History
The 1996 guidelines from the American Academy of Pediatrics (AAP) and American College of Obstetrics and Gynecology (ACOG) for hypoxic-ischemic encephalopathy (HIE) indicate that all of the following must be present for the designation of perinatal asphyxia severe enough to result in acute neurologic injury [8, 9] :
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Profound metabolic or mixed acidemia (pH < 7) in an umbilical artery blood sample, if obtained
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Persistence of an Apgar score of 0-3 for longer than 5 minutes
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Neonatal neurologic sequelae (eg, seizures, coma, hypotonia)
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Multiple organ involvements (eg, kidney, lungs, liver, heart, intestines)
In rare instances, some babies will not fit the aforementioned criteria and the timing of the insult cannot be precisely known; however early magnetic resonance imaging of the brain can sometimes provide some insights.
Physical Examination
CNS Manifestations
Clinical central nervous system (CNS) manifestations and course vary depending on hypoxic-ischemic encephalopathy (HIE) severity.
Mild hypoxic-ischemic encephalopathy
The infant seems hyperalert, muscle tone may be slightly decreased initially, and deep tendon reflexes may be brisk during the first few days.
Transient behavioral abnormalities, such as poor feeding, irritability, or excessive crying or sleepiness (typically in an alternating pattern), may be observed.
Typically resolves in less than 24 hours without any consequences.
Moderately severe hypoxic-ischemic encephalopathy
The infant is lethargic, with significant hypotonia and diminished deep tendon reflexes.
The grasping, Moro, and sucking reflexes may be sluggish or absent.
The infant may experience occasional periods of apnea.
Seizures typically occur early within the first 24 hours after birth.
Full recovery within 1-2 weeks is possible and is associated with a better long-term outcome.
An initial period of well-being or mild hypoxic-ischemic encephalopathy may be followed by sudden deterioration, suggesting ongoing brain cell dysfunction, injury, and death; during this period, seizure intensity might increase.
Severe hypoxic-ischemic encephalopathy
Stupor or coma is typical. The infant may not respond to any physical stimulus.
Breathing may be irregular, and the infant often requires ventilatory support.
Generalized hypotonia and depressed deep tendon reflexes are common.
Neonatal reflexes (eg, sucking, swallowing, grasping, Moro) are absent.
Disturbances of ocular motion, such as a skewed deviation of the eyes, nystagmus, bobbing, and loss of "doll's eye" (ie, conjugate) movements may be revealed by cranial nerve examination.
Pupils may be dilated, fixed, or poorly reactive to light.
Seizures are delayed, can be severe and may be initially resistant to conventional treatments. The seizures are usually generalized, and their frequency may increase during the 24-48 hours after onset, correlating with the phase of reperfusion injury. As the injury progresses, seizures subside and the EEG becomes isoelectric or shows a burst suppression pattern. At that time, wakefulness may deteriorate further, and the fontanelle may bulge, suggesting increasing cerebral edema.
Irregularities of heart rate and blood pressure (BP) are common during the period of reperfusion injury, as is death from cardiorespiratory failure.
Infants who survive severe hypoxic-ischemic encephalopathy
The level of alertness improves by days 4-5 of life.
Hypotonia and feeding difficulties persist, requiring tube feeding for weeks to months.
Multiorgan Dysfunction
Multiorgan systems involvement is a hallmark of HIE. [33, 34] Organ systems involved following a hypoxic-ischemic events include the following:
Heart (43-78%)
May present as reduced myocardial contractility, severe hypotension, passive cardiac dilatation, and tricuspid regurgitation.
Lungs (71-86%)
Patients may have severe pulmonary hypertension requiring assisted ventilation.
Renal (46-72%)
Renal failure presents as oliguria and, during recovery, as high-output tubular failure, leading to significant water and electrolyte imbalances.
Liver (80-85%)
Elevated liver function test results, hyperammonemia, and coagulopathy can be seen. This may suggest possible GI dysfunction. Poor peristalsis and delayed gastric emptying are common; necrotizing enterocolitis is rare. Intestinal injuries may not be apparent in the first few days of life or until feeds are initiated.
Hematologic (32-54%)
Disturbances include increased nucleated RBCs, neutropenia or neutrophilia, thrombocytopenia, and coagulopathy. Severely depressed respiratory and cardiac functions and signs of brainstem compression suggest a life-threatening rupture of the vein of Galen (ie, great cerebral vein) with a hematoma in the posterior cranial fossa.
Neurologic Findings
Cranial nerves
Lack of reflex activity mediated by the cranial nerves can indicate brainstem dysfunction.
Full-term infants should blink and sustain eye closure in response to a sustained light stimulus. Repeated flashes of light should produce habituation (eg, attenuated blinking) after 3-4 stimuli. Virtually all full-term newborns can track a ball of red wool, and the movement of stripes of at least one eighth of an inch or bigger can elicit opticokinetic nystagmus. Objects and pictures with round contours and facial appearances also make good targets for tracking in the newborn. Tracking is possible in infants with complete destruction of the occipital cortex by virtue of a subcortical pulvinar-collicular system. Retinal hemorrhages are commonly observed in the neonate after vaginal delivery and can result in decreased pupil response. Destruction of the occipital cortex will also not affect pupillary response, because the responsible pathways leave the optic nerve and travel to the Edinger-Westphal nucleus, which sends back axons via the bilateral oculomotor nerves (consensual pupillary reflex).
Neurologic examination may be difficult in the small and frail premature infant, but weakness of the lower extremities sometimes reflects the neuropathologic substrate of periventricular leukomalacia. Over time, the patient with periventricular white-matter lesions develops spastic diplegia affecting the lower extremities more than the upper extremities.
Blinking to light starts at 26 weeks’ gestational age, sustained eye closure to light is seen around 32 weeks, and 90% of newborns track a ball of red wool by 34 weeks. Opticokinetic reflexes can be seen at 36 weeks. The pupil starts reacting to light around 30 weeks, but the light reflex is not consistently assessable until the gestational age of 32-35 weeks. Pupillary reflexes are reliably present at term. Extraocular movements can be elicited by performing the doll's-eye maneuver at 25 weeks’ gestation and by performing caloric stimulation at 30 weeks’ gestation.
In infants aged 32-34 weeks’ gestation, suck and swallow are reasonably coordinated with breathing, but the actions are not perfected until after term.
Patients with mild HIE often have mydriasis. Progression of the disease may produce miosis (even in the dark) responsive to light, and in severe cases (stage 3 of Sarnat classification), the pupils are small or midpositioned and poorly reactive to light, reflecting sympathetic or parasympathetic dysfunction.
The lack of pupillary, eye movement, corneal, gag, and cough reflexes may reflect damage to the brainstem, where the cranial-nerve nuclei are located. Decreased respiratory drive or apnea can be from lesions of the respiratory center, which overlap with vagal nuclei (ambiguous and solitaire) or medullary reticular formation. Ventilatory disturbances in HIE may manifest as periodic breathing apnea (similar to Cheyne-Stokes respiration) or just decreased respiratory drive.
Motor function
Begin the motor examination of an infant with suspected HIE by qualitatively and quantitatively observing his or her posture and spontaneous movements. Asymmetry in the amount of movement and posture is a subtle sign of hemiparesis, but it may be the only focal feature of the examination. Slight stimulation (eg, gently touching the patient) can increase motor activity in the term neonate and may be helpful in demonstrating asymmetrical hemiparesis.
Eliciting the Moro reflex may be an excessive stimulus and mask a subtle asymmetry in limb movement. Asymmetry in the Moro reflex is seen in peripheral lesions (eg, those due to brachial plexus injury).
Total absence or paucity of spontaneous movements, especially if associated with no reaction to painful stimuli and generalized hypotonia, indicates brainstem dysfunction or severe, diffuse, or multifocal cortical damage.
Specific patterns of motor weakness indicate cerebral injury patterns. Patients with borderzone parasagittal injury (ulegyria) tend to have proximal greater than distal weakness and upper extremity more than lower extremity weakness (man-in-the-barrel). A unilateral, focal infarct, especially one involving the middle cerebral artery, causes contralateral hemiparesis and focal seizures. Patients with selective neuronal necrosis may have severe hypotonia, stupor, and coma.
Motor examination of a newborn with large unilateral lesions may reveal mild hemiparesis and seizures in as many as 80%. The seizures are often partial (focal) and contralateral to the cortical lesion. Neonates with severe bilateral infarcts may have quadriparesis. Moro and tonic neck reflexes do not habituate, reflecting the lack of cortical modulation, which attenuates the response after repeated trials or sustained stimulus. Newborns with diencephalic lesions cannot regulate their temperature and have problems with sleep-wake cycles. The long-term sequelae of focal or multifocal cerebral necrosis include spastic hemiparesis and quadriparesis (eg, bilateral hemiparesis), cognitive deficits, and seizures.
Foot-ankle dorsiflexion or triple flexion (eg, foot-ankle dorsiflexion, knee and hip flexion) after plantar stimulation reflects only an intact spinal cord and sensory and motor nerves. Extensor movements (eg, arm elevation above the level of the shoulders) are more sophisticated motor actions than the dorsiflexion or triple flexion and require some cortical function.
A tonic neck reflex is performed by turning the patient's head to one side. The patient demonstrates arm and leg extension on the side to which the head is turned and flexion on the opposite side (fencer's posture). The tonic neck reflex posture should go away after several seconds, and its persistence is a sign of cortical dysfunction.
Spasticity is a velocity-dependent increase in tone that is generally most prominent with limb extension in muscle groups with antigravitational action (arm flexion, plantar extension). This sign can be seen over time in infants with corticospinal tract damage caused by a hypoxic-ischemic insult. In the neonatal period, spasticity is commonly noted first and is most prominent in the distal parts of the extremities. All fingers are flexed with the thumb under the second to fifth fingers, a pattern commonly referred to as cortical thumbs. Fewer than 5-10 beats of ankle clonus may be present in healthy neonates, but infants with damage to the corticospinal tract may have sustained ankle clonus. However, the initial motor manifestation will be flaccid hypotonia with spasticity later developing.
When assessing muscle tone, the state of arousal and prematurity must be taken into account. In the acute phase, tone is decreased in a generalized fashion affecting trunk and extremities. The flexor tone in the limbs is best assessed in term infants by showing a discrepancy in the scoring system between Dubowitz neurologic examination and morphologic examination. The infant looks like a “rag doll” when supported by a hand under the chest (vertical suspension). Head lag is demonstrated by traction of the hands in a supine position. The infant folds around the examiner's hand when lifted prone with a hand supporting the chest (horizontal suspension).
Hip abduction may be seen with increased tone and even with decerebrate posturing (frog-leg posture). Another manifestation of CNS dysfunction in the neonatal period is increased axial extensor tone with arching of the back and neck extension or opisthotonus. Many infants simultaneously have decreased axial flexor tone (eg, major head lag on arm traction maneuver) and increased axial extensor tone. In many cases, limb and axial hypotonia are present for several months before increased axial extensor tone or limb spasticity can be detected. Increased active neck and trunk extensor tone are predictors of quadriparesis. Another sign of spasticity that can develop relatively early is scissoring, where the previously abducted legs extend, become rigid, and have extreme hip adduction such that they cross with stimulation or crying.
Seizures
HIE is often reported to be the most frequent cause of neonatal seizures. They usually occur 12-24 hours after birth and are difficult to control with anticonvulsants. Large, unilateral infarcts occur with neonatal seizures in as many as 80% of patients. Seizures are often partial (focal) and contralateral to the cortical lesion. About two thirds of newborns with cerebral venous infarcts have seizures. Those with multiple or diffuse lesions and cerebral venous infarcts often have multifocal or migratory seizures. Seizures are observed during physical examination and may confirm the diagnosis. Observation often reveals clonic rhythmic contractions. When holding the limb affected by clonic seizures, the examiner's hand shakes or feels limb movement. Limb flexion or extension does not suppress the clonic activity, as it does in jitteriness and clonus. Newborn infants cannot have generalized seizures due to immaturity of the neuronal pathways connecting the 2 halves of the brain.
Tonic, unilateral, or focal seizures consistently have an EEG signature. In the seizures, unilateral arm and leg posturing is often accompanied by ipsilateral trunk flexion. Generalized tonic posturing (eg, extension of the upper and lower extremities or extension of the legs and flexion of the arms) is related to an EEG seizure in 15% of affected neonates.
Tonic seizures can be seen in neonates with local anesthetic intoxication. Although generalized tonic posturing is infrequently associated with electrical seizures, it is not a benign sign. Of neonates with tonic posturing and an abnormal EEG background, 13% have normal development.
Mizrahi and Kellaway suggested the name brainstem release phenomena because tonic posturing and some subtle seizure-like motor automatisms are probably the result of primitive brainstem and spinal motor patterns liberated because the lack of inhibition from damaged forebrain structures. [35] However, this tonic posturing is not a seizure and, thus, treatment with antiepileptics does not have benefit unless the infant is having other semiology consistent with seizures.
Subtle seizures may be a part of the HIE picture. Subtle manifestations of neonatal seizures are confirmed on EEG and include apnea; tonic eye deviation; sustained eye opening; slow, rhythmic, tongue thrusting; and boxing, bicycling, and swimming movements. Most still accept that some subtle seizures may be correlated with EEG results. However, publications since the late 1980s have shown that seizures are not as frequent as previously thought and that they are unusual in patients close to term. Several other patterns of subtle neonatal seizures are described without EEG confirmation. The lack of an EEG signature does not exclude CNS pathology because neonates with HIE often have motor automatisms without EEG seizures. Management is controversial, but treatment is not usually beneficial unless more overt seizure activity is noted. [36]
Seizures may be difficult to clinically diagnose in the premature neonate. Subtle seizures associated with ictal EEG changes are not rare in premature infants. The subtle patterns of neonatal seizures in the premature infant include sustained eye opening, oral-buccal-lingual movements (smacking, drooling, chewing), pedaling movements, grimacing, and autonomic manifestations.
Sarnat Staging System
The staging system proposed by Sarnat and Sarnat in 1976 is often useful in classifying the degree of encephalopathy. [37] Stages I, II, and III correlate with the descriptions of mild, moderate, and severe encephalopathy described above.
Table. Modified Sarnat Clinical Stages of Perinatal Hypoxic Ischemic Brain Injury [37] (Open Table in a new window)
|
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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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.
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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.
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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.
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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.
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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.
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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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