CT PERFUSION PHYSICS AND ITS APPLICATION IN NEUROIMAGING

Dr. Suhas BasavaiahResident (MD Radio-

diagnosis)

INTRODUCTION

• In 1979, Leon Axel first proposed a method of determining the tissue perfusion from dynamic contrast enhanced CT data.

• First attempt was made with stable Xenon.• Due to requirement of rapid image acquisition and processing, it was confined to research studies.• The advent of spiral CT systems in 1990s enabled perfusion CT to be performed with conventional

CT.• It is a technology that allows functional evaluation of tissue vascularity.• It measures the temporal changes in tissue density after intravenous injection of a contrast

medium bolus using a series of dynamically acquired CT images. • Because of rapid technologic advancements in multidetector CT (MDCT) systems and the

availability of commercial software, perfusion CT offers a wide array of clinical and research applications.

INTRODUCTION (CONTD.)

• major clinical applications - acute stroke and oncology.• rapid scan timing and faster image processing - modality of choice for evaluation of the

status of cerebral vasculature.• In the field of oncology it has found use in diagnosis, staging, prognostic evaluation,

and monitoring of response to therapies. • perfusion CT has the potential to become the preferred technique for the assessment of

tumor response to antiangiogenic drugs.

PERFUSION CT TECHNIQUE: BASIC PRINCIPLES

• The fundamental principle - temporal changes in tissue attenuation after intravenous administration of iodinated contrast.

• enhancement of tissues - iodine concentration is an indirect reflection of tissue vascularity and vascular physiology.

• After intravenous injection of the iodinated contrast, the ensuing tissue enhancement can be divided into two phases based on its distribution in the intravascular or extravascular compartment.

• In the initial phase, the enhancement is due to the contrast within the intravascular space, and this lasts approximately first 40 to 60 seconds.

• Later, in the second phase, due to passage of contrast from intra to extra-vascular compartment, tissue enhancement results from contrast distribution.

• Thus, in the initial phase, the enhancement is determined by blood flow (BF) and blood volume (BV), whereas in the second phase, by the vascular permeability to the contrast.

• The temporal changes in tissue attenuation after contrast injection can be recorded quickly, and by applying appropriate mathematic modeling, tissue perfusion can be quantitated.

TERMS COMMONLY USED IN CT PERFUSION

Blood Flow or Perfusion • Flow rate through vasculature in tissue region (mL per 100 g/min)BV or Blood volume• Volume of flowing blood within a vasculature in tissue region (mL per 100 g)MTT or Mean transit time• Average time taken to travel from artery to vein (Seconds)PS or Permeability surface• Total flux from plasma to interstitial space (mL per 100 g/min)Time to peak enhancement• the time from the beginning of contrast material injection to the maximum

concentration of contrast material within a region of interest (ROI)

CT perfusion parameters can be analyzed by –• Compartmental analysis• Deconvolution analysis

Both the analytical methods require obtaining time attenuation data from the arterial input for estimation of tissue vascularity and to correct for inter patient variations in bolus geometry.

SINGLE COMPARTMENT MODEL

• Fick’s principle - tissue perfusion based on conservation of mass within the system• maximal slope or the peak height of the tissue concentration curve normalized to

the arterial input function

DUAL COMPARTMENT MODEL

• Patlak analysis - determine the rate constant of tissue uptake of a tracer from the vascular space by using the value of tracer concentration in tissue and blood

• quantifies the passage of contrast from intravascular space into the extra vascular space.

DECONVOLUTION ANALYSIS• It is the most commonly used algorithm because of its advantages over other methods:I. the absence of unrealistic assumptions about venous outflowII. the ability to use lower intravenous infusion rates.• Mean Transit Time is calculated by performing a deconvolution of the regional (tissue)

time-attenuation curve with respect to the arterial time-attenuation curve (arterial input function).

• Cerebral Blood Volume is calculated by dividing the area under the time-attenuation curve in a parenchymal pixel by the area under the time-attenuation curve in an arterial pixel.

• The central volume equation then can be solved to obtain the cerebral blood flow.• visual assessment of the venous time-attenuation - normalization of perfusion parameters

because it helps correct the data for partial volume averaging effects.

• In the ideal case, we would examine the inflow to, and the outflow from every region (i.e., pixel).

• Thus, we would expect the outflow signal to be equal to the inflow signal convolved with the impulse response:

hSS inout

Tracer Measurement over time

• The response to an impulse input is the distribution of all possible transit times through the system.

• h(t)dt is the fraction of “particles” that leave the system between t and t+Dt

• The Mean transit time is at the center of mass of the distribution, h(t). I.e., 1st moment.

0

)( dtthtt

• Rather than measure at inflow and outflow, we make observations of something equivalent to

I. signal at ~inflow (the arterial function) and, II. signal from the entire pixel.

• The integral H(t), of the histogram is all the tracer that has LEFT the system.• The residue function, R(t), describes all tracer still remaining, at time t and NOT yet

drained from the system.

Our observations are related to R(t)

• In the case of an ideal input, the view from within the pixel would look like:

Why measure CBV?• 1. Vasodilation (increased CBV ) may occur distal to narrowed carotid

arteries.

• 2. Decreased CBV/CBF may reflect slowed cerebral circulation.

• 3. CBV necessary to measure residual Oxygen in tissue

• The evaluation of brain perfusion is based on the central volume principle, according to which

CBF = CBV/MTT

• The two most commonly used CT perfusion imaging techniques are dynamic contrast material–enhanced perfusion imaging and perfused-blood-volume mapping.

DYNAMIC CONTRAST-ENHANCED CT

• Based on the multicompartmental tracer kinetic model and performed by monitoring the first pass of an iodinated contrast agent bolus through the cerebral circulation.

• The contrast agent bolus causes a transient increase in attenuation that is linearly proportional to the amount of contrast material in a given region.

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

• The perfusion parameters then can be calculated by employing mathematical modeling techniques such as deconvolution analysis

• Both the arterial and the venous ROIs are chosen in large vessels that course in a direction nearly perpendicular to the plane of CT acquisition (the axial plane).

• Color-coded perfusion maps of cerebral blood volume, cerebral blood flow, and mean transit time are then generated at the workstation

TECHNICAL IMPLEMENTATIONS• The baseline CT study should have 3 components: unenhanced CT, vertex to-arch CT

angiography (CTA), and dynamic first-pass CTP.• cardiac multidetector row CT (MDCT) for the detection of possible left atrial appendage

thrombus is optional.• Contrast Administration - A contrast bolus of 35–45 mL is administered via power injector

at a rate of 7 mL/s, with a saline “chaser” of 20–40 mL at the same injection rate. The contrast used should typically be a high concentration, ideally 350–370 g/dL of iodine.

• The CTP imaging protocol has been performed at 80 kV, rather than the more conventional 120–140 kV. Theoretically, given a constant milliampere-second (typically 200 mAs), this kilovolt setting would reduce the administered radiation dose.

• maximum degree of vertical coverage could potentially be doubled for each bolus by using a “shuttle-mode” technique.

Acquisition type DynamicTube voltage 80 - 100kVTube current 200 mAs/ Auto mAsDetector coverage 40mmScan time 31 secondsTable pitch 1:0.984; 39.37Noise index 11.57Gantry rotation time 0.4 secDFOV 35cmSlice interval 5mmReconstruction slice thickness 0.625Reconstruction intervals 3.75 to 5.0mmNumber of shuttle pass 18Scan type HelicalFilter kernel SoftImage Matrix 512×512

PERFUSION CT PROTOCOL• A typical perfusion CT protocol consists of a baseline acquisition without contrast enhancement, followed

by a dynamic acquisition performed sequentially after intravenous injection of CM • The dynamic image acquisition includes a first-pass study, a delayed study, or both, depending on the

pertinent physiologic parameter that needs to be analyzed.Unenhanced CT Acquisition• Provides wide coverage to include the organ of interest. • Serves as a localizer to select the appropriate tissue area to be included in the contrast-enhanced dynamic

imaging range.Dynamic CT Acquisition• The imaging volume is chosen on the basis of the unenhanced CT images• The first-pass study for perfusion measurements comprises images acquired in the initial cine/helical

phase for a total of approximately 40 to 60 seconds.• For permeability measurements with the compartmental model, images are acquired every 10 to 20

seconds.

POST PROCESSING

• Define ROIs for artery and vein. Most commonly selected artery is ACA and vein is superior sagittal sinus.

• The new CT perfusion software has automated vessel selection capability.

Normal :By convention, all color maps are coded RED for higher values and BLUE for lower values.

Base image

CBF

CBV

MTT

OTHER TECHNICAL CONSIDERATIONS

• Motion during data acquisition can lead to image misregistration and can cause errors in the estimation of perfusion values.

• breath-holding instructions to the patient, use of abdominal Straps , use of motility-inhibiting agents, to curtail bowel peristalsis during the perfusion examination of bowel.

• In addition, luminal distention with water or saline is encouraged for studies of hollow viscera to enable optimal tumor delineation.

• Metallic stents, prostheses, and surgical implants cause beam-hardening artifacts and can negatively influence the perfusion measurements.

• areas with excessive tumor necrosis or those located along organs with motion (in chest examinations) and areas near metallic prostheses or stents should be avoided.

• A major concern of perfusion CT is the risk for exposure to ionizing radiation, especially in patients who require serial perfusion studies.

• In patients with compromised renal function, contrast-induced nephropathy is a valid concern and should be dealt with cautiously

PERFUSED-BLOOD-VOLUME MAPPING

• Unenhanced CT followed by CT angiography of the brain can be used to assess arterial patency and tissue perfusion during the infusion of a single bolus of contrast.

• Cerebral blood volume values are obtained by subtracting the unenhanced CT image data from the CT angiographic source image data.

• degree of parenchymal enhancement depends on the actual cerebral blood volume and the quantity of contrast material reaching the tissue during the image acquisition - the subtracted images are referred to as perfused-blood-volume maps.

• Can depict entire brain parenchyma, however cannot quantitate CBF and MTT.

PITFALL AND CONTROVERSIES• the accuracy of the flow values obtained has not been fully validated.• Perfusion CT uses an intravascular tracer to measure CBF, which reflects a different physiologic

mechanism than that of PET and xenon CT.• Few studies reported systematically low values for CBF as measured with perfusion CT, compared with

xenon CT.• Larger ROIs may result in greater volume averaging of gray and white matter - lower quantitative

values for CBF, compared with the results obtained when smaller ROIs are used.• It is probably more accurate to use an input artery from the normal side. Extra-cranial arteries can be

better choices.• The reproducibility of perfusion CT has also not been fully validated.• restricted anatomic coverage• Increased radiation exposure.

APPLICATIONS IN NEUROIMAGING

CTP IN STROKE

• Stroke is a leading cause of mortality and morbidity in the developed world. • The goals of an imaging evaluation are I. to establish a diagnosis as early as possible II. to obtain accurate information about the intracranial vasculature III. to identify critically ischemic or irreversibly infarcted tissue (“core”) and to identify

severely ischemic but potentially salvageable tissue (“penumbra”). • This information can guide triage and management in acute stroke.

ACUTE STROKE IMAGING PROTOCOL

• When acute stroke patients present within 6 hours of the onset of symptoms - un-enhanced CT or with conventional/MR imaging.

• Hemorrhage at unenhanced CT or >1/3 MCA territory - not treated with thrombolytic drugs.

• ischemia of < 1/3 MCA territory, those who present <3 hours after the onset of acute stroke - intravenous thrombolytic drugs

• 3–6 hours after the onset of symptoms - CT angiography and CT perfusion imaging to assess the intracranial and neck vessels and detect any penumbra.

• Intraarterial therapy is usually considered for patients in whom a penumbra is seen.• Patients in whom no penumbra is seen are not usually treated with thrombolytic drugs

ROLE OF CT IN ACUTE STROKE EVALUATION

The three key CT techniques— Unenhanced imaging CT Angiography CT Perfusion Imaging

UNENHANCED CT• Widely available• Performed quickly• Does not involve the administration of intravenous contrast material. • It can:I. help identify a hemorrhage (a contraindication to thrombolytic therapy)II. help detect early-stage acute ischemia by depicting features such as the hyperdense

vessel sign, the insular ribbon sign, and obscuration of the lentiform nucleus. III. identification and quantification of parenchymal involvement in acute stroke.

Hyperdense Vessel sign Axial unenhanced CT images in a proximal segment of the left MCA in a 53-year-old man (a) and a distal segment of the left MCA in a 62-year-old woman (b), obtained 2 hours after the onset of right hemiparesis and aphasia, show areas of hyperattenuation (arrow) suggestive of intravascular thrombi

Obscuration of lentiform nucleus Acute ischemia of the

lenticulostriate territory result in obscuration of the lentiform nucleus, which appears hypoattenuated

May be seen within 2 hours after the onset of a stroke

Axial unenhanced CT image obtained in a 53-year-old man shows hypoattenuation and obscuration of the left lentiform nucleus (arrows), which, because of acute ischemia in the lenticulostriate distribution, appears abnormal in comparison with the right lentiform nucleus.

Insular Ribbon Sign• Acute ischemia of the

insular cortex, which is susceptible to early and irreversible ischemic damage, also causes local hypoattenuation, which results in the so-called insular ribbon sign Axial unenhanced CT image, obtained in a

73-year-old woman 21/2 hours after the onset of left hemiparesis, shows hypoattenuation and obscuration of the posterior part of the right lentiform nucleus (white arrow) and a loss of gray matter–white matter definition in the lateral margins of the right insula (black arrows).

CT ANGIOGRAPHY

• Widely available technique for assessment of both the intracranial and extracranial circulation.

• Its utility in acute stroke lies in –I. demonstrating thrombi within intracranial vessels and II. evaluating the carotid and vertebral arteries in the neck .

• (a) Unenhanced CT image in a 72-year-old woman with acute right hemiplegia shows hyperattenuation in a proximal segment of the left MCA (arrows). Axial (b) and coronal (c) reformatted images from CT angiography show the apparent absence of the same vessel segment (arrows). The presence of an intravascular thrombus in this location was confirmed by comparing the reformatted images with the CT source images (not shown).

• Intra-arterial thrombolysis may be more efficacious - acute stroke and a significant thrombus burden

• demonstration of a significant thrombus burden can guide appropriate therapy in the form of intraarterial or mechanical thrombolysis.

• identification of carotid artery disease and visualization of the aortic arch - cause ischemic event and guidance for the interventional neuroradiologist.

CT PERFUSION IMAGING• The imaging volume is chosen on the basis of the unenhanced CT images• The arterial ROI is typically chosen in either of the two anterior cerebral arteries (if they

are unaffected) or in the unaffected MCA. • The venous ROI is usually placed over the superior sagittal sinus, transverse sinus, or

torcular herophili. • At least one of the axial sections passes through the level of the basal ganglia.• cerebral blood volume, cerebral blood flow, and mean transit time are quantitated.• CT perfusion maps then can be generated in a short time at an appropriate workstation • A penumbra can be evaluated based on perfusion parameter mismatch.

SIGNIFICANCE OF A PENUMBRA

• brain tissue is exquisitely sensitive to ischemia, because of the absence of neuronal energy stores.

• complete absence of blood flow, the available energy for 2–3 minutes. • In acute stroke, ischemia is incomplete and injured area of the brain receives

collateral blood supply from uninjured arterial and leptomeningeal territories.• Acute cerebral ischemia may result in a irreversibly infarcted tissue core

surrounded by a peripheral region of stunned cells that is called a penumbra .• Evoked potentials in the peripheral region are abnormal, and the cells have ceased

to function, but this region is potentially salvageable with early recanalization .

Schematic of brain involvement in acute stroke shows a core of irreversibly infarcted tissue surrounded by a peripheral region of ischemic but salvageable tissue referred to as a penumbra. Without early recanalization, the infarction gradually expands to include the penumbra.

CBF CBV MTT

Infarcted core Markedly decreased(<30%)

Decreased (<40%)

Increased

Penumbra Moderately decreased Normal or increased

Increased

Gray matter White matterCBF 60 – 85 ml/100

g/min25 – 40 ml/100

g/minCBV 4 ml/100 g 2 ml/100 g

MTT (s) 4 s 4.8 s

Normal Perfusion CT Parameters

CTP Parameters in Ischemic stroke

HYPOTHESIS IN STROKE

• The clinical application of CT perfusion imaging in acute stroke is based on the hypothesis - • the penumbra shows either (a) Increased MTT with moderately reduced CBF and normal or increased CBV - autoregulatory mechanisms or(b) increased MTT with markedly reduced CBF and moderately reduced CBV,• the infarcted tissue shows severely decreased CBF (<30%) and CBV with increased MTT • quick visual analysis for color changes that are indicative of perfusion deficits or with a

more tedious measurement of perfusion parameters within ROIs placed in multiple regions.

• CT perfusion maps of (a )cerebral blood volume (b ) cerebral blood flow show, in the left hemisphere, a region of decreased blood volume (white oval) that corresponds to the ischemic core and a larger region of decreased blood flow (black oval in b) that includes the ischemic core and a peripheral region of salvageable tissue. The difference between the two maps (black oval = white oval) is the penumbra.

• Acute stroke in a 65-year-old man with left hemiparesis. CT perfusion maps of ( a )cerebral blood volume (b) cerebral blood flow (c ) and mean transit time show mismatched abnormalities (arrows) that imply the presence of a penumbra. The area with decreased blood volume represents the ischemic core, and that with normal blood volume but decreased blood flow and increased mean transit time is the penumbra.

Acute stroke: Infarct

Acute stroke with ischemic penumbra: Thrombolytic therapy useful.

75 Years female with Rt. side hemiparesis and aphasia 1 hr duration.

PRE-THROMBOLYSIS

POST THROMBOLYSIS

PRE

POST

RESULTS

• CTP imaging is more accurate than unenhanced CT for detecting stroke and determining the extent of stroke

• MTT more sensitive, while CBF & CBV maps are more specific for detection of acute stroke.

• Hence CT angiography and CT perfusion studies in patients with acute stroke could be performed, processed, and interpreted quickly

• Investigators in subsequent trials showed good clinical outcomes of thrombolytic drug therapy.

• Thrombolytic therapy may be made more effective by performing appropriate CTP rather than relying on the time of onset as the sole determinant of selection.

OTHER APPLICATIONS OF CT PERFUSION IN NEUR0IMAGING

CEREBROVASCULAR RESERVE

• chronic cerebral ischemia from carotid artery stenosis - CBF is preserved initially because of the cerebrovascular reserve.

• The cerebrovascular reserve - vasodilatation ability of cerebral arteries to compensate for CBF

• It is necessary to quantify - risk of ischemia, which can be triggered by any hemodynamic stress, and requires intervention to increase CBF.

• Endovascular Hemodynamic stress - tolerance test (acetazolamide administration)

VASOSPASM

• Frequent complication after aneurysmal subarachnoid hemorrhage (SAH)• MTT maps are reviewed for arterial territories with prolonged MTT values.

Such territory is considered at risk for vasospasm and then evaluated.• If CTA of the corresponding artery is abnormal, the diagnosis of vasospasm is

made• Finally, the arterial territories are carefully assessed for a decrease in cortical

CBF values. • If present, the latter prompts a conventional angiogram for possible

endovascular treatment.

HEAD TRAUMA

• distinguishing between patients with preserved and deranged autoregulation.

• detect altered brain perfusion - compression by an epidural/subdural hematoma

• require more aggressive and early treatment to prevent intracranial hypertension.

• Normal brain perfusion or hyperemia - favorable outcome, and oligemia in case of unfavorable outcome .

Patient who fell from a 6-m height, admitted with a Glasgow Coma Scale score of 9. Neurological examinationin the emergency room revealed an asymmetry of tone and deep tendon reflex involving both right upper and lower limbs. Admission contrast-enhanced cerebral CT demonstrated a displaced left parietal skull fracture, associated with a large cephalhematoma. A small left parieto-occipital epidural hematoma (white arrowhead) and a small contusion area (white star) could also be identified on the conventional CT images. PCT demonstrated a much wider area of brain perfusion compromise (white arrows), with involvement of the whole left temporal and parietal lobes, the latter showing increased mean transit time (MTT) and decreased cerebral blood flow (CBF) and volume (CBV). Thus, PCT afforded a better understanding of the neurological examination findings on admission than conventional CT

TEMPORARY BALLOON OCCLUSION• Performed in patients in whom prolonged temporary occlusion is considered as part of the surgical

or endovascular therapy.• in conjunction with a quantitative analysis of CBF can help identify patients who will not tolerate

permanent occlusion.• use of an absolute CBF value of < 30 mL/100 g/min as a criterion for the success or failure.• patients undergo angiography and balloon occlusion, during which time they are clinically

evaluated for 30 minutes. • Patients who pass the clinical portion of the examination are brought to the CT suite with the

balloon in place. • A perfusion CT scan is obtained with the balloon inflated and again with the balloon deflated. • The balloon is reinflated, 1,000 mg of acetazolamide is injected intravenously, and a final perfusion

CT scan is obtained.

ONCOLOGY

Utility of perfusion CT in oncology include:(1) lesion characterization (differentiation between benign and malignant lesions); (2) identification of occult malignancies; (3) provision of prognostic information based on tumor vascularity (4) monitoring therapeutic effects of the various treatment regimens, including chemoradiation and antiangiogenic drugs

• increased angiogenic activity and neovascularization results in increased blood volume and hyperpermeability related to the immature vessels – increase in rCBV

• Microvascular permeability increase - aggressiveness of tumors; reduction in permeability in response to antiangiogenic therapy correlates with decreased tumor growth.

• quantification of the abnormal vasculature within tumors - assessment of tumor aggressiveness.

• measure vascular physiologic changes by virtue of changes in the contrast enhancement characteristics of tissues.

• perfusion CT allow earlier assessment of response with treatment with newer antiangiogenic drugs effect than conventional methods, which rely on tumor size.

CONCLUSION

• perfusion CT is clearly a viable alternative to other modalities used to measure cerebral perfusion. • technique is fast and available for most standard spiral CT scanners equipped with the appropriate

software. • It is indispensable in imaging of patients with acute stroke.• It can also be utilized in evaluation of patients with other cerebrovascular diseases.• It may also be helpful in diagnosis and subsequent treatment response in patients with a variety of

tumors.• By virtue of its temporal resolution, it can replace PET in tumor imaging.• It can also be utilized in imaging the disorders of liver, lungs, pancreas and pelvis.• Further investigations are necessary to determine the accuracy, reliability, and reproducibility of

the quantitative results.

Thank You