Vascular Diseases of the Brain

Clinical Features

Thromboembolic disease consequent to atherosclerosis is the principal cause of ischemic cerebrovascular disease (surprise, surprise). The most common causes of infarction include large-artery atherosclerosis, cardioembolism, and lacunes (small vessel occlusions). Outcomes differ depending on subtype. Large artery lesions have a higher mortality than lacunes. Recurrent strokes are most common in patients with cardioembolic stroke, and have the highest 1-month mortality. Identifying the cause of the infarct has important implications for treatment and prevention of future cerebrovascular events. For example, carotid endarterectomy or stenting might be the more appropriate treatment of choice for large vessel disease whereas anticoagulation therapy is most useful in patients with small vessel disease.

Nonatherosclerotic causes of ischemic stroke include vasculopathies, migraine headache, and systemic/metabolic events (e.g., anoxia/profound hypoxia). They make up a small proportion of strokes in patients over 50 years of age. In younger patients these nonatherosclerotic causes of ischemic stroke are more common in particular in the absence of cardiovascular risk factors (hypertension, diabetes, and hyperlipidemia).

Thromboembolic emboli can arise from arterial stenosis and occlusion in the head and neck arterial vasculature, atherosclerotic debris and ulceration, in the setting of right to left shunts, or cardiac sources (a cardiac source of emboli is responsible for 15% to 20% of ischemic strokes; Box 3-1 ).

The extent to which narrowing of the arterial lumen contributes to stroke is complex. Even in the absence of severe stenosis, the reduction in flow may decrease the ability to “wash out” distal emboli before they produce ischemia. On the other hand, blood flow may be preserved and infarction may not occur even with complete occlusion of a vessel because of collateral circulation (circle of Willis and leptomeningeal vessels). Patients with complete internal carotid artery (ICA) occlusions in the neck may still have cerebral infarctions from emboli. Emboli may be multiple and simultaneous or a single embolus may break up and produce multiple infarctions.

Atherosclerosis is common and typically affects multiple extracranial and proximal intracranial vessels and/or multiple regions within the same vessel. Thirty-five percent of patients over 50 years of age have severe stenosing atherosclerotic changes in cervical cerebral arteries but only one third of these individuals have symptoms of vascular disease. Primary stenosis/occlusion most often results in infarction when there is a preexistent stenosis with either new occlusion and/or a period of systemic hypotension. Acute extracranial carotid occlusion may produce large areas of infarction involving the deep (ganglionic) and superficial (cortical) middle cerebral artery (MCA) distribution ( Fig. 3-1 ). In these cases the infarcts are likely the result of large distal emboli associated with the proximal occlusion. The anterior cerebral artery (ACA) territory is typically spared because of collateral supply from the contralateral anterior cerebral artery via anterior communicating artery of the circle of Willis. Combined MCA/ACA (“holo-hemispheric”) infarcts are rare and usually fatal. They most often occur in patients with acute myocardial infarction and atrial fibrillation because of the combination of large emboli and poor cardiac output.

Carotid stenosis or occlusion can result in “watershed” or borderzone infarction. Vascular watersheds are the distal arterial territories often at borders between two vascular distributions, which are relatively less well vascularized compared with other territories. Major borderzones are found between the anterior and middle cerebral arteries and the middle and posterior cerebral arteries. Borderzone infarcts occur in the posterior parietal region (middle and posterior cerebral arteries borderzone), the frontal lobes (the anterior and middle cerebral arteries borderzone) and the basal ganglia ( Fig. 3-2 ). These infarcts are often small and may be confused with lacunar infarcts. The key to diagnosis is the presence of multiple infarcts at the interface between different vascular territories and evidence of carotid occlusion, stenosis or slow flow. Other sites in the brain are selectively jeopardized by hypoxia and/or hypotension because of increased susceptibility to ischemia resulting from increased metabolic rate and a lack of redundancy of blood supply. These include the hippocampus (Ammon’s horn), globus pallidus, amygdala (anterior choroidal artery–posterior cerebral artery watershed territory), cerebellum and occipital lobes, in that order. In utero and perinatal, watershed zones are much different and center along the deep gray matter interfaces (see Chapter 8 ).

Interest in the detection and treatment of extracranial carotid artery disease has been heightened by the results of two large trials for the treatment of symptomatic and asymptomatic patients, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and Asymptomatic Carotid Atherosclerosis Study (ACAS). The NASCET trial demonstrated benefit of endarterectomy in patients with 70% or higher stenosis of the cervical ICA in symptomatic patients, and the ACAS study showed benefit of endarterectomy in patients with more than 60% cervical ICA stenosis in asymptomatic patients. The widespread availability of noninvasive vascular imaging (ultrasound, MRA and CTA) and the introduction of stent devices for the carotid artery have resulted in a dramatic increase in the number of individuals being treated for carotid stenosis without the same strength of evidence that these treatments provide similar significant benefits to patients. The assessment of degree of stenosis is complicated by the existence of various methods for measuring stenosis. NASCET uses the ratio of the tightest point of carotid stenosis to the “normal lumen” distal to the stenosis while ACAS and the European based studies use the degree of stenosis relative to the estimated normal lumen at the same site. Each method has its limitations. The NASCET criteria can lead to underestimation of stenosis when the distal lumen narrows as a result of the severe proximal stenosis “string sign.” The ACAS method is problematic because the observer must extrapolate what is thought to be the true lumen ( Fig. 3-3 ).

Intracranial embolic occlusion most commonly produces infarction in the midsection (posterior frontal, anterior parietal and superior temporal) of the MCA distribution. Emboli entering the carotid artery preferentially lodge in these MCA branches (not because these branches are cuter, but because they are along the straightest route an embolus can take). Pure ACA embolic infarcts are rare. Isolated ACA infarcts typically occur as a result of intrinsic arterial disease and occlusion (e.g., diabetes, hypertension, vasospasm, and vasculitis) or from severe subfalcine herniation rather than emboli. The location and extent of the infarct are determined by the site of embolic occlusion and extent and location of collateral supply to the brain distal to the occlusion. Occlusion of the distal carotid bifurcation and proximal MCA and ACA vessels (“T” occlusions) may result in infarction of the cortical (superficial) and ganglionic (deep) portions of the MCA territory. If there is good cortical collateral supply, the infarct may be confined (at least initially) to the basal ganglia and insula in part because of lenticulostriate branch obstructions. Embolic infarcts in the vertebrobasilar system may affect single or multiple vessels. Complete basilar occlusion produces cerebellar and brain stem infarcts and variable bilateral infarction of the inferior medial temporal and occipital lobes and posterior thalami while basilar tip occlusions spare the posterior fossa structures. The extent of posterior cerebral artery involvement is dependent upon the status of the posterior communicating arteries. Focal occlusion of the distal vertebral artery produces infarcts in the distribution of the posterior inferior cerebellar artery (PICA) leading to infarcts in the inferior cerebellum and lateral medulla (Wallenberg syndrome; Fig. 3-4 ). Multiple infarcts in several vascular distributions in both cerebral hemispheres raise concern for central embolic source, such as the heart ( Fig. 3-5 ).

Lacunar infarcts are small lesions produced by occlusion of deep perforating arteries. “Lacune” is a venerable pathologic term indicating a fluid filled hole in the brain ( Fig. 3-6 ). A lacune by definition is an infarct less than 15 mm in size. Lacunes have a predilection for the basal ganglia, internal and external capsules, pons, and corona radiata. Occlusion of brain stem perforating arteries produces distinctive infarcts that are paramedian, unilateral and tubular in appearance on axial imaging reflecting the location and course of the pontine perforating arteries. Although originally thought to arise from small vessel atherosclerosis and lipohyalinosis associated with hypertension, many other causes of lacunar infarcts have been proposed including emboli, hypercoagulable states, vasospasm, and small intracerebral hemorrhages.

Transient ischemic attack (TIA) is a sudden functional neurologic disturbance limited to a vascular territory that usually persists for less than 15 minutes, with complete resolution by 24 hours. The diagnosis of TIA is difficult because it is by definition retrospective. Although TIAs have a variety of causes, the common pathway is temporarily inadequate blood supply to a focal brain region. TIAs are not benign events. Almost one third of patients will eventually progress to completed cerebral infarction (20% within 1 month of the initial TIA). Quantitative measurement of apparent diffusion coefficients (ADCs) from magnetic resonance (MR) diffusion-weighted images (DWIs) may reveal mild decreased diffusion (<25%) in symptomatic areas without signal abnormality on DWI indicating that while there is no permanent functional deficit, neurons have been lost (25% in some animal studies). Thus proceeding with the workup after the TIA is urgent, with the goal to treat the cause before the development of a completed cerebral infarct. A reversible ischemic neurologic deficit (RIND) lasts less than 7 days and symptoms should resolve. MRI DWI is positive in about 50% of these cases even with symptom resolution.

Brain

CT has been the mainstay of stroke imaging since its inception in the mid-1970s. Unenhanced CT scans are fast and readily available. They are excellent for detecting large ischemic infarcts of over 6 to 8 hours’ duration. Nonischemic causes of stroke including hemorrhage, infection, and tumor are readily detected although often poorly characterized. There are, however, significant limitations to CT. It does not reliably detect infarcts of less than 4 hours’ duration and the extent of the infarct is often difficult to characterize. Acute lacunar infarcts often go undetected and are typically difficult to distinguish from chronic lacunar infarcts. Overall detection rates for acute infarction are approximately 58% in the first 24 hours.

Detection of hyperacute infarction (<6 hours) on unenhanced CT is not for the tame of heart! It is a skill that requires expertise and experience, and shockingly, a good clinical history. Knowing the neurologic deficit and time of onset of symptoms can really help in picking up the subtle changes of infarct that would otherwise be below the threshold for calling abnormal. No, it’s not cheating; it’s good patient care! Narrow CT window widths and levels should be applied to detect early infarct evidenced by loss of the gray-white matter distinction. Unenhanced CT can sometimes identify a dense vessel sign of acute embolic occlusion ( Fig. 3-7 ) but often provides no information on the status of the brain that surrounds the already infarcted tissue.

MRI is much more sensitive than CT in the detection of hyperacute infarction. Certainly, the advent of DWI has greatly enhanced our ability to detect hyperacute infarction and characterize all infarctions. While “routine” MR has 85% sensitivity for infarction within 24 hours, MR with DWI has a sensitivity of approximately 95% in this period including the first 3 hours after infarction when CT typically does not demonstrate any detectable parenchymal abnormality.

Diffusion imaging is a technique that is sensitive to the movement of water molecules (Brownian motion). In pure water, protons move about and jostle each other, and the extent of water molecule motion (self-diffusion) will be determined by temperature. The higher the temperature the more energy the protons possess and the further they will move. Biologic tissues are more complex. The water molecule encounters various barriers and impediments to motion including cell membranes, intracellular organelles and extracellular proteins. The term “apparent” is applied to modify the word “diffusion” connoting the uncertainty of the water motion in biologic samples caused by these barriers. In gray matter these structures are relatively randomly arrayed so diffusion is the same in all directions (isotropic). In white matter diffusion is constrained by the orientation of the white matter tracts. Water will diffuse preferentially along rather than across these tracts and is therefore anisotropic. The distance traveled by a particular proton will depend on the number of impediments it encounters and period of time during which the molecule is “observed” during the MR sequence. If the observation time is too short, the paths of most molecules will not be differentially affected by cellular barriers (membranes, proteins, etc.); however, when the observation time is long enough encounters with barriers will restrict diffusion. Thus DWI is unique among all imaging techniques in that it is a direct window into the spatial scale of molecules and cells.

You still with us? Good! The ADC can be calculated by using images with varied gradient strengths (different b values). At a minimum, ADC can be calculated if there are at least two b values, one of which must be set to approximately 0 sec/mm ² , that is, with no diffusion weighting. In clinical practice two b values are generally used; however, four or more b values can be measured to improve accuracy of measurement. Commonly used values include a b value of 800 to 1200 sec/mm ² , TE 90 to 120 msec.

In clinical practice, DWI sequences include approximately 30 slices with individual images obtained in approximately 20 msec. Four acquisitions are obtained at each location (total acquisition time for the brain <1 minute). One acquisition is acquired with no diffusion gradients (the b0 image—a T2 and susceptibility-weighted image) and three sets of orthogonal (anterior-posterior, superior-inferior, and right-left) images are acquired with a b value of around 1000. The three orthogonal images are averaged to produce a “trace” image that is insensitive to the anisotropy created by the orientation of white matter tracts. For instance, on a DWI acquired with the diffusion gradients applied in the anterior-posterior direction, the corpus callosum will appear bright because there is almost no anterior-posterior motion of water molecules in the highly organized right to left oriented callosal fibers. On the other hand, on images where the diffusion gradients are applied in a right-left orientation, the vertically oriented white matter of the corticospinal tract will appear bright. The trace image is the average of these three acquisitions that eliminates the effects of fiber tract orientation on signal intensity. In clinical practice only the trace image is viewed because in processes like infarction and other diseases it is the magnitude not the directionality of diffusion that is important.

However, information on the direction of diffusion and the degree of anisotropy are obtained and can be used to create images that record the direction and integrity of white matter tracts. This technique called diffusion tensor imaging (DTI) requires image acquisition in at least six planes rather than the three planes used for clinical DWI to completely describe the diffusion tensor (a tensor—aside from the radiology boards—is any measurement with at least three components).

The diffusion data can be used to generate ADC maps by performing a voxel by voxel calculation of ADC using the trace diffusion and b0 image. Subtractions of the diffusion and b0 data can also be used to generate “exponential” diffusion images. Generation of these maps is fast and simple. In clinical practice it is common to generate and view DWI, ADC and exponential images. ADC maps and exponential maps eliminate the T2 component of intensity (“T2 shine through”) on diffusion sequences (see later).

All DWIs start as T2-weighted images (T2WI) from which signal is subtracted based on the extent of diffusion, and therefore with routine DWI there is always a contribution of T2 to signal intensity. It is also helpful to have the b0 images available for viewing. Because of speed of acquisition, these images are rarely motion degraded, and therefore in uncooperative patients or in patients having very rapid MR studies the b0 can serve as a “poor man’s” T2-weighted and/or susceptibility-weighted image (SWI).

Substances that most nearly approximate water will have the highest rates of diffusion (high ADC) and will lose signal more rapidly than those with low ADC. Thus cerebrospinal fluid (CSF) appears dark on diffusion-weighted images as the water molecules can freely diffuse for relatively large distances, while gray matter is light gray and white matter is slightly darker gray in adults. On ADC maps, contrast is reversed. Increased diffusion is bright and therefore CSF is bright while brain tissue is dark. Some clinicians prefer exponential diffusion images to ADC maps because the relative signal intensities are the same as with DWIs (high diffusion such as CSF is bright). In reality the reversal of signal between DWI and ADC maps is not a problem if one simply remembers that CSF has the highest diffusion and that lesions with low diffusion will appear as the opposite of CSF. In tissues where diffusion is more restricted than in normal brain (e.g., hyperacute infarction) there will be less water molecule motion than in normal tissue and therefore less signal loss during the diffusion acquisition. These regions will appear bright on DWI and dark on ADC maps. When water motion is increased in tissue because of vasogenic edema (increased extracellular water) or gliosis (decreased cellularity), tissue will appear isointense on DWI and hyperintense on ADC maps. Tissues with increased diffusion are typically isointense rather than hypointense on DWI because of T2 effects. Increased tissue water (vasogenic edema) increases the T2 of the tissue, and therefore the effects of increased T2 (increased signal) and increased diffusion (decreased signal) tend to cancel each other out. In circumstances when diffusion is equal to normal brain but T2 is increased (subacute infarction) the tissue will look bright on DWI and isointense on ADC maps, a phenomenon known as “T2 shine through.” Phew!

T2-weighted fluid-attenuated inversion recovery (FLAIR) scans have a sensitivity of 85% within the first 24 hours. Some have suggested that a DWI positive, FLAIR negative stroke suggests a time frame of less than 6 hours, but this will vary depending on type and location of the stroke and the collateral substrate. MR has been shown to also be more sensitive than CT (even in the hyperacute phase) in the detection of hemorrhage (either within the infarct or as an independent cause of stroke). Detection of hemorrhage has been greatly facilitated by the routine use of gradient echo (GrE) and more recently SWI sequences. Other causes of stroke including venous thrombosis, vascular malformations, infections, and tumors are detected and characterized with greater accuracy than is possible with CT. Arterial and venous occlusion and/or slow flow can be detected on MR, in particular with the use of gradient echo scans and FLAIR ( Fig. 3-8 ). Focal acute embolus in a major vessel (the corollary of the dense vessel sign on CT) is best detected on gradient echo scans (see below), and slow flow can be seen on FLAIR and enhanced T1-weighted images (T1WI). Towel off for the time being, but come back soon—there’s more to come.

Vessels

It is obviously important to have knowledge of the arteries and veins in assessing individuals presenting with “stroke.” Identification of occlusion and/or stenosis of extracranial and intracranial arteries can confirm the ischemic nature of a lesion and help to determine whether an infarct is because of slow flow, proximal (e.g., MCA) embolic occlusion or small vessel disease. Direct visualization of the dural venous sinuses and cortical veins is often critical to the correct diagnosis of venous thrombosis in particular given the protean clinical manifestations, etiologies and imaging findings in this disorder. In the past, assessment of vascular structures required invasive catheter angiography, but there are now multiple noninvasive ways of assessing the cervicocerebral vessels, including CTA, MRA, and ultrasound. Each of these techniques has its advantages and limitations, and therefore the choice of the technique or combination of techniques to be utilized will depend on the clinical circumstances, diagnostic questions and treatment options in each case. Catheter angiography is reserved for those cases in which noninvasive studies do not provide a definitive diagnosis and most importantly when endovascular intervention (e.g., angioplasty, stenting, aneurysm coiling) is performed.

Carotid Ultrasound/Transcranial Doppler

Ultrasound uses sound waves to image structures or measure the velocity and direction of blood flow. Color-coded Doppler ultrasound can depict the residual lumen of the extracranial carotid artery more accurately than conventional duplex Doppler. However, the results from color-coded Doppler ultrasound examinations are operator dependent and can be confounded by artifacts related to plaque contents and limited by vessel tortuosity. Problems include distinguishing high-grade stenosis from occlusion, calcified plaques interfering with visualization of the vascular lumen, inability to show lesions of the carotid near the skull base, difficulty with tandem lesions, and inability to image the origins of the carotid or the vertebral arteries. In the NASCET study, Doppler measurements were 59.3% sensitive and 80.4% specific for the detection of stenosis greater than 70%.

Transcranial Doppler ultrasound is a noninvasive means used to evaluate the basal cerebral arteries through the infratemporal fossa. It evaluates the flow velocity spectrum of the cerebral vessels and can provide information regarding the direction of flow, the patency of vessels, focal narrowing from atherosclerotic disease or spasm, and cerebrovascular reactivity. It can determine adequacy of middle cerebral artery flow in patients with carotid stenosis and evidence of embolus within the proximal middle cerebral artery. It is very useful in the detection of cerebrovascular spasm following subarachnoid hemorrhage or after surgery in the intensive care unit setting on site, and can rapidly assess the results of intracranial angioplasty or papaverine infusions to treat vasospasm.

Magnetic Resonance Angiography

MRA is a critical and important tool for assessing the extracranial and intracranial vascular system. The technique is noninvasive and does not involve use of ionizing radiation. MRA can be performed without or with contrast. In some cases, injection of contrast material may be problematic in patients with compromised renal function, given recent concern for development of nephrogenic systemic sclerosis in patients with relatively low glomerular filtration rates (<30 mL/min/1.73 m ² ).

There are three different techniques used to generate MRA: time-of-flight (TOF), phase contrast (PC), and contrast-enhanced angiography. Once the imaging data is gathered it may be processed by several display techniques. The one most commonly used is termed maximum intensity projection (MIP), which finds the brightest pixels along a ray and projects them along any viewing angle. MIP is fast and insensitive to low-level variations in background intensity.

In two-dimensional and three-dimensional TOF MRA (the most commonly used technique), protons not immediately exposed to an applied radio frequency (RF) pulse (unsaturated spins) flow into the imaging volume and have higher signal than the partially saturated stationary tissue (which has lost signal secondary to the RF pulse). This is a T1 effect and flowing blood will appear bright. To visualize the arteries without interference from the veins, an initial superiorly positioned nonspatially localized saturation pulse is applied. With TOF magnetic resonance venography (MRV), the saturation pulse is applied inferiorly to saturate the arterial blood.

The two-dimensional TOF techniques are very sensitive to slow or moderate flow (as flow related enhancement is maximized), whereas three-dimensional techniques are better than two-dimensional MRA for rapid flow and have higher resolution. A pitfall in the evaluation of TOF MRA can occur when there are T1 hyperintense lesions or structures within the tissues. These areas of T1 hyperintensity will be visible on the MRA images because the MIP images will include all regions with signal intensity above a predefined threshold. Thus subacute hematomas and fat containing lesions will appear bright and might confound interpretation of the MRA. Subacute intramural clot in dissections and venous sinus thrombosis will also appear bright and may be mistaken for flow.

The advent of 3 Tesla MR scanners has produced a dramatic improvement in TOF MRA. At 1.5T visualization of second order intracranial branches (e.g., intrasylvian MCA branches) is limited, and therefore detection of distal occlusions, vasculopathy, and arterial spasm is not reliable. At 3T these vessels and even smaller arteries (e.g., lenticulostriate arteries) are well visualized in most cases ( Fig. 3-9 ). Therefore it is preferable to perform MRA studies on 3T scanners if available.

In phase contrast (PC) MRA, bipolar flow-sensitizing gradients of opposite polarity are used to “tag” moving spins (protons) that are then identified owing to their position change at the time of each gradient application. The operator chooses the flow velocities that the angiogram will be sensitive to, termed the VENC, ranging from about 30 cm/sec for arterial flow to 15 cm/sec for venous flow. Complex subtraction of data from the two acquisitions (one of which inverts the polarity of the bipolar gradient) will cancel all phase shifts except those resulting from flow. This technique provides excellent background suppression to differentiate flow from other causes of T1 shortening such as subacute hemorrhage or fat. However, PC MRV is routinely used for suspected venous thrombosis because of its ability to differentiate between flow and subacute (bright) thrombus that obviates the need for TOF MRV.

Contrast enhanced MRA (CEMRA) provides rapidly acquired (<30 seconds) high-resolution images of the extracranial and proximal intracranial vessels with typical coverage from the aortic arch to the circle of Willis ( Fig. 3-10 ). Timing is critical as enhancement of veins confounds the ability to demonstrate arterial anatomy. Because it is not affected by turbulence, it is superior to noncontrast MRA for evaluation of carotid bifurcations and cervical and intracranial vertebrobasilar system. It also can decrease ambiguity in cases with flow reversal such as subclavian steal ( Fig. 3-11 ).

MRA is a good tool for the noninvasive evaluation of the extracranial vasculature for the presence of a hemodynamically significant lesion of the carotid arteries, dissection of the vertebral and carotid arteries, extracranial traumatic fistula, extracranial vasculitis such as giant cell arteritis, or congenital abnormalities of the vessels such as fibromuscular disease. Because it is noninvasive and does not utilize ionizing radiation, it is an excellent screening test for cervical vascular disease. Keep in mind that cervical MRA tends to overestimate moderate stenosis, particularly if only unenhanced two-dimensional TOF methods are used. Thus, an apparent severe stenosis (>85%) may actually be moderate (∼50%).

Intracranial MRA can be used to reliably detect proximal stenosis and occlusion as well as vasculopathy (at 3T). MRA has been shown to accurately detect aneurysms (90% accuracy for aneurysms >3 mm). It is therefore a useful tool for screening asymptomatic patients with a risk of intracranial aneurysm (e.g., patients with polycystic kidney disease or individuals with a first degree relative with a history of ruptured aneurysm). It can also be used to follow patients with known nonruptured aneurysms and patients who have undergone endovascular coiling of aneurysms. In the setting of acute subarachnoid hemorrhage, however, detectability of aneurysms by MRA is limited as the flow related enhancement in vessels may be camouflaged behind the T1 hyperintense signal of acute subarachnoid blood in the cisterns. Although MRA may easily detect arteriovenous malformations (AVM), the superimposition of feeding arteries and draining veins limits the value of this technique in evaluating AVMs. Four-dimensional CTA and MRA in which a time element is superimposed to show inflow and outflow have shown promise with more detailed noninvasive imaging of arteriovenous malformations and fistulas, although conventional catheter angiogram remains the gold standard for imaging of these lesions.

Computed Tomographic Angiography

CTA ( Fig. 3-12 ) has emerged as an alternative to MRA for imaging both the extracranial and intracranial blood vessels with the development of multirow detector scanners. Current 16-128 row scanners can provide excellent visualization of extracranial and intracranial vessels without venous contamination (assuming accurate timing of contrast bolus injection). New 320 row detector scanners can acquire data from the entire brain simultaneously and therefore, with multiple acquisitions, produce time resolved angiographic studies that mimic catheter angiography in their appearance.

Dual-energy CT acquires two image datasets using two different tube energies applied in the form of kVp. Tissue density may be variable between a high-energy spectrum and a low-energy spectrum, and this attenuation difference allows a more nuanced examination of tissue characteristics. Iodine and calcification in vessels may be more easily differentiated on images because they have different responses to high (120 kVp) and low energy (50 kVp) radiation.

CTA requires the placement of a catheter usually in the antecubital vein with rapid injection of approximately 50 to 125 mL of iodinated contrast material. After a short delay following contrast injection, calculated by test bolus run before the formal CTA exam to optimize arterial of venous flow sensitivity, imaging commences and a three-dimensional data set is acquired. CT advances have resulted in thinner images improving resolution. Computer postprocessing is necessary for MIP images and excluding the bony base of the skull structures.

As an imaging technique, CTA has several advantages when compared with MRA at the cost of radiation exposure and iodinated contrast dye. Faster imaging acquisition and higher spatial resolution allow for accurate assessment of vascular morphology, such as in the setting of aneurysms or extracranial stenoses. Calcification does not cause the same artifacts that are seen on MR and extremely slow flow and tandem lesions are more reliably detected on CTA than MRA. Intracranial embolic occlusion is more easily seen and focal thrombus within proximal intracranial vessels may be directly visualized. The superb quality of CTA has prompted many neurosurgeons to operate directly on the basis of CTA findings reserving catheter angiography for those cases where CTA findings are inconclusive or when endovascular treatment is to be performed.

The limitations of CTA include (1) risks of intravenous iodinated contrast injection; (2) exposure to radiation; (3) obscuration of vessels at the base of the skull because of bone; (4) obscuration of aneurysms by extensive subarachnoid hemorrhage; (5) extensive atherosclerotic calcifications in the walls of the vessels which can obscure opacification within the vessel; (6) normal osseous structures such as the anterior clinoid process may obscure the adjacent vessel and less frequently mimic the appearance of an aneurysm on CTA surface rendered reconstructions; and (7) the three-dimensional reconstruction process is still operator dependent. While workstations have improved the ability to detect aneurysms near the skull base, in particular within and adjacent to the cavernous sinus, skill (of the nunchuck, bow hunting, and computer hacking variety) at image manipulation is often required to make aneurysms in this region visible.

Conventional Catheter Angiography

Arterial catheter angiography is the definitive imaging modality for vascular lesions of the brain and great vessels of the neck but has been relegated to a secondary role in the diagnosis of stroke. In the hyperacute strike setting, catheter angiography is primarily used in stroke treatment for planning and execution of thrombolysis and stenting.

Patients are referred for angiography for the following reasons: (1) if the MRA, CTA, or/and carotid ultrasound are equivocal; (2) if MRA is contraindicated (e.g., in patients with pacemakers); (3) if cardiac output is too low to produce a diagnostic CTA; (4) to evaluate complex aneurysms or vascular malformations responsible for an intracranial hemorrhage; and (5) for the evaluation of vasculitis. The advent of rotational three-dimensional digital subtraction angiography has made it possible to combine the advantages of selective arterial injection of contrast and that of the three-dimensional imaging intrinsic to CTA ( Fig. 3-13 ).

For assessment of arteriovenous malformations and fistulas, selective catheter angiography is necessary to obtain time resolved images that separate arterial and venous components of the malformations. While high field MRA and CTA may suggest the correct diagnosis of vasculitis, the absence of evidence of vasculopathy does not exclude this diagnosis. Because the treatment of this disorder is not without risk, catheter angiography may be performed to confirm or exclude the diagnosis and may be used to determine the best site for biopsy if necessary. Catheter angiography is a safe (but not completely harmless) study and in many situations provides crucial information. The incidence of all complications for femoral artery catheterizations is approximately 8.5% with the range of permanent complications (the most significant of which is stroke) from 0.1% to 0.33%, a 2.6% incidence of transient complications, and a 4.9% incidence of local complications.

In individuals with acute or chronic ischemic disease, catheter angiography is used in selective cases, in particular if endovascular intervention is contemplated. It is an excellent albeit invasive method for determining whether a lesion is hemodynamically significant in the carotid circulation ( Box 3-2 ). Assessment of collateral circulation distal to a stenosis or occlusion is most easily determined with catheter angiography, where serial images show the presence, source, and extent of collateral supply to the brain.

Detection of ulcerated plaques is more accurate with conventional catheter angiography than noninvasive angiography. However, on all types of angiographic exams, it is difficult to distinguish ulceration from irregularity. The most reliable angiographic sign is the penetrating niche, but depression between adjacent plaques and intraplaque hemorrhage may produce a similar appearance ( Fig. 3-14 ). Luminal bulging secondary to destruction of the media with an intact intima can also appear as an ulcer. One should appreciate that the association of ulcer and stroke is also controversial. Many asymptomatic plaques are ulcerated, and many symptomatic plaques are not. Generally, however, ulceration is frequently found on the symptomatic side in association with significant stenosis. High-resolution surface coil enhanced MR is an excellent way to evaluate ulcerated plaque but requires hands-on study to optimize planes of section and flow suppression. The best approach presently is for the radiologist to describe the plaque as smooth or irregular, and if niche is present, the term ulceration can be used. It is in the province of the physician caring for the patient to base therapy on the severity of findings and on the patient’s symptoms.

Perfusion

Perfusion imaging aims to characterize microscopic flow at the capillary level. The key concept to remember in perfusion imaging is the central volume principle:

Cerebral blood flow (CBF) is determined by the ratio of cerebral blood volume (CBV) divided by the mean transit time (MTT). The CBF of the normal brain ranges between 45 and 110 mL/min/100 g of tissue. Cerebral oligemia (about 20 to 40 mL/min/100 g) is defined as underperfused asymptomatic region of brain that will recover spontaneously, whereas an ischemic hypoperfused brain is symptomatic and at risk to develop irreversible infarct without revascularization. The ischemic threshold identified in animal experiments when there is cessation of action potential generation occurs around 20 mL/min/100 g and the infarction threshold, associated with irreversible neuronal damage, is at approximately 10 mL/min/100 g. Therefore, ultimately it is CBF that determines whether tissue will live or die, but changes in MTT and CBV reflect the pathophysiologic processes that precede and then determine when CBF decreases to nonviable levels. The initial event is an increase in MTT because of an occlusion or stenosis. MTT will be determined by the site of occlusion or stenosis and the presence and type of collateral supply to the affected brain. The autoregulatory response of the brain is vasodilatation of vascular bed distal to the occlusion or stenosis and increased oxygen extraction from the blood. Vasodilatation increases CBV, and therefore initially CBF is maintained or at least does not decrease to the level where neuronal death occurs. However, once maximal vasodilatation is achieved, any further increases in MTT (because of progressive occlusion, new embolization, or decrease in systemic blood pressure) will result in decrease in central perfusion pressure, collapse of the vascular bed and decrease in CBV and consequent decrease in CBF.

Perfusion imaging can be performed in a number of ways, but by far the most common technique in clinical practice involves an intravenous injection of contrast material on CT or MRI. Rapid sequential imaging of all or part of the brain allows the visualization of the effect of the contrast agent as it traverses the vascular system. This “bolus tracking” technique is used for both MR perfusion (MRP) and CT perfusion (CTP). In CTP the density of the brain increases while the iodinated contrast agent passes the vascular supply, and with MRP the intensity of the brain decreases because the paramagnetic gadolinium agent causes T2 shortening (dynamic susceptibility imaging). In both cases one obtains direct measurement of CBV (it is the area under the curve of the density/intensity change). The time that it takes the contrast to traverse the brain is the MTT, and therefore the CBF can be calculated using the central volume principle. However, to precisely measure CBV and MTT it is necessary to eliminate the contribution of contrast within small arterioles and venules. This requires mathematical “deconvolution” of the data. This is easy with CTA where data from the arterial input and venous output (obtained by measuring the changes in density within large arteries such as the anterior cerebral arteries and large venous channels such as the superior sagittal sinus) can be obtained. With MR this is more difficult because of the contribution of flow effects within large vessels. Therefore the values obtained from CTA are precise mathematical measures of the three perfusion parameters, whereas those obtained with MRP are relative values (e.g., rCBV, rCBF, rMTT). With both CTA and MRA, parametric “MTT,” “CBV,” and “CBF” maps are generated and evaluated qualitatively. Advances in software now allow for quantitative measurement of these parameters as well.

The parametric maps provide somewhat different information and each has its advantages and limitations. Because the initial event in an infarct is increase in MTT, the MTT maps are the most sensitive to early ischemic changes, but because not all areas of elevated MTT go on to infarction, MTT maps tend to overestimate final infarct volume. What measure best correlates with the size of the final infarct? It depends upon many factors including what literature you read. CBV maps appear to have the best correlation with the ultimate infarct volume. However, this is controversial, with some reports indicating that relative CBV (rCBV) underestimates final infarct volume, whereas relative CBF (rCBF) can more accurately estimate it or overestimate it. Such differences may, in part, be related to when the measurement is made (12 hours versus 24 hours) and also by the type of postprocessing techniques employed.

Perfusion imaging is critical to determining whether or not there is salvageable brain that can be protected by use of intravenous (IV) or intraarterial thrombolytic (tPA) or clot retraction/removal therapy, or medical therapy ( Figs. 3-15, 3-16 ). All of these treatments are associated with an increased risk of intracranial hemorrhage and therefore treatment should be reserved for individuals who can benefit from recanalization. Individuals in whom the area of infarction matches the area of abnormal perfusion should not be treated regardless of other factors (time from onset of symptoms, extent of infarcted brain) because there is no brain tissue to protect. On the other hand, in patients where volume of brain at risk is greater than the already infarcted brain by more than 20%, treatment may result in improved outcome. More recent data indicate that the extent of collateralization of distal branches beyond the occlusion has a major impact on outcome as well (the better the collaterals, the better the prognosis), and must also be taken into consideration when triaging patients for recanalization. However, large volumes of at-risk brain tissue are also susceptible to complications of reperfusion hemorrhage, and therefore should be considered for potential treatment only with great caution.

The brain at risk is described as the ischemic penumbra. On MR, the penumbra is the brain tissue surrounding the core diffusion “positive” (hyperintense on DWI) infarcted brain that has normal diffusion but abnormal relative perfusion (diffusion-perfusion mismatch). On CT there is no easy direct way to measure the extent of the already infarcted brain, and therefore it is necessary to use quantitative measures of perfusion to define the predicted infarcted brain (<10 mL/min/100 g) and the penumbra (10 to 30 mL/min/100 g; Fig. 3-17 ).

There are other methods of measuring brain perfusion that deserve brief attention. Nuclear medicine studies including positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be used to generate perfusion maps but have little use in the work-up of acute infarction. Xenon CT involving inhalation of stable xenon gas to act as a contrast agent to estimate cerebral blood flow can be performed quickly but is not readily available in most centers. Arterial spin labeling (ASL) is an MRP technique that requires no exogenous contrast agent (see Fig. 3-40, E ). In this technique the protons in arteries at the base of the brain are subjected to an MR pulse that inverts their spins. The tagged protons can then be measured as they pass through the brain. In both xenon CT and ASL the perfusion agent (xenon and tagged water molecules, respectively) freely diffuses across the blood-brain barrier and therefore it is possible to directly measure CBF. However, while CBF is the critical determinant of brain tissue viability, knowledge of MTT and CBV allows for understanding of the status of the vascular system, not just the brain. ASL is technologically demanding and not in common clinical use in many imaging centers. One advantage of the technique is that, because no contrast injection is necessary, ASL perfusion studies can be repeated as often as necessary.

Dynamic susceptibility contrast (DSC) enhanced MRP is often measured in CBF and CBV; however, another parameter commonly used in MRP studies is time to peak (TTP) contrast concentration. This refers to the time it takes until the maximum T2 shortening effect of the first-pass gadolinium in the vessel (the lowest signal intensity). When highly concentrated as in an MRP bolus, the primary effect seen is a T2 shortening within the vessel and the subsequent parenchyma from the bolus and perfusion of tissue respectively. TTP maps can be measured directly from the time-intensity curve of an MRP study by comparing the ischemic and the contralateral normal voxels. Using a TTP delay of more than 4 seconds relative to the contralateral hemisphere can correctly identify 84% of hypoperfused and 77% of normoperfused tissue. Other sites are currently using an area under the curve Tmax parameter between 5 and 6 seconds to identify the ischemic penumbra. A Tmax bolus delay of 6 seconds has become the accepted threshold for the definition of a relevant hypoperfusion in recent stroke thrombolysis trials (EXTEND, EPITHET).

Hyperacute Infarction (0 to 6 hours)

The initial event that leads to infarction is vascular insufficiency because of focal proximal or distal occlusion or stenosis. In most instances routine imaging will not demonstrate the occlusion except when there is embolic occlusion of large vessels (e.g., dense MCA or basilar artery sign). Vascular occlusion leads to decreased perfusion, which when sufficiently severe and/or sufficiently prolonged initiates the “ischemic cascade.” Within 5 minutes of hypoxia, the membrane pumps that maintain the disparity between the normal high concentration of extracellular sodium and the lower intracellular sodium fail. Sodium enters the cell and the influx of sodium produces an osmotic gradient and water passively enters the cell creating “cytotoxic” edema. In addition, calcium enters the cell, which in turn activates intracellular enzymes that begin to lyse intracellular organelles and precipitates proteins. This produces cell lysis and the release of excitatory amino acids (glutamine and glutamate) and vasoactive substances, which further compromise the metabolic status of adjacent cells. Hence apoptosis.

CT: During the hyperacute phase, CT may be normal or may demonstrate the “dense vessel” sign when there is an embolic occlusion of a proximal vessel (see Figs. 3-7, 3-18 ). The dense vessel can sometimes be more conspicuous on thinner section CT imaging (i.e., <1 mm thick cuts). The initial parenchymal finding is loss of normal gray matter density without mass effect. The gray matter becomes isodense to adjacent white matter leading to loss of the normal “cortical ribbon” and/or loss of the ability to differentiate the basal ganglia and/or thalamus from the internal capsule ( Figs. 3-19, 3-20 ). Loss of cortical density may occur as early as 3 hours but more typically takes 4 to 6 hours to develop. This finding is subtle and is often missed by inexperienced observers and those without the advantage of the specific clinical history. The advent of PACS reading stations has facilitated detection of hyperacute infarction. One can improve detection of loss of gray matter density by narrowing the window on CT images thus accentuating gray/white density differences ( Fig. 3-21 ).

Loss of cortical density is typically described as cytotoxic edema. Although it is true that cytotoxic edema is occurring, it is likely that the loss of normal gray matter density is not a direct result of this process. We think of edema as hypodense because the most common cause of brain edema is disruption of the blood brain-barrier (vasogenic edema) leading to increased tissue water that in turn produces hypodensity. In cytoxic edema there is shift of water from the extracellular space to the intracellular space without an increase in the total amount of tissue water. In addition, at this stage of infarction there is often little or no hyperintensity on FLAIR and T2WI (see later). Because T2WI is much more sensitive than CT to changes in tissue water, it is unlikely that subtle changes in water would be detected on CT and not MR.

A more likely cause of the initial changes on CT is decreased cerebral blood volume. Gray matter is denser than white matter in large part because it has a higher blood volume. Decreased blood volume renders gray matter isodense to white matter. This concept helps to explain several observations concerning acute infarction. For instance, it typically takes approximately 24 hours for ganglionic hypodensity to be seen in acute anoxic injury (e.g., smoke inhalation and near drowning). This relative delay in development of hypodensity likely reflects the fact that in anoxic injury there is no decrease in blood flow, but rather there is a decrease in blood oxygen level. It has been observed that infarcts that become apparent on CT within 4 hours of symptom onset have a worse prognosis than similar sized infarcts that do not become apparent until 6 to 12 hours. This most likely is the result of the more profound perfusion deficit that must be necessary for these infarcts to become apparent in the first few hours. One way to improve infarct detection is to evaluate CTA “source” images. The normally perfused gray matter becomes hyperdense compared with the underperfused infarcted brain ( Fig. 3-22 ).

Although large infarcts in the middle cerebral artery distribution can be detected within 6 hours in about 75% of cases (at least by experienced readers) the overall sensitivity for detection of all infarcts by CT is only 45% in the first 24 hours. The low rate occurs because of the poor performance of CT in detecting small cortical infarcts, cerebellar infarcts and white matter infarcts. In addition, even when an infarct is detected, its true extent is difficult to determine. One of the major contraindications to the use of IV tPA is large infarct size (infarcts that involve more than one third of the MCA distribution or 70 mL or core infarct). Therefore noncontrast CT is not in and of itself an accurate tool for assessment of infarction, in particular if IV or intraarterial therapy is contemplated. Its major role is to identify hemorrhagic infarctions and hyperdense clots in vessels and to exclude processes such as nonischemic hemorrhage (e.g., hypertensive hemorrhage), masses or infections presenting as stroke. Note that the vast majority of infarcts in the first 24 hours are not hemorrhagic.

Some neurologists and interventionalists find the Alberta stroke program early CT score (ASPECTS) useful in patient selection for thrombolytic therapy in patients presenting with MCA strokes. Starting with an initial score of 10, 1 point is deducted if infarction in the following structures is evident on the initial unenhanced CT: caudate, putamen, internal capsule, insular cortex, frontal operculum (M1), anterior temporal lobe (M2), posterior temporal lobe (M3), anterior MCA territory superior to M1 (M4), lateral MCA territory superior to M2 (M5), posterior MCA territory superior to M3 (M6) ( Fig. 3-23 ). An ASPECTS score of 7 or under predicts worse functional outcome as well as symptomatic hemorrhage.

CT evaluation of infarction in the hyperacute phase should be performed in conjunction with CTA of the head and neck. CTA can demonstrate the presence and location of stenosis, tandem stenoses or occlusion. CTP can also be performed to determine if there is viable brain that can be saved by thrombolytic therapies.

MR: There are several MR findings indicative of flow-limiting stenosis that can be detected even without the benefit of MRA. Remember that the typical intraluminal hypointensity is a result of flow effects rather than the intrinsic signal of blood. Blood is a proteinaceous fluid that is relatively T1 isointense and T2 hypointense. After contrast administration, slow flowing blood becomes T1 hyperintense. The MR correlate of the CT dense vessel sign of acute embolic occlusion is focal “blooming” at the level of intraluminal thrombus (marked hypointensity that often extends beyond the lumen of the vessel) on GrE or SWI. If diffusion images are reviewed carefully, restricted diffusion at the site of the thrombus can often be appreciated as well. Chronic occlusion and/or extremely slow flow in large vessels (e.g., cavernous carotid artery) is manifested by isointensity to hyperintensity on T1WI and hyperintensity on T2WI rather than typical dark flow voids seen on T2WI. In the presence of proximal occlusion or severe stenosis, intraluminal hyperintensity is present on FLAIR images in distal branches because of slow flow (see Fig. 3-8 ). If contrast is given, intraluminal hyperintensity will be more extensive distal to an occlusion than in normal circulation.

With regard to parenchymal signal changes on MRI, hyperacute infarction is T1 isointense and T2 isointense to mildly hyperintense. T2 hyperintensity is best appreciated on FLAIR (sometimes only in retrospect) and is typically confined to the gray matter in thromboembolic infarction. In the first 24 hours, FLAIR hyperintensity is seen in approximately 80% of cases, but it is seen in less than two thirds of cases studied within 6 hours ( Figs. 3-24, 3-25 ). DWI increases the sensitivity for detection of acute infarction to greater than 90% in the hyperacute (<6 hours) period. DWI hyperintensity with ADC map hypointensity can be seen within minutes of the onset of ischemia in animal models and in clinical cases where patients have the misfortune of developing an infarct during or just preceding the MR exam. These early changes are the result of cytotoxic edema. In the vast majority of cases the restricted diffusion is an indicator of irreversible neuronal damage and death.

In less than 5% of cases diffusion changes are reversible (thank goodness for small miracles!). In most of these instances there is early (<3 hours) spontaneous or therapeutic recanalization of the occluded vessels. The initial ADC reduction is often less than that seen in most infarcts (∼25% as compared with >75%). It should be noted that in some of these cases subsequent exams reveal return of restricted diffusion and DWI hyperintensity. These unusual cases probably represent examples of borderline ischemia. If flow is rapidly reestablished, damaged cells may return to normal metabolic function at least transiently. These cells may fully recover, but many will go on to cell death (with return of DWI hyperintensity) because of continued ischemia or apoptosis (programmed cell death). Venous ischemia is another setting where ADC values may reverse with restoration of normal flow patterns.

In 5% to 10% of cases the initial DWI study is normal when an infarct is present (as confirmed by clinical findings and/or subsequent imaging studies; Fig. 3-26 ). Most of these cases are small inferior brain stem or cerebellar infarcts that are obscured by susceptibility artifact from the skull base. In some cases the normal initial DWI study may be because of pseudo-normalization. DWI sensitivity seems to drop in the 8- to 16-hour range, a period of time where partial recovery of cellular function may result in transient resolution of DWI and ADC abnormalities.

As opposed to CT, unenhanced MR is sufficient to detect essentially all hyperacute infarcts. Therefore multimodal MR (MRI, MRA and MRP) is of most value when thrombolytic therapy, clot retraction, or other aggressive medical interventions are contemplated. Craniocervical MRA allows for detection of stenosis, occlusion and dissection of the entire cerebrovascular system. MRP allows for identification of areas of hypoperfusion that might be the target of thrombolytic therapy.

Hyperacute Stroke Management

To appreciate how multimodal CT and MR are used in treatment decisions it is necessary to understand the risks and benefits of those options. It has been shown that IV administration of tPA improves outcomes (e.g., residual disability) in stroke patients in the following circumstances: (1) treatment must begin within 4.5 hours of symptom onset; (2) no CT evidence of hemorrhage; and (3) infarct must not be large (exceed one third of the distribution of the MCA territory or 70 mL). With multimodal imaging, additional criteria have been established including (a) no evidence of occlusion of the distal internal carotid artery and proximal MCA and ACA (“T” occlusion) and (b) the presence of a penumbra of salvageable brain that represents at least 20% of the overall region of abnormal perfusion. Application of these criteria eliminates more than 90% of patients presenting to emergency departments with signs of acute infarction. These criteria are strict because IV tPA treatment is not benign. The risk of intracerebral hemorrhage, often massive, is high in particular in patients treated too late or in whom an infarct is too large. IV tPA is ineffective if there is no salvageable brain or there is a proximal occlusion that is unlikely to lyse with IV treatment.

Intraarterial (IA) treatment can extend the therapeutic window to up to 8 hours in the anterior circulation and up to 24 hours in the vertebrobasilar or retinal circulation. In addition to extending the time window for treatment, IA therapy can be used to eliminate proximal clots that are unlikely to lyse with IV tPA. IA treatments include direct injection of tPA into the clot via super-selective catheter placement, manual clot disruption, and removal of the clot with a mechanical device.

The process of patient selection for IA treatment continues to evolve as we learn more about the hemodynamics of ischemic strokes. Several major recent trials have shown that in patients presenting with proximal vessel occlusion in the anterior circulation up to 8 hours following stroke onset, endovascular thrombectomy showed improvement in patient disability and function at 90 days posttreatment compared with medical management (including IV tPA) alone. The endovascular treatment for small core and proximal occlusion ischemic stroke (ESCAPE) trial showed that in patients with proximal vessel occlusion and small infarct core but good collateral circulation, prompt endovascular treatment resulted in improved functional outcomes and lower mortality. This trial and other investigations have found that identification of good collateral circulation should be a strongly considered criterion in patient selection for endovascular treatment of stroke and may be more important than time between symptom onset and directed treatment. Mechanical thrombectomy and clot retrieval devices also continue to evolve, with new generation devices showing improvement in outcomes compared with previous generation devices just in the past few years.

Based on these evolving concepts, in the clinical setting of hyperacute stroke with potential for IA therapy, many stroke centers now advocate excluding hemorrhage (noncontrast head CT), assessing core infarct size (noncontrast head CT/ASPECTS versus diffusion MRI), identifying vessel occlusion and presence of adequate collateralization (CTA), and assessing clinical penumbra at the bedside (NIH stroke scale/neurologist evaluation). The addition of perfusion imaging by CT or MR remains of questionable value in the hyperacute stroke setting.

Currently, in those centers that have access to interventional neuroradiology, IV tPA is being followed by intraarterial clot retrieval in the hyperacute (<6 hours setting) setting of anterior circulation strokes with proximal vessel occlusions. Such were the recommendations from the MR CLEAN EXTEND-IA, SWIFT-PRIME, and ESCAPE trials. Most of these trials required demonstration of good collateral flow either by CTA or, by inference, CTP (or MRP).

Acute Infarction (6 to 36 hours)—Cytotoxic and Vasogenic Edema

With continued ischemia, neuronal damage and death (cytotoxic edema) increases. Endovascular cells are damaged resulting in opening of the blood-brain barrier and leakage of fluid into the extravascular space. With increased tissue water, local brain swelling occurs. Red cell extravasation may also occur although hemorrhage is usually absent or mild. Clot within proximal vessels may persist or dissolve and wash “downstream” into distal vessels. Leptomeningeal collateral vessels can dilate to provide some perfusion to the affected brain. The extent and rate at which vasogenic edema develops depends on the blood flow to the affected brain. If there is no reperfusion, edema is mild and takes longer to develop. If flow is rapidly reestablished (spontaneously or because of treatment) and the vascular bed is damaged, edema will develop rapidly and hemorrhage may occur. This is known as reperfusion hemorrhage.

CT: Vasogenic edema produces hypodensity in the affected brain. In thromboembolic infarcts the gray matter becomes hypodense and swollen resulting in sulcal effacement. The hypodensity is initially confined to the gray matter but then progresses with loss of gray-white distinction. It is homogeneous and has well-defined smooth to convex borders. Lacunar infarcts are visible as discrete round to oval foci of hypodensity without mass effect. When these areas of hypodensity are subcentimeter in size it can be difficult to distinguish between acute, subacute, and chronic lacunar infarcts. Hemorrhage is typically not detected in the acute stage. Clot within a proximal vessel will still be visible. There is no parenchymal enhancement at this stage of infarct evolution.

MR: T1 isointensity and T2 hyperintensity (best appreciated on FLAIR) are present in the infarcted brain. In thromboembolic infarcts the T2 hyperintensity is confined to the gray matter ( Fig. 3-27 ). Focal swelling and sulcal effacement are present. The infarct is DWI hyperintense and there is ADC hypointensity (indicating reduced ADC) indicative of restricted diffusion. While the extent and degree of T2 hyperintensity increases during the acute phase of infarction, the extent of DWI abnormality remains relatively stable unless there is actual progression of the infarct. DWI lesion volume measured within 48 hours has been suggested to be a reasonable predictor of outcome in stroke. Lacunar infarcts present as foci of T1 isointensity and T2 hyperintensity. As is true with CT, it is difficult to distinguish acute from chronic infarcts on T2WI without DWI, in particular when there is a background of white matter T2 hyperintense foci from small vessel chronic ischemic injuries. DWI makes detection of acute lacunar infarcts simple because the acute lesions are hyperintense while chronic white matter lacunar infarction is DWI isointense. Hypointensity on susceptibility-weighted sequences (GrE and SWI) may be present, indicative of hemorrhage ( Fig. 3-28 ). Several studies have shown that susceptibility-weighted sequences are more sensitive than CT in detecting subtle hemorrhagic transformation of infarction. In addition, these sequences allow for detection of chronic petechial hemorrhages (microhemorrhages) typically the result of hypertension and/or cerebral amyloid angiopathy (CAA). The presence of microhemorrhages implies vascular fragility and carries an increased risk of hemorrhagic transformation of infarction and an increased risk of future infarction. Evidence of proximal intraluminal clot and/or slow flow (see above) can be seen at this stage of infarction although with slightly lower frequency than in hyperacute phase, because of clot resolution. If contrast is given, slow flow within vessels distal to a clot may be present, and sulcal enhancement may be seen as a result of leptomeningeal collaterals.

Early Subacute Infarction (36 hours to 5 days): Reperfusion

Blood flow to the affected portion of the brain is typically reestablished 24 to 72 hours after infarction. Proximal and distal clots are lysed or break up and move downstream. Leptomeningeal collaterals become prominent during this phase. By day 3 or 4, ingrowth of new vessels into the area of infarction commences. These immature vessels have “leaky” blood-brain barriers. As a result of these changes, vasogenic edema increases with progressive mass effect that typically peaks at around 5 days. In large infarcts, mass effect can lead to transfalcine and/or transtentorial herniation. Hemorrhagic transformation most commonly occurs during this phase of infarction. While vasogenic edema increases, cytotoxic edema may actually decrease as neuronal death leads to cell lysis. Of course if there is ongoing ischemia, new areas of infarction with cytotoxic may develop.

CT: The infarcted area is hypodense. In thromboembolic infarcts hypodensity involves both the gray matter and adjacent white matter. Density is more heterogeneous than in the acute phase with streaky mild “gyral” hyperdensity representing either reperfused cortex or hemorrhagic transformation. Frank hyperdense gyriform hemorrhage may occur. The margins of the infarct are indistinct. Mass effect increases. The degree of edema and mass effect is determined by the size of infarction and the extent of arterial recanalization. In severe cases (“malignant infarct”) there may be transfalcine and/or transtentorial herniation ( Fig. 3-29 ) for which craniectomy may be required for decompression. Contrast enhanced scans may demonstrate parenchymal enhancement in the infarcted territory. In cortical infarction the enhancement is typically gyriform. In deep gray matter (ganglionic and thalamic), enhancement is often peripheral and may mimic that seen in necrotic masses.

MR: The infarcted brain is mildly T1 hypointense and markedly T2 hyperintense. The T2 hyperintensity involves both gray and white matter and the margins are ill-defined. Differentiation between bland reperfused gray matter and hemorrhagic transformation is straightforward on MR. Hemorrhagic transformation produces mild to moderate T2 hypointensity and marked hypointensity on susceptibility-weighted sequences. Intensity on DWI and ADC maps is variable at this stage reflecting the balance of the extent of cytotoxic edema (decreased ADC) and vasogenic edema (increased ADC; Fig. 3-30 ). In most cases DWI hyperintensity persists, but ADC hypointensity becomes less apparent or resolves if cytotoxic edema decreases and/or there is extensive vasogenic edema. In some cases DWI hyperintensity may decrease or completely resolve during this phase. If contrast is administered, parenchymal gyriform enhancement may be encountered that is similar to that seen on CT. Leptomeningeal enhancement becomes less apparent or resolves.

Late Subacute (5 to 14 days): Resolving Edema and Early Healing

Over time edema is resorbed with resultant decreased mass effect. Macrophages and glial cells enter the area of infarction and begin to remove dead neuronal tissue. Cytotoxic edema resolves. Blood flow is reestablished. Mild reperfusion hemorrhage can occur but symptomatic hemorrhagic transformation is rare.

CT: Density becomes more heterogeneous. The infarct typically remains hypodense. However, as edema resolves and cortical density is at least partially reestablished, there may be transient period when the infarct is isodense to normal brain (“fog effect”; Fig. 3-31 ). Mass effect resolves and there may be early evidence of focal atrophy. If significant hemorrhagic transformation has occurred the hemorrhage will undergo typical evolutionary changes. Lacunar infarcts appear as nonspecific foci of hypodensity in the deep gray matter or periventricular white matter. If contrast is administered, parenchymal enhancement often occurs and is increased in extent compared with that seen in the early subacute phase. The presence of enhancement in isodense regions of subacute infarction improves detection but may create a diagnostic dilemma because it may be mistaken for neoplastic or inflammatory disease. As always, clinical information is critical in differentiating between disease processes, in particular if the initial imaging occurs during the late subacute phase of infarction.

MR: T1 hypointensity and T2 hyperintensity persists. There is no MR equivalent with the “fog effect” seen on CT. In thromboembolic infarcts these intensity changes are most marked in the subcortical white matter beneath the infarcted cortex. The overlying infarcted gray matter may be nearly isointense to normal cortex on T1- and T2-weighted sequences. DWI reveals isointensity to mild hyperintensity. ADC maps demonstrate hyperintensity indicative of increased diffusion. Therefore residual DWI hyperintensity is the result of “T2 shine through.” Susceptibility-weighted sequences may reveal hypointensity because of subacute to chronic hemorrhage (hemosiderin staining). Since pathologic studies reveal small amounts of hemorrhage in most infarcts, improvements in detection of susceptibility effects (e.g., high-field MR, SWI) will inevitably lead to increased detection of small amounts of hemorrhage that are not clinically significant. Lacunar infarcts are T1 hypointense and T2 hyperintense. DWI hyperintensity has typically resolved although mild residual hyperintensity because of T2 shine through may be present (see Fig. 3-31 ). ADC maps reveal increased intensity because of vasogenic, not cytotoxic, edema. Enhancement frequency and pattern are similar to that seen on CT with the same caveats about differentiation between subacute infarction and other disease processes. When the infarct involves the corticospinal tract (e.g., posterior limb of internal capsule), wallerian degeneration occurs resulting in mild T2 hyperintensity and mass effect in the ipsilateral cerebral peduncle and pons that should not be mistaken for an additional area of infarction.

Chronic Infarction (More Than 2 Weeks): Healing

Edema has completely resolved. Dead neuronal tissue is removed and replaced by gliosis and cystic degeneration (cystic encephalomalacia). Infarcted cortex demonstrates pseudo-laminar necrosis (pseudo-laminar because it is not confined to a specific cortical layer). Lacunar infarcts are typically small fluid filled cavities surrounded by zones of gliosis (a “true” pathologic lacune). There is focal volume loss. Depending on the size and location of the infarct, this results in focal cortical atrophy and/or focal dilatation of the adjacent ventricle. If the infarct involves the corticospinal tract there will be wallerian degeneration producing atrophy of the ipsilateral cerebral peduncle and ventral pons.

CT: Hypodensity is present in the infarcted brain. With thromboembolic infarction, this is most marked in the subcortical white matter with portions of the overlying gray matter appearing normal to mildly hyperdense. Note that while the overlying cortex may be normal in density, it is not functional. Cortical CT hypodensity that is present in the hyperacute and acute phase of infarction evolves into subcortical hypodensity with relative cortical hyperdensity. Lacunar infarcts appear as discrete foci of hypodensity that are difficult to differentiate from acute lacunar infarcts and chronic ischemic white matter disease. Focal atrophy leads to sulcal enlargement and/or local ventricular dilatation ( Fig. 3-32 ). Mild enhancement may persist for up to 2 months but more often has resolved by the end of 3 weeks. Wallerian degeneration is manifested by focal atrophy of the ipsilateral cerebral peduncle and ventral pons. Laminar necrosis can lead to mild hyperdensity to the cortical margin of the infarcted tissue.

MR: The infarcted brain is T1 hypointense and T2 hyperintense. The affected cortex is often T1 hyperintense secondary to laminar necrosis (not hemorrhage or calcification; see Fig 3-31 ). Cystic encephalomalacia appears as a central region of cerebrospinal fluid intensity (T1 hypointense, T2 hyperintense and FLAIR hypointense) surrounded by T2 hyperintensity representing gliosis that is best appreciated on FLAIR. On DWI chronic infarction is isointense to mildly hypointense. On ADC maps the infarct is hyperintense because of increased diffusion in the hypocellular infarcted brain. Lacunar infarcts have the same intensity characteristics as cystic encephalomalacia albeit on a smaller scale. FLAIR is critical for differentiating chronic lacunar infarcts from chronic ischemic change (absence of central hypointensity with chronic ischemic change) and dilated perivascular spaces (absence of peripheral FLAIR hyperintensity). As on CT, mild enhancement can persist for up to 2 months. Wallerian degeneration produces focal atrophy and minimal T2 hyperintensity in the cerebral peduncle and pons ( Fig. 3-33 ). Laminar necrosis is usually seen as hyperintensity on T1WI ± hypointensity on T2WI. Be careful, without looking at precontrast T1WI the postgadolinium images may look like gyriform enhancement.

Extracranial and Extradural Arteries