Major events in human brain development and their peak times of occurrence include the following:

• Primary neurulation - Weeks 3-4 of gestation

• Prosencephalic development - Months 2-3 of gestation

• Neuronal proliferation - Months 3-4 of gestation

• Neuronal migration - Months 3-5 of gestation

• Organization - Month 5 of gestation to years postnatal

• Myelination - Birth to years postnatal

Given the complexity of the brain and its vulnerability during many stages of development, it is subject to injury at several times. Cerebral ischemia before the 20th week of gestation can result in a neuronal migration deficit; between the 26th and 34th weeks, periventricular leukomalacia; and between the 34th and 40th weeks, focal or multifocal cerebral injury.

Brain injury due to vascular insufficiency depends on various factors at the time of injury, including vascular distribution to the brain, efficiency of cerebral blood flow and regulation of blood flow, and biochemical response of brain tissue to decreased oxygenation.

The physical stress on the premature infant as well as the immaturity of the brain and cerebral vasculature likely explain why prematurity is a significant risk factor for CP. Prior to term, the distribution of fetal circulation to the brain results in the tendency for hypoperfusion to the periventricular white matter. Hypoperfusion can result in germinal matrix hemorrhages or periventricular leukomalacia, which is associated with a spastic diplegic presentation.

At term, when circulation to the brain most resembles adult cerebral circulation, hypoperfusion mostly targets injury to the watershed areas of the cortex (eg, end zones of the major cerebral arteries), resulting in a spastic quadriplegic phenotype. The basal ganglia also can be affected, resulting in an extrapyramidal (eg, choreoathetoid or dystonic) presentation. Vascular injuries at term tend to occur most often in the distribution of the middle cerebral artery, resulting in a spastic hemiplegic phenotype.

No set rule exists as to where vascular injury can occur, and injury may occur at more than 1 stage of fetal brain development. The autoregulation of cerebral blood flow in the human newborn is sensitive to perinatal asphyxia, which can result in vasoparalysis and cerebral hyperemia. The extent of injury is thought to be related to regional vascular and metabolic factors and the regional distribution of excitatory synapses.

Between weeks 26 and 34 of gestation, the periventricular white matter areas near the lateral ventricles are most susceptible to injury. Since these areas carry fibers responsible for the motor control and muscle tone of the legs, injury can result in spastic diplegia (i.e., predominant spasticity and weakness of the legs, with or without arm involvement of a lesser degree). When larger lesions extend past the area of descending fibers from the motor cortex to involve the centrum semiovale and corona radiata, both the lower and upper extremities may be involved.

Periventricular leukomalacia is generally symmetric and thought to be due to ischemic white matter injury in the premature infant. Asymmetric injury to the periventricular white matter can result in 1 side of the body being more affected than the other. The result mimics a spastic hemiplegia but is best characterized as an asymmetric spastic diplegia. The germinal matrix capillaries in the periventricular region are particularly vulnerable to hypoxic-ischemic injury due to their location at a vascular border zone between the end zones of the striate and thalamic arteries. In addition, since they are brain capillaries, they have a high requirement for oxidative metabolism.

Many grade the severity of periventricular hemorrhage-intraventricular hemorrhage using a classification system originally described by Papile et al in 1978

• Grade I - Subependymal and/or germinal matrix hemorrhage

• Grade II - Subependymal hemorrhage with extension into the lateral ventricles without ventricular enlargement

• Grade III - Subependymal hemorrhage with extension into the lateral ventricles with ventricular enlargement

• Grade IV - A germinal matrix hemorrhage that dissects and extends into the adjacent brain parenchyma, irrespective of the presence or absence of intraventricular hemorrhage is also referred to as an intraparenchymal hemorrhage when found elsewhere in the parenchyma. Hemorrhage extending into the periventricular white matter in association with an ipsilateral germinal matrix hemorrhage/ intraventricular hemorrhage is termed a periventricular hemorrhagic venous infarction.

Acute hyperbilirubin encephalopathy can result in a dyskinetic (or extrapyramidal) form of CP that can occur in either the full-term infant with marked hyperbilirubinemia or the premature infant without marked hyperbilirubinemia. Kernicterus refers to encephalopathy from hyperbilirubinemia that includes both the staining of specific nuclear groups and neuronal necrosis. These effects involve predominantly the basal ganglia, particularly the globus pallidus and subthalamic nucleus; hippocampus; substantia nigra; various cranial nerve nuclei—particularly the oculomotor, vestibular, cochlear, and facial nerve nuclei; brainstem nuclei such as the reticular formation of the pons; the inferior olivary nucleus; the cerebellar nuclei such as the dentate; and the anterior horn cells of the spinal cord.

Given the distribution of injury in kernicterus, hearing loss and movement disorders (primarily choreoathetosis or dystonia) are predominant features of hyperbilirubin encephalopathy. With improvement in early management of hyperbilirubinemia, more cases of dyskinetic (or extrapyramidal) CP are associated not with a history of hyperbilirubinemia but instead relate to presumed hypoxic injury to the basal ganglia. In the absence of hyperbilirubinemia, prematurity, or hypoxia, the possibility of a metabolic or neurodegenerative disorder as a basis for this phenotype must be considered.

Status marmoratus is the neuropathological result of a neonatal hypoxic-ischemic encephalopathy and is thought to affect term infants more than premature infants. This lesion is notable for a marbled appearance due to an abnormal myelin pattern. It involves the basal ganglia and thalamus and results in a dyskinetic CP phenotype.

The underlying brain anomaly in CP is thought to be static, whereas the motor impairment and functional consequences may vary with time. By definition, cases due to underlying disorders of a progressive or degenerative nature are excluded when diagnosing CP.