Advanced Stroke Protocol

ADVANCED STROKE PROTOCOLDr Obaid Ashraf

• Stroke is defined by the abrupt onset of neurological deficit that is attributable to a focal vascular cause.

• If the cessation of flow lasts for more than a few minutes, infarction results.

• When blood flow is quickly restored, brain tissue can recover fully and the patient's symptoms are only transient---TIA

• The standard definition of TIA requires that all neurologic signs and symptoms resolve within 24 h regardless of whether there is imaging evidence of new permanent brain injury; stroke has occurred if the neurologic signs and symptoms last for >24 h.

Significance of Penumbra• The concept of ‘ischemic penumbra’ was originally

introduced by Astrup et-al in 1981 and defined as an area of reduced CBF with electrical failure but preserved ion homeostasis

• The transition from ischemia to irreversible infarction depends on both the severity & the duration of the diminution of blood flow.

• A penumbra can be evaluated both on CT (on which it is evidenced by a discrepancy in perfusion parameters) and on MRI (on which it is indicated by a mismatch between diffusion and perfusion parameters).

Acute Stroke Evaluation on CT

Unenhanced CT

• Widely available.• Can be performed

quickly.• IV Contrast not

required.• Can easily rule out

hemorrhage and other stroke mimics

• Low sensitivity in 1st 24hrs.

NCCT 2 hrs after onset of hemiparesis: shows hyperdense L MCA s/o IV thrombosis.

NCCT :hypodensity & obscuration in Rt lentiform nucleus & loss of gray-white interface in lateral insula (Insular Ribbon Sign)

Importance of Window Settings• Lev et al showed sensitivity and specificity of 57% &

100%, respectively, for acute ischemic stroke detection at unenhanced CT with the use of standard window settings (width, 80 HU; center, 20 HU). Sensitivity increased to 71% with a change of window width and center level settings to 8 HU and 32 HU, respectively, without a loss in specificity.

NCCT 2 hrs after onset of left hemiparesis

Quantitation of Ischemic Involvement• European Cooperative Acute Stroke Study trial

showed that involvement of more than 1/3rd of the MCA territory depicted at unenhanced CT was a criterion for the exclusion of patients from thrombolytic therapy because of a potential increase in the risk for hemorrhage.

• Subsequent studies with use of the one third rule showed poor interobserver correlation.

• Alberta Stroke Program Early CT Score (ASPECTS) was proposed in 2001 as a means of quantitatively assessing acute ischemia on CT images by using a 10-point topographic scoring.

10 regions of MCA territory each with a score of 1 (to be deducted from a total of 10)

CT Angiography• CT angiography typically involves a thin-section

volumetric helical acquisition that extends from the aortic arch to the circle of Willis using time-optimised bolus of iodinated contrast (350-400mg/ml) @ 3.5-4ml/sec

• Post-processing : MIP ; MPR images are viewed on the work-station.

• Assess the status of carotid and vertebro-basilar system for thrombi, atherosclerotic disease, dissection, collateral flow.

• Helpful in treatment planning by localising occlusion site.

• Helpful in basilar artery strokes as post fossa is not well assesed on NCCT and brainstem is frequently not included in Perfusion CT.

• Helps detect the presence of a filling defect in the vessel caused by true arterial thrombosis with a sensitivity of 89%.

• However, Minor thrombi are frequently missed in the daily clinical setting if no correlation is performed with perfusion.

Acute stroke in a 43-year-old woman: Initial CT normal. F/U CT at 36 hrs and CTA reveal BA thrombosis

Acute Stroke :1.5 hrs evolution (NCCT, CTA source image and MIP)

• CTA can also be used to asses the collateral flow which affects prognosis:

• 0 No collaterals.• 1 Visible collaterals to peripheray of ischemic site.• 2 Complete irrigation of ischemic site by collateral

flow.• 3 Normal antegrade flow.

• CTA source Imaging: includes a whole-brain analysis of the source images with a narrow window provides a whole-brain “perfused blood vol map” showing areas of ischemic hypoattenuation (more sensitive than NCCT in early phases, good correlation with DWI).

• CTA source Imaging provides accurate whole brain information for perfusion CT maps.

CT Perfusion Imaging• Perfusion CT is performed by monitoring only the first

pass of an iodinated contrast agent bolus through the cerebral circulation.

• Continuous cine imaging over the same slab of tissue (1–32 sections) during the dynamic administration of a small (50-mL), high-flow contrast material bolus (injection rate, 4–5 mL/sec).

• The contrast agent passes through the brain tissue, causing a transient hyperattenuation that is directly proportional to the amount of contrast material in the vessels and blood in that region.

• This principle is used to generate time-attenuation curves for an arterial ROI, a venous ROI, and each pixel.

Time attenuation curves for arterial and venous ROI’s

• The generated arterial and venous curves must be studied to detect possible poor timing of the contrast material bolus (the curve must have included an initial plane before rising and a decline before the end of the acquisition) and to distinguish good arterial input function or venous outflow function (the venous curve must be higher than and represent a 1–2-second delay after the arterial curve).

• The evaluation of perfusion imaging data requires the use of complex deconvolution algorithms to produce perfusion maps.

Perfusion Parameters

• 1. CBV: It is the volume of blood per unit of brain tissue (normal 4-5 ml/100gm).

• 2. CBF: It is the vol of blood flow per unit of brain tissue per minute. (normal 50-60 ml/100g/min)

• 3. MTT : Time diff b/w arterial inflow and venous outflow.

• 4. Time to peak enhancement.• CBF = CBV/MTT.

1. MTT is calculated by performing a mathematical technique called deconvolution on the regional time-attenuation curve of each pixel with respect to the arterial curve (arterial input function).

2. CBV is calculated by dividing the area under the curve in a parenchymal pixel by area under the curve in an arterial pixel.

3. CBF is calculated by the formula : CBF=CBV/MTT.

• CT perfusion imaging in acute stroke is based on the hypothesis that the penumbra shows either:

• (a) increased mean transit time with moderately decreased cerebral blood flow (60%) and normal or increased cerebral blood volume (80%–100% or higher) secondary to autoregulatory mechanisms or

• (b) increased mean transit time with markedly reduced cerebral blood flow (30%) and moderately reduced cerebral blood volume (60%), whereas infarcted tissue shows severely decreased cerebral blood flow (30%) and cerebral blood volume (40%) with increased mean transit time.

CT perf map of CBV & CBF

Types of CT Perfusion Imaging Techniques• 1. Dynamic Contrast-enhanced .• 2. Perfused blood vol mapping : Unenhanced CT followed by CTA.Quantitative CBV values are obtained by

subtracting unenhanced CT image data from CTA source image data. Subtracted image is reffered to as “Perfused Blood-vol map”.

Advantage : Whole brain can be evaluated.Disadv: cannot evaluate CBV & MTT and hence the

penumbra.

Results of CT Perfusion Mapping• The greatest regional abnormalities on CT perfusion

maps in acute stroke have been demonstrated for MTT values, followed by CBF and CBV values.

• The MTT maps also may be the most sensitive indicators of stroke, with changes in CBF & CBV being more specific for distinguishing ischemia from infarction.

• Several studies have shown that the CBV map depicts the lesions seen at DWI, helping predict the infarcted brain tissue & the CBF map depicts the altered area seen at perfusion MR imaging, which is related to the ischemic area. Hence, the salvageable brain tissue is equivalent to CBF – CBV.

• Some authors have reported a threshold for core infarction when CBV is less than 2L/min and for ischemic tissue when MTT is over 145%.

• Wintermark et al,showed that CT perfusion imaging was more accurate than was unenhanced CT for detecting stroke (75.7%–86.0% vs 66.2%, P .01) and determining the extent of stroke (94.4% vs 42.9%, P .01).

• MTT maps were more sensitive, while cerebral blood flow and cerebral blood volume maps were more specific for detection of acute stroke.

Acute Stroke (2.5 hrs from onset) ; NCCT, CBV and CBF maps

Summary map and post-thrombolysis CT

CBV, CBF and MTT maps

Role of MR Imaging in Acute Stroke Evaluation• A thorough evaluation of acute stroke can be

performed by using a combination of 1. Conventional MR imaging.2. MR angiography.3. DWI.4. Perfusion-weighted MR imaging.

Conventional MR Imaging• More sensitive and specific than CT within 1st few

hours.• MR sequenses typically used include:1. T1-SE.2. T2 FSE.3. FLAIR.4. T2W GRE.5. Post GAD T1W-SE. Conventional MR is less sensitive than DWI in 1st

few hrs after stroke.

• Typical findings include :1. Hyperintense signal on FLAIR & T2W with resultant

loss of grey-white differentiation.2. Sulcal effacement.3. Mass effect.4. Loss of arterial flow-voids on T2W.5. Stasis of contrast within vessels in the affected

area. 6. Low-signal-intensity or high-signal-intensity vessel

sign due to intravascular thrombus can be seen on MR images obtained with a T2*GRE or FLAIR, respectively.

7. T2WGRE sequences are sensitive for ICH.

MRA• Like CTA, MRA is useful for detecting intravascular

occlusion due to a thrombus and for evaluating the carotid bifurcation in patients with acute stroke.

• Time-of-flight MRA and contrast-enhanced MR angiography are commonly used to evaluate the intracranial and extracranial circulation.

TOF MR Images.

Diffusion-weighted MR Imaging• Underlying Principles: Stroke causes excess

intracellular water accumulation, or cytotoxic edema, with an overall decreased rate of water molecular diffusion within the affected tissue.

• Mearsurement of net water molecular motion was 1st attempted by Stejskal & Tanner using T2W SE with two extra equal gradients in opposite directions. This technique resulted in signal loss. Tissues with higher rate of diffusion undergo a greater signal loss in a given period of time.

• Therefore areas of cytotoxic edema (with restricted water diffusion) appears bright on DWI.

Acute Post Circulation Stroke on DWI

• Current diffusion-weighted MR imaging techniques employ echo-planar sequences that are highly resistant to patient motion.

• Image acquisition can be performed in a few minutes and has increased sensitivity to signal changes due to molecular motion.

• Diffusion coefficient obtained from orthogonal diffusion-weighted MR images in all three planes is called the apparent diffusion coefficient (ADC).

Time Course of Thromboembolic infarction

• For acute ischemia detection within the first 6 hours after onset, diffusion-weighted imaging is reported to have high sensitivity and specificity, of 88%–100% and 86%–100%.

False Negative DWI• Small lacunar brainstem

infarcts.• Small Deep grey nuclei

infarcts.• Ischemic areas that are still

viable (may have abnormal perfusion)

False Positive DWI• Abscess.• Tumor.

Perfusion-weighted MR Imaging• While diffusion-weighted MR imaging is most useful

for detecting irreversibly infarcted tissue, perfusion-weighted imaging may be used to identify areas of reversible ischemia as well.

1. Exogenous Method (using MR contrast agent).2. Endogenous Method (Arterial spin labelling).

Underlying Principle• Exogenous techniques are typically susceptibility based

and depend on T2* effects and use Dynamic susceptibility-weighted T2* sequence.

• The passage of an intravascular MR contrast agent through the brain capillaries causes a transient loss of signal because of the T2* effects of the contrast agent.

• MR perfusion imaging technique involves tracking of the tissue signal changes caused by susceptibility (T2*) effects to create a hemodynamic time–signal intensity curve.

• Perfusion maps (CBV, CBF, MTT) are calculated in a similar fashion as in CT perfusion using deconvolution analysis.

• Arterial spin labeling technique exploits the spins of endogenous water protons to measure perfusion.

• The spin polarity of arterial protons flowing into the imaging plane is inverted by applying radiofrequency pulses upstream from the imaging section. The effect on image intensity is measured as these protons perfuse the brain tissue.

• Two sets of images are obtained, one that is flow sensitive and one that is insensitive to flow. The image obtained by subtracting the flow-sensitive image from the flow-insensitive image provides a measure of the labeled protons that perfused the imaging plane.

• Perfusion parameters then can be calculated from the subtracted image.

APPLICATIONS OF PERFUSION-DIFFUSION MISMATCH• PDM is defined as a ratio of a perfusion:diffusion

lesion vol >1.2 or a diff of >10-15ml. • The PDM theory introduced in the late 1990s was

used:1. As a practical selection tool for stroke treatment.2. Second, to test the hypothesis that patients with

PDM pattern will benefit from treatment, while those without mismatch pattern will not.

3. Third, PDM was applied as a surrogate measure for stroke outcome. Some studies suggested that the abnormality from PWI can be used to predict the lesion growth or final infarct volume.

Acute stroke (2 hrs) :PWI >DWI

PWI >DWI

OPTIMAL DEFINITION OF PDM• Concept of conventional PDM has been challenged

by many studies indicating that DWI overestimates the infarct core by including a part of penumbra ; and PWI overestimates penumbra by including regions of benign oligemia.

• Many methods have been advised to optimise the conventional PDM:

1. Serial measurements of PDM: PDM is strictly time-dependent and most cases of

PDM occur within 6 hrs of onset.

2. Threshold method for defining PDM:Rohi et al reported that cutoff values of relative CBF <

0.59 and MTT > 1.63 were optimal in distinguishing the benign oligemia and real penumbra.

Oppenheim et al suggested that the ADC values best excluded penumbra (7.82 ± 0.82×10-4 mm2/s) from benign oligemia (8.23 ± 0.41×10-4 mm2/s)

POTENTIAL ALTERNATIVES FOR PDM1. pH-weighted imaging-PWI or DWI mismatch:There is decrease in pH in the area of penumbra due

to anaerobic metabolism. Sun et-al detected pH-dependent amide proton

tranfer b/w endogenous peptides and tissue water and obtained pH-WI.

pHW-DWI mismatch then represented the true penumbra whereas PWI-pHWI mismatch would represent benign oligemia.

2. MR Thermometry-DWI mismatch:Increased temp of brain tissues is common in acute

ischemia.Brain temperature (T) can be measured noninvasively

with MRSI.For each voxel, temperature can be calculated from the

apparent chemical shift of NAA peak, using the following formula: T = 37 + 100 (NAA℃ peak - 2.035), where a chemical shift of 2.035 ppm was found in healthy control subjects with an assumed brain temperature of 37 . ℃

Using this approach, Karaszewski et-al found tissues were hotter in ‘potential penumbra’ than ‘likely infarct core’ which was in turn hotter than normal brain

3. BOLD Imaging based penumbra:Based on the fact that OEF is significantly increased

in penumbra.DeoxyHb is used as a marker for OEF that can be

visualised on T2* based BOLD imaging as signal loss.Geisler et-al applied quantitaive T2* based BOLD

imaging in acute stroke and found signal reduction in penumbra due to increased OEF.

4. MRA-DWI mismatch:Defined as MRA score of 3 (for intracranial ICA &

M1 ; 1=normal flow , 2= reduced flow, 3=occlusion) and DWI lesion vol of < 25ml ; or a MRA score of 2 and DWI vol < 15ml.

More prevalent in intracranial large artery atherosclerotic stroke.

5. PET based estimation of penumbra:Gold standard for detection of penumbra.No readily available/affordable.

THANK YOU