Stroke Update

Serum Markers for Acute Neurologic Conditions

Introduction

• Same diagnostic challenges that exist for stroke exist for myocardial infarction

• Technology used in MI now being applied to stroke

Overview

• >700,000 strokes annually

• 10% of strokes involve intracerebral hemorrhage

• Large proportion of patients die or do badly

• 35-52% of patients die with hemorrhage within 30 days

• Half of deaths occur within 48 hrs

Risk factors for hemorrhagic Stroke

• Increase with age

• Race (Blacks at least twofold over whites)

• Prior stroke

• Hypertension

• Use of anticoagulant or thrombolytic agents

• Alcohol and/or Cocaine

Location of intracerebral Hemorrhages

• Lobar

• Putaminal

• Cerebellar

• Intraventricular

• Posterior fossa (require surgery)

Clinical Features Of hemorrhage

• Headache

• Vomiting

• Seizures

• 82% mental status change

• >75% have hemiplegia or hemiparesis

• 63% have headache

• 22% vomit

Providing Prognostic data

• Volume of hemorrhage: estimated by using simplified formula ABC/2

• A determined by measuring CT slice with largest diameter of hemorrhage in millimeters

• B determined by measuring largest diameter of hemorrhage 90* to A on Same slice

• C determined by adding number of slices on which hemorrhage seen multiplied by slice thickness

• GCS

Prognosis

• 91% of patients with bleeding >60 ml and GCS of <=8 die in 30 days

• All patients will bleeding >90 ml die

• 19% of patients with bleeding <= 30 ml and GCS >= 9 die in 30 days

Hemorrhage growth

• Ongoing process rather than single episode• 38% of patients will have one-third increase in

hemorrhage size in first 24 hrs• Presentation not subtle in most cases• Intraventricular extension significantly increases

morbidity and mortality• 30% of hemorrhages in regions around basal ganglion

expand• Hemorrhages in thalmus expand significantly• Lobar most amenable to therapy

Lobar Hemorrhage

• Open skull and evacuate blood

• Endoscopic evacuation

• Stereostactics

• No good science, yet sterotactic and endoscopic techniques make most sens in lobar hemorrhage

Neuronal Markers

• Released from dying and ischemic neurons into cerebrospinal fluid and can be used to diagnose various neurologic emergencies

• May be able to discriminate between patients with reversible vs irreversible events

• Greatest Potential in prehospital setting• Maybe used to identify patients at higher risk for

complications if treated by thrombolytics

Cardiac Vs Neuronal Markers

• Heart simple homogeneous muscle

• Brain has complex populations of cells (neurons have various functions and distributions and variety of support cells)

• Ideal marker must be able to pass blood-brain barrier

Markers Under Investigation

• Neuron-specific Enolase

• Structural proteins

• Direct Neuronal Markers

• Myelin Basic protein

• S-100• Thrombomodulin

• D-dimer

Neuron-specific Enolase

• Cytoplasmic enzyme

• Any small stress allows NSE to egress across cell membrane

• Cell does not need to die to release NSE – It just has to be leaky. Sensitive yet not specific

Structural Proteins

• Significant injury to cell and enzymatic degradation required before structural proteins found in CSF. More specific yet harder to see in early phases

Direct Neuronal Markers

• NSE and tau proteins most important

• Complement each other because NSE from cytoplasm and tau from structural molecule

Myelin basic protein

• Used extensively in multiple sclerosis and other demyelinating disorders as a way to diagnose and predict outcome

S-100

• Most studied neurolgic marker

Thrombomodulin

• Most promising for assessing integrity of vascular wall

D-Dimer

• Not specific but indicates abnormality

• May be used to confirm that activation/coagulation pathway involved, and patients headache not migraine

C-Reactive Protein

• Used to measure inflammation

Ideal Marker

• Small molecular size

• Must be sensitive for early ischemia (within 3 hrs)

• Predictable and rapid and accurate

NSE and tau protein

• Specific for neurons

• NSE also found in red blood cells

• Levels can be falsely elevated if extensive hemolysis present

Similarities to heart technology

• Since no perfect marker available, variety of markers used as panel of tests to increase sensitivity an specificity

Statistics

• Stroke leading cause of adult disability

• Patients fear stroke more than heart attack because stroke leaves victims cognitively impaired

• 800,000 new strokes annually

• 85% of strokes ischemic

Why serum markers for stroke?

• Stroke remains diagnosis of exclusion

• MRI helpfully, but usually cannot be obtained in timely fashion

• CT can be sensitive but not always

• 70% who present weak and dizzy have clinically silent event

Hemorrhage

• Can be detected on CT

• Diagnostic utility of markers may not be high in this setting, but may help determine which patients at risk for complications and which will extend infarct

• MBP found in deep white matter where hemorrhages usually occur.

Traumatic brain injury

• Currently have poor tools to determine which patients have had cognitive deficit secondary to concussion and which are at risk for second impact syndrome

• Markers have potential for diagnosing minor head injury

• Markers shown to detect edema in animal modem • Markers very predictive of outcome in patients

with negative head CTS

Limitations

• Time delay in serum

• Some markers do not cross blood-brain barrier

• No single marker sufficient

Future

• Goal to have marker by 2010 that will take 5 min and one drop of blood to make diagnosis

Conclusion

• No markers currently approved by FDA for routine use, although approved for scientific research purposes

• Expect markers in 2-3 years