Hypoxic-Ischemic Encephalopathy Workup
- Author: Santina A Zanelli, MD; Chief Editor: Ted Rosenkrantz, MD more...
There are nor specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made based on the history, physical and neurological examinations, and laboratory evidence. Many of the tests are performed to assess the severity of brain injury and to monitor the functional status of systemic organs. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.
Laboratory studies should include the following:
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
Renal function studies
Serum creatinine levels, creatinine clearance, and BUN levels suffice in most cases.
Cardiac and 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 bowel. In addition, early evidence suggest that cardiac troponin I may be correlated to HIE severity.
Coagulation system evaluation
This includes prothrombin time, partial thromboplastin time, and fibrinogen levels.
Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.
MRI is the imaging modality of choice for the diagnosis and follow-up of infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE).[40, 41, 42, 43] 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.
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 neurological injury.
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 neurological outcome when compared with infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been associated with poor neurological outcome. In a recent 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.
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. The investigators noted severe brain injury and impaired growth patterns were independently associated with perinatal risk factors and delayed cognitive development.
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.
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.
Although portable and convenient, cranial ultrasonography has a low sensitivity (50%) for the detection of anomalies associated with hypoxic-ischemic encephalopathy. 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 is helpful upon admission, particularly in patients evaluated for hypothermia therapy, to rule out intracerebral or intraventricular hemorrhages.
Head CT scanning
Head CT is a rapid mode of screening and is very effective in detecting hemorrhage with the added advantadge of limited sedation need. However, evidence suggests that even a single CT scan exposes children to potentially harmful radiation.[48, 49, 50] Additionnally, CT is not a sensitive modality for evaluation of HIE because of the high water content in the neonatal brain and high protein content of the cerebrospinal fluid, which result in poor parenchymal contrast resolution. Because of these concerns and the superiority of MRI in evaluating brain structures, MRI has now largely supplanted head CT in the evaluation of neonates with hypoxic-ischemic encephalopathy.
In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects, if any.
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.[52, 53, 54] The abnormalities seen in infants with moderate-to-severe hypoxic-ischemic encephalopathy include the following:
Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
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.[24, 34, 55] However, some evidence argues against the use of aEEG as a tool to exclude infants with hypoxic-ischemic encephalopathy 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).
Note that considerable training is required for conducting and properly interpreting the aEEG findings.
Traditional, multichannel EEG is an integral part of the evaluation of infants diagnosed with hypoxic-ischemic encephalopathy. It is a valuable tool to assess the severity of the injury and evaluate for subclinical seizures.[57, 58] This is particularly important for infants on assisted ventilation requiring sedation or paralysis.
Changes in hypoxic-ischemic encephalopathy and EEG wave patterns may change over time and indicate the severity of the brain injury. EEG abnormalities may be apparent before anomalies seen on ultrasonography.
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. 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.
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.
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 neuropathological 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.
Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present in 35-85% of infants with hypoxic-ischemic encephalopathy.
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.
Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
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.
Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see the image below).
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).
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).
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|Level of Consciousness||Alternating (hyperalert, lethargic,irritable)||Lethargic or obtunded||Stuporous|
|Posture||Normal||Decorticate (arms flexed/legs extended)||Intermittent decerebration (arms and legs extended)|
|Stretch reflexes||Normal or hyperactive||Hyperactive or decreased||Absent|
|Suck||Weak||Weak or absent||Absent|
|Moro||Strong; low threshold||Weak; incomplete; high threshold||Absent|
|Oculovestibular||Normal||Overactive||Weak or absent|
|Autonomic Function||Generalized sympathetic||Generalized parasympathetic||Both systems depressed|
|Pupils||Mydriasis||Miosis||Variable; often unequal; poor light reflex|
|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
Typically < 24h
|2-14 days||Hours to weeks|