1. cerebral ischemia in neonates: from sonography to ct to mri
FERRACIOLLI SF, MD; TUFIK SB, MD; OLIVEIRA NETO A, MD; COMMANDER CW, MD; FEITOSA EAF, MD; MATSUOKA MW, MD, PhD; LUCATO LT , MD, PhD; LEITE CC, MD, PhD; CASTILLO M, MD.
UNIVERSITY OF SÃO PAULO - BRAZIL
UNIVERSITY OF NORTH CAROLINA - USA

2. INTRODUCTION
Perinatal ischemic stroke occurs around the time of birth with pathological or imaging evidence of focal or diffuse infarctions. It is caused by a heterogeneous group of conditions that lead to disruption of cerebral blood flow secondary to arterial or venous thrombosis or emboli between 20 weeks of fetal life through the 28th postnatal day.
Incidence of neonatal acute ischemic stroke is about 1:4,000-5,000 full-term newborns.
Perinatal ischemic stroke is an under diagnosed condition as not all such infarctions are symptomatic during the neonatal period and may go on unrecognized without brain imaging.

3. INTRODUCTION
Diffuse hypoxic-ischemic brain injury results in neonatal hypoxic- ischemic encephalopathy (HIE). Because of differences in brain maturity at time of insult, severity of hypotension, and duration of insult, there are 4 distinct patterns of injury. Cranial US and CT reveal periventricular leukomalacia, germinal matrix hemorrhage, and hydrocephalus. MRI is the most sensitive modality for evaluating these injuries.
In preterm neonates, mild hypotension causes periventricular injury while severe hypotension causes infarction of the deep gray matter, brainstem, and cerebellum. In term neonates, mild hypotension causes parasagittal cortical and subcortical injury while severe hypotension causes injuries of the lateral thalami, posterior putamina, hippocampi, corticospinal tracts, and sensorimotor cortex.

4. GOALS
To review the spectrum of acute cerebral neonatal ischemia from regional infarcts to diffuse anoxia emphasizing the benefits of MRI vs. CT and sonography.
Pertinent literature is reviewed and cases showing the importance of MRI in each of these settings compared to CT and sonography were selected from the teaching files of 2 academic institutions.

5. CLINICAL FINDINGS
Clinical presentation of perinatal stroke varies from nonspecific symptoms to obvious neurological symptoms. Seizures are most common in children with ischemia, especially newborns. Many patients are symptomatic in the first 48 hours of life while in n a few patients, the event may be clinically silent.
Newborns are particularly susceptible to stroke due to the perinatal activation of coagulation mechanisms and the most involved vascular territory is the middle cerebral artery, especially the left side. The predominance of left side lesions is probably due to differences in vulnerability/maturation or presence of vascular asymmetries. The left hemisphere may be more vulnerable to embolic lesions due to hemodynamic differences from a patent ductus arteriosus or through a direct route involving the left common carotid artery.

6. CLINICAL FINDINGS
Perinatal stroke is a common cause of long-term neurologic disability and the leading cause of hemiplegic cerebral palsy; 41% of children after neonatal stroke have cognitive impairments.
Perinatal asphyxia is the most important cause of HIE resulting in hypoxemia and hypercapnia. The exact pathophysiology of HIE is not understood but lack of sufficient blood flow and decreased blood oxygen lead to loss of cerebral autoregulation and diffuse injury. The nature of the injury depends on the severity of hypotension and degree of brain maturation.
An encephalopathic neonate has low Apgar scores at delivery and metabolic acidosis in cord blood. Within 24 hours of life an infant may develop apnea, seizures and abnormal EEG which is helpful in predicting outcome including likelihood of death and significant long-term neurologic sequelae such as spastic quadriplegia or diplegia.

7. CLINICAL FINDINGS
Perinatal asphyxia is the most important cause of Hypoxic Ischemic Encephalopathy (HIE), resulting in hypoxemia and hypercapnia. Although the exact pathophysiology of HIE is not completely understood, lack of sufficient blood flow in conjunction with decreased oxygen content in blood leads to loss of cerebral autoregulation and diffuse injury. The exact nature of the injury depends on the severity of hypotension and the degree of brain maturation.
An encephalopathic neonate may have low Apgar scores at delivery and metabolic acidosis documented in cord blood. Within the first 24 hours of life, an infant may develop symptoms of apnea and seizures with abnormal EEG. Abnormal EEG may be helpful in predicting outcome including likelihood of death and significant long-term neurologic sequelae such as spastic quadriplegia or diplegia.

8. IMAGING FINDINGS
SONOGRAPHY CT
MRI
Selected Cases

9. SONOGRAPHY (US)
US provides an easy, accessible, convenient, noninvasive, relatively low-cost screening examination at bed-side. It imparts no ionizing radiation exposure and is sensitive for detection of hemorrhage, periventricular leukomalacia (PVL), and hydrocephalus. Doppler interrogation and assessment of resistive index (RI) provide information on cerebral perfusion.
It is operator dependent and less sensitive to structural abnormalities in the cerebral convexities and brainstem. Parenchymal abnormalities identified at US can be non-specific and the cystic lesions that characterize HIE appear aproximately 4 weeks after the ischemic event, not allowing an early diagnosis of this pathology.

10. CT
CT is the least sensitive modality for evaluation of HIE and focal infarcts because of the high water content in the neonatal brain and high protein content of CSF which result in poor parenchymal contrast resolution. In addition, CT has the inherent disadvantage of radiation exposure.
However, CT provides a rapid mode of cranial screening for hemorrhage in sick neonates without the need for sedation.

11. MRI
It is the most sensitive and specific technique for examining infants with suspected HIE and has no ionizing radiation.
MR imaging is often not possible because the need for sedation of sick neonates, lack of optimal safe transport, and limited access to a unit at smaller facilities.
Studies have focused on the utility of early MRI (firsts days of life) compared to later MRI (after 1 week) and concluded that early MRI does not underestimate lesions.

12. MRI
DWI obtained between 24 hours and 8 days of life is very sensitive for detection of cytotoxic edema but does not correlate well with extent of ischemic injuries and does not predict outcome.
MR spectroscopy reveals an elevation of lactate in ischemic areas.
Conventional MRI sequences can rule out other causes of encephalopathy (cerebral infarction, cancer, hemorrhage).

13. MRI PATTERNS OF INFARCTIONS
I. Watershed
Between cortical arterial territories.
Subcortical brain infarcts in white matter along and slightly above the lateral ventricles.
II. Focal.
Involves only a part of the brain usually an arterial territory.
III. Diffuse
Involves the entire brain, white and gray matter
Involves predominantly the posterior temporal, occipital and parietal regions as in hypoglycemia.
Involves the basal ganglia and thalami.

14. IMAGING FINDINGS COMPARISON
Imaging findings of focal/regional cerebral ischemia are straightforward and easily diagnosed with MRI. CT is less helpful but superior to US.
In cases of diffuse acute anoxia, US may show subtle findings such as cortical sulci effacement and increased echogenicity in the central brain. MRI especially with DWI clearly shows the abnormalities while CT does not contribute to the diagnosis.
MRI is the best tool to show the diffuse acute anoxia.

15. IMAGING FINDINGS COMPARISON
SELECTED CASES

16. WATHERSHED INFARCTIONS
Severe HIE. Axial CT and DWI//T2 MR images. There are multiple acute infarcts in watershed distributions including the corpus callosum. The findings are subtle on CT and DWI/T2 are clearly superior.

17. WATHERSHED INFARCTIONS
Severe HIE. US reveals increased echogenicity in periventricular white matter and CT low density in same regions. T2 image show high signal in white matter and prominence of deep medullary veins while DWI show periventricular and callosal infarctions.

18. FOCAL INFARCTION
RIGHT PARIETAL
Focal infarct in a neonate. US, CT and DWI/T2 MR images show a focal right parietal infarction. In this example, MRI is clearly superior to CT and US where the lesion is not seen.

19. FOCAL INFARCTION
INFARCT NEWBORN ADC
Focal infarction. CT shows subtle left frontal hypodensity (arrowhead). The lesion is seen more clearly as high signal on DWI and T2 image shows loss of cortical ribbon in same location (arrow).

20. FOCAL INFARCTIONS
INFARCT NEWBORN ADC
Focal infarctions. US is normal while T2 image obtained 1 hour later shows loss of posterior cortical ribbon and DWI show high signal in the cortex posteriorly.

21. DIFFUSE INJURY
Diffuse HIE. US shows an area of increased echogenicity in the right posterior brain (arrowhead) and a CT shows subtle edema and loss of gray/white matter differentiation in same location. MR T2 image shows diffuse injuries with loss of cortical ribbon and high signal in white matter and deep gray nuclei.

22. DIFFUSE INJURY
Severe hypoxic-ischemic injury. US shows questionable high echogenicity in basal ganglia (arrowheads). T2 and DWI MR images show near complete absence of cortical ribbon, high signal from deep gray matter, and diffusely hyperintense white matter and restricted diffusion especially anteriorly and posteriorly.

23. CENTRAL INFARCTIONS
Severe HIE. US shows subtle increased echogenicity in basal ganglia especially on the left. Axial T1 pre- and post contrast images show high pre contrast T1 signal and contrast enhancement in basal ganglia and thalami. Cortical ribbon is absent. In this example, MRI is clearly superior to US although findings are seen on US.

24. TAKE-HOME MESSAGES
Acute anoxic brain injury in neonates results in severe neurologic disability and mortality. Recognition of the typical imaging findings can lead to an earlier diagnosis which may aid in determining therapy, outcome and family counseling. Although US is the screening method of choice, findings tend to be subtle and need MRI confirmation in most patients.
MRI is the gold standard because its higher sensitivity and findings are more specific than US and CT.

25. REFERENCES
Rutherford, MA et al: Magnetic resonance imaging of white matter diseases of prematurity. Neuroradiology (2010) 52:505–521.
Huang, BY; Castillo, M: Hypoxic-Ischemic Brain Injury: Imaging Findings from Birth to Adulthood. RadioGraphics March-April 2008, Volume 28 Number 2.
Ghei, SK et al: MR Imaging of Hypoxic-Ischemic Injury in Term Neonates: Pearls and Pitfalls. RadioGraphics 1048 July-August 2014, Volume 34
Chao, CP et al: Neonatal Hypoxic - Ischemic Encephalopathy: Multimodality Imaging Findings. RadioGraphics October 2006, Volume 26.
Liauw, L et al: Hypoxic-Ischemic Encephalopathy: Diagnostic Value of Conventional MR Imaging Pulse Sequences in Term-born Neonates. Radiology April 2008, Volume 247: Number 1.
Charon, V et al: Comparison of early and late MRI in neonatal hypoxic–ischemic encephalopathy using three assessment methods. Pediatric Radiology. 2015 Dec; 45(13):
Agut, T et al: Early identification of brain injury in infants with hypoxic ischemic encephalopathy at high risk for severe impairments: accuracy of MRI performed in the first days of life. BMC Pediatr. 2014 Jul 8;14:177.
Shankaran, S et al: Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov; 167(5): e3.
Machado, V et al: Perinatal ischemic stroke: a five-year retrospective study in a level-III maternity. Einstein (Sao Paulo). 2015 Jan-Mar.
Martinez-Biarge, M et al: Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology. 2011 Jun 14;76(24):  
Spring in ’t Veld, LG et al: Serial 1- and 2-Dimensional Cerebral MRI Measurements in Full-Term Infants after Perinatal Asphyxia. Neonatology. 2016 Mar 12; 110(1):27-32.
Dinan, D et al: Easily Overlooked Sonographic Findings in the Evaluation of Neonatal Encephalopathy: Lessons Learned From Magnetic Resonance Imaging. Semin Ultrasound CT MR. 2014 Dec; 35(6):
Cauley, KA et al: Apparent diffusion coefficient histogram analysis of neonatal hypoxic–ischemic encephalopathy. Pediatr Radiol. 2014 Jun; 44(6):
Okabe, T: Early magnetic resonance detection of cortical necrosis and acute network injury associated with neonatal and infantile cerebral infarction. Pediatr Radiol. 2014 May; 44(5):  
Badve, CA et al: Neonatal ischemic brain injury: what every radiologist needs to know. Pediatr Radiol. 2012 May.
Gunny , RS et al: Imaging of Perinatal Stroke. Magn Reson Imaging Clin N Am. 2012 Feb;20(1):1-33.
Izbudak, I et al: MR Imaging of theTerm and Pre term Neonate with Diffuse Brain Injury. Magn Reson Imaging Clin N Am. 2011 Nov; 19(4):
Kitamura, G et al: Hypoxic-Ischemic Injury: Utility of Susceptibility-Weighted Imaging. Pediatr Neurol. 2011 Oct; 45(4):220-4.
Vermeulen, RJ et al: Diffusion-weighted and Conventional MR Imaging in Neonatal Hypoxic Ischemia. Radiology. 2008 Nov; 249(2):631-9.