Imaging the Brain in Neonatal Encephalopathy Steven P. Miller MDCM CIHR Clinician Scientist & MSFHR Scholar Associate Professor, Pediatrics (Neurology) University of British Columbia

Neonatal Encephalopathy Neurological emergency Evolves over time The 2 Questions What is the Diagnosis? What is the Prognosis?

T1 T2 DWI CT Normal with day 10 confirmation FLAIR NOT HELPFUL!

CT, MRI, or DW-MRI Chau V et al Pediatrics 2009 Patterns of Injury Basal Nuclei Predominant Watershed Predominant Total Focal- Multifocal CT, MRI, or DW-MRI Chau V et al Pediatrics 2009

Basal Nuclei with Cortical Injury CT MRI ADC BN pattern agrees for all modalities, but cortical injury not seen on CT: Basal Nuclei with Cortical Injury

Watershed Pattern Perinatal Events Important! WS lower bwt BG more seizures and intensive resusc

Images Courtesy of Dr. Hannah Glass UCSF

CT MRI ADC A B C D Total pattern: Total Chau V et al Pediatrics 2009

White Matter Injury Stroke Li A, et al. Pediatric Research, 2009

FIGURE 1. A-D, Axial T2WI at the level of cerebellum (A), mid-brain (B), internal capsule (C), and corona radiata (D) shows the classic MSUD edema in the deep cerebellar white matter, cerebral peduncles, posterior limb of internal capsules, and the corona radiata, respectively. Note the relatively normal splenium of the corpus callosum (D). E-H, Isotropic diffusion-weighted images at the corresponding levels show marked hyperintensity in the deep cerebellar white matter, cerebral peduncles, dorsal brainstem, posterior limb of the internal capsules, and the corona radiata, suggestive of restricted diffusion. I-L, Apparent diffusion coefficient (ADC) maps in the same location reveal decrease in the ADC values. The areas with restricted diffusion and decreased ADC value appear as dark areaa in these maps. M-P, Fractional anisotropy (FA) maps at the corresponding levels as T2WI show that the FA values are diminished in the corresponding areas. The splenium of the corpus callosum (P) was unaffected and served as a comparative benchmark for the other areas. Parmar H et al. Journal of Computer Assisted Tomography; 2004. 29: 93-97

Day 3 CT vs DW-MRI Agreement= 66.7% Kappa= 0.56 13 1 2 7 3 6 4 Sum 16 Normal Watershed Basal Nuclei Total Multi-Focal 13 1 2 7 3 6 4 Sum 16 8 Agreement= 66.7% Kappa= 0.56 Chau V et al Pediatrics 2009

Dav: A Window on Timing Time course of the diffusion abnormality following perinatal brain injury in newborn infants. Dav has been normalized to reference values for newborn infants (Dav ratio). The maximum reduction in Dav ratio of approximately 35% occurs between days 2 and 3. Pseudonormalization is noted after the seventh day. Figure 3. Images from Patient 10 with basal ganglia injury (status marmoratus pattern) following delivery complicated by shoulder dystocia. The region of interest used for analysis is the area of hyperintensity in the posterior putamina and ventrolateral thalami shown in the T1-weighted image at 7.8 days (arrow). T2-weighted images at the same time show corresponding signal hypointensity. These findings are consistent with petechial hemorrhage developing in regions of central gray matter infarction. The Dav scan at 1.9 days clearly shows an area of reduced diffusion in the region of the lentiform nuclei and thalami (arrow). As in figure 2, the Dav maps show the injury earlier than the conventional MR images. From McKinstry RC et al. Neurology. 2002 59:824-33.

Dav T1 Day 3 Courtesy Dr. Ken Poskitt, UBC

Dav T1 Day 3 Day 8 Courtesy Dr. Ken Poskitt, UBC

MR Spectroscopy Lactate/NAA more predictive than quantitative T2 Miller SP et al. Pediatric Research 2001 Lactate/NAA more predictive than quantitative T2 Shanmugalingam, S. et al. Pediatrics 2006;118:1467-1477

34 Hours Barkovich AJ, Miller SP et al. AJNR 2006 Cho NAA Home delivery complicated by LGA infant and shoulder dystocia. After prolonged delivery, infant was cyanotic, limp. Infant was given CPR for 40 minutes before spontaneous respirations. Seizures at about 5 hours, treated with phenobarbital New involvement of white matter pathways on second study. Studies performed at day 2 and day 7. A-C. Axial Dav maps at 34 hours show reduced diffusivity (Dav reduced by about 50%, black arrows) in the ventrolateral thalami, posterior limbs of internal capsules, and corticospinal tracts in centrum semiovale. No other areas of reduced diffusivity are identified. D. Proton MRS from the left basal ganglia at 34 hours shows mild lactate (Lac) elevation. E-H. Axial Dav maps at 148 hours show that diffusivity in the deep gray nuclei has normalized (values were within 5% of normal). However, new areas of reduced diffusivity are seen in what are believed to be the optic radiations (medium white arrows in E), corpus callosum (small white arrows in F and smaller white arrows in G), cingulum (medium white arrows in H), and superior longitudinal fasciculus (larger arrows in G). I. Proton MRS from left basal ganglia at 148 hours shows that lactate (Lac) has increased in comparison with NAA, choline, and creatine. NAA is the most reduced metabolite. Barkovich AJ, Miller SP et al. AJNR 2006

34 Hours Day 7 Barkovich AJ, Miller SP et al. AJNR 2006 Cho NAA Home delivery complicated by LGA infant and shoulder dystocia. After prolonged delivery, infant was cyanotic, limp. Infant was given CPR for 40 minutes before spontaneous respirations. Seizures at about 5 hours, treated with phenobarbital New involvement of white matter pathways on second study. Studies performed at day 2 and day 7. A-C. Axial Dav maps at 34 hours show reduced diffusivity (Dav reduced by about 50%, black arrows) in the ventrolateral thalami, posterior limbs of internal capsules, and corticospinal tracts in centrum semiovale. No other areas of reduced diffusivity are identified. D. Proton MRS from the left basal ganglia at 34 hours shows mild lactate (Lac) elevation. E-H. Axial Dav maps at 148 hours show that diffusivity in the deep gray nuclei has normalized (values were within 5% of normal). However, new areas of reduced diffusivity are seen in what are believed to be the optic radiations (medium white arrows in E), corpus callosum (small white arrows in F and smaller white arrows in G), cingulum (medium white arrows in H), and superior longitudinal fasciculus (larger arrows in G). I. Proton MRS from left basal ganglia at 148 hours shows that lactate (Lac) has increased in comparison with NAA, choline, and creatine. NAA is the most reduced metabolite. Barkovich AJ, Miller SP et al. AJNR 2006

Hypothermia: protects the Basal Nuclei Basal nuclei OR 0.36 (P=0.02) White matter OR 0.3 (P=0.01) Cerebral Cortex OR 0.62 (P=0.25) Rutherford M et al. Lancet Neurol 2009 E Pub

Imaging at BC Children’s Day 3 MRI: T1, T2 DWI MRSI Day 10 If cooled If exam and imaging discordant NEED CONSISTENCY FOR INTERPETATION!

Differential Diagnosis

Take Home Neonatal Encephalopathy is a neurological emergency What is the diagnosis? What is the prognosis? Neuroimaging key Need standardized protocols and high quality review Neonatal Encephalopathy is a neurological emergency that evolves over time

UBC UCSF Support CIHR Michael Smith Foundation Neonatal Brain Disorders Center Donna Ferriero MD A. James Barkovich MD Hannah Glass MD Sonia Bonifacio MD David V Glidden PhD MR Science Center Daniel Vigneron PhD Support CIHR Michael Smith Foundation NIH:NS35902, RR01271(PCRC) Hospital for Sick Children Foundation Canada Foundation for Innovation CFRI and UBC BC Children’s Hospital Foundation Neurology Steven Miller MD Vann Chau MD Sandy Belanger RN Mark Chalmers RRT Janet Rigney Alan Hill MD PhD Elke Roland MD Bruce Bjornson MD Neonatology Anne Syness MD Brian Lupton MD Ruth Grunau PhD Rebecca Sherlock MD Radiology Ken Poskitt MD Michael Sargent MD

Miller SP, et al. J Peds 2005