist. If they were Center, Houston, USA. “Our deemed eligible, this patient study confirmed that patients was included in the study. who are treated early benefit The primary outcome for from a complete reversal this study was patient utilityof stroke symptoms and weighted modified Rankin avoidance of disability. This Scale (mRS) at three months. suggests that in the first hour Assessments carried out at after a stroke occurs, the brain 90 days were performed by is not yet irreversibly damaged an investigator blinded to and is very amenable to James C Grotta treatment assignment. effective treatment.” Investigators examined data from According to researchers, MSUs 1,047 patients who suffered an ischaemic are special ambulances equipped to stroke and who were eligible for tPA diagnose and treat stroke quickly. The treated at seven US centres (Houston, team on board the mobile stroke unit can Aurora, New York City, Indianapolis, treat the patient right away with tissue Los Angeles, Memphis, and Burlingame) plasminogen activator (tPA). between 2014 and 2020. Researchers This study is a phase III, alternating compared outcomes of stroke patients week, cluster-controlled trial, and is part

brought to the emergency department by a mobile stroke unit versus those who arrived by standard emergency medical services (617 patients via mobile stroke unit, and 430 patients via standard ambulance). Overall, 97% of eligible patients transported by a mobile stroke unit received tPA, compared to 80% of those brought to the emergency department by a regular ambulance. One-third of

Houston mobile stroke unit

Our study confirmed that patients who are treated early benefit from a complete reversal of stroke symptoms and avoidance of disability.”

German study shows use of mobile stroke units improves clinical outcomes

In a study published in The Journal of the American Medical Association (JAMA), researchers have found that stroke patients in Berlin for whom STEMOs (Stroke-Einsatz-Mobile) were dispatched were more likely to survive without long-term disability. ACCORDING TO CHARITÉ – Universitätsmedizin Berlin, (Berlin, Germany) where the research was carried out, STEMOs are a special purpose emergency response vehicle designed to evaluate and treat patients with stroke. It is reported that vehicles are fitted with a computed tomography (CT) scanner, a small laboratory, and thrombolysis capabilities on board. Additionally, a STEMO is managed by a neurologist who is supported by a specially trained emergency response team. STEMOs were first launched in Berlin in 2011. The study looked at 1,543 cases between February 2017 and October 2019. In 749 (49%) cases a mobile stroke unit was dispatched. If no STEMO was available at the time of the emergency call, only a conventional ambulance was dispatched to ensure transport to a specialist hospital. In 794 (51%) cases, patients were cared for within the conventional emergency medical system. Using a standardised protocol, the researchers then determined survival at three months post-stroke and the extent of any neurological impairment affecting the patients. Researchers found that a greater number of STEMO patients received thrombolysis, 60% vs. 48% in the

non-STEMO group. Additionally, patients received thrombolysis on average 20 minutes earlier than in controls. They further found that after three months, approximately 7% of patients in the STEMO dispatch group had died, compared with 9% in the control group. Furthermore, while approximately 51% of patients in the STEMO group reported no stroke-related impairments in day-to-day functioning, the corresponding figure in the control group was only 42%. “In our study, dispatch of a mobile stroke unit was linked to increased survival and reduced risk of disability,” says Heinrich J Audebert (Center for Stroke

In our study, dispatch of a mobile stroke unit was linked to increased survival and reduced risk of disability,” - Heinrich J Audebert


the patients treated by a mobile stroke unit were treated within one hour after the onset of stroke symptoms, compared to only 3% of patients transported by a standard ambulance. A total of 53% of the patients treated by a mobile stroke unit made a complete recovery from the stroke after three months, while 43% of the patients treated by a standard ambulance achieved a full recovery. For their primary outcome, researchers found that the utility-weighted mRS had a mean of 0.726 for the MSU, and a mean of 0.657, giving a difference of 0.069. According to Grotta, this difference is statistically significant at a p value of 0.002. When looking at the population of the study, Grotta noted that the groups were “very well compared” on baseline characteristics. Additionally, he commented that their population was diverse, with equal representation of men and women; around 40% of patients were Black, approximately 17% were Hispanic or Latino, and 20% had a baseline mRS greater than two, meaning they had some pre-existing disability. “Our results mean that, on average, for every 100 patients treated on a mobile stroke unit rather than standard ambulance, 27 will have less final disability and 11 of the 27 will be disability free,” Grotta said. “More widespread deployment of mobile stroke units may have a major public health impact on reducing disability from stroke,” he added. “Although mobile stroke units are costly to equip and staff, they reduce the time to treatment. We also expect that more treatment via mobile stroke units can reduce the need for downstream utilisation of long-term care.”

Research Berlin, Charité – Universitätsmedizin Berlin). He adds: “The relative odds of these patients having significant disabilities three months after stroke was 29% lower than in patients cared for by the conventional emergency medical services. STEMO dispatch therefore results in significantly more stroke patients returning to an independent life after stroke.” Researchers note that clinical trials in other regions are warranted.


60% vs 48%

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April 2021 | Issue 41

12 Complete reperfusion

Complete reperfusion may not offer better outcomes than nearcomplete reperfusion Ching-Jen Chen

90-day functional outcomes were similar between patients who achieved mTICI 2c and those who achieved mTICI 3 reperfusion 42.4% vs. 45.1%

Comment & Analysis Ching-Jen Chen (Charlottesville, USA) discusses his recent publication in the BMJ entitled, “Is a picture-perfect thrombectomy necessary in acute ischaemic stroke?”


hether imaging findings translate into outcomes of clinical importance is often a point of contention in imaging-dependent medical specialties such as neurology and neurosurgery. As techniques and technologies for acute ischaemic stroke (AIS) thrombectomy continue to improve, whether some of these advances result in better patient outcomes deserves further investigation. Due to its strong correlation with clinical outcome, recanalisation is often regarded as an important surrogate marker for therapeutic activity in recent AIS thrombectomy trials. As higher rates of recanalisation led to concomitant improvements in patient outcomes, efforts to increase recanalisation rates, through improvements in catheters and thrombectomy techniques, have garnered increasing attention. Although the American Heart Association (AHA) guidelines defined successful reperfusion as a modified Thrombolysis in Cerebral Infarction (mTICI) score of 2b or higher, there is mounting evidence to suggest better outcomes in patients who achieved reperfusion beyond the recommended 50% threshold. Consequently, the mTICI 2c grade (90–99% reperfusion) was added to differentiate outcomes of patients with near-complete reperfusion from those with closer to 50% reperfusion. However, whether there is diminishing returns beyond this threshold remains unclear. Should picture-perfect angiographic reperfusion be the goal of AIS thrombectomy? To answer this question, we compared the outcomes between patients who achieved mTICI 2c and those who achieved mTICI 3 reperfusion in AIS thrombectomy. The study was retrospective in nature, included data from 33 centres, and derived from the Stroke Thrombectomy and Aneurysm Registry (STAR). The study was limited to adult patients with anterior circulation arterial vessel occlusion. The total sample size of the study was 2,442, comprising 519 and

1,923 patients in the mTICI 2c and 3 cohorts, respectively. Rates of good functional outcome (primary outcome; modified Rankin Scale [mRS] score 0–2) at 90 days were similar between patients who achieved mTICI 2c and those who achieved mTICI 3 reperfusion (42.4% vs. 45.1%; odds ratio [OR]=1.118 [0.919– 1.360]; p=0.264). Secondary outcomes, including functional and neurological outcomes at discharge and 90 days, intracerebral haemorrhage (ICH), and procedure-related complications were also comparable between the two cohorts. To control the effects of potential confounders, the two cohorts were matched, and the resulting matched cohorts comprised 191 patients each. Although mTICI 3 reperfusion resulted in an absolute increase in the proportion of patients with the primary outcome of 7.8%, this difference was not significant (39.8% vs. 47.6%; OR=1.377 [0.918– 2.066]; p=0.122). This was associated with a lower 90-day mRS score for the matched mTICI 3 cohort in shift analysis (median 3 vs. 3; OR=0.702 [0.493–

independence. Older age, diabetes mellitus, higher pre-stroke mRS score, higher admission National Institute of Health Stroke Scale (NIHSS) score, longer symptom onset to puncture time, use of combined aspiration and stent retriever technique, higher number of passes, and procedurerelated complications were predictors of dependence. White race and higher ASPECTS remained predictors of 90-day functional independence after adjusting for missing data, while older age, diabetes mellitus, higher pre-stroke mRS score, and higher admission NIHSS score remained predictors of dependence after adjusting for missing data. Reperfusion status (mTICI 2c vs. 3) was not a predictor of functional independence. Finally, we also explored potential interactions between patient subgroups and functional independence. In patients with a pre-stroke mRS score ≥2, those who achieved mTICI 3 had a higher odd of 90-day functional independence (36% vs. 7.7%; adjusted OR [aOR]=15.734 [1.869–132.438],

Complete reperfusion in patients with anterior circulation AIS who underwent thrombectomy did not appear to confer better outcomes compared to near-complete reperfusion.” 0.999]; p=0.049). The remainder of the secondary outcomes were comparable between the two matched cohorts. Taken together, complete reperfusion was associated with a 7.8% increase in the rate of functional independence compared to near-complete reperfusion. However, this was not statistically significant and its clinical significance is unknown. In the study, we identified white race, hyperlipidaemia, and higher Alberta Stroke Program Early Computed Tomography Score (ASPECTS) as predictors of 90-day functional

p=0.011; p-interaction=0.014). There was also a greater likelihood of functional independence in patients with a history of stroke who achieved mTICI 3 reperfusion (42.3% vs. 15.4%; aOR=15.594 [1.377– 176.595]; p=0.027; p-interaction=0.041). These findings may warrant the pursuit of a more aggressive revascularisation in patients with a history of stroke or prestroke disability. The limitations of our study should be recognised. Most importantly, all imaging data and interpretation were self-reported by the treating neurointerventionalist,

and a centralised imaging core laboratory was not available. Furthermore, the revised mTICI grading scale that includes 2c was not universally adopted by all centres, and thus, some mTICI 2c outcomes may have been categorised as grade 3. Consequently, this may have diluted a potential outcome difference between the mTICI 2c and 3 cohorts, thereby effectively increasing the type II error rate. Procedural characteristics that can influence the degree of reperfusion, including difficulties in navigating to the occlusion site and extent of clot burden, may not have been fully captured in our data. The decision to pursue revascularisation of occluded distal branches could not be determined, as the stopping point for each centre and neurointerventionalist is subject to variation. However, it is important to note that core laboratory adjudication is not practical in the real-world setting when determining the threshold of successful reperfusion and procedural stopping point, as this is determined intra-procedurally by the treating neurointerventionalist. In conclusion, complete reperfusion in patients with anterior circulation AIS who underwent thrombectomy did not appear to confer better outcomes compared to near-complete reperfusion. Patients with pre-stroke disability and those with a history of stroke may have better functional outcomes after complete reperfusion in our exploratory analyses. Therefore, aggressive pursuit of complete angiographic reperfusion as interpreted by the treating neurointerventionalist may not be necessary, and the benchmark of success for emerging AIS thrombectomy techniques and technologies may not need to be picture perfect. Ching-Jen Chen is a chief resident at the Department of Neurological Surgery, University of Virginia Health System, Charlottesville, USA. Disclosures: Ching-Jen Chen reports no disclosures.

April 2021 | Issue 41

14 Interview


Mitchell Elkind

Mitchell Elkind is a professor of Neurology and Epidemiology at Columbia University Irving Medical Center, and chief of the Division of Neurology Clinical Outcomes Research and Population Sciences (Neuro CORPS) in the Neurology Department of Columbia University, New York, USA. He is the current American Heart Association (AHA) president. Elkind talks to NeuroNews about his neurology career.

What initially attracted you to medicine and neurology?

I was a reluctant medical student, but an enthusiastic neurologist! Growing up with a physician father, I felt the need to distinguish myself in some way. He was a nephrologist, and acid-base balance just did not excite me. So in college, I studied philosophy, trying to understand the meaning of life. It turned out that the most interesting aspects of philosophy, to me, were understanding the philosophy of the mind, how the brain works and what it tells us about who we are. I never figured all that out, but along the way I discovered that I wanted to take care of people with brain disorders, since neurological problems were the most informative window into people’s lives that I have found.

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

I am fortunate to have had terrific mentors. I learned from several people who I consider to be the best neurologists in the world. C Miller Fisher at Massachusetts General Hospital described many of the syndromes of stroke that we take for granted today. He demonstrated that patience and attention to an individual patient’s story can teach us things never before seen. Walter Koroshetz shared that same passion for clinical detail, and combined it with a scientific approach. The brilliant Anne Young showed me how to do a neurological examination with style, and demonstrated what academic and scientific leadership looks like. JP Mohr at Columbia has an incredible awareness of neurological history and the most intimate understanding of the neurological literature of anyone I have met. Ralph Sacco, the first neurologist to serve as president of the AHA, showed me the value of studying populations, as well as individual patients, as a way to best understand the causes of disease in an unbiased fashion. I learned different things from all of them, and I hope I am able to bring together their skills in meaningful new ways.

Has COVID-19 impacted your practice and what were the lessons learned from this?

I lived through the height of the pandemic in New York City in March–April 2020, and it affected the way I think about my career and practice in many ways. I had never feared for myself and my family while practicing before, but I did then. It was almost reminiscent of the uncertainty we faced after 9/11 in New York. There was a sense of heightened awareness, and every day I learned something new. But the people who most impressed me during that period were our residents, fellows, and med students. They rose to the occasion, took on the challenges of caring for these incredibly sick patients, and risked their own lives and careers. I learned more from them than they did from me, I am certain.

What has your experience been as president of the American Heart Association during the pandemic?

Serving as AHA president during a pandemic was obviously not what I had planned for the year! I was intending to focus on expanding AHA’s work on brain

health, engaging other neurologists in the work of the AHA, and increasing the research funding going to brain disease. Who knows what we will be asked to do when called to serve? I am extremely proud of the work of the AHA during my tenure. Instead of focusing only on brain stuff, I learned about COVID-19 and heart disease, worked on several COVID-19-related research projects, and tried to educate people about seeking help during the pandemic and getting their vaccines. This pandemic was not only about the coronavirus: another major area of focus for us was addressing the impact of structural racism on health disparities, a problem made even more acute by the pandemic.

What has been the most important development in the neurology field during your career?

The rapid changes in stroke care have been incredible. The acceleration of stroke care from thrombolysis in 1996, to the proven benefits of thrombectomy in 2015, to treatment in extended time windows just a few short years later, has been astounding. The fact that we can now treat stroke, and not just watch it occur, is a testament to the tireless work of so many phenomenal colleagues.

What has been the biggest disappointment?

I do feel that for all the great advances in acute stroke care, we still cannot prevent stroke as well as we should. Stroke mortality has been inching back up. Large segments of the population, including rural populations

The fact that we can now treat stroke, and not just watch it occur, is a testament to the tireless work of so many phenomenal colleagues.” and communities of colour, do not have access to adequate care. Obesity, diabetes, and substance abuse continue to be major problems. We know what needs to be done for the most part, but social and economic barriers seem to trip us up. We need to address these problems with the same intensity that we do the technological advances.

What questions would you like to see answered in the field?

I have two major areas of interest right now. One is understanding the relationship of heart disease, like atrial fibrillation and atrial cardiopathy, to stroke risk and prevention. My colleagues and I have focused on the idea that patients with abnormalities of the left atrium can have strokes even without developing atrial fibrillation, and that anticoagulation can prevent those strokes. We are now conducting a federally-funded,

international trial, called ARCADIA, testing these ideas. The second major area is one that has excited me since the beginning of my fellowship: whether infections can cause stroke and worsen outcomes after stroke. That concept, of course, has become even more relevant since the onset of the coronavirus pandemic, since we do indeed see strokes occurring in patients with COVID-19. In a way, there is an irony that I am AHA president during this pandemic since this is something I have been exploring as an epidemiologist for the past 25 years.

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

I think the most exciting advance of this crazy pandemic year has been the record-breaking speed of development of the mRNA vaccines for COVID-19. Within days of the virus being identified, investigators at the National

Issue 41 | April 2021

Interview 15 Institutes of Health (NIH) and elsewhere had produced the mRNA sequences for the spike protein that would become the basis for the vaccines. Almost before the virus was on our shores, we had a vaccine ready for testing. Within less than a year, we had solid evidence that this entirely new category of vaccines worked extremely well, better than anyone had hoped. The flip side of this great scientific advance, of course, was the great failure of the USA to take the virus seriously enough until the vaccines became available, allowing rapid spread, variant mutations, and massive death and societal upheaval.

What advice would you give to those beginning their neuro career?

Find a mentor with whom you really connect. I was fortunate to have great mentors who not only taught me and modelled the highest forms of professional accomplishment, but also made opportunities available for me. Then find an area of the field that makes you excited to wake up and think about. Keep chipping at it from different angles, put your own stamp on it, and try to find others who share your passion because it is usually more fun to work with others on big projects. And be patient: big ideas generally take time to mature.

Could you tell us about a particularly memorable case you have had, and what you learned from it?

My most challenging case was a diagnostic dilemma that played out over several years. The patient was a young man who presented with episodic visual loss due to intracranial carotid stenosis, involving the ophthalmic artery, as well. After extensive evaluation, we thought he might have vasculitis, and treated him for that, but he also had some unusual immunological and haematological features, as well as a rash. Eventually, when a family member convinced him to stop his immunosuppressive medication, he developed a rapidly progressive and ultimately fatal multisystem disorder. It turned out that he had POEMS syndrome, a rare plasma cell disorder that can be rarely associated with a paraneoplastic vasculopathy and strokes. He was especially unusual in that he presented with strokes as an initial manifestation. I was devastated that we were unable to save him. He might have been saved by an earlier bone marrow transplant. It is a humbling business. Now I always try to think of what I might be missing when things do not add up fully.

What are your interests outside of medicine?

Fact file Current appointments:

Jan 2014–current: Professor of Neurology and Epidemiology in the Sergievsky Center; Columbia University College of Physicians and Surgeons; Mailman School of Public Health, Columbia University, New York, USA Chief, Division of Neurology Clinical Outcomes Research and Population Sciences (Neuro CORPS), Department of Neurology, Columbia University, New York, USA


September 1983–June 1987: BA in Philosophy at Harvard College, Cambridge, USA September 1987–August 1988: M.Phil in History and Philosophy Science at Darwin College as a National Science Foundation Graduate Fellow, Cambridge University, Cambridge, UK. September 1988–June 1992: M.D., Harvard Medical School, Boston, USA July 1996–June 1998: M.S. in Epidemiology Columbia University School of Public Health New York, New York, USA

My interests outside of medicine are enjoying nature and the outdoors, primarily in Northwest Connecticut, in whatever way the season permits: gardening in the spring, paddle boarding on our lake in the summer, hiking the hills in the fall, skiing in the winter, and after it all, enjoying a single malt while watching the sun set!

Honours (selected):

American Heart Association Stroke Council Award, Chicago, 2018 AHA/ASA Stroke Hero Award, 2019, New York City CycleNation event President-Elect, American Heart Association, 2019–2020 President, American Heart Association, 2020–2021

April 2021 | Issue 41

16 Asymptomatic carotid artery stenosis USPSTF RECOMMENDS

USPSTF recommends against general screening for asymptomatic carotid artery stenosis In a recommendation statement published on 2 February in The Journal of the American Medical Association (JAMA), the US Preventive Services Task Force (USPSTF) advises against screening for asymptomatic carotid artery stenosis in the general adult population. This recommendation is consistent with the task force’s 2014 statement on the topic.

DURING A REVIEW OF ALL the available data on screening for carotid artery stenosis in the general population, authors Alex H Krist (Virginia Commonwealth University, Richmond, USA) and colleagues detail that the USPSTF “found no new substantial evidence” that could change its 2014 recommendation. Therefore, the statement concludes “with moderate certainty that the harms of screening for asymptomatic carotid artery stenosis outweigh the benefits”. The authors detail that asymptomatic carotid artery stenosis refers to stenosis in persons without a history of ischaemic stroke, transient ischaemic attack, or other neurologic symptoms

referable to the carotid arteries. The prevalence of asymptomatic carotid artery stenosis is low in the general population but increases with age, Krist et al note. The authors further adding that, while asymptomatic carotid artery stenosis is a risk factor for stroke and a marker for increased risk for myocardial infarction, it causes a relatively small proportion of strokes. Although the USPSTF do not recommend screening of the general population for asymptomatic carotid artery stenosis, the authors acknowledge that several factors increase a person’s risk, including older age, male sex, hypertension, smoking, hypercholesterolaemia, diabetes, and heart disease. However, they also state that “there are no externally validated, reliable methods to determine who is at increased risk for carotid artery stenosis, or who is at increased risk for stroke when carotid artery

stenosis is present”. Krist and colleagues highlight data gaps in this field, writing: “More research is needed to evaluate the benefits and harms of screening for asymptomatic carotid artery stenosis in the general adult population.” Considering the direction of future research, they suggest that this would include trials with long-term follow-up (>5 years) that compare carotid endarterectomy or carotid artery angioplasty and stenting plus contemporary best medical therapy with best medical therapy alone, including completion of ongoing trials. In addition, they recommend the development and validation of tools to determine which persons are at high risk for carotid artery stenosis and for stroke due to carotid artery stenosis and who might experience harm from treatment with compare carotid endarterectomy or carotid artery angioplasty.

Issue 41 | April 2021

Racial/ethnic disparities 17

Differences found in stroke severity and post-stroke care among Black and Hispanic women

chi-squared test and partial corrections. A logistic regression model was used to look at differences in disposition. This model was formed with race/ethnicity, age-groups, their primary interaction, stroke score, stroke type, smoking, obesity, diabetes, hypertension, and insurance status. Gaillard commented that, “stroke type, stroke severity, and obesity were statistically significantly associated Preliminary research presented at the Nursing Symposium Oral abstracts session of the with disposition.” International Stroke Conference (ISC) 2021 meeting (17–19 March, virtual) has found that Researchers found that Black and Hispanic women Black and Hispanic women aged 65–74 years old hospitalised with stroke had more severe aged 65–74 years old, hospitalised with stroke, had more strokes than their white counterparts. severe strokes than white women of the same age group. Nearly 99% of the women had March 2019. The patients were categorised ccording to Trudy R Gaillard, an associate health insurance, although Black women were by age group: 65–74 years old (young), 75– professor at Florida International University’s the most likely to be without health insurance. 84 years old (middle) and 85 years or older College of Nursing and Health Sciences After controlling for age, race, and stroke (older). The data analysed included stroke (Miami, USA), stroke is the leading cause of death severity, Black and Hispanic women in the type and severity; other health issues; age; for women in the USA. Furthermore, non-Hispanic younger and middle age groups had a greater race/ethnicity; and discharge information— Black women are twice as likely to have a stroke when chance of being sent to a skilled nursing or whether patients were discharged home, to compared to non-Hispanic white women, she added. rehabilitation centre when compared to white a skilled nursing centre or to a rehabilitation “The Black and Hispanic female stroke survivors women in the oldest age group (85 years and facility. 65–84 years old were younger and had a greater chance older). Black women with stroke accounted for of being sent to a skilled nursing or rehabilitation Trudy R Gaillard In her conclusion, Gaillard commented that, about 27% of all patients; while 37.5% centre when compared to older white females who were “interaction of age and race together, is more valuable were Hispanic and about 35% were white. Among the discharged home after their stroke,” said study author than looking at each independently.” participants aged 85 years or older hospitalised for Gaillard. “Future studies are needed to explore the type of stroke, 18.4% were Black women, 36% were Hispanic Gaillard reported that the aim of the study was to healthcare facilities that women are discharged to after women and about 40% were white women. examine disposition of type of stroke, stroke severity, stroke and to examine the quality of care received,” Subjects were further categorised using the Pearson and comorbidities (diabetes, hypertension, obesity, Gaillard continued. “This type of study should be smoking) among older female patients by race/ethnicity done in multiple cities, across care settings, including and age after inpatient hospitalisation with a diagnosis inpatient rehabilitation facilities, skilled nursing of stroke. facilities or home with or without home health and Researchers analysed data from the Get With The outpatient rehabilitation services.” Guidelines-Stroke Programme by the American Heart Limitations of the study include that it was done in Association/American Stroke Association, detailing only one hospital and the researchers did not examine 1,587 female patients who were discharged after a stroke patients’ outcomes after discharge. from Baptist Hospital of Miami from April 2014 to


Interaction of age by race is more valuable than looking at each independently.”

Discriminatory housing policy may have contributed to higher stroke rates, study suggests A poster presented at the International Stroke Conference (ISC) 2021 meeting (17–19 March, virtual) reports that neighbourhoods affected by the historic housing policies in the USA, known as redlining, were associated with higher rates of stroke. INVESTIGATORS REPORTED that redlining policies were discriminatory housing policies that restricted the sale or purchase of homes by race (discriminating largely against the Black population) in certain neighbourhoods across the USA. These policies were established nearly a century ago and outlawed by the Fair Housing Act of 1968. “Differences in stroke rates, whether we are studying ischaemic or haemorrhagic stroke, are usually attributed to biological differences or differences in underlying conditions,” said lead study author Jeffrey J Wing, an assistant professor of epidemiology in the College of Public Health at The Ohio State University, Columbus, USA. “Yet, our findings suggest the difference we found in the Columbus area may actually be the result of structural racism.” According to researchers, beginning in 1936, the Home Owners’ Loan Corporation began restricting the sale of homes in certain neighbourhoods

across the country by redlining or marking neighbourhoods by “risk for investment,” which equated to race. As a result, residents who lived within these redlined areas were denied home loans, which lowered tax revenues in these communities, thereby reducing investment in schools and services, and creating numerous inequities for residents for multiple generations. “Even though redlining was abolished in 1968, redlining is a form of structural racism that perpetuated segregation and racial inequities. Accumulating evidence shows this divisive and exclusionary housing practice continues to have long-term effects on the health of many people, even today—more than 80 years later,” said study co-author Helen Meier, an assistant research scientist at the University of Michigan’s Institute for Social Research, Ann Arbour, USA. “Our study is one of the first to link historic redlining in a US city to frequency of stroke.” Researchers examined the association

level data. They assessed the between the discriminatory association between historic housing policies of redlining redlining scores and stroke and stroke rates in Columbus rates across neighbourhoods in neighbourhoods in 2017. They Columbus in 2017. calculated historic redlining Researchers found scores for neighbourhoods that higher historic within the boundaries of Neighbourhoods redlining scores were Columbus based on the in the highest associated with greater degree of redlining. group of historic rates of stroke, when Thus, the greater the redlining scores comparing the highest redlining, the higher the to the lowest quartile redlining score. had a 1.48% higher of historic redlining Researchers then stroke rate scores. Additionally, matched the redlining neighbourhoods in the scores with stroke highest group of historic rates measured in the same redlining scores had a 1.48% higher neighbourhoods from the 500 Cities stroke rate, compared to those with the Project. The 500 Cities Project is from lowest redlining scores. “As different cities across the country declare racism as a public health crisis, it is important to have more research that shows the link between racism and health disparities,” Wing said. “Our research ha s the potential to help change how we treat and care for all individuals and promote equitable access to care that can lead to improved health outcomes.” Study limitations highlighted by the authors were inclusion of people who had a history of stroke may not have always resided in the same census tract, leading to unmeasured variability in redlining exposure. In addition, this is an ecologic-designed study, where redlining the US Centers for Disease Control and exposure was combined with stroke rate Prevention (CDC) and reports on 27 to a neighbourhood level, which limits chronic disease measures for the 500 the assessment of individual associations, largest American cities in all 50 states, Wing added. quantified by city and census tract-


Health disparities in stroke are going to persist until we address the legacy of structural racism, of which historical redlining is one form.”

April 2021 | Issue 41

18 Stroke developments

Overestimation of ischaemic core on computed tomography perfusion Álvaro García-Tornel Garcia-Camba Comment & Analysis Álvaro García-Tornel Garcia-Camba discusses his recent publication in Stroke, which aimed to evaluate the influence of time and collateral status on ischaemic core overestimation. This was a retrospective, single-centre study, including patients with anterior circulation large-vessel stroke that achieved reperfusion after endovascular treatment.


urrent volumetric estimation of ischaemic core on computed tomography perfusion (CTP) in patients with large vessel stroke is based on fixed thresholds, derived from studies that compared baseline CTP to follow-up diffusion weighted magnetic resonance imaging (DW-MRI). While this approach might be practical for daily treatment decisions, it also carries a major limitation that is related to an inherent assumption that has been widely accepted. The assumption is that, for any given patient with a large vessel stroke, the accuracy of currently used thresholds for ischaemic core estimation

(relative reduction of cerebral blood flow below <30% compared to contralateral hemisphere) is independent of patients’ baseline characteristics. Previous studies have shown that the general rule which points to CTPischaemic core (Regional cerebral blood flow [rCBF] <30%) as a predictor of minimal final infarct volume is, in fact, overestimating the final infarct in a non-negligible number of patients. Our study focused on predictors of ischaemic core overestimation, rather than on core underestimation, or on the magnitude of both types of error, for one reason: if we consider CTP derived thresholds, the

Neuroprotectant delivered to the brain in nanoparticles may improve stroke treatment Preliminary research presented at the International Stroke Conference (ISC) 2021 meeting (17–19 March, virtual) has found that when NA1, a neuroprotectant, was delivered to the brain in nanoparticles, it reduced stroke severity and improved survival in a mouse model of stroke. IN AN EARLIER HUMAN TRIAL (THE ESCAPE-NA1 trial), NA1, a small peptide designed to save brain cells from death after stroke, showed mixed results when administered to patients undergoing clot removal for severe stroke. Some patients in the trial also received the intravenous clot-busting medication tissue plasminogen activator (tPA), and these patients, in particular, showed a lack of improvement in functional outcomes from NA1. “NA1 binds many organs, cells and proteins in the body. Without protection, it cannot get into the brain with high efficiency and specificity and may otherwise get into cells where we do not want it, or bind and deactivate other treatments, such as the clot-busting medicine tPA,” said Jiangbing Zhou, co-senior author

biomarker to assess the real core at the point that image is performed, it should be impossible (the ground truth) for the core to decrease over time. Juxtaposed to this, among patients in which follow-up infarct is larger than estimated infarct, two hypotheses should be considered: the core has been underestimated by a CTP technical pitfall (real underestimation) and/or infarct has increased its size until the point that is larger than estimated infarct (infarct growth). The main finding of our study is that the odds of ischaemic core overestimation on CTP is influenced by collateral circulation. In particular, a poor collateral status, determined by CTP-derived hypoperfusion intensity ratio (HIR) ≥0.4 in patients imaged within four hours from onset, increases the chances of overestimation. While previous evidence supports that CTP thresholds are time-dependent, there is a lack of evidence regarding how cerebral haemodynamic state influences the interpretation of perfusion maps. Patients with poor collateral status, leading to rapid conversion from tissue at risk to infarcted tissue, are those who

The odds of ischaemic

core overestimation on CTP is influenced by collateral status.”

of the study and associate professor of neurosurgery and biomedical engineering at Yale University, New Haven, USA. To deliver NA1 precisely, the research team in this study created stroke-targeting nanoparticles to encapsulate and deliver NA1 to portions of the Jiangbing Zhou brain being deprived of oxygen in a stroke mouse model. In the mouse model study conducted from 2016 to 2020, researchers compared the ability of nanoparticles filled with NA1 and non-encapsulated NA1 to improve survival, reduce stroke size, and reduce brain swelling. Both treatments contained the same dose of NA1 (50mcg) delivered intravenously to mice with blockage of a brain artery.

Researchers found:

Stroke size was reduced by 69.8% among mice treated with NA1-loaded nanoparticles, compared with 0.7% for those treated with NA1 that was not Stroke size encapsulated. was reduced by Brain swelling was 69.8% among mice reduced by 60.3% treated with NA1among mice treated loaded nanoparticles, compared with 0.7% with NA1-loaded for those treated with nanoparticles, NA1 that was not compared with 3.3% encapsulated encapsulated. Median days of survival

show larger ischaemic core on admission CTP but are also those in which core prediction may be most misleading. In our study, severe hypoperfusion influence on core overestimation differed according to onset-to-imaging time, with a stronger size of effect being seen in patients imaged early after onset.Perfusion imaging has been widely promoted as the tool to shift acute stroke management from a time-based to a tissue-based paradigm. An important limitation in perfusion imaging interpretation is that volumetric calculation of CTPderived core is forecasted based on hypoperfusion severity rather than real tissue fate. Our results emphasise that collateral circulation status should also be considered when forecasting final infarct on admission CTP maps. We consider that major limitations of our study are related to its retrospective design, the fact that it is a single-cent study, and that a selection bias cannot be excluded, as some patients with a large core on baseline imaging, either in non-contrast CT or CTP, were excluded from treatment. Moreover, as mentioned before, all findings of our study are conditioned to the assumption that reperfusion is achieved, a variable that is unknown at the time of imaging. Álvaro García-Tornel Garcia-Camba practices at the Stroke Unit, Neurology Department,Hospital Universitari Vall d’Hebron, Barcelona, Spain. Disclosures: Álvaro García-Tornel Garcia-Camba reports no disclosures.

were more than 14 days among mice treated with NA1-loaded nanoparticles (mice in this model usually survive significantly less than 14 days), compared to six days for those treated with NA1 that was not encapsulated. “When delivered by nanoparticles, the same dose of Kevin Sheth NA1 that was not effective in an earlier study reached the stroke area and provided a surprising degree of effectiveness. The use of nanoparticles in stroke treatment may open new doors to delivering NA1 and other promising therapies to the brain,” said Kevin Sheth, co-senior author of the study and professor of neurology and neurosurgery at Yale University, New Haven, USA. According to researchers, since the nanoparticles act as antioxidants and may improve stroke outcome, some of the mice were also treated with nanoparticles not containing NA1. Those mice had intermediate improvements: stroke size reduced by 52.2%, brain swelling reduced by 30.2% and a median survival of 10 days was observed. “We have not had any recent major advances in the delivery of brainprotective agents for stroke. These results suggest a significant effort to change that landscape,” Sheth said.

April 2021 | Issue 41


Improvement in opioid withdrawal symptoms achieved through non-invasive neuromodulation technique A late-breaking abstract presented at the North American Neuromodulation Society (NANS) 2021 virtual meeting (15–16, January) has shown that noninvasive neuromodulation may bring about a significant reduction in clinical opiate withdrawal scale (COWS) score. THE RESULTS WERE PRESENTED BY CARLOS Tirado (Austin, USA), chief medical officer at Carmahealth and principal investigator of this study. The focus of the study was on the transcutaneous auricular neurostimulation (tAN) device—the Sparrow Therapy System (Spark Biomedical)—for the treatment of opioid withdrawal symptoms. According to figures presented by Tirado, in the USA, there are five to eight million people using opioids for chronic pain management, 2.1 million people with an opioid-use disorder, and fewer than one million active heroin users. Tirado stated that there had been a “levelling off” of this opioid trend over the last few years but, “with the pandemic, we have seen an unprecedented increase occurring within a very short period of time”. Tirado claimed that a critical element in the treatment of opioid use disorders (and opioid analgesia for dose modification) is the management of withdrawal. He stated that once dependent, individuals experience

currently has 26 enrolled. Individuals were withdrawal anywhere from 6–12 hours after admitted to an inpatient drug treatment the use of a short-acting opioid and 7–10 COWS scores saw facility for a five-day drug treatment days for longer-acting opioids. a reduction from period. The primary endpoint was a In his presentation, Tirado showed baseline by 50.4% significant reduction in COWS score after that the two most common symptoms of at 60 minutes and 60 minutes. The secondary endpoint was a withdrawal are pain and anxiety. Pain 54.6% at clinically significant reduction of COWS creates a problem because a patient 120 minutes. between days two and five. may struggle to tell the difference Tertiary endpoints included treatment between withdrawal pain and the pain they retention, continuation of treatment, passing originally complained of. Other withdrawal a naloxone challenge test, and other patientsymptoms included chills, nausea, fatigue, reported quality of life measures. cramps, sleeplessness, tremors, muscle Tirado presented the results from the 26 tension, increased heart rate, running patients. The mean age was 34.4 years, nose, and yawning. Additionally, patients 65.4% were male, 84.6% were white, the often describe withdrawal as unbearable, mean duration of opioid use was 12 years, incapacitating, and cite fear of withdrawal and 92% of patients were using heroin as a primary reason for the continued use of prior to treatment. Common psychiatric opioids. comorbidities included depression (38.5%), The study, titled ‘Using transcutaneous anxiety (38.5%), and bipolar disorder (30.8%). auricular neurostimulation in the reduction of In this group of 26, the COWS scores saw a reduction symptoms associated with opioid withdrawal’, used from baseline by 50.4% at 60 minutes and 54.6% at 120 a wearable non-invasive tAN device, placed around the minutes. On day two, COWS scores were reduced from ear, connected to a patient controller and app for the baseline by 60.8%, 63.8% on day three, 68.3% on day doctor. The device targets cranial nerve branches 10 and four, and 75% on day five. A total of 92.3% of patients five. had a 30%-or-greater reduction in COWS on day one. Tirado reported that a larger study is currently The symptoms with the greatest reduction were being run with the aim of randomising 40 patients and parasympathetic neurological symptoms, such as restlessness, which saw an 82.5% reduction from baseline, and tremor, which saw a 73.7% reduction from baseline. All of the patients who completed the study passed the naloxone challenge on either day three or day five, and 92.9% were amenable to continuation of addiction treatment at exit study. Commenting on the findings, Tirado stated, “we were able to demonstrate that individuals were more likely to remain engaged and continue to their next phase Carlos Tirado of treatment.”

We were able to demonstrate that individuals were more likely to remain engaged and continue to their next phase of treatment.”

Future stroke rehabilitation could include robotic therapy

physiologically. The hypothesis of Edwards’ current trial is that robot therapy and tDCS would lead to a greater improvement than robot therapy with sham tDCS on the upper extremity Fugl-Meyer Dylan J Edwards, director of the Moss Rehabilitation Research (UEFM) scale. They also assessed Institute and director of Human Motor Recovery Laboratory motor function using the Wolf motor (Philadelphia, USA), presented results at NANS (15–16, January) for function test. Eighty-two patients with a study he led looking at transcranial electrical stimulation (TES) right hemiparesis completed the trial. paired with robotic-assisted therapies in stroke recovery. Each patient had three sessions of tDCS per week for 12 weeks. Sessions lasted when you are looking to apply a dwards noted that TES can be supplementary therapy so that you have a one hour, and were accompanied by used as a monotherapy, but alternating shoulder, elbow and wrist stable behavioural therapy upon which to he is interested in its use in robotic training, amounting to about combination with other therapies (speech, test the supplement.” one thousand repetitions. The primary Edwards reported he carried out a occupational, physical, robotics, drugs). endpoint was measured at 12 weeks and study in 2009 investigating transcranial In this case, the combination is physical there was a six-month follow-up. stimulation in chronic post-stroke therapy using robot-assisted therapies. The subjects were randomised between hemiparesis in a small group of subjects. Edwards stated this current research the real and the sham stimulation, They showed that anodal transcranial was motivated by a 2010 clinical trial although participants wore the same direct current stimulation (tDCS) of published in the New England Journal electrodes and were all tDCS 2mA for 20 minutes could raise the of Medicine (NEJM), which compared naïve. excitability of the corticospinal robot-assisted therapy with intensive Edwards explained how they tract. Edwards said that this led comparison therapy, over 12 weeks and carried out robot therapies. Patients to the question as to whether 36 sessions. place their affected limb into the robotic training for a period 45 to The primary endpoint of this study robot handle, which has a display 60 minutes after the tDCS session was the Fugl-Meyer Assessment, and, monitor in front of it. Then, and what would happen to according to Edwards, it showed a, using the robotic device, that potential. “small but significant improvement in patients aimed to hit certain From this, Edwards motor function that was sustained after targets represented on claims that he and his the 12 week intervention”. the display. Edwards colleagues showed that the Edwards commented: “Robot therapy noted that this can increase in corticospinal is not the only method of performing be used as either intensive physical-type therapy, however, excitement could be an assessment or a it makes sense because the robot does not sustained during that robot training tool. therapy. So, these therapies tire, and the therapy is really structured Dylan J Edwards While Edwards was able could plausibly coexist and consistent, and that is important


to point to other studies which showed positive results for TES and robotassisted therapy, he reported that, in the case of his study, “The tDCS did not confirm an advantage over sham stimulation in this context.” However, he added, “We have not ruled out a potentially faster recovery trajectory in the tDCS group, and the results for that could not be answered by the design of this study—but that does warrant further exploration given that the two other studies I presented did have a shorter number of sessions, by about a third of what we did. If tDCS could indeed lead to fewer sessions being required for the same clinical benefit, that warrants further investigation.”

We have not ruled out a potentially faster recovery trajectory in the tDCS group, and the results for that could not be answered by the design of this study.” Dylan J Edwards

Issue 41 | April 2021


Closed-loop neuromodulation could restore memory after traumatic brain injuries

only when a participant’s memory was recordings for each subject. predicted to fail. Researchers observed According to the study team’s findings, an 18% improvement in word recall the classifier performed “well above with closed-loop stimulation of LTC. In chance” discriminating between words contrast, closed-loop stimulation outside recalled and non-recalled words with of the lateral cortex showed temporary an area under the curve of 0.64, which impairments of list learning ability. Gross reported as statistically significant. A follow-up study tested closed-loop All eight patients showed an average stimulation of temporal cortex in eight improvement of 19% was observed epilepsy patients with a history of TBI. in word recall for stimulated lists Compared with age-matched controls, compared with non-stimulated lists. these participants had one standard Gross reported a significant variability Results of a randomised controlled trial presented at NANS (15–16, deviation impairment in memory in memory enhancement across this January) by Robert E Gross (Emory University School of Medicine, function. cohort, ranging from a 5% decrease Atlanta, USA), suggest an average increase of 19% in word recall As in their previous study, machine in memory in one subject, to a 40% for traumatic brain injury (TBI) patients after receiving stimulation of learning classifiers were trained on increase in another. Gross attributed this the lateral temporal cortex (LTC). the brain activity from these patients, variability in efficacy to the variability and then stimulation was of the placement of stimulating ccording to data Gross presented, used as well, these have not been proven administered to LTC when to be effective in randomised controlled electrodes, further noting over four million people in the participant’s studies. that greater data will be the USA live with TBI, with All eight memory was Gross cited a previous, needed to acquire the the most common complaint from patients showed an predicted to related work, upon which he optimal stimulation these patients being impaired memory. average improvement fail. was a collaborator, published target. Gross claimed that memory function is of Gross in Nature Communications Gross commented directly related to levels of disability reported that in 2018, which demonstrated on the significance of and productivity. He further stated that patients were this memory increase: recovery of verbal memory function after that closed-loop stimulation presented of LTC reliably improves “Patients with a injury predicts long-term reductions in with 24 memory function and was used moderate to severe disability, the ability to return to work, lists of 12 as a proof-of-concept for this TBI have a 0.8 and on-the-job performance. Robert E Gross words, one current study. standard deviation According to Gross, existing at a time, and asked In this 2018 study, machine learning memory function treatments for TBI lack efficacy and, at to recall those words classifiers were trained on brain activity compared with present, there are no US Food and Drug after a delay. Participants age-matched controls. Administration (FDA) approved therapies in 25 patients. According to Gross, the classifiers learned to predict which words typically recalled three A 19% improvement for TBI patients. Gross states that to six items per list. Half of would be recalled and which would be in memory is equivalent to a although cognitive rehabilitation, which the lists would be randomly assigned 0.4 standard deviation improvement, involves teaching some patients strategies forgotten during a list learning task. to be stimulated and the participant’s Using a randomised controlled blinded which translates to a greater than 50% for remembering information, such as brain activity was recorded during study design, participants were tested restoration in memory function for the calendar information and setting phone item presentation, and later sorted into average TBI patient.” reminders, is sometimes used, “its impact on lists of words with and without recalled and forgotten classes. These stimulation, with each participant acting on memory function is limited, and it is data were then used to train a logistic as their own control. Disclosures: Robert E Gross has often not reimbursed by insurance due to regression classifier to predict whether Participants did not know which received consulting fees from Abbott a lack of efficacy.” a given word would be recalled based lists were stimulated. Researchers Labs, Medtronic and has equity in Gross further stated that while some solely on the electrophysiological Nia Therapeutics. off-label pharmaceutical interventions are administered stimulation to the LTC



New study reports directional DBS provides superior results to omnidirectional DBS in Parkinson’s patients Results of a multicentre, prospective, blinded, crossover study, presented at NANS (15–16, January) by Jan Vesper (Heinrich-Heine University, Düsseldorf, Germany) indicate better results from directional deep brain stimulation (DBS) in the subthalamic nucleus for Parkinson’s disease compared to omnidirectional DBS. Vesper defined directional stimulation as single-segment activation and any combination of segments. VESPER SAID: “EVEN WITH WELL-PLACED DBS leads we might get in trouble regarding precision because of the complex regional anatomy, and limited therapeutic effect because of the proximity to neighbouring structures, resulting in problems with axial asymmetric stimulation.” Vesper therefore stated that the purpose of this study was to find out whether optimised stimulation settings with directional leads might be more beneficial for the long-term effects of DBS. In the study, all of the patients (234) underwent surgery to implant directional leads. For the first three months of treatment patients received omnidirectional DBS, then for the following three months, they received directional DBS. Researchers continued to collect results from directional DBS up to 12 months. According to Vesper, the primary endpoint of this study was to achieve a wider therapeutic window for directional stimulation in >60% of subjects. The secondary endpoint was to achieve a wider therapeutic

window for directional stimulation in >40% of subjects. Vesper described this cohort as a “normal” Parkinson’s population. There were 234 subjects in total, mean age was 61.7±8.4, 67.1% (157) were male, mean years of Parkinson’s symptoms was 11.7±7.6, 64.5% (151) enrolled before implant, and 35.5% enrolled after implant. Additionally, Vesper noted that these patients had a lower than usual Unified Parkinson’s Disease Rating Scale (UPDRS III) of 36.5±12.9. Vesper noted some adverse events, claiming, however, that there were no intracranial haemorrhages. In total, there were 13 adverse events related to device, procedure or stimulation in 12 subjects (5.1%). The presenter reported the study met their primary endpoint, achieving a 40% wider therapeutic window with directional stimulation at three months. Additionally, after three months of directional stimulation, 90.7% (185/204) of patients achieved a wider therapeutic window. Vesper also presented

the results from 12 months, showing a 32% wider therapeutic window with 89.3% (159/178) of patients achieving a wider therapeutic window. Vesper claimed this showed sustained results. Additionally, he reported an improvement in patients’ UPDRS III score by 40% at three and 12 months. According to Vesper, this is the largest prospective trial for directional DBS, with the largest number of subthalamic nucleus (STN) DBS implants in a single study. Vesper commented, “We could prove that the vast majority of our patients were able to use just one single segment, for the same effect. This not only required less amplitude, but was more effective.” Disclosures: Jan Vesper has received consulting fees from Abbott and UniQure, has done contracted research for Medtronic, and is on the speakers bureau at Abbott.

We could prove that the vast majority of our patients were able to use just one single segment, for the same effect. This not only required less amplitude, but was more effective.”

Jan Vesper

April 2021 | Issue 41


Repetitive TMS demonstrates ability to reduce suicidal thoughts and behaviours The use of transcranial magnetic stimulation (TMS) has a modest yet promising history in suicide reduction, according to the authors of a study published in Neuromodulation. IN THIS SEED-BASED FUNCTIONAL connectivity analysis, Jennifer Barredo et al evaluated whether changes in frontostriatal functional connectivity would accompany suicidality reductions following TMS, with the aim of optimising future treatment. This study was a secondary analysis of an open-label trial of 5Hz TMS of the left dorsolateral prefrontal cortex (DLPFC) in patients with post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). A total of 25 participants were included in this secondary study. For inclusion in the parent study, participants were required to meet criteria from the Diagnostic and Statistical Manuel of Mental Disorders, fifth edition (DSM-V) for both PTSD and MDD. Patients’ overall illness severity rating were at least “moderately ill” on the clinical global impressionsseverity scale for each diagnosis. However, imminent suicidal intent was exclusionary. Patients received eight weeks of 5Hz TMS administered to the left DLPFC. Clinical symptoms were measured using the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and the PTSD checklist from the DSM-V (PCL-5). Investigators derived suicidality from IDS‐SR item 18, the thoughtsof-suicide item. Possible responses to item 18 include: (0) “no thoughts of death or suicide”, (1) “feeling that life is empty or wondering if it is worth living”, (2)

“thinking of suicide or death several times a week for several minutes”, or (3) “thinking of suicide or death in detail multiple times each day, having a specific suicide plan, or having made an attempt”. Functional magnetic resonance imaging (fMRI) was collected before TMS, and at the treatment endpoint. Researchers entered these data into analyses of covariance, evaluating the effect of suicidality change across treatment on striatal and thalamic functional connectivity, while controlling for overall changes in other PTSD and depression symptoms. Suicidal ideation of “any severity” was reported by 68% of participants at study baseline, with 10 participants reporting a score of one, five and two participants reporting scores of two and three, respectively. Researchers found that after TMS, suicidality decreased by a minimum of one point in 65% of participants, though it did increase in 12% of patients, including one who did not endorse at baseline. Across participants, the mean change in overall PCL-5 and Jennifer Barredo IDS‐SR scores was 41.8%

Suicidality decreased by a minimum of one point in 65% of participants.

Minimally invasive, personalised neuromodulation could alleviate severe depression symptoms Researchers at the University of California, San Francisco’s (UCSF) Dolby Family Center for Mood Disorders (San Francisco, USA) have demonstrated a novel personalised approach in one patient, which they report was able to provide relief from symptoms of severe treatment-resistant depression within minutes.


atherine Scangos, an assistant professor in the Department of Psychiatry and Behavioral Sciences and lead study author, UCSF, stated, “Prior attempts to develop neuromodulation for depression have always applied stimulation in the same site in all patients, and on a regular schedule that fails to specifically target the pathological brain state. We know depression affects different people in very different ways, but the idea of mapping out individualised sites for neuromodulation that match a patient’s particular symptoms had not been well explored.” In a case study, published in January 2021 in Nature Medicine, Scangos and colleagues mapped the effects of mild stimulation of several mood-related

and 42.6%, respectively, in this subset of the original study cohort. In the parent sample, the average decrease in PCL‐5 was 35.5% and IDS‐SR was 37.6%. The authors’ imaging findings indicated that suicidality reductions were associated with attenuated functional connectivity between the dorsal striatum and the frontal pole. Complementary evidence from diffusion imaging, a method used to examine the integrity of the brain’s white matter connections, indicated that the integrity of frontostriatal white matter at study baseline partially accounted for functional changes associated with reductions in suicidality. “Though our results await replication in a shamcontrolled trial, we feel a strength of the present study is the anchoring our functional observations to the anatomy supporting regional interactions,” commented Barredo. In their conclusion, the study’s authors commented: “Collectively, findings argue that the precise targeting of frontopolar circuits via diffusion-guided individualised targeting may enhance neuromodulation delivery precision to our highest-risk patients. Combing these methodologies with innovations in 5Hz TMS delivery, such as pulse energy optimisation, may further improve its efficacy as an antisuicidal treatment.”

brain sites in a patient with severe treatment-resistant depression. Authors found that stimulation at different sites could alleviate distinct symptoms of the brain disease, reducing anxiety, boosting energy levels, and/or restoring pleasure in everyday activities. Additionally, it is noted that the benefits of different stimulation sites depended on the patient’s mental state at the time. This proof-of-concept study lays the groundwork for a five-year clinical trial led by Scangos, called the PRESIDIO trial, according to UCSF. “We have developed a framework for how to go about personalising treatment in a single individual, showing that the distinctive effects of stimulating different brain areas are reproducible, long-lasting and state-dependent,” said Andrew

Collectively, findings argue that the precise targeting of frontopolar circuits via diffusion‐ guided individualised targeting may enhance neuromodulation delivery precision to our highest‐risk patients.”

Krystal, director of UCSF’s Dolby Center and co-senior author of the study. Researchers used a minimally invasive approach called stereo electroencephalography (EEG) to place 10 intracranial electrode leads into the brain of the first patient enrolled in the trial. The patient then spent 10 days at the UCSF Helen Diller Medical Center while researchers systematically mapped effects of mild stimulation across a number of brain regions that prior research had shown were likely to have an effect on mood. The investigators found that 90-second stimulation of a several different brain sites could reliably produce an array of distinctive positive emotional states, as measured by a set of clinical scales that were used to assess the patient’s mood and depression severity throughout the study. It was observed by investigators that the effects of stimulation could be tailored to the patient’s mood, and that positive effects lasted for hours, well beyond the 40-minute window designed into the study protocol. The patient’s symptoms also got significantly better over the course of the 10-day study, leading to a temporary remission lasting six weeks.

“The fact that we could eliminate this patient’s symptoms for hours with just a few minutes of targeted stimulation was remarkable to see,” Krystal said. “It emphasises that even the most severe depression is a brain circuit disease that may just need a targeted nudge back into a healthy state. Unlike antidepressant drugs, which might not have an effect for one to three months, probably by altering brain circuits in ways we do not understand, our hope is that this approach will be effective precisely because it only requires brief, mild stimulation when the undesired brain state we want to change is present.” “We hope that providing gentle neuromodulation throughout each day will be able to prevent patients from falling into long-lasting depressive episodes,” said Scangos. “The idea is that keeping neural circuit activity functioning along the correct track, the pathways that support pathological negative thought processes in depression can be unlearned.” In the trial’s next phase, the patient will switch between six weeks with the device turned on and six weeks with it off, without being aware of which is which, in order to assess possible placebo effects.

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April 2021 | Issue 41


Wireless brain implants could improve mobility after stroke In a single-patient study conducted at Thomas Jefferson University (Philadelphia, USA), researchers have initiated a clinical trial using a brain implant and robotic brace which they are testing as an option for stroke patients with long-term disability.


his is the first person ever with this very common type of stroke to be implanted with brain electrodes that send neuronal signals to an arm brace that then controls movement,” says principal investigator of the study Mijail Serruya, an assistant professor of neurology at Thomas Jefferson University. “This study serves as a proof of concept, a necessary bridge to future studies that would use fully implanted wireless electrodes to improve movement after stroke.” Previous clinical trials of brain-computer interface (BCI) focused on patients with the much more rarer and more devastating form of brainstem stroke or spinal cord injury that causes paralysis from the neck down, or even locked-in syndrome that renders patients incapable of movement. “Fully implantable BCI implants are currently being developed by a number of companies,” says neurosurgeon Robert Rosenwasser, who led the implantation surgery for the patient, and is also the chair of the department of Neurological Surgery and president of the Vickie and Jack Farber Institute for Neuroscience at Jefferson Health, Philadelphia, USA. “This trial will pave the way for a future in which a patient with permanent disability from stroke can get an implant, train with rehab and artificial intelligence experts to use it, and go home with finer control of a mechanised brace. This study lays the groundwork for that future.” Serruya’s team have been working with the patient daily to train his control of the brain-implant to drive

Mijail Serruya and patient

movement of a robotic brace fitted for his weaker arm, as well as how to overcome his abnormal muscle tone. The patient, like many stroke patients, has an inclination to tighten his left arm across his body, with wrist and fingers clenched. In order to move that weakened hand, the patient needs to both release the tension in his arm— something he does involuntarily—while at the same time think about moving it, through his brain-controlled robotic brace. “This study will be the first patient implanted

What we are studying is much more relevant to all of the people who live with disability from stroke. But for that reason, it is also more challenging.”

Development of wearable ultrasound treatment for ischaemic stroke

Researchers at the South Korean Institute of Science and Technology (KIST; Seoul, South Korea) announced that the research team at the Center for Bionics, led by Hyungmin Kim, have developed a wireless rehabilitation treatment technology for brain nervous system damaged after stroke. Their device is a wearable, wireless, low-intensity focused ultrasound brain stimulator. This brain stimulator has already been applied to animal models of stroke. ACCORDING TO THE KOREAN National Research Council of Science and Technology (NST), of which KIST is a member research institute, in 2018, Kim’s research team developed a treatment method in which low-intensity focused ultrasound was applied to the cerebellar core to recover motor functions that deteriorated owing to hemiplegia. Additionally, in 2020, they proved that low-intensity focused ultrasound applied to the cerebellar core after a stroke is closely related to the changes in a delta wave in the brain. NST states that to harness this technology efficiently in rehabilitating

stroke patients in various environments, the ultrasound device should be easy to use in everyday life. However, the existing brain stimulator is heavy and fixed, and is therefore only applicable to experiments involving anaesthetised or restrained animals, thereby making it difficult to be commercialised. NST reports that the research team at KIST have developed a wearable, lightweight brain stimulator, which weighs approximately 20g, and can be wirelessly controlled. In addition, they verified the rehabilitation effectiveness after assessing

with electrodes who can walk and still live semiindependently,” says Serruya. “Although that might seem like an easier task than a fully paralysed patient, it is not. Patients with stroke often develop abnormal movements in order to compensate for what is lost. We have to overcome this abnormal muscle tone, all while learning to use the implants to control the patient’s arm via the brace.” Unlike prior BCI studies, conducted on relatively healthy brains, researchers have implanted electrodes in an area adjacent to the stroke. As a result, the researchers have had to regularly adjust and refine the artificial intelligence algorithms in order to interpret the patient’s intention to move with better fidelity. “What we are studying is much more relevant to all of the people who live with disability from stroke. But for that reason, it is also more challenging,” says Serruya. “We see our patients go home and struggle with simple daily tasks like picking up a cup of coffee or brushing their teeth,” says Rosenwasser. “This approach, which helps restore function, could be a game changer for stroke patients.”

ultrasound, thereby restoring the motor ability of a rat the nervous system damaged stroke model with the device. by a stroke, NST claims. The Ultrasound was applied with results obtained from their a pressure of approximately current study are expected 426kPA (kilopascals) to to soon contribute to the the part of the brain that development of a wearable controls motor functions in ultrasound brain stimulation a rat stroke model. Motor Hyungmin Kim technology at a clinical level. functions were significantly Kim commented: “Recently, wearable improved after three days compared to brain stimulation technology is advancing the rat stroke model to which ultrasound rapidly, and the significance of this was not applied; the motor functions study is in verifying the possibility of were improved to a level similar to non-invasive neurorehabilitation therapy that of normal rats after seven days of using a wearable ultrasound device,” rehabilitation. and he added that “In order to ensure the The brain stimulator developed by safety and effectiveness of the treatment, Kim’s research team is light in weight further research is required to optimise and operates wirelessly, which does not stimulation protocol by determining the limit the physical movements of a body molecular and cellular mechanisms of as it continues stimulating the part of the ultrasonic neuromodulation.” brain that controls motor functions via

Wearable brain stimulation technology is advancing rapidly, and the significance of this study is in verifying the possibility of non-invasive neurorehabilitation therapy using a wearable ultrasound device.”

Issue 41 | April 2021

Market watch 25

Product News Penumbra recalls Jet 7 catheters with Xtra Flex technology

The US Food and Drug Administration (FDA) announced the urgent voluntary recall of Penumbra’s Jet 7 catheters with Xtra Flex technology (Jet 7 Xtra Flex) due to increased risk of mortality and serious injury. Penumbra initiated the recall on 15 December 2020. This recall is due to where the catheter distal tip is plugged and pressurised. According to the FDA, the Jet 7 Xtra Flex is not able to withstand the same burst pressures to failure as Penumbra’s other large bore aspiration catheters used to remove thrombus in acute ischaemic stroke. This recall applies to the Jet 7 Xtra Flex catheter, originally cleared 16 June 2019, and the Jet 7 Max configuration (which includes the Jet 7 Xtra Flex catheter and Max delivery device), originally cleared 27 February 2020. This does not apply to the Penumbra Jet 7 reperfusion catheter with standard tip. The FDA reports receiving over 200 medical device reports (MDRs) associated with the Jet 7 Xtra Flex catheter, including deaths, serious injuries, and malfunctions. Twenty of these MDRs describe 14 unique patient deaths, which include reports from

different sources for a single adverse event. Penumbra reports a total of 17 events involving patient injury, of the 30,000 distributed units. Other MDRs describe serious patient injury such as vessel damage, haemorrhage, and cerebral infarction. Device failure modes reported in the MDRs include ballooning, expansion, rupture, breakage or complete separation, and exposure of internal support coils near the distal tip region of the Jet 7 Xtra Flex catheter.

Emulate unveils Brain-Chip

Emulate has unveiled a Brain-Chip aimed at enhancing neuroinflammatory disease research and drug discovery. According to a press release by Emulate, the comprehensive neurovascular unit model imitates features of the human brain and blood–brain barrier. Emulate claims the Brain-Chip is designed for neuroscience researchers investigating neuroinflammatory disease and for drug developers seeking to improve drug discovery for neurodegenerative diseases such as Alzheimer’s and Parkinson’s. The model incorporates cells from the human brain, including the blood–brain barrier, in a dynamic microenvironment which enables cell–cell interaction. Emulate organ-chips, including the

Brain-Chip, are designed to enable researchers to investigate the safety and efficacy of therapeutic treatments in development, in order to reduce the high drug development failure rates that result from a poor understanding of drug mechanism of action, toxicity, pharmacokinetic profile, or overall applicability and translation of animal and in vitro models used in preclinical research. According to their press release, the Emulate Brain-Chip is a comprehensive model of a neurovascular unit, including the blood–brain barrier, containing five human primary and induced pluripotent stem cell-derived (iPSC) cell types (neurons, microglia, astrocytes, pericytes, and brain microvascular endothelial cells) in a dynamic, tuneable microenvironment, resulting in in vivo-like gene expression. The incorporation of microglia allows

Emulate Brain-Chip

researchers to reproduce key features of neuroinflammation—including microglial activation, astrogliosis, and pro-inflammatory cytokines—presenting a more human-relevant model for evaluating new therapeutics than animal testing or conventional cell culture. The development of the Emulate brain-chip was partially supported by grant funding received from the US National Institutes of Health and the Michael J Fox Foundation in 2018.

Rapid Medical receives FDA clearance for steerable neurovascular guidewire

Rapid Medical has announced its Drivewire novel guidewire with a steerable distal top has received US Food and Drug Administration (FDA) clearance. According to a company press release, Drivewire is the first neurovascular guidewire with a controllable distal end that can change course and shape on-demand for more precise navigation. Rapid Medical states that, with Drivewire, physicians control the direction and shape of the guidewire’s tip while it is inside the vessel, precisely navigating the neuro and peripheral vasculature. Rapid Medical adds that this intravascular steering provides access to difficult anatomical locations, increasing the physician’s ability to treat vascular diseases with less invasive interventional approaches. The company press release states that guidewires are key components for

April 2021 | Issue 41

26 Market watch

Product News treating intravascular diseases such as ischaemic and haemorrhagic strokes. Rapid Medical claims that, currently, physicians do not have direct control over the guidewire tip and often remove the guidewire several times to reshape it before reaching the desired location. Erez Nossek (NYU Langone, New York, USA), commented: “The development of Drivewire has been an exciting collaboration. I can now easily navigate through complex anatomies by varying the shape of the wire tip inside the vessel, something that cannot be performed with the current neurovascular guidewires.”

Vercise Genus DBS system received FDA approval

Boston Scientific has announced that it has received US Food and Drug Administration (FDA) approval for its fourth-generation Vercise Genus deep brain stimulation (DBS) system. According to a company press release, the portfolio, approved for conditional use in a magnetic resonance imaging (MRI) environment, consists of a family of Bluetooth-enabled, rechargeable and non-rechargeable, implantable pulse generators (IPGs) that power Cartesia directional leads, designed to provide optimal symptom relief. “We have used the Vercise Gevia system with the Cartesia directional leads to provide our patients with a small device, a battery life of at least 15 years and optimal symptom control by delivering the right dose of stimulation precisely where it is needed,” said Jill Ostrem, medical director and division chief, University of California, San Francisco Movement Disorders and Neuromodulation Center, San Francisco, USA.

Medtronic launches aDBS trial in Parkinson’s disease patients

Medtronic has announced the first enrolment in its trial evaluating the safety and efficacy of adaptive deep brain stimulation (aDBS) in patients with Parkinson’s disease (PD). Medtronic reports that aDBS is an investigational feature of its Percept PC device, that could be enabled if approved. The investigational feature used in this study allows for automated adjustment of brain stimulation to provide therapy to manage symptoms of Parkinson’s disease based on a patient’s

clinical state. The trial, entitled aDBS algorithm for personalised therapy in Parkinson’s disease (ADAPT-PD), is a randomised study across 12 study sites at leading movement disorder research centres in the USA, Europe, and Canada. An estimated 36 subjects will undergo a total evaluation period of 15 months. The company reports that the primary endpoint of ADAPT-PD will compare standard continuous DBS (cDBS) to aDBS for hours of “On” time without troublesome dyskinesias, a measure of treatment efficacy versus side effects, as reported by patient diary. Qualifying subjects in the study will receive cDBS at baseline followed by randomised evaluation of two different aDBS algorithms in a blinded manner. Helen Bronte-Stewart (Stanford University, Stanford, USA), North American principal investigator for ADAPT-PD enrolled the first patient at the Stanford Movement Disorders Center. According to Medtronic, BronteStewart and her collaborators previously laid the foundation for ADAPT-PD by performing the first closed-loop DBS studies in Parkinson’s disease using an investigational prototype research-only system (Activa PC+S-Nexus D3). The company states that opportunities exist to improve the efficacy of DBS therapy. Current commercially-approved DBS systems deliver stimulation cDBS and are adjusted manually within physician-defined limits to optimise therapy for the patient. In contrast, aDBS therapy may individualise and optimise PD therapy for the same motor symptoms as with cDBS by automatically adjusting stimulation within physician-defined limits, based on brain signals detected by the DBS system. ADAPT-PD will be using the Percept PC DBS system with investigational aDBS feature. While the aDBS feature is investigational and has not been approved for commercial use, the Percept PC device, when using cDBS, was approved by the US Food and Drug Administration (FDA) in June 2020. Medtronic states that the Percept PC device (cDBS) utilises proprietary BrainSense technology making it the only DBS system with the ability to capture patient-specific brain signals. The sensing feature of the Percept PC system is intended for use in patients receiving DBS where chronicallyrecorded bioelectric data may provide useful, objective information regarding patient clinical status. Clinical benefits of brain sensing have not been established.

Vesalio receives peripheral FDA clearance and CE mark Vercise Genus

Vesalio has announced in a company press release that it has received 510(k) clearance from the US Food and Drug

Percept PC

Administration (FDA) and its fourth CE mark. According to Vesalio, the FDA 510(k) indication is for the removal of thrombi in peripheral blood vessels and the CE approval expands the NeVa neuro-thrombectomy portfolio. The press release further states that Vesalio’s fourth CE mark will expand its NeVa portfolio of approved neurothrombectomy designs to include a 5.5mm diameter with three Drop Zones. The company states that the Vesalio’s Drop Zone technology, designed to remove the full spectrum of clots from vascular anatomy, has been acclaimed for consistently achieving high first-pass rates, a key parameter associated with better patient outcomes in stroke.

Cerus Endovascular receives FDA breakthrough device designation for Contour neurovascular system

Cerus Endovascular has received breakthrough device designation from the US Food and Drug Administration (FDA) for its Contour neurovascular system. The Contour neurovascular system is indicated for the treatment of intracranial aneurysms. The company states that the product is composed of a fine mesh braid and represents a unique intrasaccular advancement in the market, as it targets the neck of the aneurysm, away from the vulnerable dome. Cerus Endovascular further claims that the system is designed to be selfanchored for stability, re-sheathable for precise placement, and because it is deployed across the neck, sizing criteria are less restrictive than other commercially-available intrasaccular devices.

Abbott announces NeuroSphere Virtual Clinic

Abbott has announced the US launch of its NeuroSphere Virtual Clinical, a first-of-its-kind technology that allows patients to communicate with physicians, ensure proper settings and functionality, and receive new treatment settings remotely as needed. According to a press release from the company, the Neurosphere Virtual Clinic has received approval from the US Food and Drug Administration (FDA). It is further stated that the NeuroSphere Virtual Clinic has the potential to increase access to optimal treatment for patients suffering from chronic pain or movement disorders who do not live close to a care provider, have difficulty accessing care, or are unable to go to the doctor because of circumstances

like COVID-19. The company claims that the NeuroSphere Virtual Clinic gives patients the flexibility and comfort of receiving care anywhere with cellular or Wi-Fi by connecting with their doctor via secure in-app video chat and an integrated remote programming feature, now available within the proprietary Abbott patient controller app. NeuroSphere Virtual Clinic enables clinicians to prescribe new treatment settings remotely to the patient’s neurostimulation device using the clinician programmer app and a new, simple and secure remote care connection. This advancement gives patients confidence in their care and the convenience to manage their therapy in a way that fits their lifestyle. The NeuroSphere Virtual Clinic can also be helpful for people who live in areas—both rural and urban—with inadequate access to medical services. On average, people living with movement disorders will travel over 150 miles to access specialists offering deep brain stimulation (DBS). Without alternative solutions, such as digital and/ or telehealth options, these patients are more likely to delay or forgo muchneeded care. NeuroSphere Virtual Clinic brings the convenience and flexibility of telemedicine to neurostimulation therapy, further benefiting chronic pain and movement disorder patients with Abbott devices. Medicare will cover remote programming services as a telehealth benefit through the duration of the public health emergency. Abbott states the NeuroSphere Virtual Clinic is compatible with its suite of neuromodulation technologies, including Infinity DBS system for patients with Parkinson’s disease and tremors of the upper extremities in adults with essential tremors; Proclaim XR SCS system for patients living with chronic pain of the trunk and/or limbs; and Proclaim DRG neurostimulation system for patients with chronic pain in the lower limbs caused by complex regional pain syndrome or causalgia. This integration across all Abbott neuromodulation technologies highlights Abbott’s relentless pursuit of patientcentred research and development methodologies that use neuroscience combined with cutting-edge technology to go beyond physical symptom relief to improve the lives of people with neurological disorders.

NeuroSphere Virtual Clinic

Issue 41 | April 2021

Market watch 27

Industry News Cognoptix makes new appointments

Cognoptix has announced new appointments to their senior management team. Carl Sadowsky (Nova SE University, West Palm Beach, USA) has been appointed as chief medical officer, and Mike Kaswan (New York, USA) as chief financial officer. Cognoptix is a company dedicated to the early detection of Alzheimer’s disease (AD). According to their press release, Sadowsky is nationally renowned physician and researcher in AD and neurodegenerative diseases. Sadowsky has conducted over 300 Alzheimer’s clinical trials, including the amyloid PET Amyvid trial and the IDEAS trial. He served on the scientific review board for Alzheimer’s Drug Discovery Foundations (ADDF) and serves on the Alzheon scientific advisory board. He is a fellow of the American Academy of Neurology. Cohnoptix’s press release states that Sadowsky also serves on Cognoptix’s Scientific Advisory Board which

operates to advance clinical testing of Cognoptix’s Sapphire II device-drug combination eye scanner for early detection of AD.

Phenox GmbH opens UK office

Phenox GmbH has announced the opening of a permanent UK office in the south of Birmingham, UK. The company states in a press release that this is in light of Brexit. Phenox GmbH states that its UK orders will now be processed through its UK entity. Hermann Monstadt, Bochum, Germany, a managing partner at phenox GmbH commented, “This is a very exciting time for Phenox GmbH; going direct in Italy and the UK after a very challenging, yet successful, 2020.”

Stryker partners with Brainomix for AI stroke software

Stryker has announced a new partnership with Brainomix that provides an option for European customers to purchase Brainomix’s

e-Stroke software. According to a press release from Stryker, the e-Stroke tool is an artificial intelligence (AI) powered software platform that provides real-time interpretation of brain scans, enabling physicians to more quickly diagnose stroke and make treatment and transfer decisions for patients. This allows more patients to get the right treatment in the right place, at the right time. “We are pleased to hear about this new partnership between Brainomix and Stryker – who offer a complete and comprehensive stroke solution within their portfolio. The partnership with Brainomix will improve stroke patient care across Europe, the Middle East and Africa (EMEA),” said Markus Mӧhlenbruch, Interventional Neuroradiologist at Heidelberg University Hospital, Heidelberg, Germany. “We are now able to offer customers software that can more quickly diagnose patients,” said Mark Paul, president of Stryker’s Neurovascular division, Salt Lake City, USA. “Helping our customers deliver the be Michalis Papadakis, CEO and cofounder of Brainomix, Oxford, UK, noted: “Partnerships have long played a key role for us at Brainomix, as a way of broadening our reach and expanding the

solutions we can provide to hospitals. Together with Stryker we will be able to offer an end-to-end solution for hospitals, covering both imaging and treatment. We look forward to joining forces with Stryker Neurovascular, with whom we share a mutual commitment to improving stroke care by expanding patient access to life-saving treatments.”

Inbrain Neuroelectronics secures funding for AIpowered graphene-brain interface

Inbrain Neuroelectronics has announced that it has raised US$18.8 million in series A funding for its artificial intelligence (AI)-powered, graphene neuromodulation technology.  According to the company, Inbrain’s technology harnesses the power of graphene, a two-dimensional material first isolated in 2004 made of a lattice of carbon atoms only one atom thick. Inbrain states that its graphene electrodes take advantage of some of the properties of graphene to enable ultrahigh signal. According to Inbrain, its system’s machine learning software detects therapy-specific biomarkers to deliver highly focused, adaptive neuromodulation therapy that is personalised for each patient.

Calendar of events

Event details correct at time of publication. Please check www. neuronewsinternational. com/events for updates in the wake of COVID-19.

19–22 April CX 2021 Vascular and Endovascular Controversies Digital Edition Virtual

19–22 June 7th Congress of the European Academy of Neurology Virtual

22–25 June ECMINT (European Course in Minimally Invasive Therapy) 4.1 Virtual

26–30 July SNIS 18th Annual meeting and fellows course Colorado Springs, USA

25–26 June NANS-NIC Joint Meeting Virtual

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

15–17 July NANS Mid-Year Meeting Florida, USA


2019 | Issue


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8–10 September ESMINT Congress 2021 Nice, France

14–16 September LINNC Paris 2021 Paris, France

17–20 November SVIN 2022 Pheonix, USA

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