Pathophysiology
Major events in human brain development and their peak times of occurrence include the following[19] :
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
Cohort studies have shown an increased risk in children born slightly preterm (37-38 weeks) or postterm (42 weeks) compared with children born at 40 weeks.[20]
Brain injury or abnormal brain development
Given the complexity of prenatal and neonatal brain development, injury or abnormal development may occur at any time, resulting in the varied clinical presentations of cerebral palsy (whether due to a genetic abnormality, toxic or infectious etiology, or vascular insufficiency). For example, cerebral injury before the 20th week of gestation can result in a neuronal migration deficit; injury between the 26th and 34th weeks can result in periventricular leukomalacia (foci of coagulative necrosis in the white matter adjacent to the lateral ventricles); injury between the 34th and 40th weeks can result in focal or multifocal cerebral injury.
Brain injury due to vascular insufficiency depends on various factors at the time of injury, including the vascular distribution to the brain, the efficiency of cerebral blood flow and regulation of blood flow, and the biochemical response of brain tissue to decreased oxygenation.
Prematurity and cerebral vasculature
The physical stress on premature infants and the immaturity of the brain and cerebral vasculature likely explain why prematurity is a significant risk factor for cerebral palsy. Before 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. Between weeks 26 and 34 of gestation, the periventricular white matter areas near the lateral ventricles are most susceptible to injury. Because these areas carry fibers responsible for the motor control and muscle tone of the legs, injury can result in spastic diplegia (ie, predominant spasticity and weakness of the legs, with or without arm involvement of a lesser degree).
Periventricular leukomalacia
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 premature infants. Asymmetric injury to the periventricular white matter can result in one 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 because of their location at a vascular border zone between the end zones of the striate and thalamic arteries. In addition, because they are brain capillaries, they have a high requirement for oxidative metabolism.
Periventricular hemorrhage-intraventricular hemorrhage
Many authorities grade the severity of periventricular hemorrhage-intraventricular hemorrhage using a classification system originally described by Papile et al in 1978 (see Periventricular Hemorrhage-Intraventricular Hemorrhage), as follows[21] :
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.
Term cerebral vascular and hypoperfusion injuries
At term, when circulation to the brain most resembles adult cerebral circulation, vascular injuries at this time tend to occur most often in the distribution of the middle cerebral artery, resulting in a spastic hemiplegic cerebral palsy. However, the term brain is also susceptible to hypoperfusion, which mostly targets watershed areas of the cortex (eg, end zones of the major cerebral arteries), resulting in spastic quadriplegic cerebral palsy. The basal ganglia also can be affected, resulting in extrapyramidal or dyskinetic cerebral palsy.