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(Radiology. 2001;218:825-833.)
© RSNA, 2001

Pediatric Imaging

Quantitative Apparent Diffusion Coefficient Measurements in Term Neonates for Early Detection of Hypoxic-Ischemic Brain Injury: Initial Experience1

Ronald L. Wolf, MD, PhD, Robert A. Zimmerman, MD, Robert Clancy, MD and John H. Haselgrove, PhD

1 From the Section of Neuroradiology, University of Pennsylvania Medical Center, Ground Floor, Founders Building, 3400 Spruce St, Philadelphia, PA 19104 (R.L.W.); and the Children’s Hospital of Philadelphia, Pa (R.A.Z., R.C., J.H.H.). Received December 28, 1999; revision requested February 8, 2000; revision received June 29; accepted August 1. Supported in part by National Institutes of Health training grant T32 CA 7478. Address correspondence to R.L.W. (e-mail: wolf@oasis.rad.upenn.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the utility of using quantitative apparent diffusion coefficient (ADC) values as an objective means of early detection of brain injury caused by hypoxic-ischemic encephalopathy (HIE) in term neonates.

MATERIALS AND METHODS: Conventional images, diffusion-weighted images, ADC maps, and clinical charts from 13 term neonates clinically suspected of having HIE were retrospectively reviewed. Four term neonates without HIE served as control subjects. ADC values were calculated in predefined regions in patients and compared with those in control subjects. A Student t test was performed for each region to compare patients and control subjects.

RESULTS: Abnormalities were more easily detected on diffusion-weighted images and ADC maps, compared with conventional images. ADC values in patients with HIE were significantly different from those of control subjects in the posterior limb of the internal capsule, corona radiata, posterior frontal white matter, and parietal white matter bilaterally.

CONCLUSION: Evaluation of ADC maps can improve conspicuity of hypoxic-ischemic injury in the acute and/or subacute setting (within 12 days of insult), and calculation of ADC values can provide an objective measure of hypoxic-ischemic injury.

Index terms: Brain, ischemia, 10.591 • Hypoxia • Magnetic resonance (MR), diffusion study, 10.121411, 10.121413, 10.121416, 10.121417, 10.12144 • Magnetic resonance (MR), in infants and children


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Hypoxic-ischemic encephalopathy (HIE) is an important cause of morbidity and mortality in the neonate. Early and accurate diagnosis is helpful not only for assessing prognosis but also for making treatment decisions (eg, use of neuroprotective agents or antiepileptic drugs) (1). Clinical signs of HIE include low Apgar scores, need for resuscitation, delayed spontaneous respirations, metabolic acidosis, and encephalopathy (seizures, depressed mental status, and hypotonia). Clinical evaluation alone is often inadequate to provide an accurate prognosis (2). Conventional magnetic resonance (MR) imaging techniques have been applied in both acute and chronic stages of perinatal HIE, but they are limited in the detection of the presence and extent of hypoxic-ischemic injury (HII) due to incomplete myelination and the high water content of the neonatal brain (3,4). Different patterns of injury have been described on early MR imaging studies, and several investigators have reported a correlation between patterns of injury on imaging studies and outcome (3–7). Early detection of HII has also been demonstrated with MR spectroscopy (8–13).

While the apparent diffusion coefficient (ADC) follows relaxation properties (T1, T2) in the developing brain, the ADC diverges from T1 and T2 in the hypoxic-ischemic brain and thus provides an additional source of contrast in the detection of HII in the high-water-content neonatal brain (14). Diffusion-weighted imaging has been shown (15–19) to be sensitive to restricted diffusion in regions of early HII changes in animal models and in human studies. In early studies (7,20), diffusion-weighted imaging has been applied in this setting with promising results. However, interpretation of diffusion-weighted images may be complicated by preexisting injuries where the T2 of abnormal tissue is elevated (T2 shine-through). Even in early HII, the signal intensity on diffusion-weighted images has a large contribution from increasing T2 within a few days, potentially causing problems in the assessment of the timing of injury (21).

Early detection of HII could be improved by viewing ADC maps and by calculating ADC values to verify restricted diffusion. We sought to test the hypothesis that evaluation of ADC maps can improve conspicuity of HII in the acute and/or subacute setting (within 12 days of insult) and that calculation of ADC values can provide an objective measure of HII.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Images and clinical charts from 13 term neonates with clinically diagnosed HIE were retrospectively reviewed. Inclusion criteria were as follows: term infant (37–42 weeks), MR imaging within 12 days of birth, and high clinical suspicion of HIE (low Apgar scores, need for resuscitation, metabolic acidosis, hypotension, hypoglycemia, acute encephalopathy [eg, hypotonia, coma, seizures], and abnormal electroencephalographic findings).

In addition, four term neonates examined for indications other than suspected HIE were evaluated as a control group. The indications for examinations in control subjects were presymptomatic cobalamin C deficiency detected with prenatal screening, aspiration pneumonia and acidosis, polycythemia with concern for dural sinus thrombosis, and neonatal jaundice with optic nerve atrophy and colobomas.

The interval between delivery and imaging was recorded for patients and control subjects. Study patients underwent imaging for the first time within 12 days of birth, and control subjects underwent imaging within 11 days of delivery. All studies were performed within the guidelines of the institutional review board; all studies were performed for defined clinical indications and were acceptable for patient care.

MR Imaging
All studies were performed with a 1.5-T machine (Vision; Siemens Medical Systems, Erlangen, Germany). Routine imaging consisted of sagittal T1-weighted spin-echo imaging (repetition time msec/echo time msec, 650/14; flip angle, 70°), transverse T2-weighted turbo spin-echo imaging (6,000/99), transverse fluid-attenuated inversion-recovery imaging (repetition time msec/echo time msec/inversion time msec, 9,000/119/2,200), transverse T1-weighted spin-echo imaging with or without magnetization transfer contrast (600–800/14–20), transverse gradient-echo imaging (susceptibility sequence; 636/40; flip angle, 10°), and diffusion-weighted imaging. Single-shot spin-echo echo-planar sequences were implemented for diffusion-weighted imaging (6,000/100) by varying the diffusion gradient strength along each of three orthogonal directions. Corresponding b values generated were 0, 160, 360, 640, and 1,000 sec/mm2. Images were corrected for eddy current distortions and mean ADC (mean of ADC along each of the three orthogonal axes) calculated as described by Haselgrove and Moore (22).

Analysis
Images were interpreted independently by two authors (R.L.W., R.A.Z.) with knowledge of clinically suspected HIE but without knowledge of the outcome or specific clinical data. Abnormal imaging findings sought with conventional imaging sequences included T2 prolongation and T1 shortening or prolongation in patterns suggestive of HII, with special attention to dorsal basal ganglia, ventrolateral thalamus, dorsal brainstem, deep and subcortical white matter, and cerebral cortex (4,23). Abnormal increased signal intensity on diffusion-weighted images and decreased intensity on ADC maps were noted. Disagreements were resolved by consensus. The few disagreements typically regarded the dominant pattern of injury for assignment to groups of injury patterns (see later).

Circular regions of interest (ROIs) were drawn manually by one author (R.L.W.) over the following loci for calculation of ADC: cerebellar white matter, cerebral peduncles, medial thalami, lateral lentiform nuclei, heads of the caudate nuclei, anterior limbs of the internal capsules, corona radiata, anterior and posterior frontal white matter, parietal white matter, frontal and parietal gray matter, and posterior limbs of the internal capsule ventrolateral thalami dorsal lentiform nuclei. The area of each ROI was 0.3 cm2. ROIs for the anterior and posterior limbs of the internal capsules were centered on these structures. With a standard 0.3-cm2 ROI, small portions of the head of the caudate nucleus and anterior lentiform nuclei were unavoidably incorporated in the anterior limb of the internal capsule measurements. No attempt was made to separate the posterior limb of the internal capsule, ventrolateral thalamus, and dorsal lentiform nucleus. All other ROIs were placed to be entirely within the structure of interest. Care was taken to avoid inclusion of CSF in any ROI. Measurements in the genu and splenium of the corpus callosum were also obtained when these structures could be confidently visualized (eight of 13 patients, four of four control subjects).

Clinical Evaluation
Charts were reviewed by a pediatric neurologist (R.C.) for demographic and clinical data regarding events surrounding labor, delivery, and short-term outcome. Data recorded included type of delivery, placenta pathologic findings, Apgar scores, arterial blood gases, need for resuscitation, hypoglycemia, hypotension, neurologic status, presence of seizures, electroencephalographic findings, estimated gestational age, age at imaging, and outcome, if available.

Statistical Tests
An unpaired two-tailed Student t test was performed for each ROI locus to compare ADC values in patients to those in control subjects. Due to the small numbers of patients and control subjects, a Wilcoxon rank sum test was also performed for each locus. ADC values on the left and right were pooled for each locus after we verified that there were no significant differences between the sides for each locus measured (paired Student t tests and Wilcoxon signed rank tests). P values less than .05 were considered to indicate a statistically significant difference. The Spearman correlation coefficient was calculated for patients to compare their age at imaging with the ADC measurements for each ROI.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Clinical data and information regarding perinatal events and clinical status of patients with HIE are shown in Tables 1 and 2. Control subjects and patients underwent imaging a mean of 9 days after birth (range, 7–11 days) and 5.2 days after birth (range, 1–12 days), respectively. All were term infants (mean estimated gestational age, 39.62 weeks; range, 37–42 weeks), and the degree of HIE was judged as moderate to severe. Seizures were present in 11 patients. The electroencephalographic background activity was judged to be mildly (n = 1), moderately (n = 3), or markedly (n = 8) abnormal. Two (15%) of 13 patients died, and eight (80%) of 10 known survivors were neurologically abnormal; most had evidence of cerebral palsy, hypotonia, seizures or infantile spasms, developmental delay or mental retardation, and tube-feeding requirements or gastroesophageal reflux. Thus, adverse outcomes occurred in at least 10 (77%) of 13 patients.


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  		TABLE 1. Clinical Data: History and Outcome
 

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  		TABLE 2. Clinical Data: Perinatal Physiology
 
Figure 1 contains selected images from a control neonate at 9 days of age and shows short T1 and T2 along myelinated pathways and long T2 in white matter consistent with immature myelination. Diffusion-weighted images along each orthogonal axis are shown, as is the ADC map. Figures 2–4 show the diffusion-weighted image with diffusion sensitization along the z axis only for the sake of brevity, although images along all three axes were obtained and reviewed. The ADC maps shown are the mean of the ADC values calculated for each of the three orthogonal axes.



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  		Figure 1a. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 1b. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 1c. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 1d. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 1e. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 1f. Control subject (9 days old). Transverse (a) T2-weighted turbo spin-echo (6,000/99) and (b) T1-weighted spin-echo (650/14) MR images show appropriate myelination in a term infant. (c-e) Anisotropic diffusion is demonstrated on transverse diffusion-weighted images (6,000/100, b = 1,000 sec/mm2) for the (c) z, (d) x, and (e) y axes, especially along large white matter tracts, such as the internal and external capsules (arrows in d) and genu of corpus callosum (arrow in e). (f) ADC map (mean of the ADC along three orthogonal axes) demonstrates high ADC in frontal, temporal, and occipital white matter, which is normal for a term infant.

 


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  		Figure 2a. Group 1 injury in patient 3 (1 day old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) is unremarkable except for possible subtle T2 prolongation in the ventrolateral thalamus (arrows). T1-weighted spin-echo MR images (not shown) were normal. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion centered in the posterior limb of the internal capsule and involving ventrolateral thalamus and dorsal lentiform nucleus (arrowheads).

 


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  		Figure 2b. Group 1 injury in patient 3 (1 day old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) is unremarkable except for possible subtle T2 prolongation in the ventrolateral thalamus (arrows). T1-weighted spin-echo MR images (not shown) were normal. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion centered in the posterior limb of the internal capsule and involving ventrolateral thalamus and dorsal lentiform nucleus (arrowheads).

 


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  		Figure 2c. Group 1 injury in patient 3 (1 day old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) is unremarkable except for possible subtle T2 prolongation in the ventrolateral thalamus (arrows). T1-weighted spin-echo MR images (not shown) were normal. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion centered in the posterior limb of the internal capsule and involving ventrolateral thalamus and dorsal lentiform nucleus (arrowheads).

 


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  		Figure 3a. Group 2 (watershed or border zone) injury in patient 8 (4 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) reveals blurring of the gray-white junction in the frontal, temporal, and occipital lobes. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter (including the corpus callosum [open arrows] and external capsules [solid arrows]. Cortex (black arrowheads) was also involved and is best depicted in the right frontal and parieto-occipital cortex at this level. There is relative sparing of the basal ganglia (white arrowheads). (d) Transverse T2-weighted turbo spin-echo MR image obtained 1 month later shows diffuse white matter loss.

 


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  		Figure 3b. Group 2 (watershed or border zone) injury in patient 8 (4 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) reveals blurring of the gray-white junction in the frontal, temporal, and occipital lobes. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter (including the corpus callosum [open arrows] and external capsules [solid arrows]. Cortex (black arrowheads) was also involved and is best depicted in the right frontal and parieto-occipital cortex at this level. There is relative sparing of the basal ganglia (white arrowheads). (d) Transverse T2-weighted turbo spin-echo MR image obtained 1 month later shows diffuse white matter loss.

 


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  		Figure 3c. Group 2 (watershed or border zone) injury in patient 8 (4 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) reveals blurring of the gray-white junction in the frontal, temporal, and occipital lobes. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter (including the corpus callosum [open arrows] and external capsules [solid arrows]. Cortex (black arrowheads) was also involved and is best depicted in the right frontal and parieto-occipital cortex at this level. There is relative sparing of the basal ganglia (white arrowheads). (d) Transverse T2-weighted turbo spin-echo MR image obtained 1 month later shows diffuse white matter loss.

 


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  		Figure 3d. Group 2 (watershed or border zone) injury in patient 8 (4 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) reveals blurring of the gray-white junction in the frontal, temporal, and occipital lobes. (b) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (c) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter (including the corpus callosum [open arrows] and external capsules [solid arrows]. Cortex (black arrowheads) was also involved and is best depicted in the right frontal and parieto-occipital cortex at this level. There is relative sparing of the basal ganglia (white arrowheads). (d) Transverse T2-weighted turbo spin-echo MR image obtained 1 month later shows diffuse white matter loss.

 


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  		Figure 4a. Group 3 (diffuse) injury in patient 2 (6 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) shows diffusely increased T2, especially in white matter. Probable blurring of the gray-white junction is also present, primarily in frontal lobes, although a thin cortical ribbon can be seen in most regions. Myelination in the posterior limb of the internal capsule (arrows) is not well seen, and there is increased signal intensity in the thalamus (arrowheads). (b) Transverse T1-weighted spin-echo MR image (650/14) also shows the white matter abnormality, with subtle prolonged T1 in the deep white matter and thalamus. (c) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (d) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter and also cortex (open arrows), with relative sparing of the occipital cortex. The basal ganglia (solid arrows) were also affected, as was the corpus callosum.

 


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  		Figure 4b. Group 3 (diffuse) injury in patient 2 (6 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) shows diffusely increased T2, especially in white matter. Probable blurring of the gray-white junction is also present, primarily in frontal lobes, although a thin cortical ribbon can be seen in most regions. Myelination in the posterior limb of the internal capsule (arrows) is not well seen, and there is increased signal intensity in the thalamus (arrowheads). (b) Transverse T1-weighted spin-echo MR image (650/14) also shows the white matter abnormality, with subtle prolonged T1 in the deep white matter and thalamus. (c) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (d) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter and also cortex (open arrows), with relative sparing of the occipital cortex. The basal ganglia (solid arrows) were also affected, as was the corpus callosum.

 


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  		Figure 4c. Group 3 (diffuse) injury in patient 2 (6 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) shows diffusely increased T2, especially in white matter. Probable blurring of the gray-white junction is also present, primarily in frontal lobes, although a thin cortical ribbon can be seen in most regions. Myelination in the posterior limb of the internal capsule (arrows) is not well seen, and there is increased signal intensity in the thalamus (arrowheads). (b) Transverse T1-weighted spin-echo MR image (650/14) also shows the white matter abnormality, with subtle prolonged T1 in the deep white matter and thalamus. (c) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (d) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter and also cortex (open arrows), with relative sparing of the occipital cortex. The basal ganglia (solid arrows) were also affected, as was the corpus callosum.

 


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  		Figure 4d. Group 3 (diffuse) injury in patient 2 (6 days old). (a) Transverse T2-weighted turbo spin-echo MR image (6,000/99) shows diffusely increased T2, especially in white matter. Probable blurring of the gray-white junction is also present, primarily in frontal lobes, although a thin cortical ribbon can be seen in most regions. Myelination in the posterior limb of the internal capsule (arrows) is not well seen, and there is increased signal intensity in the thalamus (arrowheads). (b) Transverse T1-weighted spin-echo MR image (650/14) also shows the white matter abnormality, with subtle prolonged T1 in the deep white matter and thalamus. (c) Transverse diffusion-weighted MR image with diffusion-weighting along the z axis (6,000/100, bz = 1,000 sec/mm2) and (d) ADC map (mean of ADC along three orthogonal axes) show restricted diffusion throughout the white matter and also cortex (open arrows), with relative sparing of the occipital cortex. The basal ganglia (solid arrows) were also affected, as was the corpus callosum.

 
There were no clinically important imaging findings in the control subjects. In many cases, artifactual increased signal intensity on diffusion-weighted images was noted in the most anterior frontal cortex, which was often accompanied by slight distortion of the frontal lobes. This artifact occurs with echo-planar imaging techniques due to background gradients, such as those created by the frontal sinuses (24). Findings in the frontal lobes were always interpreted with caution as a result of this artifact.

Patients were grouped into four categories based on the dominant pattern of injury, as shown by abnormal signal intensity on diffusion-, T1-, and/or T2-weighted images in the following distributions: group 1, posterior limb of the internal capsule, ventromedial thalamus, posterolateral basal ganglia, corona radiata, and occasionally along the central sulcus (n = 4); group 2, parasagittal (watershed) (n = 4); group 3, diffuse gray and/or white matter (n = 2); and group 4, mixtures of the first three patterns (n = 3).

Figure 2 illustrates the first injury pattern (group 1). The diffusion-weighted image clearly shows abnormal signal intensity centered in the posterior limbs of the internal capsules, with involvement of dorsal basal ganglia and ventrolateral thalami as well. The abnormalities are poorly depicted on conventional T2-weighted turbo spin-echo images, although there is probable subtle prolongation of T2 in the ventrolateral thalamus.

The pattern of injury in group 2 patients is shown in Figure 3. Conventional images are abnormal, with blurring of the gray-white junction in bilateral frontal, temporal, and occipital regions. However, the true extent of the white matter involvement is more striking on diffusion-weighted images and ADC maps. At follow up, global white matter loss was seen.

Diffuse injury in gray and white matter is shown in Figure 4, typical of images in group 3 patients. The extent of the white matter injury is more striking on diffusion-weighted images and ADC maps than on conventional images. Injury to deep gray matter is reflected on both diffusion-weighted images or ADC maps and T2-weighted images. Restricted diffusion was also seen in the corpus callosum in Figures 3 and 4. Follow-up studies in five patients (patients 1, 6, 9, 11, 13; 1–130 weeks after initial examination) showed findings consistent with chronic or evolving HII, including combinations of extensive white matter loss and/or gliosis, atrophy, signal intensity abnormalities in basal ganglia and thalamus, and laminar necrosis.

In the 13 ROIs, mean ADC values averaged across the four control subjects ranged from 1.01 to 1.62 µm2/msec; in the 13 patients, they ranged from 0.90 to 1.32 µm2/msec (Table 3). The minimum ADC in an individual control subject for any ROI was 0.92 µm2/msec, and the maximum ADC was 1.82 µm2/msec. The minimum ADC in an individual patient for any ROI was 0.45 µm2/msec, and the maximum ADC was 2.00 µm2/msec. ADC values in patients were significantly different from those of control subjects in the posterior limb of the internal capsule ventrolateral thalamus dorsal lentiform nucleus, corona radiata, posterior frontal white matter, and bilateral parietal white matter (unpaired Student t test).


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  		TABLE 3. ADC Calculation Summary: All Patients versus Control Subjects
 
When a Wilcoxon rank sum test was applied, only differences in the measurements in the corona radiata and posterior frontal white matter were statistically significant. There was a weak positive correlation of the age of patients with HIE and ADC measurements in each ROI (Spearman correlation coefficient, 0.01 < r < 0.46). Table 4 lists the mean ADC values and standard errors of the mean for patients and control subjects.


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  		TABLE 4. ADC Calculation Summary: Patient Groups
 
Mean ages for each group were as follows: control subjects, 9 days (range, 7–11 days); group 1, 5.25 days (range, 1–11 days); group 2, 3 days (range, 2–4 days); group 3, 5 days (range, 4–6 days); and group 4, 8.3 days (range, 3–12 days). Since ADC values in the genu and splenium of the corpus callosum were not available in all patients, they were not included in the analysis. For those patients with available ADC values, the mean ADCs for genu and splenium were 1.03 µm2/msec (standard error of the mean, 0.10) and 1.02 µm2/msec (standard error of the mean, 0.10), respectively. In control subjects, the mean ADCs for the genu and splenium were 1.21 µm2/msec (standard error of the mean, 0.07) and 1.16 µm2/msec (standard error of the mean, 0.08), respectively. For patients 2, 8, and 11, the mean ADC was as low as 0.58, 0.67, and 0.62 µm2/msec for the genu or splenium. The greatest decreases in ADC values compared with those of control subjects were seen in group 3, followed by groups 2, 1, and 4.

Signal intensity abnormalities were more easily detected on diffusion-weighted images and/or ADC maps compared with conventional images in 11 (85%) of 13 subjects. One of two exceptions was patient 12, who had T1-weighted images that showed abnormally increased signal in a pattern suggestive of a group 1 injury, but who had no definite signal abnormalities on diffusion-weighted images or abnormal ADC values in these regions. Also, multifocal cortical hemorrhages were seen in both infratentorial and supratentorial locations; these were suggestive of infarcts. Blood products created susceptibility artifact on diffusion-weighted images, precluding accurate measurement of ADC.

The other exception was patient 4. Although subtly increased signal intensity was seen in the left corona radiata and frontal gray matter on diffusion-weighted images, bilaterally increased signal intensity on T1- and T2-weighted images in a group 1 pattern was also noted, which was not well depicted on diffusion-weighted images. ADC values were not decreased in any of these regions. Conventional images in one patient (patient 3) were initially interpreted as normal. In retrospect, subtle T2 prolongation was present in the ventrolateral thalamus (Fig 2a).

Note was made of additional findings in some patients. In patient 5, abnormal increased signal was seen on diffusion-, T1-, and T2-weighted images in a predominantly group 1 pattern. However, the abnormal regions did not show decreased ADC values. Prolonged T1 and T2 were also noted in the dorsal brainstem, without abnormality on diffusion-weighted images. Patient 7 had a group 2 pattern of injury; but conventional images showed additional signal intensity abnormality in the dorsolateral midbrain, which was not evident on diffusion-weighted images or ADC maps. Finally, patient 13 did not have clear abnormalities on diffusion-weighted images; however, ADC maps revealed a subtle decrease in ADC in a group 1 pattern. T1-weighted images showed subtly increased signal intensity in a typical group 1 injury pattern as well.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Hypoxic-ischemic brain injury results from an inadequate supply of oxygen to meet the metabolic demand of brain tissue, with a final common pathway of energy failure leading to neuronal and glial cell injury or death (1,2). The specific type of pathologic injury depends on several parameters, including the nature and timing of the insult (2). Early descriptions of acute or subacute HII with conventional MR imaging relied primarily on findings on T1 and T2-weighted images. For example, subtly increased signal intensity in cortical and/or subcortical structures, blurring of the gray-white junction, and increased signal intensity on T2-weighted and T1-weighted images in specific patterns are consistent with HII (4,23). Previously described (23) imaging patterns of HII include abnormalities in deep gray matter, cortical gray and subcortical white matter, periventricular white matter, or combinations thereof. The groups in this study are similar to those described by Barkovich et al (4). In the acute or subacute setting, detection of neonatal HII can be difficult. Contrast is low in the first 18–24 months due to the high water content of the neonatal brain, and ongoing myelination continually changes the contrast during the first 24 months (2,25).

In this study, abnormal diffusion was seen in 11 (85%) of 13 patients on the basis of diffusion-weighted images and/or ADC maps. By evaluating ADC maps and by calculating ADC values, an objective measure of diffusion abnormality was obtained. When a Student t test was used, ADC values in patients with clinically diagnosed HII were significantly decreased in the posterior limb of the internal capsule ventrolateral thalamus dorsal lentiform nucleus, corona radiata, posterior frontal white matter, and bilateral parietal white matter. When a Wilcoxon rank sum test was used, only the differences in corona radiata and posterior frontal white matter measurements were statistically significant. This finding likely reflects the heterogeneity of injury patterns in the patient population (Table 4).

While not included in statistical analyses, HII in the corpus callosum was also apparent in some patients. Use of the ADC maps and values improved conspicuity of injuries because, while contrast with diffusion-weighted imaging is improved over that of conventional T2-weighted images in the setting of acute HII, the contribution of decreased ADC to contrast at diffusion-weighted imaging wanes over the first few days while contribution to image contrast from prolonged T2 in injured tissue steadily increases. T2 shine-through thus presents a potential pitfall, since preexisting injuries may be misinterpreted as acute (21). Depiction of subtle injury on diffusion-weighted images may be also be complicated by variations in image display. In the acute and/or subacute setting, HII typically shows decreased ADC values, at least for the first several days. ADC values are higher in the normal neonate and correlate with T1 and T2 values (26).

When patients were grouped according to the dominant pattern of injury, the greatest decreases in ADC were seen in group 3, followed by groups 2, 1, and 4. In group 4, more substantial ADC decreases may have been masked by the presence of mixed patterns and cancellations between ROIs. There was no significant correlation between age and pattern of injury. An association between magnitude of ADC decrease and pattern of injury cannot be confidently made due to small study numbers. Poor neurologic outcome has been associated with T2 alterations in deep gray matter and diffuse hemispheric parenchymal changes (3). In another study (6), a scoring system based on signal intensity abnormalities in the basal ganglia and in a watershed distribution was described, with a ratio of basal ganglia to watershed injury scores predictive of neuromotor outcome.

Of interest, four patients in this study had one or more ROIs with signal intensity abnormalities on conventional and/or diffusion-weighted images without decreased ADC values. Patient 5 had abnormal findings on diffusion-weighted images, but ADC values were not decreased. Abnormal signal intensity was seen in the dorsal midbrain on conventional image but was not seen on diffusion-weighted images or ADC maps. Patient 7 had clear abnormalities on diffusion-weighted images and ADC maps consistent with HIE, but this patient also had abnormal signal intensity in the dorsal midbrain that was not visible on diffusion-weighted images or ADC maps. Patient 12 had conventional imaging findings consistent with HII, but diffusion-weighted images and ADC maps showed no definite abnormality. A similar result was noted for patient 4, although this patient did have subtle abnormal increased signal intensity on diffusion-weighted images in regions separate from the conventional imaging abnormalities.

Patients 4 and 5 did not undergo imaging until 12 and 11 days after birth, respectively, and ADCs may have normalized by this time. Patients 7 and 12 each underwent imaging within 3 days of birth, and an alternate explanation must be sought. Since conventional imaging abnormalities were seen in the regions that did not show restricted diffusion, the most likely explanation is that the ADC had normalized by the time of imaging. One possibility is that the regions without decreased ADC represent old or prenatal injuries. Alternatively, ADC normalization has been shown in animal experiments (27) to occur within 72 hours; in some cases, increases in T2 can precede decreased ADC. Another possibility is that these regions represent the recovery phase after the initial ADC decrease in a biphasic response to ischemia; that is, the ADC could have shown a secondary decrease if the patients had been scanned again a few days later (27–30).

Detection of HII with diffusion-weighted imaging has been reported. Early studies (20,31) were based on a cardiac-gated pulsed gradient spin-echo technique. In a recent study (7), neurologic deficit was seen in 83% of patients with abnormal findings at diffusion-weighted imaging, but diffusion weighting was applied only along the section-select axis (7). This approach could lead to misinterpretation due to anisotropic orientation of nerve fibers. In another recent study (30), a line-scan diffusion-weighted imaging technique was used to examine patients with diffuse, symmetric HII. Our results are consistent with these, including the lack of an ADC decrease in some patients within the first 72 hours.

Other potential objective measures of HII have been reported as well, including MR spectroscopy and scoring systems with conventional MR techniques. A recent study (13) in which proton spectroscopy was used demonstrated increased {alpha}-CH protons of brain glutamate/glutamine in patients with moderate or severe HIE. Other study findings (12) demonstrated elevated lactate and decreased N-acetylaspartate levels in patients with HIE with abnormal follow-up findings at 12 months. A scoring system based on the combinations of basal ganglia and watershed distribution signal intensity abnormalities on T1-weighted and first- and second-echo T2-weighted spin-echo sequences appeared to be predictive of neuromotor outcome (6). The potential use of ADC measurements either alone or in combination with these techniques requires further evaluation.

Our study has several limitations. Only limited follow-up data are available for study patients. Furthermore, all study patients had a moderate to severe degree of HIE. It would be useful to include patients with mild injuries for a correlation of imaging results with the prognosis. A prospective study will be necessary to fully assess the relationship of quantitative ADC measurements and outcome. Also, although some of the tested ROIs showed statistically significant decreases in ADC when patients were considered as a whole, the mixing of different injury patterns probably obscured significant changes in ADC in some ROIs. Increased numbers of patients with a range of injuries will be necessary to define the clinical relevance of different injury patterns. Finally, the mean age at imaging for patients was 5 days. The time to imaging must be reduced for early diagnosis and intervention to be meaningful, a challenge in unstable neonates. Since injury patterns may evolve over time, more than one time point may need to be assessed (30).

In conclusion, diffusion-weighted imaging and ADC measurements are helpful in improving the detection and depiction of extent of injury in the setting of acute and/or subacute HIE. Review of the ADC maps and measurements of ADC values provide an objective measure of diffusion abnormalities.


   FOOTNOTES
 
Abbreviations: ADC = apparent diffusion coefficient, HIE = hypoxic-ischemic encephalopathy, HII = hypoxic-ischemic injury, ROI = region of interest

Author contributions: Guarantors of integrity of entire study, all authors; study concepts, R.A.Z., R.L.W.; study design, all authors; definition of intellectual content, all authors; literature research, R.A.Z., R.L.W.; clinical studies, R.A.Z.; data acquisition, all authors; data analysis, all authors; statistical analysis, R.L.W., J.H.H.; manuscript preparation, R.L.W.; manuscript editing, R.L.W.; manuscript review and manuscript final version approval, all authors.


   REFERENCES
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RESULTS
 DISCUSSION
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