new Trends for acute stroke treatment

1. The Recent Therapy for Acute
Stroke
Dr. Doha Rasheedy
Lecturer of Geriatrics& Gerontology
CME 5-12-2013

2. In fact clinical management
of stroke, with the exception
of thrombolytic therapy is
based primarily on
supportive care.

3. Reperfusion therapy:
1. Thrombolytics (plasminogen activators) (direct
fibrinolytics)
2. Sonothrombolysis
3. Laser thrombolysis
4. Endovascular thrombectomy
Neuroprotective therapy:
1. ↓excitatory neurotransmitters
2. ↓reperfusion injury
Neuronal regeneration therapy: (neurogenesis)
1. gene therapy,
2. neurotrophic factors
3. neural stem cells (NSCs).

4. THROMBOLYTICS

5. Intravenous thrombolytics
Intravenous rt-PA within 3 h
• is the only treatment approved by the FDA
• was proven clinically effective in multiple
randomized clinical trials for acute ischemic
stroke.
• The effectiveness of t-PA is time-dependent;
treatment beyond 4.5 hours from stroke onset
does not result in improved clinical outcome.
• alteplase has been shown in animal and tissue
culture models to be neurotoxic, which may
exacerbate ischemic damage after successful
recanalization.

6. Indications within 3 hours(AHA/ASA) 2007:
1. Diagnosis of ischemic stroke causing measurable neurologic deficit
2. Neurologic signs not clearing spontaneously
3. Neurologic signs not minor and isolated
4. Symptoms not suggestive of subarachnoid hemorrhage
5. Onset of symptoms less than 3 hours hours before beginning treatment
6. No head trauma or prior stroke in past 3 months
7. No MI in prior 3 months
8. No GI/GU hemorrhage in previous 21 days
9. No arterial puncture in noncompressible site during prior 7 days
10. No major surgery in prior 14 days
11. No history of prior intracranial bleed
12. Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110
mm Hg
13. No evidence of acute trauma or bleeding
14. Not taking an oral anticoagulant, or if so, INR under 1.7
15. If taking heparin within 48 hours, a normal activated prothrombin time (aPT)
16. Platelet count of more than 100,000/μL
17. Blood glucose greater than 50 mg/dL
18. No seizure with residual postictal impairments
19. CT scan does not show evidence of multilobar infarction (hypodensity over
one-third hemisphere)
20. The patient and family understand the potential risks and benefits of therapy

7. 2009, AHA/ASA
• revised to expand the window of treatment from
3 hours to 4.5 but excluded those patients
1. Patients older than 80 years
2. All patients taking oral anticoagulants are
excluded regardless of the international
normalized ratio (INR)
3. Patients with baseline NIHSS score > 25
4. Patients with a history of stroke and diabetes

8. The National Institutes of Health Stroke Scale
(NIHSS)
• 0 to 3 -------->minor,
• 4 to 7 -----mild,
• 8 to 15 ----- moderate
• >15 ----- severe
• scores between 8 and 20 are more likely to
benefit from reperfusion and are less likely to
have hemorrhagic transformation, making
them better candidates for treatment.

9. Intra-arterial Thrombolysis
• Recanalization rate after intra-arterial delivery is
60% - 70%, while it is 30% to 40% for intravenous
delivery.
• Patients with moderate-to-severe ischemic strokes
usually have an occlusion of large cerebral arteries
(internal carotid artery [ICA], vertebrobasilar
arteries and M1 MCA) or a large clot burden.
• up to 6 h following stroke
• intravenous thrombolysis, about 6% of patients
intra cerebral hemorrhage while IA 10%.

10. sequenced intravenous and
intra-arterial thrombolysis
• IV t-PA at 0.6 mg/kg followed by 22 mg IA via a
2-h infusion or until thrombolysis.
• The recanalization rate was 79.3% in
compared to 55.9% in the intra arterial
thrombolysis alone group.
• Significant ICH in (20.7%) while in (11.8%) in
the intra arterial thrombolysis alone group.

11. New thrombolytics:
• desmoteplase, (r-DSPAα1), a recombinant
protein derived from the saliva of bat.
• The advantages of r-DSPA α 1 include
increased fibrin selectivity as well as absence
of neurotoxic effects.
• has a long half-life, enabling it to be given as a
single bolus

12. Reteplase
• third-generation thrombolytic.
• longer half-life
• better penetration into a thrombus.
• high rate of recanalization + acceptable risk for
bleeding complications.
• early reocclusion similar to rt-PA. dt platelet
activation. So, combination of thrombolysis with
platelet-inhibiting agents may offer an advantage.

13. Tenecteplase
• high-level fibrin selectivity
• long half-life
• increased thrombolytic potency on platelet-
rich clots.
• It is only approved for use in acute myocardial
infarction.

14. Direct Fibrinolytics
• Newer drugs that do not depend on the
availability of plasminogen are being
evaluated in the setting of acute stroke
treatment. offers selectivity to plasmin
formation at the site of the clot and
theoretically reduces systemic hemorrhagic
risk.
• V10153
• Microplasmin
• Alfimeprase

15. Mechanical thrombus disruption
• Sonothrombolysis
• Laser thrombolysis

16. Sonothrombolysis
the use of high frequency sound waves to penetrate
the skull and disrupt the clot, increasing exposure of
fibrin to plasmin. It accelerates enyzymatic fibrinolysis
by increasing penetration of drug molecules into the
clot
Using: transcranial Doppler ultrasound probe
. the CLOTBUST phase II trial showed that the
combination of alteplase plus 2 hours of continuous
transcranial Doppler (TCD) increased recanalization
rates, producing a trend toward better functional
outcomes compared with alteplase alone.

17. Laser thrombolysis
• Endovascular photoacoustic Laser Therapy
• Transcranial Laser Therapy

18. Transcranial Laser Therapy
• This noninvasive technique uses near-infrared wavelengths
applied to the scalp within 24 h of symptom onset.
• The mechanism is incompletely understood but may
involve increased mitochondrial adenosine triphosphate
production.
• NEST-1 (phase 2) and NEST-2 (phase 3) confirmed the
safety of transcranial laser therapy, although efficacy was
not found in NEST-2.
Pooled analysis of NEST- 1 and NEST-2 revealed a significantly
improved success rate in patients treated with laser therapy.
Further phase 3 testing is planned and may create a new
paradigm for the treatment of acute ischemic stroke

19. The endovascular photoacoustic
recanalization device (EPAR)
is a mechanical clot-fragmentation device based on laser technology.
The photonic energy is converted to acoustic energy at the fiberoptic
tip through creation of microcavitation bubbles, causing emulsification
of the thrombus which is a mechanical thrombolysis and not a direct
laser-induced ablation.
• Recanalisation rate in phase 1 was 41% (14 out of 34 patients). 11
(61%) had good-to-complete recanalization,,16 patients the
treatment was incomplete.
• Technical difficulties with the device occurred in four patients.
• There was one fatal device-related adverse event caused by
aneurysmal dilatation.
• Symptomatic ICH occurred in two patients (6%)

20. Mechanical thrombectomy
• Merci retriever device
• The penumbra device

21. Mechanical Thrombectomy
Two FDA-approved devices are available.
For :
• large-vessel intracranial occlusions within 8h of
onset.
and
• Occlusion ineligible for or refractory to IV t-PA
The Merci retriever: Designed for placement distal
to the thrombus, retrieval allows en bloc thrombus
removal (Fig. 1).
The penumbra device (Fig. 2), by contrast, works
proximally to disrupt and aspirate the thrombus.

22. Merci:
The device is placed distal to the
clot (top), engages the clot
(middle), and
then pulls the clot back into the
guide catheter (bottom
Penumbra:
(Bottom) Model of Penumbra
aspiration catheter and separator
proximal to intraluminal thrombus

23. • revascularization in (54%) with retriever alone
and in (69%) after additional therapy (IA t-PA
as bridging therapy
• (9.0%) ------------ICH

24. Percutaneous Angioplasty
• Intracranial angioplasty and stenting is technically
possible only in the larger segments of the Circle of
Willis – that is, vertebral and basilar arteries,
intracranial ICA and the M1 segment of the MCA.
• Partial or complete recanalization could be achieved in
91% of patients treated with direct PTA versus 64%
treated with thrombolytic therapy alone. ICH was seen
in 3% versus 19%, and good outcome occurred in 73%
versus 50% of the patients, respectively.
• PTA may also be particularly useful in the cases of
atherothrombotic disease, in which the residual
stenosis may reduce flow sufficiently to lead to
rethrombosis

25. Neuroprotection

26. • Deprivation of oxygen supply to the brain
tissue leads to activation of the ischemic
cascade with a series of molecular
mechanisms being activated.
• There is depletion of adenosine
triphosphate and consequent high levels of
lactate and unbuffered hydrogen ions.
• These hydrogen ions facilitate the
generation of ferrous iron-mediated free
radicals that result in astroglial injury.
Ischemic insult

27. • Failure of energy dependent mechanisms
including ion pumps leads to deterioration of
membrane ion gradients, opening of selective
and unselective ion channels, and
equilibration of most intracellular and
extracellular ions (anoxic depolarisation).
• Thus potassium ions leave the cell, sodium,
chlorine and calcium enter and many
excitatory neurotransmitters (glutamate,
aspartate) are released in potentially toxic
concentrations

28. • Calcium activates phospholipases which
hydrolyse membrane-bound glycero-
phospholipids to free fatty acids and these in
turn facilitate free radical peroxidation of other
membrane bound lipids. Calcium similarly
activates both proteases that lyse structural
proteins as well as nitric oxide synthase that
initiates free radical .
• The intracellular entry of calcium is made largely
possible by the activation of two types of
receptors: Voltage gated (L-type) and/or
several N-methyl-D-aspartate (NMDA

29. Reperfusion insult
• Despite the good outcome generally associated with
reopening a blood vessel, additional brain injury may result
when reperfusion occurs.
• When white blood cells reenter a previously hypoperfused
region via returning blood, they can occlude small vessels,
producing additional ischemia. Leukocytes release toxic
products that can lead to free radical and cytokine
formation.
• Agents that prevent white blood cells from adhering to
vessel walls, limit formation of free radicals, or promote
neuronal repair may protect the brain from additional
injury during reperfusion.
• Neuroprotective agents that work primarily during
reperfusion may have a longer window of therapeutic
effect than drugs that work earlier in the ischemic cascade.

30. Neuro-protective agents
• limits acute injury to neurons in the ischemic
penumbra.
• Many of these agents modulate neuronal receptors to
reduce release of excitatory neurotransmitters, which
contribute to early neuronal injury.
• Other neuroprotective agents prevent potentially
detrimental events associated with return of blood
flow.

31. REDUCE RELEASE OF EXCITATORY
NEUROTRANSMITTER

32. N-methyl-D-aspartate receptor antagonists
• Dextrorphan, a noncompetitive NMDA
antagonist, hallucinations and agitation;
hypotension, which limited its use
• Selfotel, a competitive NMDA antagonist>>>>
studies terminated dt ↑ mortality.
• aptiganel HCl (Cerestat)>>>> concerns regarding
benefit-to-risk ratios
• glycine-site NMDA antagonists (↓hallucination) A
large efficacy trial using the agent GV150526 on
1367 patients was completed in 2000. Although
the drug was reported to be safe and well
tolerated, no improvement was observed in any
of the 3-month outcome measures

33. Magnesium
• It may reduce ischemic injury by increasing
regional blood flow, antagonizing voltage-
sensitive calcium channels, and blocking the
NMDA receptor.
• the Intravenous Magnesium Efficacy Study
phase III no benefit (window gap 12hours)
• Field Administration of Stroke Therapy -
Magnesium Phase III (FAST-MAG) not finished
(2/2014) but administer mg within 1 hour

34. Nalmefene
• a narcotic receptor antagonist that reduces
levels of excitatory neurotransmitters
contributing to cellular injury in early ischemia.
• early studies suggest that the drug may have
more benefit in patients younger than 70 years
• Phase III CT>>>>> no clinical benefit was found,
No further trials are planned.

35. Lubeluzole
• The drug may block sodium channels in cells.
In addition, it may reduce the release of nitric
oxide, Clinical stroke research with this drug
has been abandoned.

36. Clomethiazole
• a gamma-aminobutyric acid agonist, decreases
excitatory neurotransmission by increasing activity of
inhibitory pathways.
• A large phase III trial was then performed in 1198
patients, focusing on patients with large strokes, which
were defined by the presence of higher cortical
dysfunction, limb weakness, and visual field
disturbances.
• The results were negative, with 42% of the
clomethiazole group and 46% of the placebo group
showing a good outcome.

37. Calcium channel blockers
• Studies of calcium channel blockers did not
show efficacy in stroke treatment. The most
recent clinical trial, which assessed the
usefulness of oral nimodipine given within 6
hours of symptom onset, was terminated early
after analysis of the first 439 patients
predicted no beneficial effect of the drug

38. High-dose human albumin treatment
• In animal models of focal cerebral ischemia, albumin
infusion at the doses ranging from 0.6-2.5 g/kg are
neuroprotective.
• Apart from functioning as a haemodiluent, albumin
induces systemic mobilization of polyunsaturated
fatty acids and help to replenish polyunsaturated
fatty acids lost from neural membranes.
• A phase III trial investigated albumin versus placebo
given within 5 hours of symptom onset (In preclinical
studies, albumin appears to have both antioxidant
properties and the ability to increase blood flow to
the penumbra. The trial, however, was stopped early
for futility

39. Therapeutic Hypothermia
Effects:
1. ↓brain damage from ischemia by preventing
disruption of the brain-blood barrier.
2. ↓the basal metabolic rate and counteracts the
ischemic cascade in the penumbra.
3. Hypothermia might enhance the effects of
neuroprotective drugs
4. extends the therapeutic window for systemic
thrombolysis or endovascular reperfusion
techniques.

40. • (32°C to 34°C).
• including endovascular cooling catheters placed
in the vena cava and surface cooling methods
such as ice-water immersion techniques.
• Still unanswered are questions such as the ideal
depth of cooling, duration of hypothermia, rate of
re-warming, and whether cooling before
reperfusion therapy is essential.
• Studied alone or combination with caffeine+
alcohol

41. Free-radical scavenger
• Edaravone.
• NXY-059

42. Free-radical scavenger Edaravone
• The Japanese Guidelines for the management of stroke 2009
suggest edaravone for the treatment of acute ischemic stroke as a
grade B recommendation. Therefore, edaravone is now widely
used to treat acute ischemic stroke in Japan.
• It is currently only approved in Japan.
• Clinical trial data show that administration of edaravone within 72
h of ischemic stroke onset significantly reduces infarct volume,
extend the narrow therapeutic time window of t-PA in rats.
• long-term treatment with edaravone suppressed the progression
of disuse muscle atrophy and improved leg locomotor function to
a greater extent than did short-term treatment

43. Free-radical trapping NXY-059
• SAINT I showed promise 90 days outcome
using modified Rankin score
• SAINT II did not show any difference between
the treatment and control arms

44. PREVENTION OF REPERFUSION INJURY

45. Prevention of Reperfusion Injury
• Enlimomab
• Hu23F2G
• Tetracycline antibiotics
• Antiplatelet antibodies
• Citicoline: membrane stabilization
• GSK249320

46. Enlimomab
• Monoclonal antibodies can block an intercellular
adhesion molecule (ICAM) on the endothelium to
prevent adhesion of white blood cells to the vessel
wall.
• Trial was –ve:
• Treated subjects were found to have higher mortality
rates and worse outcomes than subjects in the placebo
group. A marked increase in fevers occurred in patients
who received enlimomab. Elevated temperatures had
previously been found to worsen stroke outcome.

47. human antileukocytic antibody,
Hu23F2G,
• A phase III trial was then done by using a
human antileukocytic antibody, Hu23F2G, no
clinical benefit was seen with Hu23F2G on any
of the planned measures. No further studies
with this agent are planned,

48. Tetracycline antibiotics
• A phase I dose-finding trial
using minocycline to treat ischemic stroke (6-h
window) was completed.
• In addition to providing potential
neuroprotection, minocycline also appears to
decrease levels of matrix metalloproteinase-9,
which has been associated with recombinant
tissue plasminogen activator (rtPA)–associated
cerebral hemorrhage.

49. Citicoline
• Citicoline may reduce ischemic injury by
stabilizing membranes and decreasing free radical
formation.
• A large international trial, the International
Citicoline Trial on acUte Stroke (ICTUS), enrolled
2298 patients with moderate-to-severe strokes
within 24 hours of stroke onset.
• Unfortunately, this trial did not show efficacy for
citicoline compared with placebo

50. GSK249320
• a monoclonal antibody that blocks myelin-
associated glycoprotein, a molecule inhibiting
axon outgrowth.
• A dosage-finding study showed that the drug
was well tolerated and additional trials are in
progress

51. NEUROGENESIS

52. Neurogenesis Enhanced by Gene
Therapy
• Recent studies have shown that a single injection of
adenoviral brain derived neurotrophic factor into the
lateral ventricle substantially augmented the
recruitment of new neurons into both neurogenic
and non-neurogenic sites in the adult rat brain.
• Matsuoka et al reported recently that adenovirus-
mediated intraventricular gene transfer of FGF-2,
which increased FGF-2 level in brain tissues and the
cerebrospinal fluid (CSF), is more effective in
promoting neurogenesis after ischemia than
continuous infusion of FGF-2 peptide, which
increased FGF-2 level only in the CSF

53. Neurogenesis Enhanced by Growth
Factors
• Fibroblast growth factor-2 and epidermal
growth factor (EGF) act as mitogens for adult
stem and progenitor cells.
• The infusion of EGF into the lateral ventricle of
adult mouse forebrain for 6 consecutive days
resulted in a substantial increase in cellular
proliferation and in the total number of
subependymal cells.

54. Fiblast
• a basic fibroblast growth factor.
• In a phase II safety trial, Fiblast was administered
IV for up to 24 hours in acute stroke patients.
• Safe but transient leucocytosis may occur
• . A large trial was begun to evaluate the efficacy
of Fiblast in stroke patients presenting within 6
hours of symptom onset. However, the trial was
terminated because of poor risk-to-benefit ratios.

55. Adult stem cell therapy in stroke
• Stem cell therapy for ischaemic stroke focuses on
a regenerative strategy required to restore not
only neural elements, but also supporting
structures such as blood vessels.
• Human NSCs delivered intravenously or
stereotactically surrounding the lesion have been
shown to survive, migrate towards the lesion and
differentiate (mainly neurones and astrocytes),
while improving functional recovery in rodent
models of stroke.

56. • In order for stem cells to produce successful
neuroregeneration, several conditions must
be met:
1. they must be able to produce multiple types
of neurons and glia.
2. the new cells must be able to migrate to the
site of injury.
3. and they must be able to integrate with
existing circuitry by initializing and
maintaining appropriate functional
connections with neighboring cells.

57. • studies showed an amplification of endogenous
neurogenesis following global ischemia, but did
not show any replacement of the CA1 pyramidal
cells that are lost in ischemia.
• One of the drawbacks of endogenous
neurogenesis as a therapy for stroke is that the
new cells have limited capabilities to migrate to
the site of injury.
• Granulocyte colony stimulating factor (G-CSF)
has arisen as a potential therapy to allow for the
migration of endogenous stem cells to the site of
ischemic injury.

58. • There is currently a phase I trial planned
using a commercially developed (foetally
derived) NSC line delivered by stereotactic
injection in patients with ischaemic stroke
(ReNeuron, UK)

60. Unresolved issues in the translation of
stem cell therapy.
• (1) choice of cell type,
• (2) cell numbers to be given,
• (3) optimum timing of treatment,
• (4) optimum route of delivery. IV IA IC
• (5) optimum tracking of cells after delivery.

61. • Iv : many of the injected cells end up being
caught in peripheral organs such as the liver,
spleen and lungs
• IA delivery is more invasive, infusing cells directly
into the artery that is perfusing the ischemic
tissue. The benefit of this method is that it allows
the cells to bypass any peripheral organs and go
directly to the site of injury. Some concerns with
this method of delivery are the potential for the
injected cells to form microvascular occlusions,
thus worsening the ischemia.
• Finally, direct intra-cerebral injection is highly
invasive and carries many risks, such as initial
human studies showing adverse side effects such
as seizures, subdural hematoma and worsening
of motor function

62. Stem cells for neuroprotection
• studies have revealed that iv exogenous
stromal stem cells in rodents provided
multiple benefits, including reduced stroke
volumes, improved functional outcomes, and
an extended time window for treatment—up
to 48 h following stroke onset.