Stroke

1
Stroke

• Core Rounds
• Mark Y. Wahba
• Preceptor Dr. Ian Rigby
• Oct. 16th, 2003

2
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

3
WHO definition Transient Ischemic Attack

• neurological events that have a duration shorter
  than 24 hours, followed by complete return to
  baseline

4
Outline

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

5
Facts

• Leading cause of adult disability
• 3rd leading cause of death in US
• 75 of all strokes occur in pts gt65yrs 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

6
Emergency Care Facts

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

7
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

8

• 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)

9
Risk Factors

• Hypertension-primary risk factor
• Atrial fibrillation
• Increasing age (particularly gt 65)
• Cigarette smoking
• Diabetes
• Black population
• Hx of TIA
• Male Female 32

10
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

11
Pathophysiology

• Cerebral blood flow provides brain with oxygen
  and glucose for energy at rate of 40-60ml/100g of
  brain/min
• When rate is lt10ml/100g of brain/min cell
  membrane failure occurs
• ? extracellular K, ? intracellular Ca
• ? ATP, profound cellular acidosis
• Cell death
• Electrical silence

12
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

13
What are the types of stroke?

• Ischemic

• Hemorrhagic

14
Ischemic Stroke

• 85 of strokes
• Thrombotic or Embolic
• One month mortality 15

15
Ischemic Thromboticlocal origin of clot

• Usually develops at night during sleep
• Symptoms perceived in morning
• Suspect in hx of atherosclerosis, hypercoaguable
  states, and collagen vascular disorders

16
Ischemic Embolicproximal 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

17
Hemorrhagic Stroke
18
Hemorrhagic Stroke

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

19
Hemorrhagic

• One month mortality
• 50 for SAH
• 80 for intracerebral hemorrhage

20
Vascular Anatomy
21
Cerebral Blood Supply

• Anterior Circulation
• From carotid system
• Supplies 80 of brain

• Posterior Circulation
• From vertebral system
• Supplies 20 of brain

22
Internal carotid territory
23
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

24
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
  199021984-988.
• Ingall T, Homer D, Whisnant J, et al. Predictive
  value of carotid bruit for carotid
  atherosclerosis. Arch Neurol. 198946418-422

25
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

26
Vertebrobasilar System
Posterior cerebral arteries
Basilar artery
Vertebral arteries
27
Stroke Patterns
28
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 Brocas and sensory
  Wernickes) and apraxia

29
Nondominant Hemisphere

• Less predictable syndromes
• Attention defects extinction and neglect
• Behavioral changes acute confusion and delirium

30
Aphasia Important?

• Yes usually localizes a lesion to the dominant
  cerebral cortex in the middle cerebral artery
  distribution
• Rosens Emergency Medicine 5th edition
• Aphasia and dysphasia are used interchangeably
• Dont confuse with Dysphagia

31
Case

• 80 yr old male
• Sudden onset right side hemiplegia,
  hemianesthesia
• eyes deviated to left
• babbling

32
MCA territory(image is of vascular territory,
not specifically of previous case)
33
Middle Cerebral Artery
34
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

35
MCA stroke

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

36
Case

• 80 yr old female
• Awoke with weakness in right leg
• Slight right side weakness leggtarm
• Family states she has impaired judgment and
  insight
• seems like a baby sucking and grasping

37
Anterior Cerebral Artery
38
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

39
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)

40
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

41
Posterior Circulation
42
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

43
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

44
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)

45
Case

• 85 yr old black male
• Diabetic, hypertension
• Sudden onset of being unable to move left side of
  body
• Able to talk
• Sensation intact

46
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

47
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

48
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

49
Case

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

50
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

51
Transient Ischemic Attack
52
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

53
Common causes of ischemic stroke and transient
ischemic attack
54
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 19863151041
• Morris PJ et al, Transient Ischemic Attacks New
  York Marce, Dekker, 1982

55
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

56
TIA Management

• If low risk D/C home after seeing stroke team
• FASTER trial Fast Assessment of Stroke and TIA
  to prevent Early Recurrence
• lt12 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

57
What if they are already on ASA?

• In Calgary start patient on Clopidogrel (Plavix)
  as well

58
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

59
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. 200334
  1056-1083.

60
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 12288-293

61
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.
  19821328-331
• Unrecognized seizures, confused states, syncope,
  brain tumors subdural hematoma hypoglycemia and
  other toxic or metabolic disorders

62
Differential Diagnosis

• Complex migraine headache with hemiparesis
• Post-ictal paresis (Todds paresis)
• Hypoglycemia
• Cerebral tumor

• Cerebral infection
• Subdural hematoma
• Drug intoxication
• Malignant hypertension

63
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

64
Neurologic Examination

• The examination recommended by the National
  Institutes of Health is broken down into 6 areas
• Level of consciousness
• Visual assessment
• Motor function
• Cerebellar function
• Sensation and neglect
• Cranial nerves

65
Imaging and Lab - All patients should have

• Brain CT
• ECG
• Serum Glucose
• Electrolytes

• Creatinine
• CBC
• PT/INR
• aPTT

66
Selected Patients

• LFTs
• Tox screen and EtOH (if uncertain about hx)
• Preg test
• ABG (if hypoxic)

• CXR (if lung pathology suspected)
• LP (if suspecting SAH and CT is negative)
• EEG (suspecting seizures )

67
Imaging

• MRI vs CT

68
MRI

• Standard MRI (T1, T2 weighted) is relatively
  insensitive to changes of acute ischemia within
  first few hours of stroke
• Show abnormalities in lt50 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.
  199242 1717-1723

69
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. 200334
  1056-1083.

70
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 261111-1118

71
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 MDs 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. 200334
  1056-1083

72
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

73
Currently ImagingGoal 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.

74
Other management issues
75
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. 199210167-176
• Dimant J et al. ECG changes and myocardial damage
  in patients with acute CVA. Stroke. 19778 448-455

76
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

77
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. 1996941167-1174

78
Hypoglycemia

• Can cause focal neurological signs that mimic
  stroke
• Can itself lead to brain injury
• Therefore prompt measurement and rapid correction
  are indicated

79
Hyperglycemia

• Uncertainty whether hyperglycemia worsens stroke
  outcomes
• Weir CJ et al. Is hyperglycemia an independent
  predictor of poor outcome after acute stroke?
  BMJ.19973141303-1306.
• No data evaluating the impact of maintaining
  euglycemia during the period of acute stroke
• Reasonable goal is to lower markedly elevated
  glucose levels to lt16.63 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

80
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. 199651499-502
• test is of little use in absence of an
  appropriate clinical indication (grade B)

81
Oxygen?

• Pts with acute stroke should be monitored with
  pulse ox with a target O2 sat of gt95 (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.
  199545640-644

82
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. 199526
  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

83
Hypertension

• Optimal management has not been established
• Brott T et al. Hypertension and its treatment in
  the NINDS rtPA stroke trial. Stroke.
  1998291504-1509
• 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. 199343461-467

84
Hypertension

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

85
Consensus on Hypertension

• Antihypertensive agents should be withheld unless
  the diastolic BP is gt120 mmHg or unless the
  systolic BP is gt220mmHg
• Aim for a 10 to 15 reduction of BP
• Use parenteral agents that are easily titrated
  labetalol, sodium nitroprusside
• level V evidence

86
Hypertension in candidate for thrombolytics

• Systolic BP must be lt185 mmHg
• Diastolic BP must be lt110 mmHg
• Pretreatment Labetalol 10-20mg IV over 1-2min
• During treatment monitor BP q 15min for 2h
• Use labetalol, Na nitroprusside infusions

87
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)

88
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. 200334
  1056-1083

89
Antiplatelets

• 2 large trials with aspirin
• Chinese Acute Stroke Trial
• International Stroke Trial

90
Chinese Acute Stroke Trial (CAST)

• Prospective, randomized, placebo controlled trial
  of gt21000 pts, where ASA 160mg/day or placebo was
  given within 48h of stroke onset
• Aspirin reduced early mortality
• 3.3 vs 3.9 p0.04
• No effect on the proportion of patients who were
  dead or dependent at hospital discharge
• 30.5 vs 31.6 p0.08
• (CAST randomized placebo-controlled trial of
  early aspirin use in 20000 patients with acute
  ischemic stroke. Lancet 1997 349 1641-1649

91
International Stroke Trial (IST)

• Prospective, randomized, open-label trial of ASA
  and unfractionated heparin in gt19000 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
  19973491569-1581

92
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 2002331934-1942.

93
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. 200334
  1056-1083

94
Thrombolysis for Acute Ischemic Stroke

• Are we doing the right thing?

95
EMR Oct 13, 1997. Stroke Comprehensive
Guidelines for Clinical Assessment and Emergency
Management (Part II)
96
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)

97
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

98
ECASS

• compared rtPA (1.1 mg/kg) to placebo in patients
  with lt6 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
  19952741017-25

99
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

100
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,
  p0.277), 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)

101
ECASS-II

• no significant differences in 30- or 90-day
  mortality
• subgroup analysis showed a trend towards improved
  neurological outcomes in patients with lt3 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 19983521245-51

102
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

103
PROACT II

• administered intra-arterial pro-urokinase (vs.
  placebo) to patients with lt6 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 19992822003-11

104
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 19992822019-26

105
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)

106
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
  p0.008)
• Compared to controls, t-PA recipients had a 12
  absolute (32 relative) increase in the
  proportion with minimal or no disability

107
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 19953331581

108
Number Needed to Treat

• NNT 1/Absolute Risk Reduction
• ARRCER-EER
  ARR (165-65)/165 - (168-80)/168 ARR
  0.08225
• about 8 absolute risk reduction if treated with
  tPA
• NNT1/0.08225 12.
• This means you need to treat 12 patients to see
  an improvement in outcome at 90 days

109
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

110
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

111
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

112

• 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

113
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)

114
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)

115
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

116
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

117
Canadian Association of Emergency Physicians

• Position Statement on Thrombolytic Therapy for
  Acute Ischemic Stroke

118
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

119

• 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

120
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

121
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 294-11
• May be used in occlusion of large intracranial
  arteries basilar or middle cerebral
• Requires adequate equipment and skilled clinician

122
Summary
123
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

124
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
  19952741017-25
• The National Institute of Neurological Disorders
  and Stroke rt-PA Stroke Study Group. Tissue
  plasminogen activator for acute ischemic stroke.
  N Engl J Med 19953331581
• 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 19983521245-51
• 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 19992822003-11

125
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 19992822019-26
• Taking the Initiative! An ED Based Stroke Team in
  a Community Teaching Hospital Jonathan A. Maise
  http//emedhome.com/features_archive-detail.cfm?SF
  ID090400SFTIDnews
• Schmidley JW, Messing RO. Agitated confusional
  states inpatients with right hemispheric
  infarctions. Stroke 1984 15 883
• Rosens Emergency Medicine 5th edition

126
Extras
127
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
128
Embolic stroke
129
Motor Homunculus
130
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

131

• 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

132
Clinical Features

• Sudden devlpt of focal neurological deficit
• Transient loss of consciousness is rare
• Seizure
• Headache in a minority of patients

133
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

134
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 gt20 had a 17
  chance of ICH, risk of bleeding was only 3 if
  lt10
• Prognostic tool to predict outcome
• Brott T Utility of the NIH Stroke Scale,
  Cerebrovasc Dis 2241, 1992
• Adams HP et al. Baseline NIHSS score strongly
  predicts outcome after stroke. Neurology. 1999
  53126-131