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N I C O L E J . W I L L I A M S D O O N A N , M D

D I V I S I O N O F P E D I A T R I C N E U R O L O G Y

G I L L E T T E C H I L D R E N ’ S S P E C I A L T Y H E A L T H C A R E

N o v e m b e r 2 , 2 0 1 6

Neonatal Encephalopathy: Case Studies

� Nothing to disclose.

Learning Objectives

� Recognize and evaluate encephalopathy in newborns

� Describe the utility of brain MRI and EEG for diagnosis and prognosis in neonatal encephalopathy

� Identify treatments available for neonatal encephalopathy

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Outline

� Define neonatal encephalopathy and hypoxic-ischemic encephalopathy

� Clinical evaluation of encephalopathy

� Therapeutic hypothermia

� Neuromonitoring

� Neonatal seizures

� Neuroimaging

� Perinatal stroke

Background

� Injury to the developing brain is a major cause of death and neurologic disability worldwide

� For survivors� Cerebral Palsy

� Intellectual disability

� Epilepsy

Case 1

� Term male LGA infant

� Uncomplicated pregnancy

� Delivery via stat C/S for prolapsed cord

� Depressed at birth, HR undetectable, apneic

� Apgar 1 at 1 min, 4 at 5 min, 6 at 10 min

� Resuscitation in delivery room

� PPV, intubation, spontaneous respiratory effort at 19 minutes

� Laboratory results� Cord VBG pH 6.9, base deficit 14

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Case 1

� Transfer to Children’s Hospital and Clinics- St. Paul NICU

� Initial neurologic exam� Bicycling movements concerning for seizures

� Minimal spontaneous movement, decreased level of consciousness, hyperreflexia

Neonatal Encephalopathy

� Decreased level of consciousness� Seizures� Abnormal muscle tone or strength� Abnormal reflexes� Abnormal cranial nerves� Feeding difficulties� Respiratory insufficiency or apnea� Irritability� Autonomic dysfunction� Encephalopathy

Evaluation of Neonatal Encephalopathy

� Clinical history � Pregnancy, delivery, gestational age, postnatal course, family

history

� Neurologic exam including severity of encephalopathy

� Diagnostic studies

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Causes of Encephalopathy in Newborns

� Hypoxic-ischemic insult

� 50-80%

� Intracranial hemorrhage

� Perinatal stroke

� Traumatic brain injury

� Meningitis/encephalitis

� Congenital brain malformation

� Epileptic encephalopathies

� Inborn errors of metabolism

� Hypoglycemia

� Electrolyte imbalance

� Hypocalcemia

� Severe hyperbilirubinemia

� Systemic illness (organ failure, sepsis)

Neonatal Hypoxic-Ischemic Encephalopathy

� Mechanism of injury� Interruption in blood flow or gas exchange to and from fetus

� Hypoxic-ischemic injury

� Most common cause of acute neurologic impairment and seizures in term neonates

� 1-6 per 1000 live births in developed countries

� Cause of 1 in 5 neonatal deaths worldwide

Neonatal Hypoxic-Ischemic Encephalopathy

� Clinical features consistent with acute peripartum or intrapartum event

� Apgar scores <5 at 5 and 10 minutes

� Metabolic acidosis

� Cord arterial pH <7.0 or base deficit ≥12 mmol/L

� Brain MRI/MRS consistent with hypoxia-ischemia

� Multisystem organ failure

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Neonatal Hypoxic-Ischemic Encephalopathy

� Sentinel hypoxic or ischemic event immediately before or during labor and delivery

� Ruptured uterus

� Placental abruption

� Umbilical cord prolapse

� Amniotic fluid embolus with severe/prolonged maternal hypotension and hypoxemia

� Maternal cardiovascular collapse

� Maternal fetal hemorrhage

� Fetal hemorrhage secondary to vasa previa

� Specific patterns in fetal heart trace can suggest hypoxic-ischemic event

Clinical Encephalopathy: Mild

� Increased muscle tone

� Deep tendon reflexes brisk

� Transient behavioral abnormalities

� Poor feeding

� Excessive crying, irritability

� Excessive sleeping

� Normalize 3-4 days of life

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Clinical Encephalopathy: Moderate

� Lethargic

� Low tone

� Depressed deep tendon reflexes

� Primitive reflexes sluggish or absent

� Apnea

� Seizures

� Possible full recovery 1-2 weeks

� Initially well or mild encephalopathy followed by sudden deterioration

Clinical Encephalopathy: Severe

� Stupor or coma� Low tone� Depressed deep tendon reflexes� Irregular breathing� Absent primitive reflexes� Abnormal eye movements� Pupils dilated, fixed or poorly reactive� Early seizures� Irregular HR and BP� Increased alertness 4-5 days of life� Persistent feeding and tone abnormalities

Modified Sarnat Scale

Severity Stage Stage 1 Stage 2 Stage 3

Level of consciousness

Alert, hyperalert Lethargic, obtunded

Stuporous

Spontaneousactivity

Normal Decreased No activity

Posture Normal Distal flexion, full extension

Decerebration

Tone Normal or hypertonia

Hypotonia Flaccid

Primitive reflexes: SuckMoro

NormalExaggerated

WeakIncomplete

AbsentAbsent

Autonomic function:PupilsHeart Rate

Respirations

NormalNormal

Normal

ConstrictedBradycardia

Periodic breathing

Dilated/non-reactiveVariable HR

Apnea

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Case 1

� Intrapartum event: prolapsed cord

� Laboratory evidence of hypoxic-ischemic insult

� Metabolic acidosis

� Clinical syndrome of neonatal encephalopathy

� Does the patient meet criteria for therapeutic hypothermia?

Therapeutic Hypothermia: Inclusion criteria

� ≥36 weeks gestation and birth weight > 1800 grams

� Hypothermia can be initiated <6 hrs of life

� Evidence of HIE or perinatal depression/asphyxia

� Laboratory criteria� Cord or infant blood gas within 1 hr of age

� pH <7.00 OR base deficit ≥16 meq/L

� OR blood gas with pH 7.01-7.15 or base deficit 10-15.9 AND Apgar ≤5 at 10 min or ventilation required for at least 10 min

� Neurologic exam� Moderate or severe encephalopathy based on modified Sarnat

Score (Stage 2 or 3)

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Therapeutic Hypothermia: Exclusion criteria

� Major congenital anomalies

� Chromosomal syndromes

� Major head trauma causing intracranial hemorrhage

� Condition not compatible with survival

Cochrane Review 2013: Cooling for newborns with hypoxic-ischemic encephalopathy

� 11 randomized controlled trials through May 2012

� 1505 term and late preterm infants

� Moderate/severe encephalopathy and evidence peripartum asphyxia

� Cooling instituted <6 hours of age

� Outcome at 18 months� Statistically significant and clinically important

� Reduction in death, RR 0.75, NNT 11 (11 studies, 1468 infants)

� Reduction in neurodevelopmental disability of survivors, RR 0.77, NNT 8 (8 studies, 917 infants)

� Adverse effects of cooling minimal

� Benefits of cooling outweigh short-term adverse effects

Jacobs SE et al. 2013 RR=relative risk. NNT=number needed to treat.

Neuroprotective Mechanisms of Hypothermia

� Reduction in cerebral metabolism� Prevents edema and loss of membrane potential

� Reduces accumulation of glutamate, lactate, nitric oxide

� Inhibits platelet activating factor, inflammatory cascade

� Inhibits excito-oxidative cascade leading to secondary energy failure

� Inhibits enzymes responsible for apoptosis

� Reduces extent of brain injury

� Decrease in seizures???

Shankaran 2012, Johnston 2011

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Case 1 Follow Up

� Whole body hypothermia for 72 hours

� EEG mild encephalopathy (discontinuous)

� Brain MRI normal

� Home on AED, tapered off outpatient

� Development and neurological exam at 12 months normal

Case 2

� Term AGA female infant delivered via uncomplicated repeat C/S following normal pregnancy

� Events at 7 hrs of life in well baby nursery� Stiffening with apnea followed by limpness and pallor

� Brief, self-resolved

� During feeding and during bath

� Labs: normal electrolytes, CRP, CBC

� Transferred to NICU for further evaluation

Case 2

� Spells recurred

� Clinical encephalopathy emerged

� Feeding difficulties

� Hypotonia

� Decreased level of alertness

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Diagnostic Studies for Neonatal Encephalopathy

� Neuromonitoring� aEEG

� Conventional EEG- routine

� Conventional EEG- prolonged video

� Laboratory studies� Blood

� Urine

� CSF

� Neuroimaging� Head Ultrasound

� Head CT

� Brain MRI

Neuromonitoring in the NICU

� Indications� Evaluate seizures

� Differential diagnosis of paroxysmal events

� Electrographic seizures in high risk infants

� Assess risk for seizures

� Monitor anticonvulsant therapy

� Prognosis

� Severity and duration of abnormalities predictive

� Diagnostic evaluation of encephalopathy

Shellhaas et al. 2011

Neuromonitoring in the NICU

� Conventional EEG� Pro: Gold standard

� Con: Limited access to techs, interpretation

� aEEG� Pro: Apply and interpret at bedside, track trends

� Con: Lower sensitivity and specificity for seizures

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EEG for Prognosis in HIE

� cEEG� Burst suppression or low voltage poor prognosis >48 hrs

� aEEG

� Normalization of record by 48 hrs good prognosis

Nash et al. 2011, Thoresen et al. 2010

Burst Suppression EEG

Neonatal Seizures

� Neonatal brain predisposed to seizures� Excitation predominates in neuronal networks

� Inhibition relatively underdeveloped

� Incidence seizures 22-64% in mod-severe HIE� Decreased by hypothermia?

� Increasing evidence seizures increase neurologic injury

Volpe 2008, Wusthoff et al. 2011, Scher et al. 1993, Jensen 2006.

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Focal Seizure

Rhythmic sharp waves in left hemisphere associated with clonic jerking right arm and leg

Pinto LC and Gilberti P 2001

Case 2

� EEG: seizures confirmed, burst-suppression background

� Extensive neurometabolic and genetic lab evaluations (blood, urine, CSF)

� Brain MRI normal

� Multiple anticonvulsant medications � Phenobarbital, levetiracetam, lorazepam

� Seizures controlled on therapeutic phenytoin

Neonatal Epileptic Encephalopathies

� Inborn errors of metabolism� Nonketotic hypyerglycinemia (glycine encephalopathy) � Sulfite oxidase/molybdenum cofactor deficiency

� Pyridoxine deficiency or dependency� Folinic-acid responsive syndrome� Menke’s disease

� GABA transaminase deficiency� GLUT-1 deficiency syndrome � Peroxisomal disorders� Mitochondrial disorders

� Organic acidemias

� Structural brain malformation� Focal or multifocal cortical dysplasia� Hemimegalencephaly

� Infantile epileptic encephalopathies� Channelopathies� Other gene mutations

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Case 2 Follow Up

� Infantile epilepsy gene panel identified a clinically significant gene mutation

� At 18 months, she is seizure free on medication and has mild global developmental delay

Case 3

� Term baby boy, NSVD at home

� Perinatal depression: poor respiratory effort, received bag-mask ventilation, Apgars 4,6,8

� Seizures began at 1 ½ hrs of life (bicycling,

lipsmacking)� sodium 119, loaded phenobarbital

� Subsequent seizures within first 12 hrs of life

� tongue thrusting, lip smacking, rhythmic jerking both

arms and legs, clonic left arm only

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Case 3

� Exam: decreased movement and low tone of L arm

� EEG: initially discontinuous but normal by 2nd day of life, no epileptic activity

� Next diagnostic study?

Goals of Neonatal Neuroimaging

� Etiology of brain injury

� Evolution of brain injury

� Monitor effect of intervention

� Prognosis for future neurodevelopment

Imaging Modalities: Pros and Cons

� Head Ultrasound

� Head CT

� Brain MRI

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Brain MRI in HIE

• Brain MRI• Signal abnormalities on T1/T2 sequences appear 3-4 days

and best seen >7 days after injury

• Diffusion-weighted imaging

• Sensitive for acute ischemia

• Diffusion abnormalities most prominent 24-96 hrs of life

• Pseudonormalization 6-8 days (>10 days if cooled)

• MR spectroscopy

• High lactate within few hrs, NAA declines in days-week

• Severity of changes correlates with severity of brain injury

Bednarek et al. 2011

MRI for Prognosis

� Presence and severity of brainstem injury strongest predictor of neonatal death

� Abnormal signal posterior limb of internal capsule predicts inability to walk independently by 2 years

� Sensitivity 0.92, specificity 0.77

� MRI after hypothermia remains accurate predictor

Martinez-Biarge et al. 2011, Rutherford et al. 2010

Case 3

� MRI: acute stroke in right MCA territory

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Perinatal Stroke

� Focal or multifocal disruption in cerebral blood flow� Arterial or venous� Thrombosis or embolization

� Age between 20 weeks fetal age to 28 days postnatal age

� Confirmed by neuroimaging or neuropathologicalstudies

� Symptoms in neonates� Seizures� Encephalopathy� Abnormal neurologic examination

Perinatal Arterial Stroke

� Incidence:� As high as rates of large-vessel arterial strokes in adults

� >1:2500-4000 live births

� 90% occur within first week of life

� Risk factors for perinatal stroke� Infection, complex congenital heart disease,

preeclampsia, maternal drug use, traumatic delivery, inherited or acquired defect in coagulation, placenta pathology

� Recurrence rate <3%

Lee et al. 2005, Lynch 2009.

Case 3 Follow Up

� Remaining NICU course� Sodium normal by second day of life

� No seizures after 12 hrs of life

� Normal exam, weakness resolved by day 3

� At 19 months, mild left arm weakness and seizure-free

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Conclusions

� Causes of neonatal encephalopathy are diverse

� History, clinical examination and special diagnostic studies all contribute to determining the underlying diagnosis

� Effective treatments require recognition of the syndrome of neonatal encephalopathy and specific diagnosis of underlying etiology

� Newborn nurses have a critical role in recognizing encephalopathy in their patients

References-1

� Bednarek et al. Impact of therapeutic hypothermia on MRI diffusion changes in neonatal encephalopathy. Neurology 2011;78:1420-7.

� D’Alton ME et al. Neonatal Encephalopathy and Neurologic Outcome, Second Edition. Obstetrics & Gynecology 2014;123(4):896-901.

� Jacobs SE et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013.

� Jensen FE. Developmental factors regulating susceptibility to perinatal brain injury and seizures. Curr Opin Pediatr. 2006;18:628-33.

� Johnston et al. Treatment advances in neonatal neuroprotection and neurointensive care. Lancet Neurol 2011;10:372-82.

� Lee et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Annals of Neurology 2005;58:303-308.

� Lynch JK. Epidemiology and classification of perinatal stroke. Seminars in Fetal & Neonatal Medicine 2009;14:245–249.

� Martinez-Biarge et al. Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. Neurology 2011;76:2055-61.

� McAdams RM and Juul SE. Neonatal encephalopathy: update on therapeutic hypothermia and other novel therapies. Clin Perinatol 2016;43:485-500.

� Nash et al. Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia Neurology 2011;76(6):556-62.

References-2

� Nelson et al. Antecedents of neonatal encephalopathy in the Vermont Oxford Network encephalopathy registry. Pediatrics 2012;130:878-886.

� Pinto LC and Giliberti P. Neonatal seizures: background EEG activity and the electroclinicalcorrelation in full-term neonates with hypoxic-ischemic encephalopathy. Analysis by computer-synchronized long-term polygraphic video-EEG monitoring. Epileptic Disorders 2001;3(3):125-32.

� Rutherford et al. Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischemic encephalopathy: a nested substudy of a randomized controlled trial. Lancet Neurol 2010;9:39-45.

� Scher et al. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 1993;91(1):128-34.

� Shankaran S. Hypoxic-ischemic encephalopathy and novel strategies for neuroprotection. ClinPerinatol 2012;39:919-929.

� Shankaran S et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84.

� Shellhaas RA et al. The American clinical neurophysiology society’s guideline on continuous EEG monitoring in neonates. J Clin Neurophys 2011;28(6):611-7.

� Thoresen et al. Effect of hypothermia on amplitude-integrated electroencephalogram in infants with asphyxia. Pediatrics 2010;126(1):e131-9.

� Volpe JJ. Neurology of the newborn, 5th Ed. 2008.� Wusthoff et al. Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-

ischemic encephalopathy. J Child Neurol 2011;26(6):724-8.