Hypoxic-ischemic Encephalopathy Stages and Symptoms

Table II.

	Score = 0	Score = 1
Feeding	Normal	Gavage feeding, gastrostomy tube or not tolerating feedings
Alertness	Alert	Irritable, poorly responsive, or comatose
Tone	Normal	Hypo- or hypertonia
Respiratory status	Normal	Respiratory distress
Reflexes	Normal	Hyporreflexia, hyperreflexia, or absent
Seizures	None	Suspected or confirmed

What other disease/condition shares some of these symptoms?

The symptoms of HIE can be vague and often overlap many neurologic and metabolic conditions in the newborn. Common conditions in the term newborn that may be mistaken for HIE include infection (i.e., sepsis), metabolic derangements or inborn errors of metabolism, other seizures (structural, metabolic, genetic), arterial ischemic or hemorrhagic stroke, or cerebral sinus venous thrombosis. Because of this commonality of symptoms, it is imperative to rule out life-threatening or treatable causes of these symptoms.

What caused this disease to develop at this time?

The ultimate pathophysiology of HIE is poorly understood, despite a wealth of research. It is known that labor and delivery is a high-risk period for cerebral vascular insults. Immaturity of the cerebral vasculature and autoregulation, along with increased white matter vulnerability in the newborn, contribute to ischcemic disease. Inflammation, excitotoxicity, and oxidative stress are all important mediators of HIE and cell death from apoptosis or necrosis. Apoptosis most likely plays a prominent role in neonatal brain injury associated with HIE rather than necrosis. Apoptosis is an essential element in normal brain development, pruning and defining cell pathways and connections. Aberrant apoptosis puts the developing brain at increased risk for neurodevelopmental impairment.

Perinatal asphyxia, hypotension, or anoxia are known major risk factors for HIE. However, many of these infants do not have a clear history of perinatal aspyhxia and thus the entire mechanism of injury is still unknown.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Because the symptoms can overlap many neurologic and metabolic conditions in the newborn, it is imperative to rule out life-threatening or treatable causes of these symptoms. Important laboratory studies that should be ordered to help rule out these conditions include the following:

Complete blood count with differential

Helps to rule out infection

Platelets can be low in HIE

Comprehensive metabolic panel, including liver function tests (LFTs) and ammonia and lactate determinations

Helps to rule out metabolic disturbance

Elevated ammonia points to a urea cycle deficit and requires emergency dialysis

Lactate levels can be increased in metabolic disease or with HIE alone

LFTs and blood urea nitrogen/creatinine levels can be abnormal in HIE

Blood cultures

Rule out sepsis

Lumbar puncture (LP) including cell count, culture, and protein and glucose levels

Rule out central nervous system infection

Low glucose levels may indicate glucose transport disorder

Increased lactate levels may indicate metabolic disorder

Second LP may be required for further metabolic or neurotransmitter evaluation

Would imaging studies be helpful? If so, which ones?

Head imaging studies can be particularly useful in both the diagnosis and prognosis of HIE. Magnetic resonance imaging (MRI) is the preferred head imaging of choice (see below).

Cranial ultrasonography (CUS) is often the first head image obtained in a newborn because of ease and availability. CUS can rule out intracranial hemorrhage, and in the hands of an experienced ultrasonographer, may identify ischemia. However, a normal scan on CUS does not rule out ischemia, as most ischemia is missed by CUS.

Brain MRI is the preferred imaging modality of choice. It is extremely helpful in identifying ischemic injury patterns. However, MRI may not fully characterize the extent of injury given immature myelination. In centers where newborn MRIs are performed frequently, sedation is not required. Most importantly, MRI can be helpful with prognosis (see below).

Head computed tomography is not ideal because of the radiation and the high water content of newborn brains. However, it can be ordered if MRI is not readily available and there are concerns of hemorrhage. A normal computed tomographic scan of the head does not rule out ischemia, and follow-up MRI should always be performed.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Term newborns with HIE should be transferred to an intensive care nursery given their critical nature. Treatment can be separated into immediate/hospital management and long-term treatment.

Immediate/hospital management

• Respiratory support
• Arterial line/umbilical artery catheter for blood pressure and arterial blood gas monitoring
• Umbilical vein catheter for drawing blood
• Maintenance of cerebral perfusion by controlling hypotension, bradycardia, and/or apnea
• Acidosis correction as needed
• Maintenance of euglycemia
• Fever control
• Seizure medication
• Lorazepam 0.5 mg intravenously (IV) as needed for seizure
• Phenobarbital 20 mg/kg IV for persistent seizures/status epilepticus; maintenance dose usually around 5 mg/kg/d, but newborns can metabolize this quickly and the dose may need to be increasingly tritrated to effect (weighed with side effects)
• Levetiracetam 20-30 mg/kg IV for persistent seizures/status epilepticus; maintenance starting dose 15 mg/kg IV or orally twice daily
• Hypothermia (see below)

Long-term treatment may include the following:

• Seizure medication if needed (most seizures desist 3-4 days after birth)
• Physical therapy
• Occupational therapy
• Speech therapy
• Behavioral or cognitive therapy
• Special education
• Assistive devices (i.e., ankle-foot arthosis, wrist splint)

What are the adverse effects associated with each treatment option?

Any treatment in the intensive care nursery carries risk. Adverse effects seen with common treatments in HIE include the following:

Umbilical catheters

Thrombus formation

Seizure medication

Increased sleepiness

Poor feeding secondary to sleepiness

Hypothermia

Relatively safe in clinical trials

Cardiac arrhythmias

Coagulation disturbances

What are the possible outcomes of this disease?

As described above, the outcome of HIE is dependent on the degree of encephalopathy and the areas of brain injury. Mild encephalopathy is associated with normal neurocognitive and motor outcome. Severe encephalopathy results in early death; those newborns that survive go on to have poor neurocognitive and motor outcomes.

Moderate encephalopathy is the most heterogeneous group and is therefore associated with the broadest range of both cognitive and motor outcomes. MRI can be particularly useful in prognosis in this population. Injury to the basal ganglia results in the most severe cognitive and motor outcomes, whereas watershed injury usually results in isolated cognitive deficits. Further, neurocognitive impairment usually does not manifest until school age. Therefore, ongoing neuropsychological screening should be done for early recognition and intervention.

What causes this disease and how frequent is it?

HIE is fairly common, and occurs in approximately 1-6/1000 live births. One fifth of children with HIE die in the newborn period. HIE is also associated with high morbidity; up to one quarter of survivors go on to have recognizable motor and/or cognitive impairment. At this time, there is no known genetic predisposition to HIE.

Known risk factors for HIE include birth asphyxia or prolonged reduction of cerebral blood flow (such as placental abruption or hypotension). However, many cases of HIE do not have a clear history of asphyxia or compromised cerebral blood flow. Because of this disconnect, some providers prefer to use the term “neonatal encephalopathy” or “NE” instead of HIE.

How do these pathogens/genes/exposures cause the disease?

As described above, the neonatal brain is particularly susceptible to injury, especially during labor and delivery. Selective vulnerability of immature oligodendria accounts for white matter injury seen in HIE. It is known that prolonged reduction of cerebral blood flow causes oxygen and glucose deprivation. Decreased cerebral blood flow also hampers clearance of toxic substrates (i.e., nitric oxide). Inflammation, excitotoxicity, and oxidative stress further mediate injury and cell death (apoptosis). Yet, many cases of HIE do not have obvious asphyxic/hypoxic insult, and therefore the exact mechanism of injury remains unclear.

Other clinical manifestations that might help with diagnosis and management

Continuous electroencephalographic monitoring is increasingly recognized as an important tool for the treatment and prognosis of HIE In newborns treated with hypothermia. A normal electroencephalogram (EEG) is predictive of a normal or mildly abnormal MRI scan, whereas a sustained severely abnormal EEG (burst suppression or extremely low voltage) over the course of cooling confers a poor prognosis. Amplitude-integrated electroencephalography may be an adjunctive measure of outcome in HIE; studies are ongoing.

What complications might you expect from the disease?

Complications outside the neuroaxis can often be seen in HIE. Complications seen (but not limited to) follow:

Acute

• Multiorgan involvment including liver and kidney failure, disseminated intravascular coagulation
• Bowel ischemia
• Seizures

Long term

• Spastic paresis (“cerebral palsy”)
• Epilepsy
• Vision impairment or blindness
• Hearing loss
• Feeding difficulties
• Learning disabilities
• Mental retardation
• Behavioral issues

How can this disease be prevented?

At this time there is no prophylactic drug or intervention that can prevent HIE. Therapeutic hypothermia is a commonly used therapy to help prevent ongoing brain injury acutely in HIE. Although therapeutic hypothermia cannot prevent HIE, it has been shown to decrease morbidity and neurologic mortality at 18-24 months of age.

What is the evidence?

Miller, SP, Latal, B, Clark, H, Barnwell, A. “Clinical signs predict 30-month neurodevelopmental outcome after neonatal encephalopathy”. Am J Obstet Gynecol. vol. 190. 2004. pp. 93-9. (The authors propose a new encephalopathy score that incorporates additional clinical characteristics to predict 30-day outcome in term newborns with perinatal asphyxia. Sixty-eight term newborns were scored on alertness, feeding, tone, respiratory status, reflexes, and seizure activity. Scores range from 0 (no encephalopathy) to 6 (severe encephalopathy). Mental Developmental Index, motor outcomes, and death were assessed at 30 days. The authors found that a higher encephalopathy score correlated with worse outcome.)

Shankaran, S, Laptook, AR, Ehrenkranz, RA. “National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy”. N Engl J Med. vol. 353. 2005. pp. 1574-84. (This is the first randomized, controlled clinical trial of therapeutic hypothermia in term asphyxiated newborns. It was found that whole-body hypothermia decreased the risk of death and disability in infants with moderate to severe encephalopathy. It should be noted there was no significant difference in cerebral palsy or mean Mental Developmental Index of all survivors, regardless of hypothermia.)

Jacobs, SE, Morley, CJ, Inder, TE. “the Infant Cooling Evaluation Collaboration.Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial”. Arch Pediatr Adolesc Med. 2011. (The authors sought to determine the safety and effectiveness of whole-body hypothermia for asphyxiated newborns in hospitals without a neonatal intensive care unit or hypothermia equipment. Newborns were randomized to hypothermia versus standard care. Hypothermia was supplied by turning off the radiant warmer and applying cold gel packs. Therapeutic hypothermia was found to reduce the risk of death or major disability at 2 years. The authors concluded that this method of hypothermia was safe and effective if applied within 6 hours of birth.)

Ongoing controversies regarding etiology, diagnosis, treatment

At present, most major academic institutions and tertiary care referral centers institute therapeutic hypothermia as standard of care. Studies are ongoing as to the utility of continuous amplitude-integrated electroencephalography or continuous conventional electroencephalographic monitoring of newborns with HIE, and the utility of treating subclinical seizures.