Use the labels in the right column to find what you want. Or you can go thru them one by one, there are only 29,356 posts. Searching is done in the search box in upper left corner. I blog on anything to do with stroke. DO NOT DO ANYTHING SUGGESTED HERE AS I AM NOT MEDICALLY TRAINED, YOUR DOCTOR IS, LISTEN TO THEM. BUT I BET THEY DON'T KNOW HOW TO GET YOU 100% RECOVERED. I DON'T EITHER BUT HAVE PLENTY OF QUESTIONS FOR YOUR DOCTOR TO ANSWER.
Changing stroke rehab and research worldwide now.Time is Brain!trillions and trillions of neuronsthatDIEeach day because there areNOeffective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.
What this blog is for:
My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.
You'll have to ask your doctor to come up with prevention protocols for this. But that won't occur, your doctor has had decades to come up with protocols for stroke and completely failed, so failure will occur here also. It won't make a difference, you'll be dead before anything is done with this. https://www.rdmag.com/news/2018/08/vicious-circle-leads-loss-brain-cells-old-age?
The
so-called CB1 receptor is responsible for the intoxicating effect of
cannabis. However, it appears to act also as a kind of "sensor" with
which neurons measure and control the activity of certain immune cells
in the brain. A recent study by the University of Bonn at least points
in this direction. If the sensor fails, chronic inflammation may result -
probably the beginning of a dangerous vicious circle. The publication
appears in the journal Frontiers in Molecular Neuroscience.
The activity of the so-called microglial cells plays an important
role in brain aging. These cells are part of the brain's immune defense:
For example, they detect and digest bacteria, but also eliminate
diseased or defective nerve cells. They also use messenger substances to
alert other defense cells and thus initiate a concerted campaign to
protect the brain: an inflammation.
This protective mechanism has undesirable side effects; it can also
cause damage to healthy brain tissue. Inflammations are therefore
usually strictly controlled. "We know that so-called endocannabinoids
play an important role in this", explains Dr. Andras Bilkei-Gorzo from
the Institute of Molecular Psychiatry at the University of Bonn. "These
are messenger substances produced by the body that act as a kind of
brake signal: They prevent the inflammatory activity of the glial
cells."
Endocannabinoids develop their effect by binding to special
receptors. There are two different types, called CB1 and CB2. "However,
microglial cells have virtually no CB1 and very low level of CB2
receptors," emphasizes Bilkei-Gorzo. "They are therefore deaf on the CB1
ear. And yet they react to the corresponding brake signals - why this
is the case, has been puzzling so far."
Neurons as "middlemen"
The scientists at the University of Bonn have now been able to shed
light on this puzzle. Their findings indicate that the brake signals do
not communicate directly with the glial cells, but via middlemen - a
certain group of neurons, because this group has a large number of CB1
receptors. "We have studied laboratory mice in which the receptor in
these neurons was switched off," explains Bilkei-Gorzo. "The
inflammatory activity of the microglial cells was permanently increased
in these animals."
In contrast, in control mice with functional CB1 receptors, the
brain's own defense forces were normally inactive. This only changed in
the present of inflammatory stimulus. "Based on our results, we assume
that CB1 receptors on neurons control the activity of microglial cells,"
said Bilkei-Gorzo. "However, we cannot yet say whether this is also the
case in humans."
This is how it might work in mice: As soon as microglial cells detect
a bacterial attack or neuronal damage, they switch to inflammation
mode. They produce endocannabinoids, which activate the CB1 receptor of
the neurons in their vicinity. This way, they inform the nerve cells
about their presence and activity. The neurons may then be able to limit
the immune response. The scientists were able to show that neurons
similarly regulatory the other major glial cell type, the astroglial
cells.
During ageing the production of cannabinoids declines reaching a low
level in old individuals. This could lead to a kind of vicious circle,
Bilkei-Gorzo suspects: "Since the neuronal CB1 receptors are no longer
sufficiently activated, the glial cells are almost constantly in
inflammatory mode. More regulatory neurons die as a result, so the
immune response is less regulated and may become free-running."
It may be possible to break this vicious circle with drugs in the
future. It is for instance hoped that cannabis will help slow the
progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a
powerful CB1 receptor activator - even in low doses free from
intoxicating effect. Last year, the researchers from Bonn and colleagues
from Israel were able to demonstrate that cannabis can reverse the
aging processes in the brains of mice. This result now suggest that an
anti-inflammatory effect of THC may play a role in its positive effect
on the ageing brain.
Well this just joins all this other research about dementia risk after stroke. I bet this is still not enough for your stroke hospital to create a protocol to prevent such dementia. Double the risk tells you absolutely nothing.
In
the largest study of its kind ever conducted, new UK research has found
that people who suffer a stroke could be around twice as likely to
develop dementia.
Led
by researchers at the University of Exeter Medical School, the new
meta-analysis looked at data on stroke and dementia risk gathered from
48 studies with a total of 3.2 million people around the world.
After
taking into account other risk factors for dementia, such as blood
pressure, diabetes and cardiovascular disease, the researchers found
that having a stroke still significantly increased the risk of the
condition, providing the strongest evidence yet that stroke plays a role
in dementia risk.
The
findings also support previous research which has also found an
association between the two conditions, however previous studies did not
establish to what extent a stroke may increase the risk of dementia.
"We
found that a history of stroke increases dementia risk by around 70%,
and recent strokes more than doubled the risk. Given how common both
stroke and dementia are, this strong link is an important finding.
Improvements in stroke prevention and post-stroke care may therefore
play a key role in dementia prevention," said study author Dr. Ilianna
Lourida, of the University of Exeter Medical School.
"Around
a third of dementia cases are thought to be potentially preventable,
though this estimate does not take into account the risk associated with
stroke. Our findings indicate that this figure could be even higher,
and reinforce the importance of protecting the blood supply to the brain
when attempting to reduce the global burden of dementia," added Dr.
David Llewellyn.
The
team noted that as most people who have a stroke do not go on to
develop dementia, further research is now needed to assess whether other
factors could modify the increased risk of dementia, and whether
differences in care and lifestyle following a stroke can reduce the risk
of dementia further.
According to the World Health Organization, 15 million people have a stroke each year and around 50 million people have dementia.
The findings can be found published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
Over
the last 10 years, evidence has emerged that too much sedentary time
(e.g. time spent sitting down) has adverse effects on health, including
an increased risk of cardiovascular disease incidence and mortality. A
considerable amount of media attention has been given to the topic. The
current UK activity guidelines recommend that all adults should minimize
the amount of time spent being sedentary for extended periods. How best
to minimize sedentary behavior is a focus of ongoing research.
Understanding the impact of sedentary behaviors on the health of people
with stroke is vital as they are some of the most sedentary individuals
in society. Implementing strategies to encourage regular, short breaks
in sedentary behaviors has potential to improve health outcomes after
stroke. Intervention work already conducted with adults and older adults
suggests that sedentary behaviors can be changed. A research priority
is to explore the determinants of sedentary behavior in people with
stroke and to develop tailored interventions.
Well Ms. Lahiff-Jenkins what the hell are you doing to get the stroke medical world to get all survivors 100% recovered to accomplish this exercise? This is just another victim blaming exercise. https://www.podbean.com/media/share/pb-gy5qp-989950#.W4kmqKDZjt8.facebook
Over the last 10 years evidence has emerged that too much sedentary
time (e.g. time spent sitting down) has adverse effects on health,
including an increased risk of cardiovascular disease incidence and
mortality. A considerable amount of media attention has been given to
the topic. The current UK activity guidelines recommend that all adults
should minimise the amount of time spent being sedentary for extended
periods. How best to minimise sedentary behaviour is a focus of ongoing
research.
I’m Carmen Lahiff-Jenkins, Managing Editor of the International
Journal of Stroke and I spoke to Dr Sarah Morton lead author of the
opinion piece Sedentary behaviour after stroke: a new target for
therapeutic intervention.
The International Journal of Stroke is the flagship publication of
the World Stroke Organization - please consider becoming a member. https://www.world-stroke.org/membership/join-wso
On one of my long driving trips I managed to get my affected hand open and spread on top of my left leg. Normally the thumb loses its position soon and the whole arm falls into the abyss between the seat and the door. Then I have to hope like hell I never get T-boned on that side because I can't lift the arm out without using my right hand. This particular time it stayed there for about an hour. By which time the thumb muscles were very painful. It is completely disgusting that 12 years after my stroke spasticity still prevents my recovery. Don't suggest botox or muscle relaxants, they don't do anything for recovery.
The objective of this research is completely wrong. It should be to create stroke protocols that recover Somatosensory functions. Hell, that was figured out in a Margaret
Yekutiel book about this from 2001, 'Sensory Re-Education of the Hand After Stroke'? And I bet 17 years later your stroke hospital is still incompetent, not having the book in the library or making sure every doctor and therapist has read it and applied the protocols to all stroke survivors.
Background:
Proportional motor recovery in the upper limb has been investigated,
indicating about 70% of the potential for recovery of motor impairment
within the first months poststroke. Objective:To investigate
whether the proportional recovery rule is applicable for upper-limb
somatosensory impairment and to study underlying neural correlates of
impairment and outcome at 6 months. What a fucking lazy piece of shit objective. Methods: A total of 32
patients were evaluated at 4 to 7 days and 6 months using the Erasmus MC
modification of the revised Nottingham Sensory Assessment (NSA) for
impairment of (1) somatosensory perception (exteroception) and (2)
passive somatosensory processing (sharp/blunt discrimination and
proprioception); (3) active somatosensory processing was evaluated using
the stereognosis component of the NSA. Magnetic resonance imaging scans
were obtained within 1 week poststroke, from which lesion load (LL) was
calculated for key somatosensory tracts. Results: Somatosensory
perception fully recovered within 6 months. Passive and active
somatosensory processing showed proportional recovery of 86% (95% CI =
79%-93%) and 69% (95% CI = 49%-89%), respectively. Patients with
somatosensory impairment at 4 to 7 days showed significantly greater
thalamocortical and insulo-opercular tracts (TCT and IOT) LL (P
< .05) in comparison to patients without impairment. Sensorimotor
tract disruption at 4 to 7 days did not provide significant contribution
above somatosensory processing score at 4 to 7 days when predicting
somatosensory processing outcome at 6 months. Conclusions: Our
sample of stroke patients assessed early showed full somatosensory
perception but proportional passive and active somatosensory processing
recovery. Disruption of both the TCT and IOT early after stroke appears
to be a factor associated with somatosensory impairment but not outcome.
Background:
In the chronic phase after stroke, cortical excitability differs
between the cerebral hemispheres; the magnitude of this asymmetry
depends on degree of motor impairment. It is unclear whether these
asymmetries also affect capacity for plasticity in corticospinal tract
excitability or whether hemispheric differences in plasticity are
related to chronic sensorimotor impairment. Methods: Response to
paired associative stimulation (PAS) was assessed bilaterally in 22
individuals with chronic hemiparesis. Corticospinal excitability was
measured as the area under the motor-evoked potential (MEP) recruitment
curve (AUC) at baseline, 5 minutes, and 30 minutes post-PAS. Percentage
change in contralesional AUC was calculated and correlated with paretic
motor and somatosensory impairment scores. Results: PAS induced a significant increase in AUC in the contralesional hemisphere (P = .041); in the ipsilesional hemisphere, there was no significant effect of PAS (P = .073). Contralesional AUC showed significantly greater change in individuals without an ipsilesional MEP (P = .029). Percentage change in contralesional AUC between baseline and 5 m post-PAS correlated significantly with FM score (r = −0.443; P = .039) and monofilament thresholds (r = 0.444, P = .044). Discussion:
There are differential responses to PAS within each cerebral
hemisphere. Contralesional plasticity was increased in individuals with
more severe hemiparesis, indicated by both the absence of an
ipsilesional MEP and a greater degree of motor and somatosensory
impairment. These data support a body of research showing compensatory
changes in the contralesional hemisphere after stroke; new therapies for
individuals with chronic stroke could exploit contralesional plasticity
to help restore function.
Worthless, survivors want to know what protocol will fix those reaching deficits but you instead did nothing useful. Your senior researchers and mentors need to be fired.
Detailed kinematics of motor
impairment of the contralesional (“affected”) and ipsilesional
(“unaffected”) limbs in children with hemiparetic cerebral palsy are not
well understood. We aimed to 1) quantify the kinematics of reaching in
both arms of hemiparetic children with perinatal stroke using a robotic
exoskeleton, and 2) assess the correlation of kinematic reaching
parameters with clinical motor assessments.
Methods
This prospective, case-control
study involved the Alberta Perinatal Stroke Project, a population-based
research cohort, and the Foothills Medical Center Stroke Robotics
Laboratory in Calgary, Alberta over a four year period. Prospective
cases were collected through the Calgary Stroke Program and included
term-born children with magnetic resonance imaging confirmed perinatal
ischemic stroke and upper extremity deficits. Control participants were
recruited from the community. Participants completed a visually guided
reaching task in the KINARM robot with each arm separately, with 10
parameters quantifying motor function. Kinematic measures were compared
to clinical assessments and stroke type.
Results
Fifty children with perinatal
ischemic stroke (28 arterial, mean age: 12.5 ± 3.9 years; 22 venous,
mean age: 11.5 ± 3.8 years) and upper extremity deficits were compared
to healthy controls (n = 147,
mean age: 12.7 ± 3.9 years). Perinatal stroke groups demonstrated
contralesional motor impairments compared to controls when reaching out
(arterial = 10/10, venous = 8/10), and back (arterial = 10/10,
venous = 6/10) with largest errors in reaction time, initial direction
error, movement length and time. Ipsilesional impairments were also
found when reaching out (arterial = 7/10, venous = 1/10) and back
(arterial = 6/10). The arterial group performed worse than venous on
both contralesional and ipsilesional parameters. Contralesional reaching
parameters showed modest correlations with clinical measures in the
arterial group.
Conclusions
Robotic assessment of reaching
behavior can quantify complex, upper limb dysfunction in children with
perinatal ischemic stroke. The ipsilesional, “unaffected” limb is often
abnormal and may be a target for therapeutic interventions in
stroke-induced hemiparetic cerebral palsy.
Originally published1 Jan 2018Stroke. 2018;0:STROKEAHA.118.022041
Abstract
Background and Purpose—
Prehospital
routing algorithms for patients with suspected stroke because of large
vessel occlusions should account for likelihood of benefit from
endovascular therapy (EVT), risk of alteplase delays, and transport
times. We built a mathematical model to give a real-time, location-based
optimal emergency medical service routing location based on local
resources, transport times, and patient characteristics.
Methods—
Using
location, onset time, age, sex, and prehospital stroke severity, we
calculated odds of a favorable outcome for a patient with suspected
large vessel occlusions under 2 scenarios: direct to EVT-capable
hospital versus transport to the nearest alteplase-capable hospital with
transfer to EVT-capable hospital if appropriate. We project lifetime
outcomes incorporating disability, quality of life utility, and cost.
Multiple parameter sets of center-specific times (eg, door to alteplase)
were randomly selected within a clinically plausible range to account
for the model sensitivity to these estimates; for each iteration, the
optimal strategy was defined as the most cost-effective outcome
(threshold, $100 000 per quality-adjusted life-years gained). After 1000
simulations, the most frequently occurring optimal strategy was the
final recommendation, with its strength measured as the proportion of
runs for which it was optimal.
Results—
Routing
recommendations were highly sensitive to small changes in model input
parameters. Under many scenarios, the recommendations for direct
transfer to the EVT site increased with increasing stroke severity and
geographic proximity but did not vary substantially with respect to sex,
age, or onset time.
Conclusions—
We
present a mathematical decision model that determines ideal prehospital
routing recommendations for patients with suspected stroke because of
large vessel occlusions, with consideration of patient characteristics
and location at onset. This model may be further refined by
incorporating real-time data on traffic patterns and actual EVT and
alteplase timeliness performance. Further studies are needed to verify
model predictions.
Nothing here talks about results, just safety, so followup will be needed https://www.benzinga.com/pressreleases/18/08/r12276499/long-term-study-shows-endothelial-progenitor-cells-are-safe-for-treati DURHAM, N.C., Aug. 29, 2018
A new study recently published in STEM CELLS Translational Medicine
demonstrates the long-term safety of laboratory-expanded endothelial
progenitor cells for treating ischemic stroke. This could be good news
for the 15 million people who, according to to the World Stroke
Organization, suffer from this dangerous condition each year.
Ischemic stroke is the most
common type of stroke, affecting nearly 90 percent of all cases. It is
caused by a blocked blood vessel in the brain. In the normal central
nervous system, endothelial progenitor cells (EPCs) play an active role
in building blood vessels. This has led researchers to wonder whether
EPCs circulating in the blood could be recruited after a stroke to
assist in repairing damaged vessels in the brain. However, there is one
major problem with this idea: The number of circulating EPCs is too low
to provide much regenerative capacity – a number that further decreases
in the aging or in those with heart problems.
This makes ex vivo (lab) expanded EPCs an attractive alternative.
"Transplantation of EPCs was
already determined in animal experiments to be a safe and effective
method for treating ischemic stroke. However, their safety and efficacy
had yet to be determined in humans," said Zhenzhou Chen, M.D., Ph.D., Southern Medical University, Guangzhou, China,
and a corresponding author on the study. "In our trial, we tested the
safety and feasibility of transplanting an acute ischemic stroke patient
with his or her own (autologous) ex vivo expanded EPCs."
Eighteen patients were recruited
for the randomized, single-blinded study. Each received conventional
treatment after their stroke then, seven days after symptom onset,
underwent a bone marrow aspiration to collect EPCs and bone marrow
stromal cells (BMSCs) for expansion in the lab. The patients were
divided into three groups and, beginning at week four after the
aspiration, one group was intravenously infused with their own EPCs,
while the other two groups received either their own BMSCs or a saline
placebo as the controls.
Each patient was then monitored for 48 months. Study co-author Xiaodan Jiang,
M.D., Ph.D., also from Southern Medical University, explained, "We
watched for mortality of any cause, adverse events and any new-onset
diseases or conditions. Changes in neurological deficits were also
assessed at different time points."
In the end the researchers found
no toxicity events nor did they see any infusional or allergic
reactions in any of the patients. "The EPC group had less serious
adverse events compared to the placebo-controlled group, although there
were no statistical differences in mortality among the three groups,"
Dr. Chen reported. "Ex vivo expansion always raises concerns that it may
cause instability in the chromosomes or maybe lead to tumors. However,
in our long-term study we observed no increased tumorigenicity. This
safety indicator was also confirmed by many animal studies and other
trials using expanded bone marrow-derived stem cells for treatment of
ischemic stroke."
The researchers did note
limitations in their study, including lack of patient-centered quality
of life outcomes. "Moreover, because of the small size of the cohorts
involved, we could neither identify the neurological or functional
benefits of EPCs on ischemic stroke, nor determine the pros and cons
between EPCs and BMSCs for stroke treatment," Dr. Jiang said. "Thus, we
believe a larger phase 2 trial is warranted."
"This is a promising line of cell therapy research using a novel treatment method that is simple and non-invasive," said Anthony Atala,
M.D., Editor-in-Chief of STEM CELLS Translational Medicine and director
of the Wake Forest Institute for Regenerative Medicine. "We look
forward to larger phase 2 trial results."
The full article, "Autologous
endothelial progenitor cells transplantation for acute ischemic stroke: A
four-year follow-up study," can be accessed at http://www.stemcellstm.com.
About STEM CELLS Translational
Medicine: STEM CELLS Translational Medicine (SCTM), published by
AlphaMed Press, is a monthly peer-reviewed publication dedicated to
significantly advancing the clinical utilization of stem cell molecular
and cellular biology. By bridging stem cell research and clinical
trials, SCTM will help move applications of these critical
investigations closer to accepted best practices. SCTM is the official
journal partner of Regenerative Medicine Foundation.
With any brains at all in stroke leadership this research would be matched up with this post-stroke problem and research started to see if this SCI intervention would help in stroke.
Traumatic
spinal cord injury is a devastating condition that leads to significant
neurological deficits and reduced quality of life. Therapeutic
interventions after spinal cord lesions are designed to address multiple
aspects of the secondary damage. However, the lack of detailed
knowledge about the cellular and molecular changes that occur after
spinal cord injury restricts the design of effective treatments. Li and
colleagues using a rat model of spinal cord injury and in vivo
microscopy reveal that pericytes play a key role in the regulation of
capillary tone and blood flow in the spinal cord below the site of the
lesion. Strikingly, inhibition of specific proteins expressed by
pericytes after spinal cord injury diminished hypoxia and improved motor
function and locomotion of the injured rats. This work highlights a
novel central cellular population that might be pharmacologically
targeted in patients with spinal cord trauma. The emerging knowledge
from this research may provide new approaches for the treatment of
spinal cord injury.
I see absolutely nothing here that even remotely suggests that there is any strategy and leadership that will solve all theproblems in stroke.
This is just puffery, no one is taking responsibility. The WSO has no leadership role that I have ever seen in stroke.
What fucking laziness and trying to run away from responsibility. WSO,
stroke is in your name, that usually means YOU are responsible. I guess
you are NO leader and would
rather just sit on the sidelines, crying that governments and private
entities need to solve stroke. Fuck, get the hell out of the way and let
some leaders run your organization.
In a few weeks world leaders will gather at the UN HLM in New York
to review progress toward their commitment to reduce premature deaths
from NCDs by 30% by 2030.
The World Stroke Organization, along with our partners in the NCD
Alliance, has been active in advocating for increased awareness, access
and action on NCD and stroke prevention. Our leadership recently made a
statement as part of the UN preparations for the UN HLM which you can read elsewhere on this blog. Wow, ALL HAT AND NO CATTLE, get the hell out of the way and let some real leaders run things. No action verbs anywhere in here.
From
September 3rd, the WSO is getting behind the Enough NCDs Week of Action
and advocating for urgent action on stroke prevention and treatment as a
mechanism to achieve global health and development goals.
We have had enough of slow progress and failed promises on stroke
prevention and treatment and we know that our impatience is shared by
stroke survivors, caregivers, support and professional organisations
around the world.
To add your voice to ours and to increase the pressure on our leaders to
take stroke seriously we are calling on the stroke community to get
involved in the campaign. Our Enough Stroke! Enough NCDs Campaign Brief provides
background information and resources including suggested tweets and
Facebook posts to help you put stroke at the centre of the NCD debate.
Other things you can do
Check out the campaign resources that can complement your stroke messaging available from NCD Alliance campaign website.
Find out if your local NCD Alliance has any on the ground activities planned and mobilise stroke supporters to get involved.
Join the conversation on social media using hashtags #EnoughNCDs #EnoughStroke
Originally published27 Aug 2018Stroke. 2018;49:2261-2267
The central nervous system and the immune system are tightly interconnected through complex communicating networks.1
Immune cells are distributed in specific central nervous system
compartments. Microglia are the innate immune cells resident in the
brain parenchyma. Macrophages surround the blood vessels and also line
the leptomeninges and the choroid plexus together with dendritic cells
and lymphocytes, among other immune cells, where they play
immunosurveillance functions. Therefore, the immune system keeps a close
watch on brain function and reacts when brain homeostasis is lost
because of injuries or diseases. Sterile organ damage may turn immune
cells into harmful agents and for this reason they are regarded as
targets for therapeutic intervention in acute stroke.2
Stroke induces strong inflammatory reactions involving the local
production of cytokines, such as TNF-α (tumor necrosis factor-α) by
various brain cells, including human neurons,3
activation of glial and endothelial cells, blood-brain barrier damage,
and infiltration of different types of leukocytes after an orchestrated
time course.4
Given the variety of leukocyte subsets trafficking to the ischemic
brain tissue, this review will focus on neutrophils,
monocyte/macrophages, and T and NK (natural killer) lymphocytes. For
further information, the readers are addressed to previous reviews on
dendritic cells5 and B lymphocytes.6
The different immune cells are considered separately in the next
sections, but leukocyte infiltration surely comprises intercellular
crosstalks by mechanisms that are not entirely known.
Neutrophils
Neutrophils
are among the first cells attracted to the brain after ischemic stroke
where they are detected in the microvessels within the first hour7 and peak at 1 to 3 days.4,7,8
Neutrophils are short-lived innate immune cells containing different
types of granules with antimicrobial pro-oxidant and proteolytic enzymes
that can damage the tissues. Accordingly, neutrophils are regarded as
detrimental following compelling evidence associating these cells with
blood-brain barrier breakdown and brain injury.7,9 Also, higher blood neutrophil counts are associated with larger infarct volumes in acute ischemic stroke patients.10
Nevertheless, the pathogenic role of neutrophils in ischemic stroke is
still not conclusive. For instance, there are conflicting results in the
literature on the potential benefit of neutrophil depletion in
experimental ischemia models.9,11
Furthermore, we lack entire demonstration that neutrophils reach the
ischemic tissue before substantial neuronal death has occurred.11
Nonetheless, neutrophils can exert detrimental effects already from the
vessel wall. Adhesion of neutrophils to the inflamed endothelium after
ischemia/reperfusion is involved in the no-reflow phenomenon,
obstructing blood flow in precapillary arterioles, postcapillary
venules, and the capillary bed.7,12
In addition, neutrophils in the vessel lumen and at perivascular
locations can damage the blood-brain barrier by releasing proteolytic
enzymes and pro-oxidant molecules (Figure).9 Moreover, neutrophils can produce NETs (neutrophil extracellular traps) promoting clot formation.13 NETs can precipitate thrombotic events and impair tPA (tissue-type plasminogen activator)-induced thrombolysis.14
In turn, thrombolysis may exacerbate detrimental effects of neutrophils
because tPA promotes neutrophil transmigration to the reperfused tissue
by proteolytic activation of plasmin and matrix metalloproteinases.15
These effects might contribute to explain why neutrophilia and high
neutrophil-to-lymphocyte ratio are associated with the risk of
hemorrhagic transformation in ischemic stroke patients treated with tPA.16
After permanent middle cerebral artery occlusion (MCAo) in mice, we
observed the formation of intravascular NETs and found NETs in
perivascular locations and in the brain parenchyma.17
Figure.
Schematic representation of leukocyte infiltration to the ischemic
brain tissue. Neutrophils are attracted to the activated endothelium and
reach perivascular spaces after extravasation from intracerebral
venules and leptomeningeal vessels. Activated neutrophils are
prothrombotic and can damage the blood-brain barrier (BBB). The presence
of neutrophils in the brain parenchyma is observed only under certain
circumstances, but the conditions determining that neutrophils remain in
perivascular spaces or reach the parenchyma are still poorly defined.
Attracted by certain chemokines, immature proinflammatory monocytes
infiltrate the ischemic tissue where they mature to macrophages, acquire
signs of alternative polarization, and seem to be involved in tissue
repair. Current experimental evidence suggests that lymphocytes, in
particular T cells and γδ T cells, play detrimental roles in the acute
phase of stroke by promoting thromboinflammation and tissue damage.
Natural killer (NK) cells are attracted to the ischemic tissue, but
their function is not fully clear. RBC indicates red blood cells.There
is also some controversy on whether neutrophils actually reach the
ischemic brain parenchyma at all. An elegant study by Enzmann et al18
noticed the massive accumulation of neutrophils in perivascular spaces
surrounding venules within the ischemic tissue after
ischemia/reperfusion in mice. Most neutrophils remained perivascular,
and only a few were detected in the brain parenchyma.18
This is an important observation because it highlights that
perivascular spaces are a niche for neutrophils where they accumulate
after transient MCAo. We also detected neutrophils in perivascular
locations and leptomeningeal spaces in the mouse after permanent MCAo.17
These results suggest that, besides extravasating from intracerebral
venules, neutrophils extravasate from leptomeningeal vessels and migrate
from the subpial space along the vessels penetrating the cortex.17 However, our study17 and previous studies7
found neutrophils in the ischemic brain parenchyma using models of
permanent MCAo. Ischemic conditions involving severe endothelial damage,
vessel rupture, and microbleeds or hemorrhagic transformation, are
expected to facilitate the presence of neutrophils in the brain
parenchyma. Other conditions, such as high blood glucose, also promote
neutrophil infiltration.19 A recent study20
analyzed the postmortem brain of 16 ischemic stroke patients and
confirmed the presence of neutrophils in the leptomeninges and
perivascular spaces, but neutrophils were rare in the infarcted
parenchyma with the exception of 1 patient deceased 3 days after stroke
with no signs of infection. Interestingly, the time to death of this
series of patients was 1 day in 2 cases, 3 days in the case above
mentioned, and then times ranged from 8 days to 240 days poststroke.20
Neutrophils display a specific time-window of attraction to the damaged
tissues after acute injuries, and they have a short life in tissues.
Therefore, the time to death of ischemic stroke patients is critical to
look for the presence of neutrophils in the brain parenchyma. More
studies of human tissue within the first days poststroke are necessary
to understand under which conditions neutrophils might gain access to
the infarcted brain parenchyma.
Despite
many advances, there are aspects of neutrophil behavior in stroke that
are still difficult to interpret. For instance, neutrophils with
anti-inflammatory and repair phenotypes were found in the ischemic brain
tissue of experimental animals,21 neutrophils of ischemic stroke patients show a reduced oxidative burst and NET formation,22 and microglia surrounding blood vessels phagocyte neutrophils.23
The possibility that neutrophils were passive bystanders under some
circumstances but active players in others depending on specific
features of the ischemic lesion needs further consideration.
Monocyte/Macrophages
After
brain ischemia, microglia acquire a reactive morphology resembling
macrophages. Classically, immunohistochemical studies have described the
presence of reactive microglia/macrophages peaking at ≈4 days
postischemia in rats or mice, but it was not possible to distinguish
whether these cells derived from resident microglia or they infiltrated
from the periphery. Nowadays, flow cytometry, cell type-specific
fluorescent reporter mice, adoptive transfer of fluorescent cells,
generation of chimeras, and recently identified specific microglia
markers, allow differentiating resident reactive microglia from
infiltrating macrophages. Monocyte infiltration is detected within the
first 24 hours postischemia, peak at 4 days, and some of these cells
persist for weeks and acquire features of tissue macrophages. Immature
CCR2+Ly6Chi proinflammatory monocytes are the subset of monocytes first attracted to the ischemic brain tissue.24–26
These cells might be released by the bone marrow, but a study reported
that monocytes reaching the ischemic brain originate in the spleen.25
Infiltrating
macrophages were classically associated with inflammation and brain
damage after ischemic stroke. In mice, monocyte infiltration is largely
dependent on CCR2 (C-C motif chemokine receptor type 2), the receptor of
the chemokine CCL2 (C-C motif chemokine ligand 2), also known as MCP1
(monocyte chemoattractant protein 1). To investigate the role of
monocytes, several studies used CCR2-deficient mice or CCR2 inhibitors,
with the limitation that besides the subset of Ly6Chi monocytes other cells, like some T cells, also express CCR2. CCR2-deficiency reduced the ischemic brain lesions in mice.27 Challenging this view, CCR2 drug inhibitors exacerbated the brain lesion.28 Furthermore, anti-CCR2 blocking antibodies impaired spontaneous long-term functional recovery,29 depletion of monocytes/macrophages worsened the ischemic lesion,30 and infiltrating macrophages prevented hemorrhagic transformation of the ischemic lesion.24
By systemic injection of fluorescent monocytes after brain ischemia, we
observed fluorescent cells in the subpial space, and along the vessels
penetrating the cortex,26
supporting the view that a subset of infiltrating macrophages establish
persistent interactions with the blood vessels (Figure).
The
phenotype of activated macrophages depends on the environmental
stimuli. The M1 and M2 phenotypes are prototypical states of macrophage
polarization achieved in culture after exposure to certain cytokines.
The M1 phenotype is proinflammatory whereas the M2 phenotype promotes
resolution of inflammation and repair. Macrophages infiltrating the
ischemic tissue, including the Ly6Clo population and some of the Ly6Chi monocytes, acquire features of alternatively polarized M2 macrophages during the first week postischemia.26,28–30
Studies of human ischemic infarcts reported that macrophages initially
showed proinflammatory features that with lesion maturation transformed
into anti-inflammatory phenotypes.20
Interestingly, a study noticed that after ischemia in mice, the
expression of M2 markers increased within the first week but then
decreased, whereas proinflammatory markers persisted and predominated at
week 2, suggesting a long-lasting inflammatory status.31
The
factors that contribute to the time-dependent changes in macrophage
phenotypes in the ischemic brain tissue are not entirely identified.
Increased anaerobic glycolysis and activation of the hypoxia-inducible
factor-1 are associated with proinflammatory M1 phenotypes, whereas
energy production in M2 phenotypes rather relies on fatty acid
oxidation.32
In M1 activated macrophages, arginine metabolism occurs through
inducible nitric oxide synthase leading to generation of reactive oxygen
and nitrogen species that damage proteins, lipids, and DNA. In
contrast, M2 macrophages metabolize arginine through arginase-1
generating polyamines involved in cell division and collagen synthesis,
among other functions.32
However, under pathological conditions 1 single phenotypic feature may
not be sufficient to attribute any specific phenotype to the cells.
Likely, cellular metabolic adaptations to ischemia and reperfusion
together with the cytokine environment and phagocytic activity have an
impact on the phenotype and function of macrophages and microglia.
Lymphocytes
T Cells
Severe stroke reduces the numbers of lymphocytes in the circulation and lymphoid organs.33 In contrast, T-cell numbers increase in the ischemic brain within the first 24 hours and can persist for long times.4
During the first hours after ischemia/reperfusion, T cells facilitate
adhesion of platelets and leukocytes to the vascular endothelium34 causing a phenomenon called thromboinflammation35
by which molecular and cellular players in thrombosis and coagulation
promote proinflammatory pathways exacerbating the brain lesion.36
However, the interaction of T cells with platelets may also have
hemostatic effects preventing hemorrhagic transformation after severe
ischemic stroke.37 T cells are found in subpial and cortical vessels and infiltrating the ischemic lesion.38,39 In addition, the choroid plexus is a gateway for T cells migrating to the periphery of cortical infarction.40 Importantly, CD8+ cytotoxic T cells were detected in human ischemic infarcts.20 Also, ischemic stroke patients show increased frequency of CD4+CD28null cells in blood associated with stroke severity and serum levels of proinflammatory cytokines.41 CD4+CD28null
T cells are an interesting subset of T cells because they have enhanced
effector functions, are associated with senescent T cells, and expand
under inflammatory conditions.42 At later phases, CD4+ cells accumulate in the brain of mice peaking at day 14 and persisting at day 30 after ischemia/reperfusion.43
Furthermore, emerging evidence suggests that antigen-mediated T-cell
responses take place in subacute or chronic stages after stroke and may
worsen stroke outcome.43–47
However, in central nervous system trauma, protective autoimmunity
mediated by T-cell responses is involved in promoting recovery.48
Overall, T cells seem to play innate functions and interact with
players in thrombosis and hemostasis in the acute phase of stroke,
whereas at later stages they exert adaptive functions that could affect
stroke outcome in the long term.
γδ T Cells
Subsets
of unconventional innate T cells with invariant T-cell receptor could
play a role in acute ischemic brain damage. Growing evidence supports
that γδ T cells are pathogenic in experimental brain
ischemia/reperfusion by secreting IL (interleukin)-17 and exacerbating
the inflammatory response.49–51 Moreover, IL-17A+ lymphocytes were detected in the postmortem brain of stroke patients.50 Interestingly, γδ T cells are abundant in the gut from where they seem to traffic to the leptomeninges after brain ischemia.52
T helper 17 cells (Th17) and γδ T cells increase in the blood of stroke
patients in association with increased levels of IL-17A, IL-23, IL-6,
and IL-1β.53
In spite of the fact that IL-17 producing cells are a small subset of
cells, they seem to play a prominent role in orchestrating the
inflammatory response in acute stroke and exacerbating the lesion
(Figure).
Regulatory Lymphocytes
Regulatory
lymphocytes exert immunomodulatory and immunosuppressor functions.
Several lines of evidence support beneficial effects of regulatory T
cells (Treg)54 and regulatory B cells55 in experimental brain ischemia. However, other studies found acute detrimental effects of Treg in brain ischemia/reperfusion56 as previously reviewed.57
Although the number of Treg found in the ischemic brain parenchyma
during the first days poststroke is low, Treg strongly accumulate in the
ischemic lesion 15 days poststroke where potentially they could inhibit
autoimmune responses.43
Increased apoptosis of Tregs, loss of Tregs in peripheral blood, and
impaired suppressive function of the remaining Treg population has been
reported in ischemic stroke patients.53,58,59
However, other studies reported upregulation of Tregs in stroke
patients in spite that decreased Treg function was observed,
particularly in female patients.60 Notably, an increased proportion of Treg cells was reported in the spleen of mice 4 days after transient MCAo.61
NK Cells
NK innate lymphocytes show a rapid and transient increase in the ischemic brain tissue.4,8 A study reported no benefits of depleting NK cells in permanent or transient MCAo.44 In contrast, another study suggested pathogenic actions of NK cells by promoting inflammation and neuronal cytotoxicity.62
This study reported infiltration of NK cells in the ischemic brain
tissue of humans and mice where NK cell numbers peaked as soon as 3
hours postischemia and then declined.62
Interestingly, the β2-nACh-R (nicotinic acetylcholine) receptor seems
to be involved in the NK cell decline observed in the ischemic tissue
from 3 hours postischemia.63
Induced-persistence of NK cells in the ischemic tissue achieved by
interfering with this cholinergic receptor did not modify lesion size
but increased systemic IFNγ (interferon γ), protected from bacterial
infection, and enhanced poststroke survival.63
More studies are needed to validate the putative capacity of brain
infiltrating NK cells to prevent poststroke infection, the role of
central acetylcholine in this process, as well as the suggested rapid
pathogenic effect of NK cells worsening the acute ischemic brain lesion.
Therapeutic Intervention
Strategies
designed to prevent negative actions of leukocytes have been taken to
the clinic in acute ischemic stroke patients but with no success to
date.64 Several studies with drugs blocking the action of neutrophils were investigated.11,64
As an example, the ASTIN trial (Acute Stroke Therapy by Inhibition of
Neutrophils) investigated a compound known as UK-279 276, a recombinant
neutrophil inhibitory factor that selectively binds the CD11b integrin
of macrophage-1 antigen (CD11b/CD18).65
The treatment did not improve recovery above placebo. This trial
followed encouraging results of a few preclinical studies with
UK-279 276 in experimental models of brain ischemia/reperfusion.66 However, only a fifth of patients in the ASTIN trial received tPA.65
Monocyte/macrophages
may acutely exacerbate the inflammatory responses, but experimental
studies have identified their involvement in resolution of inflammation,
vascular protection, and recovery of function,24,27–29
possibly linked to the phagocytic and vasculoprotective roles of these
cells. These protective actions of monocytes are in line with the
beneficial effects of administration of autologous bone marrow–derived
mononuclear cells (MNC) after experimental ischemic stroke.67
MNC contain myeloid and lymphoid cells, as well as hematopoietic and
mesenchymal stem cells. MNC administration 24 hours after MCAo improved
functional recovery, reduced lesion size and proinflammatory cytokines,
and enhanced vessel density and neurogenesis,68 and these benefits were long lasting.69
Furthermore, MNC reduced blood-brain barrier permeability and decreased
the severity of hemorrhagic transformation after tPA in an embolic
stroke model.70 However, MNC therapy did not improve outcome in hypertensive rats.71 MNC reach the periphery of brain infarction soon after administration,68
and then the cells seem to differentiate into smooth muscle cells and
endothelial cells, incorporate into vessel walls, and enhance the growth
of leptomeningeal anastomoses, the circle of Willis, and basilar
arteries.69
Phase I trials administering MNC to ischemic stroke patients have shown
safety, but the clinical efficacy of this cell therapy awaits
demonstration.72
Anti-inflammatory treatments, such as minocycline, have not been successful in the clinic.64 Experimental evidences, including a cross-laboratory preclinical study in mouse models of brain ischemia,73
support the therapeutic potential of the IL-1Ra (IL-1β receptor
antagonist). A recent clinical trial with subcutaneous administration of
IL-1Ra showed safety and reduction of plasma IL-6.74
However, the analysis excluded a major clinical benefit of the
treatment, and negative effects potentially attributable to interactions
of IL-1Ra with tPA became apparent.74
Experimental
studies support damaging effects of T lymphocytes in the acute phase of
stroke. Accordingly, fingolimod, a drug approved for
remitting-relapsing multiple sclerosis that sequesters lymphocytes in
the lymph nodes preventing lymphocyte access to the inflamed tissues,
showed beneficial effects in preclinical studies and small clinical
trials in acute ischemic stroke patients, including patients receiving
thrombolysis.64
By acting on S1P1 (sphingosine-1-phosphate receptor 1), fingolimod
induces sustained lymphopenia, but current data do not show higher
incidence of poststroke infection in patients receiving fingolimod.
Fingolimod also acts on endothelial S1P1 receptor increasing vascular
barrier function that might contribute to the observed benefits of this
drug in ischemic stroke. Given that the benefits of fingolimod seem to
be mediated by S1P1, whereas certain side effects are dependent on other
S1P receptors, selective S1P1 agonists were studied in experimental
stroke showing reduced lesion size after ischemia/reperfusion in mice.75
In contrast to the benefits of blocking T-cell trafficking, systemic
administration of regulatory T lymphocytes in rodent models of ischemic
stroke reduced infarct size, ameliorated the neurological functions,76 and reduced hemorrhagic transformation after tPA.77
Leukocyte
recruitment to inflammatory sites is attenuated by blocking α4β1
integrin (VLA-4 [very late antigen-4]) with natalizumab, an antibody in
clinical use for multiple sclerosis treatment. Blockade of VLA-4 with
CD49d antibody was investigated in a multicentric preclinical study in
mice using 2 different models of cerebral ischemia.78
CD49d antibody attenuated leukocyte infiltration and reduced infarct
volume in small cortical lesions but not in large infarctions.
Natalizumab was investigated in ischemic stroke patients in the ACTION
trial (Effect of Natalizumab on Infarct Volume in Acute Ischemic
Stroke).79
Natalizumab did not meet the primary end point of the study, but
secondary and exploratory end points suggested improvement of clinical
outcomes,64,79
encouraging the second ACTION2 trial. This phase-IIb trial was recently
completed and the notes released by the sponsor (Biogen) state that
natalizumab did not improve clinical outcomes compared with placebo.
Final Remarks
Experimental
studies support detrimental effects of certain types of leukocytes in
acute ischemic stroke. However, to date, this knowledge has not been
translated into clinical treatments. No doubt immunomodulatory
interventions in the acute phase of stroke need fine-tuning and
long-term experimental studies to ensure that repair processes in
subacute and chronic phases are not disturbed and the neurological
deficits are attenuated. Cell therapies based on administration of
autologous MNC have shown promising results in preclinical studies by
promoting functional recovery, but clinical efficacy remains to be
demonstrated. Results of various experimental models of brain ischemia
suggest the possibility that the putative pathogenic contribution of
certain leukocytes to the acute ischemic lesion might differ depending
on lesion severity, regions affected, and degree of reperfusion.
Importantly, most of the studies described above were obtained in young
healthy male mice in spite of the fact that aging, sex, and
comorbidities influence the phenotype and function of immune cells.
Identification of the ischemic conditions where leukocytes might have a
meaningful contribution to the brain lesion, the relevant subsets of
leukocytes, and the time-window for intervention, requires more
investigation. Combining immunomodulatory strategies with reperfusion
therapies offer the opportunity to attenuate negative responses of the
immune system that might impair reperfusion at the microvascular bed or
trigger detrimental effects on the brain tissue.
Acknowledgments
I acknowledge relevant studies used to prepare this article that could not be cited because of word count restriction.
Sources of Funding
Supported by the Spanish Ministerio de Economía y Competitividad (SAF2017-87459-R).
Disclosures
None.
Footnotes
Correspondence
to Anna M. Planas, PhD, Institut d’Investigacions Biomèdiques de
Barcelona (IIBB), Consejo Superior de Investigaciones Científicas
(CSIC), Rosselló 161, Planta 6, 08036-Barcelona, Spain. Email anna.planas@iibb.csic.es
