PEDIATRICS Vol. 114 No. 4 October 2004, pp. 999-1003 (doi:10.1542/peds.2003-0935-L)
Apparent Diffusion Coefficient in the Posterior Limb of the Internal Capsule Predicts Outcome After Perinatal Asphyxia
* Department of Neonatal Neurology, Royal Children's and Royal Women's Hospitals, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia
Paediatric Neurology, St Louis Children's Hospital, St Louis, Missouri
Department of Medical Imaging, Royal Children's Hospital, Melbourne, Australia
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ABSTRACT |
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Objective. Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) is a difficult task. Magnetic resonance imaging, particularly diffusion imaging, holds promise in this regard as it is more sensitive to brain injury than any other available imaging modality. Previous studies have suggested that abnormal signal intensity in the posterior limb of the internal capsule (PLIC), detectable on inversion-recovery T1-weighted imaging, is a strong predictor of outcome. The aim of this study was to assess the relationship between apparent diffusion coefficient (ADC) values from the PLIC, measured by diffusion imaging, and neuromotor outcome in term infants with HIE.
Methods. Twenty-eight term infants with a clinical diagnosis of HIE underwent magnetic resonance imaging as soon as practicable after birth (mean age: 5.6 days), including diffusion-weighted imaging, from which ADC values in the PLIC were measured. Motor outcome was assessed in 12 of 16 survivors.
Results. The ADC value in the PLIC was significantly associated with survival in term infants with HIE. For survivors, the mean ADC value in the PLIC was 0.89 ± 0.17 µm2/ms, whereas the mean ADC value for nonsurvivors was 0.75 ± 0.17 µm2/ms (t = 2.25). Among survivors, the ADC value in the PLIC was also associated with neuromotor outcome (F = 5.60).
Conclusion. The ADC value in the PLIC is an indicator of ischemic injury and may be of use as an objective prognostic marker for infants with HIE.
Key Words: apparent diffusion coefficient • perinatal asphyxia • magnetic resonance imaging
Abbreviations: MRI, magnetic resonance imaging • HIE, hypoxic-ischemic encephalopathy • PLIC, posterior limb of internal capsule • DWI, diffusion weighted imaging • ADC, apparent diffusion coefficient
Magnetic resonance imaging (MRI) is established as the most useful neuroimaging modality in assessing the extent of neurologic injury in term infants with hypoxic-ischemic encephalopathy (HIE).1,2 The patterns of cerebral ischemic injury on conventional MRI in the term encephalopathic infant have been described and linked with both the type of ischemic insult3 and later impairments in neurologic outcome.4 The prediction of long-term neurodevelopmental outcome in these infants, particularly for those with moderate disease,5 remains problematic. Early studies focused on conventional MRI for detection of injury within the first 10 days after an ischemic insult,6 and these changes were correlated with neonatal neurologic examination4 and later childhood neurodevelopmental outcomes.7 More recently, changes in the signal in the posterior limb of the internal capsule (PLIC), detected by T1-weighted inversion-recovery imaging, have been found to be highly predictive of poor neurodevelopmental outcome after an asphyxial insult in the term infant.8
One of the limitations of conventional MRI in evaluating the term encephalopathic infant is the delay of 5 to 7 days for abnormalities to become reliably apparent on conventional T1- and T2-weighted imaging after an ischemic insult. In contrast to this delay, other MR techniques, such as MR spectroscopy9 and diffusion-weighted imaging (DWI), provide a means for the earlier detection of injury.10 For example, DWI detects ischemic changes within 24 hours of an ischemic insult in the term newborn brain.9,11–13 The explanation for the differences between conventional MRI and DWI for detection of injury may lie in fundamental differences in the source of image contrast between the 2 methods. For conventional MR images, contrast derives from differences in water MR relaxation properties (ie, T1 and T2 relaxation time constants for the 1H nuclei of water in different brain areas), whereas for DWI, the contrast is based on differences in the translational motion of water molecules. This motion can be described quantitatively as a water apparent diffusion coefficient (ADC). Water ADC values decrease within minutes after a variety of central nervous system insults, including stroke, HIE, seizure, and excitotoxic injury. In addition, water diffusion within the brain is dependent on both maturation and region14 in infants, with normative data documented from infants of 38 to 42 weeks' gestation.15,16
In this study, ADC values from the PLIC were evaluated. Because it has been reported that qualitative changes in water T1 relaxation properties of the PLIC are predictive of neuromotor outcome in infants with HIE,8 we sought to determine whether the more quantitative measure of water ADC is also predictive.
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METHODS |
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Subjects
From January 2001 to September 2002, infants who were admitted to the Women's and Children's Health Network in Melbourne with a clinical diagnosis of HIE were considered for this observational study. The clinical diagnosis of HIE was made on the grounds of clinical encephalopathy and evidence of perinatal compromise, with or without a sentinel hypoxic event. Perinatal compromise was defined as fetal distress detected by cardiotocograph, Apgar score <6 at 5 minutes, and fetal or neonatal acidemia (base excess >12 mmol/L). The severity of the encephalopathy was staged according to Sarnat criteria.5 Perinatal data were collected from the mothers' and infants' medical records.
All subjects were followed up in a dedicated neonatal neurology outpatient clinic by 2 of the investigators (T.E.I. and R.W.H.). Outcomes were classified as survival or death. Survivors were assessed for severity of developmental disability. Disability was defined as mild (abnormal neuromotor tone), moderate (hemiparesis or diparesis), or severe (spastic quadriparesis).
Image Acquisition
Infants with HIE were underwent MRI as soon as practicable after birth, at a time determined by the treating physician as a standard of clinical care. The images were obtained with a 1.5-Tesla General Electric LX Echospeed system (version 9.0). Transverse T1 fast spin echo (TR/TE 1400/10, ETL 2, BW ± 20 kHz, FOV 20 cm, slice thickness 3.5 mm; 256 x 224 matrix, 2 averages) and transverse fast spin echo T2 (TR/TE 3600/16, ETL 18, BW ± 20.83 kHz, FOV 18 cm, slice thickness 3.0 mm, 256 x 224 matrix, 3 averages), epi-DWI (3 directions, b = 1 ms/µm2, TR/TE 10 000/104, BW ± 100 kHz, FOV 25 cm, slice thickness 4.0 mm, 192 x 128 matrix, 2 averages) were obtained. Conventional images were graded on a systematic scale by 3 independent reviewers (T.E.I., L.C., and R.W.H.) for the extent of injury. The integrity of the PLIC was also assessed on conventional images as normal, impaired (being half or less of the expected signal intensity), or absent.
An ADC map was generated from the diffusion-weighted images using Functool (ADW 3.0, GEMS). A region of interest with standardized size (15-20 mm2) was placed over the middle third of the left and right PLIC, and the ADC values were measured (Fig 1).
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Statistical Analysis
Statistics were performed using SPSS. Means were compared with t test or analysis of variance. Correlation was sought, using univariate linear regression, between the lowest ADC value from the left or right PLIC and a number of continuous perinatal variables, including Apgar scores at 1, 5, and 10 minutes and time to first breath. Univariate logistic regression was used for categorical variables such as need for mechanical ventilation, first pH, seizures in the perinatal period, and Sarnat staging. In addition, appearance of the PLIC on conventional MRI was correlated with neuromotor outcome. P < .05 was considered statistically significant.
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RESULTS |
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Subject Population
During the study period, 34 infants were admitted to our unit with a diagnosis of HIE. Of these, 2 infants died before acquisition of an MRI scan, and an additional 4 infants were found to have a diagnosis other than HIE (cerebral dysgenesis [n = 2] or established in utero injury [n = 2]).
Perinatal Characteristics
The remaining 28 infants had a mean birth weight of 3488 g (SD: 461 g) and median gestation of 40 weeks (range: 37–42 weeks). Ten infants were delivered by unassisted vaginal delivery, 5 by assisted vaginal delivery (1 Ventouse, 2 Neville Barnes forceps, and 1 midcavity rotational forceps delivery), and 13 by emergency cesarean section. The median Apgar score at 1 minute was 1 (minimum, 0; maximum, 7) and at 5 minutes was 4 (minimum, 0; maximum, 8). The median pH at first blood gas (cord or arterial) was 7.14 (range: 6.55–7.42). Nineteen of the 28 infants had seizures in the perinatal period, and of these, 6 received only 1 anticonvulsant, 3 received 2 anticonvulsants, 8 required 3 anticonvulsants, and 2 required 4 anticonvulsants. According to Sarnat staging criteria, 9 infants had stage 1 HIE, 4 had stage 2, and 15 had stage 3.
MRI Findings
Infants were scanned at a mean age of 5.6 days (range: 1–12 days; SD: 2.8 days). There was no significant difference in the time of scan for infants with stage 1, 2, or 3 HIE. Patterns of injury on MRI scanning were as follows: 2 infants had a normal scan, 4 infants had isolated basal ganglia injury, 3 had isolated white matter injury, 2 had cortical and white matter injury only, and 17 infants had evidence of injury in 3 or more anatomic structures.
Neurodevelopmental Outcome
Of these 28 infants, 16 survived and 12 died in the perinatal period. Follow-up data are currently available for 12 of the 16 survivors. Three have normal outcome, 4 have mild or moderate impairment, and 5 are left with severe neuromotor impairment. The mean age at follow-up was 12.9 months (SD: 7 months).
ADC Values
There was no clear relationship between age at scan and the lowest ADC value in the PLIC among study infants. The ADC value (mean ± SD) in the PLIC was significantly greater for infants who survived (0.89 ± 0.17 µm2/ms) compared with those who died (0.75 ± 0.17 µm2/ms; t = 2.25, P = .03). When ADC values for surviving infants were analyzed according to their neuromotor outcome, a significant difference was found between the groups (Fig 2). The lowest ADC values in the PLIC were significantly different between infants in relation to the pattern of injury on conventional MRI, with global injury associated with lowest ADC values (F = 5.53, df = 4, P = .003; Fig 3).
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The appearance of the right PLIC on conventional imaging was compared with both outcome and ADC values in the right PLIC. (The right PLIC was chosen to ensure consistent comparison for this part of the analysis.) Fifteen infants had a normal PLIC, 2 had an abnormal PLIC, and 11 had an absent PLIC on conventional MRI. The mean ADC values for each of these groups were significantly different, reflecting some degree of consistency between subjective interpretation of conventional imaging and ADC values (F = 4.65, P < .02; Fig 4). Appearance of the PLIC on conventional MRI was strongly associated with motor outcome (F = 6.69, df = 2, P = .008). There was no significant relationship between the ADC value and any clinical perinatal variable, with the exception of Sarnat staging (F = 5.53, df = 4, P = .003).
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A receiver operator curve was generated to determine which lowest ADC value had the greatest utility as a predictor of survival with or without severe neurodevelopmental impairment. At a lowest ADC value of 0.74 µm2/ms, this parameter predicted outcome with a sensitivity of 80% and a specificity of 100%. This relationship was statistically significant using the Fisher exact test (P = .01).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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ADC in the PLIC is a quantitative assessment correlating with changes on conventional MRI and neuromotor outcome. We have demonstrated that the ADC value in the PLIC, as well as the appearance of the PLIC on conventional imaging, is significantly associated with survival in a cohort of infants with HIE. In surviving infants, ADC in the PLIC is significantly associated with motor outcome.
One potential confounding factor in our analysis of the relationship of the MRI findings to outcome relates to the fact that the findings on MRI are considered in the decision-making process with regard to withdrawal of care. Despite this limitation, we found a significant relationship between ADC values and later neuromotor outcome in survivors. This highlights the potential importance of measuring ADC values to assist in the long-term prognosis of term infants with HIE. Our findings suggest that infants who have an ADC in the PLIC of <0.74 µm2/ms and survive will be left with severe neuromotor impairment. This is in keeping with findings of Wolf et al.17 In their study, control subjects had ADC values >1.0 µm2/ms in the PLIC. None of the infants in our cohort who had severe neuromotor impairment had an ADC value in the PLIC >1.0 µm2/ms. Although these findings should be validated with greater numbers and with outcome data over a longer period, their significance is encouraging.
Within our study, the group of infants who had HIE and remain problematic are those who subsequently developed moderate neurodevelopmental impairment. It is important to note that our study population was skewed, with >50% of the infants having severe encephalopathy (Sarnat stage 3). Thus, in relationship to the moderate neurodevelopmental impairment group, we found a wider spread of ADC values than for the other 2 groups (mean: 0.98; SD: 0.13 µm2/ms; see Fig 2), suggesting that ADC in the PLIC may be less useful in clearly defining this population. A greater sample size with a single defined time point of MRI scanning may well assist in narrowing the range for this group. Until the optimal time for scanning can be better defined for the moderate group, the value of the ADC in the PLIC may lie with the severe group, for whom a clear cutoff has been established, below which severe neuromotor outcome can be predicted.
Previous studies of ADC values in the newborn brain after HIE have demonstrated the phenomenon of pseudonormalization, in which ADC values are depressed in the first few days after injury and then recover to within the normal range toward the end of the first week.13 There was no such trend observed in the ADC values of the PLIC in our study. We postulate that pseudonormalization was not observed because the axonal fiber tracts that constitute the PLIC undergo a more prolonged secondary injury as a result of Wallerian degeneration. In the study by McKinstry et al,13 ADC values were measured in areas of brain directly injured, rather than those undergoing Wallerian degeneration. The phenomenon of a reduced ADC in white matter as a consequence of Wallerian degeneration has been previously reported in a case report18 and a series of term infants with ischemic brain injury.19
We demonstrated a strong relationship between the ADC value in the PLIC and observed changes on conventional MRI within the PLIC. This raises the possibility that the signal abnormality within the PLIC, first reported by Rutherford et al,8 is related to Wallerian degeneration of the motor pathway after ischemic injury to the parasagittal motor cortex, a lesion that common occurs in term newborn infants who sustain HIE.20
In summary, we presented a cohort of infants who had HIE and for whom the ADC value in the PLIC was predictive of both survival and neuromotor disability among survivors. Furthermore, we showed a significant association between the ADC value in the PLIC and appearance of the PLIC on conventional MRI. The ADC value in the PLIC is an objective measure of ischemic injury and may be of use as an objective prognostic marker for infants with HIE.
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FOOTNOTES |
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Accepted Feb 17, 2004.
Reprint requests to (T.E.I.) Department of Neonatal Neurology, Level 2, Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia. E-mail: terrie.inder{at}rch.unimelb.edu.au
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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