Perinatal hypoxia in full-term neonates is a vital cause of long-term neurologic complications ranging from mild behavioral deficits to intractable seizures, mental retardation, and cerebral palsy. With improvements in care of at-risk neonates, more and more children survive. Thus, it is increasingly important to evaluate, soon after birth, the prognosis of neonates with perinatal hypoxic ischemic encephalopathy .
In order to answer the question of the title of the study and understand the role of advanced MRI techniques mainly DTI in the prognosis of perinatal HIE, the current study tried to find an answer for the following questions: Are conventional MRI sequences and DWI sufficient for early identification of perinatal HIE and prediction of cerebral palsy? Does DTI have a role in diagnosis and prognosis of perinatal HIE? And lastly, what is the recommended imaging roadmap in cases of perinatal HIE?
Taking into consideration the first question (Are conventional MRI sequences and DWI sufficient for early identification of perinatal HIE and prediction of cerebral palsy?), the current study showed that although MRI is still the study of choice in cases of perinatal HIE, yet its main role is evident in cases of acute profound insult with deep gray matter affection pattern. This was clearly evident in the current study as all cases with such pattern (six cases) were accurately detected within the neonatal period and they turned out to have CP by the end of their first year.
On the other hand, conventional MRI as well as DWI showed poor results with high false-negative cases in neonates with mild to moderate hypoperfusion, as seven out of the ten cases (70%) who turned to have periventricular leukomalacia at the end of the first year showed initial normal MRI with even no evidence of diffusion restriction.
Explanation for such false-negative results of conventional MRI and DWI was found in previous studies of Agut et al.  and Hayakawa et al. , who studied early MRI features of 40 and 17 full-term neonates, respectively, and concluded that despite the higher sensitivity of DWI compared to conventional MRI in the characterization of brain injury in the acute phase of HIE, yet DWI shows restricted diffusion with decrease of ADC values only in the first hours after the anoxic-ischemic event. Low ADC values tend to progressively increase in the first week after the event, resulting in a pseudonormalization of values between days 4 and 6. Being strictly dependent on the timing of the scan, both studies [17, 18] have demonstrated that the diagnostic and prognostic values of ADC in the subacute stage of HIE are significantly decreased.
This was clearly found in the current study as all neonates were imaged around the tenth day of life, the time of which pseudonormalization of ADC was expected. Such fact resulted in normal appearance of DWI in all cases and lead to reduction in sensitivity, negative predictive value, and overall accuracy of routine MRI (including conventional MRI and DWI) to 56.25%, 70.83%, and 78.79%, respectively. In other words, conventional MRI sequences and DWI are likely not sufficient alone in early diagnosis of all cases of perinatal HIE especially in cases with moderate hypoperfusion or partial prolonged insult.
“Does DTI have role in diagnosis and prognosis of perinatal HIE?” was the second question for which we tried to find an answer.
DTI carries extra information about directional diffusivity (both longitudinal and radial) and fractional anisotropy (FA) which can improve the detection of disruption of white matter tracks. It is thought that reduced FA values are linked to cell death and loss of structural components of white matter fibers. Rutherford et al.  reported that apoptosis was more noticeable than necrosis in children in the subacute stage of HIE, which could explain why FA values decreased, but ADC values were normal.
Our results verified that FA values had high diagnostic and prognostic values. In particular, FA values were remarkably decreased in most of the dense white matter tracts, mainly the corpus callosum and posterior limbs of the internal capsules (PLIC) as well as the centrum semiovale (CSO). Significant differences in FA values were detected between newborns with CP outcome and those with normal outcome with detectable cutoff values of FA within the corpus callosum, PLIC, and CSO averaging ≤ 0.45, ≤ 0.435, and ≤ 0.235, respectively. Significant predictive power of FA within the PLIC had the highest value of accuracy (AUC 1.0) showing 100% sensitivity, specificity, and negative and positive predictive values. Again, all neonates with normal appearing MRI who developed periventricular leukomalacia later on (false-negative cases) showed initially abnormally reduced FA values within the examined brain regions.
Diagnostic accuracy of DTI in neonatal HIE was previously documented by Barkovich et al. , who studied sequentially ten neonates with encephalopathy within the first 2 weeks of life and found that DTI-derived parameters were consistently abnormal even at times where MRI were completely unremarkable.
Similar results were also obtained by Ward et al. , in 20 neonates with HIE as they observed that FA stayed reduced, while ADC pseudonormalized with time. At the same time, the authors stated that FA decreased not only in severe basal ganglia and white matter injury but reduced in all moderate basal ganglia and white matter injuries. The authors’ assumption was that FA represents an important marker in neonates, mainly in moderate HIE predominantly when results of ADC values are normal.
As regards the prognostic role of DTI, the current results were also matching with the previous study of Brissaud et al. , who studied 22 full-term neonates with HIE and found that FA values in PLIC areas showed best correlation with outcome, where the lower the FA values in the PLIC, the worse the infants’ neurologic outcome. Cutoff value for FA within the PLIC in their study was 0.38 (lower than the cutoff in the current study).
The only explanation which we found for such difference in FA values in the PLIC is brain cooling application which was adopted in all of our examined neonates, as a routine protocol done in the NICU for neonates with moderate or severe perinatal HIE, while not routinely mentioned in the other studies. Brain cooling is a neuroprotective therapy that reduces the extent of brain injury via at least the following three mechanisms. Firstly, hypothermia results in a graded reduction in cerebral metabolism that reduces accumulation of excitotoxic neurotransmitters, and suppresses oxygen free radical release. Secondly, it has a particular role in suppressing apoptotic processes in the developing brain (i.e., programmed cell death). Thirdly, there is good evidence that cooling can suppress the release of pro-inflammatory cytokines and interleukins, reducing direct neurotoxicity, such via suppression of microglial activation .
We believe that brain cooling has protective effect on FA of white matter, limiting its damage, as mentioned before in the study of Chan et al. , regarding effect of brain cooling as a neuroprotective method on alteration of brain metabolites on MR spectroscopy.
“What is the recommended imaging roadmap in cases of perinatal HIE?” was our last question. From the aforementioned results, we suggest that conventional MRI with DWI is sufficient for early identification as well as prediction of development of CP in cases of acute profound hypoxia with central pattern of affection. In cases with normal appearing MRI and suspected mild to moderate HIE, doing DTI with emphasis of accurate measurement of FA values within the posterior limbs of the internal capsules is likely to reduce the possibility of missing these cases and increase the accuracy of MRI in early prediction of pathological outcome namely cerebral palsy.
The main limitation of the current study is represented by the relatively limited number of HIE newborns recruited. The present results should be confirmed in a larger population. For ethical reasons, there was no control group of normal neonates for comparison, as no informed consent could be obtained from parents of normal appearing neonates. Another limitation of this study is noted in most studies of neonatal encephalopathy that exact time of injury was not known in most of the patients. The extent and pattern of injury differ temporally. Particularly in the case of DTI, some regions will appear more severely damaged and some less damaged, depending on the timing of the examination with respect to the injury. Lastly, and to illuminate the full quantitative assessment power of DTI versus the qualitative power of conventional MRI and DWI, extended follow-up at the age of 2 years (at which complete myelination is acquired) should have been done.
In summary, among imaging-based parameters, DTI values closely correlated with the Bayley scores. Such technique can be carried out in a single individual, which has important clinical significance, as it can accurately and objectively assess the prognosis of full-term neonates with HIE which can guide the treating clinicians for early intervention.