Approach Considerations
Diagnostic investigations of infants with hypoxic-ischemic encephalopathy (HIE) are directed at establishing the severity and involvement of other organs, as well as to initiate an assessment of the prognosis. To that extent, initial laboratory testing should include determination of cardiac, renal and liver dysfunction.
In the era of therapeutic hypothermia, continuous video-electroencephalographic (EEG) monitoring is essential to assess encephalopathy severity and to monitor for seizures. Brain magnetic resonance imaging (MRI) is typically delayed until after rewarming is complete, although earlier MRI may be helpful in circumstances in which redirection of care is being considered.
Laboratory Studies
There are no specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made on the basis of the history, physical, neurologic examinations, and laboratory evidence. Many of these tests are performed to assess the likelihood of severe brain injury and to monitor the functional status of the organ systems. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from the physical examination.
Laboratory studies should include the tests below.
Serum electrolyte levels
In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves. Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or syndrome of inappropriate antidiuretic hormone (SIADH) secretion, particularly during the initial 2-3 days of life.
Similar changes may be seen during recovery; increased urine flow may indicate ongoing tubular damage and excessive sodium loss relative to water loss
Cardiac function studies
A cardiac enzymatic study gives an estimation of the extent of cardiac injury from asphyxia.
Renal function studies
Serum creatinine levels, creatinine clearance, and blood urea nitrogen (BUN) levels suffice in most cases.
Liver enzymes
These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These findings may also provide some insight into injuries to other organs, such as the liver. [40]
Coagulation system evaluation
This includes prothrombin time, partial thromboplastin time, fibrinogen levels, and serial platelet counts to assess the synthetic functions of the liver as well as assess for consumptive coagulopathy or bone marrow suppression.
Arterial blood gas (ABG)
Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia. During the period of shock, capillary blood gases may not be reliable.
Imaging Studies
Brain magnetic resonance imaging (MRI)
MRI is the imaging modality of choice for the diagnosis and follow-up of infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). [41, 42, 43, 44] Conventional MRI sequences (T1w and T2w) provide information on the status of myelination and preexisting developmental defects of the brain. When performed after the first day (and particularly after day 4), conventional images may accurately demonstrate the injury pattern as area of hyperintensity. Conventional images are most helpful at age 7-10 days, when the diffusion-weighted imaging (DWI) findings have pseudonormalized.
Following a severe asphyxial event, a central pattern of injury is seen with injury to (1) the deep gray matter (ie, putamina, ventrolateral thalamus, hippocampi, dorsal brainstem, or lateral geniculate nucleus) and (2) the perirolandic cortex. These areas contain the highest concentration of N-methyl-D-aspartate (NMDA) receptors and are actively myelinating.
Less severe or partial insult results in injury to the intervascular boundaries areas and is also called watershed injury. This type of lesions manifests in the infants as proximal extremity weakness or spasticity.
Decreased signal in the posterior limb of the internal capsule (PLIC) on T1w images may be noted. The absence of normal signal (high intensity on T1w images) in the PLIC of infants older than 38 weeks' gestation is a strong predictor of abnormal motor outcomes in these infants. [45]
DWI allows earlier identification of injury patterns in the first 24-48 hours. The MRI sequence identifies areas of edema and, hence, injured areas. DWI changes peak at 3-5 day and pseudonormalizes by the end of the first week. In neonates, DWI changes may underestimate the extent of injury, most likely because of the importance of apoptosis in the ultimate extent of neurologic injury. [41]
MRI is also a useful tool in the determination of prognosis. Studies indicate that infants with predominant injuries to the basal ganglia or thalamus (BGT) have an unfavorable neurologic outcome when compared with infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been associated with poor neurologic outcome. In one study, severe BGT lesions on early MRI (performed at a median of 10 d; range, 2-42 d) were strongly associated with motor impairment at 2 years. In addition, abnormal PLIC signal was also highly correlated with inability to walk independently at 2 years, with a sensitivity of 0.92 and a specificity of 0.77. [46]
In a study of MRIs at term-equivalent age from 3 cohorts of 325 very preterm infants, Kidokoro et al found 33% (n=107) had some grade of brain injury (eg, periventricular leukomalacia, intraventricular/cerebellar hemorrhage) and 10% (n=33) had severe brain injury. [47] The investigators noted severe brain injury and impaired growth patterns were independently associated with perinatal risk factors and delayed cognitive development. [47]
Both conventional images (T1- and T2-weighted) and diffusion techniques (DWI and ADC maps) have a good specificity (>90%) and positive predictive value (>85%) in predicting death or major disability at age 2 years. However, sensitivity and negative predictive values are low. [48]
MRI is also useful for follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered because it may help in establishing the cause. Note that the interpretation of MRI in infants requires considerable expertise.
Magnetic resonance spectroscopy (MRS) allows for quantification of intracellular molecules. Proton MRS allows identification of cerebral lactate, which persist for weeks following a significant hypoxic-ischemic injury. Phosphorous MRS allows for real-time quantification of ATP, phosphorus creatinine, inorganic phosphorous, and intracellular pH levels.
Cranial ultrasonography
Although portable and convenient, cranial ultrasonography has a low sensitivity (50%) for the detection of anomalies associated with HIE. Findings include global increase in cerebral echogenicity and obliteration of cerebrospinal fluid (CSF) containing spaces suggestive of cerebral edema. Increase in the echogenicity of deep gray matter structures may also be identified, typically when ultrasonography is performed after 7 days of life. Finally, head ultrasonography has a very limited role to rule out intracerebral or intraventricular hemorrhages, and it is not very useful to learn the extent of brain injury.
In small studies, ultrasonography-based semi-quantitative markers such as the white matter/gray matter echogenicity ratio, as well as the resistive index, have emerged as potentially helpful tools to assess HIE severity and to assist in prognosis formulation early in the disease course. These studies indicate that in infants with HIE, white matter/gray matter echogenicity ratios are increased. Furthermore, neonates with a resistive index below 0.6 have an increased risk of neurodevelopmental impairment at age 20-32 months. [49, 50]
Head computed tomography (CT) scanning
Head CT scanning is a rapid mode of screening and is very effective in detecting hemorrhage with the added advantage of limited sedation need. However, evidence suggests that even a single CT scan exposes children to potentially harmful radiation. [51, 52, 53] Additionally, CT scanning is not a sensitive modality for evaluation of HIE because of the high water content in the neonatal brain and the high protein content of the cerebrospinal fluid, which result in poor parenchymal contrast resolution. [54] Because of these concerns and owing to the superiority of MRI in evaluating brain structures, head CT scanning is not recommended in the evaluation of neonates with HIE.
Echocardiography
Obtain an echocardiogram to evaluate the cardiac contractility and ejection fraction. Note that neonates with HIE receiving therapeutic hypothermia may experience a reduction in cardiac output and descending aorta blood flow. [125] Systemic organ perfusion and cerebral metabolism may be affected by preferential cerebral distribution of cardiac output in conjunction with an increase in systemic peripheral vascular resistance. [125]
Other Tests
Amplitude-integrated electroencephalography (aEEG)
Several studies have shown that a single-channel aEEG performed within a few hours of birth can help evaluate the severity of brain injury in the infant with hypoxic-ischemic encephalopathy (HIE). [55, 56, 57] The abnormalities seen in infants with moderate-to-severe HIE include the following:
-
Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
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Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without variability and occasional high voltage bursts (>25 mV)
-
Continuous low voltage pattern characterized by a continuous low voltage background (< 5 mV)
-
Inactive pattern with no detectable cortical activity
-
Seizures, usually seen as an abrupt rise in both the lower and upper margin
In addition, aEEG findings have been used as criteria for inclusion in the CoolCap trial of selective head cooling. [27, 37, 58] However, some evidence argues against the use of aEEG as a tool to exclude infants with HIE from receiving hypothermia therapy.
Although normal aEEG findings may not necessarily mean that the brain is healthy, a severe or moderately severe aEEG abnormality may indicate brain injury and poor outcome. However, a rapid recovery (within 24 h) of abnormal aEEG findings is associated with favorable outcome in 60% of cases. Finally, in a meta-analysis of 8 studies, Spitzmiller et al concluded that aEEG can accurately predict poor outcome with a sensitivity of 91% (95% CI, 87-95) and a negative likelihood ratio of 0.09 (95% CI, 0.06-0.15). [59]
Note that considerable training is required for conducting and properly interpreting the aEEG findings. With more recent advancement in technology, aEEG can alert the caregivers regarding seizure activity based on the software recognition of a pattern.
Standard EEG
Traditional multichannel EEG is an integral part of the evaluation of infants diagnosed with HIE. It is a valuable tool to assess the severity of the injury and evaluate for electrographic-only seizures (which are very common in neonates with HIE). [60, 61] This is particularly important for infants on assisted ventilation requiring sedation or paralysis. EEG can be very useful to help a clinician decide treatment options based on the report's findings.
Changes in EEG wave patterns evolve over time and are a reliable early indicator of the brain injury. [62]
Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are early findings. EEG characteristics associated with abnormal outcomes include (1) background amplitude of less than 30 mV, (2) interburst interval of more than 30 seconds, (3) electrographic seizures, and (4) absence of sleep-wake cycle at 48 hours.
Caution in interpreting early severe background abnormalities needs to be applied because reverting to normal background pattern in few days of life can be associated with normal outcomes. Note that large doses of anticonvulsant therapy may alter the EEG findings.
Serial EEGs should be obtained to assess seizure control and evolution of background abnormalities. Early EEGs are important not only to evaluate the degree of encephalopathy and the presence of seizures but may also help establish early prognosis. [63] Serial EEGs are also helpful in establishing prognosis. Improvement in the EEG findings over the first week, in conjunction with improvement in the clinical condition, may help predict a better long-term outcome. [64]
Special sensory evaluation
Screening for hearing is now mandatory in many states in the United States; in infants with hypoxic-ischemic encephalopathy, a full-scale hearing test is preferable because of an increased incidence of deafness among infants with hypoxic-ischemic encephalopathy that require assisted ventilation.
Retinal and ophthalmic examination
This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the brain.
Spectral-domain optical coherence tomography (SD-OCT) shows promise in the evaluation of prematurity on early optic nerve development and of central nervous system development and anomalies. [65]
Histologic Findings
The impressive array of neuropathologic findings that can result from a hypoxic-ischemic event can be primarily explained by the gestational time frame in which the event occurs. Prior to 20 weeks' gestation, fetal macrophages are capable of removing necrotic debris via phagocytosis, resulting in a smooth cavity without a gliotic response. Examples of lesions that can result from hypoxic-ischemic events in the second trimester include hydranencephaly, porencephaly, and schizencephaly.
After 20 weeks' gestation, hypoxic-ischemic insults result in astrocyte activation with subsequent gliosis. Subependymal germinal matrix hemorrhage is most common in premature infants, with hemorrhage involving the germinal matrix, lateral ventricles, and/or the adjacent parenchyma. In the full-term infant, hypoxic-ischemic events primarily result in lesions of the cerebral cortex, basal ganglia, thalamus, brain stem, or cerebellum. The location and severity of the lesions correlate with clinical symptoms, such as disturbances of consciousness, seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties. The major neuropathologic patterns of injury in hypoxic-ischemic encephalopathy are listed below. More than one pattern can be present.
Selective neuronal necrosis is the most common pattern of injury observed in hypoxic-ischemic encephalopathy and is characterized by neuronal necrosis selective to areas with higher energy demands. The following 5 major patterns have been described:
-
Diffuse: Sites of predilection for diffuse neuronal necrosis include the cerebral cortex (particularly the hippocampus), deep nuclear structures (thalamus, basal ganglia), brain stem, cerebellum, and anterior horn of the spinal cord.
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Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present in 35-85% of infants with hypoxic-ischemic encephalopathy.
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Brain stem (deep nuclear): Brain stem (deep nuclear) is the predominant lesion in 15-20% of infants with hypoxic-ischemic encephalopathy. Some of these lesions can evolve to status marmoratus . The 3 major features of status marmoratus include neuronal loss, gliosis and hypermyelination. This hypermyelination is believed to be secondary to myelin sheath formation and deposition around the prominent processes of reactive astrocytes. Patchy, white discoloration of the gray matter ("marbling") is sometimes observed on gross examination. This marbling is the macroscopic correlate of the hypermyelination and glial scarring seen on histologic examination. It is not seen in its complete form until the end of the first year of life.
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Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
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Cerebellar: This primarily occurs in premature infants.
An example of severe acute hypoxic-ischemic neuronal change with associated gliosis is shown in the images below.
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.
Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see the image below).
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.
The regions of the cortex most susceptible to this type of injury are the end-artery zones between the anterior, middle, and posterior cerebral arteries. These so-called watershed regions are particularly vulnerable to global hypoperfusion events; the parieto-occipital cortex is most susceptible. Parasagittal cerebral injury is most commonly seen in the full-term infant. Although most of these lesions are ischemic, approximately 25% are associated with hemorrhagic events in the perinatal period.
Focal and multifocal ischemic brain necrosis lesions vary in terms of distribution and can be limited to a region supplied by an occluded artery or can be diffuse in cases of global hypoperfusion. Ulegyria may result, with preserved gyral crests adjacent to sulci marked by dyslamination, neuronal loss, and disorganized white myelinated fibers (see the images below).
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.
Periventricular leukomalacia (PVL), also called "white matter necrosis," is macroscopically characterized by the presence of discrete cavities or foci of parenchymal softening in the periventricular areas. In some cases, PVL can not be grossly appreciated. PVL is believed to be the result of compromised boundary zone perfusion between the ventriculofugal and ventriculopetal arteries. This area is particularly vulnerable secondary to the increased metabolic demands of white matter undergoing myelination. Microscopically, PVL manifests early as geographic coagulative necrosis. As the lesion evolves, reactive astrocytes, activated microglia, and macrophages become prominent in the lesional rim (see the images below).
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).
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Fetal response to asphyxia illustrating the initial redistribution of blood flow to vital organs. With prolonged hypoxic-ischemic insult and failure of compensatory mechanisms, cerebral blood flow falls, leading to ischemic brain injury.
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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.
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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.
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Randomized controlled trials of therapeutic hypothermia for moderate-to-severe hypoxic-ischemic encephalopathy (HIE).
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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).
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Summary of potential neuroprotective strategies.
Tables
|
MILD |
MODERATE |
SEVERE |
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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- Overview
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- Medical Care
- Initial Resuscitation and Stabilization
- Supportive Care in Patients with Hypoxic-ischemic Encephalopathy
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