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Hypoxic-Ischemic Encephalopathy Differential Diagnoses

  • Author: Santina A Zanelli, MD; Chief Editor: Ted Rosenkrantz, MD  more...
Updated: Jan 16, 2015

Diagnostic Considerations

Important considerations

Birth asphyxia, birth injury, and perinatal asphyxia are terms often used incorrectly to describe hypoxic-ischemic encephalopathy (HIE).

Birth injury is a condition in which fetal or neonatal injury has occurred during the process of birth (ie, during the first and second stages of labor). Examples include brachial plexus injury; fracture of the clavicle; forceps-induced damage to the facial nerve or soft tissues; and cuts or bruises from scissors, clips, or scalp monitors.

Birth asphyxia is similar to birth injury in that asphyxia occurs during the first and second stages of labor when the fetus was otherwise normal.

Perinatal asphyxia signifies that asphyxia occurred at any time in the perinatal period, namely, from conception through the first month of life.

The AAP and ACOG recommend using hypoxic-ischemic encephalopathy because this term accurately describes the clinical condition, encephalopathy from asphyxia, without implying the time of brain injury. The AAP and ACOG also advise not using the terms perinatal asphyxia or birth asphyxia because it is difficult to identify the time of brain injury and nearly impossible to ascertain that the brain had been "normal" before such injury.

All professional societies encourage accurate recording of objective information in the medical records, including maternal and neonatal history and the clinical and laboratory findings.

The findings from brain imaging procedures and EEG help in the total assessment of the infant's clinical status.

No diagnostic tests conclusively prove that a given magnitude of asphyxia has led to a specific neurological injury. Acute perinatal and intrapartum events have been found in only about 20% of children diagnosed as having cerebral palsy.

Counseling the parents with realistic explanations about their infant's clinical status and prognosis is always recommended.

Other problems to be considered

Several inborn errors of metabolism can present in the neonatal period with features of hypoxic-ischemic encephalopathy (HIE).[37] Those include the following:

  • Nonketotic hyperglycinemia
  • Disorders of pyruvate metabolism
  • Urea cycle defects
  • Zellweger syndrome
  • Mitochondrial disorders

Other diagnosis should also be included in the differential diagnosis, including the following:

  • Neuromuscular disorders including neonatal myopathies
  • Brain tumors
  • Developmental defects
  • Infections
  • Sulphite oxidase deficiency [38]

Differential Diagnoses

Contributor Information and Disclosures

Santina A Zanelli, MD Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System

Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics, Society for Neuroscience, Society for Pediatric Research

Disclosure: Nothing to disclose.


David A Kaufman, MD Professor of Pediatrics, Division of Neonatology, University of Virginia School of Medicine

David A Kaufman, MD is a member of the following medical societies: American Academy of Pediatrics, Medical Society of Virginia, Pediatric Infectious Diseases Society, Society for Pediatric Research, European Society for Paediatric Infectious Diseases

Disclosure: Nothing to disclose.

Dirk P Stanley, MD Resident Physician, Department of Pathology, University of Virginia Health System

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center

Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Pediatric Society, American Society for Bioethics and Humanities, American Society of Law, Medicine & Ethics, Society for Pediatric Research, National Hospice and Palliative Care Organization

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.


The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous author Tonse NK Raju, MD, to the development and writing of this article.

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Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged asphyxial insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
Pathophysiology of hypoxic-ischemic brain injury in the developing brain. During the initial phase of energy failure, glutamate mediated excitotoxicity and Na+/K+ ATPase failure lead to necrotic cell death. After transient recovery of cerebral energy metabolism, a secondary phase of apoptotic neuronal death occurs. ROS = Reactive oxygen species.
Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.
Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in the previous image to demonstrate the prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury. This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status marmoratus over months to years.
Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery zones between the anterior, middle, and posterior cerebral arteries.
A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination, neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.
A Luxol-Fast Blue stain was performed on the same tissue shown in the previous image to demonstrate the haphazard arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.
Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic encephalopathy (HIE).
Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden macrophages around the lesional rim.
Periventricular leukomalacia is depicted. This figure depicts the lesion seen in the previous image at higher magnification. Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of the lesion to the ependymal lining of the lateral ventricle (far right).
Summary of potential neuroprotective strategies.
Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury [34]
Level of Consciousness Alternating (hyperalert, lethargic,irritable) Lethargic or obtunded Stuporous
Neuromuscular Control
Muscle tone Normal Hypotonia Flaccid
Posture Normal Decorticate (arms flexed/legs extended) Intermittent decerebration (arms and legs extended)
Stretch reflexes Normal or hyperactive Hyperactive or decreased Absent
Segmental myoclonus Present Present Absent
Complex Reflexes
Suck Weak Weak or absent Absent
Moro Strong; low threshold Weak; incomplete; high threshold Absent
Oculovestibular Normal Overactive Weak or absent
Tonic neck Slight Strong Absent
Autonomic Function Generalized sympathetic Generalized parasympathetic Both systems depressed
Pupils Mydriasis Miosis Variable; often unequal; poor light reflex
Heart Rate Tachycardia Bradycardia Variable
Bronchial and Salivary Secretions Sparse Profuse Variable
GI Motility Normal or decreased Increased; diarrhea Variable
Seizures None Common; focal or multifocal Delayed
EEG Findings Normal (awake) Early: low-voltage continuous delta and theta

Later: periodic pattern (awake)

Seizures: focal 1-to 1-Hz spike-and-wave

Early: periodic pattern with Isopotential phases

Later: totally isopotential

Duration 1-3 days

Typically < 24h

2-14 days Hours to weeks
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