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					       Stroke



     Core Rounds
    Mark Y. Wahba
Preceptor: Dr. Ian Rigby
    Oct. 16th, 2003
 WHO definition: Stroke

• “a neurological deficit of sudden onset
  accompanied by focal dysfunction and
  symptoms lasting more than 24 hours that
  are presumed to be of a non-traumatic
  vascular origin”
WHO definition: Transient
   Ischemic Attack
• “neurological events that have a duration
  shorter than 24 hours, followed by complete
  return to baseline”
                 Outline

• Introduction
    • clinical features, pathophysiology, types of
      stroke, differential diagnosis
•   Vascular Anatomy
•   Stroke Patterns
•   TIA
•   Management in the ED
•   Thrombolysis: good or bad?
                         Facts

• Leading cause of adult disability
• 3rd leading cause of death in US
• 75% of all strokes occur in pts >65yrs of
  age
• In the US annual medical costs of stroke
  care is $30 billion
• 20% of expenditures occur in the first 90
  days after an event
  •   The National Stroke Association. The brain at risk – Understanding and
      preventing stroke. 1998
 Emergency Care Facts

• 2% of all 911 calls
• 4% of all hospital admissions from the ED
  involve patients with potential strokes
           Prognosis

• Many pts present to ED with a „devastating
  neurological picture‟
• Substantial improvement may occur over
  time, even in the absence of specific therapy
• 20% of patients who survive the initial
  event eventually have full or partial
  resolution of hemiparesis
• Risk of repeated stroke is highest within the
  first 30 days
• 25-40% of patients will have a repeat stroke
  within 5 yrs

• EMR Sept 29,1997. Stroke: Comprehensive Guidelines for Clinical
  Assessment and Emergency Management (Part 1)
           Risk Factors

•   Hypertension-primary risk factor
•   Atrial fibrillation
•   Increasing age (particularly > 65)
•   Cigarette smoking
•   Diabetes
•   Black population
•   Hx of TIA
•   Male : Female 3:2
 Stroke in the young Pt

• 3-4% of strokes occur in people aged 15-45
• Sickle Cell anemia
• Hypercoaguable states
  • Pregnancy, OCP use, antiphospholipid
    antibodies, protein C and S deficiencies
• Drugs
  • Cocaine, phenylpropanolamine, amphetamines
        Pathophysiology

• Cerebral blood flow provides brain with
  oxygen and glucose for energy at rate of 40-
  60ml/100g of brain/min
• When rate is <10ml/100g of brain/min cell
  membrane failure occurs:
  •    extracellular K,  intracellular Ca
  •    ATP, profound cellular acidosis
  •   Cell death
  •   Electrical „silence‟
      Pathophysiology:
     Ischemic penumbra
• the area surrounding the primary injury
• CBF is 10-18ml/100g of brain/min
• Electrical silence but irreversible damage has not
  yet occurred
• Animal studies:
   • reversible neurologic deficit if cerebral vessel occlusion
     lasts less than 2h
   • after 6h of occlusion: irreversible neurologic deficit
   • Thus the 2-6 hour therapeutic window for thrombolysis
What are the types of stroke?

  •   Ischemic   •   Hemorrhagic
      Ischemic Stroke

• 85% of strokes
• Thrombotic or Embolic
• One month mortality: 15%
  Ischemic: Thrombotic
         local origin of clot

• Usually develops at night during sleep
• Symptoms perceived in morning
• Suspect in hx of atherosclerosis,
  hypercoaguable states, and collagen
  vascular disorders
      Ischemic: Embolic
         proximal origin of clot
• Occurs at any time
• Frequently during periods
  of vigorous activity
• Hx of Atrial fibrillation,
  valvular vegetations,
  thromboembolism from
  MI, ulcerated plaques in
  carotid system
• Seizures in 20% of cases
Hemorrhagic Stroke
   Hemorrhagic Stroke

• 15% of strokes
• intracerebral hemorrhage > subarachnoid
  hemorrhage
• Occur during stress or exertion
• Focal deficits rapidly evolve
• Confusion, coma or immediate death
         Hemorrhagic

• One month mortality:
• 50% for SAH
• 80% for intracerebral hemorrhage
Vascular Anatomy
 Cerebral Blood Supply

Anterior Circulation      Posterior Circulation
• From carotid system     • From vertebral system
• Supplies 80% of brain   • Supplies 20% of brain
Internal carotid territory
  Internal Carotid Artery
• Anterior portion of the brain involving the frontal,
  temporal, and parietal lobes, is supplied by the carotid
  arteries (CA)
• CA arises from the innominate artery on the right and
  aortic arch on the left. At level of upper neck CA branches
  into internal and external
• the internal carotid artery terminates into the middle
  (MCA) and anterior (ACA) cerebral arteries
• MCA perfuses the cortex, parietal lobe, temporal lobe,
  internal capsule, and portions of the basal ganglia
• ACA forms the anterior portion of the circle of Willis and
  supplies portions of the frontal lobe
             Carotid Artery

• Approximately half of patients with
  moderate stenosis (greater than 50%
  occlusion) will have a carotid bruit
• about 90% of patients with a carotid bruit
  have at least moderate stenosis

• Wiebers D, Whisnant J, Sanok B, et al. Prospective comparison of a
  cohort with asymptomatic carotid bruit and a population-based cohort
  without carotid bruit. Stroke 1990;21:984-988.
• Ingall T, Homer D, Whisnant J, et al. Predictive value of carotid bruit
  for carotid atherosclerosis. Arch Neurol. 1989;46:418-422
 Vertebrobasilar System
• Perfuses the posterior part of the brain including
  the occipital lobe, cerebellum, and brainstem
• vertebral arteries arise from the subclavian arteries
• give off branches supplying the medulla and
  portions of the cerebellum
• basilar artery is formed by the junction of the two
  vertebral arteries and gives off a variety of
  penetrating arteries supplying the brainstem and
  portions of the basal ganglia before dividing into
  the posterior cerebral arteries
        Vertebrobasilar System



                           Posterior cerebral
                           arteries
Basilar artery
                          Vertebral arteries
Stroke Patterns
    Dominant Hemisphere

•   Majority of right handed and most left
    handed patients have dominance for
    speech and language located in the left
    hemisphere
•   Left hemisphere infarction is characterized
    by aphasia (both motor [Broca‟s] and
    sensory [Wernicke‟s]) and apraxia
Nondominant Hemisphere

• Less predictable syndromes
• Attention defects: extinction and neglect
• Behavioral changes: acute confusion and
  delirium
   Aphasia: Important?

• Yes: usually localizes a lesion to the
  dominant cerebral cortex in the middle
  cerebral artery distribution
  • Rosen‟s Emergency Medicine 5th edition



• Aphasia and dysphasia are used
  interchangeably
• Don‟t confuse with Dysphagia
               Case

• 80 yr old male
• Sudden onset right side hemiplegia,
  hemianesthesia
• eyes deviated to left
• “babbling”
                  MCA territory
(image is of vascular territory, not specifically of previous case)
Middle Cerebral Artery
 Middle Cerebral Artery

• Embolism from ICA or heart to MCA is
  most common cause of cerebral infarction
• Supplies most of the convex surface of
  brain
• Deep tissue: basal ganglia, putamen, and
  parts of globus pallidus, caudate nucleus,
  and internal capsule
          MCA stroke

• Contralateral hemiplegia and
  hemianesthesia: arm and face > leg
• Deviation of the head and eyes toward side
  of infarct “Gaze preference”
• Global aphasia (in dominant hemisphere)
• Hemianopia, Hemineglect
               Case

• 80 yr old female
• Awoke with weakness in right leg
• Slight right side weakness leg>arm
• Family states she has “impaired judgment
  and insight”
• “seems like a baby: sucking and grasping”
Anterior Cerebral Artery
Anterior Cerebral Artery

• Supplies basal and medial aspects of the
  cerebral hemispheres
• Extends to anterior two thirds of parietal
  lobe
• Perforating branches supply anterior
  caudate nucleus, parts of internal capsule,
  putamen and anterior hypothalamus
Anterior Cerebral Artery
       Infarction
•   weakness of the leg
•   +/- proximal muscle weakness in the
    upper extremities
•   Affect frontal lobe: impaired judgment
    and insight, change in affect
•   Presence of primitive grasp and suck
    reflexes
•   Language impairment (common finding)
               Case

• 77 yr old male
• Sudden onset of dizziness, double vision
• On exam has pain and temp deficit on half
  of face and on opposite side of body
Posterior Circulation
  Posterior Circulation/
 Vertebrobasilar System
• 2 Vertebral arteries  basilar artery
  posterior cerebral arteries
• Supplies brainstem, cerebellum, thalamus,
  auditory and vestibular centers of the ear,
  visual occipital cortex
 Vertebrobasilar System

• Heterogeneous syndromes and presentations
• Cranial nerve deficits and involvement of
  cerebellum and neurosensory tracts
• diplopia, dysphagia, dysarthria, dizziness,
  vertigo, ataxia
• pain and temp deficits in face occur on
  opposite side of body
 Vertebrobasilar System

• Thalamic lesions: sensory symptoms
  involving loss of tactile, temp, and pain
  sensation, „numbness‟ on side of body
  opposite face
• Occipital lesions: homonymous visual field
  defect (hemianopia or quadrantanopia)
               Case

• 85 yr old black male
• Diabetic, hypertension
• Sudden onset of being unable to move left
  side of body
• Able to talk
• Sensation intact
      Lacunar Infarction
• Lesion of small penetrating branch arteries into
  BG, thalamus, pons, internal capsule
• “Pure” strokes
   • Motor, sensory, ataxic hemiparesis
• Usually result in hemiparesis of face, arm and leg
• Lack of impairment of consciousness, aphasia, or
  visual disturbances
• More common in blacks and hx of HTN, DM
• 60% of patients with lacunar infarctions will be
  independent at one year following stroke
                 Case

•   85 yr old female
•   In ICU, post AAA rupture repair
•   GCS 15/15
•   Complaining of difficulty moving her leg
    and that it feels numb
    Watershed Infarction
• occurs in vulnerable areas supplied by distal distribution
  cerebral arteries during periods of hypotension
• infarction between the anterior and middle cerebral arteries
  presents with hemiparesis and hemianesthesia,
  predominantly in the leg
• dominant hemisphere infarctions: decrease in verbal ability
  with preserved comprehension
• Infarction involving the posterior watershed area presents
  with homonymous hemianopia +/- hypoesthesia in the face
  and legs
                Case

•   77 yr old male
•   Sudden onset headache, vomiting
•   went unresponsive
•   GCS 3/15, elevated BP
•   What has happened?
   Hemorrhagic Stroke

• Classic: sudden onset HA, vomiting,
  elevated BP
• Focal neurologic deficits that progress over
  minutes
• May present with agitation and lethargy but
  progresses to stupor or coma
Transient Ischemic Attack
Transient Ischemic Attack

• Neurological deficit of sudden onset
  accompanied by focal dysfunction that has a
  duration of shorter than 24 hours
• Most resolve within 15-30 minutes
• Straightforward definition but complex and
  controversial management
Common causes of ischemic stroke and transient ischemic attack
                        TIA

• Harbinger of ischemic cerebral infarction
• In the absence of treatment:
• 5-10% of pts will have a stroke within a
  month and 12% within a year
• After 2 years a stroke will have occurred in
  20-40% of TIA patients
  • Tuhrim S, Reggia JA. Management of TIA. American Family
    Physician 1986;315:1041
  • Morris PJ et al, Transient Ischemic Attacks New York: Marce,
    Dekker, 1982
      TIA management

• Is the pt high risk?
  • Multiple TIA in last 2/52, severe deficit,
    crescendo symptoms, TIA caused by
    cardioembolic events
• If so: CT head, admit for workup
• Same for first time TIA
      TIA Management
• If low risk: D/C home after seeing stroke team
• FASTER trial: Fast Assessment of Stroke and TIA
  to prevent Early Recurrence
• <12 hours of onset of TIA or minor stroke:
• randomized to Anti-platelet therapy with ASA or
  ASA + clopidogrel (Plavix)
• + randomized to Statin therapy with simvastatin
  vs. placebo
  • Outcome: stroke at 90 days, combined outcome of MI,
    stroke, or vascular death at 90 days, stroke severity
What if they are already on
           ASA?
• In Calgary: start patient on Clopidogrel
  (Plavix) as well
Do we thrombolyse or is this
        just a TIA?
 • 312 pts randomized to placebo group in the
   NINDS trial
 • Medial time to treatment was 90 minutes
 • Only 2% were symptom free at 24 hours
 • “unlikely that patients with a persistent
   neurologic deficit of longer than 90 minutes
   will resolve spontaneously”
   • Borg KT et al TIA: an emergency medicine approach. Emergency
     Medicine Clinics of North America. Vol 20, 3, Aug 2002
Management of Patients with
     Ischemic Stroke


  Guidelines for the Early Management of Patients With Ischemic
  Stroke. A Scientific Statement From the Stroke Council of the
  American Stroke Association. Adams HP et al Stroke. 2003;34:
  1056-1083.
          Hx and Physical

“in general, the diagnosis of stroke is
  straightforward”
• Emergency physicians correctly identified
  152 or 176 consecutive stroke patients (sens
  86.4%) and 1818 of 1835 patients without
  stroke (spec 99.1%)
  •   Von Arbin M et al. Accuracy of bedside diagnosis in stroke. Stroke. 1981: 12:288-
      293
                     But…

• Errors in clinical diagnosis can occur
• One series of 821 patients diagnosed with
  stroke: 13% were later determined to have
  other conditions
  • Norris JW. Misdiagnosis of stroke. Lancet. 1982;1:328-331

• Unrecognized seizures, confused states,
  syncope, brain tumors subdural hematoma
  hypoglycemia and other toxic or metabolic
  disorders
  Differential Diagnosis

• Complex migraine     •   Cerebral infection
  headache with        •   Subdural hematoma
  hemiparesis          •   Drug intoxication
• Post-ictal paresis   •   Malignant
  (Todd‟s paresis)         hypertension
• Hypoglycemia
• Cerebral tumor
             History

• Time of onset is critical
• For treatment: the onset is assumed to be
  last time pt was symptom free
• Recent medical or neurological events:
  Trauma, hemorrhage, surgery, MI, previous
  stroke
• Meds: oral anticoagulants, antiplatelets
Neurologic Examination

• The examination recommended by the
  National Institutes of Health is broken
  down into 6 areas
  1.   Level of consciousness
  2.   Visual assessment
  3.   Motor function
  4.   Cerebellar function
  5.   Sensation and neglect
  6.   Cranial nerves
    Imaging and Lab -
All patients should have:
•   Brain CT        •   Creatinine
•   ECG             •   CBC
•   Serum Glucose   •   PT/INR
•   Electrolytes    •   aPTT
      Selected Patients

• LFTs                      • CXR (if lung
• Tox screen and EtOH         pathology suspected)
  (if uncertain about hx)   • LP (if suspecting SAH
• Preg test                   and CT is negative)
• ABG (if hypoxic)          • EEG (suspecting
                              seizures )
Imaging



MRI vs CT
                       MRI

• Standard MRI (T1, T2 weighted) is
  relatively insensitive to changes of acute
  ischemia within first few hours of stroke
  • Show abnormalities in <50% of patients (class A)
• But, diffusion weighted imaging (DWI)
  visualizes ischemic regions within minutes
  of symptoms
  • Warach S et al. Fast MRI diffusion-weighted imaging of acute
    human stroke. Neurology. 1992;42: 1717-1723
       Limitations of MRI

• Difficulty in identifying ICH
• Cost, limited availability, patient CI
  (claustrophobia, pacemakers, metal
  implants)
• “Additional research is needed to determine
  the utility of MRI in place of CT for
  identifying hemorrhage among patients with
  suspected stroke”
  •   Guidelines for the Early Management of Patients With Ischemic Stroke. A
      Scientific Statement From the Stroke Council of the American Stroke Association.
      Adams HP et al Stroke. 2003;34: 1056-1083.
                        CT

• CT is the gold standard to which other
  brain imaging studies are compared
• CT accurately identifies most cases of ICH
  and helps discriminate nonvascular causes
  of neurological symptoms (brain tumor)-
  grade B
  • Jacobs et al. Autopsy correlations of computerized tomography:
    experience with 6000 CT scans. Neurology. 1976; 26:1111-1118
With r-tPA, interest in CT in:
 • Subtle early signs of infarction might affect
   treatment decisions:
    • hyperdense middle cerebral artery sign and loss of gray-white
      differentiation in the cortical ribbon are associated with poor
      outcome (class A evidence)
 • Presence of widespread signs of early infarction as
   this correlates with a high risk of hemorrhagic
   transformation (level 1)
 • But… MD‟s ability to reliably and reproducibly
   recognize early CT changes is variable (class B)
    •   Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement
        From the Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34:
        1056-1083
Other CT scan techniques

• Xenon enhanced CT provides a quantitative
  measurement of cerebral blood flow
• Perfusion CT measures CBF by mapping
  the appearance of an IV contrast bolus
• further studies are needed to determine their
  clinical utility
          Currently: Imaging
Goal for patients who are candidates for thrombolysis:


    • Complete CT within 25 minutes of arrival
      to ED
    • Study interpreted within 20 min
    • Thus: door to interpretation time of 45 min
       • Marler JR et al. Proceedings of a national symposium on rapid
         identification and treatment of acute stroke; 1997. (GENERIC) Pamphlet.
Other management issues
                     ECG?

• Acute MI can lead to stroke and acute
  stroke can lead to MI
• Arrhythmias can occur in pts with ischemic
  stroke
• Atrial fibrillation detected in the acute
  setting
  • Oppenheimer sm et at. The cardiac consequences of stroke. Neurol
    Clin. 1992;10:167-176
  • Dimant J et al. ECG changes and myocardial damage in patients
    with acute CVA. Stroke. 1977;8 448-455
      Cardiac Rhythm

• Pts with Right hemisphere infarcts have
  high risk of arrhythmias
• Thought to be due to disturbances in
  sympathetic and parasymp nervous system
  function (level V)
• ECG changes in stroke include: ST seg dep,
  QT prolongation, inverted T waves,
  prominent U waves
              Blood Tests?

• “Use of rtPA should not be delayed while waiting
  for INR or aPTT unless there is a clinical
  suspicion of a bleeding abnormality or unless the
  patient has been taking warfarin and heparin or
  their use is uncertain.”
• Determination of platelets and INR is required in
  pts taking warfarin prior to administration of
  thrombolytics
   • Adams et al. Guidelines for thrombolytic therapy for acute stroke.
     Circulation. 1996;94:1167-1174
        Hypoglycemia

• Can cause focal neurological signs that
  mimic stroke
• Can itself lead to brain injury
• Therefore prompt measurement and rapid
  correction are indicated
           Hyperglycemia
• Uncertainty whether hyperglycemia worsens
  stroke outcomes
   • Weir CJ et al. Is hyperglycemia an independent predictor of poor outcome
     after acute stroke? BMJ.1997;314:1303-1306.
• “No data evaluating the impact of maintaining
  euglycemia during the period of acute stroke”
• Reasonable goal is to lower markedly elevated
  glucose levels to <16.63 mmol/L (grade C)
• Overly aggressive fluid therapy should be avoided
  because it can result in fluid shifts that may be
  detrimental to the brain
Does everyone need a CXR?

 • Was previously recommended for all pts
   with acute ischemic stroke
 • A study found that clinical management
   was altered in only 3.8% of patients having
   routine CXR at time of admission for stroke
   • Sagar G et al. Is admission chest radiography of any clinical value
     in acute stroke patients? Clin Radiology. 1996;51:499-502

 • test is of little use in absence of an
   appropriate clinical indication (grade B)
                Oxygen?

• Pts with acute stroke should be monitored
  with pulse ox with a target O2 sat of >95%
  (level V)
• An endotracheal tube should be placed if
  the airway is threatened (level V)
• 50% of patients requiring endotracheal
  intubation will die within 30 days of stroke
• Grotta J et al. Elective intubation for neurologic
  deterioration after stroke. Neurology. 1995;45:640-644
                       Fever?

• Increased temp in setting of acute stroke has been
  associated with poor neurological outcome
   • Azzimondi G et al. Fever in acute stroke worsens prognosis: a prospective
     study. Stroke. 1995;26 :2040-2043

• “Source of any fever following stroke should be
  ascertained and the fever should be treated with
  antipyretics”
• Studies investigating hypothermia for treatment of
  patients with stroke but efficacy has yet to be
  established
            Hypertension

• Optimal management has not been
  established
  • Brott T et al. Hypertension and its treatment in the NINDS rtPA
    stroke trial. Stroke. 1998;29:1504-1509
• In the absence of organ dysfunction or
  thrombolytic therapy there is little scientific
  basis and no clinically proven benefit for
  lowering BP among patients with acute
  ischemic stroke
  • Powers WJ et al Acute hypertension after stroke: the scientific
    basis for treatment decisions. Neurology. 1993;43:461-467
          Hypertension

• Situations that may require treatment:
  •   Hypertensive encephalopathy
  •   Aortic dissection
  •   Acute renal failure
  •   Acute pulmonary edema
  •   Acute MI
Consensus on Hypertension

 • Antihypertensive agents should be withheld
   unless the diastolic BP is >120 mmHg or
   unless the systolic BP is >220mmHg
 • Aim for a 10 to 15% reduction of BP
 • Use parenteral agents that are easily titrated:
   labetalol, sodium nitroprusside
 • level V evidence
Hypertension in candidate for
       thrombolytics
  • Systolic BP must be <185 mmHg
  • Diastolic BP must be <110 mmHg
  • Pretreatment: Labetalol 10-20mg IV over 1-
    2min
  • During treatment: monitor BP q 15min for
    2h
  • Use labetalol, Na nitroprusside infusions
      Anticoagulants?

• Several studies with heparin, LMW
  heparins, heparinoid
• Conclusion:
  • parenterally administered anticoagulants are
    associated with an increased risk of serious
    bleeding complications (level I)
  • early administration of the rapidly acting
    anticoagulants does not lower the risk of early
    recurrent stroke, including among patients with
    cardioembolic stroke (level I)
            Anticoagulants

• Recommendations:
• Urgent routine anticoagulation with the goal
  of improving neurological outcomes or
  preventing early recurrent stroke is not
  recommended for the treatment of patients
  with acute ischemic stroke (grade A)
  •   Guidelines for the Early Management of Patients With Ischemic Stroke. A
      Scientific Statement From the Stroke Council of the American Stroke Association.
      Adams HP et al Stroke. 2003;34: 1056-1083
          Antiplatelets

• 2 large trials with aspirin:
   • Chinese Acute Stroke Trial
   • International Stroke Trial
Chinese Acute Stroke Trial
         (CAST)
• Prospective, randomized, placebo controlled trial
  of >21000 pts, where ASA 160mg/day or placebo
  was given within 48h of stroke onset
• Aspirin reduced early mortality
   • 3.3 vs 3.9%; p=0.04
• No effect on the proportion of patients who were
  dead or dependent at hospital discharge
   • 30.5 vs 31.6%; p=0.08
   • (CAST: randomized placebo-controlled trial of early aspirin use in 20000
     patients with acute ischemic stroke. Lancet 1997; 349: 1641-1649
International Stroke Trial (IST)
  • Prospective, randomized, open-label trial of ASA
    and unfractionated heparin in >19000 pts
  • half received ASA and half were instructed to
    avoid ASA, then half of pts in each group received
    unfractionated heparin
  • Significant reduction in recurrent events but acute
    mortality was not reduced (level I)
  • Small significant (0.1% absolute) significant
    increase in the incidence of intracranial
    hemorrhage (level I)
     •   IST: a randomized trial of aspirin, subcutaneous heparin, both or neither among
         19435 patients with acute ischemic stroke. Lancet 1997;349:1569-1581
                Antiplatelets

• Combined analysis revealed:
• ASA had a small but statistically significant
  reduction of 9 (+/-3) fever deaths or
  nonfatal strokes per 1000 treated patients
• Absolute RR of 0.9%
• NNT of 111
  •   Anticoagulants and Antiplatelet Agents in Acute Ischemic Stroke. Report of the
      joint stroke guideline development committee of the American academy of
      neurology and American stroke association. Stroke 2002;33:1934-1942.
                   Antiplatelets

• Conclusion: use of aspirin within 24-48h
  after stroke in attempts to reduce death and
  disability is reasonable (level I)
• Recommendation: Aspirin should be given
  within 24 to 48 hours of stroke onset in
  most patients (grade A)
• Not recommended within 24 hours of
  thrombolytic agents (grade A)
  •   Guidelines for the Early Management of Patients With Ischemic Stroke. A Scientific Statement From the
      Stroke Council of the American Stroke Association. Adams HP et al Stroke. 2003;34: 1056-1083
Thrombolysis for Acute
   Ischemic Stroke




  Are we doing the right thing?
EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical
Assessment and Emergency Management (Part II)
  Thrombolysis: History

• U. S. Food and Drug Administration approval of
  rtPA (recombinant tissue plasminogen activator)
  for the treatment of acute stroke in June of 1996
• based on the National Institute of Neurological
  Disorders and Stroke (NINDS) rt-PA Stroke Study
• less than 10 percent of stroke patients are eligible
  for thrombolytic therapy
   •   EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical Assessment and
       Emergency Management (Part II)
                               To date:

• 6 grade-one multi-center RCTs of thrombolytics
  for acute stroke demonstrated lack of benefit or
  worse outcomes with treatment
• 3 trials of streptokinase were halted prematurely
  because of an excess of poor outcomes or deaths
  (level I)
• the NINDS trial is the only published RCT of
  intravenous thrombolytic therapy that has been
  positive in favor of thrombolysis
   •   Position Statement on Thrombolytic Therapy for Acute Ischemic Stroke, The CAEP Committee on Thrombolytic Therapy
       for Acute Ischemic Stroke http://www.caep.ca/002.policies/002-01.guidelines/thrombolytic.htm
                                      ECASS

• compared rtPA (1.1 mg/kg) to placebo in patients with <6
  hours of symptoms
• early intracranial hemorrhage, fatal cerebral edema and
  early mortality were more common in treated patients than
  in controls
• surviving t-PA recipients were more likely to have
  minimal or no disability at 3 months
• authors concluded: while some patients benefit, the rate of
  negative outcomes was prohibitively high
• Intravenous rtPA was not more effective than placebo in
  improving neurological outcomes at 3 months after stroke
  (level I)
   •   Hacke W, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke, the
       European cooperative acute stroke study (ECASS). JAMA 1995;274:1017-25
      ECASS vs NINDS

• ECASS: higher dose, longer window of
  treatment
• Post hoc analysis concluded that pts treated
  within 3 hours appeared to benefit from
  rtPA
                 ECASS-II
• applied the same eligibility criteria and used the same 0.9
  mg/kg rtPA dose, but enrolled patients within 6 hours of
  symptom onset
• More than 1/3 of pts in each group made and excellent
  recovery and no significant benefit was noted from
  treatment
• rtPA did not significantly increase the rate of favorable 90-
  day outcomes (40.3% vs. 36.6%, p=0.277), and was
  associated with a higher incidence of parenchymal
  hemorrhage (11.8% vs. 3.1%), symptomatic intracranial
  hemorrhage (8.8% vs. 3.4%), and early death due to
  intracranial hemorrhage (11 vs. 2 cases)
                        ECASS-II

• no significant differences in 30- or 90-day
  mortality
• subgroup analysis showed a trend towards
  improved neurological outcomes in patients with
  <3 hours of symptoms, but the numbers were
  small and statistically insignificant
• ECASS-II therefore failed to reproduce the
  positive results of NINDS
   •   Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D et al. Randomized
       double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase
       in acute ischemic stroke (ECASS II). Lancet 1998;352:1245-51
            ECASS-II

• Recruitment bias?
• Avoided recruitment of pts with Multilobar
  infarctions
• Thus severity of strokes was less than in
  other trials
• Generally more favorable prognosis may
  have reduced the likelihood of detecting a
  therapeutic effect
                           PROACT II
• administered intra-arterial pro-urokinase (vs. placebo) to
  patients with <6 hours of symptoms
• At 90 day follow-up, thrombolytic patients had a higher
  rate of favorable outcomes (40% vs. 25%; p = 0.04),
  defined as a modified Rankin score of 2 or less
• ICH with early neurological deterioration was more
  common in prourokinase patients (10% vs. 2%; p = 0.6),
  and 90-day mortalities were similar between groups (25%
  vs. 27%)
• suggests that intra-arterial prourokinase may confer some
  benefit, but at substantially increased risk of symptomatic
  intracranial hemorrhage
   •   Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic
       stroke. The PROACT II study: a randomized controlled trial. JAMA 1999;282:2003-11
                     ATLANTIS

• placebo-controlled, randomized clinical trial
  addressing the efficacy and safety of rtPA
  administered 3 to 5 hours after stroke onset
• found no beneficial treatment effect, but a
  significantly higher rate of asymptomatic
  (11.4 vs. 4.7%) and symptomatic (7.0% vs.
  1.1%) intracerebral hemorrhage with rtPA
  •   Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S.
      Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to
      5 hours after symptom onset. (The alteplase thrombolysis for acute
      noninterventional therapy for ischemic stroke [ATLANTIS] study). JAMA
      1999;282:2019-26
                  NINDS
• multicentre, randomized, placebo-controlled trial
• 624 patients with ischemic stroke were treated with
  intravenous t-PA (0.9 mg/kg) within 3 hours of the onset
  of stroke symptoms.
• Part 1: primary endpoint was neurological improvement at
  24h (complete neuro recovery or improvement of 4 points
  or more on NIHSS)
• Part 2: primary end point was global odds ratio for
  favorable outcome (defined as complete or nearly complete
  neurological recovery at 3 months after stroke)
                NINDS

• Part 1: t-PA recipients did not suddenly improve,
  and there were no significant outcome differences
  at 24 hours
• Part 2: patients treated with t-PA were more
  likely to have a favorable neurological outcome at
  90 days (odds ratio 1.7; 95% CI, 1.2-2.6; p=0.008)
• Compared to controls, t-PA recipients had a 12%
  absolute (32% relative) increase in the proportion
  with minimal or no disability
                            But…
• The benefit was similar at 1 year after stroke (level 1)
• t-PA was associated with a 10-fold increase in
  symptomatic intracerebral hemorrhage (6.4% vs. 0.6%)
  (level 1)
• the overall intracerebral hemorrhage rate (symptomatic +
  asymptomatic) was 10.1%
• Mortality rate in the two treatment groups was similar at 3
  months (17% vs 20%) and 1 year (24% vs 28%)
   •   The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study
       Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med
       1995;333:1581
Number Needed to Treat

• NNT = 1/Absolute Risk Reduction
• ARR=CER-EER
  ARR =(165-65)/165 - (168-80)/168
  ARR =0.08225
• about 8% absolute risk reduction if treated
  with tPA
• NNT=1/0.08225 = 12.
• This means you need to treat 12 patients to
  see an improvement in outcome at 90 days
Number Needed to Harm
• NNH 1/ARR
• Absolute RR = 8/165 - 21/168
  ARR=-0.0765
• In other words you have 8% absolute increased
  risk for CNS bleed if given tPA
• NNH = 1/ARR which is 13
• Thus for every 13 patients you treat you will get a
  CNS bleed
• take the asymptomatic bleeds out of the
  calculation the NNH is now about 17
• or treat 17 patients to get a symptomatic CNS
  bleed
                So…

• You have to treat 12 patients to get a good
  outcome overall as per NINDS definition
• That's not bad, except that for every 17 you
  treat you get a symptomatic/fatal CNS
  bleed.
• Thus the cautious approach in EM to CNS
  lytics and the strict eligibility criteria
Cochrane Stroke Group Trials
         Register
  • Up to January 2003
  • Objective: assess safety and efficacy of
    thrombolytic agents in patients with acute
    ischemic stroke
  • Selection criteria: randomized trials of any
    thrombolytic agent compared with control
    in patients with definite ischemic stroke
• 18 trials, 5727 patients
• Urokinase, streptokinase, recombinant
  tissue plasminogen activator, recombinant
  pro-urokinase
• 2 trials: intra arterial administration
• 16 trials: intra venous administration
• 50% of data from tPA
• Little data over age 80
  Thrombolytic therapy:
• administered up to six hours after ischemic stroke,
  significantly reduced the proportion of patients who were
  dead or dependent at the end of follow-up at three to six
  months (OR 0.84, 95% CI 0.75 to 0.95)
• a significant increase in: the odds of death within the first
  ten days (OR 1.81, 95% CI 1.46 to 2.24), the main cause of
  which was fatal intracranial hemorrhage (OR 4.34, 95% CI
  3.14 to 5.99)
• Symptomatic intracranial hemorrhage was increased
  following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22)
       Thrombolytic therapy:

• also increased the odds of death at the end of follow-up at
  three to six months (OR 1.33, 95% CI 1.15 to 1.53)
• For patients treated within three hours of stroke,
  thrombolytic therapy appeared more effective in reducing
  death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with
  no statistically significant adverse effect on death (OR
  1.13, 95% CI 0.86 to 1.48)
 Cochrane conclusions:

• Overall, thrombolytic therapy appears to result in
  a significant net reduction in the proportion of
  patients dead or dependent in activities of daily
  living.
• However, this appears to be net of an increase in
  deaths within the first seven to ten days,
  symptomatic intracranial hemorrhage, and deaths
  at follow-up at three to six months
• The data from trials using rtPA suggest that it may
  be associated with less hazard and more benefit
 Cochrane conclusions:
• The data are promising and may justify the use of
  thrombolytic therapy with intravenous recombinant tissue
  plasminogen activator in experienced centers in highly
  selected patients
• However, the data do not support the widespread use of
  thrombolytic therapy in routine clinical practice at this
  time
Canadian Association of
 Emergency Physicians


Position Statement on Thrombolytic Therapy for Acute
                   Ischemic Stroke:
              basically
• Similar to Cochrane findings
• “The data show that t-PA therapy must be
  limited to carefully selected patients within
  established protocols”.
• “Until it is clear that the benefits of this
  therapy outweigh the risks, thrombolytic
  therapy for acute stroke should be restricted to
  use within formal research protocols or in
  monitored practice protocols that adhere to the
  NINDS eligibility criteria”
• “Stroke thrombolysis should be limited to centers with
  appropriate neurological and neuro-imaging resources that are
  capable of administering treatment within 3 hours
• In such centers, emergency physicians should identify eligible
  patients, initiate low risk interventions and facilitate prompt CT
  scanning
• Only physicians with demonstrated expertise in neuroradiology
  should interpret head CT scans used to determine whether to
  administer thrombolytic agents to stroke patients.
• Neurologists should be directly involved prior to the
  thrombolytic administration”
     So what can we do?
• “The Canadian Association of Emergency Physicians
  enthusiastically endorses the promotion of stroke therapies
  where the benefits clearly outweigh the risks. These
  include the use of ASA, prevention of aspiration, early
  rehabilitation, and the establishment of stroke units and
  protocols”
Intra-arterial Thrombolyis
• Still in experimental stages
• Prospective, randomized, placebo control trial
  used intra-arterial r-prourokinase: successful in
  recanalizing more frequently but had increased
  risk of intracranial bleeding
   •   Del Zoppo et al. Gent M. PROACT: a phase II randomized trial of recombinant
       pro-urokinase by dircet arterial devlivery in acute middle cerebral artery stroke:
       PROACT investigators: Prolyse in Acute Cerebral Thrombolembolism. Stroke.
       1998; 29:4-11

• May be used in occlusion of large intracranial
  arteries: basilar or middle cerebral
• Requires adequate equipment and skilled clinician
Summary
            Summary

• Be familiar with stroke patterns
• Be familiar with general medical
  management of stroke patients
• Controversy regarding Thrombolytic
  therapy

• Thanks to Dr. Ian Rigby for his help
                         References
•   EMR Sept 29,1997. Stroke: Comprehensive Guidelines for Clinical
    Assessment and Emergency Management (Part 1)
•   EMR Oct 13, 1997. Stroke: Comprehensive Guidelines for Clinical
    Assessment and Emergency Management (Part II)
•   Thrombolysis for acute ischaemic stroke. Wardlaw JM et al. Conhrane Database of Systematic Reviews. 3,
    2003
•   Position Statement on Thrombolytic Therapy for Acute Ischemic Stroke, The CAEP Committee on
    Thrombolytic Therapy for Acute Ischemic Stroke http://www.caep.ca/002.policies/002-
    01.guidelines/thrombolytic.htm
•   Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al. Intravenous thrombolysis with
    recombinant tissue plasminogen activator for acute hemispheric stroke, the European cooperative acute
    stroke study (ECASS). JAMA 1995;274:1017-25
•   The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen
    activator for acute ischemic stroke. N Engl J Med 1995;333:1581
•   Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D et al. Randomised double-blind placebo-
    controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II).
    Lancet 1998;352:1245-51
•   Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute
    ischemic stroke. The PROACT II study: a randomized controlled trial. JAMA 1999;282:2003-11
                     References
•   Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S.
    Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5
    hours after symptom onset. (The alteplase thrombolysis for acute noninterventional
    therapy for ischemic stroke [ATLANTIS] study). JAMA 1999;282:2019-26
•   Taking the Initiative! An ED Based Stroke Team in a Community Teaching Hospital
    Jonathan A. Maise http://emedhome.com/features_archive-
    detail.cfm?SFID=090400&SFTID=news
•   Schmidley JW, Messing RO. Agitated confusional states inpatients with right
    hemispheric infarctions. Stroke 1984; 15: 883
•   Rosen‟s Emergency Medicine 5th edition
Extras
SAH          High attenuation is seen diffusely within the sulci on a noncontrasted head
CT. High attenuation collections are also present within the occipital horns of the lateral
                    ventricles. Moderate hydrocephalus is present
Embolic stroke
Motor Homunculus
          Vascular Territory

Among patients undergoing angiography for
  atherosclerotic stroke:
• 62% Internal Carotid Artery
• 15% Vertebrobasilar Arteries
• 10% Middle Cerebral Artery
•   Schmidley JW, Messing RO. Agitated confusional states inpatients with right
    hemispheric infarctions. Stroke 1984; 15: 883
• Attacks in the ICA distribution that involve
  the dominant hemisphere may present with
  symptoms such as motor dysfunction,
  amaurosis fugax, numbness, and/or aphasia
• in the distribution of the ICA of the non-
  dominant hemisphere have similar
  symptomatology but without aphasia
        Clinical Features

•   Sudden devlp‟t of focal neurological deficit
•   Transient loss of consciousness is rare
•   Seizure
•   Headache in a minority of patients
        Atrial Fibrillation

• Patients with A. Fib are 5 to 17 times more
  likely to develop stroke than those who do
  not have A. Fib
• Strokes resulting from A. Fib are more
  likely to involve large cerebral vessels, be
  more severe, and have a higher mortality
  than non-A. Fib strokes
  • Jorgensen HS et al: Acute stroke with atrial fibrillation: the
    Copenhagen Stroke study, Stroke 10: 1765, 1996
  • LiuHJ et al: Stroke severity in atrial fibrillation: the Framingham
    study, Stroke 27, 1760, 1996
National Institutes of Health
       Stroke Scale
 • Quantifies neurologic deficit, found to be
   reproducible and valid
 • Correlates well with amount of infarcted tissue on
   CT scan
 • Baseline NIHSS can determine pts appropriate for
   fibrinolytic therapy and those at risk of increased
   hemorrhage
    • NINDS trial of r-tPA score of >20 had a 17% chance of ICH, risk
      of bleeding was only 3% if <10
 • Prognostic tool to predict outcome
    •   Brott T: Utility of the NIH Stroke Scale, Cerebrovasc Dis 2:241, 1992
    •   Adams HP et al. Baseline NIHSS score strongly predicts outcome after stroke.
        Neurology. 1999; 53:126-131
              NIHSS
            score out of 42

• Level of              • Motor Arm: L and R-4
  Consciousness-3         each
• LOC of questions-2    • Motor Leg: L and R-4
                          each
• LOC of Commands-2
                        • Limb Ataxia-2
• Best Gaze-2           • Sensory-2
• Visual Fields-3       • Best Language-3
• Facial Palsy-3        • Dysarthria-2
                        • Extinction and
                          Inattention-2
               NINDS

• To get the number needed to treat (to meet
  the improvement outcome) it is calculated
  by 1/Absolute Risk Reduction. For this
  data the ARR =(165-65)/165 - (168-
  80)/168. This gives you a number of
  0.08225 (or about 8% absolute risk
  reduction if treated with tPA). So the
  NNT=1/0.08225 = 12. This means you need
  to treat 12 patients to see an improvement in
  outcome at 90 days.
• To look at the NNH (number needed to harm) you look at
  table#6. It is essentially the same type of calculation.
  Absolute RR = 10/165 - 33/168 which is -0.1358 or -
  13.6%. In other words you have a 13.6% absolute
  increased risk for CNS bleed if given tPA. The NNH =
  1/ARR which is 7.36 (or about 7). Thus for every 7
  patients you treat you will get a CNS bleed.
• If you take the asymptomatic bleeds out of the calculation
  (OK, I guess), the NNH is now about 8.4 (or treat 8
  patients to get a symptomatic CNSbleed).
• So what to make of this? You have to treat 12 patients to
  get a good outcome overall (as per their definition). That's
  not bad, except that for every 8 you treat you get a
  symptomatic/fatal CNS bleed. Now I'm a little worried.
  Hence our cautious approach in EM to CNS lytics.

				
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