Effects of intensive gait-oriented physiotherapy during early acute phase of stroke

I see no comparison to the control arm to see how much spontaneous recovery there was. Am I missing something?

Effects of intensive gait-oriented physiotherapy during early acute phase of stroke

 Sinikka H. Peurala, PhD;1–2*
 Olavi Airaksinen, MD, PhD;3
 Pekka Jäkälä, MD, PhD;1
 Ina M. Tarkka, PhD;4
 Juhani Sivenius, MD, PhD1,4
1 Department of Neurology, Kuopio University Hospital, Kuopio, Finland;
2 Department of Health Sciences, The Finnish Centre for Interdisciplinary Gerontology, University of Jyväskylä, Jyväskylä, Finland;
3 Department of Physical  Medicine and Rehabilitation, Kuopio University Hospital, Kuopio, Finland;
4 Brain Research and Rehabilitation Center Neuron, Kuopio, Finland

Abstract—

We assessed the effects and strenuousness of intensive gait-oriented inpatient rehabilitation initiated very early after stroke. Therapy content and interrater reliability of the assessments were also analyzed. Of 22 patients, 19 (average 8.0 d post stroke) completed the study. Before rehabilitation, 13 patients were unable to walk or needed two assistants to walk and6 patients needed one assistant. Patients spent a daily maxi-mum of 1 h therapy time to obtain 20 min of walking. Additional physiotherapy was also provided during the 3 wk therapy period. Seven structured motor tests were recorded before and after rehabilitation and at 6 months post rehabilitation, and perceived exertion was followed during physiotherapy.After rehabilitation, 16 patients could walk unassisted and 3needed one assistant to walk. Mean +/– standard deviation exercise walking distance was 10,784 +/– 4,446 m and exercise was ranked as slightly strenuous. After 3 wk, the patients’ 10 m walking time, ankle spasticity, lower-limb muscle force, and motor scale scores improved (
 p < 0.05). The early intensive rehabilitation was well tolerated and only three patients dropped out. Improved motor abilities were seen in all stroke patients.
Clinical Trial Registration
:
ClinicalTrials.gov; Gait Trainervs Traditional Physiotherapy in Acute Stroke, NCT00307762;<http://clinicaltrials.gov/ct/show/NCT00307762>.

Effects of intensive gait-oriented physiotherapy during early acute phase of stroke

Useless, NO protocol written up and distributed to all 10 million yearly stroke survivors.  No objective damage diagnosis seems to have been done, without that none of this is repeatable either.

Effects of intensive gait-oriented physiotherapy during early acute phase of stroke

 Sinikka H. Peurala, PhD;
1–2
*
 Olavi Airaksinen, MD, PhD;
3
 Pekka Jäkälä, MD, PhD;
1
 Ina M. Tarkka, PhD;
4
 Juhani Sivenius, MD, PhD
1,4
1
 Department of Neurology, Kuopio University Hospital, Kuopio, Finland;
2
 Department of Health Sciences, The Finnish Centre for Interdisciplinary Gerontology, University of Jyväskylä, Jyväskylä, Finland;
3
 Department of Physical  Medicine and Rehabilitation, Kuopio University Hospital, Kuopio, Finland;
4
 Brain Research and Rehabilitation Center Neuron, Kuopio, Finland

Abstract—

We assessed the effects and strenuousness of intensive gait-oriented inpatient rehabilitation initiated very early after stroke. Therapy content and interrater reliability of the assessments were also analyzed. Of 22 patients, 19 (average 8.0 d post stroke) completed the study. Before rehabilitation, 13 patients were unable to walk or needed two assistants to walk and 6 patients needed one assistant. Patients spent a daily maximum of 1 h therapy time to obtain 20 min of walking. Additional physiotherapy was also provided during the 3 wk therapy period. Seven structured motor tests were recorded before and after rehabilitation and at 6 months post rehabilitation, and perceived exertion was followed during physiotherapy.After rehabilitation, 16 patients could walk unassisted and 3needed one assistant to walk. Mean +/– standard deviation exercise walking distance was 10,784 +/– 4,446 m and exercise was ranked as slightly strenuous. After 3 wk, the patients’ 10 m walking time, ankle spasticity, lower-limb muscle force, andmotor scale scores improved (
 p < 0.05). The early intensive rehabilitation was well tolerated and only three patients dropped out. Improved motor abilities were seen in all stroke patients.
Clinical Trial Registration
:
ClinicalTrials.gov; Gait Trainervs Traditional Physiotherapy in Acute Stroke, NCT00307762;

Innovation in Systems of Care in Acute Phase of Ischemic Stroke. The Experience of the Catalan Stroke Programme

Well fuck, then write it up as a protocol and get it distributed and implemented around the world. Oh wait, that should be the responsibility of our fucking failures of stroke associations. Oh well, a few more people die from stroke with no protocols, they would have died eventually anyway.
https://www.frontiersin.org/articles/10.3389/fneur.2018.00427/full?

Rosa M. Vivanco-Hidalgo^1*, Sònia Abilleira², Mercè Salvat-Plana³, Aida Ribera⁴, Guillem Gallofré³ and Miquel Gallofré³

• ¹Stroke Programme, Catalan Stroke Foundation, Barcelona, Spain
• ²Stroke Programme, Agency for Health Quality and Assessment of Catalonia, CIBER Epidemiología y Salud Pública, Barcelona, Spain
• ³Stroke Programme, Barcelona, Spain
• ⁴Cardiovascular Epidemiology Unit, Cardiology Department, Hospital Vall d'Hebron, Barcelona, Spain

Stroke, and mainly ischemic stroke, is the second cause of death and disability. To confront the huge burden of this disease, innovative stroke systems of care are mandatory. This requires the development of national stroke plans to offer the best treatment to all patients eligible for reperfusion therapies. Key elements for success include a high level of organization, close cooperation with emergency medical services for prehospital assessment, an understanding of stroke singularity, the development of preassessment tools, a high level of commitment of all stroke teams at Stroke Centres, the availability of a disease-specific registry, and local government involvement to establish stroke care as a priority. In this mini review, we discuss recent evidence concerning different aspects of stroke systems of care and describe the success of the Catalan Stroke Programme as an example of innovation. In Catalonia, reperfusion treatment rates have increased in recent years and currently are among the highest in Europe (17.3% overall, 14.3% for IVT, and 6% for EVT in 2016).

Introduction

Stroke—mainly ischemic stroke—is the second cause of death and disability worldwide (1). The stroke burden has increased across the globe in both men and women of all ages throughout the past two decades (2). However, population awareness of early symptoms, the accuracy of current brain imaging tests, and the development of acute therapies are contributing to reduce this trend (3). However, success will depend mainly on the structure of the healthcare system and it is uncertain whether systems in different countries are prepared to deal with this huge burden. Therefore, innovation in stroke systems of care is mandatory to transform them and prepare them to confront this health challenge.

Innovating in Systems of Acute Stroke Care. Organization and Cooperation to Deliver More Treatment, More Rapidly

The natural history of ischaemic stroke has changed dramatically since the 1990s. The beginning of the Intravenous Thrombolysis (IVT) Era in the late 90s (4) and recent approval of endovascular therapy (EVT) (5), the demonstration of improved stroke outcomes with stroke unit care, and the benefits of implementing organized stroke systems of care have all contributed to reduce mortality and disability in patients with acute ischaemic stroke (AIS) (3, 6).

The proportion of patients treated has increased in recent years in high-income countries, mainly in comprehensive stroke centers (CSCs), where EVT is provided (7). The effectiveness of reperfusion therapies is highly time-dependent: The sooner the patient arrives to the hospital after symptoms onset, the better. Once in hospital, highly organized workflows are of utmost importance to achieve door-to-needle times in IVT and door-to-groin-puncture times in EVT. A set of effective strategies has been successfully implemented in hospitals to reduce these critical time delays, especially pre-notification of arrival by Emergency Medical Services (EMS), direct transfer to the radiology service for brain CT scan or direct alteplase administration in the scanner (8, 9).

The eligibility of patients with AIS for reperfusion therapies is evolving as new evidence is published. Partially dependent patients, otherwise excluded from IVT trials, might benefit from thrombolysis (10) and certain patients with unknown time of stroke onset, precluded from seminal EVT trials, have shown improved outcomes after EVT (11, 12). Therefore, the overall proportion of AIS patients who might benefit from reperfusion therapies is rising and changing inclusion criteria generate uncertainty about how many more are potentially eligible.

The capacity to increase the proportion of patients treated is related to the structure of the system of care. Current evidence shows that patients who require interhospital transfer for EVT achieve reperfusion between 109 and 120 min later than those directly transported to CSCs, and have a lower absolute probability of independent outcome (13–15). These data should prompt a rethinking of systems of stroke care at national and regional levels in order to improve the “hub-and-spoke” transfer networks. This form of medical transport optimization organizes traffic routes as a series of 'spokes' that connect outlying points to a central 'hub.' In acute care for stroke, the Hubs are CSCs with great expertise that concentrate a huge volume of procedures and are connected with centers having a lower level of expertise and smaller volume of procedures.

Understanding the Singularity of Stroke to Improve Care

Management of AIS has taken lessons from acute myocardial infarction management; however, unlike heart attack, in most cases acute stroke leaves patients unable to speak and to alert EMS by themselves. Population campaigns are crucial to raise awareness about stroke symptoms and how to detect them. In addition, EMS technicians must be specifically trained to detect stroke, activate the stroke code and pre-notify arrival to the nearest hospital with proper treatment capabilities.

The possibility of diagnostic testing in the ambulance to inform hospital treatment is another huge difference between heart attack and stroke. The recent development of CT-equipped mobile stroke units is considered an important advancement. This approach is safe and feasible, has increased IVT rates, and achieved significantly shorter time-to-treatment compared to conventional care in the areas tested, mainly in Germany (16). However, a recent study found no significant difference between the proportion of patients with a modified Rankin Scale score of 1 or less who received this type of care compared with conventional care (17). Therefore, due to its high cost without clear long-term benefit, we can conclude that an efficient technology for prehospital diagnosis of stroke that can be easily implemented is lacking.

Organizing to Achieve Better Results. Organization and Cooperation at Different Levels of Care

Once the stroke code is activated, where do we transfer the patient? Given the beneficial results of bridging therapy (IVT plus EVT) in patients with large vessel occlusion (LVO) (5), it seems clear that the demand for neurointervention in coming years will grow in line with increasing numbers of EVT-capable centers. Nonetheless, it is difficult to justify the establishment of EVT-capable centers in remote areas with low population density.

Therefore, a crucial question is how to define the best transfer network for AIS patients located in remote and distant areas. The drip-and-ship model, which takes the patient to the nearest stroke center, prioritizes the initial diagnostic workup and IVT. In this model, the identification of an LVO patient is followed by interhospital transfer to a CSC. Another model is direct transfer to a CSC, thus bypassing the Primary Stroke Centre (PSC), known as the mothership model. A recent study in Canada used conditional probability modeling to find an answer, testing different transportation options to identify the better modeled outcome in specific regions. The authors concluded that a drip-and-ship model is appropriate if the treatment in a PSC is delivered in less than 30 min and the patient is then transferred to a capable CSC (18). In Catalonia, the ongoing RACECAT trial (Direct Transfer to an Endovascular Centre Compared to Transfer to the Closest Stroke Centre in Acute Stroke Patients with Suspected Large Vessel Occlusion; NCT02795962) is expected to provide answers to important questions of logistics and increase the efficient delivery of treatments and the number of acute stroke patients that have access to them.

There is still room for network innovation. In remote areas with no access to stroke experts, a possible and feasible solution is TeleStroke Centres (TSC). Using videoconferencing and image-sharing technology, stroke specialists from a CSC can examine patients at remote hospitals to help with diagnosis and recommend a plan of care.

Results from a third model, called trip-and-treat, have been recently published. This urban interhospital service delivery model consists of a shared mobile interventional stroke team that travels to PSCs in New York City to provide on-site interventional capability. The authors concluded that, in their area of reference, the trip-and-treat model had shorter time-to-treatment for EVT, compared with drip-and-ship, offering a valid alternative to current interhospital stroke transfers in urban environments (19).

Prehospital Assessment

Theoretically, the benefits of a primary transfer to a CSC would only apply to patients with LVO and may unnecessarily delay treatment in all others. Therefore, the predictive power of initial screening tools to identify patients with suspected LVO becomes of paramount importance. Various scoring systems have been developed to detect potential candidates to EVT. These scales must meet key criteria: rapid and simple to use, applicable to an unselected population with a suspected stroke, high interrater reliability, and high accuracy to avoid underdiagnosis (low false-negative rate; i.e., 1-sensitivity) and overdiagnosis that could overload the CSC (low false positive rate, i.e., 1-specificity). Finally, the scale must be validated and proven to improve patient outcomes (20). A recent observational study compared 13 validated prehospital scales and concluded that published cutoff scores to predict LVO in clinical settings were associated with high accuracy but also yielded a high false-negative rate (21).

Among them, one that showed high accuracy and a comparatively lower false-negative rate was the RACE scale. This scale is a simplification of the NIHSS scale, using only those items with a higher ability to predict the presence of LVO. The RACE scale evaluates 5 items: facial palsy, brachial paresis, crural paresis, oculocephalic deviation and aphasia/agnosia. Scores range from 0 to 9. A score > 4 allows the suspicion of a LVO with a sensitivity of 85% and specificity of 69% (22). The RACE scale was designed and validated in Catalonia with a prospective study that included 357 patients in 2011–2013. Therefore, in optimizing stroke systems of care, the prehospital assessment is a key factor to take into account.

The Stroke Code System of Catalonia as an Example

Catalonia has a population of 7.5 M and an organized and highly territorialized stroke system of care administered by the Stroke Programme, an organization created in 2004 by the Catalan Health Department. In 2006, the Stroke Programme implemented the Stroke Code System in 2006 to cover all the territory (23) (Figure 1). Current criteria for Stroke Code activation are clinical suspicion of acute stroke, less than 8 h from symptom onset (or unknown), and previous functional independence (Rankin 0–2) with no age limit (24, 25). Upon Stroke Code activation, the EMS coordinates patient transport to the nearest Stroke Centre (SC) according to predefined pathways. After initial recognition of stroke symptoms, the destination SC is pre-alerted by the EMS. The Stroke Code can be activated directly from EMS upon identification of a stroke patient in the field (60% of all Stroke Code activations) or at the Emergency Department of any hospital when patients arrive at the hospital by their own means. In recent years, our network of acute hospitals that are active in the stroke code system has grown to include 26 centers: (1) Twelve TSCs with capacity to deliver IVT via tele-consultation with a vascular neurologist who covers all tele-consultations from the 7 TSCs in the outer metropolitan area of Barcelona; the remaining 5 TSCs are located in the Catalan provinces and are usually covered by the neurologist on call at the nearest provincial PSC, with the central on-call service acting as a backup. (2) Eight PSCs with capacity to deliver IVT and admit patients to a certified Stroke Unit. (3) Six EVT-capable centers or CSCs, all of them located in the inner metropolitan area of Barcelona.

Motor Improvement of Skilled Forelimb Use Induced by Treatment with Growth Hormone and Rehabilitation Is Dependent on the Onset of the Treatment After Cortical Ablation

Demonstrated in humans already, but I bet no one is putting this into a protocol that can be used around the world for rehab. YOU will have to bring this to your doctors and DEMAND this intervention because your hospital will do nothing with this until you are dead. Can be done days after the stroke so your doctors have plenty of time to administer this.

Motor Improvement of Skilled Forelimb Use Induced by Treatment with Growth Hormone and Rehabilitation Is Dependent on the Onset of the Treatment After Cortical Ablation

Margarita Heredia ,1 Jesús Palomero ,1 Antonio de la Fuente ,1 José María Criado ,1 Javier Yajeya ,1 Jesús Devesa ,2 Pablo Devesa ,3 José Luis Vicente-Villardón ,4 and Adelaida S. Riolobos 1 1Department of Physiology and Pharmacology, Neuroscience Institute of Castilla y León (INCyL), University of Salamanca, Salamanca, Spain 2Scientific Direction, Medical Centre Foltra, Teo, Spain 3Research and Development, Medical Centre Foltra, Teo, Spain 4Department of Statistics, University of Salamanca, Salamanca, Spain
Correspondence should be addressed to Margarita Heredia; mheredia@usal.es and Jesús Devesa; devesa.jesus@gmail.com
Received 24 March 2017; Revised 20 December 2017; Accepted 8 January 2018
Academic Editor: Stuart C. Mangel
Copyright© 2018MargaritaHerediaetal.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
We previously demonstrated that the administration of GH immediately after severe motor cortex injury, in rats, followed by rehabilitation, improved the functionality of the affected limb and reexpressed nestin in the contralateral motor cortex. Here, we analyze whether these GH effects depend on a time window after the injury and on the reexpression of nestin and actin. Injured animals were treated with GH (0.15mg/kg/day) or vehicle, at days 7, 14, and 35 after cortical ablation. Rehabilitation was applied at short and long term (LTR) after the lesion and then sacrificed. Nestin and actin were analyzed by immunoblotting in the contralateral motor cortex. Giving GH at days 7 or 35 after the lesion, but not 14 days after it, led to a remarkable improvement in the functionality of the affected paw. Contralateral nestin and actin reexpression was clearly higher in GH-treated animals, probably because compensatory brain plasticity was established. GH and immediate rehabilitation are key for repairing brain injuries, with the exception of a critical time period: GH treatment starting 14 days after the lesion. Our data also indicate that there is not a clear plateau in the recovery from a brain injury in agreement with our data in human patients.
1. Introduction
Brain repair after an injury involves a number of complex processes. Abundant evidence indicates that growth hormone (GH) administration, added to rehabilitation, can significantly contribute to the recovery of an acquired brain injury, both in animal models [1–9] and in human patients [10–15], regardless of whether the patient is GH-deficient (GHD)ornot[14–18].However,itisnotclearwhetherthere is a period of time after a brain injury during which GH can
exert its positive effects for brain repair. While it seems logical that early GH administration and rehabilitation after brain damage should provide faster and better recovery [14–16], recent data from our group demonstrate that brain repair in humans can be achieved by administering GH together with rehabilitation even months or years after the injury happened [10, 16–18]. These data challenge the classical concept that there is a “plateau” for brain recovery following an injury after which few more positive improvements could be obtained.

PREGNANT women could hold the key to providing hope for stroke patients, following a breakthrough by Australian researchers.

Your doctor needs to followup this research and bring it into their hospital. Not following up is extreme incompetency. 
https://www.thesenior.com.au/health/new-hope-for-stroke-patients-2/

In a world first, scientists at Melbourne's La Trobe University have developed a groundbreaking treatment for stroke using discarded amniotic cells from pregnant women.

The teams found that injecting the stem cells - which line the amniotic sac during pregnancy and are discarded after birth - into stroke patients can significantly reduce brain injury and aid recovery.

Stroke is one of Australia's biggest killers and a leading cause of disability. Treatments for stroke are time critical and currently only a limited number of Australians have access to them.

The seven-year research project, led by La Trobe's Professor Chris Sobey and researchers from Monash University and Monash Health, found when human amnion epithelial cells were injected 90 minutes after stroke, the cells quickly homed in on the affected area of the brain, greatly reducing inflammation and nerve cell death.

"But what is particularly exciting about these new findings is that when the amniotic cells were administered as late as one or three days after stroke, there was accelerated healing and long term functional recovery was still greatly improved," Professor Sobey said.

Some of the most recent advancements in ischemic stroke treatment - strokes caused by a clot - can only be delivered within the first few hours of a stroke.

Professor Sobey said the reason this particular cell therapy was effective is because the cells are abundant, they are discarded after birth and don't require any treatment before being used.

"They already contain natural immune-suppressants, which means the patient's body won't reject them and they don't form tumours - both issues with other forms of cell therapy."

The first in-human trial in acute stroke patients will start soon, led by researchers at Monash Health and Monash University.

Recognise stroke: think FAST

F - Has their FACE drooped?

A - Can they lift both ARMS?

S - Is their SPEECH slurred and do they understand you?

T - Call 000, TIME is critical.

• More at strokefoundation.org.au

Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke

When the hell will we get this tested in humans and available as a stroke protocol? NEVER  I BET.
http://stroke.ahajournals.org/content/early/2018/01/29/STROKEAHA.117.019136

Megan A. Evans, Rebecca Lim, Hyun Ah Kim, Hannah X. Chu, Chantelle V. Gardiner-Mann, Kimberly W.E. Taylor, Christopher T. Chan, Vanessa H. Brait, Seyoung Lee, Quynh Nhu Dinh, Antony Vinh, Thanh G. Phan, Velandai K. Srikanth, Henry Ma, Thiruma V. Arumugam, David Y. Fann, Luting Poh, Cameron P.J. Hunt, Colin W. Pouton, John M. Haynes, Stavros Selemidis, William Kwan, Leon Teo, James A. Bourne, Silke Neumann, Sarah Young, Emma K. Gowing, Grant R. Drummond, Andrew N. Clarkson, Euan M. Wallace, Christopher G. Sobey, Brad R.S. Broughton

https://doi.org/10.1161/STROKEAHA.117.019136

Stroke. 2018;STROKEAHA.117.019136

Originally published January 30, 2018

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Abstract

Background and Purpose—Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke.

Methods—We tested the efficacy of acute (1.5 hours) or delayed (1–3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7–14 weeks) and aged mice (20–22 months) of both sexes, as well as adult marmosets of either sex.

Results—We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke.

Conclusions—Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

• brain ischemia
• cerebral infarction
• inflammation
• mice
• stem cells

• Received August 22, 2017.
• Revision received December 14, 2017.
• Accepted December 15, 2017.

• © 2018 American Heart Association, Inc.

'A Time Clock to a Tissue Clock' for Acute Stroke Care

Well shit, the answer is to write up protocols and modify them as needed. But we also need to know exactly the time parameters that provide 100% recovery for each type of intervention. Without that we will never provide correct solutions. 
https://www.medpagetoday.com/meetingcoverage/isc/70827?

Stroke docs struggle with message after DAWN, DEFUSE 3, new guidelines

• by Crystal Phend, Senior Associate Editor, MedPage Today January 29, 2018

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

LOS ANGELES -- Time is brain has been a hard-fought mantra in acute stroke care. Decades after introduction of IV thrombolysis, the still-slow climb in rates of use show just how difficult.
The time-focused message is butting up against the DEFUSE 3 and DAWN trials, showing that a mechanical thrombectomy treatment window out to 16 and even 24 hours still can benefit imaging-selected patients, and newly-released American Heart Association/American Stroke Association guidelines officially promoting that extended window.
A subanalysis of DEFUSE 3 presented after the main results at the International Stroke Conference (ISC) here showed just how unimportant time was for thrombectomy outcomes when patients presented beyond 6 hours were selected with perfusion imaging.
Whereas the likelihood of good functional outcome (modified Rankin Scale score 0-2) dropped precipitously as time at presentation increased from 6 hours to 16 in that trial among patients in the medical treatment-only arm, the mechanical thrombectomy arm saw exactly the same likelihood of functional independence at hour 6 as at 16.
The discussion immediately turned to how to manage the interpretation.
"How do we as practitioners manage the messaging around it? Because it could foster some complacency a little bit. You don't want any complacency," said Bruce Ovbiagle, MD, of the Medical University of South Carolina in Charleston, who chaired a press conference where the findings were presented. "We've been pushing that for a long time. We don't want to dilute our message in any way."
"We certainly don't want to give the message that it's okay to delay treatment, that it's okay to delay coming to the hospital," agreed Maarten Lansberg, MD, of Stanford University in Stanford, California, who presented the substudy. "The message here is time is still important; it is not too late when it's 6 hours. Even at 16 hours and probably up to 24 hours, there is still a subset of the population that's going to benefit."
Gregory Albers, MD, also of Stanford, presented the main DEFUSE 3 results at ISC, and said that the extended-window thrombectomy studies provide the next evolution in stroke beyond a simple time is brain mantra.
That mantra gained urgency with the approval of tissue plasminogen activator (tPA) in 1996 with just a 3-hour window. But as imaging developed in the 1990s, it also became clear that strokes developed uniquely -- some patients who came in immediately after symptom onset had massive infarcts whereas others remained small hours after onset.
In 2006, the first DEFUSE trial tested tPA out to 6 hours with MRI to predict response. Albers' group developed the RAPID software to see how much brain tissue is salvageable, which has been used in thrombectomy trials to select patients for that treatment.
"With DAWN and DEFUSE [3], the world is moving from a time clock to a tissue clock," commented Jeffrey Saver, MD, of the University of California Los Angeles But, he clarified, "it's not longer just a time clock, it's also a tissue clock."
Although imaging can find patients all along the time spectrum who still have salvageable tissue that would stand to benefit, it's still important to rush at every point along the line.
"The time is still critical because a smaller percentage of the people you check with that perfusion imaging will have that good brain," J Mocco, MD, of Mount Sinai Hospital in New York City, said in panel discussion at the DEFUSE 3 press conference. "But once you use the imaging to select the patient, it's completely reasonable that they would have a consistent treatment effect, because you've selected the ones that are going to have that benefit."
After the imaging, "we still want everyone, even at 12 hours, to move as fast as they can," Ralph Sacco, MD, of the University of Miami and president of the American Academy of Neurology, told MedPage Today. "In other studies, it is clearly shown that the longer it takes to open the vessel, the worse the outcome. So we need to keep that message going that time is brain, and that minutes count, and we need to get these vessels open pretty quickly."
"The only good thing I think for the public is, when you wake up with a stroke and you're out of that 6-hour time window, because last known well was when you went to bed, there is now hope," he added.
The changing maxim also opens up more opportunities for research, noted Ovbiagele. "What is it about these patients who, for whatever reason, their strokes are developing more slowly as opposed to the people who are developing rather quickly? People tend to say it's collaterals; we continue to study that. But I think you have 50% [of patients] with this who come in not eligible ... others somehow are going slowly. I think it will be important for us to think about this."

DEFUSE 3 was funded by the National Institute of Neurological Disorders and Stroke.
Lansberg disclosed no relevant relationships with industry.
Albers disclosed relevant relationships with iSchemaView, Medtronic outside DEFUSE 3, and a patent licensed to Stanford University for automated detection of arterial input function and venous output function voxels in medical imaging.
Mocco disclosed a relevant relationships with Penumbra.

• Primary Source

  International Stroke Conference

  Source Reference: Lansberg MG, et al "Subgroup analyses of the DEFUSE 3 study" ISC 2018; Abstract LB6.

Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke

Now we just need to update and execute that stroke strategy and run human clinical trials on this. Followup which will never occur under current stroke leadership. It will fall thru the cracks like thousands of other studies.
http://journals.sagepub.com/doi/full/10.1177/1759091416655010?utm_source=Adestra&utm_medium=email&

Mechanistic Determination of the Causal Link Between Neurovascular Regeneration and Motor Functional Recovery

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Lili Cui¹²

Lili Cui

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA2Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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, Dandan Wang¹

Dandan Wang

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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, Sandra McGillis¹

Sandra McGillis

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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Michele Kyle¹

Michele Kyle

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA
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, Li-Ru Zhao¹²

Li-Ru Zhao

1Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA2Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
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...

First Published August 9, 2016 Research Article

https://doi.org/10.1177/1759091416655010

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Article Information

Volume: 8 issue: 4,

Article first published online: August 9, 2016; Issue published: June 1, 2016
Received: February 16, 2016; Accepted: April 19, 2016

https://doi.org/10.1177/1759091416655010

Lili Cui¹, ², Dandan Wang¹, Sandra McGillis¹, Michele Kyle¹, Li-Ru Zhao¹²

¹Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, USA

²Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

Corresponding Author: Li-Ru Zhao, Department of Neurosurgery, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, New York, USA. Email: ZHAOL@upstate.edu

This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).

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Abstract

Stroke, a leading cause of adult disability in the world, is a severe medical condition with limited treatment. Physical therapy, the only treatment available for stroke rehabilitation, appears to be effective within 6 months post-stroke. Here, we have mechanistically determined the efficacy of combined two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF; SCF + G-CSF), in brain repair 6 months after cortical infarct induction in the transgenic mice carrying yellow fluorescent protein in Layer V pyramidal neurons (Thy1-YFP-H). Using a combination of live brain imaging, whole brain imaging, molecular manipulation, synaptic and vascular assessments, and motor function examination, we found that SCF + G-CSF promoted mushroom spine formation, enlarged postsynaptic membrane size, and increased postsynaptic density-95 accumulation and blood vessel density in the peri-infarct cavity cortex; and that SCF + G-CSF treatment improved motor functional recovery. The SCF + G-CSF-enhanced motor functional recovery was dependent on the synaptic and vascular regeneration in the peri-infarct cavity cortex. These data suggest that a stroke-damaged brain is repairable by SCF + G-CSF even 6 months after the lesion occurs. This study provides novel insights into the development of new restorative strategies for stroke recovery.

Keywords brain repair, chronic stroke, G-CSF, hematopoietic growth factors, SCF, live brain imaging

Introduction

Stroke is a cerebrovascular disease in which brain tissue death (infarct) and neurological deficits occur from the sudden interruption of blood flow to a specific region of the brain. Stroke progresses through three phases: the acute, subacute, and chronic phase. The pathological profiles of the three phases appear to be quite different. Unlike in the acute and subacute phases, when massive neurons undergo primary and secondary damage (Parsons et al., 2000) in the chronic phase, a stroke patient’s neurological status becomes relatively stable and the surviving neurons establish new networks in an effort to take over the function of the dead neurons (Tombari et al., 2004; Carmichael, 2012; Cui et al., 2013; Zhao et al., 2013). The duration and pathological severity of the three phases vary between individuals and depend on the infarction size, infarct location, cerebrovascular collateral response, patient’s age, and medical comorbidities. Generally, the chronic phase begins 3 months after stroke onset (Hara et al., 1993; Parsons et al., 2000).
Stroke is an enormous public health problem and the leading cause of persistent disability worldwide. Today, there is a large population of chronic stroke patients in the world suffering from stroke-induced disability. A recent study shows that in 2010, there were 102 million disability-adjusted life-years lost in the world (Feigin et al., 2014). In the United States alone, about 6.6 million stroke survivors are suffering from persistent disability (Mozaffarian et al., 2015). Targeting brain repair in chronic stroke is a highly important but much less investigated field in stroke research. Speech and physical therapies appear to be the only therapies available for chronic stroke patients. Since it would be unfeasible for stroke patients to spend every hour with physical therapists for physical performance, developing alternatives, such as a pharmaceutical approach, to help in restoring motor function for stroke survivors is needed. Importantly, the therapeutic window for traditional physical therapy appears to be limited within 6 months after stroke onset (Hendricks et al., 2002; Schaechter, 2004). Over 50% of chronic stroke patients, who are discharged from rehabilitation therapy at 6 months post-stroke, still show significant motor impairment (Gresham et al., 1975; Hendricks et al., 2002; Kelly-Hayes et al., 2003). Currently, therapies that can further improve functional restoration 6 months after stroke occurs have not yet been developed.
Recently, we have demonstrated the therapeutic efficacy of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) on brain repair and functional restoration in animal models of chronic stroke. SCF and G-CSF are well-characterized hematopoietic growth factors and play an essential role in controlling bone marrow stem cell growth, survival, and differentiation into blood cells (Welte et al., 1985; Zsebo et al., 1990). Increasing evidence, however, shows that SCF and G-CSF are also involved in neuronal plasticity, neuronal network formation, and neuronal function in learning and memory (Hirata et al., 1993; Motro et al., 1996; Katafuchi et al., 2000; Diederich et al., 2009; Su et al., 2013). Our earlier study revealed that systemic administration of combined SCF and G-CSF (SCF + G-CSF) 3.5 months after induction of cortical brain ischemia led to much greater functional improvement than SCF or G-CSF treatment alone (Zhao et al., 2007). However, it remains unanswered whether administration of SCF + G-CSF at a much-delayed time, 6 months after stroke, would be effective in brain repair.
Neurovascular network remodeling has been proposed to play an important role in stroke recovery (Moskowitz et al., 2010). Nuclear factor-κB (NF-κB), a transcription factor, is involved in synaptogenesis (Meffert et al., 2003; Memet, 2006; Boersma et al., 2011; Imielski et al., 2012) and angiogenesis (Stoltz et al., 1996). Our recent findings revealed that NF-κB mediates SCF + G-CSF-promoted neurite outgrowth in cultured primary cortical neurons (Su et al., 2013). The purpose of the present study was to determine whether administration of SCF + G-CSF at 6 months after experimental stroke would be effective in enhancing functional improvement and neurovascular network remodeling and whether NF-κB would be involved in the restorative process of SCF + G-CSF in such a delayed treatment.

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