neonatal encephalopathy approach

1. Approach to Neonatal Encephalopathy
Lalida Wisedjinda, MD.
Phisitphon Ounchokdee, MD.
Fellowship in Pediatric Neurology
Ramathibodi Hospital

2. Neonatal Encephalopathy (NE)
• Clinical syndrome defined as transient or permanent
brain dysfunction in a newborn >35 weeks GA
– Altered mental status
– Abnormal neurologic examination
• Various etiologies (in addition to HIE)
• Careful history, examination and judicious use of
investigations can help determine the cause

3. Clinical Signs of NE
• Key feature: disturbance in the degree or quality of
consciousness
• Other features:
– Seizures
– Cardiorespiratory compromise
– Abnormal tone and reflexes
– Poor feeding

4. Examination Findings Suggestive of NE
• Level of consciousness  Hyperalert or lethargic to obtunded
• Muscle tone  Hypotonic
• Posture  Distal flexion
• Deep tendon reflexes  Increased
• Suck  Weak or absent
• Moro reflex  Incomplete or absent
• Autonomic features  Tachycardia or bradycardia
 Desaturation or apnea
• Seizures  Focal/ multifocal
Russ JB, et al. Neoreviews 2021;22(3):48-62.

5. Etiologies of NE
Pressler RM, et al. Epilepsia 2021;62:615-628.

6. Determining the Etiologies
• Initial step: good resuscitation and supportive management
• Consider the etiology:
– Can lead to specific treatments
– Aid with prognosis and recurrent risk counselling
– Assist with the evaluation of medicolegal implications
• Assessment:
– Detailed history and neonatal examination
– Possibly parental examination
– Judicious use of investigations
Martinello, et al. Arch Dis Child Fetal Neonatal Ed 2017;102:346-358.

7. History
Pregnancy and labor history
• Acute event occurring around the time of birth (non-reassuring FHR, APH, cord
prolapse, etc.)
• ANC history: fetal growth, fetal abnormalities on US or MRI
• Maternal infections or carriage of GBS
• Maternal hypertension, pre-eclampsia
• Maternal hypotension
• Gestational diabetes
• Illness during pregnancy such as viral infections that may affect the fetus
• Maternal prescribed drug use
• Maternal illicit drug use, particularly cocaine
• Predisposing features to non-accidental injury of baby

8. Maternal past medical history
• Multiple miscarriages, stillbirths or
neonatal deaths
 Genetic, thrombophilia and metabolic causes
• Diabetes  Fetal thrombotic vasculopathy, hypoglycemia
• DVT or other clotting disorders  Thrombophilia
• Arterial ischemic stroke  Thrombophilia or vascular abnormalities (such as COL4A1
mutation)
• Learning disabilities  Genetic/ metabolic, including myotonic dystrophy
• Family history of cerebral palsy  Vascular abnormalities, thrombophilia
• Cataracts  IEM, myotonic dystrophy, COL4A1 mutation
• Stiffness or startling  Myotonic disorders or hyperekplexia
• Weakness or fatigue  NM problem, maternal hyperparathyroidism
• Features of autoimmune disorders  Endocrine abnormalities, heart block
• Distal weakness, foot/ toe abnormalities  Peripheral neuropathy

9. Examination of the parents
• In case of suspected neuromuscular disorder
• Neuropathies  Distal weakness, suppressed or absent reflexes,
feet/ toes deformities, possible loss of sensation
• Myopathies  Proximal weakness, facial features
• NMJ defects  Fatigability, ptosis
• Maternal myotonia  Grip/ percussion myotonia, facial features

10. Neonatal Examination
Examination
• Head circumference
• Dysmorphic features
• Abnormal fontanelle shape or size
• Features suggestive of metabolic condition:
> Dysmorphic, abnormal head size, odor, rash
> Liver involvement: hepatomegaly, jaundice
> Cardiac problems: CHF, cardiomyopathy, arrhythmia
> Eyes: cataracts, RP, cherry red spots, optic atrophy, lens dislocation
• External and internal ophthalmoplegia
• Facial weakness
• Features of peripheral involvement: weakness, reduced reflexes
• Neonatal hypertonia

11. Early Investigations to Assess NE
First line investigations
• CBC Infection, hemorrhage, thrombocytopenia
• Coagulogram HIE, sepsis, ICH, inherited coagulation disorders
• Direct Coombs test Hemolysis
• LFTs HIE, bilirubin encephalopathy, metabolic, congenital infections, sepsis
• Urea, electrolytes HIE, metabolic
• Blood glucose Hypoglycemia
• Blood lactate HIE (usually falls within days)
• Neurophysiology Identify seizures, monitor encephalopathy, Dx neonatal epilepsy syndromes
Second line investigations
• Urine ketones Pathognomonic of the metabolic disorders
• Ammonia Metabolic (esp. urea cycle defect)

12. Etiologies of NE
• Hypoxic-ischemic encephalopathy
• Infections
• Vascular conditions
• Genetic disorders
• Metabolic conditions
• Neuromuscular disorders
• CNS malformations
• Toxin/ medication related conditions

13. Hypoxic-Ischemic Encephalopathy (HIE)
• Most common cause of NE (15-35% of all cases)
• Known or highly suspected due to hypoxic-ischemic event
Fetal and neonatal signs Acute peripartum/ intrapartum event
1. Apgar scores <5 at 5 and 10 min
2. Cord or early neonatal acidemia with
pH <7 and/or base deficit >12 mmol/L
3. Pattern of brain injury on MRI or MRS
consistent with hypoxia-ischemia
4. Multi-organ failure: renal, liver,
hematologic, cardiac, GI, metabolic
derangements
1. The presence of sentinel event
immediately before or during delivery:
uterine rupture, placental abruption,
prolapsed cord, shoulder dystocia, etc.)
2. FHR abnormalities
3. No evidence of other contributing
factors: maternal infection, neonatal
sepsis, chronic placental lesions

14. Distinguishing HIE from Others Causes
Suggestive of HIE Suggestive of other NE
1. History  Sentinel event during labor or immediately
before/ during birth
 FHR abnormalities consistent with an acute
event
 Need for resuscitation at birth
 Apgar <5 at 5 and 10 min
 Encephalopathy evident immediately from
birth
 IUGR
 Oligohydramnios or polyhydramnios
 Maternal infection
 Maternal medication or substance use
 Family history of genetic disorders,
neonatal illness or seizures
 Delayed onset of symptoms after birth
2. Exam  Abnormal Sarnat exam in isolation  Abnormal Sarnat exam in association with:
- Congenital anomalies
- Microcephaly/ macrocephaly
- Contractures
- Spasticity
- Absent DTRs
- Hepatosplenomegaly
- Rashes/ stigmata of infection
Karamian AGS, et al. Seminars in Fetal and Neonatal Medicine 2021.

15. Distinguishing HIE from Others Causes
Suggestive of HIE Suggestive of other NE
3. Labs  Cord pH or blood gas with acidosis (pH <7)
 Elevated lactate
 Evidence of multisystem end-organ
dysfunction (abnormal CK, BUN, Cr, LFTs)
 Electrolytes derangement (hypocalcemia,
hypermagnesemia)
 Elevated WBC count, inflammatory markers
 Positive urine toxicology screens
 Hyperammonemia, hypouricemia
4. Imaging  HUS or MRI showing pattern of brain injury
consistent with HIE
 HUS or MRI with evidence of chronic injury
(cystic change, atrophy) soon after birth
 HUS or MRI with other brain abnormality or
injury (brain malformations, stroke,
hemorrhage, meningitis/ encephalitis)
5. Other
studies
 Acute/ subacute placental lesions on placenta
pathology with or without chronic changes
 Chronic placental lesions on placental
pathology
Karamian AGS, et al. Seminars in Fetal and Neonatal Medicine 2021.

16. MRI in HIE

17. Hypoxic-Ischemic Encephalopathy (HIE)
• Standard of care: therapeutic hypothermia according to
eligible criteria within the first 6 hours after birth
• Recommend for all neonates with encephalopathy who meet
institutional criteria, even when the cause is unknown
• Adjuvant therapies: erythropoietin

18. Infections

20. Vascular Conditions
• Most common vascular injury is arterial ischemic stroke(AIS)
• AIS presents as focal seizures; unilateral clonic jerks or unexplained
apnea with lethargy/encephalopathy
• typically, first or second day of life
• Neonatal AIS and HIE can coexist in 4-6% of cases
• Management focuses on seizure control and later rehabilitation

21. Vascular Conditions
• CSVT leads to hemorrhagic infarct or IVH can mimic HIE
• NE with refractory seizures, coagulopathy, or persistent thrombocytopenia
should be investigated for CSVT
• Additional risk: sepsis, infection, and dehydration
• Investigation: transcranial color doppler ultrasonography, MRV
• Treatment: anticoagulation in acute phase, monitor post hemorrhagic
hydrocephalus

24. Genetic Disorders
Clues to suspect genetic disorders
• Signs and symptoms of dysmorphic features, refractory
seizures, respiratory insufficiency, multi-organ dysfunction
• Prenatal history of oligo-/ polyhydramnios, decreased/
increased fetal movements, brain malformation on US or MRI
• Family history of consanguinity, recurrent pregnancy losses/
neonatal or infantile deaths, developmental delay, cognitive
dysfunction, epilepsy or congenital malformations

25. Genetic Disorders
Suggested investigations
• Dysmorphic features  karyotype and/ or CMA
• Neonatal seizure, neuromuscular findings  basic
metabolic investigations, targeted NGS or WES
• Diagnostic yield of NGS: 10-40%
• **Consider treatable disorders in differential diagnosis

26. Genetic Syndromes
Disease Clinical features Neuroimaging Genetic Ix
Prader-Willi
syndrome
• Hypotonia
• Dysmorphic (almond-shaped
eyes, thin upper lip, small
mouth, hands and feet)
Ventriculomegaly, decreased
volume of the perieto-
occipital lobe, sylvian fissure
polymicrogyria and
incomplete insular closure
 Methylation test
 Microarray deletion
 Maternal uniparental
disomy of 15q11.2-q12
Congenital
central
hypoventilation
syndrome
• Hypoventilation esp. during
sleep
• ANS dysregulation
• Some assoc. with
Hirschsprung
Multiple WM abn,
hypothalamus, posterior
thalamus, midbrain, lateral
medulla, pons, cerebellum,
insular and cingulate
changes
 Sanger sequencing
and deletion/
duplication of PHOX2B
 Multigene panel
 WES
Aicardi-
Goutières
syndrome
• IUGR
• Neonatal seizures, jitteriness
• Hepatosplenomegaly
• Thrombocytopenia, anemia
Frontotemporal WM
changes, T2 hyperintense
around ventricular horns,
basal gg calcification
 Multigene panel
(ADAR, RNASEH2A, 2B,
2C, SAMHD1, TREX1)
 WES

27. Genetic Neonatal Epileptic Encephalopathies
Disease Clinical features EEG
KCNQ2 Asymmetric tonic seizures, apnea, hypotonia  Multifocal EDs with random attenuation
 Burst suppression
KCNT1 Focal seizures with unilateral motor onset, alternating
from one side to other side, lateral deviation of heads
and eyes, limb myoclonic jerks, increased tone, apnea
 Diffuse slowing, lack of organization
 Frequent seizures with shifting laterality
SCN2A Clustering focal tonic, focal clonic seizures, apnea,
hypotonia
 Burst suppression
 Multifocal spikes
BRAT1 Diffuse hypertonia, microcephaly, multifocal myoclonic
jerk, apnea, bradycardia
 Normal initial EEG
GNAO1 Focal seizures  Burst suppression
 Multifocal sharp waves
STXBP1 Hypotonia, epileptic spasms, refractory focal seizures  Burst suppression
 Sometimes multifocal abnormalities
SLC13A5 Refractory epilepsy  Normal initial EEG
 MRI: multiple punctate WM lesions with
diffusion restriction

28. Metabolic Conditions
• Transient metabolic disturbance
• abnormal levels of sodium, calcium, and magnesium
• Hypoglycemia - prolonged and recurrent; brain injury predominantly parieto-
occipital lobes
• Profound hyperbilirubinemia: spectrum of neurological dysfunction
MRI: globus pallidi, deep nuclei of brainstem & cerebellar injury
• Hyperammonemia and hepatic encephalopathy from liver failure
• Inborn error of metabolism
• defect of encoding enzymes for utilizing macronutrients, small molecules,
vitamins, or metals
• Impaired organelle functions (mitochondrial, lysosomal, or peroxisomal
disorders)

29. Features Suggestive of IEM
• Latent encephalopathy in previously healthy appearing neonate
• Neonatal encephalopathy during highly stressful, catabolic states(e.g.,
infection, steroid use), recent dietary change
• Dysmorphic features
• Hepatomegaly, cardiomyopathy, or congenital abnormality of other
organ systems
• Abnormal odor

30. Metabolic Conditions: IEM
Disease Clinical features Imaging/EEG Genetic investigation
Urea cycle
disorders
Progressive lethargy,
hyper/hypoventilation,
seizures, posturing, coma
(hyperammonemic
encephalopathy)
MRI: insular cortex, parietal, occipital and
frontal white matter diffusion restriction
Plasma amino acids, urine organic
acid.
Sanger sequencing of CPS1, OTC,
ASS, ASL
(based on biochemical profile)
Maple syrup urine
disease (MSUD)
Hypersomnolence, irritability,
progressive encephalopathy –
lethargy, apnea, opisthotonos,
and reflexive fencing/bicycle
movements, coma
Burnt sugar odor
MRI: hyper SI T2 cerebellar white matter,
corticospinal tract, dorsal brainstem, thalami,
globi pallidi
Extensive diffusion restriction at white matter
tracts
Plasma amino acids,
Sanger sequencing of BCKDHA
BCKDHB
DBT

32. Metabolic Conditions: IEM
Disease Clinical features Imaging/EEG Genetic investigation
Organic acidurias
-Methylmalonic
acidemia
-Propionic acidemia
-Isovaleric acidemia
Progressive lethargy, poor
feeding, hypotonia, vomit,
progressive encephalopathy
(hyperammonemic
encephalopathy)
MRI: (acute) brain swelling
MMA – basal gg calcification ,globus pallidus
infarct (late)
PA -↑T2 putamen and caudate (late)
IVA – ↑T2 globus pallidus, white matter,
hemorrhage
Acylcarnitine profile
Urine organic acids
Sanger sequencing of PCCA, PCCB,
MMUT, IVD
(based on biochem profile)
Pyridoxine-
dependent
epilepsy*
Pyridoxamine 5’
oxidase(PNPO)
deficiency**
Pyridoxal phosphate
binding protein
deficiency***
NE, refractory seizures MRI: Thin corpus callosum, mega cisterna
magna*
MRI: normal **/***
Urine AASA (elevated)
ALDH7A1*
PNPO**
PLPBP***

35. Metabolic Conditions: IEM
Disease Clinical features Imaging/EEG Genetic investigation
Nonketotic
hyperglycinemia
Myoclonic jerks, hiccups,
hypotonia, lethargy, apnea,
seizure, and coma
EEG: burst suppression
MRI: Dysplastic corpus callosum,
posterior limb of internal capsule, anterior
brainstem, posterior tegmental, and
cerebellum diffusion restriction.
MRS: glycine peak
↑CSF/plasma glycine ratio
(>0.08)
Sanger sequencing for GLDC,
AMT, GCSH
or multiple gene panel /WES
Sulfite oxidase
deficiency*/
Molybdenum cofactor
deficiency**
Neonatal refractory seizures,
feeding difficulties, rapidly
progressive encephalopathy
EEG: low amp, disorganized BG, multifocal ED,
burst suppression
MRI: loss of grey-white differentiation,
cerebral edema, progression to cystic
encephalomalacia,
extensive diffusion restriction(early)**
Urine s-sulfocysteine elevated*,**
Sanger sequencing for SUOX*
MOCS1**
MOCS2**

38. Metabolic Conditions: IEM
Disease Clinical features Imaging/EEG Genetic investigation
Pyruvate
dehydrogenase
complex deficiency
NE, seizures, hypotonia,
dysmorphic (temporal
narrowing, microcephaly, frontal
bossing, wide nasal bridge, long
philtrum)
Corpus callosum agenesis, ventriculomegaly,
cerebral palsy, subependymal pseudocysts
Lactic acidosis, normal
lactate/pyruvate ratio
PDHA1, PDHX, DLAT, PDP1
Multigene panel/WES
GABA
transaminase
deficiency
NE, seizures, hypotonia EEG: multifocal spikes, diffuse slowing, burst
suppression
MRI: Dysmyelination cerebral atrophy,
CSF free GABA (elevated)
ABAT or multigene panel/WES
Zellweger
spectrum disorder
NE, seizures, hypotonia,
dysmorphic(wide open AF,
split suture, hypertelorism,
flat face, broad nasal
bridge), liver&kidney cyst,
hepatomegaly, jaundice
Cortical gyral abnormalities, germinolytic cysts
MRS: Lipid peak (some cases)
Plasma VLCFA (elevated)
RBC plasmalogens
PEX genes
Multigene panel/WES

43. - If IEM is suspected, immediate steps should be taken to restore
anabolic state and reduce catabolic factors
- Adequate IV hydration with dextrose, avoid over hypotonic solution
- Protein free nutrition (UCD, aminoacidopathies, OA)
- Hemodialysis if severe hyperammonemia/presumed small molecule
toxicity
- Targeted dietary regimens/cofactor supplement based on diagnostic
results
Metabolic Conditions

44. Neuromuscular Disorders
• HIE mimic
• “Double-trouble” pathologies
• CMD with associated brain malformations

45. Neuromuscular Disorders
• HIE mimic
– Hypotonia, abnormal posture, decreased or absent reflexes, apnea,
(depressed mental status)
• Clinical features suggestive of NMD
– Polyhydramnios (abnormal fetal suck and swallow)
– Reduced or absent fetal movements
– Joint contractures, arthrogryposis, reduced muscle bulk
– Facial or bulbar weakness/ ophthalmoparesis, ptosis
– Weakness out of proportion to the degree of encephalopathy

47. Neuromuscular Disorders
CMD with associated brain malformations
• Can present with mild to moderate encephalopathy
• Dystroglycanopathies
 Autosomal recessive
 Hypoglycosylation of α-dystroglycan
1. Walker-Warburg syndrome
2. Muscle-eye-brain disease
3. Fukuyama CMD

48. - Muscle: dystrophy, absent/
minimal motor development
- Brain:
1. Complete severe cobblestone
lissencephaly
2. Marked hydrocephalus
3. Dysplastic cerebellum
4. Kinking of the brainstem at
pontomesencephalic junction
5. Corpus callosal dysgenesis
- Eyes: congenital cataracts,
micropthalmia, buphthalmos
Walker-Warburg syndrome
Suthar R, et al. Neurol India, 2018.

49. Bosemani, et al. Article in Radiographics, 2015.
Pachygyria, cerebellar hypoplasia
and brainstem abnormalities in
muscle-eye-brain disease
Fukuyama CMD
- Cobblestone lissencephaly
- Disorganized cerebellar folia
- White matter abnormalities
Aida N, et al. AJNR Am J Neuroradiol 17:605–613,1996.

50. Neuromuscular Disorders
Investigations
• Serum CK
 Cautions**
 Normal CK does not exclude NMD
 Can be elevated in the 1st few days of life
 May be elevated in HIE
• Electrodiagnostic study: NCS, EMG
• Imaging study: muscle US, (MRI brain)
• Muscle biopsy
• Genetic testing

51. CNS Malformations
• Uncommon cause of NE
• Often diagnosed by prenatal US
• Cardinal features:
– Neonatal hypotonia
– Feeding or respiratory difficulities
– CNS features dominate the clinical presentation

52. Tubulinopathies
Mutch CA, et al. American Journal of Neuroradiology, 2016.
Miller-Dieker syndrome
Lahiri K, et al. Int J Case Rep Images 2015;6(10):610–613.

53. Lin CH, et al. Acta neurologica Taiwanica 2009.
Alobar holoprosencephaly Joubert syndrome
Jerome J, et al. Neurology 15, 2009; 73 (24).

54. Toxin/ Medication Related Conditions
• Common and reversible cause
• Prenatal medication that cross placenta or postnatal administered
medication
• Maternal drug use
• ASMs, TCA, lithium, SSRI -> neonate seizure and withdrawal syndrome
• levothyroxine -> NE with thyroid endocrinopathy
• opiate -> neonatal abstinence syndrome
• Postnatally sedatives, ASMs, opiate – suppress neonate mental status
• Toxicology screening can be performed on mother and neonate

55. Flow Chart to Determine
the Cause of NE