Neonatal encephalopathy: Clinical features and diagnosis

INTRODUCTION AND TERMINOLOGY — 

"Neonatal encephalopathy" is the term used to describe a heterogeneous, clinically defined syndrome characterized by disturbed neurologic function in the earliest days of life in an infant born at or beyond 35 weeks of gestation. It is manifested by a reduced level of consciousness or seizures, often accompanied by difficulty with initiating and maintaining respiration and by depression of tone and reflexes [1]. Neonatal encephalopathy does not imply a specific underlying etiology or pathophysiology. (See "Neonatal encephalopathy: Etiology and pathogenesis", section on 'Terminology'.)

This topic will review the clinical features and diagnosis of neonatal encephalopathy. Other aspects of neonatal encephalopathy are discussed separately. (See "Neonatal encephalopathy: Etiology and pathogenesis" and "Neonatal encephalopathy: Treatment and prognosis".)

Related topics include:

●(See "Perinatal asphyxia in term and late preterm infants".)

●(See "Clinical features, evaluation, and diagnosis of neonatal seizures".)

●(See "Treatment of neonatal seizures".)

●(See "Etiology and prognosis of neonatal seizures".)

ETIOLOGY — 

Neonatal encephalopathy can result from a wide variety of conditions. Hypoxic-ischemic encephalopathy (HIE), sometimes referred to as perinatal asphyxia, is responsible for some, but not all, cases of neonatal encephalopathy. The etiology and pathogenesis of neonatal encephalopathy are reviewed in detail elsewhere. (See "Neonatal encephalopathy: Etiology and pathogenesis".)

EPIDEMIOLOGY — 

The incidence of neonatal encephalopathy depends on how the syndrome is defined. Reported estimates range from 1.7 to 9 per 1000 term births [2-6]. In a 2010 review that pooled two large population-based studies, the pooled incidence of neonatal encephalopathy was 3.0 per 1000 live births (95% CI 2.7-3.3), while the incidence of hypoxic-ischemic encephalopathy (HIE), which represents a subset of neonatal encephalopathy, was 1.5 per 1000 live births (95% CI 1.3-1.7) [6,7]. A study using data from a large health care organization in northern California found that rates of HIE remained stable between 2012 and 2019 despite increased use of therapeutic hypothermia [7].

Antepartum and intrapartum risk factors for neonatal encephalopathy are reviewed separately. (See "Neonatal encephalopathy: Etiology and pathogenesis", section on 'Risk factors'.)

CLINICAL PRESENTATION AND DIAGNOSIS

Signs — Neonatal encephalopathy is a clinical syndrome that is apparent in the first minutes to hours after birth. The neonate who is encephalopathic will have one or more of the following signs:

●An abnormal state of consciousness (eg, hyperalert, irritable, lethargic, or obtunded)

●Diminished spontaneous movements

●Poor tone

●Abnormal posturing

●Absent primitive reflexes

●Seizure activity

●Respiratory or feeding difficulties

In the delivery room, the newborn typically exhibits low Apgar scores (calculator 1) and a weak or absent cry.

Severity — The severity of neonatal encephalopathy can be classified using the modified Sarnat scoring system (table 1) as mild, moderate, or severe according to the clinical findings. Newborns presenting with moderate to severe neonatal encephalopathy often require immediate resuscitation. (See "Neonatal resuscitation in the delivery room".)

GOALS OF EVALUATION

Determine eligibility for therapeutic hypothermia — A rapid clinical assessment (table 2) of term newborns presenting with signs of neonatal encephalopathy is necessary to assess severity and determine eligibility for therapeutic hypothermia, which is typically started within six hours of birth for neonates with evidence of hypoxic-ischemic encephalopathy (HIE). (See "Neonatal encephalopathy: Treatment and prognosis", section on 'Therapeutic hypothermia'.)

The various clinical signs of HIE (table 3), including low Apgar scores, low cord pH, neonatal seizures, and encephalopathy, are nonspecific and may occur in the absence of global hypoxic-ischemic brain injury or long-term neurologic sequelae. However, when clinical symptoms suggest that HIE is the most likely cause of neonatal encephalopathy, a diagnosis of "presumed HIE" is often appropriate while awaiting additional test results, and while instituting therapeutic hypothermia to treat HIE [8]. (See "Neonatal encephalopathy: Etiology and pathogenesis", section on 'Risk factors'.)

Determine etiology — Newborns with neonatal encephalopathy should undergo a thorough evaluation to search for potential etiologies and factors possibly contributing to neonatal encephalopathy, including obstetric antecedents and antepartum conditions (eg, intrauterine growth restriction), acute intrapartum events (eg, uterine rupture, placental abruption, cord prolapse, tight nuchal cord, maternal shock/death), inflammatory conditions (eg, maternal fever, chorioamnionitis, prolonged rupture of membranes), fetal heart rate monitoring results (table 4), and placental pathology [1].

The presence of other organ dysfunction (eg, oliguria, cardiomyopathy, abnormal liver function tests) may suggest a global hypoxic-ischemic event. A thorough maternal and family history is recommended, including a history of thromboembolic disorders, prior pregnancy loss, maternal infection, and maternal drug use. Severe metabolic derangements, dysmorphic features, and congenital anomalies may suggest the presence of an inborn error of metabolism or genetic disorder.

Neuroimaging plays a key role in the evaluation of neonatal encephalopathy and may provide information regarding the nature, pattern, and severity of brain injury [9,10]. Brain magnetic resonance imaging (MRI) yields the most useful information. (See 'Neuroimaging' below and 'Brain magnetic resonance imaging' below.)

IMMEDIATE INVESTIGATIONS — 

The following studies are recommended to evaluate the etiology and severity of neonatal encephalopathy:

Umbilical cord blood analysis — We obtain cord blood samples to determine umbilical arterial and venous pH and base deficit. (See "Umbilical cord blood acid-base analysis at delivery".)

Neonatal blood tests — Several blood tests are needed to evaluate neonatal encephalopathy and guide management:

●Arterial blood gases, serum calcium, magnesium, glucose, and electrolytes. These should be assessed early in the course, with the frequency of follow-up testing determined by the initial findings and the neonate's clinical status.

●Liver enzymes (especially aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and serum creatinine are measured to identify injury to other end organs.

●A complete blood count and differential to evaluate for anemia, hemorrhage, and/or thrombocytopenia.

●If the neonate has clinically significant bleeding or oozing from vascular catheter sites, coagulation tests (including prothrombin time [PT], partial thromboplastin time [PTT], and D-dimer) should be performed to evaluate for disseminated intravascular coagulation. (See "Disseminated intravascular coagulation in infants and children", section on 'Laboratory evaluation'.)

Placental examination — A gross and histologic examination of the placenta and umbilical cord may provide evidence of a contributing cause, such as a placental vascular lesion, infection/inflammation, or an umbilical cord thrombosis [11]. (See "Gross examination of the placenta" and "Placental pathology: Findings potentially associated with neurologic impairment in children" and "The placental pathology report".)

Microbiologic studies — Infants should be evaluated for potential infectious causes of neonatal encephalopathy (eg, bacterial sepsis, meningitis, herpes simplex virus [HSV]). This includes blood cultures and may also include viral testing for HSV. Lumbar puncture (LP) should be performed if the blood culture is positive, provided the neonate is stable enough to safely undergo the procedure, since meningitis can mimic the signs and symptoms of neonatal encephalopathy. However, LP is not routine; LP may not be done for a variety of reasons (eg, when there is clinical stability from cardiorespiratory perspective, or concern for hemorrhage in the setting of coagulopathy, thrombocytopenia, or potential for platelet dysfunction due to cooling).

Additional testing may be warranted depending on the specific clinical circumstances.

Empiric antibiotics and acyclovir should be provided pending results of cultures and HSV testing. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at or after 35 weeks gestation", section on 'Evaluation and initial management' and "Neonatal herpes simplex virus (HSV) infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

Metabolic studies — We obtain general testing for inborn errors of metabolism (including ammonia, lactate and pyruvate, serum amino acids, urine organic acids, total and free acylcarnitine, and carnitine) to rule out a metabolic cause of neonatal encephalopathy in neonates with suggestive features such as persistently elevated lactate or hypoketotic hypoglycemia. (See "Inborn errors of metabolism: Identifying the specific disorder", section on 'Laboratory evaluation'.)

Need for urgent neuroimaging? — Cranial ultrasound should be obtained urgently if there is concern for hemorrhage (eg, anemia unexplained by history, coagulopathy, thrombocytopenia, or seizures) or hydrocephalus (eg, tense/bulging fontanelle, splayed sutures, impaired upgaze, macrocephaly, or prenatal diagnosis of ventriculomegaly).

Many centers obtain cranial ultrasound at baseline for all neonates with encephalopathy undergoing therapeutic hypothermia to look for hypoxic-ischemic encephalopathy (HIE) mimics or antenatal causes of neonatal encephalopathy [12]. However, cranial ultrasound is not sensitive for detecting hypoxic-ischemic brain injury. (See 'Neuroimaging' below.)

Cranial ultrasound has the advantage of being noninvasive and generally available at the infant's bedside. Cranial ultrasound also has a high sensitivity and specificity (91 and 81 percent, respectively) for locating hemorrhages and assessing ventricular size [13]. While it may detect severe parasagittal white matter damage, cerebral edema, and cystic lesions, cranial ultrasound does not adequately image the outer limits of the cerebral cortex [14], nor is it a sensitive tool for identifying the majority of white matter abnormalities, which are best detected by brain MRI [15].

Electroencephalography — For newborns with proven or suspected acute brain injury and comorbid encephalopathy, electroencephalography (EEG) is usually obtained on the first day of life (before or during treatment) in centers where this is accessible. EEG monitoring is continued for at least 24 hours, or longer if electrographic seizures are present [16]. The gold standard for neonatal seizure diagnosis is multichannel video continuous EEG (cEEG) monitoring [17]. When cEEG monitoring is unavailable, routine-length EEG recording with simultaneous observation by clinicians or EEG technologists trained in the recognition and characterization of neonatal seizures is acceptable and can provide clinically important information. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Diagnosis'.)

EEG is necessary to:

●Determine whether there are clinical seizures or subclinical seizures (ie, electrographic-only, with no outwardly visible clinical signs)

●Distinguish neonatal seizures from other phenomena

●Evaluate the background electrical activity

These findings can impact the treatment and prognosis of neonatal encephalopathy. Electrographic-only seizures are common among neonates with HIE undergoing hypothermia and are difficult to predict based on clinical features [18]. (See "Clinical features, evaluation, and diagnosis of neonatal seizures", section on 'Diagnosis' and "Neonatal encephalopathy: Treatment and prognosis", section on 'EEG predictors'.)

Amplitude-integrated EEG (aEEG) using a continuous, single- or dual-channel recording of background cerebral electrical activity, is easy to set up and interpret at the bedside and has been used to distinguish mild from severe neonatal encephalopathy (image 1) in large clinical trials and to diagnose neonatal seizures [19]. In settings with limited EEG access, aEEG can be used for risk stratification to identify which neonates may need EEG monitoring. In settings where EEG is not available, aEEG is used in isolation.

SUBSEQUENT INVESTIGATIONS

Neuroimaging

Choice and timing of study — We recommend a brain MRI for infants with neonatal encephalopathy to establish the presence and pattern of injury and to predict neurologic outcome. Typically, brain MRI is performed at four to seven days of age when any diffusion-weighted imaging abnormalities are still apparent and after the infant has completed therapeutic hypothermia. Specific findings on brain MRI can be useful for determining the pathogenesis and prognosis of neonatal encephalopathy. (See "Neonatal encephalopathy: Treatment and prognosis", section on 'Neuroimaging predictors'.)

In addition to brain MRI, magnetic resonance spectroscopy (MRS) is done routinely at many centers and should be obtained where available. (See 'Magnetic resonance spectroscopy' below and "Neonatal encephalopathy: Treatment and prognosis", section on 'Neuroimaging predictors'.)

Head computed tomography (CT) has little to no role in the neuroimaging of infants with neonatal encephalopathy. Head CT in the acute neonatal period has poor sensitivity for injury detection; CT also imposes excessive and avoidable radiation exposure. [10]. (See "Arterial ischemic stroke in children and adolescents: Clinical presentation and evaluation", section on 'CT safety considerations'.)

Cranial ultrasound has lower sensitivity compared with MRI for hypoxic-ischemic brain injury due to hypoxic-ischemic encephalopathy (HIE), particularly in the first 24 hours after birth [20,21]. Despite this shortcoming, cranial ultrasound may provide useful information about hypoxic-ischemic injury beyond 48 hours after birth in regions where MRI availability is limited, as in many low- and middle-income countries [21]. Predominant injury to the basal ganglia and thalami can be identified on ultrasound around 48 to 72 hours after the insult [20]. Cranial ultrasound can also be helpful to evaluate for an intracranial hemorrhage or other lesions that are suggestive of an antenatal insult [20]. (See 'Need for urgent neuroimaging?' above and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Cranial ultrasound'.)

Brain magnetic resonance imaging — A brain MRI is the most sensitive imaging tool for detecting cortical and white matter injury, deep gray matter lesions, arterial infarction, hemorrhage, developmental brain malformations, and other underlying causes of neonatal encephalopathy [9,10,20,22-25].

●Patterns suggestive of hypoxic-ischemic brain injury – Certain distributional patterns of brain injury seen in term and late preterm infants are considered to be typical of hypoxic-ischemic brain injury (image 2). These are [26]:

•Central pattern – Injury to the deep gray nuclei (especially the posterior putamina and anterolateral thalami) [22,27-30], which also corresponds to brain damage seen in animal models of acute total asphyxia [31]. Injury to the perirolandic cortex and hippocampus may also be seen with this pattern [20]. In one study of 48 term neonates with encephalopathy who likely suffered acute and total oxygen deprivation due to a sentinel event, this pattern of deep gray injury on brain MRI was present in 74 percent [30]. Brainstem injury may also be common in these circumstances [8,32].

•Watershed pattern – Parasagittal injury of the cerebral cortex and subcortical white matter in the arterial watershed distribution. This occurs more commonly in the setting of milder hypoxia or ischemia of prolonged or chronic duration. However, parasagittal watershed injury can also be seen in the setting of an acute sentinel event [33].

•Global pattern – Near-total injury with widespread injury throughout the brain. This pattern almost always includes injury to the basal ganglia and thalami [20]. The cerebellum may appear relatively normal, but quantitative measures of diffusion may be abnormal [34].

Combined subacute and acute brain injury occurred in 89/500 infants in one study [35], suggesting potential implications for the development of new neuroprotective agents in neonatal encephalopathy.

●Patterns suggestive of other causes of brain injury – By contrast, some infants with neonatal encephalopathy have patterns on brain MRI other than peripartum global hypoxic-ischemic brain injury. These include [20,36]:

•Focal arterial infarction, which is identified on MRI in up to 5 percent of cases of neonatal encephalopathy [36]

•Isolated intraparenchymal or intraventricular hemorrhage

•Kernicterus

In these cases, clinical judgment is needed to determine whether peripartum global hypoxia-ischemia may have played a contributory role in causing neonatal encephalopathy.

Other patterns on brain MRI suggest that peripartum global hypoxia-ischemia did not play a role in causing neonatal encephalopathy. These include:

•MRI patterns suggesting metabolic encephalopathies

•Brain malformations

The presence of a brain malformation such as lissencephaly would suggest that the neonatal encephalopathy is a result of abnormal brain development, as opposed to an acute brain injury occurring around the time of birth. In some cases, findings of both an acute brain injury and old injury and/or brain dysgenesis can be seen, suggesting a mixed pathogenesis.

Neonatal brain MRI is the standard of care at tertiary care centers in the United States and other resource-abundant countries. However, the resources necessary for transporting, monitoring, and supporting sick babies during this procedure, as well as the highly specialized expertise needed to interpret neonatal brain MRI studies, may not be readily available at all hospitals.

Magnetic resonance spectroscopy — In addition to conventional MRI, MRS can provide useful complementary information regarding brain metabolism and the nature and prognosis of brain injury underlying neonatal encephalopathy [9,23,37]. To evaluate the presence of hypoxic-ischemic brain injury, it is most useful to obtain spectra from locations that are particularly susceptible to injury. Therefore, two regions of interest are commonly evaluated: the deep gray nuclei (putamen and/or thalamus) and the posterior white matter. An elevated ratio of lactate to N-acetyl aspartate (NAA) in the deep gray nuclei is a useful indicator of hypoxic-ischemic injury and a predictor of poor outcome [38,39]. (See "Neonatal encephalopathy: Treatment and prognosis", section on 'Neuroimaging predictors'.)

Genetic testing — Genetic testing is suggested if the infant is dysmorphic or exhibits congenital anomalies. Among 500 infants enrolled in a phase III randomized trial of erythropoietin, 5 percent were diagnosed with a genetic or congenital anomaly [40].

Genetic testing should be guided by consultation with a clinical geneticist. (See "Congenital anomalies: Approach to evaluation".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions worldwide are provided separately. (See "Society guideline links: Neonatal encephalopathy".)

SUMMARY AND RECOMMENDATIONS

●Definition – Neonatal encephalopathy is a heterogeneous, clinically defined syndrome characterized by disturbed neurologic function in the earliest days after delivery in an infant born at or beyond 35 weeks of gestation, manifested by a subnormal level of consciousness or seizures and often accompanied by difficulty with initiating and maintaining respiration and with depression of tone and reflexes. Neonatal encephalopathy can result from a wide variety of conditions. Acute hypoxic-ischemic events are responsible for some, but not all, cases of neonatal encephalopathy. (See 'Introduction and terminology' above and "Neonatal encephalopathy: Etiology and pathogenesis".)

●Rapid assessment – Term newborns presenting with encephalopathy may require immediate resuscitation and should be triaged as quickly as possible to determine eligibility for therapeutic hypothermia, which must be started within six hours of birth. (See 'Clinical presentation and diagnosis' above and 'Determine eligibility for therapeutic hypothermia' above.)

●Evaluation – All infants with neonatal encephalopathy should have a comprehensive evaluation (table 2) with assessment of neonatal clinical status and all potentially contributing factors, such as maternal medical history, obstetric antecedents, intrapartum factors (including fetal heart rate monitoring results and issues related to delivery), and placental pathology. The table summarizes the markers of acute peripartum or intrapartum hypoxemia/ischemia (table 3). (See 'Goals of evaluation' above and 'Immediate investigations' above.)

●Neuroimaging – Neuroimaging, especially brain MRI, often provides information regarding the nature, pattern, and extent of brain injury. Patterns suggestive of hypoxic-ischemic brain injury on MRI are (see 'Neuroimaging' above):

•Lesions of the deep gray nuclei, especially the posterior putamina and anterolateral thalami

•Parasagittal injury of the cerebral cortex and subcortical white matter in the arterial watershed distribution