New radiographic techniques to evaluate cerebrovascular disorders in children

New Radiographic Techniques to Evaluate Cerebrovascular Disorders in Children

Jill V. Hunter

The radiographic evaluation of the pediatric patient with cerebrovascular disease has dramatically improved during the past decade. Few new technologies have been introduced, but significant new developments in data acquisition and post-processing have resulted from refinements in both software and, to a lesser extent, hardware. This review focuses on the advantages and limitations of the different imaging modalities and their recommended role in managing the pediatric patient who presents with signs or symptoms of cerebrovascular disease. Copyright �9 2000 by W.B. Saunders Company

C ONVENTIONAL ultrasonography is an established imaging modality performed via the

anterior fontanelle using a variable 8-5 MHz transducer. This modality can be used as a noninvasive portable bedside examination in the neonatal period to diagnose germinal matrix and intraventric- ular hemorrhage and periventricular leukomalacia (PVL). A 12-8 MHz linear array probe is used to assess for extraaxial fluid collections, including subdural hemorrhage and hygromas. Examination of the posterior fossa for cerebellar hemorrhage can be done by insonating the posterolateral fontanelle in neonates.la

DOPPLER ULTRASONOGRAPHY

The transcranial Doppler (TCD) examination measures blood flow velocities within the major intracranial arteries at the circle of Willis. The mean velocity calculated by the TCD equipment is based on the time average of the outline velocity (maximum velocity envelope). Additionally, the pulsatility index (PI) is calculated (peak systolic velocity minus end diastolic velocity divided by the mean velocity) and reflects obstruction/resis- tance at points proximal and distal to the point of insonation.

Intracranial arterial velocities are determined by the volume of flow over time and the luminal area of the artery. Factors that influence cerebral blood flow velocities recorded during a TCD examination include the following: the age of the patient, hematocrit, partial pressure of arterial CO 2 (Paco2), Pao 2, fever, hypoglycemia, blood pressure, cardiac output, raised intracranial pressure (ICP), and the presence of proximal arterial obstruction, distal arterial stenosis, or arteriovenous malformation.

The examination can be performed using equipment that produces a Doppler spectral waveform (nonimaging) or with a duplex ultrasound imaging system that produces a color Doppler display of the

blood flow. Both types of TCD examination are performed using a low frequency (2 MHz) pulsed Doppler transducer. The advantage of using a duplex imaging system is that it provides the operator with anatomic landmarks that assist in the identification of the arteries, and the color Doppler display is encoded for direction of blood flow and velocity. Another innovation is power Doppler imaging, which assigns color according to the strength of the Doppler-shifted echoes. Power Doppler imaging is less angle dependent and more sensitive to slow flow; however, information regarding the direction of blood flow is no longer available. J

There are four ultrasound pathways ("windows") allowing access to the intracranial arteries. A complete TCD examination incorporates the following approaches: (1) transtemporal, (2) transorbital, (3) suboccipital, (4) submandibular. The intracracranial arteries evaluated by each approach are listed in Table 1.

The identification of the intracranial arteries is based on the following criteria: (1) depth of the sample volume, (2) angle of the transducer, (3) direction of the blood flow relative to the transducer, (4) spatial relationship of one Doppler signal to another, and (5) anatomic landmarks (for imaging technique).

Clinical applications of TCD in the pediatric population include the following: (1) Screening for

From the Department of Radiology, ChiMren's Hospital of Philadelphia, Philadelphia, PA.

Address reprint requests to Jill V. Hunter, MBBS, Depart- ment of Radiology, Children's Hospital of Philadelphia, 34th Street & Civic Center Blvd, Philadelphia, PA 19104.

This work was supported in part by the Ethel Foerderer Fund for Excellence.

Copyright �9 2000 by W.B. Saunders Company 1071-9091/00/0704-0002510.00/0 doi." l O. 1053/sperm2000.20226

Seminars in Pediatric Neurology, Vol 7, No 4 (December), 2000: pp 261-277 261

262 JILL V. HUNTER

Table 1. TCD Windows

Approach Artery

Transtemporal Middle cerebral Anterior cerebral Posterior cerebral Terminal internal carotid Anterior communicating Posterior communicating

Transorbital Ophthalmic Internal carotid (siphon)

Suboccipital Vertebral Basilar

Submandibular Internal carotid

vascnlopathy in sickle cell disease2; (2) monitoring vasospasm3; (3) monitoring embolic events at cardiac bypass surgery; (4) monitoring acute stroke, including diagnosis of intracranial dissection and intracranial arterial stenoses4; (5) detecting vascular compromise in hydrocephalusS'6; (6) document- ing a patent foramen ovale7; and (7) confirmation of brain death. Duplex Doppler can be used to look at more proximal arterial dissection in the cervical internal carotid artery.

Recently transcranial Doppler imaging has been used to evaluate the intracranial veins and venous sinuses in normal adults as well as in the diagnosis and follow-up of patients with cerebral venous thrombosis. 8 The intracranial venous system identification is based on parenchymal landmarks and the fact that venous blood flow has peak systolic velocities less than 20 cm/sec. There has been some work performed in newborns and infants with sinovenous thrombosis and other conditions. 9-12 The presence of an open anterior and posterior fontanelle provides an enhanced opportunity for detection of obstruction to flow.

Screening in Sickle Cell Disease

Stroke is a major complication of sickle cell disease (SCD). A clinical stroke occurs in approximately 11% of patients with SCD:SS by the age of 20 years, and recently clinically "silent" strokes have been reported in up to 18% of these homozygous patients. 13 Cerebral infarction resulling from a stenosis or occlusion of the large intracranial vessels most commonly involves the distal portion of the internal carotid artery (ICA), proximal middle cerebral (MCA), and proximal anterior cerebral (ACA) arteries.

In the recently published multicenter STOP (Stroke Prevention Trial in Sickle Cell Anemia)

study, children with SCD:SS were examined with TCD and classified as normal (<170 cm/sec), conditional (170 to 199 cm/sec), or abnormal (>-200 cm/sec), based on the time averaged mean velocity of blood flow in the terminal ICA/proximal MCAJ 4 One hundred and thirty children classified as abnormal by TCD were randomized to chronic blood transfusions (n = 63) or standard care (n = 67). The STOP trial results indicated that chronic blood transfusion was associated with a "92% difference in the risk of stroke." Transcranial Doppler is currently the "standard of care" and is now being used to annually screen children with SCD:SS to identify those with intracranial velocities -->200 cm/sec with a view to offering some intervention, for example, blood transfusion, hy- droxyurea therapy, or bone marrow transplantation (Fig 1).

In our practice we have encountered a small subset of patients in whom a satisfactory temporal window could not be located. A new 1 MHz transducer has been shown in adults to be more successful at finding a small temporal window and achieving better penetration, which allows evaluation of contralateral vessels in individuals with unilateral temporal windows) 5

COMPUTED TOMOGRAPHY

Computed tomographic (CT) scanning, which was the previous mainstay of brain imaging, remains the modality of choice in acute trauma and is the preferred mode to look for fresh blood and subarachnoid hemorrhage (Fig 2). Over the past decade, there has been the development of slip-ring technology enabling the introduction of continuous spiral or helical CT. This has allowed for faster image acquisition and the development of CT angiography (CTA), in which the contrast-laden blood outlining a vessel, following peripheral intravenous injection, can be imaged with less motion artefact and reconstructed to give a 3D rendering. More recently, advances in the number of banks and type of solid-state detectors lining the patient gantry have ted to even faster spiral imaging with simultaneous data acquisition from multiple (up to 4), thinner (down to 0.5 mm) slices. This allows for greater temporal and spatial resolution without additional radiation dose and with excellent 3D reconstruction. Together with im- provements in software, 3D volume renderings now allow the operator to "fly" down the lumen of

IMAGING CEREBROVASCULAR DISORDERS IN CHILDREN 263

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C

Fig 1. Transcranlal screening Doppler In a 7-year-old boy with sickle cell disease. Bilateral middle cerebral arteries are Insonatad through a transtemporal window at s depth of 48 mm and blood f low is toward the transducer. (A) The mean blood f low velocity of the right middle cerebral artery Is within normal limits for a child with sickle cell disease (116 cm/sec). (B) The mean blood f low velocity of the left middle cerebral artery Is abnormal (245 cm/sec). (C) Reconstructed MIP 3D TOF MRA same patient demonstrat ing signal dropout from the proximal M1 segment of the left middle cerebral artery (MCA) (arrow). This child proceeded to completed Infarction In the left MCA territory within 24 hours of the study and before Interventlonal therapy could be Implemented.

a vesse l - -on a workstation monitor using a joy- stick and interrogate, for example, the relationship of the neck of an aneurysm to the bifurcation of the parent vessel (see also 3D digital subtraction angiography). The whole procedure of volume rendering "nulls" the artefact from metal enabling CTA to be usefully performed even in the follow-up of treated aneurysms or arteriovenous malformations, when clips, coils, or glue may have been used by the neurosurgeon or neurointerventionalist, respectively.

3D CTA has been proposed as the method of choice for diagnosis and follow-up of dissection as differ- ences in the attenuation of blood and contrast can be used to distinguish the true and false lumens, 16 while allowing assessment of the overall external diameter of the vessel.

Stable Xenon CT

Stable xenon CT studies quantitatively determine local blood flow. A CT scan slice location is

264 JILL V. HUNTER

Fig 2. Eighteen-month-old child presenting with acute right hemiparesis. (A) Unenhanced axial CT image demonstrates the "white sign" (open arrow) in the expected position of the left MCA, consistent with acute thrombosis. (B) Axial unenhanced CT from the same patient (same day but higher plane) demonstrating low attenuation (arrows) due to a left MCA infarction.

chosen and a series of between 6 and 10 scans is acquired at intervals of 1 minute, at the same level, while the subject breathes a xenon/oxygen mixture via an inhalation system. The xenon content within the tissue causes a time-dependent increase in the CT numbers measured. This is due to the high atomic number of xenon, which makes it an x-ray contrast medium. To obtain quantitative information on blood flow, the xenon content of arterial blood is also required. This can be determined by analyzing the end-tidal air and by knowing the patient's hematocrit. A two-parameter fit method based on the Ketj~-Schmidt' equation 17 links the two measurements (CT enhancement and arterial xenon content) and then calculates a blood flow image for the region of interest.

An accurate knowledge of local blood flow (ex- pressed in mL/min/100 g of brain tissue) permits conclusions to be drawn regarding tissue properties and pathologic alterations. Work in children has been performed in ischemic neurovascular disease is and in head injury. 19'2~

Relative cerebral blood flow (rCBF) and relative cerebral blood volume (rCBV) or perfused blood volume (PBV) have also been calculated usingfirst

pass bolus techniques with conventional water soluble iodinated contrast. 21 The passage of contrast laden blood is tracked by serial 1- to 2-second scans and time-density curves are plotted. Remem- bering that there is an initial linear relationship between contrast density and Hounsfield units, the area under the curve can be "fitted" and measured to give an estimate of the blood being delivered to a particular area of the brain. Temporal information is also available regarding the time of first arrival of contrast, time to peak, and arteriovenous transit times.

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY

Radionuclide imaging offers the potential for semiquantitation of cerebral perfusion, of use, for example, in pediatric stroke. To date, the ideal brain single photon emission computed tomography (SPECT) pharmaceutical has not been developed and the modality competes with dynamic CT and magnetic resonance imaging (MRI). The currently used technetium (Tc 99m)- and iodo-amines include hexemethylpropyleneamine oxime (HM- PAO) bicisate (1,1-ECD) and isopropyl iodoam-


phetamine (IMp)2Z; the latter is not readily available in all countries. The uptake, extraction fraction, and retention of these agents vary among different regions of normal and abnormal brain, 23 and the fixation can be altered by local or regional parameters. The kinetic behavior and trapping mechanism specific to each tracer must be well understood for the correct clinical application and interpretation of the SPECT images to be made. HMPAO, being labeled with Tc99m, is probably the most readily available agent and as such has been used in determining loss of cerebral blood flow (CBF) as one of the criteria to confirm brain death. Other current applications of SPECT imaging include its use in the workup of epilepsy where an ictal versus an interictal study may demonstrate an increase or decrease in rCBF, respectively, at the site of an epileptogenic focus.

POSITRON EMISSION TOMOGRAPHY

The cerebral metabolic rate of oxygen (CMRO2), using inhaled O15, has been shown in adults to have a very close relationship to CBF under conditions of constant cerebral vascular re- sistance. However, it remains a very invasive technique requiring paired arterial and venous blood sampling. The results of C15 0 2 positron emission tomography (PET), based on the coincidence detection of electrons to localize the positional source of an introduced radioactive isotope, have been compared with HMPAO SPECT to measure rCBF, with good concordance. 24 Ol5-water has been used as an agent in established stroke to map reorganization of motor cortex during a stimulation paradigm by Muller et al. 25 This same group has performed a parallel study in children to look at language reorganization following an early left hemisphere lesion} 6 Other agents, such as 2-deoxy-2 [18F] fluoro-D-glucose (FDG) have been used to measure local cerebral metabolic rates for glucose (ICMRGIc) in six children with Sturge- Weber syndrome (SWS)} 7 The authors showed that in advanced SWS a markedly depressed 1CMRGlc extended beyond the abnormality de- picted on a matched CT examination. In two infants with SWS and recent seizure onset, interictal PET revealed a paradoxical pattern of increased 1CMRGIc in the cerebral cortex of the anatomi- cally affected hemisphere. In one of these infants, 1CMRGIc was also increased in the contralateral cerebellum, suggesting activation of the cortico-

ponto-cerebellar circuitry. This latter observation has been more extensively studied in a series of 40 children sustaining unilateral cerebral injury. 28

MAGNETIC RESONANCE IMAGING

State-of-the-art equipment in the year 2000 con- stitutes a 1.5 Tesla high-field magnet with echoplanar capability and rapid gradients. Three and 4 Tesla systems are commercially available but are not yet in routine clinical use and may not have full Food and Drug Administration (FDA) approval for use in children (because of signal absorption rate, SAR, considerations, etc.). A variety of coils including transmit/receive and whole body as well as dedicated surface coils exist, and new coil developments are being made especially in the area of spectroscopy. Rapid gradients and echoplanar imaging (EPI) allow for faster sequences, for example, turbo spin echo (TSE), with more rapid acquisition without motion artefact. With the advent of 3D volumetric acquisition, conventional TI- weighted and T2-weighted sequences can now be resolved down to submillimeter in-plane resolution.

Fetal MRI has been enabled by the introduction of faster image acquisition and may add value to the prenatal diagnostic ultrasonography. Vein of Galen aneurysms and in utero infarcts have both been diagnosed antenatally using MRI (personal communication, JV Hunter).

Gradient Echo

Gradient echo ("susceptibility" imaging) is very helpful for detecting blood and altered blood prod- ucts following a germinal matrix or parenchymal hemorrhage. It can be especially useful in prema- ture infants, post extracorporeal membrane oxygenation (ECMO), following cardiac bypass surgery or cardiac catheterization, when there is suspicion for child abuse, as well as for the detection of cavernomas.

Acute subarachnoid hemorrhage is not best shown by MRI, 29 although fluid attenuated inversion recovery (FLAIR) imaging may be capable of detecting fresh subarachnoid blood. 3~ FLAIR imaging is very good at demonstrating periventricular leukomalacia (PVL).

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA), unlike its CT equivalent, can be performed without the

266 JILL V. HUNTER

administration of intravenous contrast. The two main sequence types used are 2D or 3D time-of- flight (TOF) and phase contrast (PC) imaging. Both can be adjusted to look preferentially at either the venous system--magnetic resonance venogra- phy (MRV), (Fig 3) or the arterial system (MRA) (Fig 4). In the case of 2D PC imaging, phase and magnitude data can be displayed to give information about the direction and amount of flow. The multiple overlapping thin section acquisition (MOTSA) technique is a hybrid of PC and TOF. As with ultrasonography, MRA is a physiologic and not a strictly anatomic examination like conventional angiography, in this instance looking at the parameter of blood flow. Because of the added turbulence caused by anemia and subsequent stenosis of large vessels in SCD, we opt to perform MRA examinations in this population of children at a shorter echo time than conventionally used.

Recently, a 3D turbo spin-echo contrast-enhanced MRA sequence has been introduced. This works like a "first pass" technique in acquiring the angiographic raw data in the space of 20 seconds or less, following an intravenous bolus of Gado- linium, so that a series of MRAs can be performed back to back to capture the arterial through to the venous phase. The quality of these angiograms, which may require a double dose of contrast, is quite high, as illustrated (Fig 5).

MR Perfusion Imaging

MR perfusion imaging is currently performed in one of two ways and has the potential to provide semiquantitative information regarding the delivery of blood to the brain. Arterial spin labeling techniques 33 rely on the inherent contrast of blood, whereas "first pass" bolus techniques require the administration of a contrast agent, such as gadolinium, and use dynamic contrast-enhanced T2*-weighted echoplanar imaging. Using the latter technique areas of normal perfusion will darken with the passage of the bolus of contrast due to the T2* effects, while areas of decreased perfusion will appear relatively bright by comparison with the surrounding normal brain (Fig 6).

Diffusion-Weighted Imaging

Diffusion-weighted imaging (DWI) is an MRI technique that is extremely sensitive to acute isch-

emia and infarction. Diffusion imaging measures Brownian motion of water in tissues. The movement of individual water molecules in solution is random; however, in the intracellular and extracel- lular spaces of the brain, macromolecular proteins, intracellular organelles, cell walls, and myelin sheaths restrict or slow diffusion in certain directions. Images can be made for individual directions (usually corresponding to the three orthogonal axial, sagittal, and coronal planes of imaging the patient), or the individual directional images can be averaged to make a relatively direction-indepen- dent or isotropic diffusion image called a trace image. Although diffusion-weighted images reflect the movement of water molecules in tissue, there is a small contribution from motion of blood within capillaries. Thus, the exact diffusion coefficient of water cannot be measured in vivo, but the images can be analyzed to calculate an apparent diffusion coefficient (ADC), which reflects the rate of diffusion but includes a small component from capillary blood flow. Although diffusion images are weighted towards diffusion effects, a portion of the tissue contrast comes from the T2 relaxation of the underlying tissues. Hence regions that are bright on T2-weighted imaging can appear bright on D W I - - the so-called "T2 shine through. ''34 Misinterpreta- tion can be avoided by comparing individual DW images with the T2-weighted images or by measuring the ADC values in the region of interest (Fig 7). Other parameters can be measured using DWI including diffusion tensor imaging, which may prove helpful in demonstrating normal and dis- rupted white matter tracts, and fractional anisot- ropy (FA), which holds some promise in HIE. 35 DWI may also be used on scanners without echoplanar capability using a technique called line scan diffusion imaging (LSDI), which has some theo- retical advantages in children in that there is less inherent ditortion and it is relatively insensitive to motion. 36,37

Activation Functional MRI

Activation functional MRI (fMRI) uses the BOLD (blood oxygen level dependent) sequence to detect alterations in blood flow to an area of the brain following use of a stimulation paradigm. BOLD contrast imaging is based on the observation that the brain shows localized blood volume increases on neuronal activation. It has also been shown that these increases far exceed the oxygen


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Fig 3. Female teenager with inflammatory bowel disease presenting with headache. (A) Axial gradient echo MRI performed near the vertex demonstrates low signal In the region of the left sensorimotor cortex consistent with recent hemorrhage. (B) Saglttal MIP reconstruction from 3D TOF MRV does not demonstrate the superior saglttal sinus (arrows). (C) Axial collapsed MIP projection on the same patient confirms decreased signal f low returned from the straight and proximal transverse (arrows) sinuses as well as the torcula (confluence of sinuses). These appearances suggest extensive venous sinus thrombosis.

consumption of the tissue. Therefore, the venous oxygen content rises and yields an increase in the MRI signal observed. This is because deoxyhemoglobin is paramagnetic, which directly affects the

local susceptibility of the tissue. It generates an inhomogeneous magnetic field in tissue surrounding blood vessels, causing intravoxel dephasing and decreased signal intensity on MR images.

268 JILL V. HUNTER

Fig 4. An 11-year-old boy who hit the back of his head 24 hours earlier while jumping off a trampoline and now complains of unsteadiness and inability to walk. (A and B) Axial unenhanced CT cuts through the posterior fossa, and the plane of the basal ganglia demonstrates low attenuation lesions in the right cerebellum, left parieto-occipital region and both thalami, consistent with embolic ischemic infarctions. (C) Axial Tl-weighted MRI at the skull base shows bright signal (arrow), paralleling the left vertebral artery at the Cl level, consistent with fresh blood and a diagnosis of dissection. (D) Coronal reconstruction of 3D TOF MRA performed without contrast does not demonstrate the left vertebral artery.


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E Fig 4. (continued) (E) Repeat MRA• using same technique, performed 6 weeks later shows restoration of f low in the left vertebral

artery following anticoagulant therapy. The child developed "locked-in" syndrome and went on to make a slow but good recovery.

Fig 5. Late phase of a 3D turbo MRA of a normal neck with double dose gadolinium (Gd), demonstrating a combination of both the arterial and venous phases of the circulation.

TIw~c I,~w~LI \ari~flion~ in ~u~CCl>lihiiily in the r~.'~h.m o[ lhu' hJ~.>~.~d \',.'xscI~ cotllrihLtt~." to lhc

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sequence rcllccts changes in venous rather than capillary blood llow. MR1 in children has bccn used clinically to determine hemispheric dominance for language before temporal lobe epilepsy surgery -~s and to determine the location of sensorimotor and visual cortex before lesional surgery9 There is ongoing research using rnemory paradigms to combine the results of language and memory tasks in an attempt to replace the more invasive Wada test. Multiple other lines of research are being pursued to look at different cohorts of children, such as those with ADHD, schizophrenia, and post-traumatic brain injury.

270 JILL V. HUNTER

T1 Mapping MRI sequences using a short TR, short TE

produce a Tl-weighted anatomic image. To measure the actual T1, a different sequence needs to be run to map absolute T1 values. There is some evidence in the literature to suggest that a decrease in absolute T1 values in the gray matter can be correlated with cerebral ischemia in the absence of stroke as measured by decreasing psychometrics and a hematocrit < 27% in a homozygous sickle cell population. 4~

MAGNETIC RESONANCE SPECTROSCOPY

Proton magnetic resonance spectroscopy (MRS) is performed using the same equipment as conventional MRI but can extract information about the chemical environment of hydrogen nuclei in both a qualitative and quantitative fashion. Data analysis in MRS is carried out by changing time domain data to frequency domain spectra using Fourier transform. The resulting spectrum that we see is a frequency distribution of the nuclei in the sample, and MRS can be considered a histogram of nuclei with different precession frequencies. The area under a particular peak provides a quantitative measure of that particular metabolite.

Lactate is an indicator of anaerobic metabolism and may normally be present transiently at birth. In mild hypoxic ischemic encephalopathy (HIE) elevated lactate may be detectable as early as 4 to 8 hours after birth, likely the result of reduced oxygen delivery and subsequent anaerobic glycoly- sis. 41 In more severe HIE, this early rise in lactate does not resolve by 48 hours but rather persists and increases after 24 hours. The delayed elevation is ascribed to mitochondrial damage and may therefore be of greater significance in predicting long- term outcome. 42 Lactate levels found in mitochondrial encephalopathy lactic acidosis and stroke-like syndrome (MELAS) are generally much higher at the time of initial presentation than those seen secondary to other causes of ischemia, such as stroke and necrosis. Therefore, these conditions are easily distinguished (Fig 8).

The detection of lipid by proton spectroscopy is an almost universal accompaniment of brain injury in very young infants and is sometimes difficult to separate out from a lactate peak depending on the echo time that is used to acquire the spectra. Sometimes two different echo times are required to invert and confirm the presence of a lactate doublet

Fig 6. (A) Typical first-pass bolus curve, following a peripheral IV injection of Gd, extending out to 59 seconds on the x-axis. Note the drop in signal approximately 30 seconds into the acquisition consistent with the T2* effect of the Gd. (B) Axial MRI scan from the perfusion series at 30 seconds demonstrating relatively increased signal returned in a posterior (long arrows) and to a lesser extent anterior (shod arrows) watershed distribution. The apparent increase in signal reflects the decrease in Gd-laden blood delivered to the areas of relative ischemia.


separate from a combined lipid/lactate peak as they overlap in their position on the x axis.

N-acetyl aspartate is a marker of neuronal and axonal integrity and demonstrates a reduced peak following ischemic injury and stroke compared with age matched controls.

Glutamate serves as a neurotransmitter and is an important intermediate of amino acid catabolism; it is elevated in ischemia.

Much of the initial work using MRS in asphyxiated neonates used 31P MRS, and it was found that low concentrations of phosphocreatine and adenosine triphosphate during the first few days of life correlated with the presence of neonatal encephalopathy and poor neurodevelopmental outcome. 43 More recently, 44-47 proton MRS has been found to be particularly useful during the first few days of life when the conventional imaging abnormalities may be hard to detect. In turn, some of the diagnostic function of 1H-MRS may have been superceded by the introduction of DWI and FA; however, it may still retain a place in the prognostication of HIE. MRS has also been used as a functional MRI tool to detect changes in oxy-/ deoxy-hemoglobin during an activation paradigm. 48

NEAR-INFRARED SPECTROSCOPY

Several techniques are available for measuring cerebral activation, related to specific brain func- tions, and these have been widely applied in adults to understand the function of both the normal and diseased brain. These techniques are based either on electrical changes in activated cells (such as evoked potentials) or on local changes in cerebral perfusion. Hemodynamic changes can be measured using PET or f M R I . 49 Both require the child to lie still in a scanner while performing the activation task, which is often only possible with sedation. This raises ethical issues and can also alter the results of activation paradigms even when these are feasible in the unconscious subject. 5~ Near- infrared spectroscopy (NIRS) is a novel technique for measuring functional activation in infants, which is both noninvasive and localized.

It has recently been demonstrated that NIRS can be used in the awake infant to measure regional cerebral hemodynamic changes in response to visual stimulation. 51 The technique depends on the relative transparency of biological tissue to near- infrared light, and the absorption of light by oxy-

hemoglobin (HbO2) and deoxyhemoglobin (Hb). A modification of the Beer-Lambert law is used to convert measured changes in optical density to changes in chromophore concentration. Near-infrared light from four laser diodes is transmitted via a fiber-optic bundle to an "optode" fixed over the occipital region of the infant's head. A detecting optode placed 3.5 cm away is connected to a second fiberoptic bundle, which conveys the emerging light to to the spectrophotometer. A con- trolling computer converts the changes in optical density into changes in cerebral [HbO2] and [Hb]. The technique can therefore detect regional changes in HbO e and Hb, 52 resulting from visual stimulation. This method has been applied to the measurement of functional activation in adults by several groups. 53-57 It is ideally suited to the study of infants because the infant skull is thinner than that of adults so that the optical signal is cleaner and easier to detect. Increases have been seen in both [oxy-Hb] and [deoxy-Hb] over the occipital region in infants related to visual stimulation, 58 whereas the adult response seen both by fMRI and NIRS is for [deoxy-Hb] to decrease, while [oxy- Hb] increases. These data are consistent with the reversal of the BOLD (blood oxygen level dependent) signal seen in preliminary fMRI studies on sedated or sleeping infants. 59-61 This maturational shift in the balance between oxygen consumption and perfusion may be important in understanding vascular control mechanisms underlying cerebral function in the infant.

Studies have demonstrated an increase in the magnitude of the response with age. 6z It has proven feasible to study preterm infants down to a corrected age of 32 weeks, and to show a consistent response to stimulation with a checkerboard with pattern reversal from 36 weeks. In addition there is preliminary evidence of abnormal functional activation in infants with cerebral pathology, such as perinatal asphyxia and occipital lobe infarction. 63

DIGITAL SUBTRACTION ANGIOGRAPHY

Conventional catheter angiography is now most commonly performed using digital equipment rather than acquiring the study using individual sheets of plain "cut" film, as the resolution in most instances is strictly comparable. Biplane capability is desirable for the examination of small children because of the contrast restrictions in terms of

272 JILL V. HUNTER

Fig 7. An 8-year-old boy injured in a motor vehicle accident seen acutely. (A) Axial CT scan demonstrates acute subdural hemorrhage along the left greater than right tentorium. In addition hyperattenuation consistent with fresh blood is seen in the basal cisterns, around the left choroid plexus, and in the anterior end of the third ventricle. Intraparenchymal hematomas are noted in the left frontal lobe with subdural/subarachnoid blood outlining the anterior interhemispheric fissure, Note the dilated temporal horns consistent with hydrocephalus. (B and C) Axial diffusion-weighted and apparent diffusion coefficient image calculated from the same dataset using an imaging plane through the level of the temporal horns, T2 shine-through effects are seen on the individual DW image (B), but this is compensated for on the ADC map, (C) which shows decreased signal returned from the bifrontal lobes consistent with acute ischemia. (D) Collapsed MIP reconstruction from 3D TOF MRA dataset acquired without contrast demonstrates an anterior cerebral artery aneurysm (arrow).


thrombolytic therapy remains problematic at present as current wisdom suggests that the "window of opportunity" in children is even shorter

Fig 7. (continued) (E) Anteroposterior cerebral angiogram following selective injection of the right ICA, demonstrates a wide-necked traumatic aneurysm arising from the right anterior cerebral artery. This was treated by surgical clipping.

volume of iodinated contrast permitted based on body weight and surface area, related to renal function. There has been a new advance with the introduction of 3D DSA. As a result of rotation of the x-ray tube (camera) and image intensifier a stepped sequence of background "masks" and a matching series of stepped incremental angiograms are acquired. Following subtraction the data acquired can be used to produce 3D surface renderings of the vessels (Fig 9), as well as permitting interrogation of the interior of the vessel to exam- ine, for instance, the relationship of the bifurcation of a vessel to the neck of an aneurysm that may be arising from it. The only disadvantage for children is that this technique currently requires the administration of a triple dose of iodinated contrast and may therefore not be applicable to small infants and babies.

There have been technological advances in the size and range of superselective catheters, slippery wires, and devices such as stents and Guglielmi detachable (GDC), coils, introduced over the past 5 years for the treatment of aneurysms and other vascular malformations. Although pediatric interventional neuroradiol- ogy forms a relatively small part of any neurointerventionalist's practice, these advances have equal applicability to children as to adults.

The treatment of acute ischemic stroke with

Fig 8. A 17-yeer-old boy presenting with field cut and seizure activity. (A) A T2-welghted axial image performed at the level of the orbits demonstrates increased signal returned from the right temporo-occipltel lobe. There is evidence of swelling with some effacement of the right occipital horn. The appearances ere suggestive of infarction, although the pattern is not typical for a vascular distribution. (B) Single voxel short TE MRS (STEAM) acquisition. A grossly elevated lactate (Lac) peak is seen with an almost absent N-acetyl aspartate peak, the latter consistent with neuronal death. The degree of lactate elevation is greater than expected for simple infarction, and the patient was subsequently diagnosed with MELAS.

274 JILL V. HUNTER

than that in adults and may be of the order of 3 rather than 6 hours. It would be rare to see and diagnose a child with stroke within this time frame. Thrombolysis for (pan)venous sinus thrombosis in children is occasionally required in the symptom- atic patient, not responding to heparin.

CONTRAST AGENTS

New contrast agents have been developed both for ultrasound 64 and MRI applications, most of which are currently unavailable for pediatric use, in the United States at least, owing to FDA regu- lations. The general trend towards the use of nonionic contrast has enabled the more comfortable and possibly safer delivery of water-soluble iodinated contrast media to children 65 for CT and angiographic applications.

Applications

Venous sinus thrombosis is investigated by the following: the venous phase of CTA with contrast (C), MRV - C, imaging Doppler, venous phase DSA _+ thrombolysis.

Arterial stenosis is investigated by the following: TCD head, imaging Doppler neck, 3D CTA with C, MRA -+ Gd, conventional vs 3D DSA.

Arterial dissection is best investigated by the following: MRI/MRA or CT with CTA, using Doppler in follow-up. The indication for DSA in children is less clear unless there is some difficulty in making the diagnosis.

Stroke is best investigated by a combination of the following: TCD, CTICTA, (CT perfusion has been used in adults for rCBF, rCBV), stable Xe CT, MRI /MRA with D W I + perfusion. In the acute phase DSA _+ thrombolysis may be indicated if seen very early. Catheter angiography is also indicated when all other tests are negative.

Other Forms of Ischemic Brain Injury

Trauma + extraaxial collections: use CT - MRI with GE sequence to look for shear injury and DWI to detect ischemic damage.

PVL use conventional ultrasound in the neonatal period or MRI with FLAIR imaging.

Hypoxic ischemic encephalopathy (HIE) MRI is probably the most sensitive test _+ DWI.

Nonaccidental injury (NAI) is best investigated by a combination of CT and MR with GE and DWI with MRS for prognostication purposes.

Metabolic disease is best diagnosed by a combination of MRI with MRS.

Vascular Malformations

Cavernoma/occult cerebrovascular malformation (OCVM) may be seen on CT but is best diagnosed by MRI with GE to look for multiple cavernous hemangiomas. If the clinical diagnosis is in doubt, and there is concern about hemorrhage, angiography may be performed but will be negative unless there is an associated developmental venous anomaly (DVA). DVAs are associated with cavernous malformations in about 37% of cases and have a characteristic "caput medusa" appear- ance on contrast examinations.

Vein of Galen malformations have been detected in utero with UIS and MRI and postnatally can be diagnosed by a combination of U/S, CT, and MRI/ MRA. The latter two modalities are useful for prognostication and determination of whether or not interventional therapy is indicated, in which case conventional angiography will be required.

Arteriovenous malformation is often detected on CT with or without contrast or by MRI/MRA. However, conventional angiography is required to delineate feeding vessels and draining veins and to plan therapy.

Aneurysms often come to attention following SAH. Fresh subarachnoid blood is best diagnosed on CT but MRI /MRA will likely be required to confirm the diagnosis of aneurysm noninvasively followed by conventional angiography to demon-

Fig 9. Adult patient after aneurysm clipping undergoing 3D DSA (Siemens, Erlangen, Germany) to check aneurysm. A 3D surface rendering of angiographic data acquired following triple-dose intra-arterial nonionic water- soluble iodinated contrast demonstrates surgical aneurysm clip with three re- sidual "berry" aneurysms arising from the circle of Willis (arrows).


strate the neck and its relations. Transcranial Doppler is used to follow vasospasm, which can be a sequel to the hemorrhage.

Vasculitis and other vasculopathies can be a difficult group to diagnose but the sequelae may be detected on conventional CT and MRI. If noninvasive forms of angiography are unable to make the diagnosis then conventional cerebral angiography may be required before biopsy. High-resolution magnified views should be obtained and all four vessels studied, (even so the diagnosis may be missed!).

SCD

Some physicians now use a screening program with TCD to triage homozygous sickle cell children to identify those most at risk from stroke. DW1 has contributed enormously in the ear ly-- first 6 hours to 10 days--identification of children with a CNS crisis and evidence of cerebral ischemia. MRI detects established "silent" infarcts and MRA with an appropriate TE can demonstrate Moyamoya collateral circulation and indicate potential sites of vascular narrowing. Conventional angiography is rarely required now in this population.

Brain Death

Although several different imaging modalities have been used to measure different aspects of blood flow and perfusion, nuclear medicine Tc 99m H M P A O SPECT is probably the single best established imaging test used to make the diagnosis of brain death in clinical practice.

SUMMARY

In summary, over the past two decades, advances in both software and hardware and innovations in sequence design have led to an expansion in the number and type of imaging modalities available to evaluate cerebrovascular disorders in children. Some of the imaging modalities are complementary (MRI/ CT), whereas others stand alone and give unique information (TCD). However, it should be remem- bered that "all that glisters is not gold" (Shakespeare) and that we are still on a learning curve with some of this imaging information.

ACKNOWLEDGMENTS

The author thanks our dedicated vascular ultrasound technolo- gist Mira Katz, PhD, for her assistance in writing the section on TCD and for her excellence in patient scanning; and Judith Meek for her invaluable assistance in writing the ,section on NIRS.

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New radiographic techniques to evaluate cerebrovascular disorders in children

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