all right good afternoon so the
management of a cute stroke patient can
be thought of simply in three broad
categories the first being the acute
management as we've talked on much of
the day to lessen the severity of a
stroke to avoid the complications that
could rise relatively in the immediate
aftermath of that stroke second then is
to investigate why that stroke happened
for that patient to be able to put
together the best plan to prevent that
from happening again and then lastly is
rehab so pardon the term lastly I
shouldn't use that but the point being
is that all three of these things can be
thought of kind of at the onset of that
patient coming in and in fact
practically we're using epic the order
sets involve all three of these things
for the admission orders so it's my
privilege to talk a few words on
recovery after stroke so to start I
think back to actually the fasten really
amazing process of neural development
because it's going to lead even provide
necessary context so it's really one
fascinating feature as the synaptic
connections that are formed and
development they're critical and they're
just innumerable and they underlie
primary circuitry motor or sensory they
underlie them the adjacent supplementary
circuitry that's going to then modulate
those primary modalities and then the
the increasing complexity then to the
circuits that are spatially distributed
but yet worked together as a functional
network to underlie our more complex
functions of attending to and
interacting with our environment formed
in development these synaptic
connections are then sculpted by
experience and by use and so ultimately
the there's these cortical sometta
topographic maps that are formed and
they're necessary for
function in our environments key animal
model experiments have taught us about
the nature of neurons their natural
characteristics what they like and don't
like for example if you amputate the
digit from a limb of a mouse now you
have a sensory cortex that old bat
Mouse's life has been receiving signal
when that digit was stimulated and
receiving continuous proprioceptive
information as to where that digit is in
space that input is now gone with
amputation
what's the neuron to do well image a
voltage-gated dye imaging has allowed us
to understand that in fact that neuron
takes on function of adjacent sensory
cortex to represent neighboring digits
from that similar limb so it doesn't
want to be idle it needs that sensory
input similar if you by experimental
model induce a stroke to again in a
mouse scenario therefore limb sensory
cortex well now you have a limb that can
still be stimulated it's still in space
but the receptive field in the cortex
has been injured what's found again by
similar mechanism is that stimulation to
that four limb can those signals can be
found in adjacent in this case hind limb
sensory cortex or nearby even sometimes
in epsilon motor cortex regions so
surviving even peri infarct regions have
a a sense that they they need to have a
function they need to have a purpose and
if there's an injury such that cuts them
off from their usual supply of
information they're going to even
compete with nearby regions to have a
role so mechanism underlying development
neuro development
is very timely and perfectly
orchestrated balance of neuro trophic
factors neuro trophic factors that are
going to be promoting of axonal
sprouting elaboration of more dendritic
spines to facilitate all that synaptic
connection that's necessary balanced
with those that would inhibit that
process so it's not overdone so what's
interesting is that again in the animal
models they found that after stroke
there's a reemergence of a similar
profile of neuro trophic factors and
importantly so the balance if you focus
just on the solid lines initially favors
the promoting factors those that would
encourage axonal sprouting elaboration
of more dendritic spines if you were to
again in an animal stroke model withhold
a rehabilitative effort and delay that
until 30 days in this scenario probably
not surprising to you have very little
noticeable recovery you can attribute to
your rehab effort if you were to do that
earlier say day 14 or even day five now
you have some measurable response
actually of recovery that you can now
attribute to your rehab effort so the
point being is that with this lead time
of promoting neurotrophic factors is
there a critical period where the brain
after stroke is most receptive to rehab
intervention so a group in Australia
took on the challenge for this question
and their patients that come in with
stroke mostly one of two centers
contributed 70 patients for the plan of
a feasibility safety trial their target
was to implement early mobilization
implementing rehab early within 24 hours
of stroke symptom onset and in addition
to that they want it to be more intense
with their effort they wanted to double
the mobilization time that's accumulated
over the length of their acute care stay
compared to that of standard care so
they achieved their goals the very early
group median time to first mobilization
was 18 hours and time out of bed
basically through the stay it was 167
and it's compared to the standard listed
there below so it's feasible the bottom
line for safety was that and
statistically significance sorry there
was no statistical significance of
difference in death serious adverse
events Falls or even clinical
deterioration so with this early data
not powered necessarily for efficacy
though but just taking a look at what
they produce with just these seventy
patients again good outcome being
defined by as has been said all day
mrs is zero to two you can see when you
compare standard group on your left
compared to very early group at three
six and twelve months
there's certainly trend of improvement
or more odds of better outcome and then
when you adjust in the far right when
you adjust for the age of the patient
the stroke severity and their premorbid
functional status at least at 12 months
you get actual statistical statistical
significance of increasing the odds of
better outcome so the next step then is
to prove this effect of efficacy of the
intervention in a larger trial so a
collaborative effort fifty six stroke
centers five countries Australia
Singapore Malaysia the UK might be
missing one they all
accumulated a little over 2,000 patients
and they had similar goals to the the
phase two that I just mentioned so they
wanted to get him up out of bed time to
first mobilization target less than 24
hours they wanted to make sure they had
more intense rehab effort they also did
a for all of the patients not just the
very early group they did kind of a
dose-response excuse me a dose of rehab
that was daihlia assessed based on that
that patients functional ability that
day so two straight to the point when we
compare them modified ranking
distributions the very early
mobilization group on top the darker
blue represents your better outcomes you
can see that the line did in favor
so actually more in the usual care
slightly more in the usual care had
better outcome than the very early
mobilization so kind of a bummer so when
you take a little closer look at that
study specifically it's interesting
you'll find that the median time it's a
first mobilization in the very early
group they definitely met their target
it was eighteen point five hours but in
the usual care group their median time
to first mobilization was twenty two
hours so by definition they met the goal
of the intervention group in addition
this it took them eight years to enroll
everybody into this trial and the
researchers had the foresight to
document how quick every year are we
getting the usual care group up out of
bed and every year they got faster by a
half-hour so you could imagine enrolled
on the eighth year compared to the first
year you're in your time out of bed was
four hours earlier and this is in the
the usual care group or the control
group so a little contamination effect
they also had just three percent more
smokers in the very early group and then
they had three percent more of the
hemorrhagic stroke subtype in the very
early group as well so as I mentioned
they did a kind of a protocol-based
dose-dependent rehab intervention based
on that patients functional status and
that was applied to everybody both
groups and when they they went back and
did kind of a retrospective dose
response analysis and you keep these two
factors time to first mobilization and
minutes out of bed you keep those
constant and just look at the additional
number of sessions they got you had a
small but marginal increase in out of
having a better outcome but meeting
statistical significance alternatively
if you were to keep the number of
sessions constant keep that time to
first mobilization constant as well and
just look at the amount of time you kept
them out of bed during that hospital
stay you had again small but slight
reduction actually in the art of having
a better outcome to statistical
significance the conclusion proposed at
the end of this kind of follow-up paper
was that maybe the best thing would be a
fine balance of frequent short sessions
of rehab leaving the optimal time to
mobilization slightly still mysterious
but based on what we understand about
the nature of neurons they're not
wanting to be idle they need a role the
biology post-stroke has this interesting
parallel to that of development where
there's seems to be a good reason for a
critical period of optimal response to
therapy based on the trials that I've
mentioned to you it seems maybe the best
though the clinical significance of it
was small but maybe frequent shorter
sessions of rehab will be optimal and
then time to first mobilization based on
at least the initial phase to the
within 24 hour tardy me be fair and safe
and I think the only thing to apply
again we've talked all day about
individualizing your character the
patient that's in front of you is to
ensure clinical stability so once
earlier mentioned trivial measure of
raising the head of bed if they're
symptomatic from that if they're clearly
perfusion dependent that patient may not
be ready to come out of bed yet thank
you
[Applause]