Selective vulnerability in the neonatal brain

Selective vulnerability of specific regions and cells in the developing brain is an important principal in several serious pediatric neurological disorders. The venerable term “cerebral palsy,” originally used by William Osler, describes the special vulnerability of the immature brain’s motor control systems to damaged or disrupted development. ’ Although the term is sometimes criticized for its vagueness and the fact that it is not a disease but a cluster of motor disorders, modern neuroimaging and careful clinical studies are providing insight into the neurobiological substrate for two of the most important cerebral palsy syndromes, spastic diplegia and extrapyramidal or “dyskinetic” cerebral palsy. ’ Spastic diplegia, the syndrome in which an infant develops spasticity in the legs more than the arms, is the most common type of congenital motor disorder and is the one appearing at an increasing rate around the world as smaller infants survive with better neonatal care.3 Spastic diplegia is caused by injury or maldevelopment of the periventricular white matter (periventricular leukomalacia or PVL), which disrupts axons going to the legs preferentially. * Imaging with cranial ultrasound in the nursery can diagnose this disorder with considerable accuracy when periventricular cysts or ventricular dilatation are p r e ~ e n t . ~ PVL occurs during a temporal window of development that ends at 32 to 34 weeks’ gestation, probably related to the temporal window of vulnerability of immature oligodendroglia to oxidative stress6 Although spastic diplegia and PVL are strongly associated with prematurity and its complications such as bronchopulmonary dysplasia, some infants sustain white matter injury before 34 weeks and remain in utero to be born at term. Ischemia, cytokine-mediated damage stimulated by infection, and endocrine/metabolic factors appear to be the leading causes of PVL.237 Extrapyramidal or dyskinetic cerebral palsy (ECP) related to basal ganglia dysfunction is a less common form of cerebral palsy (13-35%) than spastic diplegia, but epidemiological studies of large populations of patients with cerebral palsy in Sweden suggest that this is the type most likely to be associated with perinatal asphyxia in term infants. ’ Children with ECP have variable tone, movement abnormalities including rigidity, dystonia, and athetosis, difficulty with fine motor movements in the hands, and expressive language disorder or mutism. Recent magnetic resonance imaging (MRI) studies of children with ECP and a history of severe perinatal asphyxia at term show selective shrinkage and gliosis in the putamen and thalamus of the basal ganglia. ’-’ ’ The observations of Roland and colleagues,12 in this issue of Annals, demonstrate that this pattern of injury is often detectable in the nursery, by using computerized tomographic (CT) scanning. They found 20 infants with decreased tissue attenuation, predominantly in thalami and basal ganglia with relative preservation of cerebral cortex and white matter. This group had a poor outcome, with 35% dying and the rest surviving with cerebral palsy. The pattern was strongly associated with profound, acute hypoxicischemic insults such as placental abruption or cord prolapse, suggesting that the pattern corresponded to animal models of “acute, total” asphyxia. l 3 The observations extend previous observations that point to a relationship between severe perinatal asphyxia at term and selective vulnerability of the basal ganglia. Recent elegant neuroanatomical studies of selective brain injury in a new model of perinatal asphyxia in newborn piglets also demonstrates the selective vulnerability of the putamen and thalamus, with more severe injury damaging the caudate and sensorimotor cortex around the Rolandic fissure. “ The precise mechanisms responsible for such “surgical” selectivity in the face of a global insult remain unclear, but it may relate in part to enhanced excitatory synaptic function in the neonate’s rapidly developing motor circuits as well as to enhanced energy metabolism in the neonatal basal ganglia. ”,” Two studies of neonates with hypoxic-ischemic encephalopathy showed a direct relationship between elevations of cerebrospinal fluid concentrations of glutamate and brain injury. I9,’O Studies of cerebral glucose metabolic rate in asphyxiated newborns, using positron emission tomography, showed selective elevation in glucose consumption in the basal ganglia several days after the insult. The elevated glucose metabolic rate could reflect enhanced glycolysis secondary to a disruption in mitochondrial function in these vulnerable regions. ’l It is noteworthy that the infant’s basal ganglia are also especially vulnerable to the types of intermittent, partial energy failure seen in genetic mitochondrial disorders associated with lactic acidosis in Leigh’s syndrome.22 Elevated extracellular glutamate can act synergistically with energy failure to damage brain tissue because the N-methyl-1)aspartate-type glutamate receptor is voltage dependent, fluxing more calcium into neurons when energy failure depolarizes neuronal membranes. If the basal ganglia are selectively vulnerable targets of injury from acute perinatal asphyxia, it would be useful to detect the earliest signs of their injury, to select patients for investigational neuroprotective interventions. An objective bedside measure of brain involvement from asphyxia is urgently needed, because most babies who meet clinical criteria for asphyxia do not go on to develop brain injury, and administering 12