PRACTICAL ISSUES IN ACUTE STROKE (Stroke 101)

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PRACTICAL ISSUES IN ACUTE STROKE(Stroke 101)

• MURRAY FLASTER M.D.,Ph.D.
• UNIVERSITY OF NEVADA SCHOOL OF MEDICINE
• 12-1-08
• INTERNAL MEDICINE RESIDENTS CONFERENCE

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OVERVIEW

• RAPID STROKE EXAMINATION/PERTINENT HISTORY.
• SCAN (CT OR MR GRE).
• IV TPA?
• LARGE VESSEL ROADMAP.
• FURTHER TREATMENT OPTIONS
• INTRAARTERIAL TPA, MECHANICAL DISRUPTION WITH
  SPECIAL CATHETERS (PENUMBRA, MERCI RETRIEVER
  OR ANGIOPLASTY) OR ?NEUROPROTECTANTS (AS IN HIGH
  DOSE ALBUMIN IN ALIAS TRIAL).
• THERAPUTIC ULTRASOUND (AS IN CLOTBUST ALEXANDROV
  et.al. NEJM 2004 351 2170).
• CONFIRM STROKE ANATOMY/ FIND ETIOLOGY (DW MRI
  ETC.)
• PREVENT FUTURE EVENTS
• LARGE VESSEL CERVICAL AND INTRACRANIAL DISEASE,
  CARDIAC SOURCES, SMALL VESSEL ANGIOPATHY.
• TIA
• RISK FACTOR EVALUATION AND MODIFICATION

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LETS THINK ABOUT IV TPA.
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THE MANY Ss OF THE ACUTE STROKE PRESENTATION

• ISCHEMIC STROKE
• HEMORRHAGIC STROKE
• IPH, SAH, SDH
• SEIZURES AND RECURRENT SPELLS
• UNWITNESSED SEIZURE
• POST-SEIZURE PARALYSIS
• COMPLEX PARTIAL SEIZURES WITH FOCAL FEATURES,
  ESPECIALLY APHASIA
• TRANSIENT GLOBAL AMNESIA
• SEPSIS
• STUPOR AND DELERIUM
• METABOLIC COMA, DRUG ASSOCIATED STATES,
  HYPOGLYCEMIA.
• THE DOUBLE FAKEOUT OF THALAMIC OR MIDBRAIN STROKE
  (RAS).
• SYNCOPE
• ESPECIALLY IN THE SETTING OF PRIOR NEUROLOGIC
  DEFICITS
• SEPHALGIAS, ESPECIALLY COMPLICATED MIGRAINE AND
  HYPERTENSIVE CRISIS (PRES)
• SEPHALITIS AND CEREBRAL INFLAMMATORY DISEASES
• SPACE OCCUPYING LESIONS
• SEREBRAL VASCULITIS
• PSEUDO-STROKE (CONVERSION DISORDERS)

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THE MANY Ss OF THE ACUTE STROKE PRESENTATION

• ISCHEMIC STROKE
• HEMORRHAGIC STROKE
• IPH, SAH, SDH
• SEIZURES AND RECURRENT SPELLS
• UNWITNESSED SEIZURE
• POST-SEIZURE PARALYSIS
• COMPLEX PARTIAL SEIZURES WITH FOCAL FEATURES,
  ESPECIALLY APHASIA
• TRANSIENT GLOBAL AMNESIA
• SEPSIS
• STUPOR AND DELERIUM
• METABOLIC COMA, DRUG ASSOCIATED STATES,
  HYPOGLYCEMIA.
• THE DOUBLE FAKEOUT OF THALAMIC OR MIDBRAIN STROKE
  (RAS).
• SYNCOPE
• ESPECIALLY IN THE SETTING OF PRIOR NEUROLOGIC
  DEFICITS
• ENCEPHALGIAS, ESPECIALLY COMPLICATED MIGRAINE AND
  HYPERTENSIVE CRISIS (PRES)
• ENEPHALITIS AND CEREBRAL INFLAMMATORY DISEASES
• SPACE OCCUPYING LESIONS
• CEREBRAL VASCULITIS
• PSEUDO-STROKE (CONVERSION DISORDERS)

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CASE

• A 54 y/o DIABETIC MAN COMES TO THE ED WITH ONE
  HOUR OF SLURRED SPEECH AND RIGHT FACIAL WEAKNESS.
• HE REPORTS VAGUELY NOT FEELING WELL WITH
  DECREASED APPETITE SINCE THE LATE MORNING.
• HE IS MILDLY HYPERTENSIVE (160s/90s), AFEVRILE
  AND HIS NIHSS IS 3.
• CTH SUGGESTS MILD DEEP WHITE MATTER CHANGES ONLY,
  CBC AND PT/PTT ARE NORMAL, BMP IS DELAYED IN THE
  LAB AS IS THEREFORE CT ANGIOGRAM. THERE ARE NO
  RECENT SURGERIES OR OTHER CONTRAINDICATIONS TO
  ACUTE THROMBOTICS.
• CAN WE TREAT?
• FINGERSTICK GLUCOSE IS 56 AND D50 REVERSES THE
  DEFICIT.

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IV TPA
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NINDS Study rtPAin Acute Ischemic Stroke

• Double-blind, placebo-controlled, randomized
  2-part study1
• IV rtPA, 0.9 mg/kg, lt3 hrs, 10 bolus, 90 over 1
  h1
• 624 patients treated within 3 hours of stroke
  onset1
• 32 more rtPA patients had minimal or no
  disability (Barthel index)1
• Odds ratio of good outcome at 6 and 12 months
  1.72
• Intracranial hemorrhage by 36 h 6.4 rtPA, 0.6
  placebo (Plt.001)1
• Mortality by 3 months 17 rtPA, 21 placebo1

1. The National Institute of Neurological
Disorders and Stroke rt-PA Stroke Study Group. N
Engl J Med. 19953331581-1587. 2. Kwiatkowski TG
et al. N Engl J Med. 19993401781-1787.
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Overall Benefits and Risks of IV tPA for Stroke

• Benefit Neurologically normal at 3 months1
• 55 relative increase 12 absolute increase
• Robust effect2
• NNT to cure7
• Risk of symptomatic ICH 6.41
• Overall benefits in spite of the ICHs
• Risk of ICH can be reduced by closely following
  tPA protocol

1. NINDS rt-PA Stroke Study Group. N Engl J Med.
   19953331581-1587.
2. Ringleb PA et al. Stroke. 2002331437-1441.

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THE EARLIER THE BETTER!
Marler et. al., Neurology 2000 55 1649
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• WHAT IF ITS A LITTLE STROKE?
• WHAT IF ITS A REALLY BIG STROKE?

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NINDS Trial Stroke Subtypes
Efficacy of rtPA by Stroke Subtype
80
75
70
60
50
49
50
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rtPA
37
Normal by Barthel Score at 3 Months
36
40
Placebo
30
20
10
0
Lacunar
Atherothrombotic
Cardioembolic
The National Institute of Neurological Disorders
and Stroke rt-PA Stroke Study Group. N Engl J
Med. 19953331581-1587.
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rtPA in Ischemic Stroke Guidelines

• NontPA-eligible patient characteristics
• Rapidly improving or NIHSS lt4 or gt221-3
• Major surgery lt14 d1-3
• Suspected subarachnoid hemorrhage1-3
• Systolic BP gt185, diastolic BP gt1101-3
• Gastrointestinal or urinary tract hemorrhage lt21
  d, arterial puncture lt7 d, use of heparin,
  seizure at stroke onset1-3
• INR ?1.5, platelets ?100K, glucose ?50, gt4001-3

1. Adams HP et al. Stroke. 2003341056-1083. 2.
Quality Standards Subcommittee of the American
Academy of Neurology. Neurology.
199647835-839. 3. Broderick JP et al.
Circulation. 20021061563-1569.
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rtPA in Ischemic Stroke Guidelines

• NontPA-eligible patient characteristics
• Rapidly improving or NIHSS lt4 or gt221-3 (BUT
  UTILITY TO THE PARTICULAR PATIENT IS FIRST
  CONSIDERATION).
• Major surgery lt14 d1-3
• Suspected subarachnoid hemorrhage1-3 (AS IN PICA
  ANEURYSM, FOR EXAMPLE, CAN YOU GIVE THROMBOLYTIC
  TO PATIENT WITH A SACCULAR ANEURYSM?)
• Systolic BP gt185, diastolic BP gt1101-3 (TREAT!)
• Gastrointestinal or urinary tract hemorrhage lt21
  d, arterial puncture lt7 d, use of heparin,
  seizure at stroke onset1-3
• INR ?1.5, platelets ?100K, glucose ?50, gt4001-3
• WHEN IMAGING GUIDES YOU, BLACK BOX RULES CAN BE
  BENT!

1. Adams HP et al. Stroke. 2003341056-1083. 2.
Quality Standards Subcommittee of the American
Academy of Neurology. Neurology.
199647835-839. 3. Broderick JP et al.
Circulation. 20021061563-1569.
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CONCLUSIONS

• TREATMENT WITH IV TPA IS EFFECTIVE. DECISION
  MAKING SHOULD BE MADE WITH AWARENESS OF THE
  GUIDELINES.
• THE EARLIER THE TREATMENT, THE BETTER THE
  OUTCOME. TREATMENT UNDER 90 MINUTES MAY BE
  PARTICULARLY EFFICACIOUS.
• IV TPA COUPLED WITH IA THERAPY, MECHANICAL
  THERAPIES AND OTHER ADJUVANTS REMAIN WORKS IN
  PROGRESS, MAY OFFER SIGNIFICANT BENEFITS BUT
  SHOULD BE RESTRICTED TO EXPERIMENTAL PROTOCOLS..
• IV TREATMENT BEYOND THE THREE HOUR WINDOW ALSO
  REMAINS A WORK IN PROGRESS BUT RECENT WORK
  SUGGESTS WE MAY EXPAND THE WINDOW TO 4.5 HOURS IN
  SOME CASES. (WHEN AND IF OFFERED, SHOULD BE
  CLEARLY DISCUSSED AS OUTSIDE OF GUIDELINES.)

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LARGE VESSEL ROADMAPS

• CATHETER CEREBRAL ANGIOGRAPHY
• ULTRASOUND
• CAROTID
• TRANSCRANIAL
• MR ANGIOGRAPHY
• CT ANGIOGRAPHY

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WHY GET LARGE VESSEL ROADMAPS?

• CUTOFFS
• INTRACRANIAL OCCLUSIONS DUE TO EMBOLIC THROMBUS
  OR STENOSIS DUE TO OTHER CAUSE
• EXTRACRANIAL DISEASE

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A 36 Y/O LADY DEVELOPED CONFUSED AND HALTING
SPEECH WHILE ON THE TELEPHONE.

• ON ARRIVAL TO THE ED HER SYMPTOMS CLEARED BUT
  THEN REAPPEARED.
• BOTH EXPRESSIVE AND AT TIMES GLOBAL APHASIA
  APPEARED TO BE PRESENT TOGETHER WITH RIGHT UPPER
  EXTREMITY AND FACIAL WEAKNESS.
• CT SCAN OF THE HEAD WAS UNREMARKABLE AND CT
  ANGIOGRAM OF THE HEAD AND NECK WERE NORMAL WITH
  THE EXCEPTION OF THE LEFT MCA WHERE A DISTAL M1
  FILLING DEFECT WAS SUSPECTED.
• HER INITIAL SYMPTOMS BEGAN AT ABOUT 115 PM, SHE
  WAS ASSYMPTOMATIC AFTER ED ARRIVAL AT 430 PM,
  AND THEN HER SYMPTOMS REAPPEARRED. HER INITIAL
  EVALUATION WAS COMPLETED BY 500 PM.

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MR ANGIOGRAM HEAD ANTERIOR CIRCULATION
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MR ANGIO 24 HRS LATER
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ANGIOGRAM LEFT CCA AP
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CT PERFUSION
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SO FLIUDS AND BLOOD PRESSURE ARE OFTEN CRUCIAL.

• BASED ON HER EXAM AND HISTORY SHE RECEIVED IV
  TPA.
• WHEN SHE CONTINUED TO FLUCTUATE IV FLUIDS WERE
  INCREASED AND SHE WAS PLACED ON PRESSORS. (SOME
  WOULD CONSIDER MECHANICAL THROMBOLYSIS AT THIS
  POINT.).
• SHE STABILIZED OVER 48 HOURS, MADE A COMPLETE
  RECOVERY, AND RETURNED TO WORK AS A FLIGHT
  ATTENDANT ONE MONTH LATER.
• REPEAT MRA EVENTUALLY SHOWED COMPLETE RESOLUTION
  OF THE FLOW IRREGULARITY.
• SMOKING AND BCPs WERE THE ONLY RISK FACTORS FOUND
  AFTER EXHAUSTIVE WORK-UP.

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CAROTID STENOSIS

• RISK ASSESSMENT
• CEA
• STENT (SAPPHIRE, CREST)

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LARGE VESSEL INTRACRANIAL DISEASE

• ESTIMATES OF ANNUAL INCIDENCE 8 TO 10 OF
  ISCHEMIC STROKES.
• STROKE RECURRENCE RATES ARE HIGH IN THIS GROUP OF
  PATIENTS, PERHAPS UP TO 15 YEARLY.
• IN WASID (CHIMOWITZ et.al NEJM 2005 325 1305)
  ISCHEMIC RISK IN THE INDEX TERRITORY WAS 12 FOR
  ASA AND 11 FOR WARFARIN WHILE OVERALL ISCHEMIC
  RISK WAS 15 IN THE FIRST YEAR.
• WASID CLEARLY SHOWED WAFARIN WAS OF NO BENEFIT
  (HEMORRHAGIC RISK 2.55 FOLD GREATER, P0.01).
• INTERESTINGLY, MI WAS MORE FREQUENT IN THE
  WARFARIN GROUP (RR 2.5, P0.02).
• STENTS MAY WORK. CURRENT ESTIMATE OF
  PERIPROCEDURAL RISK 7 TO 10 WHEN WINGSPAN STENT
  IS EMPLOYED. SAMMPRIS TRIAL NOW UNDERWAY TO TEST
  THIS HYPOTHESIS.

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ATRIAL FIBRILLATION

• THE SINGLE LARGEST CAUSE OF STROKE IN OLDER
  PATIENTS, PERHAPS 30 OF STROKE PATIENTS OVER AGE
  80.
• STROKE RISK INCREASES WITH AGE AND MAY REACH AS
  HIGH AS 10-20 YEARLY IN PATIENTS ABOVE AGE 75
  WITH OTHER RISK FACTORS..
• EMBOLIC INFARCTS SECONDARY TO ATRIAL
  FIBRILLATION ARE OFTEN LARGE, CORTICAL AND
  DEVASTATING.
• WAFARIN REDUCES STROKE RISK BY AS MUCH AS 80 IN
  SOME STUDIES. METAANALYSIS OF THE MAJOR CLASS I
  TRIALS YIELDS A 68 RISK REDUCTION.
• WAFARIN RISK PROFILE IS HIGH SO IT MUST BE USED
  VERY CAREFULLY. ESPECIALLY CLOSE MONITORING IS
  NEEDED IN PATIENTS WITH DEMENTIA OR GAIT
  DISTRUBANCE BUT OVERWITHOLDING OF TREATMENT IS
  PROBABLY MORE COMMON THAN OVERTREATMENT IN
  GENERAL CLINICAL PRACTICE.
• HISTORIC SIGNIFICANT BLEED RATES UP TO 4
  ANNUALLY BUT RECENT TRIALS (TARGET INR 2.5)
  YIELDED RATES OF 1-2.

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TIA
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STROKE AFTER TIA IN ONTARIO, CANADA
From Gladstone et.al. CMAJ 2004 170 1099
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STROKE RISK AFTER TIA IN OTHER STUDIES

• IN ONTARIO CANADA, STROKE RISK WAS 4 AT 2 DAYS
  AND 8 AT 3 MONTHS WHILE HOSPITAL READMIT RATE BY
  30 DAYS WAS 32 (CMAJ 2004 170 1099) .
• OXFORD VASCULAR STUDY FOUND AN 8 STROKE RISK AT
  7 DAYS AND A 17 RISK AT 3 MONTHS (BMJ 2004 328,
  326).
• IN SOUTHWEST GERMANY, STROKE RISK WAS 8 AVERAGED
  OVER 10 DAYS AND 13 OVER 6 MONTHS WITH 38
  DEPENDENT (mRS gt 2) AT 6 MONTHS (STROKE 2004 35,
  2435).
• GREATER CINCINNATI/NORTHERN KENTUCY STROKE STUDY
  FOUND A 2 DAY STROKE OR TIA RISK OF 6 AND A 3
  MONTH RISK OF 23 (STROKE 2005 36, 1).
• IN SOUTH TEXAS, STROKE RISK WAS ONLY 1.6 AT 2
  DAYS AND 4 AT 90 DAYS (STROKE 2004 35, 1842) ,
  BUT ASCERTAINMENT METHODOLOGY MAY HAVE DIFFERED
  SIGNIFICANTLY.
• CONCENSUS NOW IS ATLEAST 10 STROKE RISK AT 3
  MONTHS WITH ATLEAST HALF OF THAT RISK IN FIRST 48
  HOURS.

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CONCLUSIONS (2008)

• PATIENTS WITH TIA ARE AT HIGH EARLY RISK OF
  STROKE AND OTHER VASCULAR EVENTS.
• THE 2 DAY RISK OF STROKE MAY BE AS HIGH AS 5
  WHILE THE 90 DAY RISK OF STROKE AS HIGH AS 10.
• WE BELIEVE KEEPING THESE PATIENTS IN THE ED AND
  RAPIDLY EVALUATING AND MODIFYING THEIR STROKE
  RISKS IS APPROPRIATE.
• THIS POLICY IS NOW EXPLICITLY SUPPORTED BY
  EVIDENCE BASED OUTCOME STUDIES.
• WE BELIEVE STROKE NETWORKS WHERE EASILY
  DIFFUSABLE TECHNOLGY IS COMBINED WITH CENTERS OF
  EXCELLENCE WOULD BEST SERVE THE POPULATION AT
  RISK.

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RISK FACTOR CONTROL

• HYPERTENSION
• HYPERGLYCEMIA
• TOBACCO ABUSE
• HYPERLIPIDEMIA and STATIN THERAPY
• EPIDEMIOLOGICAL STUDIES HAVE NOT SHOWN A DIRECT
  LINK BETWEEN ELEVATED SERUM CHOLESTEROL AND
  STROKE COPARABLE TO THE TIGHT LINK TO CAD.
• BUT NUMEROUS STUDIES OF STATIN THERAPY AND CAD
  HVE SHOWN REDUCTIONS IN STROKE RISK AS A
  SECONDARY ENDPOINT.
• HIGH-DOSE ATORVASTATIN AFTER STROKE OR TIA
  (SPARCL ) TRIAL (NEJM 2006 355 549) .
• 4700 RECENT STROKE PATIENTS WITHOUT KNOWN CAD
  WERE RANDOMIZED TO 8O MG OF STATIN OR PLACEBO AND
  FOLLOWED FOR 5YEARS. (LDL WAS BETWEEN 100 AND 190
  mg/dl.)
• RELATIVE 5 YEAR STROKE RISK WAS REDUCED BY 16
  WHILE COMPOSITE MAJOR CARDIOVASCULAR OR STROKE
  RELATIVE RISK WAS REDUCED BY 20.
• THERE WAS A SMALL INCREASE IN HEMORRHAGIC STROKE
  RISK.

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ACUTE STROKE DOCTORS OF THE DISTANT FUTURE (once
primary care achieves perfection).
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THANK YOU.
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RISK SUMMARY

• STUDY MED/SURG
  RISK ABSOLUTE NNT PERIOP
• NASCET gt70 26/9 17 6 5.8
• ECST gt70 20/7 13 8 5.6
• NASCET gt50 22/16 6.5 15 6.9
• (2 YEAR CUMULATIVE RISK)
• ACAS gt60 11/5 6 17 2.6
• (5 YEAR CUMULATIVE RISK)

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Carotid Endarterectomy
Staikov IN et al. J Neurol. 2000247681-686.
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SAPPHIRE AT 1 YEAR

• PRIMARY ENDPOINT STENTING 12.2
• PRIMARY ENDPOINT CEA 20.1
• P 0.004 FOR NONINFERIORITY
• CONCLUSION STENTING WITH PROTECTION SHOULD BE
  CONSIDERED IN HIGH RISK SURGICAL PATIENTS.

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SMALL VESSEL ISCHEMIC ANGIOPATHY

• CAUSES 20-25 OF ISCHEMIC STROKES.
• USUALLY INVOLVES DEEP PENETRATING VESSELS,
  ARTERIOLES IN THE 200 TO 50 MICRON RANGE AND
  RESULTS IN LACUNAR INFARCTS USUALLY LESS THAN 1
  CM IN DIAMETER.
• SMALL VESSEL ANGIOPATHY MAY RESULT IN EITHER
  ISCHEMIC OR HEMORRHAGIC INJURY, SOMETIMES IN THE
  SAME PATIENT.
• DIFFUSE (MORE SUBTLE?) CHRONIC SMALL VESSEL
  HYPOPERFUSION RESULTS IN PERIVENTRICULAR DEEP
  WHITE MATTER CHANGES OR LEUKOARIOSIS.

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EVIDENCE OF TIA RISK FROM OTHER STUDIES

• GREATER CINCINNATI/NORTHERN KENTUCY STROKE STUDY
  FOUND A 2 DAY STROKE OR TIA RISK OF 6 AND A 3
  MONTH RISK OF 23 (STROKE 2005 36, 1).
• OXFORD VASCULAR STUDY FOUND AN 8 STROKE RISK AT
  7 DAYS AND A 17 RISK AT 3 MONTHS (BMJ 2004 328,
  326).
• IN SOUTHWEST GERMANY, STROKE RISK WAS 8 AVERAGED
  OVER 10 DAYS AND 13 OVER 6 MONTHS WITH 38
  DEPENDENT (mRS gt 2) AT 6 MONTHS (STROKE 2004 35,
  2435).
• IN SOUTH TEXAS, STROKE RISK WAS ONLY 1.6 AT 2
  DAYS AND 4 AT 90 DAYS (STROKE 2004 35, 1842),
  BUT ASCERTAINMENT METHODOLOGY MAY HAVE DIFFERED.

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CONCLUSIONS

• PATIENTS WITH TIA ARE AT HIGH EARLY RISK OF
  STROKE AND OTHER VASCULAR EVENTS.
• THE 2 DAY RISK OF STROKE MAY BE AS HIGH AS 5
  WHILE THE 90 DAY RISK OF STROKE AS HIGH AS 10.
• WE BELIEVE KEEPING THESE PATIENTS IN THE ED AND
  RAPIDLY EVALUATING AND MODIFYING THEIR STROKE
  RISKS IS APPROPRIATE.
• OTHERS HAVE DEVELOPED TIA CLINIC STRATEGIES.
  THESE STRATEGIES MAY HAVE REAL WORLD DRAWBACKS.
• THESE POLICY ALTERNATIVES NEED TO BE EXPLICITLY
  VALIDATED BY EVIDENCE BASED OUTCOME STUDIES.