Chapter 9. Hypoxic-Ischemic Encephalopathy: Clinical Aspects

Chapter 9

TABLE 9-1



Timing of Insults Leading to HypoxicIschemic Encephalopathy



Of 245 infants who had an MRI scan after neonatal neurological signs (‘‘neonatal encephalopathy’’), and evidence

of intrapartum perinatal asphyxia,

197 (80%) had MRI evidence of acute lesions consistent

with hypoxic-ischemic insult; only 8 (4%) also had MRI

evidence of antenatal injury.

40 (16%) had normal MRI scans.

8 (4%) had other disorders (e.g., neuromuscular or

metabolic diseases).

MRI, magnetic resonance imaging.

Data from Cowan F, Rutherford M, Groenendaal F, Eken P, et al: Origin

and timing of brain lesions in term infants with neonatal encephalopathy, Lancet 361:736–742, 2003.



ductus arteriosus or other congenital heart disease,

severe pulmonary disease) may lead to hypoxicischemic encephalopathy and may account for approximately 10% of cases.21 Most of these and related

postnatal factors are much more important in the pathogenesis of hypoxic-ischemic brain injury in the premature infant than in the term infant (see Chapters 8 and

11). Although hypoxic-ischemic injury certainly can

occur in the antepartum period (e.g., secondary to

maternal trauma, maternal hypotension, uterine

hemorrhage), this injury cumulatively accounts for

only a small proportion of neonatal hypoxic-ischemic

encephalopathy. However, antepartum factors may

predispose to intrapartum hypoxia-ischemia during the

stresses of labor and delivery, especially through threats

to placental flow. Such factors include maternal diabetes, preeclampsia, placental vasculopathy, intrauterine growth retardation, and twin gestation (see Chapter

8). In one series, such factors were present in approximately one third of cases of intrapartum asphyxia.21

Indeed, ‘‘perinatal asphyxia’’ was identified in 27% of

infants of diabetic mothers, and its occurrence correlated closely with diabetic vasculopathy (nephropathy)

and presumed placental vascular insufficiency.24 The

additional stress of labor would be expected to compromise placental blood flow. Similarly, impaired placental

function and an increased risk of perinatal asphyxia in

the infant with intrauterine growth retardation are recognized and appear to account for some of the increased

risk of subsequent neurological disability in such

infants.25-32 Other factors (e.g., dysmorphic syndromes, severe undernutrition, infection) may also

lead to increased risk of neurological disability in

intrauterine growth retardation.29,33-37 Studies in fetal

and neonatal animals suggest that the mechanisms for

the increased vulnerability of the growth-retarded fetus

relate not only to placental insufficiency but also to

diminished glucose reserves in heart, liver, and brain

and to impaired capability to increase substrate supply

to brain with the hypoxic stress of vaginal delivery.38,39

In general, more extensive use of sophisticated techniques for antepartum assessment of the fetus (see

Chapter 7) may help determine whether, when, and

to what extent hypoxic-ischemic injury to the fetus

occurs before labor or delivery.



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



401



Although the particular importance of intrauterine

asphyxia, especially intrapartum asphyxia with or without antepartum predisposing factors, in the genesis

of the clinical syndrome of neonatal hypoxic-ischemic

encephalopathy is apparent, most infants who experience intrauterine hypoxic-ischemic insults do not exhibit overt neonatal neurological features or subsequent

neurological evidence of brain injury.2,3,14,16,18,40-46

The severity and duration of the asphyxia obviously

are critical. The elegant studies of Low and others

demonstrated a striking relationship among the severity

and duration of intrapartum hypoxia, assessed by the

use of fetal acid-base studies (see Chapter 7), the subsequent occurrence of a neonatal neurological syndrome, and later neurological deficits. Current data

suggest that approximately 1.3 per 1000 live term

births experience hypoxic-ischemic encephalopathy,22,46-48 and approximately 0.3 per 1000 of these

live term births have significant neurological residua

(see later discussion).

NEUROLOGICAL SYNDROME

The neurological syndrome that accompanies serious

intrauterine asphyxia is the prototype for neonatal

hypoxic-ischemic encephalopathy. The occurrence of a

neonatal neurological syndrome, indeed, is a sine qua non for

attributing subsequent brain injury to intrapartum insult.

Indeed, I consider three features important in considering that intrapartum insult is the likely cause of

neonatal brain injury: (1) evidence of fetal distress

(e.g., fetal heart rate abnormalities, meconium-stained

amniotic fluid), (2) depression at birth, and (3) an overt

neonatal neurological syndrome in the first hours and

days of life. Important conclusions about a clinically

significant neonatal neurological syndrome in this

setting are noted in Table 9-2.

Although not discussed here in depth, important

systemic abnormalities, presumably related to ischemia,

often accompany the neonatal neurological syndrome.

The relative frequencies of manifestations of organ

injury in term infants with evidence of asphyxia were

addressed in several studies.44,45,49-52 The findings

varied as a function of the severity of asphyxia and

the definitions of organ dysfunction. In combined

data from two reports (Table 9-3),45,49 approximately

20% of infants with apparent fetal asphyxia had no

evidence of organ injury. Evidence of involvement of

the central nervous system occurred in 62% of infants.

Indeed, in 16% of infants, involvement of only the

nervous system was apparent. Central nervous system



TABLE 9-2



Neonatal Neurological Syndrome

Associated with Clinically Significant

Encephalopathy



Not subtle

Indicative of recent (e.g., intrapartum) insult

Prenatal insult (e.g., antepartum) also possible

Absence rules out intrapartum insult capable of causing

major brain injury



402

TABLE 9-3



UNIT III



HYPOXIC-ISCHEMIC ENCEPHALOPATHY



Manifestations of Organ Injury in

Term Asphyxiated Infants*

Percentage

of Total



Organ

None

CNS only

CNS and one or more other organs

Other organ(s), no CNS



22%

16%

46%

16%



*



Cumulative total of 107 term infants; definition of asphyxia in both

series included umbilical cord arterial pH < 7.2.

CNS, central nervous system.

Data from Perlman JM, Tack ED, Martin T, Shackelford G, et al: Acute

systemic organ injury in term infants after asphyxia, Am J Dis Child

143:617–620, 1989; and Martin-Ancel A, Garcia-Alix A, Gaya F,

Cabanas F, et al: Multiple organ involvement in perinatal asphyxia,

J Pediatr 127:786–793, 1995.



involvement without overt dysfunction of systemic

organs is particularly likely after severe, acute, terminal

intrapartum insults with resulting injury primarily

to deep nuclear structures (see Chapter 8).50 Systemic

organ involvement, without neurological disease,

occurred in only 16% of infants. The order of frequency of systemic organ involvement overall has

been hepatic > pulmonary > renal > cardiac. In an

autopsy series, cardiac involvement was the most

common among affection of systemic organs.53 With

careful electrocardiographic and enzymatic studies of

living infants after perinatal asphyxia, evidence of myocardial ischemia has been commonly observed.54

The following discussion is based primarily on my

findings with term infants who have sustained serious

intrauterine asphyxia. A continuum of severity is recognized readily, and various classification schemes have

been devised.8,46,55-57 Certain variations in the syndrome relate to the topography of the neuropathology,

as noted later.

Birth to 12 Hours

In the first hours after the insult, signs of presumed

bilateral cerebral hemispheral disturbance predominate

(Table 9-4).58,59 The severely affected infant is either

deeply stuporous or in coma (i.e., not arousable

and minimal or no response to sensory input).

Periodic breathing, or respiratory irregularity akin to

this pattern, is prominent, and I consider this form of

respiratory disturbance to be the neonatal counterpart



TABLE 9-4



Clinical Features of Severe HypoxicIschemic Encephalopathy: Birth to 12

Hours



Depressed level of consciousness: usually deep stupor or

coma

Ventilatory disturbance: ‘‘periodic’’ breathing or respiratory

failure

Intact pupillary responses

Intact oculomotor responses

Hypotonia, minimal movement > hypertonia

Seizures



of Cheyne-Stokes respiration, which is observed in

older children and adults with bilateral hemispheral

disease. In one series, approximately 80% of asphyxiated infants had abnormal breathing patterns, particularly periodic breathing.60 Those most severely

affected may exhibit marked hypoventilation or respiratory failure. Pupillary responses to light are intact,

spontaneous eye movements are present, and eye

movements with the oculocephalic response (doll’s

eye maneuver) are usually full. (Pupillary size is variable, although dilated reactive pupils tend to predominate in the less affected infants, and constricted

reactive pupils are common in the more severely

affected infants.55) Commonly, disconjugate eye movements are apparent. However, only in a few babies are

eye signs of major brain stem disturbance seen. Fixed,

midposition, or dilated pupils and eye movements fixed

to the doll’s eyes maneuver and to cold caloric stimulation are unusual at this stage. If either of these signs is

evident at this time, especially in the full-term infant,

injury to brain stem is likely. Most infants at this stage

are markedly and diffusely hypotonic with minimal

spontaneous or elicited movement. Less severely

affected infants have preserved tone. Others exhibit

increased tone, especially with prominent involvement

of basal ganglia. Seizures, in my experience, occur by

6 to 12 hours after birth in approximately 50% to 60%

of the infants who ultimately have convulsions. Similar

data have been recorded by others.15,46,61 The particular propensity for convulsions in asphyxiated infants is

reminiscent of the particular propensity of the immature rat (compared with the adult) to exhibit epileptic

phenomena after hypoxia-ischemia.62

Virtually every one of the infants with seizures, in

my experience, exhibits ‘‘subtle seizures,’’ manifested

by one or more of the following (see also Chapter 5):

(1) ocular phenomena, such as tonic horizontal

deviation of eyes with or without accompanying

jerking movements of eyes, or sustained eye opening

with ocular fixation; (2) sucking, smacking, or other

oral-buccal-lingual movements; (3) ‘‘swimming’’ or

‘‘rowing’’ movements of limbs; and (4) apneic spells,

usually accompanied by one or more of the foregoing.

Premature infants with hypoxic-ischemic encephalopathy often exhibit generalized tonic seizures, which

may mimic decerebrate or decorticate posturing.

(Indeed, posturing, rather than or in addition to seizure, may be present in such infants, as discussed in

Chapter 5.) Full-term infants often also exhibit multifocal clonic seizures, characterized by clonic movements that migrate in a nonordered fashion. Focal

seizures are especially common in full-term infants

with focal ischemic cerebral lesions. Indeed, approximately 40% to 80% of infants with focal cerebral

infarcts exhibit focal seizures.63-83 Infants with arterial

stroke often exhibit focal seizures without other major

signs of encephalopathy (see later).19,84,85 In one large

series of term infants with neonatal encephalopathy or

early seizures, or both, only 8 of 197 with overt neonatal encephalopathy (with or without seizures) had

acute focal infarction, whereas fully 35 of the 90 infants

with early seizures (first 3 days of life) but without



Chapter 9



major signs of encephalopathy had focal cerebral

infarction.19

Recognition of the presence and prominence of the

aforementioned abnormal neurological signs presupposes an awareness of the normal neurological findings

at various gestational ages (see Chapter 3). Thus, the

normal infant of 28 weeks of gestation requires stimulation for arousal from sleep. At 32 weeks of gestation,

spontaneous arousal occurs, but vigorous crying

during wakefulness is unusual. Only at 40 weeks of

gestation should the observer expect to see discrete

periods of attention to visual and auditory stimuli.

Similarly, periodic breathing in a full-term newborn

is much more likely to be an abnormal finding

than in a premature infant at 32 weeks of gestation.

No pupillary reaction to light is usual at 28 weeks but

is unusual at 32 to 34 weeks. However, full extraocular

movements with doll’s eyes maneuver are present in

the youngest normal infants (i.e., 28 weeks of gestation

or even younger). Finally, hypotonia in the upper

extremities is usual at 28 or 32 weeks of gestation but

is abnormal at term. Spontaneous movements also

exhibit a progression from lower to upper extremities

from 28 weeks of gestation to term, so ‘‘weakness’’ of

upper extremities must be defined with caution in the

premature infant.

12 to 24 Hours

From approximately 12 to 24 hours, the infant’s level

of consciousness changes in a variable manner (Table

9-5). Infants with severe disease remain deeply stuporous or in a coma. Infants with less severe disease often

begin to exhibit some degree of improvement in alertness. However, in some infants, this improvement is more

apparent than real, because the appearance of alertness

may not be accompanied by visual fixation or following,

habituation to sensory stimulation, or other signs of

cerebral function. The notion of apparent rather than

real improvement in such cases is supported further by

the occurrence at this time of severe seizures, apneic

spells, jitteriness, and weakness. (Approximately 15%

to 20% of infants experience the onset of seizures at this

time.) Overt status epilepticus is not unusual, and

vigorous therapy is needed urgently. Apneic spells

appear in approximately 50% of infants (65% in

one series).2,3,60 Jitteriness develops in about one

fourth of infants and may be so marked that the



TABLE 9-5



Clinical Features of Severe HypoxicIschemic Encephalopathy: 12 to

24 Hours



Variable change in level of alertness

More seizures

Apneic spells

Jitteriness

Weakness

Proximal limbs, upper > lower (full term)

Hemiparesis (full term)

Lower limbs (premature)



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



403



movements are mistaken for seizures. Distinction can

usually be made at the bedside (see Chapter 5). Infants

with involvement of basal ganglia may exhibit an

increase in their hypertonia, especially in response to

handling. In my experience, many infants manifest

definite albeit not marked weakness (see Table 9-5).

Although precise correlation is often difficult, these

infants appear from the clinical circumstances surrounding their insult to have sustained particularly

marked ischemic insults. Full-term infants most often

exhibit weakness in the hip-shoulder distribution,

with more impressive involvement usually of the proximal extremities. Distinct asymmetry of these latter

motor findings is unusual to elicit at this time,

although a few full-term infants do exhibit weakness

that is confined to or is clearly more severe on one

side than on the other. Premature infants may exhibit

primarily lower extremity weakness, although it can be

very difficult to be certain of such findings in the small,

sick baby. This pattern of weakness appears to relate to

the topography of the cerebral white matter neuropathology (see later discussion of periventricular leukomalacia [PVL]).

24 to 72 Hours

Between approximately 24 and 72 hours, the severely

affected infant’s level of consciousness often deteriorates further, and deep stupor or coma may ensue

(Table 9-6). Respiratory arrest may occur, often after

a period of irregularly irregular (‘‘ataxic’’) respirations.

Brain stem oculomotor disturbances are now more

common. These usually consist of skew deviation and

loss of responsiveness of the eyes to the doll’s eyes

maneuver and to cold caloric stimulation. (Rarely,

ocular bobbing may appear.) Pupils may become fixed

to light in the mid or dilated position. Reactive but

constricted pupils are more common in less severely

affected infants. Babies who die with hypoxic-ischemic

encephalopathy most often do so at this time, particularly if the criterion is ‘‘brain death.’’86 In one large

series of infants who died after perinatal asphyxia and

hypoxic-ischemic encephalopathy, the median age of

death was 2 days.53 The cause for the apparent delay

in progression to brain death until this period is not

known definitely, but delayed cell death has been

documented in in vivo models and in neurons in culture (see Chapters 6 and 8). The importance of excitatory amino acids, calcium-mediated deleterious

metabolic events, and free radical production has



TABLE 9-6



Clinical Features of Severe HypoxicIschemic Encephalopathy: 24 to

72 Hours



Stupor or coma

Respiratory arrest

Brain stem oculomotor and pupillary disturbances

Catastrophic deterioration with severe intraventricular hemorrhage and periventricular hemorrhagic infarction

(premature)



404



UNIT III



HYPOXIC-ISCHEMIC ENCEPHALOPATHY



been detailed in Chapters 6 and 8. Indeed, studies by

MR spectroscopy in the asphyxiated human infant (see

later discussion) have documented a delayed deterioration of cerebral energy state. However, although

delayed cell death most probably accounts for this clinical deterioration, consideration should also be given to

the occurrence of frequent subclinical electrical seizures as the reason for the deterioration. Although

electroencephalography (EEG) is required for this

determination, the potential effectiveness of anticonvulsant therapy warrants the procedure.

In my experience, most of the premature infants who

die at 24 to 72 hours experience marked intraventricular

hemorrhage, usually with periventricular hemorrhagic

infarction (see Chapter 11). This hemorrhage may

be heralded by a characteristic catastrophic clinical

syndrome (i.e., evolution in hours of bulging anterior

fontanelle, falling hematocrit, hypoventilation proceeding to respiratory arrest, generalized tonic seizure,

decerebrate posturing, pupils fixed to light, eyes fixed

to all vestibular stimulation, and flaccid quadriparesis;

see Chapter 11). In a majority of premature infants, the

intraventricular hemorrhage is accompanied by a more

saltatory deterioration or by fragments of the aforementioned syndrome; such infants are much less likely to

die with their hemorrhage.

The full-term infants who die at this time only

uncommonly have significant hemorrhage, although a

few exhibit clinical signs of increased intracranial pressure (ICP), for example, bulging anterior fontanelle and

split cranial sutures. In the large classic series reported

by Brown and co-workers,2 these signs appeared ultimately in 31% of the infants. In my experience, such

infants have sustained severe insults and exhibit major

cerebral necrosis at postmortem examination. Thus,

signs of brain swelling and increased ICP appear to

occur in infants after, rather than before, severe cerebral

injury has occurred. Systematic studies of increased

ICP in asphyxiated human infants support this notion

(see Chapter 8).87,88

After 72 Hours

Infants who survive to this point usually improve over

the next several days to weeks; however, certain neurological features persist (Table 9-7). Although the level

of consciousness improves, often dramatically, mild to

moderate stupor continues. The persistence of this

depression of consciousness may provoke, sometimes

unnecessarily, many different diagnostic procedures in



TABLE 9-7



Clinical Features of Severe HypoxicIschemic Encephalopathy: After 72 Hours



Persistent, yet diminishing stupor

Disturbed sucking, swallowing, gag, and tongue movements

Hypotonia > hypertonia

Weakness

Proximal limbs, upper > lower (full term)

Hemiparesis (full term)

Lower limbs or hemiparesis (premature)



an attempt to define a complicating process, such

as sepsis. Disturbances of feeding are extremely

common and relate to abnormalities of sucking, swallowing, and tongue movements. The power and coordination of the muscles involved (innervated by cranial

nerves V, VII, IX, X, and XII) are deranged. A few

infants require tube feedings for weeks to months.

(In the large series studied by Brown and co-workers,2,3

80% of infants required early tube feedings because

of feeding difficulty.) The abnormalities of brain

stem function are especially dramatic in infants

with the form of selective neuronal necrosis involving

deep nuclear structures (basal ganglia, thalamus)

and brain stem tegmentum (see later discussion and

Chapter 8).50,89,90 Generalized hypotonia of limbs is

common, although hypertonia, particularly with passive manipulation of limbs, is frequent on careful

examination, especially among infants with prominent

involvement of basal ganglia. The patterns of weakness

discussed in the previous section become more readily

elicited, although the weakness is rarely marked. In the

premature infant, demonstration of the lower limb pattern of PVL or the hemiparesis later seen with periventricular hemorrhagic infarction is very difficult. The

rate of improvement of each of these clinical features

is variable and is not easily predicted, but infants with

the fastest initial improvement clearly have the best

long-term outlook. Indeed, infants with an essentially

normal neurological examination by approximately

1 week of age have an excellent chance for a normal

outcome (see ‘‘Prognosis’’).55,91

DIAGNOSIS

The recognition of neonatal hypoxic-ischemic encephalopathy depends principally on information gained

from a careful history and a thorough neurological

examination. The contributing role of certain metabolic derangements requires evaluation. Determination

of the site or sites and extent of the injury is made to

an appreciable degree by the history and neurological examination, but supplementary evaluations,

including especially EEG and brain imaging studies

(ultrasonography, computed tomography [CT], MRI),

are very important. Certain other neurodiagnostic

studies, not yet widely used, may prove particularly

valuable, especially in selected instances, as discussed

later.

History

Recognition of neonatal hypoxic-ischemic encephalopathy requires awareness of those intrauterine situations

that account for most cases. Thus, information should

be sought regarding maternal disorders that could lead

to uteroplacental insufficiency and disturbances of

labor or delivery that could impair placental respiratory

gas exchange or fetal blood flow or exert a direct

traumatic effect on the fetal central nervous system.

The value of electronic fetal monitoring, particularly

when supplemented by fetal blood sampling to

determine acid-base status, is discussed inChapter 7.



Chapter 9



The occurrence of meconium-stained amniotic fluid

provides additional information when interpreted

appropriately (see Chapter 7).

Neurological Examination

Recognition of the neurological signs outlined previously provides critical information concerning the

presence, site, and extent of hypoxic-ischemic injury

in the newborn infant. The value of the carefully

performed neurological examination was doubted

by some clinicians in the past, but a growing body

of information now demonstrates conclusively the

contributions that the examination can make (see

Chapter 3). In addition to critical information about

the current state of the infant, the neurological examination provides important information for establishing

a prognosis (see ‘‘Prognosis’’).



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



405



multiorgan dysfunction observed with intrauterine

asphyxia (see earlier).

Other metabolic parameters have been studied and may

hold promise as measures of severity of the hypoxicischemic insult (Table 9-8), although currently the

precise sensitivity and specificity of these determinations require further study before general use is warranted. The metabolites and markers are best

considered in terms of their relevance to energy metabolism, excitatory amino acids, free radical metabolism,

inflammation, brain-specific proteins, and other compounds (see Table 9-8). Concerning energy metabolism,

perinatal asphyxia has been associated with hypoglycemia, elevated lactate in blood and cerebrospinal fluid

(CSF), elevated lactate/creatinine ratio in urine, and

elevated lactate and hydroxybutyrate dehydrogenases

in CSF.92,95-98 Of these, the value of early hypoglycemia

was discussed in the preceding paragraph. Of particular

interest is the ratio of lactate/creatinine in urine. In a



Metabolic Parameters

Certain metabolic derangements may contribute

significantly to the severity and qualitative aspects of

the neurological syndrome, and the diagnostic evaluation should include evaluation of such derangements.

Hypoglycemia, hyperammonemia, hypocalcemia, hyponatremia (inappropriate secretion of antidiuretic

hormone [ADH]), hypoxemia, and acidosis are among

the metabolic complications that may occur, often

because of associated disorders, and that may exacerbate certain neurological features or add new ones.

Of particular interest in this context is the occurrence of hypoglycemia and its potential role in accentuation of brain injury. In a detailed study of 185 infants

with evidence of intrauterine asphyxia (cord pH

< 7.00), fully 15% exhibited blood glucose concentrations lower than 40 mg/dL in the first 30 minutes of

life.92 The hypoglycemia may relate in large part to

enhanced anaerobic glycolysis and thereby glucose

use, in an attempt to preserve cellular energy levels

(see Chapter 6). By multivariate analysis, the odds

ratio for an abnormal neurological outcome was 18.5

when infants with blood glucose levels lower than 40

mg/dL were compared with those with levels higher

than 40 mg/dL. These data may have important implications for management (see later).

Hyperammonemia may occur in newborns with severe perinatal asphyxia.93 Although very uncommon, levels

of approximately 300 to 900 mg/mL have been detected in

the first 24 hours of life and are usually accompanied by

elevated serum glutamic oxaloacetic transaminase levels.

Clinical correlates may be difficult to distinguish from

those secondary to hypoxic-ischemic encephalopathy,

although hyperthermia and hypertension have been frequent additions in patients with hyperammonemia.

Clinical improvement is coincident with falling blood

ammonia levels. The pathogenesis of the hyperammonemia is unclear, although a combination of increased protein catabolism, secondary to hypoxic ‘‘stress,’’94 and

impaired liver function, and therefore hepatic urea synthesis, is a good possibility (see Chapter 14). Recall that

hepatic disturbance is a common feature of the systemic



TABLE 9-8



Potential Adjunctive Determinations

in Blood, Urine, or Cerebrospinal Fluid

in Assessment of Perinatal Asphyxia*



Determination

Energy Metabolism

Glucose

Lactate

Lactate/creatinine ratio

Lactate dehydrogenase

Hydroxybutyrate dehydrogenase



Blood

Blood, CSF

Urine

CSF

CSF



Excitatory Amino Acids

Glutamate

Aspartate

Glycine



CSF

CSF

CSF



Free Radical Metabolism

Hypoxanthine

Uric acid

Nonprotein-bound iron

Protein carbonyls

Isoprostanes

Ascorbic acid

Arachidonate metabolites

Nitric oxide

Antioxidant enzymes



Blood, urine

Blood, urine

Blood

CSF

CSF

CSF

CSF

Blood, CSF

CSF



Inflammatory Markers

Interleukin-6

Interleukin-10

Interleukin-1 beta

Tumor necrosis factor-alpha



Blood, CSF

CSF

Blood

Blood, CSF



Brain-Specific Proteins

Neuron-specific enolase

Neurofilament protein

Protein S-100

Glial fibrillary acidic protein

Creatine kinase-BB



Blood,

CSF

Blood,

Blood,

Blood,



Other

Erythropoietin

Nerve growth factor

Cyclic adenosine monophosphate

*



Body Fluid



Blood

CSF

CSF



See text for references.

CSF, cerebrospinal fluid.



CSF

urine, CSF

CSF

CSF



406



UNIT III



HYPOXIC-ISCHEMIC ENCEPHALOPATHY



study of 40 infants with evidence of intrapartum

asphyxia, the mean (± SD) ratio within 6 hours of life

was 16.8 ± 27.4 in the asphyxiated infants who subsequently developed the clinical features of hypoxicischemic encephalopathy versus 0.2 ± 0.1 in those who

did not develop encephalopathy and 0.09 ± 0.02

in normal infants.97 Moreover, the ratio was significantly higher in the infants who had neurological sequelae at 1 year (25.4 ± 32.0) than in those with favorable

outcomes (0.6 ± 1.5). The degree of elevation of lactate

in blood at 30 minutes of life also may be a useful predictor of the severity of perinatal asphyxia.98

Concerning excitatory amino acids, elevations of the

excitotoxic amino acids glutamate, aspartate, and glycine (through the N-methyl-D-aspartate [NMDA]

receptor) have been observed in CSF in the first day

of life (see Table 9-8).99-102 Correlations with severity

of hypoxic-ischemic encephalopathy have been shown.

Concerning free radical metabolism, many studies support involvement of reactive oxygen and nitrogen species

in the final common pathway to cell death with neonatal

hypoxic-ischemic encephalopathy (see Table 9-8).103-120

These studies have shown elevations in sources of

free radicals (e.g., hypoxanthine, non–protein-bound

iron, arachidonate metabolites), indicators of lipid

peroxidation (e.g., isoprostanes) or oxidized proteins

(e.g., protein carbonyls), and markers of free radical use

(e.g., ascorbic acid, antioxidant enzymes). Supporting

data are relevant to hypoxic-ischemic injury both in

term and in preterm infants (see Fig. 8-33).

Concerning inflammatory markers, related potentially

to hypoxic-ischemic or intrauterine infection or both,

elevations of certain cytokines (interleukin-6 [IL-6],

IL-10, IL-1beta and tumor necrosis factor-alpha) have

been documented in blood and CSF in both term and

preterm infants (see Table 9-8).121-126 The degree to

which the elevations in cytokines are primary or secondary is unclear (see Chapter 8).

Concerning brain-specific proteins, specific components of neurons (neuron-specific enolase, neurofilament protein, creatine kinase-BB [CK-BB]) and

astrocytes (S-100, glial fibrillary acidic protein, CKBB) have been studied in blood and CSF to detect

evidence of neuronal and glial injury.127-152 In general,

elevations of these markers in blood or CSF in the first

hours of life after perinatal asphyxia have correlated

approximately with severity of clinical and brain imaging findings. However, the value of studies of blood is

tempered somewhat by the finding of S-100 and

neuron specific enolase in placenta; this suggests that

these molecules are not entirely brain specific.146

Available data suggest that determination of CK-BB is

a very sensitive indicator of brain disturbance.130,132138,143,148,149 However, the extreme sensitivity of the

indicator in blood impairs the specificity of the measure

because variable but appreciable proportions of infants

with elevated concentrations of CK-BB in cord blood or

neonatal blood samples have no evidence of irreversible

brain injury and have a normal neurological outcome.

However, two studies of the concentrations of CK-BB

in CSF suggested greater specificity as well as sensitivity

concerning identification of hypoxic-ischemic brain



TABLE 9-9



Relation of Neonatal Cerebrospinal

Fluid Concentration of Creatine Kinase

to Severity of Parenchymal Involvement

in Apparent Hypoxic-Ischemic Disorders*



Neurological Disorder



Creatine Kinase-BB

Concentration

(Median, kg/L)



Control Group (total)



2.1



Postasphyxial Encephalopathy

Normal outcome

Neurological sequelae



10.3

55.6



Periventricular Intraparenchymal Echodensity

Transient

13.7

Evolution to ‘‘cystic leukomalacia’’

44.0

*



Derived from study of 84 control infants, 10 infants with postasphyxial

encephalopathy, and 13 infants with periventricular intraparenchymal echodensity.

Data from De Praeter C, Vanhaesebrouck P, Govaert P, Delanghe J,

et al: Creatine kinase isoenzyme BB concentrations in the cerebrospinal fluid of newborns: Relationship to short-term outcome,

Pediatrics 88:1204–1210, 1991.



injury than with determination of blood CK-BB concentrations (Table 9-9).138,143

Concerning other markers, elevations of erythropoietin in blood and nerve growth factor and cyclic adenosine monophosphate in CSF have been documented

after perinatal asphyxia (see Table 9-8).153-156 The

value of these markers and the significance of their

elevations remain to be established.

Currently, none of the markers has been established

to be of sufficiently high sensitivity and specificity to be

appropriate for general use. However, determinations

of the brain-specific isoenzyme, CK-BB, especially in

CSF, appear to be most promising.

Lumbar Puncture

Lumbar puncture should be performed on any infant

with hypoxic-ischemic encephalopathy in whom the

diagnosis is unclear. It is particularly important to

rule out other potentially treatable intracranial disorders (e.g., early-onset meningitis) that may mimic the

clinical features of hypoxic-ischemic encephalopathy.

Electroencephalogram

The EEG changes in hypoxic-ischemic encephalopathy

may provide valuable information concerning the

severity of the injury.55,157-186 Although a considerable

variety of tracings may be observed, the most common

evolution of EEG changes in severe hypoxic-ischemic

encephalopathy is depicted in Figure 9-1. The initial

alteration is voltage suppression and a decrease in the

frequency (i.e., slowing) into the delta and low theta

ranges. Within approximately 1 day and often less, an

excessively discontinuous pattern appears, characterized by periods of greater voltage suppression

interspersed with bursts, usually asynchronous, of

sharp and slow waves. It may be difficult in the premature infant to distinguish this change from normal per´

iodicity, and in the more mature infant, from the trace



Chapter 9

Amplitude (suppression) and frequency



Periodic pattern and/or multifocal

or focal sharp activity



Periodic pattern with fewer bursts

and more voltage suppression



Isoelectric

Figure 9-1 Evolution of the electroencephalographic changes in

severe hypoxic-ischemic encephalopathy. See text for temporal

aspects.



alternant of normal quiet sleep (see Chapter 4). Some

infants exhibit multifocal or focal sharp waves or spikes

at this time, often with a degree of periodicity. Over the

next day or so, the excessively discontinuous pattern

may become very prominent, with more severe voltage

suppression and fewer bursts, now characterized by

spikes and slow waves. This burst-suppression pattern is

of ominous significance, especially in the full-term

infant (see Chapter 4). However, it is critical to recognize that excessively discontinuous patterns with prolonged interburst intervals (IBIs) that are not as severe

as classic burst-suppression patterns nevertheless also

are associated with an unfavorable outcome (see

‘‘Prognosis’’ later and Chapter 4). Indeed, in one

large series of infants, only 16% of excessively discontinuous tracings (in patients with a generally unfavorable outcome) exhibited burst-suppression patterns

by classic definition.187 Notably, however, as many as

50% of asphyxiated term infants with a burst-suppression pattern identified by amplitude-integrated EEG

(aEEG) in the first hours of life develop normal or nearly

normal tracings within 24 hours (see later).188 In the

severely affected infant, the excessively discontinuous

EEG may then evolve into an isoelectric tracing and a

hopeless prognosis. Caution in interpretation of apparent isoelectric tracings in the newborn, especially in

the first 10 hours of life, is indicated by the findings

of Pezzani and co-workers,166 which showed that of



TABLE 9-10



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



17 asphyxiated newborns with isoelectric or ‘‘minimal’’

background activity in the first 10 hours, one was

normal and one exhibited only epilepsy on follow-up

(15 of the 17 died in the neonatal period). In general,

those asphyxiated infants whose EEG tracings revert to

normal within approximately 1 week have favorable

outcomes.55,188

aEEG, an increasingly common method for continuous monitoring of electrical activity in the newborn (see Chapter 4),189 has been of considerable

value in the assessment of the asphyxiated term newborn.188-194 This approach has been crucial in the

selection of infants for treatment with mild hypothermia (see later). The most useful tracings for detection

of severe encephalopathy have been continuous lowvoltage, flat, and burst-suppression tracings. Positive

predictive values for an unfavorable outcome with

such tracings in the first hours of life are 80% to

90% (see ‘‘Prognosis’’ later). Of infants with these

marked background abnormalities, 10% to 50% may

normalize within 24 hours. Rapid recovery is associated

with a favorable outcome in 60% of cases.

Continuous monitoring of conventional EEG with portable equipment has been found to be particularly

useful in the identification of seizure activity in

asphyxiated term infants subjected to muscle paralysis

for purposes of ventilation for respiratory failure (see

Chapter 4).168,195 Early detection of the seizures and

evaluation of response to anticonvulsant therapy are

facilitated by modern portable monitoring systems.

Currently, I recommend, when available, continual

monitoring with digital EEG of all asphyxiated infants

with seizures or other manifestations of severe hypoxicischemic disease. This approach provides insight not

only into potentially treatable conditions (frequent,

clinically silent seizures) but also into the status of

the cerebral hemispheres in an infant who is heavily

sedated or therapeutically paralyzed.

The type of EEG abnormality may indicate a specific

pathological variety of hypoxic-ischemic brain injury

(Table 9-10). Diffuse and severe abnormalities (excessive

discontinuity with prolonged IBI, burst suppression,

marked voltage suppression, isoelectric EEG) are

observed most commonly with diffuse cortical neuronal

necrosis. Excessive sharp waves, especially positive vertex

or rolandic sharp waves, positive frontal sharp waves, and

negative occipital sharp waves, are particularly suggestive

of cerebral white matter injury in the premature infant

(see Chapter 4) (Table 9-11).159,161-164,168,176,180-185 The



Most Frequent Correlations of Electroencephalographic Patterns and Topography of Neonatal

Hypoxic-Ischemic Brain Injury*



EEG Pattern



Type of Hypoxic-Ischemic Brain Injury



Excessive discontinuity, burst suppression, persistent

marked voltage suppression, isoelectric EEG pattern

Excessive sharp waves: positive vertex or rolandic, positive

frontal, and negative occipital sharp waves

Focal periodic lateralized epileptiform discharges

*



407



Diffuse cortical and thalamic neuronal necrosis



See text for references.

EEG, electroencephalographic.



Periventricular leukomalacia (also periventricular hemorrhagic infarction; see Chapter 11)

Focal cerebral ischemic necrosis (infarction)



408



UNIT III



TABLE 9-11



HYPOXIC-ISCHEMIC ENCEPHALOPATHY



Value of Electroencephalography in

Detection of Cerebral White Matter

Injury in Premature Infants*



Abnormal sharp waves of value are positive rolandic or

vertex (central), positive frontal, and negative occipital.

Frontal positive or occipital negative sharp waves or both

are present in 100% of cases of severe PVL and in

60% to 90% of cases of mild or moderate PVL.

Positive rolandic sharp waves (>0.1/minute) are present in

65% to 90% of cases of severe PVL and in 25% of cases

of mild or moderate PVL.

Abnormal sharp waves accompany echodense lesions and

precede the development of echolucent, presumed

cystic change evident on ultrasonography.

The peak period of occurrence of sharp waves is from 5 to

14 days.

*



See text for references.

PVL, periventricular leukomalacia.



sensitivity of these abnormal sharp waves increases with

the frequency of the waves (>0.1/minute) and the severity

of the white matter injury and decreases with the degree

of immaturity (especially <28 weeks of gestational age).

The EEG abnormalities appear days before the appearance of the most pronounced ultrasonographic abnormalities (see Table 9-11).

The particular value of serial EEG in assessment

of the asphyxiated infant is pronounced. This caveat

holds for both premature and term infants.161,177,

179,180,196 A single EEG study, particularly during the

acute phase of the disease, may suggest a more

ominous outcome than do subsequent EEG studies

(see earlier and Chapter 4, Table 4-11). Focal periodic

epileptiform discharges are characteristic of focal cerebral infarction197,198; in one series, approximately 90%

of infants with such discharges had infarctions.197

The role of the EEG in the assessment of brain death

in the asphyxiated newborn has not been delineated

decisively.86,199-209 Thus, an isoelectric EEG can be

observed in infants with cerebral neuronal necrosis

but not death of the entire brain (i.e., brain death).

Conversely, persistent EEG activity for many days has

been documented in infants with clinical and radionuclide evidence of brain death.86,204,205,210 Currently, I

believe that the guidelines of the Task Force for the

Determination of Brain Death in Children are most

TABLE 9-12



appropriate: declaration of brain death in infants

between the ages of 7 days and 2 months requires

two clinical examinations indicative of loss of all cerebral and brain stem function and two isoelectric EEG

tracings carried out according to standardized techniques separated by 48 hours.211 Although data are

limited,204,205 I favor a 72-hour observation period for

term infants less than 7 days of age and only when the

cause of the coma is unequivocally established.

Computed Tomography

CT, in medical centers without ready access to MRI,

has some value in the initial evaluation of the infant

with hypoxic-ischemic encephalopathy. As I discuss

later, MRI, in my view, is far preferable. Neverth-less,

CT can provide important diagnostic information in

identification of diffuse cortical injury in severe selective neuronal necrosis, injury to basal ganglia and thalamus, PVL, and focal and multifocal ischemic brain

necrosis (Table 9-12). CT has some value, albeit limited, in identification of parasagittal cerebral injury and

venous thrombosis (see later discussion). Hemorrhagic

complications of hypoxic-ischemic disease, such as

hemorrhagic infarction, are detected readily by CT.

The value of CT in the assessment of diffuse cortical

neuronal injury is most apparent several weeks after

severe asphyxial insults (Fig. 9-2). During the acute

period (i.e., the first days of life), the striking, bilateral,

diffuse hypodensity that is apparent in clinically more

severely affected term infants at least in part reflects

marked cortical neuronal injury, perhaps with associated edema (Fig. 9-3).212-220 The diffuse cerebral hypodensity with loss of gray-white differentiation but with

relatively increased density of deep nuclear structures

(see Fig. 9-3) has been termed the reversal sign.219

CT demonstrates hypoxic-ischemic injury to basal

ganglia and thalamus,220-222 although MRI is more

useful (see subsequent sections). The affected areas

exhibit a featureless appearance, with loss of distinction

of the deep nuclear structures, and usually clearly

decreased attenuation of these structures. Some infants

may exhibit increased attenuation, especially in the

presence of hemorrhagic necrosis. The subsequent

evolution is clearly decreased attenuation over several months (Fig. 9-4). Rarely, the injury develops



Major Techniques for Diagnosis of Specific Neuropathological Types of Neonatal Hypoxic-Ischemic

Encephalopathy

DIAGNOSTIC TECHNIQUE



Neuropathological Type



Magnetic

Resonance Imaging



Computed

Tomography



Ultrasound



Selective neuronal necrosis: cerebral cortical

Selective neuronal necrosis: basal ganglia and thalamus

Selective neuronal necrosis: brain stem

Parasagittal cerebral injury

Focal and multifocal ischemic brain injury

Periventricular leukomalacia



++

++

++

++

++

++



+

+

±

+

++

+



–

+

–

–

+

++*



*

Very useful for detection of focal component; not useful for detection of diffuse component or ‘‘noncystic periventricular leukomalacia’’ (see text).

++, Very useful; +, useful; ±, questionably useful; –, not useful.



Chapter 9



Figure 9-2 Computed tomography scan of residua of diffuse cortical

neuronal necrosis from a 6-week-old infant who experienced severe

perinatal asphyxia. Note the striking degree of cortical atrophy, manifested by very prominent subarachnoid spaces and shriveled gyri.

(Accompanying cerebral white matter injury is apparent from the ventricular enlargement.)



A



B



C



D



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



409



calcification, observable both by CT and by neuropathological study.223,224

Parasagittal cerebral injury is more difficult to demonstrate by CT than by MRI (see later), perhaps because

the lesion is relatively superficial and interpretation of

changes on the most superior CT images may be difficult. However, the lesion in its overt form can be visualized by CT (see example in later section on MRI).225

I consider MRI to be the imaging modality of choice

for the demonstration of parasagittal cerebral injury

(see later discussion).

The CT scan is of particular value in the identification

of focal and multifocal ischemic brain injury (Figs. 9-5 to 9-7;

see Table 9-12).63,65,66,220,226-228 The lesions depicted

in Figure 9-5 were of prenatal, antepartum origin. In

keeping with the neuropathological data (see Chapter

8), most focal ischemic lesions of perinatal origin involve

the distribution of the middle cerebral artery. The

timing of the CT scans in the neonatal period for detection is important. For example, lesions with onset near

the time of birth, and often heralded by focal seizures on

day 1, frequently are difficult to detect by CT (see Fig. 96). Only after days to a week or more does the decreased

attenuation in a vascular distribution become clearly

apparent (see Fig. 9-6). An uncommon complication

of neonatal stroke (i.e., secondary hemorrhage into the

infarct; see Fig. 9-7), is detected readily by CT.



Figure 9-3 Computed tomography (CT) scans of evolution of cortical neuronal necrosis. A and B, CT slices

obtained 5 days after severe perinatal asphyxia show loss

of cortical gray-white matter differentiation and, in B, relative increase in attenuation of basal ganglia and thalamus

(arrows). C and D, CT slices obtained at 4 weeks of age

demonstrate evidence of cortical (and white matter)

atrophy.



410



UNIT III



HYPOXIC-ISCHEMIC ENCEPHALOPATHY



visualized (parasagittal cerebral injury with difficulty,

however), as can the associated hemorrhagic complications. However, as noted later, MRI is clearly superior.

Ultrasound



Figure 9-4 Computed tomography scan of injury to basal ganglia

and thalamus. The scan is from a 2-month-old infant who experienced

severe perinatal asphyxia. Note the marked decrease in attenuation in

basal ganglia, especially putamen (arrowheads), and the thalamus

(arrows). Dilation of the third ventricle reflects the thalamic tissue

loss. (Cerebral white matter loss with dilation of lateral ventricles

is also apparent.)



CT is only modestly useful for the identification of

PVL (Fig. 9-8). A propensity for involvement of the

anterior and posterior periventricular areas of predilection around the frontal horn and trigone of the lateral

ventricles (see Chapter 8 for neuropathology) is apparent. However, considerable caution must be exercised

in the interpretation of periventricular hypodensity

in asphyxiated preterm infants.212,220,229 Indeed, lowdensity periventricular areas are the rule in apparently

normal infants, and the gradual increase in density with

maturation of the infant has been documented many

times.220,228,230-234 This maturational change is attributed to the decrease in water and increase in lipid and

protein in cerebral white matter with myelination.

Subsequently, the CT findings of PVL are reduction

in quantity of periventricular white matter, particularly at the trigone, ventriculomegaly with irregular

outline of the lateral ventricles, and deep sulci that

abut the wall of the lateral ventricles (Fig. 9-9).235

Calcification of the areas of white matter necrosis may

occur (Fig. 9-10). In a large neuropathological series

of asphyxiated infants, of 29 infants with calcification,

19 (65%) had the mineralization in white matter.224

The CT scan may also detect hemorrhagic lesions that

complicate asphyxia (see Chapters 10 and 11), including subarachnoid, intraventricular, and intracerebral

hemorrhage. Although such hemorrhagic lesions are

well described in premature infants, 10% to 25% of

asphyxiated term infants also exhibit CT evidence of

major degrees of intraventricular or intraparenchymal

hemorrhage, or both.212-214

To summarize, the CT scan is useful in the evaluation

of both the premature and full-term infant with

hypoxic-ischemic injury (see Table 9-12). The several

neuropathological varieties of the injury can be



Cranial ultrasonography, the highly effective, noninvasive, portable technique used at the anterior fontanelle

(see Chapter 4), is often of value in the urgent initial

evaluation of the infant with hypoxic-ischemic brain

injury. However, a negative study is not particularly

meaningful. In hypoxic-ischemic disease in the term

infant, the cranial ultrasound scan initially is negative

in as many as 50% of cases.236 Thus, as with CT,

I prefer MRI (see later). Nevertheless, of the major neuropathological lesions, cranial ultrasonography is

useful in the identification of injury to basal ganglia

and thalamus, focal and multifocal ischemic brain

injury, and PVL (see Table 9-12). Ultrasonography is

not useful in the definition either of selective cortical or

brain stem neuronal injury because the cortical and

brain stem lesions are too restricted or too peripherally

located to be visualized, or of parasagittal cerebral

injury, for similar reasons. (Indeed, in one correlative

study of ultrasonography and neuropathology, five

cases of cortical neuronal necrosis were observed at

postmortem examination without ultrasonographic

correlate in any.237)

Injury to basal ganglia and thalamus, a major accompaniment of selective neuronal injury of the diffuse type

and of the two deep nuclear types (see Chapter 8),

was demonstrated conclusively by real-time ultrasound

when hemorrhagic necrosis was present (Fig. 9-11).238-241

However, the technique can be also effective in demonstration of apparent nonhemorrhagic necrosis, at

least as defined by the simultaneous appearance

of hypoattenuation, rather than hyperattenuation by

CT or abnormal signal on MRI (Fig. 9-12).241-245

Ultrasound scanning has demonstrated focal and

multifocal ischemic brain lesions in the newborn.70,73,82,237,243,244,246-254 Infarcts, porencephaly,

hydranencephaly, and multicystic encephalomalacia

have been identified. The evolution of the ultrasonographic appearance of acute infarction consists in the

first week of echodensity in a vascular distribution,

usually that of the middle cerebral artery (Fig. 9-13).

(Doppler ultrasound also may show loss of vascular

pulsations in the affected vessel in the acute

period.255) The CT scan may show relatively little or

no abnormality at this stage (see Fig. 9-13). After

approximately 1 week, decreased attenuation on CT

develops, whereas the echodensity persists on ultrasonography. Over the ensuing 6 to 12 weeks, the echodensity evolves to echolucency, often passing through

a stage of heterogeneous appearance termed checkerboard.251 Several long-standing hypoxic-ischemic

lesions of prenatal onset (e.g., hydranencephaly) are

visualized readily ultrasonographically (Fig. 9-14).

Nevertheless, the sensitivity of ultrasound for detection of focal ischemic injury is not optimal. In two large

studies, the sensitivity of early ultrasound scan (1 to

3 days) for detection of MRI-proven arterial cerebral



Chapter 9



Hypoxic-Ischemic Encephalopathy: Clinical Aspects



A



B



C



D



E



411



F



Figure 9-5 Computed tomography scans of ischemic brain injury of prenatal origin. A and B, Hydranencephaly in a 1-day-old infant; note the

symmetrical and diffuse loss of virtually all cerebral tissue. C and D, Scans obtained from a 1-day-old infant demonstrating bilateral symmetrical

loss of cerebral tissue in the distribution of the middle cerebral arteries. E and F, Scans obtained from a 1-day-old infant demonstrating unilateral

loss of cerebral tissue in the distribution of the middle cerebral artery (arrows).



A



B



Figure 9-6 Computed tomography scans of focal ischemic brain injury (i.e., stroke). A, Scan obtained on the first postnatal day from a full-term

infant with right focal seizures. Note the subtle area of decreased attenuation in the left posterior parietal region (arrows) and the lack of visualization of the left trigone of the lateral ventricle. B, Scan obtained from the same infant at 13 days of age. Note the markedly decreased attenuation

in the distribution of the posterior division of the middle cerebral artery (arrows).