<sec id="sec001"><title />Notwithstanding the huge advances in our understanding of the mechanisms that contribute to the injuries of the developing brain and many efforts at prevention, perinatal brain injury continues to be a major cause of neonatal mortality and is associated with long-term neuro-developmental sequelae. The incidence of asphyxia reported from the developed world varies from 1.8 to 6.7 per 1000 live births depending on the clinical definition used (<xref ref-type="bibr" rid="bib001">1</xref>) whereas death or severe neurological impairment following asphyxia occurs in 0.5-1.0 per 1000 live births. In developing countries, the incidence is much higher varying from 9.4 per 1000 live births (<xref ref-type="bibr" rid="bib002">2</xref>) to 229 per 1000 live births (<xref ref-type="bibr" rid="bib003">3</xref>). As per NNPD report of 2000, perinatal asphyxia was present in 1.4% of all intramural births and it was the primary cause in 20%ofalldeaths (<xref ref-type="bibr" rid="bib004">4</xref>).Although many organ systems can be affected by hypoxia-ischemia, it is the nervous system that bears the brunt of perinatal asphyxia in the long run. Cerebral palsy is the most important long-term outcome of birth asphyxia and may be accompanied by mental retardation, seizure disorder, or other associated neurologic or sensory (visual, auditory) disabilities. In this review, we will discuss the long-term outcomes of babies who suffer from perinatal asphyxia, predictors of abnormal outcome in these babies and finally a plan for the follow up and management of those disabilities.<sec id="sec002"><title>Clinicopathological correlates

JNNFI

Journal of Neonatology

0973-2179

National Neonatology Forum

jn-18-2-004

Symposium on Follow-up Care of NICU Graduates

Follow up of neonates with perinatal asphyxia

Angiti

Rajeshwar Reddy

Senior ResidentKumar

Praveen

Associate Professor

Department of Pediatrics, Advanced Pediatric Center, Post Graduate Institute of Medical Education and Research, Chandigarh-160012

4-62004

1822227

<sec id="sec001"><title />Notwithstanding the huge advances in our understanding of the mechanisms that contribute to the injuries of the developing brain and many efforts at prevention, perinatal brain injury continues to be a major cause of neonatal mortality and is associated with long-term neuro-developmental sequelae. The incidence of asphyxia reported from the developed world varies from 1.8 to 6.7 per 1000 live births depending on the clinical definition used (<xref ref-type="bibr" rid="bib001">1</xref>) whereas death or severe neurological impairment following asphyxia occurs in 0.5-1.0 per 1000 live births. In developing countries, the incidence is much higher varying from 9.4 per 1000 live births (<xref ref-type="bibr" rid="bib002">2</xref>) to 229 per 1000 live births (<xref ref-type="bibr" rid="bib003">3</xref>). As per NNPD report of 2000, perinatal asphyxia was present in 1.4% of all intramural births and it was the primary cause in 20%ofalldeaths (<xref ref-type="bibr" rid="bib004">4</xref>).Although many organ systems can be affected by hypoxia-ischemia, it is the nervous system that bears the brunt of perinatal asphyxia in the long run. Cerebral palsy is the most important long-term outcome of birth asphyxia and may be accompanied by mental retardation, seizure disorder, or other associated neurologic or sensory (visual, auditory) disabilities. In this review, we will discuss the long-term outcomes of babies who suffer from perinatal asphyxia, predictors of abnormal outcome in these babies and finally a plan for the follow up and management of those disabilities.<sec id="sec002"><title>Clinicopathological correlates

The type of long-term deficit often correlates with the type and site of neuropathology. Table 1 shows the possible neurological deficits, which may occur in babies with perinatal asphyxia based on the pathological changes (5). Table 1

Long term outcome based on neuropathology

Neuropathology	Long term deficits

Selective neuronal necrosis Affected areas: Cerebral cortex, striatum, hypothalamus cranial nerve (bulbar and pseudobulbar), anterior horn cells, brainstem	Mental retardation, seizures, cortical blindness, early sexual maturation, impairments of sucking, swallowing and facial movements, fixed facial expression with drooling of saliva, persistent hypotonia-atonic cerebral palsy
Status marmoratus Basal Ganglia and Thalami	Extra pyramidal abnormalities -Athetoid Cerebral Palsy
Parasagittal Injury	Spastic quadriparesis or hemiplegia with upper limb involvement more than lower limbs, multiple cognitive deficits
Periventricular Leucomalacia	Spastic diplegia with greater affection of lower than upper limbs
Focal and multifocal ischemic necrosis	Unilateral-hemiparesis, seizures, cognitive dysfunction; Bilateral-quadriparesis, cognitive dysfunction (100%), seizures in majority

Neurodevelopmental sequelae

Motor Disabilities

Periventricular leucomalacia (PVL) is the most common cause of motor impairment in premature infants. It results in spastic diplegia, which is spastic paresis of extremities with greater affection of lower than upper limbs. Spastic diplegia affects as many as 10% of low birth weight infants, with the incidence rising to 20% in infants who are even more immature. Extensive insults to the periventricular area affect motor fibers placed more laterally and controlling the upper body and extremities. Such severe insult results in spastic quadriplegia, along with intellectual deficits.

Asphyxiated term infants show major tone and motor abnormalities because of hypoxic-ischemic damage to motor cortex, thalamus, basal ganglia, and brainstem. Spastic quadriplegia and choreo-athetoid cerebral palsy are more frequent pattern of motor abnormalities in the term infants

Impairment of sucking, swallowing and facial movements may relate to nuclear injury (bulbar palsy) although some infants exhibit the features of upper motor neuron type of involvement (pseudobulbar palsy), probably cerebral in origin. Involvement of anterior horn cells may explain the characteristic persistence of hypotonia in the first months of life and when severe, this topography of involvement may explain the unusual persistence into childhood of the hypotonia and weakness i.e. atonic cerebral palsy. With the involvement of basal ganglia and thalamus, subsequent extra pyramidal abnormalities are common. The combination of choreoathetosis and dystonia is due to bilateral involvement of basal ganglia and intact pyramidal tracts. The onset of the extra pyramidal abnormalities is not clearly apparent until after 6-12 months and often much later. Thus the large majority of infants develop overt choreoathetosis or dystonia or both between 1 and 4 years of age. Abnormal motor development is commonly obvious prior to this time. Intellectual function is relatively preserved in these babies.

Mental retardation

Mental retardation is especially common in severely asphyxiated term infants and is a consequence of injury to the parasagittal cortex. Intellectual function is more adversely affected if the thalamus is injured, even if the injury to the parasagittal cortex is limited.

Even in the absence of mental retardation, general cognitive abilities in asphyxiated premature infants are in the lower range of normal and clearly lower than in controls (6). Preterm infants show significantly poorer sensory-motor, visual-motor, auditory and language processing, short-term memory, and new learning skills (7, 8).

Epilepsy

The risk of subsequent epilepsy after neonatal seizures is approximately 30% and EEG is good tool for determining the prognosis after the occurrence of seizures during the acute stages of perinatal asphyxia. If the interictal EEG is normal or has minimal/mild depression the risk of subsequent epilepsy is practically nil.

Hearing, Speech and Communication

These deficiencies are particularly common with quadriplegic and choreoathetotic (dyskinetic) type of cerebral palsy. Children with later type of cerebral palsy have difficulty in initiating voluntary movements as well as suppressing unwanted movements, which produce chaotic voice control and swallowing at every level of motor control.

Visual function

Term infants may develop visual impairment as a result of hypoxic-ischemic damage to visual cortex in the parieto-occipital region, which is a watershed zone between posterior and middle cerebral arteries (9). Visual cortex atrophies in 60% of these infants. Visual impairment ranges from squint with failure to develop conjugate vision, through field defects and visual agnosis to total amblyopia. Particularly in severely affected infants impairment of the cortical visual function occurs with markedly decreased or no visual responses with intact papillary response (cortical blindness). The preterm babies develop visual disturbances mainly due to damage to the optic radiations, which are located in the periventricular regions and crossed by pyramidal tracts (10). The preterm babies are at additional risk of retinopathy of prematurity (ROP) causing retinal blindness and PVL may destroy the optic radiation. If they develop post hemorrhagic hydrocephalus following IVH the raised intracranial pressure can compress the posterior cerebral arteries causing calcarine infarction.

Feeding problems

Feeding problems are usually due to bulbar palsy. The children are prone to oral hypersensitivity and to bite on what ever is put in their mouth. Parents can be taught to desensitize the child's mouth before feeds. There may be aspiration of feed with consequent respiratory symptoms. Food thickeners can be used along with upright position after feeds (7). Gastrostomy may be considered for those children with unsafe swallow or whose intake is insufficient for growth.

Predictors of long-term neurologic outcome

Table 2 summarizes the various parameters, which can predict poor long-term outcome. Apart from these, prematurity per se is an important prognostic factor on its own. Table 2

. Predictors of long-term neurological outcome in perinatal asphyxia

Parameter	Abnormalities and long term outcome

Fetal acid base measurements (11)	Umbilical artery pH <7.1, Base deficit >11: major neurological deficits in 14%
Extended Apgar score (12)	At 20 minutes <3: CP in 57% survivors
Severity of the encephalopathy	Mild-no neurological sequelaeModerate-∼25% have neurological sequelae Severe-100% have neurological sequelae
Seizures	Early onset and refractory seizures
Elevated CPK BB	>5 IU
Oliguria	Persistently <1 ml/kg/hr for the first 36 hours of life
Background EEG	Burst suppression pattern on any dayIsoelectric tracing on any day
Brainstem auditory, Visual and Somatosensory evoked potentials	Abnormal latencies and amplitude ratios
Neurologic Examination at end of 1st week of life	If abnormal, predicts long term abnormality
Head growth (13)	If slow in the first month, is a poor prognosis

Electroencephalogram (EEC)

The severity of EEG abnormalities and the duration are of prognostic importance. Recovery of normal EEG background by day 7 is associated with a normal outcome. In contrast a burst suppression pattern or isoelectric pattern on any day is invariably associated with a poor outcome (14,15).

Amplitude-integrated EEG recordings (Cerebral function monitor) obtained continuously from to bipolar electrodes have recently been advocated as an objective tool for early prediction of poor outcome (16). It was able to predict the neurological outcome as early as within 12 hours of life in a recent study (17). Their use may lie in the use of newer therapies which have to be administered within a short window period after birth.

Radiologic InvestigationsCT scan

CT scan is most useful as a prognostic help when done about 4-6 weeks after asphyxia. Durin acute stages, CT shows reversal sign - diffuse cerebral hypodensity with loss of gray white differentiation but with relatively increased density of deep nuclear structures (18). In chronic cases CT shows changes in basal ganglia and thalamus (although the MRI is more sensitive). These areas express a featureless appearance, with loss of distinction of deep nuclear structures and usually clearly decreased attenuation of these structures, which gradually deteriorates overseveral months. Rarely the injury can develop calcification (19).

Because of relatively superficial nature of the parasagittal cerebral injury it is more difficult to appreciate it on CT scan unless it is very severe. Periventricular leucomalacia in preterm infants can be seen in CT scans as periventricular hypo density with a propensity for involvement of anterior and posterior periventricular areas. But the definite evidence of PVL in CT are findings of reduction in quality of periventricular white matter, particularly at the trigone, vetriculomegaly with irregular outline of lateral ventricles and deep sulci that abut the wall of lateral ventricles.

Ultrasound

Ultrasonogram can pick up acute lesions of PVL as bilateral linear or flare echo-densities adjacent to the external angles of lateral ventricles. Over approximately 1-3 weeks these echodensities form multiple small echolucent cysts. Over next 1-3 months the echolucenies disappear to produce enlarged ventricles with decreased myelin. More commonly the cysts are never apparent and the result is ventriculomegaly, representing a deficit in white matter volume.

However, the correlation between radiologic findings and long-term outcomes are not uniform. Echodensities particularly in poster!or parietal and parieto-occipital regions (regions of predilection for PVL) are common in the brain of premature infant with no neuropathological sequelae. The most crucial finding on ultrasound that distinguishes such normal or transient benign echodensities is the evolution to echolucencies, cyst or ventricular dilation secondary to tissue loss or both.

MRI

Magnetic resonance imaging is very sensitive for the demonstration of all neonatal hypoxic-ischemic lesions subsequent to neonatal period. Atrophy of thalamus, basal ganglia usually accompanied by increased signal on T2W images is prominent especially in children with extrapyramidal affection. The sequelae of PVL are distinctive and consist of decreased periventricular white matter, especially in peritrigonal area, compensatory ventricular dilation and increased signal in periventricular white matter on T2W images.

Limitations of interpreting long-term outcome studies

In enquiring the long-term neurologic outcome of birth asphyxia, it has to be remembered that there is no easy validated means for the objective measurement of birth asphyxia, allowing surety as to whether nonspecific clinical signs in the neonate are attributable to asphyxia or not. Second, there are very few good studies of the natural history of birth asphyxia; studies in defined populations that were not selected for factors that might have an impact on outcome, that included clear and reasonable criteria for asphyxia, that followed the studied children to a time when some reasonably homogeneous outcome could be reliably established, and that were large enough to permit conclusions about relationships between uncommon events and uncommon outcomes (20).

In addition to these difficulties, the term birth asphyxia has been used to mean a number ofdifferent things by different investigators. Birth asphyxia occurs in a wide range of degrees, from the normal low oxygen tension of the intrauterine environment and of birth, to acute totaland prolonged absence of gas exchange.

Post discharge follow-up and management

All infants who have suffered significant asphyxia with obvious neurological signs during neonatal period should be closely followed up for early detection of motor and cognitive disabilities. This requires multiple, longitudinal assessments which include neurologic, developmental, and psychological, and possibly electrophysiologic and neuroimaging evaluations (5).

Tone abnormalities are very common during first year of life in preterm babies, but the majority of these abnormalities will improve by 18 months of life. 20 In contrast the abnormal tone patterns in the term infants are usually permanent and are antecedent of motor impairments later in the childhood. Nevertheless any asphyxiated infant with tone abnormalities should be evaluated in detail for other neurological abnormalities and referred to physical therapist for early intervention (21).

Oral-motor and swallowing difficulties interfere with normal feeding and lead to growth failure including decreased rate of growth of head circumference. Therefore these children should be monitored closely for early features of growth failure and appropriate steps to provide nutrition should be employed at the earliest. Gastrostomy may be needed in some of them.

All asphyxiated infants should undergo routine ophthalmologic examination once before discharge from the hospital and again between 6 and 12 months of corrected age. Additional evaluationshould be done whenever there is concern regarding the infant's visual capabilities. Premature infants will require more frequent evaluations, for retinopathy of prematurity. Routine hearingscreening should be performed in asphyxiated infants by auditory brainstem evoked response before hospital discharge, between 6 and 12 months of age and again at the time of entrance to the school. If at anytime during the follow up if there is any concern regarding hearing, speech orlanguage, articulation or quality of localization these children should be subjected to hearingevaluation promptly for early detection and intervention. Developmental and psychological testing, including evaluations of cognitive and behavioral skills and academic abilities, is recommended beginning at 1 year of age and extending through school age. The early detection of learning disabilities is critical to the introduction of appropriate educational interventions at theearliest possible age to maximize academic potential (21).

For parents of children with cerebral palsy, there may be more than one medical specialist needed because of many associated potential problems. Coordination of investigation and treatment is best carried out through a multidisciplinary child development team.

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