This document discusses acute ischemic stroke interventions. It provides details on: - The typical size and duration of untreated ischemic strokes - How many neurons and synapses are lost each hour and minute of untreated stroke - Guidelines for emergency evaluation, diagnosis, and imaging of acute ischemic strokes - Details on different imaging techniques like CT, MRI, CTA, and perfusion imaging - Guidelines and recommendations for intravenous thrombolysis with rtPA within 3-4.5 hours of stroke onset.

1. ACUTE STROKE
INTERVENTIONS
Dr Javed Ahamed T P
SRMC
NEUROLOGY

2. TIME
IS
BRAIN

3. Time Is Brain—Quantified

4. •Typical final volume of large vessel,
supratentorial ischemic stroke is 54 mL
•Average duration of nonlacunar stroke
evolution is 10 hours (range 6 to 18 hours)
•Average number of neurons in the human
forebrain is 22 billion.

5. A TYPICAL LARGE VESSEL ACUTE
ISCHEMIC STROKE
• Each hour 120 million neurons, 830 billion
synapses, and 714 km (447 miles) of myelinated
fibers are lost
• Each minute, 1.9 million neurons, 14 billion
synapses, and 12 km (7.5 miles) of myelinated
fibers are destroyed

6. WHAT DO WE DO??

8. EMERGENCY TRIAGE AND INITIAL EVALUATION

9. EMERGENCY EVALUATION AND DIAGNOSIS OF
ACUTE ISCHEMIC STROKE
•An organized protocol for the emergency evaluation
of patients with suspected stroke is recommended
•The use of a stroke rating scale, preferably the
NIHSS, is recommended
•A limited number of hematologic, coagulation, and
biochemistry tests are recommended during the initial
emergency evaluation, and only the assessment of
blood glucose must precede the initiation of intra-
venous rtPA

10. Early Diagnosis: Brain and Vascular Imaging
Parenchymal Brain Imaging

12. NECT AND CONTRAST-ENHANCED CT
SCANS OF THE BRAIN
•Identifies most cases of intracranial hemorrhage and
helps discriminate nonvascular causes of neurological
symptoms (eg, brain tumor)
•NECT may demonstrate subtle visible parenchymal
damage within 3 hours
•Identify subtle, early signs of ischemic brain injury (early
infarct signs) or arterial occlusion (hyperdense vessel
sign)

13. LOSS OF GRAY-WHITE DIFFERENTIATION
•May manifest as loss of distinction among the nuclei
of the basal ganglia (lenticular obscuration) or
•A blending of the densities of the cortex and
underlying white matter in the insula (insular ribbon
sign) and over the convexities (cortical ribbon sign)

15. LENTICULAR OBSCURATION
• Lentiform nucleus obscuration is due to cytotoxic
edema in the basal ganglia.
• This sign indicates proximal middle cerebral artery
occlusion, which results in limited flow to
lenticulostriate arteries.
• Lentiform nucleus obscuration can be seen as early
as one hour post onset of stroke

17. SULCAL EFFACEMENT
• Diffuse hypodensity and sulcal effacement is the most
consistent sign of infarction.
• Extensive parenchymal hypodensity is associated with
poor outcome.
• If this sign is present in greater than 50% of the middle
cerebral artery territory there is, on average, an 85%
mortality rate

19. DENSE MIDDLE CEREBRAL ARTERY SIGN
• Signifies a thrombus within the blood vessel resulting in stasis
of blood flow, thus resulting in the artery to appear dense.
• Patients with significant atherosclerosis and calcification of the
arteries (e.g. in patients with end stage renal failure) would also
have relatively hyper-dense arteries but often not restricted to a
single cerebral artery.
• The radiological findings should therefore be interpreted in the
clinical context.

20. •Other sites where the hyperdense vessel sign can
be found include
•the intracranial internal carotid artery, basilar
artery, and MCA branches within the sylvian
fissure

22. OTHER SIGNS
• DISAPPEARING BASAL GANGLIA SIGN
• VENTRICULAR COMPRESSION SIGN

23. •Detection is influenced by the size of the infarct,
severity of ischemia, and the time between symptom
onset and imaging.
•Detection may increase with the use of a structured
scoring system such as the Alberta Stroke Program
Early CT Score (ASPECTS)

24. ASPECTS SCORING
• The purpose of this score is to help an evaluatIng clinician to
systematically examine a CT scan of brain to identify early signs of
ischaemia. It divides the Middle Cerebral Artery into 10 areas
• SUBCORTICAL
• The Caudate Nucleus. (C)
• The Lentiform Nucleus. (L)
• The internal capsule (Genu and posterior limb only).(IC)
• CORTICAL
• The insula (I)
• 6 areas of cortex M1-M6 are also scored

26. •Another CT sign is the hyperdense MCA “dot” sign.
•The MCA dot sign represents a clot within a branch of
the MCA and is thus typically smaller than the thrombus
volume in the MCA and possibly a better target for
intravenous rtPA

27. MRI OF THE BRAIN
•Diffusion-weighted imaging (DWI) The most sensitive
and specific imaging technique for acute infarct
•The visible diffusion lesion will include both regions of
irreversible infarction with more severe apparent diffusion
coefficient changes and regions of salvageable penumbra
with less severe apparent diffusion coefficient changes

28. ADVANTAGES OF MRI FOR PARENCHYMAL
IMAGING INCLUDE
•Ability to distinguish acute, small cortical, small
deep, and posterior fossa infarcts
•Ability to distinguish acute from chronic ischemia
•Identification of subclinical satellite ischemic
lesions that provide information on stroke
mechanism
•Avoidance of exposure to ionizing radiation
•Greater spatial resolution

29. CT ANGIOGRAPHY
• Accuracy for evaluation of large-vessel intracranial stenoses
and occlusions; is very high
• Sensitivity and specificity of CTA for the detection of
intracranial occlusions ranges between 92% and 100% and
between 82% and 100%, respectively.

30. •Direct comparisons of CTA source images (CTA-SI) and
MRI/DWI have demonstrated very similar sensitivity of
these 2 techniques for detecting ischemic regions
•DWI being better at demonstrating smaller abnormalities
(reversible or irreversible) and those in the brainstem and
posterior fossa

31. PERFUSION CT AND MRI
• Combined with parenchymal imaging, perfusion- weighted
MRI or perfusion CT imaging permits delineation of the
ischemic penumbra.
• Perfusion imaging can also indicate areas that are severely and
probably irretrievably infarcted.
• Several recent trials have studied MRI perfusion/diffusion
mismatch

32. EPITHET (ECHOPLANAR IMAGING
THROMBOLYTIC EVALUATION TRIAL)
•Designed to answer the question of whether intravenous
rtPA given 3 to 6 hours after stroke onset promotes
reperfusion and attenuates infarct growth in patients
who have a “mismatch” between perfusion-weighted
and diffusion-weighted MRI.
•Intravenous rtPA was nonsignificantly associated with
lower infarct growth but significantly associated with
increased reperfusion in patients who had mismatch.

33. RECOMMENDATIONS
•Emergency imaging of the brain is recommended
before initiating any specific therapy to treat acute
ischemic stroke (Class I; Level of Evidence A)
•In most instances, NECT will provide the necessary
information to make decisions about emergency
management

34. •Either NECT or MRI is recommended before intra-
venous rtPA administration to exclude ICH (absolute
contraindication) and to determine whether CT
hypodensity or MRI hyperintensity of ischemia is
present (Class I; Level of Evidence A)

35. •Intravenous fibrinolytic therapy is recommended in
the setting of early ischemic changes (other than
frank hypodensity) on CT, regardless of their extent
(Class I; Level of Evidence A)

36. •A noninvasive intracranial vascular study is strongly
recommended during the initial imaging evaluation
of the acute stroke patient if either intra-arterial
fibrinolysis or mechanical thrombectomy is
contemplated for management but should not delay
intravenous rtPA if indicated
(Class I; Level of Evidence A)

37. •CT perfusion and MRI perfusion and diffusion
imaging, including measures of infarct core and
penumbra, may be considered for the selection of
patients for acute reperfusion therapy beyond the time
windows for intravenous fibrinolysis.
•These techniques provide additional information that
may improve diagnosis, mechanism, and severity of
ischemic stroke and allow more informed clinical
decision making (Class IIb; Level of Evidence B)

38. •Frank hypodensity on NECT may increase the risk
of hemorrhage with fibrinolysis and should be
considered in treatment decisions.
•If frank hypodensity involves more than one third of
the MCA territory, intravenous rtPA treatment
should be withheld (Class III; Level of Evidence A)

39. RECOMMENDATIONS FOR PATIENTS WITH CEREBRAL
ISCHEMIC SYMPTOMS THAT HAVE RESOLVED
•Noninvasive imaging of the cervical vessels should be
performed routinely as part of the evaluation of
patients with suspected TIAs (Class I; Level of
Evidence A)
•Patients with transient ischemic neurological
symptoms should undergo neuroimaging evaluation
within 24 hours of symptom onset or as soon as
possible in patients with delayed presentations.

40. •MRI, including DWI, is the preferred brain
diagnostic imaging modality. If MRI is not available,
head CT should be performed (Class I; Level of
Evidence B)

41. INTRAVENOUS
THROMBOLYSIS

43. •Intravenous fibrinolytic therapy for acute
stroke is now widely accepted.
•Thrombolytic agents convert plasminogen to
plasmin, which degrades fibrin at the site of
thrombus formation

44. • The US FDA approved the use of intravenous rtPA in 1996
• This was on the basis of the results of the 2-part NINDS rtPA
Stroke Trial, in which 624 patients with ischemic stroke were
treated with placebo or intravenous rtPA (0.9 mg/kg IV,
maximum 90 mg) within 3 hours of symptom onset
• Approximately one half treated within 90 minutes.

45. •In the First trial (Part I), the primary end point was
neurological improvement at 24 hours, as indicated by
complete neurological recovery or an improvement of 4
points on the NIHSS.
•In the second trial (Part II), the pivotal efficacy trial, the
primary end point was a global OR for a favorable
outcome, defined as complete or nearly complete
neurological recovery 3 months after stroke.

46. • Four subsequent trials,
• the European Cooperative Acute Stroke Study (ECASS I and
ECASS II) and
• the Alteplase Thrombolysis for Acute Noninterventional
Therapy in Ischemic Stroke (ATLANTIS A and ATLANTIS B)
• enrolled subsets of patients in the ≤3-hour time period and
found largely similar effects in this time window to those
observed in the 2 NINDS rtPA trials

47. •Maximum time window in which fibrinolytic therapy
may be given in many patients has been expanded to 4.5
hours
•Preclinical, cerebrovascular imaging, and clinical trial
evidence indicate the fundamental importance of
minimizing total ischemic time and restoring blood flow
to threatened but not yet infarcted tissue as soon as
feasible.

48. PATIENTS WITH MINOR AND ISOLATED OR RAPIDLY
IMPROVING NEUROLOGICAL SIGNS
•Minor and isolated symptoms are those that are not
presently potentially disabling. Although most patients
with potentially disabling symptoms will have NIHSS
scores ≥4
•Certain patients, such as those with gait disturbance,
isolated aphasia, or isolated hemianopia, may have
potentially disabling symptoms although their NIHSS
score is just 2

49. • Approximately one third of patients who are not treated
with intravenous rtPA because of mild or rapidly improving
stroke symptoms on hospital arrival have a poor final stroke
outcome.

56. RECOMMENDATIONS
• Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is
recommended for selected patients who may be treated
within 3 hours of onset of ischemic stroke (Class I; Level of
Evidence A).

57. •In patients eligible for intravenous rtPA, benefit of
therapy is time dependent, and treatment should be
initiated as quickly as possible. The door-to-needle
time (time of bolus administration) should be within
60 minutes from hospital arrival (Class I; Level of
Evidence A)

58. • Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is
recommended for administration to eligible patients who
can be treated in the time period of 3 to 4.5 hours after
stroke onset (Class I; Level of Evidence B).
• The eligibility criteria for treatment in this time period are
similar to those for people treated at earlier time periods
within 3 hours, with the following additional exclusion
criteria:

59. • patients >80 years old
• those taking oral anticoagulants regardless of INR
• those with a baseline NIHSS score >25
• those with imaging evidence of ischemic injury involving
more than one third of the MCA territory
• or those with a history of both stroke and diabetes mellitus.

60. •Intravenous rtPA is reasonable in patients whose
blood pressure can be lowered safely (to below
185/110 mm Hg) with antihypertensive agents, with
the physician assessing the stability of the blood
pressure before starting intravenous rtPA (Class I;
Level of Evidence B)

61. • In patients undergoing fibrinolytic therapy, physicians
should be aware of and prepared to emergently treat
potential side effects, including bleeding complications and
angioedema that may cause partial airway obstruction
(Class I; Level of Evidence B)

62. •Intravenous rtPA is reasonable in patients with a
seizure at the time of onset of stroke if evidence
suggests that residual impairments are secondary to
stroke and not a postictal phenomenon (Class IIa;
Level of Evidence C)

63. •The usefulness of intravenous administration of
tenecteplase, reteplase, desmoteplase, urokinase, or
other fibrinolytic agents and the intravenous
administration of ancrod or other defibrinogenating
agents is not well established, and they should only
be used in the setting of a clinical trial (Class IIb;
Level of Evidence B)

64. INDIAN SCENARIO
•Gennova Biopharmaceuticals Limited has
approached the Drug controller of India for
approving Tenecteplase for Stroke thrombolysis.
•Submitted a study conducted in 100 patients
•Pending full approval for use in Acute stroke
thrombolysis
•Dosage used is 0.2 mg/Kg as a bolus dose

65. • Use of intravenous fibrinolysis in patients with conditions of
mild stroke deficits, rapidly improving stroke symptoms,
major surgery in the preceding 3 months, and recent
myocardial infarction may be considered, and potential
increased risk should be weighed against the anticipated
benefits
• (Class IIb; Level of Evidence C). These circumstances
require further study.

66. • The use of intravenous rtPA in patients taking direct
thrombin inhibitors or direct factor Xa inhibitors may be
harmful and is not recommended unless sensitive
laboratory tests such as aPTT, INR, platelet count, or
appropriate direct factor Xa activity assays are normal, or
the patient has not received a dose of these agents for >2
days (assuming normal renal metabolizing function)

67. MANAGEMENT DURING AND AFTER
THROMBOLYTIC TREATMENT
•According to American Heart Association
recommendations
•blood pressure monitoring -
•every 15 minutes for 2 hours from the start of t-PA
infusion,
•every 30 minutes for 6 hours,
•every 60 minutes over the rest of the 24 hours after
initiation of t-PA treatment

69. • Central lines and arterial puncture should be restricted in
the first 24 hours after thrombolytic treatment.
• Serum half-life of t-PA is very short, and after 20 minutes,
there is very little systemic thrombolytic activity.
• If clinical circumstances require a central line for
monitoring of cardiopulmonary pressures, such a line
could be safely established an hour or more after
thrombolysis was complete.

70. •Urinary tract instrumentation (placement of a Foley
catheter) should be avoided during infusion of t-PA
and at least 30 minutes after the infusion ends.
•Placement of a nasogastric tube should be avoided
during the first 24 hours after initiation of treatment

71. AREAS OF CONTROVERSY
Wake-Up Stroke (WUS) or Unknown Time of Onset
• Patients with WUS with no or early ischemic changes, less than
one-third of the middle cerebral artery (MCA) territory on
computed tomography (CT) of the head, had similar risk of SICH
and benefit from tPA as those presenting within 4.5 hours
• A perfusion CT protocol used in selection of patients with WUS or
unknown last well failed to improve patients’ outcome after
thrombolysis
• Conversely, mismatch between presence of a lesion in DWI but ab-
sent on fluid attenuated inversion recovery sequence on brain MRI,
helps select the patients within the 4.5-hour window

72. PRESENCE OF CEREBRAL VASCULAR MALFORMATIONS
• Retrospective reviews have demonstrated similar safety and
benefit of thrombolysis in patients with and without
unruptured aneurysms
• Diagnosis of cerebral cavernous malformation was not
associated with a raise in the risk of SICH in 9 patients who
underwent thrombolysis
• In a case series of 15 patients with acute stroke evaluated
with early CT angiography there was one incidental
aneurysm that eventually ruptured even without tPA
administration, suggesting caution when considering tPA in
patients with known aneurysm

73. TUMORS WITH OR WITHOUT METASTATIC LESIONS TO BRAIN
•32,576 thrombolysed patients, the patients with
stroke with any cancer and those without had
similar rates of home discharge, inpatient mortality,
or ICH
•Subgroup analysis showed that after tPA, solid
tumors had worse in-hospital mortality and home
discharge than liquid tumors.
•Metastatic cancer had the worst prognosis, but was
not associated with a higher risk of ICH

74. PREGNANCY AND MENSTRUATION
• Pregnancy was excluded from the stroke clinical trials and is a
relative contraindication for IV tPA
• Selected pregnant patients with stroke were treated with tPA
successfully.
• Two pregnant women had massive subchorionic hematoma,
one of which resolved spontaneously.
• Miscarriage has been reported.
• Thrombolysis was used successfully in several menstruating
women with stroke without increased risk of bleeding, although
blood transfusion may be needed

75. COAGULOPATHY
•Any coagulopathy leading to bleeding tendency is a
major contraindication for thrombolysis
•The NINDS tPA Stroke Trial did not find aspirin to
increase the risk of SICH or improve outcome
•Data from a single-center prospective observational
cohort study showed that antiplatelet medication used
before thrombolysis was associated with greater benefit
in spite of a higher incidence of SICH

76. •In retrospective analysis of tPA given within 3
hours, no correlation was found between previous
antiplatelet use and SICH, recanalization rate, or
good outcome
•However, dual antiplatelet treatment before tPA
use was associated with a higher rate of SICH

77. BLEEDING POST THROMBOLYSIS
•choice of hemostatic therapy remains controversial
•Antifibrinolytics such as aminocaproic acid
(Amicar) seem to be a logical antidote to fibrinolytic
therapy
•risk of inadvertent prothrombotic activity

78. •tPA induces systemic fibrinogenolysis
•fibrinogen replacement in the form of fresh frozen
plasma or cryoprecipitate would be a logical choice
for patients with low fibrinogen levels
• However, no cases were found in which patients
developed fibrinogen levels of less than 100 mg/dL

79. •Clot lysis releases D-dimers, which can exert an
antiplatelet effect by binding to the platelet
fibrinogen receptor, there is a theoretical basis for
infusion of platelets as a rescue therapy.

81. MODIFIED TREATMENT IN CEREBRAL ISCHAEMIA
(MTICI) SCORE

82. PHYSICIAN QUALIFICATIONS FOR
THROMBOLYSIS
•1. Successful recanalization (modified TICI 2b or 3)
in at least 60% of cases.
•2. Embolization to new territory of less than 15%.
•3. Symptomatic intracranial hemorrhage (i.e.
Parenchymal Hematoma on imaging with clinical
deterioration) rate less than 10%.

83. HOSPITAL REQUIREMENTS
• 1. Angiography suites suitably equipped to handle these patients, as
well as equipment and capability to handle the complications.
• 2. Dedicated stroke and intensive care units (preferably dedicated
neuro-intensive care unit), staffed by physicians with specific
training in those fields.
• 3. Vascular neurology and Neurocritical care expertise.
• 4. Neurosurgery expertise, including vascular neurosurgery
• 5. All relevant neuroimaging modalities (CT/CTA, MR/MRA,
Trans-cranial Doppler [TCD]), including 24/7 access to CT and
MRI