Cerebral palsy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2], Iqra Qamar M.D.[3], Ahmed Younes M.B.B.CH [4]

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. Cerebral palsy can be classified based on the number of limbs involved, physiologically and functionally. 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 and periventricular leukomalacia are the two main pathologies that play a vital role in the development of cerebral palsy. Birth asphyxia is believed to be the principal etiology for cerebral palsy. However, recent studies demonstrated that 70% to 80% of cases of cerebral palsy are due to antenatal factors, while only 10% to 28% of cases are due to birth asphyxia in term and near-term infants. The incidence of cerebral palsy is approximately 150-250 per 100,000 live births worldwide. Decline in the trends of cerebral palsy is due to advances in perinatal care. The prevalence of different motor patterns of cerebral palsy has remained remarkably static over the last 20 years. Common risk factors in the development of cerebral palsy include prematurity, fetal birth asphyxia, multiple births, and maternal illness. The most common symptoms of cerebral palsy include abnormal [[muscle tone]- early hypotonia followed by spasticity, gross motor developmental delay, definite hand preference before age 1 year, failure to crawl, failure to thrive or growth failure. The d]iagnosis of cerebral palsy is clinical and there is no specific test to confirm the diagnosis of cerebral palsy. MRI is the diagnostic neuroimaging study of choice and findings include hypoxic-ischemic lesions, cortical malformations, and lesions of the basal ganglia. Pharmacologic medical therapies for cerebral palsy include botulinum toxin, intrathecal baclofen, and oral antispastics.

The first detailed medical descriptions for cerebral palsy dates back to the era of Hippocrates in his work “Corpus Hippocraticum”. Although there is lack of detailed medical descriptions from before the 19th century, mentions to cerebral palsy can be found in representational art, literary sources and paleopathology. In 1827, Jean Baptiste Cazauvieilh was the first to report cerebral atrophy in individuals with congenital paralysis and tried to distinguish between lesions in the developing brain with those related to trauma. In 1853, Little named spastic diplegia as Little’s disease. In 1861, after twenty years of experience and nearly 200 cases, Little put forth a theory that asphyxia at birth could cause permanent central nervous system damage in cerebral palsy patients. Between 1891 and 1897, Sigmund Freud was the first to describe a classification system for cerebral palsy in his several volumes entitled “Cerebral Palsy”. In 1953, Virginia Apgar generated a scoring system, “APGAR” that forced obstetricians to examine the condition of newborns at birth and assess the need for treatment.

Cerebral palsy can be classified based on number of limbs involved, physiologically and functionally. Based on number of limbs involved cerebral palsy can be classified into monoplegia, hemiplegia, diplegia, paraplegia and quadriplegia. Physiologically, cerebral palsy can be divided into a spastic type (pyramidal), and an extrapyramidal type. The extrapyramidal types of cerebral palsy include athetoid, choreiform, ataxic, rigid, and hypotonic. The Manual Ability Classification System (MACS) and the Gross Motor Function Classification System (GMFCS) are two most commonly employed systems for functional classification of cerebral palsy. The Manual Ability Classification System (MACS) classifies children with cerebral palsy into five levels. The levels are based on the children’s self-initiated ability to handle objects and their need for assistance or adaptation to perform manual activities in everyday life. The Gross Motor Function Classification System (GMFCS) also classifies children with cerebral palsy into five levels. The levels are based on self-initiated movement abilities, in particular sitting and walking.

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.

Birth asphyxia is believed to be the principal etiology for cerebral palsy. However, recent studies demonstrated that 70% to 80% of cases of cerebral palsy are due to antenatal factors, while only 10% to 28% of cases are due to birth asphyxia in term and near-term infants. Causes of cerebral palsy are often multifactorial.

Cerebral palsy must be differentiated from other diseases that cause spasticity, hypotonia, ataxia and dystonia such as inherited metabolic disorders, intellectual disability, metabolic myopathies, metabolic neuropathy, traumatic peripheral nerve lesions, tumors of the conus and cauda equina and vascular malformations of the spinal cord.

The incidence of cerebral palsy is approximately 150-250 per 100,000 live births worldwide. Decline in the trends of cerebral palsy is due to advances in perinatal care. The prevalence of different motor patterns of cerebral palsy has remained remarkably static over the last 20 years. Most patients are identified by 2 years of age due to delayed motor milestones. Cerebral palsy usually affects individuals of the black non-Hispanic children race. White non-Hispanic children are less likely to develop cerebral palsy. Males are more commonly affected by cerebral palsy than females. The male to female ratio is approximately 1.5 to 1.

Common risk factors in the development of cerebral palsy include prematurity, fetal birth asphyxia, multiple gestation, maternal illness, fetal brain malformation, maternal teratogen exposure, low socioeconomic status, nonvertex presentation, postmaturity, and head injury.

There is insufficient evidence to recommend routine screening for cerebral palsy. Serial follow-up exams of all newborns from neonatal intensive care are warranted until it is evident that there is no failure in developmental milestones or development of spasticity.

Although the neurologic deficit is permanent and non-progressive, if cerebral palsy is left untreated it can have a dynamic effect on growth and development of the patient resulting in gait abnormalities. Cerebral palsy affects multiple systems. Common complications include contractures, hip dislocation, scoliosis, failure to thrive, dental caries (enamel dysgenesis, malocclusion, and gingival hyperplasia), increased risk of aspiration pneumonia, bronchiolitis/asthma, epilepsy, and mental retardation.

The diagnosis of cerebral palsy is clinical and there is no specific test to confirm the diagnosis of cerebral palsy. Diagnostic evaluation may include magnetic resonance imaging (MRI) of the brain, electroencephalography (EEG), lumbar puncture, metabolic and genetic testing and, screening for thrombophilia.

A positive history of failure to meet the expected developmental milestones, failure to suppress the primitive reflexes, intellectual disability or mental retardation, visual or hearing problems, speech or language problems, and oromotor dysfunction is suggestive of cerebral palsy. The most common symptoms of cerebral palsy include abnormal muscle tone– early hypotonia followed by spasticity, gross motor developmental delay, definite hand preference before age 1 year, failure to crawl, failure to thrive or growth failure. Less common symptoms of cerebral palsy may include hypotonia with decreased resistance to movement.

Patients with cerebral palsy usually have abnormal neck or truncal tone, asymmetric posture, abnormal strength, gait and coordination. Physical examination of patients with cerebral palsy is usually remarkable for neuromuscular findings such as tremors or involuntary movements, athetosis, chorea, muscle rigidity, sensory loss, diplegia/hemiplegia/quadriplegia, intellectual disability, dystonia, normal/increased/decreased tone, persistent or asymmetric fisting, abnormal oromotor patterns, tongue retraction and thrust, tonic bite, oral hypersensitivity, grimacing, poor head control and spastic cerebral palsy presents with features of upper motor neuron lesion.

There are no diagnostic laboratory findings associated with cerebral palsy. The American Academy of Neurology (AAN) recommends lab studies if there is no specific structural abnormality present-, the presence of atypical features in history or physical examination and cerebral palsy associated with brain malformation. Following labs may help to rule out other diseases and may include thyroid function tests, lactate and pyruvate levels, organic and amino acids, ammonia levels and chromosomal analysis

There are no diagnostic ECG findings associated with cerebral palsy. Findings on an ECG suggestive of cerebral palsy may include increased heart rate, shorter PR interval and shorter QRS duration.

There are no diagnostic x-ray findings associated with cerebral palsy. An x-ray may be helpful in the diagnosis of complications of cerebral palsy which include recurrent aspirations and scoliosis.

Cranial ultrasonographic findings may include intraventricular hemorrhage, hypoxic-ischemic injury to the periventricular white matter and periventricular leukomalacia.

CT scan findings suggestive of cerebral palsy may include congenital malformations, intracranial hemorrhage and periventricular leukomalacia.

MRI is the diagnostic neuroimaging study of choice especially for older children and is preferred over CT scan. The diagnostic yield of MRI depends upon the type of CP (mixed > quadriplegic > hemiplegic > diplegic > ataxic > dyskinetic) and the timing of birth. MRI findings in patients with CP may include hypoxic-ischemic lesions (eg, periventricular leukomalacia-PVL), cortical malformations and lesions of the basal ganglia.

There are no other imaging findings associated with cerebral palsy.

Other diagnostic studies for cerebral palsy may include electroencephalography, EMG and nerve conduction studies, placental examination, and screening for associated conditions such as intellectual disability, visual impairment, hearing impairment, speech and language impairment.

Pharmacologic medical therapies for cerebral palsy include botulinum toxin, intrathecal baclofen, and oral antispastics. The management of cerebral palsy should be individualized according to the patient’s need and status of disease. The disease itself is not progressive but the presentations might change with the maturation of the brain and the development of the skeletal system. Medical therapy aims at improvement of the motor function through relieving the spasticity of the limbs and preventing the occurrence of convulsions.

Surgery is not the first-line treatment option for patients with cerebral palsy. Surgery is usually reserved for patients with severe disease causing functional abnormalities. Surgical interventions include selective dorsal rhizotomy and tendon lengthening or transfer. n lengthening or transfer.

Effective measures for the primary prevention of cerebral palsy include avoiding preterm birth, avoiding complicated delivery and avoiding head trauma in the neonate.

There are no established measures for the secondary prevention of cerebral palsy.

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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]

The first detailed medical descriptions for cerebral palsy dates back to the era of Hippocrates in his work “Corpus Hippocraticum”. Although there is lack of detailed medical descriptions from before the 19th century, mentions to cerebral palsy can be found in representational art, literary sources and paleopathology. In 1827, Jean Baptiste Cazauvieilh was the first to report cerebral atrophy in individuals with congenital paralysis and tried to distinguish between lesions in the developing brain with those related to trauma. In 1853, Little named spastic diplegia as Little’s disease. In 1861, after twenty years of experience and nearly 200 cases, Little put forth a theory that asphyxia at birth could cause permanent central nervous system damage in cerebral palsy patients. Between 1891 and 1897, Sigmund Freud was the first to describe a classification system for cerebral palsy in his several volumes entitled “Cerebral Palsy”. In 1953, Virginia Apgar generated a scoring system, “APGAR” that forced obstetricians to examine the condition of newborns at birth and assess the need for treatment.

• In 1827, Jean Baptiste Cazauvieilh was the first to report cerebral atrophy in individuals with congenital paralysis and tried to distinguish between lesions in the developing brain with those related to trauma.^[1][2]
• In 1829, Jean Cruveilhier and Carl Rokitansky reported isolated cases of cerebral atrophy in children.
• In 1842, Eduard Heinrich Henonch in his dissertation, “Die Atrophia Cerebri”, described the cerebral changes associated with infantile hemiplegia.
• In 1832, William John Little, the founder of orthopedic surgery in England successfully corrected his own clubfoot using George Fredrick Louis Stromeyer’s technique of subcutaneous tenotomy.
• In 1853, Little named spastic diplegia as Little’s disease.
• In 1861, after twenty years of experience and nearly 200 cases, Little put forth a theory that asphyxia at birth could cause permanent central nervous system damage in cerebral palsy patients.
• In 1868, Jean Louis Cotard, under the guidance of Jean Martin Charcot (1825–1893), a French neurologist, analyzed the different etiologies of cerebral paralysis, especially trauma, and described partial atrophy of the brain in these conditions.
• In 1882, James Ross proposed the idea that most cases of spastic paraplegia in infancy are due to a porencephalic defect of the cortical motor centers.
• In 1887, Victor Hutintel suggested that congenital hemiplegia might result from localized encephalomalacia, which is secondary to venous congestion, stasis, thrombosis, and hemorrhage.
• Between 1891 and 1897, Sigmund Freud was the first to describe a classification system for cerebral palsy in his several volumes entitled “Cerebral Palsy”.
• In 1925, Schaltenbrand was the first to describe normal motor development in great detail and was later elaborated on by McGraw in 1943.
• In 1947, Strauss and Lehtinen noticed for the first time that behavioral and emotional abnormalities are common in children with cerebral palsy.
• In the 1950’s, Andreas Peto developed conductive education with the objective to enable children with cerebral palsy to walk in order to be able to integrate them as well as possible into the regular educational system.
• In 1953, Virginia Apgar generated a scoring system, “APGAR” that forced obstetricians to examine the condition of newborns at birth and assess the need for treatment.
• In 1959, Crothers and Paine pioneered a multidisciplinary approach for the evaluation of cerebral palsy, based on the classification of muscle tone and neurological syndromes.
• In 1961, Erich Saling & Damaschke developed the micro-assay for sampling blood gas which allowed the diagnosis of acidosis and hypoxia using small quantities of blood.
• In 1964, Crothers and Paine, along with Ingram, studied cerebral palsy patients with cerebellar involvement and discovered a form of cerebral palsy in which ataxia is present.
• In 1964, Prechtl and Beintema developed an examination system based on primitive reflex status and their relevance as a diagnostic tool to functionally assess the young nervous system, is especially important in predicting cerebral palsy and minor neurological deficits.
• In 1967, Christensen and Melchior published in detail the first book on cerebral palsy concentrating on clinical and neuropathological studies and related these to aetiological and pathogenic factors.

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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]

Cerebral palsy can be classified based on number of limbs involved, physiologically and functionally. Based on number of limbs involved cerebral palsy can be classified into monoplegia, hemiplegia, diplegia, paraplegia and quadriplegia. Physiologically, cerebral palsy can be divided into a spastic type (pyramidal), and an extrapyramidal type. The extrapyramidal types of cerebral palsy include athetoid, choreiform, ataxic, rigid, and hypotonic. The Manual Ability Classification System (MACS) and the Gross Motor Function Classification System (GMFCS) are two most commonly employed systems for functional classification of cerebral palsy. The Manual Ability Classification System (MACS) classifies children with cerebral palsy into five levels. The levels are based on the children’s self-initiated ability to handle objects and their need for assistance or adaptation to perform manual activities in everyday life. The Gross Motor Function Classification System (GMFCS) also classifies children with cerebral palsy into five levels. The levels are based on self-initiated movement abilities, in particular sitting and walking.

Based on number of limbs involved cerebral palsy can be classified into 4 subtypes

TYPE	Involved Limb
Monoplegia	One extremity involved, usually lower
Hemiplegia	Both extremities on the same side involved  Usually, upper extremity involved more than lower extremity
Paraplegia	Both lower extremities equally involved
Diplegia	Lower extremities more involved than upper extremities  Fine-motor/sensory abnormalities in upper extremity
Quadriplegia	All extremities involved equally  Normal head/neck control
Double hemiplegia	All extremities involved, upper more than lower

Physiologically, cerebral palsy can be divided into a spastic type, which affects the corticospinal tracts (pyramidal) , and an extrapyramidal type, which affects the other regions of the developing brain. The extrapyramidal types of cerebral palsy include athetoid, choreiform, ataxic, rigid, and hypotonic.^[1]

Cerebral palsy

Pyramidal

Extrapyramidal

Spastic

Spastic diplegia

Spastic hemiplegia

Spastic quadriplegia

Athetoid

Choreiform

Rigid

Ataxic

Hypotonic

• Spastic cerebral palsy is the most common form of cerebral palsy.^[2]
• Spastic cerebral palsy is usually associated with injury to the pyramidal tracts in the immature brain.
• Spasticity is caused due to exaggeration of the normal musclepassive stretch reflex.
• Histologically altered muscle function leads to the deposition of type I collagen in the endomysium of the affected muscle, leading to thickening and fibrosis, the degree of which correlated to the severity of the spasticity.
• Simultaneous co-contraction of normally antagonistic muscle groups leads to fatigue, loss of dexterity and coordination, and balance difficulties.

• Athetoid cerebral palsy is caused by an injury to the extrapyramidal tracts.
• Athetoid cerebral palsy is characterized by dyskinetic, purposeless movements that may be exacerbated by environmental stimulation.
• With the improvements in prevention of Rh incompatibility leading to kernicterus, the incidence of athetoid cerebral palsy is decreasing.
• Dystonia, characterized by an increased overall tone and distorted positioning in response to voluntary movements, or hypotonia also can occur with athetoid cerebral palsy.

• Choreiform cerebral palsy is characterized by continual purposeless movements of the patient’s wrists, fingers, toes, and ankles.
• This continuous movement can make bracing and sitting difficult.

• Patients with rigid cerebral palsy are the most hypertonic of all cerebral palsy patients.
• Hypertonicity occurs in the absence of hyperreflexia, spasticity, and clonus, which are common in spastic cerebral palsy.
• Patients with rigid cerebral palsy have a “cogwheel” or “lead pipe” muscle stiffness that often requires surgical release.

• Ataxic cerebral palsy is a very rare type.
• Ataxic cerebral palsy is characterized by the disturbance of coordinated movement as a result of an injury to the developing cerebellum.
• It is important to distinguish true ataxia from spasticity because with treatment many children with ataxia are able to improve their gait function without surgery.

• Hypotonic cerebral palsy is characterized by weakness in conjunction with low muscle tone and normal deep tendon reflexes.
• Many children who ultimately develop spastic or ataxic cerebral palsy pass through a hypotonic stage lasting 1 or 2 years before the true nature of their brain injury becomes apparent.
• Persistent hypotonia can lead to difficulties with sitting balance, head positioning, and communication.

The Manual Ability Classification System (MACS) and the Gross Motor Function Classification System (GMFCS) are two most commonly employed systems for functional classification of cerebral palsy.^[3]

The Manual Ability Classification System (MACS) classifies children with cerebral palsy into five levels. The levels are based on the children’s self-initiated ability to handle objects and their need for assistance or adaptation to perform manual activities in everyday life.^[4]

Does the child handle most kind of daily activities independently ( during play and leisure, eating and dressing)

Yes

No

Does the child handle even more difficult tasks with fair speed and accuracy and does not need alternative ways to perform

Does the child perform number of mannual tasks which commonly need to prepared or adapted and help is needed occasionally

Yes

No

Yes

No

Level 1 Handles objects easily and successfully

Level 2 Handles most objects with reduced quality and speed of acheivement

Level 3 Handles objects with difficulty but needs preparation

Can the child perform easy activites with frequent support

Yes

No

Level 4 Handles easy activites with limitations and support

Level 5 Cannot handle daily activites has severely limited abilities to perform even simple actions

The Gross Motor Function Classification System (GMFCS) also classifies children with cerebral palsy into five levels. The levels are based on self-initiated movement abilities, in particular sitting and walking.^[5]

Level	Description
1	Can walk at home, school, outdoors and in the community without any support. Can climb stairs without the use of a railing. Can perform gross motor skills such as running and jumping, but speed, balance, and coordination are limited.
2	Can walk in most settings and climb stairs holding onto a railing. May experience difficulty walking long distances and balancing on uneven terrain, inclines, in crowded areas or confined spaces. Can walk with physical assistance, a handheld mobility device or used wheeled mobility over long distances. Have only minimal ability to perform gross motor skills such as running and jumping.
3	Can walk using a hand-held mobility device in most indoor settings. Can may climb stairs holding onto a railing with supervision or assistance. Can use wheeled mobility when traveling long distances and may self-propel for shorter distances.
4	Can use methods of mobility that require physical assistance or powered mobility in most settings. Can walk for short distances at home with physical assistance or use powered mobility or a body support walker when positioned. At school, outdoors and in the community children are transported in a manual wheelchair or use powered mobility.
5	Children are transported in a manual wheelchair in all settings. Children are limited in their ability to maintain antigravity head and trunk postures and control leg and arm movements.

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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]

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.

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

• 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

• 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

Intraventricluar hemorrhage

Periventricular watershed zones

Immature autoregulatory mechanisms

Ischemia/hypoxia

Cytokines

Reactive oxygen species

Exitotoxicity by glutamate

Periventricular leukomalacia

Cerebral Palsy

• 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.

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

• 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.

• 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 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.

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.

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

Template:WH Template:WS

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

Birth asphyxia is believed to be the principal etiology for cerebral palsy. However, recent studies demonstrated that 70% to 80% of cases of cerebral palsy are due to antenatal factors, while only 10% to 28% of cases are due to birth asphyxia in term and near-term infants. Causes of cerebral palsy are often multifactorial.

Birth asphyxia is believed to be the principal etiology for cerebral palsy. However, recent studies demonstrated that 70% to 80% of cases of cerebral palsy are due to antenatal factors, while only 10% to 28% of cases are due to birth asphyxia in term and near-term infants. Causes of cerebral palsy are often multifactorial. For example, an intrauterine infection may result in growth restriction, maternal fever, and prematurity, all of which have been associated with cerebral palsy.^{[1][2][3][4][5][6]}

• Placental insufficiency
• Intrauterine infection
• Chromosomal abnormalities
• Maternal illness
  • Chorioamnionitis
  • Thyroid disease
  • Thrombotic disorders including factor V Leiden mutations
  • TORCH infections (toxoplasmosis, syphilis, rublla, cytomegalovirus, varicella zoster, HIV, herpes viruses)
• Multiple births
• Teratogen exposure
• Metabolic disorders
• Fetal brain malformation

• Thrombotic lesions
• Placental ischemia has been associated with spastic diplegia
• Chronic villitis
• Preeclampsia

• Hypoxia–ischemia
• Neonatal encephalopathy
• Periventricular leukomalacia
  • Periventricular leukomalacia increases the risk of cerebral palsy, independent of gestational age.
  • Approximately 75% of infants with cystic periventricular leukomalacia develop cerebral palsy.
• Fetal/neonatal stroke
• Hyperbilirubinemia
• Hemolytic disease
• Kernicterus

• Stroke
• Trauma
• Infection

Cerebral palsy

Antenatal

Perinatal

Postnatal

Prematurity and low birth weight Intrauterine infections Multiple gestations Pregnancy complications

Birth asphyxia complicated labour and delivery

Head trauma Meningitis Cardio-pulmonary arrest

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

Cerebral palsy must be differentiated from other diseases that cause spasticity, hypotonia, ataxia, and dystonia such as inherited metabolic disorders, intellectual disability, metabolic myopathies, metabolic neuropathy, traumatic peripheral nerve lesions, tumors of the conus and cauda equina and vascular malformations of the spinal cord.

• Cerebral Palsy must be differentiated from other slowly progressive diseases such as neurodegenerative disease or metabolic disorders.^[1][2][3][4]
• Presence of any of the following factors may suggest an alternative diagnosis:^[5]
  • Family history of any CNS disease
  • Progressive worsening of neurological symptoms
  • Symptoms worsened during stress such as illness or fasting
  • Absence of any specific risk factor causing cerebral palsy
  • Hypotonia with weakness
  • Failure to develop milestones normally
  • Clinical findings such as muscle atrophy, ataxia, sensory disturbances and involuntary movements
• Cerebral palsy must be differentiated from
  • Inherited metabolic disorders
  • Intellectual disability
  • Metabolic myopathies
  • Metabolic neuropathy
  • Traumatic peripheral nerve lesions
  • Tumors of the Conus and Cauda equina
  • Vascular malformations of the spinal cord

Diseases	Type of motor abnormality				Clinical findings	Laboratory findings and diagnostic tests	Radiographic findings
	Spasticity	Hypotonia	Ataxia	Dystonia
Leigh syndrome	–	–	+	+	Progressive psychomotor regression Seizures External ophthalmoplegia Lactic acidosis Vomiting	Increased lactate levels in blood and CSF Genetic testing	MRI: abnormal white matter signal in the putamen, basal ganglia, and brainstem on T2 images
Niemann-Pick disease type C	–	–	+	+	Progressive neurodegeneration Hepatosplenomegaly Systemic involvement of liver, spleen, or lung preceedes neurologic symptoms	Abnormal liver function tests Fibroblast cell culture with filipin staining	MRI: Cerebral and cerebellar atrophy Thinning of the corpus callosum
Infantile Refsum disease	–	+	+	–	Abnormalities of the optic nerve and disc Retinitis pigmentosa Sensorineural hearing loss Hepatomegaly and cirrhosis Neurologic deterioration is slower than in Zellweger syndrome or ALD	Elevated plasma VLCFA levels	—
Adrenoleukodystrophy	+	–	–	–	Cognitive and behavioral abnormalities Adrenal insufficiency Hyperpigmented skin Gonadal dysfunction Neurologic deterioration progresses at a variable rate	Elevated plasma VLCFA levels Molecular genetic testing for mutations in the ABCD1 gene	—
Zellweger syndrome	–	+	–	–	Craniofacial dysmorphism Hepatomegaly Neonatal seizures Profound developmental delay MRI findings include cortical and white matter abnormalities Neurologic deterioration is rapid and infants rarely survive beyond six months of age	Elevated plasma VLCFA levels Elevated levels of phytanic acid, pristanic acid, and pipecolic acid in plasma and fibroblasts Reduced plasmalogen in erythrocytes Molecular genetic testing for mutations in the PEX1 or PEX6 genes	—
Pyruvate dehydrogenase deficiency	+	+	+	–	Lactic acidosis Seizures Intellectual disability	Elevated lactate and pyruvate levels in blood and CSF Abnormal PDH enzymatic activity in cultured fibroblasts	—
Arginase deficiency	+	–	–	–	Hyperammonemia Encephalopathy Respiratory alkalosis	Elevated ammonia level Elevated arginine level	—
Holocarboxylase synthetase deficiency	–	+	–	–	Ketoacidosis Dermatitis Alopecia Seizures Developmental delay	Elevated levels of: Beta-hydroxyisovalerate Beta-methylcrotonylglycine Beta-hydroxypropionate Methylcitrate Tiglylglycine	—
Glutaric aciduria type 1	–	–	–	+	Episodes of metabolic decompensation and encephalopathy often precipitated by infection and fever Rarely presents in the newborn period Microencephalic macrocephaly Seizures (approximately 20 percent) Cognitive function is preserved	Elevated levels of: glutaric acid 3-hydroxyglutaric acid	MRI: Frontal and temporal atrophy
Ataxia telangiectasia	–	–	+	–	Progressive cerebellar ataxia Abnormal eye movements Oculocutaneous telangiectasias Immune deficiency Increased risk of malignancy	Elevated serum alpha-fetoprotein level Low IgA and IgG levels Lymphopenia Genetic testing for mutation in the ATM gene	—
Pontocerebellar hypoplasias	–	+	–	–	Progressive muscle atrophy Microcephaly Developmental delay	Genetic testing for PCH gene mutations	MRI : Small cerebellum and brainstem including the pons
Metachromatic leukodystrophy	–	+	+	–	Regression of motor skills Seizures Optic atrophy Reduced or absent deep tendon reflexes Intellectual disability	Deficient arylsulfatase A enzyme activity in leukocytes or cultured skin fibroblasts	—
Pelizaeus-Merzbacher	+	–	+	–	Nystagmus Cognitive impairment Onset in infancy Slowly progressive Language development may be normal	Genetic testing for mutations in PLP1 gene	MRI: White matter abnormalities
Angelman syndrome	–	–	+	–	Profound intellectual disability Postnatal microcephaly Typical abnormal behaviors (paroxysmal laughter, easily excitable)	Methylation studies and chromosome microarray to detect chromosome 15 anomalies and UBE3A mutations	—
Rett syndrome	+	–	–	+	Occurs almost exclusively in females Normal development during first six months followed by regression and loss of milestones Loss of speech capability Stereotypic hand movements Seizures Autistic features	Clinical diagnosis Genetic testing for MECP2 mutations	—
Lesch-Nyhan syndrome	+	–	–	+	Self-mutilating behavior Urinary stones due to hyperuricemia	Elevated uric acid level Abnormal enzymatic activity of HPRT in cultured fibroblasts Genetic testing for HPRT gene mutations	—
Miller-Dieker lissencephaly	+	+	–	–	Lissencephaly Microcephaly Dysmorphic features Seizures Failure to thrive	Cytogenetic testing for 17p13.3 microdeletion	—
Dopa-responsive dystonia	+	–	–	+	Onset in early childhood Symptoms worsen with fatigue and exercise	Positive response to a trial of levodopa	—

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

The incidence of cerebral palsy is approximately 150-250 per 100,000 live births worldwide. Decline in the trends of cerebral palsy is due to advances in perinatal care. The prevalence of different motor patterns of cerebral palsy has remained remarkably static over the last 20 years. Most patients are identified by 2 years of age due to delayed motor milestones. Cerebral palsy usually affects individuals of the black non-Hispanic children race. White non-Hispanic children are less likely to develop cerebral palsy. Males are more commonly affected by cerebral palsy than females. The male to female ratio is approximately 1.5 to 1.

• The incidence of cerebral palsy is approximately 150-250 per 100,000 live births worldwide.^[1]
• Decline in the trends of cerebral palsy is due to advances in perinatal care.
• Patients with mild forms of cerebral palsy that do not result in severe functional impairment may remain undiagnosed, leading to underestimation of the true prevalence of cerebral palsy.

The prevalence of different motor patterns of cerebral palsy has remained remarkably static over the last 20 years.^[2]

• The prevalence of bilateral spastic cerebral palsy is approximately 120-150 per 100,000 individuals worldwide.
• The prevalence of unilateral or hemiplegic cerebral palsy is approximately 60-80 per 100,000 individuals worldwide.
• The prevalence of bilateral dystonic cerebral palsy is approximately 150-250 per 100,000 individuals worldwide.

• Cerebral palsy is more common in children who are born very prematurely.
• Most patients are identified by 2 years of age due to delayed motor milestones.

• Cerebral palsy usually affects individuals of the black non-Hispanic children race. White non-Hispanic children are less likely to develop cerebral palsy.

• Males are more commonly affected by cerebral palsy than females. The male to female ratio is approximately 1.5 to 1.

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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]

Common risk factors in the development of cerebral palsy include prematurity, fetal birth asphyxia, multiple gestation, maternal illness, fetal brain malformation, maternal teratogen exposure, low socioeconomic status, nonvertex presentation, postmaturity, and head injury.

Common risk factors in the development of cerebral palsy include prematurity, fetal birth asphyxia, and multiple births.^[1][2]

• Prematurity
• Fetal birth asphyxia
• Multiple gestation
• Maternal illness
• Fetal brain malformation
• Major birth defects
• Familial metabolic/genetic disorder
• Neonatal complications(kernicterus)
• Maternal teratogen exposure
• Low socioeconomic status

• Nonvertex presentation
• Postmaturity
• Head injury

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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]

There is insufficient evidence to recommend routine screening for cerebral palsy. Serial follow-up exams of all newborns from neonatal intensive care are warranted until it is evident that there is no failure in developmental milestones or development of spasticity.

• There is insufficient evidence to recommend routine screening for cerebral palsy.
• Serial follow-up exams of all newborns from neonatal intensive care are warranted until it is evident that there is no failure in developmental milestones or development of spasticity.^[1]

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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]

Although the neurologic deficit is permanent and non-progressive, if cerebral palsy is left untreated it can have a dynamic effect on growth and development of the patient resulting in gait abnormalities. Cerebral palsy affects multiple systems. Common complications include contractures, hip dislocation, scoliosis, failure to thrive, dental caries (enamel dysgenesis, malocclusion, and gingival hyperplasia), increased risk of aspiration pneumonia, bronchiolitis/asthma, epilepsy, and mental retardation.

• Although the neurologic deficit is permanent and nonprogressive, if cerebral palsy is left untreated it can have a dynamic effect on growth and development of the patient.
• Growth, along with altered muscle function across joints, can lead to progressive loss of motion, contracture, and eventually joint subluxation or dislocation, resulting in degeneration that may require orthopedic intervention.^[1][2]
• Injury to the developing brain can occur at any time and can result in delayed development and may affect cognition, vision, hearing, language, cortical sensation, attention, vigilance, and behavior.

Cerebral palsy affects multiple systems. Common complications include:^[3][4][5]

• Decubitus ulcers and sores
• Contractures
• Hip dislocation
• Scoliosis
• Failure to thrive due to feeding and swallowing difficulties secondary to poor oromotor control
• Obesity
• Gastroesophageal reflux
• Constipation
• Dental caries (enamel dysgenesis, malocclusion, and gingival hyperplasia)
• Increased risk of aspiration pneumonia
• Bronchiolitis/asthma
• Epilepsy
• Hearing loss
• Visual-field abnormalities due to cortical injury
• Strabismus
• Mental retardation
• Attention-deficit/hyperactivity disorder
• Learning disabilities

• Prognosis of cerebral palsy depends on the type and severity of motor impairment.^[6]
• Average life expectancy of patients with cerebral palsy is 44% of normal.
• The strongest predictors of early mortality are immobility and impaired feeding ability.^[7]
• Retention of asymmetric and symmetric tonic neck reflex, moro reflex, neck righting reflex, and presence of lower-extremity extensor thrust response in early infancy are associated with poor prognostic factors for the development of independent walking
• Long-term monitoring depends on the degree of involvement:^[8][9]
  • Patients with a gross motor function classification system (GMFCS) level of I or II need less monitoring.
  • Patients with level III should be monitored every other year.
  • Patients with level IV or V need assessment every year during active growth.

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