Neonatal Encephalopathy

Hannah C. Glass, MDCM, MAS Professor Neurology & Pediatrics University of California, San Francisco

February 2020

15th Hot Topics in Neonatal Medicine

Jeddah, Saudi Arabia

San Francisco

Objectives

List the causes of neonatal

encephalopathy

Explain the evidence for hypothermia

therapy

Understand prognosis after hypothermia.

therapy

Arterial/Venous Stroke Hemorrhage

Infection

HIE

Inborn Error of

Metabolism Malformation Epileptic

Encephalopathy

Many Causes of Encephalopathy

Hypoxic-Ischemic Brain Injury

• Neonatal encephalopathy due to peripartum asphyxia

• Perinatal asphyxia affects 3-5 per 1000 live births – 0.5-1 per 1000

will have HIE

HIE - Etiology

• Impaired placental or pulmonary gas exchange

• Placental abruption, cord rupture, uterine rupture, nuchal cord, true knot

Primary energy failure

(minutes) Early cell death -

necrosis

Hypoxic-Ischemic

Injury

Depletion of glucose & ATP

Anaerobic metabolism

Failure of ATP dependent pump

Membrane depolarization

Na+

Intracellular Ca++

Extracellular glutamate

Therapeutic

window for

hypothermia

Secondary energy failure

(hours to days) Late cell death -

apoptosis

Reperfusion

Chronic brain injury

(weeks to months)

Delayed cerebral

atrophy and cell

loss

Partial recovery of oxidative

metabolism

Inflammation

Excitatory amino acids

Extracellular Ca++ NO, H2O2

Cell death

Inflammation Oxidative Stress R

esp

on

se

Hours Days Weeks

Timing: Injury and Repair

Excitotoxicity

Ferriero DM, NEJM

Repair

HIE - Clinical Features

• Low Apgar scores

• Acidotic cord gas

• Advanced resuscitation (ventilation, chest compressions, epinephrine)

• Multi-organ failure – hypotension, high liver enzymes, coagulopathy

• Abnormal mental status, abnormal neurological examination, seizures

Clues that NE is not HIE

Condition

• No event/normal delivery

• Seizure onset at birth

• Seizures don’t stop within 4 days

• Difficulty extubating

What to consider

• Genetic, inborn error of

metabolism, infection

• SSRI

• Genetic epilepsy, inborn

error of metabolism

• Neuromuscular

Sarnat Staging 1976

Barkovich et al. AJNR 2006

T1

ADC

NAA

Cho

Cr

Lactate

Basal Ganglia/

Thalamus

Injury

HIE - Neuroimaging

Slide courtesy of Dr. Sonia Bonifacio

Watershed

Injury

T2

ADC

NAA

Cho

Cr

NAA

Cho Cr

Lactate

Barkovich AJ AJNR 2001

Slide courtesy of Dr. Sonia Bonifacio

HIE - Outcomes

• 10-20% mortality

• Additional 25% develop severe impairment

• Cerebral palsy, intellectual disability, epilepsy

Hypothermia

Hypothermia optimization

Add-on therapies/alternate agents

Neurocritical care – “brain focused care”

Neuroprotective Strategies

Hypothermia

Hypothermia optimization

Add-on therapies/alternate agents

Neurocritical care – “brain focused care”

Neuroprotective Strategies

• Core temperature of 33.5°C x 72 hours – Passive cooling

initiated at referral center

Hypothermia Overview

Slide courtesy of Sonia Bonifacio

• Brain Monitoring – with aEEG/cEEG - Provides information about prognosis

- Seizures are common (34 – 65%)

• MRI at completion of treatment

• Most discharged at 7-15 days

Favors hypothermia for death/disability at 18-22 months

Increased rate of normal survival

Lower death/severe disability at school age

Number needed to treat = 6-9

The Evidence: Moderate/Severe HIE

Tagin et al. JAMA Pediatrics 2013

Shankaran S et al, NEJM 2012

The Conundrum of “Mild” HIE

Shankaran S et al. N Engl J Med 2005

NICHD Trial: Moderate/Severe HIE

>3 criteria at <6 hours after birth

Shankaran S et al. N Engl J Med 2005

“Mild” excluded as these infants were thought to have a good outcome

The Conundrum of “Mild” HIE

Sarnat Stages are Not Static

21 participants

Stage 1 Stage 2 Stage 3

7 (33%)

9 (43%)

4 (19%)

1 (5%)

Stage 1 lasted >6 hours for >70% Sarnat & Sarnat 1976

MRI in “Mild” HIE

• Injury in 20-40%

– Includes severe

lesions that are

highly predictive of

poor outcome

– Watershed is the

predominant

pattern

Walsh B & Inder T, Early Hum Dev 2018

Neurodevelopment in “Mild” HIE

• PRIME study – International cohort

– 16% with disability

• Systematic review

– 16 observational studies

• 22% had an abnormal outcome

– 4 RCT

• Abnormal outcome - cooled 29% vs not cooled

37% (p=0.6)

Chalak LF et al, Pediatri Res 2018

Conway JM et al, Early Hum Dev 2018

“Mild” HIE does not have a uniformly good outcome!

“Not fulfilling NICHD moderate-severe”

Shankaran S et al. N Engl J Med 2005.

The Conundrum of “Mild” HIE

Which newborns will evolve from mild moderate?

How should we define “mild”

encephalopathy?

When should we perform the encephalopathy exam?

What is the role of ancillary testing?

The Conundrum

Can we accurately determine the degree of

encephalopathy <6 hours? Can clinical signs determine who will or will not

benefit from cooling?

UCSF Cooling Criteria

Thoresen et al, Pediatrics 2010

Nash et al, Neurology 2011

Normalreassuring

Persistent abnormal

brain injury, death, disability

EEG/aEEG and Prognosis

MRI and Prognosis

Rutherford, Lancet Neurol, 2009

•Decreased lesions - Basal ganglia & thalamus > white matter

• Excellent accuracy - Normothermia 0·81 (0·71 – 0·91)

- Hypothermia 0·84 (0·74 – 0·94)

Normal Mild injury Moderate-severe injury

Predicting Outcome:

Counseling Families

203 Cooled neonates from 3 centers internationally

Outcome = death/severe disability

Birth/

Resuscitation Factor

1.0 (0.4-2.6) P=0.97

Persistent Abnormal

aEEG at 24 hours

5.4 (1.4-21.3)

P = 0.015

Moderate-Severe MRI

Injury

8.2 (2.9-32.4)

P<0.0001

Day 1 Day 2 Day 4-5

Bonifacio SL et al, PAS 2013

Summary

• Hypothermia is standard of care for neonatal encephalopathy due to perinatal asphyxia (HIE) – Always consider the differential diagnosis of NE

– Lower risk of death and disability

• Risk/benefit of treating “mild” encephalopathy not known

• Prognosis – Neonates with normal/near normal aEEG/EEG and normal

MRI have a good outcome

– Neonates with basal ganglia injury spastic/dyskinetic quadriparesis

– Watershed injury usually do very well

– Severely abnormal EEG/MRI death/severe disability

Acknowledgements Neurology

Donna M. Ferriero, UCSF

Dawn Gano, UCSF

Sharon Wietstock, UCSF

Yvonne Wu, UCSF

Steven Miller, Hospital for Sick Children

Vann Chau, Hospital for Sick Children

Emily Tam, Hospital for Sick Children

Taeun Chang, DC National Children’s Hospital Janet Soul, Boston Children’s Hospital Faye Silverstein, U Michigan

Kevin Staley, Mass General Hospital

Monica Lemmon, Duke

Cameron Thomas, Cincinnati Children’s

Neonatology/Pediatrics

Sonia Bonifacio, UCSF/Stanford

Elizabeth Rogers, UCSF

Michael Kuzniewicz, Kaiser Permanente

Patrick McQuillen, UCSF

Neuroradiology

A. James Barkovich, UCSF

Duan Xu, UCSF

Olga Tymofiyeva, UCSF

Yi Li, UCSF

Neurophysiology Joseph E. Sullivan, UCSF Maria Roberta Cilio, UCSF Adam Numis, UCSF Renee A. Shellhaas, U Michigan

Nicholas Abend, CHOP Courtney Wusthoff, Stanford Tammy Tsuchida, DC National Children’s Hosp Catherine Chu, Mass General Hospital Shavonne Massey, CHOP

Biostatistics and Epidemiology Charles McCullough, UCSF David Glidden, UCSF Nursing Linda Franck, BSN, PhD Susan Peloquin, Elizabeth Papp, Jeannie Chan NICN Nurses, UCSF

Psychology Shannon Lundy, UCSF Bridget Johnson, UCSF Research Assistants Laurel Haeusslein

Manogna Manne Jessica Kan Vedder Isheeta Madeka Bria Bailey Rebecka Craig Olivia Girvan

Children

&

Families