Cerebral palsy pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Aditya Ganti M.B.B.S. [2]

## Overview

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Cerebral palsy is defined as a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy often are accompanied by disturbances of sensation, perception, cognition, communication, and behavior, by epilepsy, and by secondary musculoskeletal problems. Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL)are the two main pathologies that play a vital role in the development of cerebral palsy. 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. 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. Ischemia and infection are two important factors that play a vital role in the pathogenesis of periventricular leukomalacia. Since preterm and even term neonates have low cerebral blood flow, the periventricular white matter is susceptible to ischemic damage resulting in motor damage.

## Pathophysiology

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Cerebral palsy is defined as a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy often are accompanied by disturbances of sensation, perception, cognition, communication, and behavior, by epilepsy, and by secondary musculoskeletal problems. Generally there are three distinctive features common to all patients with cerebral palsy:[1][2][3][4][5][6][7]

* Motor impairment, which distinguishes it from global developmental delay or autism.
* An initial insult to the developing brain
* A neurologic deficit that is nonprogressive

### Initial Insult

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* 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.

Major events in human brain development  | Peak times of occurrence

|

Primary neurulation  | Weeks 3-4
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

### Pathogenesis

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* Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are the two main pathologies that play a vital role in the development of cerebral palsy.
* Corticospinal tracts composing of descending motor axons traverse through the periventricular region which is commonly injured in PVL and IVH leading to cerebral palsy.
* 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.

| Prematurity|

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| Intraventricluar
hemorrhage|

| Periventricular
watershed zones|

| Immature autoregulatory
mechanisms

| Ischemia/hypoxia|

| Cytokines|

| Reactive
oxygen species|

| Exitotoxicity
by glutamate

| Periventricular
leukomalacia|

| Cerebral Palsy|

### Intraventricular hemorrhage

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* 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

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

#### Ischemia/hypoxia

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* 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

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* This process involves microglia (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

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* 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.

### Inflammatory Response

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Ischemic and hemorrhagic injuries results in:

* Injury to watershed areas where the three major cerebral arteries end in the cortex.
* Basal ganglia damage can cause extrapyramidal or dyskinetic CP.

## Associated Conditions

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Cerebral palsy is often accompanied by other disorders of cerebral function. Associated abnormalities may affect cognition, vision, hearing, language, cortical sensation, attention, vigilance, and behavior. Common conditions associated with cerebral palsy include:

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

## References

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1. ↑ Nelson KB (2008). "Causative factors in cerebral palsy". Clin Obstet Gynecol. 51 (4): 749–62. doi:10.1097/GRF.0b013e318187087c. PMID 18981800.
2. ↑ Koman LA, Smith BP, Shilt JS (2004). "Cerebral palsy". Lancet. 363 (9421): 1619–31. doi:10.1016/S0140-6736(04)16207-7. PMID 15145637.
3. ↑ Longo M, Hankins GD (2009). "Defining cerebral palsy: pathogenesis, pathophysiology and new intervention". Minerva Ginecol. 61 (5): 421–9. PMID 19749673.
4. ↑ Hankins GD, Speer M (2003). "Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy". Obstet Gynecol. 102 (3): 628–36. PMID 12962954.
5. ↑ Marret S, Vanhulle C, Laquerriere A (2013). "Pathophysiology of cerebral palsy". Handb Clin Neurol. 111: 169–76. doi:10.1016/B978-0-444-52891-9.00016-6. PMID 23622161.
6. ↑ Johnston MV, Hoon AH (2006). "Cerebral palsy". Neuromolecular Med. 8 (4): 435–50. doi:10.1385/NMM:8:4:435. PMID 17028368.
7. ↑ Boog G (2011). "[Cerebral palsy and perinatal asphyxia (II--Medicolegal implications and prevention)]". Gynecol Obstet Fertil (in French). 39 (3): 146–73. doi:10.1016/j.gyobfe.2011.01.015. PMID 21354846.CS1 maint: Unrecognized language (link)

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