Cerebral palsy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Pathophysiology

Cerebral palsy is a heterogeneous disorder of movement and posture that has a wide variety of presentations, ranging from mild motor disturbance to severe total body involvement. Because of this variability in clinical presentation and the absence of a definitive diagnostic test, defining exactly what cerebral palsy is has been difficult and controversial. It is generally agreed that there are three distinctive features common to all patients with cerebral palsy:

• Some degree of motor impairment, which distinguishes it from other conditions, such as global developmental delay or autism.
• An insult to the developing brain, making it different from conditions that affect the mature brain in older children and adults
• A neurologic deficit that is nonprogressive, which distinguishes it from other motor diseases of childhood, such as the muscular dystrophies.

Initial Insult

• The insult to the brain is believed to occur between the time of conception and age 2 years, at which time a significant amount of motor development has occurred.
• A similar injury to the brain after age 2 years can have a similar effect, however, and often is results in classic picture of cerebral palsy.
• By 8 years of age, most of the development of the immature brain is complete, as is gait development, and an insult to the brain results in a more adult-type clinical picture and outcome.

Pathogenesis

• The premature neonatal brain is susceptible to two main pathologies intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL).
• Although both pathologies increase the risk of cerebral palsy, periventricular leukomalacia is more closely related to cerebral palsy and is the leading cause in preterm infants.
• Both IVH and PVL cause cerebral palsy because of the corticospinal tracts, composed of descending motor axons, course through the periventricular region.

Prematurity

Intraventricluar hemorrhage

Periventricular watershed zones

Immature autoregulatory mechanisms

Ischemia/Hypoxia

Cytokines

Reactive oygen species

Exitotoxicity by glutamate

Periventricular leukomalacia

Cerebral Palsy

Disease progression

• Although the neurologic deficit is permanent and nonprogressive, the effect it can have on the patient is dynamic, and the orthopaedic aspects of cerebral palsy can change dramatically with growth and development.
• Growth, along with altered muscle forces across joints, can lead to progressive loss of motion, contracture, and eventually joint subluxation or dislocation, resulting in degeneration that may require orthopaedic intervention.*Injury to the developing brain can occur at any time from gestation to early childhood and typically is categorized as prenatal, perinatal, or postnatal.

Intraventricular hemorrhage

• Intraventricular hemorrhage is defined as a condition in which bleeding from the subependymal matrix occurs into the ventricles of the brain.
• Preterm infants are at increased risk of intraventricular hemorrhage because of underdeveloped blood vessels.
• The risk of cerebral palsy increases with the severity of intraventricular hemorrhage.

Periventricular leukomalacia

Ischemia and infection are two important factors that play a vital role in the pathogenesis of periventricular leukomalacia.

Ischemia/hypoxia

• The periventricular white matter of the neonatal brain is supplied by the distal segments of adjacent cerebral arteries.
• Although collateral blood flow from two arterial sources protects the area when one artery is blocked (e.g., thromboembolic stroke), this watershed zone is susceptible to damage from cerebral hypoperfusion (i.e., decreased cerebral blood flow in the brain overall).
• Since preterm and even term neonates have low cerebral blood flow, the periventricular white matter is susceptible to ischemic damage.
• Autoregulation of cerebral blood flow usually protects the fetal brain from hypoperfusion, however, it is limited in preterm infants due to immature vasoregulatory mechanisms and underdevelopment of arteriolar smooth muscles.

Infection and inflammation

• This process involves microglial (brain macrophage) cell activation and cytokine release, which causes damage to a specific cell type in the developing brain called the oligodendrocyte.
• The oligodendrocytes are a type of supportive brain cell that wraps around neurons to form the myelin sheath, which is essential for white matter development.
• Intrauterine infections activate the fetal immune system, which produces cytokines (e.g., interferon γ and TNF-α) that are toxic to premyelinating oligodendrocytes.
• Infections also activate microglial cells, which release free radicals. Premyelinating oligodendrocytes have immature defences against reactive oxygen species (e.g., low production of glutathione, an important antioxidant).
• IVH is hypothesized to cause PVL because iron-rich blood causes iron-mediated conversion of hydrogen peroxide to hydroxyl radical, contributing to oxidative damage.

Excitotoxicity

• Excitotoxicity is a process where increased extracellular glutamate levels stimulate oligodendrocytes to increase calcium influx, which stimulates reactive oxidative species release.
• Glutamate is increased because hypoxia causes white matter cells to reduce reuptake of glutamate due to lack of energy to operate glutamate pumps.
• Glutamate is also released from microglial cells during the inflammatory response.

Associated Conditions

• Seizures
• Scoliosis
• Deafness
• Mental retardation
• Strabismus, nystagmus, optic atrophy
• Speech deficits
• Feeding difficulties
• Urinary incontinence
• Attention deficit hyperactivity disorder
• Learning disabilities
• Depression
• Autism

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].