Imaging Evaluation of Neonatal

Hypoxic-Ischemic
Encephalopathy
(HI Injury)

Kenneth D. Williams, MD
 Disclosures
• Financial Disclosures – None

• Off-Label Applications – None

• Acknowledge
– Dr. Krista L. Birkemeier
– Dr. Matthew B. Crisp
 Key Points
• Hypoxic-Ischemic Injury findings depend on:
– Brain Maturity at the time of the event
– Severity and Duration of Hypoperfusion
• 4 Basic Patterns
• Appearance evolves over time. “ITITL”
• Modalities available:
– US – Easiest to obtain
– CT – Limited Role for Hemorrhage / Mass
– MRI – Best examination overall
 Key Points
• HII is a metabolic insult and therefore it is
generally bilaterally symmetric in
appearance, i.e. can be tough to detect.

• We talk of patterns but, neonates can’t

read the medical literature.
– Mixture of various patterns
– Wild and crazy appearances
Proper History is Vital
 Hypoxic-Ischemic Injury
• Combination of :
Hypoxia (Reduced Blood Oxygenation) &
Ischemia (Reduced Blood Flow).
• Vulnerable areas depend on brain maturity and
whether blood flow can be redistributed to
preserve the areas of greatest metabolic
demand.
• Severe insult – CBF cannot redistribute.
– Areas of highest metabolic activity are injured.
• Mild to Moderate insult – CBF can redistribute
– Vascular border zones are injured.
 Brain Maturation
• Term Infant - 37 Weeks EGA or greater

• Preterm - < 37 Weeks EGA

– Late Preterm - 34 – 36 Weeks EGA
– Moderately Preterm - 32 – 33 Weeks EGA
– Severely Preterm - 28 – 31 Weeks EGA
– Extremely Preterm - < 28 Weeks EGA
 Birth Weight
• Low Birth Weight < 2,500 g (35 wks)
– 11% of all births – 90% of neonatal deaths

• Very Low Birth Weight < 1,500 g (30 wks)

– 500 – 1,500 gm - 1% of all births – 60% deaths

• Extremely Low Birth Weight < 1,000 g (27wks)

500 g (22 wks)

 Vulnerable Structures
• Areas at highest risk:
– Most myelinated
– Highest perfusion
– Most mature metabolism
– Greatest glucose uptake
• Cellular vulnerabilities
– Preoligodendrocytes
– Subplate neurons
– Germinal matrix capillary endothelium
 Vascular Border Zones
Now cellular vulnerability

Premature Infant Term Infant

Periventricular WM Parasagittal

Ventriculopedal Ventriculofugal

Transition at 34 to 36 weeks gestation

Chao Radiographics 2006;26:S159-S172
 Event Severity & Duration
• Mild to Moderate Hypoperfusion (Partial)
– 30 Minutes to several hours (Prolonged)
– CBF can redistribute

• Severe Hypoperfusion (Profound)

– Complete / Near complete cessation of blood flow
– > 10 - 15 minutes (Acute)
– Inadequate CBF redistribution
 4 Major Patterns of Injury
Term Preterm

Mild/Mod Parasagittal BZ GMH

WMIP

Severe Lat Th/Post Put/GP Thal/BS

Hippo/Peri Rol/BS Cbll
 Modalities
• Ultrasound – GMH > 5mm
Hydrocephalus
Cavitary WMIP

• CT – Evaluation of Large Hemorrhages

• MRI – Most sensitive test for Ischemic Injury

Non-cavitary WMIP
 US – When ?
• Symptomatic neonate – Immediately
– Hemorrhage / Mass / Anomaly / Hydrocephalus
– Edema of early HII +/-
• GMH screening – Asymptomatic
– <1,500 gm and / or < 32 weeks EGA
– Initial at Day 7 (Range 4 – 14)
– Negative – FU Day 30, 42, 60, 36 w EGA, D/C
• Periventricular leukomalacia / Hydrocephalus
– Positive GMH - IVH – 1 week FU R/O PVD
• Progressive Posthemorrhagic Ventricular Dilatation
Ct – When ?
• Large Hemorrhages

• Large Masses

• Pre-surgical

• Ionizing Radiation

• Insensitive
MRI
www.mrineonatalbrain.com
 MRI
• Coordination to insure a safe study
• STABLE patient / Monitor ABC’s
• Minimize delays in transit and scanning
• Dedicated neonatal head or knee coil
• Feed and Swaddle / Rare Chloral Hydrate
• Ear protection
• Real time image evaluation
 MRI
• Prioritize sequences – more useful 1st
– Diffusion weighted imaging b 800 / 1,000
• Trace diffusion & ADC maps
– T1 weighted images - Inc TR 800+ msec
– T2 weighted images - Inc TR 9,000+ msec
– T2* weighted images (Hemorrhage)
• GRE / SWI
– Magnetic resonance spectroscopy
• Early scan < 48 hours or metabolic disorder ?
– High resolution 3D images / MRA or MRV
 Diffusion Weighted Imaging
• Based on random molecular motion
– Infarction – cellular swelling constricts the
extracellular space leading to restricted
(reduced) free diffusion.
• Two main types of images
– Trace Diffusion Images - T2 & Diffusion
– ADC Maps - Diffusion only
• Restricted diffusion is always opposite the
signal of CSF which freely diffuses.
 Arterial Ischemic Stroke

• Light bulb bright

restricted diffusion on
Trace images. Trace DWI

• ADC reduction
confirms it is not
T2 shine through
ADC Map
• Very rapid onset –
minutes.
 DWI in HII
• More subtle abnormalities may be seen.
– Not a light bulb.
• More gradual onset.
– Can underestimate disease 24 – 48 hrs.
• Will return to normal – pseudonormalize –
at 5 – 7 days.
• Best at Day 3 to 5.
 MRI – When ?
• Early < 24 – 48 hours
– MR Spectroscopy will be needed
– DWI and Standard images may underestimate extent
of injury
– Follow-up in 4 – 10 days may be needed
• Short term delay 3 to 5 days
– DWI reliable & not pseudonormalized
– T1 and T2 changes likely present
– Normal probably needs no later FU
• Second week imaging may best predict outcome.
• Longer term follow-up 3 to 6 months.
 NICHD Cooling Protocol
• Meet Inclusion Criteria
– Term or Late Preterm Infant EGA => 36 w
– < 6 hours old
• Cooled for 72 hours to 34o C
– Whole-body Cooling
– Head Cooling Cap
• Rewarmed over 6 hours
Cooling for infants < 36 weeks EGA is unproven.
 MR Spectroscopy
• Most important for:
– Early MRI < 24 – 48 hours
– Other metabolic disorders that emulate HII
• Lactate is a key finding
– Not present in a term neonate but is normal in a
premature infant and in the CSF.
• Elevated glutamate / glutamine
• Reduced NAA (normally lower in neonates)
• Sample Basal Ganglia & Parasagittal
Lactate @ 1.33 ppm

Chao Radiographics 2006;26:S150-S172.

 Term Normal MRI

T1 T2
 Term Normal MRI

Trace DWI ADC Map

30 Week EGA Normal MRI
 Term – Mild / Moderate
• Parasagittal Borderzone injury
– Cortex and underlying white matter
– Between ACA, MCA, PCA territories

• MRI best modality

Term 3,860g Ap 8/9 Sz 10 hr

MRI Day 3
Term 3,670g Abruption Sz 5hr

MRI Day 8
Term 3,670g Abruption Sz 5hr

MRI 7 Months
 Term - Severe
• Lateral Thalamus / Posterior Putamen
• Globus Pallidus
• Hippocampi
• Brainstem (dorsal)
• Sensorimotor cortex and corticospinal tracts

• Modalities – MRI best by far

US in very skilled hands
Vulnerable Areas
Term Apneic Episode Day 3 Sz

CT 24 Hours
Term Apneic Episode Day 3 Sz

MRI 4 days after Sz

Term Apneic Episode Day 3 Sz

5 Weeks Later
Term 3,700g Ap 0/3/4

Cooled US Day 4
Term 3,700g Ap 0/3/4

MRI Day 12
 Preterm - Severe
• Thalamus

• Brainstem

• Cerebellum – Anterior vermis

• Modalities – MRI best by far

US in very skilled hands
36 W EGA 1,900 g Ap 1/4/4

MRI Day 10
31 w EGA 1,260 g

MRI Day 16
 Total Cortical Injury Pattern
“White Cerebrum”
• Uncommon diffuse brain injury pattern.
– Barkovich 2 % of patients at UCSF.

• Cortex and subcortical injury.

• Cerebellum relatively spared.

Late Term Birth Anoxia Sz

MRI Day 2
Late Term Birth Anoxia Sz

23 Months Later
 Preterm – Mild / Moderate
• Most often < 32 weeks EGA
• Germinal Matrix Hemorrhage (GMH)
– 4 Grades
• White Matter Injury of Prematurity (WMIP)
– Periventricular Leukomalacia (PVL)
• Cellular vulnerability > Border zone
• Modalities – US / MRI in some cases
 Germinal Matrix
• Vascular area of neuron and glia
generation along ependymal surface.
– Most active weeks 8 to 28.
• Involutes in the third trimester.
• Ganglionic eminence at the caudothalamic
groove is the last to involute.
• GM Hemorrhage generally < 32 wk EGA
and < 1,000 gm
– Rare after 34 weeks / 90 % by Day 4 of life
 GMH Grades – Papile 1978
• Grade 1 – Intraparenchymal at Gang Em
No intraventricular extension
• Grade 2 – Intraparenchymal with extension
Into the ventricle – NO dilatation
• Grade 3 – Intraparenchymal with ventricle
Extension and ventricular dilatation
• Grade 4 – Periventricular Hemorrhagic
Infarction (PVHI)
 PVHI
• New term for Grade 4
GMH recognizing
etiology
• Terminal vein
compression by small
bleed leads to vein
occlusion and larger
venous infarction with
hemorrhage in the
medullary vein
territory
Germinal Matrix – Intraventricular Hemorrhage

Periventricular Venous Congestion

Periventricular Ischemia

Periventricular Hemorrhagic Infarction

Grade 1 Hemorrhage
Grade 2
Grade 2
Grade 3
Grade 3
Grade 4
 Cerebellum
• 10 to 25 % of preterm
neonates have GMH
in the posterior fossa.
• External granular cell
layer of the
cerebellum is GM
• Supplemental
Posterior or Mastoid
Fontanelle views are
recommended
Cerebellar GMH US

MEDPIX from http://rad.usuhs.mil/medpix

27.5 w EGA 1,140 g Twin

GRE MRI at 2 Months

 White Matter Injury
of Prematurity
• Older term – Periventricular Leukomalacia
– Not just from HII
• Infections, metabolic disease, hydrocephalus can
injure the periventricular white matter.
– It’s not just the periventricular white matter.
• Cavitary and Noncavitary
– US can detect cavitary disease but is
insensitive to noncavitary. (5 – 10 % neonates)
– Autopsy & MRI WMIP prevalence is 50 %
27.5 w EGA Asymptomatic

Day 18 Day 30

Cavitary WMIP
27.5 w EGA Asymptomatic

Day 60

Cavitary WMIP
 Noncavitary WMIP MRI
• Punctate short T1 within larger areas of
long T2 seen at Day 3 to 4.
• Mild T2 shortening appears at Day 6 to 7.
– Areas of reactive astrogliosis
– Not hemorrhage (Lower T2 and GRE/SWI+)
• May be seen on DWI early on as well
34 w EGA 1,520 g Apgars 2/4/6

MRI Day 6
34 w EGA 1,520 g Apgars 2/4/6

MRI Day 6
34 w 3 d EGA Ap 2/6/8 Sz

MRI Day 4
 Poor Prognosis
• Brainstem Injury – Death
• Total Cortical Injury pattern (Global)
• Abnormal PLIC –Ability to Walk
– Only for >36 weeks EGA
• Abnormal thalamus & basal ganglia - Motor
• Grade 3 and 4 GMH - Neurodevelopmental
• Abnormal MRS – Poor Outcome
 ADC and Prognosis
• Hunt Pediatrics 2004
– PLIC < 0.74 um2/ms Survives – Bad Outcome
– Mean ADC PLIC
• Nonsurvivor 0.75 +/- 0.17
• Survivor 0.89 +/-0.17
• Wolf Radiology 2001
– > 1.0 um2/ms PLIC Controls
• Rutherford Pediatrics 2004
– WM infarctions <1 .1x10-3 mm2/s
– Thalamic infarctions < 0.8x10-3 mm2/s
• Vermuelen Radiology 2008
– PLIC < 85x10-5 mm2/s Poor Outcome
Radiology November 2008
 Differential Diagnosis
• Neonatal Hypoglycemia
• Kernicterus
• Infection
– Type II Herpes encephalopathy
– Human parechovirus
• Metabolic disorders
– Maple syrup urine disease
– Non-ketotic hyperglycinemia
– Urea cycle disorders
– Leigh syndrome – Pyruvate dehydrogenase
• Nonaccidental trauma