eMedicine Specialties > Neurology > Pediatric Neurology

Hypoxic-Ischemic Brain Injury in the Newborn: Differential Diagnoses & Workup

Author: Marcio Sotero de Menezes, MD, Associate Professor, Department of Neurology, Division of Pediatric Neurology, Children's Hospital of Seattle, University of Washington
Coauthor(s): Dennis WW Shaw, MD, Professor, Department of Radiology, Department of Radiology, University of Washington School of Medicine; Consulting Staff, Children's Hospital and Regional Medical Center of Seattle
Contributor Information and Disclosures

Updated: Apr 4, 2006

Differential Diagnoses

Other Problems to Be Considered

• Patients with CNS malformations commonly have perinatal depression and low Apgar scores.
• Maternal administration of CNS depressants or magnesium (fetal hypermagnesemia) can lead to a picture of decreased arousal, hypotonia, and respiratory failure, which may be confused with that of HIE.
• Neonatal bacterial sepsis, especially meningitis, may occur with most or all of the symptoms of HIE-NE. Enteroviral infection may also produce a picture of sepsis. In clinical neonatology practice, most patients with an HIE-like picture are evaluated for sepsis. This evaluation likely includes a blood culture, CBC determination, and CSF examination. Broad-spectrum antibiotic therapy is often started until the results of the evaluation are known and HIE is diagnosed with confidence.
• Hyperactivity and jitteriness suggesting mild HIE-NE, resembling Sarnat stage 1 disease, may occur in hypocalcemia and drug withdrawal syndrome. In hypocalcemia, the EEG may be abnormal, showing multifocal discharges and electrographic seizures.
• Myopathies (eg, myotonic dystrophy, congenital myopathies) or spinal muscular atrophy may cause hypotonia. Patients are often alert and responsive, and they do not have brainstem reflex depression; this feature easily differentiates this condition from HIE. Bifacial weakness may occur in congenital myopathies, and hypotonia may be noted in some inborn errors of metabolism, such as the peroxisomal disorders.
• Perinatal intoxication with local anesthetic may be difficult to differentiate from HIE. Mepivacaine administered as a paracervical block during delivery is the most common cause of an inadvertent injection of a local anesthetic. The anesthetic is commonly injected into the scalp of the fetus, and seizures are almost universal, beginning before 6 hours of life. Seizures are most often tonic, followed by apneic and multifocal types. EEG shows epileptiform discharges (temporal spikes) or may be normal. Many neonates have low 5-minute Apgar scores, apnea or hypoventilation, bradycardia, hypotonia, fixed and dilated pupils, and decreased eye movements to oculocephalic reflex (doll's eyes); this clinical picture is similar to that of HIE-NE.
  • Patients with local anesthetic intoxication become worse in the first 6 hours of life improve with supportive care alone. Pupillary and oculocephalic reflex abnormalities are seen in the first 12 hours and are presumably due to continued absorption of the drug from the subcutaneous tissue, which improves over the first and second days of life.
  • Patients with HIE have neurologic deterioration, which most often starts after 12 hours. Abnormalities in pupillary and oculocephalic reflexes are seen only after 12-24 hours.
  • The picture in patients with transplacental intoxication caused by local anesthetics can be difficult to characterize because hypoxic-ischemic injury may occur in this setting. The outcome of patients with local anesthetic intoxication caused by direct scalp injection is good if they are given appropriate supportive treatment.
• Pyridoxine dependency is associated with neonatal seizures and developmental delay responsive to high doses of pyridoxine. Some patients may have early-onset seizures (before 6 h of life) that often become intractable to regular anticonvulsants. Unless pyridoxine is administered, many patients have recurrent seizures that may lead to an encephalopathic picture, on both clinical evaluation and on EEG. Pyridoxine dependency is diagnosed by injecting 100-200 mg during EEG and checking for immediate improvement in epileptiform discharges and seizures.
• Several inborn errors of metabolism may occur in the neonatal period. Most patients do well initially but deteriorate 1-3 days after feedings begin, with a progressive decline in level of consciousness, seizures, and vomiting. A family history of neonatal death or seizures followed by neurologic deterioration suggests this condition. Many patients are depressed at birth and considered to have intrapartum hypoxia-ischemia. Unexplained vomiting should suggest this diagnosis. Affected neonates may be symptomatic. Examples of such errors are hyperammonemias due to urea-cycle defects, organic acidurias, lactic acidosis due to carbohydrate and mitochondrial metabolism dysfunction, and peroxisomal disorders.
  • Hyperammonemias due to urea-cycle defects commonly cause obtundation and neonatal seizures, which can be confused with those of HIE. High serum ammonia levels suggest the diagnosis. Newborns with urea-cycle defects do well initially and deteriorate 1-3 days after feedings start.
  • Organic acidurias may cause neonatal feeding difficulties, lethargy, vomiting, seizures, metabolic acidosis, hyperammonemia, and hyperglycinemia. Propionic acidemia and methylmalonic acidemia occur in the neonatal period. Nonketotic hyperglycinemia is a defect in the glycine-cleavage system, which often results in depressed mental status and seizures of early onset that are refractory to medical management. Myoclonus, hiccups, apnea, and lethargy are common symptoms. Diagnosis is based on verification of a high CSF-to-serum glycine ratio.
  • Neonates with pyruvate dehydrogenase complex deficiency often have the E1 or pyruvate decarboxylase deficiency and present with hypotonia, seizures, myoclonus, mild dysmorphic facies, and severe metabolic acidosis. The diagnosis is suspected when a metabolic acidosis is associated with elevated lactate pyruvate and alanine levels in the serum; however, urine organic acid values may be normal.
  • Generalized peroxisomal disorders can cause seizures, lethargy, hypotonia, and poor feeding in the neonatal period. Both Zellweger syndrome and neonatal adrenoleukodystrophy may occur in the immediate newborn period. The typical facial stigmata (high forehead, widow's peak, hypertelorism) and hepatomegaly are almost always present in Zellweger syndrome and may help in the diagnosis.

Workup

Laboratory Studies

• Acid-base measurements
  • Acid-base disturbance, assessed by means of umbilical-artery pH measurement, are correlated with neonatal seizures and death only in extreme cases when the pH is <7.04.
  • In studies, the overwhelming majority of patients with extreme acidosis and pH <7 had no seizures and did not die.
  • Low umbilical-artery pH may be due to causes other than ischemia, such as sepsis.
  • The association of low pH and long-term neurologic outcome is also weak.
  • In summary, most neurologically symptomatic neonates are not markedly acidotic, and most newborns with acidosis are not neurologically symptomatic.
• The serum concentration of brain-specific creatine kinase isoenzyme BB (CK-BB) appears to be somewhat correlated with the outcome after an episode of HIE-NE; however, the correlation for CSF CK-BB, especially with short-term outcome, is better.
• Other serum factors studied include the following:
  • Blood lactate
  • Hypoxanthine
  • Aspartate-aminotransferase
  • Erythropoietin beta-endorphin
• Factors measured in the CSF include the following:
  • Lactate
  • Neuron-specific enolase
  • Lactate dehydrogenase
  • Hydroxybutyrate dehydrogenase
  • Fibrinogen degradation products
  • Ascorbic acid
• The utility of most of these blood and CSF determinations in predicting long-term neurologic outcomes have not been validated in large, well-controlled studies.

Imaging Studies

• Head ultrasonography
  • Ultrasonography is most useful for the detection of PVL, and experienced technicians may detect lesions of the basal ganglia as well. Selective neuronal injury and parasagittal or watershed lesions are frequently missed on sonography.
  • Ultrasonography has poor specificity in differentiating increased echogenicity due to ischemic or hemorrhagic lesions.
  • Focal and multifocal ischemic lesions, especially small cortical infarcts, may be missed on sonography but detected on CT or MRI.
  • Early, large ischemic infarcts (eg, large infarct of the middle cerebral artery) may be observed on ultrasonography before it is apparent on CT.
• Cranial CT
  • CT depicts focal, multifocal, and generalized ischemic lesions. In the first few days after a severe hypoxic-ischemic insult, bilateral hypoattenuations are seen and probably reflect both neuronal injury and edema. CT neuropathologic studies show that areas of edema are correlated with hypoattenuation lesions when autopsy is performed within 10 days of CT, but generalized edema may obscure focal ischemic lesions. Diffuse cortical injury is not initially detected on CT. After days to weeks, diffuse hypoattenuation may appear, with loss of the gray matter–white matter differentiation. Diffuse cerebral atrophy with ex vacuo ventricular dilatation due to severe hypoxemic insult may take several weeks to develop. Atrophy is a consequence of cortical and white-matter destruction.
  • Areas of hypoattenuation can be challenging to interpret in premature infants, and autopsy studies show poor correlation between this finding and neuropathologically documented ischemic damage. CT scanning can be performed to help reliably diagnose generalized edema in the premature newborn.
  • After 48 hours, CT may depict focal ischemic infarcts well. On the first day after a focal thromboembolic event, the ischemic area may not be visible on CT. A CT scan depicting hypoattenuation in the distribution of the left middle cerebral artery in the first day of life suggests prenatal-onset of ischemia. Symptoms of a focal infarct (usually seizures) on the first day of life with normal CT findings and with hypoattenuation developing over the first week suggest perinatal-onset ischemia. Hemorrhagic conversion of a focal ischemic lesion is uncommon in the neonatal period, but CT can depict it easily.
  • A CT scan demonstrating generalized, diffuse hypoattenuation after a hypoxic-ischemic event is predictive of both neonatal death and long-term severe disability, whereas normal CT findings are predictive of mild disability or a normal outcome. Interpret normal results with caution because hypoattenuation may take a few weeks to develop.
  • CT may depict hemorrhagic lesions, which are seen in 10-25% of patients with HIE-NE. These lesions include intraparenchymal, intraventricular, and subarachnoid hemorrhages. Basal ganglia–thalamic lesions and selective neuronal injury can be detected on CT, but they are more reliably visualized on MRI than on CT.
  • On CT, PVL can be visualized around the frontal horns or posteriorly around the trigonal area of the lateral ventricles. PVL appears as a region of decreased attenuation, occasionally intermixed with areas of increased attenuation due to secondary hemorrhage. Periventricular hypoattenuations should be interpreted carefully because maturation and myelination processes increase the lipid and protein content but the water content of the white matter. These changes explain the findings of hypoattenuations in neonates with normal development.
    • The long-term changes seen on a CT scan of patients with PVL are thinning of the periventricular white matter (especially in the region of the trigone) and ventriculomegaly with an irregular outline and deep sulci on the wall of the lateral ventricles.
    • Areas of white-matter necrosis may become calcified over time.
  • In thrombosis of the sagittal sinus, CT may depict the delta sign (clot in the sinus) or the empty delta sign (partially recanalized clot in the sinus).The sagittal sinus may be hyperattenuating, but CT scans often do not show cerebral venous thrombosis in the neonatal period; this thrombosis is better visualized on MRI than on CT.
• MRI in term HIE
  • MRI is the imaging modality of choice in the assessment of HIE, and it is sensitive in detecting focal and multifocal ischemic lesions.
  • In general, diffusion-weighted imaging (DWI) is the most sensitive technique for detecting ischemia, though it can delay the detection of ischemia in neonates compared with adults. Changes on DWI are correlated with clinical outcomes and have been reported within 6-8 hours of life in neonates who had presumed HIE. Nonetheless, these changes may not be reliably seen until after 24 hours.
  • The radiologic classification of ischemic lesions is simpler than the pathologic one. Barkovich and Triulzi divide the lesions presumably due to HIE in term neonates into 3 categories that somewhat depend on the severity and the mechanism of the insult, as follows:
    • Mild-to-moderate insult, primarily hypotensive injuries: Lesions are in the arterial watershed zone between major brain arteries (also referred to as a parasagittal pattern).
    • Severe insult, primarily energy-failure injuries due to a combination of decreased oxygen delivery and local relatively higher metabolic rate: Bilateral abnormalities are seen primarily in the lateral thalami, posterior putamina, hippocampi, and perirolandic cortices leading to lesions of the corticospinal tract. The dorsal mesencephalon is involved less frequently than the other areas.
    • More severe insult: A third and most severe pattern with diffuse cortical abnormalities can be seen in dramatic cases.
  • In a 2005 multicenter study, the watershed pattern was most prevalent, followed by the basal ganglial–perirolandic pattern. Compared with other patients, those with the abnormalities of the deep gray matter required more aggressive resuscitation, they had more severe NE and seizures, and they had worse motor and cognitive outcomes.
  • The location, pattern of abnormalities and order of appearance on the various sequences are summarized on table 1. Initially only DWI changes may be seen on the first 24-72 hours. Some investigations have found measurement of the apparent diffusion coefficient (ADC), which is calculated from the DWI, to be more sensitive than visual inspection of the DWI sequence early on.
  • In the first 2 days of life after birth injury a transient decrease T1 signal may be seen particularly in the lateral thalami and posterior putamen. This T1 signal rapidly becomes hyperintensity, attributed to lipid break down or mineralization. At the same time an increased T2 signal may be seen.
  • Abnormalities if the basal ganglia, thalamus, and internal capsule have been correlated with motor dysfunction on the first 3 years of life. Motor impairments appear to be most severe when these lesions also have high lactate-to-choline: ratios on magnetic resonance spectroscopy (MRS) (see below).
  • The watershed or parasagittal pattern of insult is associated with late cognitive impairment.
  • MRI is also the imaging modality of choice to demonstrate parasagittal injuries, which appear as areas of increased signal intensity in the watershed distribution on coronal and axial T2-weighted images.
  • In patients with early MRI changes suggestive of cortical necrosis, follow-up examinations may show cortical atrophy and multicystic encephalomata.
• Magnetic resonance spectroscopy
  • Proton MRS may reveal indirect evidence of neuronal damage by showing a decreased ratio of N -acetylaspartate (NAA) to choline and by showing elevated lactate peaks. These findings are somewhat correlated with subsequent neurologic deficits.
  • High lactate-to-choline ratios with basal ganglial and thalamic abnormalities appear to be correlated with poor neurologic function after the neonatal period.
  • Phosphorus-31 MRS in patients with presumed hypoxic-ischemic exposure shows a pattern of elevation inorganic phosphate levels associated with decreased phosphocreatine values. This finding belies a loss of high-energy phosphates. A decreased adenosine triphosphate (ATP) level is associated with death in the neonatal period. Changes on³¹ P MRS occur mostly in the first 24-72 hours, with return to normal in subsequent days.
• Timing of MRI and MRS changes
  • During the first 24 hours, DWIs may still be normal. Proton MRS may show an increase in lactate, which may be seen during the first day of life. After the first 24 hours, proton MRS also shows a decreased NAA-to-choline ratio.
  • Restricted diffusion of water molecules can reliably be seen on DWI after 1-3 days. The reason for this slow onset of DWI changes in neonates compared with older children and adults is unknown. Table 2. Summary of MRI and MRS Findings in HIE

    Open table in new window

    [ CLOSE WINDOW ]

    Table

    Time	Finding
    24 h	Increased lactate peak
    24-72 h	Increased NAA-to-choline ratio and DWI signal intensity
    >72 h	Increased T2-weighted signal intensity
    1-3 wk	Generalized atrophy (ex vacuo hydrocephalus), cystic changes (polycystic encephalomata)

    Time	Finding
    24 h	Increased lactate peak
    24-72 h	Increased NAA-to-choline ratio and DWI signal intensity
    >72 h	Increased T2-weighted signal intensity
    1-3 wk	Generalized atrophy (ex vacuo hydrocephalus), cystic changes (polycystic encephalomata)

• MRI in pre-term infants - PVL
  • In the premature infant, an acute PVL lesion can be demonstrated on MRI. MRI can be more sensitive than sonography, particularly to noncystic PVL. The sequelae of PVL are visualized better on MRI than on CT. PVL and its sequelae are often seen in premature infants who have severe respiratory and other medical complications leading to poor oxygenation, decreased blood pressure, or both.
  • MRI signs of remote PVL include thinning and increased T2 signal intensity of the white matter, particularly in the peritrigonal area. This pattern has been correlated with spastic diplegia in formerly premature infants with a history of PVL, but it is also frequently observed in term infants after HIE.

Other Tests

• Electroencephalograph
  • EEG allows for the diagnosis of neonatal seizures and helps in determining the prognosis for infants with HIE-NE.
  • EEG studies of neonates with HIE showed that low-voltage (5- to 15-mV) activity, electrocerebral inactivity (voltage, <5 mV), and burst-suppression patterns are predictive of a poor outcome on follow-up neurodevelopmental examination. Normal EEG activity and maturational delay were not associated with excess morbidity on follow-up. Some data suggest that EEG performed in the first 2 weeks of life may be better than physical-neurologic examination because it increases the specificity for predicting abnormal outcomes.
  • One pattern that portends a poor prognosis is the burst-suppression pattern. This pattern contains bursts of high-voltage activity composed of a mixture of delta-theta rhythms and spikes and sharp waves of 1-10 seconds alternating with low amplitude (background suppression) with <5 V. During the bursts, no age-appropriate activity is seen. The burst-suppression pattern is associated with a grim prognosis.
    • EEGs may show burst-suppression during sleep but a continuous tracing when the patient wakes up. In these patients, burst-suppression is seen during most of the recording and only vigorous stimulation wakes the patient.
    • The outcomes of patients with reactive burst suppression are somewhat better than those of neonates with nonreactive burst suppression. Approximately 20% of patients with reactive burst suppression have severe disability on follow-up, and the rest have mild-to–moderately severe sequelae.
    • Nonreactive burst suppression is associated with an 86-100% risk of death or severe sequelae on follow-up. Use caution and serial EEGs in premature infants born at less than 33 weeks' gestational age before confirming the diagnosis of a burst-suppression pattern.
  • Besides HIE, the following have been associated with a burst-suppression pattern:
    • Acquired and congenital infections
    • Inborn errors of metabolism (eg, nonketotic hyperglycinemia)
    • Chromosomal abnormalities
    • Brain dysgenesis
    • Intraventricular or periventricular hemorrhage
    • PVL
    • Focal cerebral infarcts
    • Pontosubicular necrosis
  • Separating the prognostic value of EEG seizure patterns from the EEG background is difficult. In some studies, EEG seizures had no independent prognostic value above that of the background abnormalities. However, low-frequency (1- to 1.5-Hz) discharges in a suppressed background are correlated with a poor prognosis.
  • EEG background patterns of low voltage (<15 mV), burst suppression, and the ominous isoelectric EEG (<2 mV) are associated with a poor outcome in HIE. Neonatal seizures confirmed on EEG are associated with a poor prognosis, especially if the seizures are accompanied by background abnormalities. Normal EEG findings are correlated with a normal neurologic outcome, unless signs of severe brainstem damage are noted after an episode of complete ischemia.
• Amplitude-integrated EEG (aEEG)
  • Although the bulk of the studies have used standard neonatal EEGs, the body of evidence in regard to aEEG and HIE has been growing in the last 10 years.
  • Integrating the amplitude domain (generally by using fast-Fourier transformation) makes the EEG easier to interpret than before so that pediatric house staff without previous training in neonatal EEG can both read the amplitude and detect neonatal seizures. Learning to read neonatal EEG takes 1-2 years.
  • aEEG studies have used criteria that take in consideration both the upper margin of the aEEG band and the lower margin or lowest amplitude of the EEG voltage.
    • Normal is an upper range of >10 µV and a lower margin of >5 µV.
    • Moderate abnormalities have an upper range of >10 µV and a lower margin of 5 µV or less.
    • Severe abnormalities have an upper range of <10 µV and a lower margin of <5 µV, usually with a burst-suppression pattern.
  • An experienced neonatal encephalographer immediately notices the potential for overlapping of normal and moderate ranges because the lowest possible voltage is less reliable than the maximum voltage in neonatal EEG. The transition from non–rapid-eye-movement (REM) sleep to REM sleep (or REM-2) occurs when neonates behaviorally appear to be asleep, sometimes for over an hour. The start of REM-2 is associated with a notable reduction in background amplitude.
  • Although this method is promising, further validation of the accuracy of aEEG in trials of patients undergoing both aEEG and standard EEG are needed. Also needed is a demonstration that aEEG adds to the accuracy of other modalities (eg, DWI, MRS, evoked-potential testing).
• Evoked-potential testing
  • In several studies of neonates at high risk for poor neurologic outcomes, both somatosensory evoked potentials (SSEPs) and visual evoked potentials (VEPs) have utility in predicting the long-term outcome of HIE-NE. Persistently and bilaterally absent SSEP cortical potentials in high-risk term neonates are correlated with adverse neurologic sequelae after HIE-NE.
  • SSEPs obtained by the end of the first week of life appear to have the highest predictive value. Bilateral absence or prolonged latencies of cortical potentials in premature infants are predictive of an adverse neurodevelopmental outcome. However, preterm infants with normal SSEPs may have a decreased likelihood of a normal outcome. SSEP can be abnormal owing to lesions of the median nerve or of the median nerve fibers as they go through the brachial plexus or posterior cervical roots (C6-T1). Spinal-cord lesions, especially posterior lesions, affecting the proprioceptive large-fiber system and diseases that affect the peripheral myelin in the neonatal period (eg, congenital hypomyelinating neuropathy) also cause abnormal SSEPs.
  • High-risk neonates with a clinical picture suggestive of HIE and abnormal VEPs (obtained on days 3-7 of life) have a high risk of dying in the neonatal period or of having severe neurologic deficits on follow-up. Normal VEPs have negative predictive values lower than those of SSEPs. (A normal VEP does not guarantee a normal outcome.) VEPs that are initially abnormal but that improve over time still tend to indicate poor prognosis. Bilateral eye and optic-nerve lesions invalidate VEP results. Retinal function can be assessed by simultaneously registering the electroretinogram during recording of the VEP. When both the VEP and the electroretinogram are absent in a neonate, prognostication regarding HIE-NE is invalid.
  • In neonates with an HIE-NE picture, SSEPs and VEPs are best for predicting the outcome by the end of the first week of life. The combination of normal VEPs and SSEPs is a strong predictor of a normal outcome.
  • Scalp edema, subdural hematomas, and epidural hematomas can produce falsely abnormal results with either SSEPs or VEPs.
  • Brainstem auditory evoked potentials (BAEPs) may be useful in evaluating potential brainstem injury, but they lack the predictability of VEPs and SSEPs.
  • The combination of SSEP, VEP, and BAEP neurophysiologic tests is ideal to predict the neurologic outcome after HIE.
• Near-infrared spectroscopy: Near-infrared spectroscopy appears to be a promising modality for monitoring ischemic events in the CNS. It is used to monitor cerebral oxygenated hemoglobin levels, and it can depict clinically significant changes that occur during acute hypoxemic events.
• Intracranial pressure (ICP) monitoring: In HIE, brain edema is a consequence of severe cerebral necrosis, and it is not a common cause of ischemic cerebral injury. ICP is generally increased in severely asphyxiated term newborns after 24-48 hours of life. However, elevated ICP is not common in HIE of the premature infant unless concomitant posthemorrhagic hydrocephalus is present. ICP is not routinely monitored in neonates with HIE because it rarely leads to changes in their care.
• Technetium scanning: This technique, now rarely used, reflects the increased uptake of radionucleotides by damaged brain tissue that occurs after the blood-brain barrier is disrupted.

Procedures

• Although findings on lumbar puncture are almost never diagnostic of HIE-NE, they help exclude other entities, such as meningitis and hemorrhage. In addition, the opening CSF pressure may help in detecting increased ICP.
• Several CSF markers of HIE-NE are currently under investigation for their usefulness and validity in predicting long-term outcomes. Those most studied are CK-BB, lactate, and neuron-specific enolase.

Histologic Findings

Neuropathologic patterns and pathogenesis of neonatal HIE

According to Volpe, 5 major neuropathologic patterns described in patients are believed to be related to perinatal insults due to HIE. They are parasagittal cerebral injury, PVL, selective neuronal necrosis, status marmoratus of the basal ganglia and thalamus, and focal and multifocal ischemic brain necrosis. Most cases of neonatal HIE result from antenatal injuries. Nonetheless, the exact timing of these perinatal insults is often hard to pinpoint. In addition, some neuropathologic patterns of injury, like PVL, are related to the gestational age of the newborn infants.

Parasagittal cerebral injury

Parasagittal cerebral injury is a major ischemic lesion of the term infant. The timing of injury is primarily perinatal. The characteristic distribution of the injury, as indicated by the name, is in the parasagittal or superomedial aspect of the cerebral convexities. This topographic distribution corresponds to the locations of arterial end zones and border zones of the anterior, medial, and posterior cerebral artery territories. The pattern results because systemic hypotension preferentially affects the watershed areas. Injury usually is bilateral and symmetric, and the posterior portions of the cerebral hemispheres are affected more than the anterior parts.

The most extensive injury seen in the posterior cerebrum, probably because this region represents the watershed of the anterior, middle, and posterior cerebral arteries. In addition, posterior cortex is metabolically more active and therefore more vulnerable than other areas.

In the neonatal period, a parasagittal cerebral injury clinically manifests as weakness in the proximal extremities, arms more than legs. The long-term correlates of the parasagittal cerebral injury include proximal greater-than-distal and arm-more-than-leg involvement of spastic quadriparesis. Specific cognitive deficits, such as language dysfunction and visuospatial or visuomotor impairment, have been described and are probably due to temporoposterior parieto-occipital involvement.

Periventricular leukomalacia

PVL is most common in premature infants who survive at least a few days, and it is considered the main ischemic lesion in this population. Infants with low birth weight (<1.5-2 kg) and with a history of cardiorespiratory disturbances, especially those requiring ventilatory support, have an increased incidence of PVL. The offending ischemic insults can be either prenatal or postnatal.

PVL is characterized by necrosis of the periventricular white matter, dorsolateral to the external angles of the lateral ventricles, that occasionally becomes hemorrhagic. Hemorrhagic PVL in association with intraventricular hemorrhage may be indistinguishable from the periventricular hemorrhagic venous infarct that commonly accompanies intraventricular bleeding. Two common sites for PVL are around the anterior horns of the lateral ventricles (ie, white matter around the foramen of Monro) and around the trigones at the level of the parieto-occipital junction or optic radiation. A potentially deleterious effect of PVL is destruction of subplate zone neurons, which may interfere with cortical organization and thalamic and cortical connectivity.

The pathogenesis of PVL is related to a combination of vascular, metabolic, local, and systemic circulating factors. Before a gestational age of 32 weeks, and especially before 28 weeks, the long, penetrating cerebral arteries have few anastomoses with the short penetrators, which are few. Between 24 and 28 weeks gestational age, the periventricular arterial end zone, including areas of the white matter relatively distant from the immediate periventricular zone, is relatively large.

In addition, the pressure-passive cerebral circulation and the increased sensitivity of oligodendroglia cells to injury in premature neonates increase their susceptibility to ischemic injury. For this reason, extremely premature infant brains are most susceptible to even mild degrees of hypotension. From 28 weeks' gestational age to term, the periventricular vasculature increases progressively, decreasing the neonate's susceptibility to PVL.

In the premature infant, many common systemic problems have been associated with PVL. These include severe respiratory distress, apnea, myocardial failure, patent ductus arteriosus, hypotensive episodes (<30 mm Hg), hypovolemia, acidosis, and hypocarbia. About one third of patients with a patent ductus arteriosus that has retrograde flow during diastole develop PVL. Premature infants who are small for their gestational age are particularly vulnerable to PVL.

During the neonatal period, identifying a specific pattern of neurologic deficit in the patient with PVL may be difficult. On occasion, weakness in the legs may be observed in a neonate with PVL. The major long-term neurologic correlate of PVL is spastic diplegia involving the lower extremities more than the upper extremities. This pattern of injury to the corticospinal tract is thought to be a direct consequence of damage to the leg fibers as they go through the zone of periventricular necrosis. Corticospinal-tract fibers bound to the trunk, arm, face, and mouth have a relatively direct trajectory as they go from the cortex to the centrum semiovale and internal capsule, often avoiding the PVL area; however, large lesions with lateral extension can affect these fibers.

Patients with clinically significant spasticity involving the upper and lower extremities are most likely to have intellectual deficits. On the contrary, patients with sonographically depicted noncavitary lesions may have substantial improvement of spastic diplegia in the first several years of life. Patients with PVL may also have visuomotor and visual-field disturbances, which are probably related to damage to the optic radiations and visual association fibers.

Selective neuronal necrosis

Selective neuronal necrosis is a prominent injury pattern in infants who have hypoxic-ischemic injury in the postnatal period, and it is often associated with other patterns of HIE injury. Although the neuropathologic injury pattern seems to mirror the regional distribution of glutamatergic neurons (which can mediate neurotoxicity), some regional vascular factors may also play a role, as the neuronal injury is most prominent in the depths of sulci and watershed zones. Neuronal injury occurs at specific sites of the cerebral cortex, such as the Sommer sector of the hippocampus and, in severe cases, the calcarine and central cortices.

Other affected sites in the CNS include the diencephalon, brainstem, Purkinje cells of the cerebellum, and spinal cord. In the less commonly affected premature infants, sites of predilection include the subiculum in the hippocampus, basis pontis, internal granular layer of the cerebellum, and inferior olivary nuclei.

During the neonatal period, selective neuronal necrosis produces a clinical picture of stupor and coma or of hypotonia with oculomotor, sucking, and swallowing disturbances, as well as seizures and abnormal tongue movements. The major long-term sequelae are cognitive deficits, spastic quadriparesis, seizure disorder, ataxia, bulbar and pseudobulbar palsies, hyperactivity, and inattention.

In rare cases, presumed perinatal total asphyxia is followed by a lack of body movements and no brainstem, cranial-nerve, or mediated reflexes. In these cases, pupillary constriction to light is often absent, as are facial and eye movements (spontaneous or induced by an oculocephalic maneuver). The vulnerable pontine area is the watershed zone between the paramedian and short and long circumferential branches of the basilar artery. In the medulla, the vulnerable area is between the anterior and posterior branches of the spinal and vertebral arteries. Structures in the pontomedullary watershed zone, which hypoperfusion may affect, are parts of the respiratory center. As a result, the clinical correlates of this lesion include decreased respiratory drive, apnea, and decreased arousal.

Status marmoratus

Status marmoratus is the least common pattern of HIE-related neuropathologic injury, and it is more common in term infants than preterm infants. This injury is thought to be of postnatal onset, though prenatal factors may play a role in some patients. The terms status marmoratus and état marbré refer to the marbled appearance of the deep nuclear structures, especially the putamen, caused by hypermyelination surrounding the astrocytic fibers.

Neuronal injury primarily occurs in the putamen (particularly the dorsal part), globus pallidus, and thalamus (ie, ventral, medial, lateral nuclei). Marked changes in the thalamus occur in 80-90% of patients. Microscopic features include neuronal loss, astrogliosis, and hypermyelination around astrocytic fibers. The physiopathology also invokes the neurotoxicity mechanism, since the distribution of lesions is related to the distribution of N -methyl D-aspartate (NMDA)–glutamate receptors.

During the neonatal period, no clear-cut pattern of neurologic deficit can be attributed to status marmoratus. Long-term survivors have movement disorders or cognitive deficits. The movement disorder is often occult until the child is aged 1-4 years, and it may be preceded by a history of delayed motor development and hypotonia. However, in many instances, motor development may be normal until the movement disorder appears. In rare cases, the onset of choreoathetosis and dystonia may be delayed until the child is aged 7-14 years. Spastic quadriparesis occurs in about one third of patients, more commonly among patients with dystonia and less commonly in those with choreoathetosis. Cognitive deficits can occur, but normal intelligence is possible, especially in patients with delayed-onset movement disorder.

Focal and multifocal ischemic brain necrosis

An estimated 20% of infants with HIE have focal or multifocal lesions. These lesions are most common in term infants with postnatal ischemic insults. Some experts prefer to exclude focal lesions (eg, single vessel occlusion) from HIE-NE because, in many cases, focal cerebral infarcts are not associated with systemic ischemia or hypoxemia. However, in many cases both focal (eg, embolic) and generalized (eg, heart failure) ischemia coexist, as in the case of sepsis with disseminated intravascular coagulation causing thromboembolic phenomena. The hallmark of focal and multifocal ischemic brain necrosis is the destruction (necrosis) of all cellular elements in the distribution of a single vessel or several vessels (ie, single or multiple infarcts, respectively).

When these infarcts develop cavitation due to the dissolution of brain parenchyma, a porencephalic cyst (if single), multicystic encephalomalacia (if multiple), or even hydranencephaly (if multiple and extensive) forms. These cavitated lesions may communicate with the ventricular system. The tendency of the fetal neonatal brain to develop cavitation after ischemic insults is likely related to its high water content, low numbers of myelinated fibers, and poor astroglial response. Distinction between this focal or multifocal necrosis, parasagittal injury, and PVL may be difficult, and, in some cases, these injury patterns coexist.

The incidence of arterial occlusion varies with gestational age. It is rare in infants younger than 28 weeks and gradually increases with advancing maturation, affecting about 15% of full-term infants in the autopsy series. The middle cerebral artery is affected in more than one half of patients, and the lesions are usually unilateral.

Focal or multifocal infarcts may be the result of cerebral venous thrombosis. The superior sagittal sinus is involved in about 85% of patients (most often posteriorly), and the rest affect the lateral sinuses and the galenic system deep veins. Hemorrhagic conversion is common in cases of venous infarcts.

The pathogenesis involves thromboembolic vessel occlusion, vasculopathy, vasospasm due to vasoconstricting drugs (eg, cocaine, methamphetamine), or a vascular malformation.

• Embolic phenomena may be due to placental fragments, an embolus originating from a dead twin (detritus), catheterized vessels, congenital heart disease with right-left shunting, fragments of cardiac tumors (eg, atrial myxoma and rhabdomyoma in tuberous sclerosis), involuting vessels (eg, umbilical vein, ductus arteriosus), and isoimmune neonatal thrombocytopenia. Isoimmune neonatal thrombocytopenia may be associated with obstruction of the middle cerebral artery in utero, perhaps due to endothelial injury. Pathologically documenting an intra-arterial embolus is often difficult.
• A thrombotic tendency that may lead to vessel occlusion is seen in hypercoagulable states, disseminated intravascular coagulation, dehydration, trauma, meningitis (eg, arteritis or phlebitis), and neck or cranial trauma (eg, vascular injury). Hypercoagulable states with neonatal manifestations include protein C and S deficiencies, antithrombin III deficiency, antiphospholipid antibody syndrome, and polycythemia with hyperviscosity.
• ECMO is a multifactorial cause of focal, multifocal, and generalized ischemia. Most lesions are hemorrhagic, with or without superimposed ischemia; however, isolated ischemic lesions represent 40% of the imaging abnormalities in patients who received ECMO. Explanations for ECMO-related cerebrovascular insults include anticoagulation with heparin (eg, hemorrhagic conversion of a previous ischemic lesion), jugular-vein ligation, decreased blood-flow velocity in the venous system, retrograde flow in the right vertebral artery, increased blood-flow velocity in the left internal carotid artery, and changes in blood-flow direction in the circle of Willis.
• Approximately one third of focal ischemic lesions have evidence of a generalized-systemic circulatory insufficiency of either prenatal or postnatal origin. However, the pathophysiology of the focal nature of the resulting lesion is not clear.
• Despite progress in evaluating focal cerebrovascular ischemia, the etiology in more than one half of patients remains undiagnosed.

Neonatal seizure is the presenting symptom for at least 80% of patients with a focal unilateral cerebral infarct. Mild hemiparesis may be noted in the newborn infant with large unilateral lesions. The long-term sequelae of focal or multifocal cerebral necrosis include spastic hemiparesis and quadriparesis (ie, bilateral hemiparesis), cognitive deficits, and seizures. Follow-up examination of patients with unilateral neonatal infarction shows hemiparesis in only 55%, but a lower incidence of residual weakness has been reported. This relatively low frequency of residual hemiparesis is probably related to both the severity of the lesions and the subsequent reorganization of cortical function. Cognitive dysfunction is reported in about 30% of patients with focal infarcts. Patients with cerebral venous infarcts frequently have seizures as a presenting symptom.

Staging

• Stage 1
  • Hyperalertness
  • Decreased sleep
  • Uninhibited reflexes
  • Excessive reaction to stimuli
  • Weak suck but normal tone
  • Sympathetic overactivity - Eyes wide open, decreased blinking, mydriasis, and EEG normal
  • Duration less than 24 hours
  • Good prognosis - No long-term neurologic sequelae
• Stage 2
  • Lethargy or obtundation (ie, delayed and incomplete response sensory stimuli)
  • Mild hypotonia
  • Cortical thumbs
  • Suppressed primitive reflexes
  • Seizures
  • Hypotonia
  • Lethargy
  • Parasympathetic activation with miosis (even on dim light), heart rate less than 120 beats per minute, increased peristalsis, and copious secretions)
  • EEG early (first day): Relatively low voltage, less than 25 microvolts (slow theta and delta)
  • EEG late (second day): Bursting pattern (awake or obtunded) and multifocal low-frequency (1-1.5 Hz) electrographic seizures
  • Good prognosis if clinical and EEG recovery within 5 days
  • Poor prognosis if periodic EEG with interburst intervals totally isoelectric, bursting frequency less than every 6 seconds, bursting pattern (every 3-6 seconds) lasting more than 7 days
• Stage 3
  • Stupor response only to strong stimuli with withdrawal or decerebrate posturing only
  • Rarely coma
  • Severe hypotonia (ie, flaccidity)
  • Suppression of deep tendon and primitive (ie, Moro, tonic neck, oculocephalic, suck) reflexes
  • Suppression of brainstem reflexes (corneal or gag)
  • Clinical seizures less frequent than stage 2
  • Deep, periodic EEG pattern with high amplitude and frequency of bursts less than every 6-12 seconds, very-low-voltage or isoelectric EEG
  • Major neurologic sequelae, including microcephaly, mental retardation, CP, seizures (all cases)

• Search for CME/CE on This Topic »

• Neuroinflammation and MMPs: Potential Therapeutic Targets in Neonatal Hypoxic-ischemic Injury