1. STROKE
Dr. Arthur Rosen

2. The presenter has no financial interest with the manufacturer of any product or services discussed in this presentation.
Financial disclosure

3. OBJECTIVES Know incidence and demographics of stroke
Recognize presenting symptoms of stroke
Know indications and contraindications for use of thrombolytic treatment
Understand need to act quickly in management of stroke
Understand benefits and limits of clot retrieval
Understand benefits of post acute treatment for stroke

4. Definitions: Stroke
A stroke is an injury to the brain caused by interruption of blood flow, or by bleeding into or around the brain
Two major types of stroke:
Ischemic (loss of blood flow to the brain)
Hemorrhagic (bleeding into or around the brain)
Produces neurologic symptoms that have sudden onset
Symptoms usually last more than 24 hours

5. Definitions: TIA TIA = transient ischemic attack
Commonly called a “mini-stroke” by laypersons
A TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction
No tissue damage is evident on brain imaging (ideally MRI within 24 hours of the event
Symptoms last minutes to hours but completely resolve
Clinical diagnosis: in the absence of MRI, the diagnosis is made based on complete resolution of symptoms within 24 hours
However, 50% of patients with symptoms < 24 hours have corresponding acute ischemic infarction on brain MRI

6. Statistics 800,000 strokes per year 130,000 deaths per year
Leading cause of long term disability
One third occur under age 65
Annual cost $54 billion per year
African Americans twice as likely to have stroke and more likely to die

7. CEREBROVASCULAR SUPPLY

12. Cerebral blood supply:
ACA: supplies leg/hip portion of motor cortex
MCA: supplies arm/face portion of motor cortex
PCA: supplies occipital cortex (+ thalamus, inferior temporal lobe)

13. Types of Stroke
Hemorrhagic
Ischemic
Thrombotic
Embolic

15. Two main types of hemorrhagic stroke: Intracerebral (ICH) and subarachnoid (SAH)

16. Hemorrhagic Stroke Incidence Predisposing factors Hypertension
Diabetes
Blood dyscrasias
Anticoagulation
Symptoms – Sudden onset of
Headache
Emesis
Confusion or diminished level of consciousness
Focal deficits
Diagnosis CT
Management
Steroids
Anticonvulsants
Surgery

18. Ischemic stroke etiologic subtypes

19. Stroke syndromes Three common hemispheric syndromes:
Middle cerebral artery (MCA) stroke
Anterior cerebral artery (ACA) stroke
Posterior cerebral artery (PCA) stroke
Lacunar (small vessel) stroke syndromes
Brainstem stroke syndromes
Spinal cord stroke

22. Anterior cerebral artery syndrome
Symptom
Brain structure(s) involved
Contralateral leg weakness (no face or hand weakness, perhaps minor shoulder weakness)
Leg/hip motor neurons in cortex and/or descending supranuclear axons
Lack of initiative, abulia
Inferior medial frontal lobe
Isolated ACA territory is a rare location for ischemic strokes

23. Middle cerebral artery syndrome
Symptom
Brain structure(s) involved
Contralateral central (lower) facial weakness
Facial motor neurons in cortex and/or descending supranuclear axons
Contralateral arm (more than leg) weakness
Arm/hand motor neurons in cortex and/or descending supranuclear axons
Contralateral sensory loss
Sensory motor neurons and/or descending axons
Aphasia
Left (dominant) hemisphere frontal cortex
Spatial or visual neglect
Right (non-dominant) hemisphere parietal association cortex
MCA territory is the most common location for ischemic strokes

24. Posterior cerebral artery syndrome
Symptom
Brain structure(s) involved
Contralateral hemianopsia
Occipital cortex
Contralateral sensory loss
Thalamus
Short term memory loss
Medial inferior temporal lobe

25. Lacunar syndromes Syndrome Symptoms Localization Vascular supply
Pure motor
Contralateral hemiparesis
-Internal capsule
-Corona radiata
-Ventral pons
-Small MCA (lenticulostriate) or basilar penetrating arteries
Pure sensory
Contralateral hemisensory loss
VPL nucleus of thalamus
-Lenticulostriate MCA arteries
-PCA penetrating arteries
Sensorimotor
Contralateral weakness and sensory loss
Thalamus and adjacent internal capsule
Dysarthria-clumsy hand
Slurred speech, contralateral hand weakness
Pons
-Penetrating basilar arteries
Ataxia-hemiparesis
Contralateral limb ataxia and mild contralateral weakness
-Posterior limb internal capsule
-Pons
-MCA or basilar penetrating arteries

26. Brainstem stroke syndromes
Variable based on location
Some hallmarks:
Frequent involvement of the oculomotor system
Diplopia, various gaze palsies
Frequent involvement of the cerebellar pathways
Ataxia, coordination deficits
“Crossed” deficits
Weakness or sensory loss on one side of the face but on the other side of the body

27. Basilar occlusion syndromes
Life threatening if proximal or mid-basilar
“Locked-in” syndrome: infarction of ventral pons including corticospinal, cerebellar, and oculomotor systems
Quadriplegia (bilateral corticospinal tracts
Aphonia (bilateral corticobulbar fibers)
Patients communicate with vertical eye movements (vertical gaze centers in the superior colliculus spared)
Infarctions of the medial medulla may involve cardiac and respiratory control centers
Distal basilar embolization can cause bilateral occipital infarcts
Cause bilateral hemianopia, cortical blindness

28. Spinal cord stroke Symptoms:
Bilateral loss of motor function below the lesion
Bilateral loss of pain and temperature sensation below the lesion
Loss of bowel and bladder function
Retained vibration and proprioception (posterior columns are spared)
Anterior spinal artery

29. Ischemic Stroke Incidence Predisposing factors Hypertension Diabetes
Dyslipidemia
Smoking
Symptoms – Sudden onset of
Focal deficits
Weakness
Numbness
Vision problems
Language problems
Confusion or diminished level of consciousness
Diagnosis
Clinical
CT vs MRI
Management – Early treatment is key
tPA
Anticoagulation

34. Ischemic stroke treatment
Goal for all ischemic stroke treatments is to save brain tissue that is salvageable
“Time is brain”

35. Stroke treatments are directed at salvage of the penumbra
Penumbral tissue has low blood flow, neurons are not working normally, but the cells haven’t been irreversibly damaged.
So how can something as common as stroke result in so few patients able to be treated and drug companies categorizing stroke treatments as orphan drugs? Well, to answer this question we need to understand a little bit about brain physiology and about behavior. The brain is exquisitely sensitive to loss of blood flow—much more sensitive than heart muscle, for example. Brain tissue at the core of a stroke therefore dies very rapidly…within minutes. One of the things that the tPA studies showed us was that therapy had to be delivered very rapidly after stroke, and the sooner you get treatment, the more likely you are to benefit. So for tPA, treatment must be given within three hours of the first onset of the symptoms. Here is where the behavior part comes in…most people having a stroke do not come to the hospital within three hours after the start of their symptoms.
Neurons are highly dependent on continuous glucose and oxygen delivery
Every second of a stroke 32,000 neurons die

36. Acute stroke treatment options
Only one medication FDA approved to treat acute ischemic stroke:
Alteplase (tissue plasminogen activator, tPA)
Initiates fibrinolysis by binding to fibrin, enhances the conversion of plasminogen to plasmin
Approved 6/18/1996
Few patients receive tPA
Well, it’s not quite a blank slate, but almost…there is only one medication that is FDA approved to treat people who are having a stroke, in order to reduce the damage being done in the brain. That medication is Alteplase, or tPA, and it works by dissolving blood clots. People who receive tPA are 30% more likely to be independent after their stroke, which is nothing to sneeze at but isn’t exactly a home run treatment either. But even more shocking, this drug was approved in 1996….almost 20 years ago. Since then, there has been no new drug approved to treat people who are having a stroke.

37. tPA contraindications and warnings: Avoid use in patients with high risk of bleeding
Absolute contraindications:
Current intracranial hemorrhage
Subarachnoid hemorrhage
Active internal bleeding
Recent (< 3 mos) intracranial or intraspinal surgery or serious head trauma
Other intracranial conditions that may increase bleeding risk (e.g. tumor, AVM)
Bleeding diathesis
Current severe uncontrolled HTN (> 185/110)
Warnings and Precautions:
Recent major surgery
Recent stroke
Recent GI/GU bleeding
Recent trauma
Pericarditis or endocarditis
Severe hepatic or renal disease
Pregnancy
Diabetic hemorrhagic retinopathy
Advanced age
Currently receiving warfarin

38. tPA for acute stroke time windows
Within 3 hours of symptom onset
FDA approved
Between 3 and 4 ½ hours of symptom onset
Supported by AHA/ASA guideline statement, one large randomized controlled trial
Not FDA approved in this time window
Common practice is to give it using additional exclusion criteria from the RCT:
NIHSS > 25
Diabetes and prior stroke
On an anticoagulant regardless of INR
Age > 80

39. The problem: late presentation
Most patients do not present to the hospital within 3 hours of symptom onset
Approximately 20% nationally present within 3 hours
Only about 8% of stroke patients nationally receive tPA
If patients wake up with stroke symptoms, the time of onset is unknown, and generally they are not eligible for thrombolysis

40. The problem: lack of recognition
In multiple studies, only about 50% of people can name common stroke symptoms.
Nicol MB et al. 2005
Jones SP et al. 2010

41. Functional independence at 90 days
tPA benefits and risks
Functional independence at 90 days
Symptomatic ICH
tPA
Control
Original NINDS trial (N = 624)
3 hours
38%
21%
6.4%
0.6%
Pooled meta-analysis (N = 6756)
3 hours1
3-4.5 hours2
33%
35%
1OR 1.75 ( )
2OR 1.26 ( )
23%
30%
6.8%
1.3%

42. endovascular therapy
Patients with clot in the internal carotid, MCA origin, or M1 MCA segment
Treatment started within 6 hours of symptom onset

43. What is the efficacy of endovascular therapy?
Independent in basic activities at 90 days
Symptomatic ICH
% recanalized
Trial
Treat
Control OR
(95% CI)
P-value
SWIFT PRIME
60%
35%
1.7
( ) 0% 3% NS
88%
EXTEND-IA
71%
40%
4.2
( ) 6%
86%
REVASCAT
44%
28%
2.1
( ) 2%
66%
Patients mainly with clots in the distal internal carotid or MCA-M1
Usually with at least moderate to severe symptoms
All studies allowed IV-tPA (most patients got that prior to clot retrieval)
Treatment initiated within 6 hours of symptom onset

44. Take Home Points
800,000 strokes per year in the U.S., 1/3 in people under age of 65
Ischemic strokes account for 90% of all strokes
Thrombolytic treatment is effective when administered within 4 hours from onset of symptoms
Contraindications to thrombolytic treatment include use of anticoagulants, bleeding from any source, recent surgery, cerebral hemorrhage, and severe uncontrolled hypertension.
Endovascular treatment (clot retrieval) along with thrombolytic treatment provides the best long term benefit for ischemic stroke.