Received: 17 March 2020 | Revised: 8 May 2020 | Accepted: 9 July 2020

DOI: 10.1111/1440-1681.13379

REVIEW ARTICLE

Cerebral palsy: Aetiology, pathophysiology and therapeutic

interventions

Jyoti Upadhyay1 | Nidhi Tiwari2 | Mohd Nazam Ansari3

1
School of Health Sciences, University of
Petroleum and Energy Studies, Dehradun, Abstract
India Cerebral palsy (CP) is the most common non-progressive neurodevelopmental disor-
2
Department of Pharmaceutical Sciences
der in which the impairment of motor and posture functions occurs. This condition
and Drug Research, Punjabi University,
Patiala, India may be present in many different clinical spectra. Various aetiological and risk fac-
3
Department of Pharmacology and tors play a crucial role in the causation of CP. In various cases, the causes of CP may
Toxicology, College of Pharmacy, Prince
Sattam Bin Abdulaziz University, Alkharj,
not be apparent. Interruption in the supply of oxygen to the fetus or brain asphyxia
Saudi Arabia was considered to be the main causative factor explaining CP. Antenatal, perinatal,

Correspondence
and postnatal factors could be involved in the origin of CP. Understanding its patho-
Mohd Nazam Ansari, Department of physiology is also crucial for developing preventive and protective strategies. A major
Pharmacology & Toxicology, College of
Pharmacy, Prince Sattam Bin Abdulaziz
advancement in the brain stimulation techniques has emerged as a promising status
University, Alkharj, Saudi Arabia. in diagnostic and interventional approaches. This review provides a brief explanation
Email: nazam.ansari@gmail.com
about the various aetiological factors, pathophysiology, and recent therapeutic ap-
Jyoti Upadhyay, School of Health Sciences,
proaches in the treatment of cerebral palsy.
University of Petroleum and Energy Studies,
Bidholi, Dehradun, Uttarakhand- 248007,
India. KEYWORDS
Email: jyotsna_pharma07@yahoo.co.in birth asphyxia, cerebral palsy, congenital aetiologies, conventional methods, unilateral spastic
cerebral palsy

1 | I NTRO D U C TI O N The incidences rate of CP varies by an order of magnitude; a re-

A brain is an organ that serves as the centre of the nervous system in
all vertebrate and most invertebrate animals. The brain has to con-
trol all the body functions. Every muscle movement of the body is
controlled by the motor area of the brain's outer layer (called the ce-
rebral cortex). Therefore, any damage or poor development of these
areas of the brain leads to cerebral palsy (CP). The term “cerebral”
refers to the brain and “palsy” means paralysis, weakness, or lack
of muscle control. Therefore, CP disorder is defined as a disorder
of muscle control caused by impairment of part of the brain. It is
the commonest permanent disorder of motor development in in-
fants which causes limitations of activity attributed to disturbances
that are non-progressive occurring during the fetal developmen-
tal period. The motor disorders include disturbances in cognition,
perception, sensation, behaviour, and communication, epilepsy and
musculoskeletal problems.1
cent report of CP from the Centre for Disease Control (CDC) shows
3.6 per thousand live births. 2 CP is a static lesion in the developing
brain which causes permanent motor impairment in children. Lesions
are caused by developmental defects like lissencephaly, infarction
i.e. middle cephalic occlusion of the artery in neonates, trauma
during pregnancy, and after delivery. Minor lesions do not cause
motor impairment and CP.
It is a clinical condition, defined by physical conditions and his-
tory of the patient, therefore the diagnosis of this disease in general
guided by clinical manifestations or suspension of reported abnor-
malities.3 Children suffering from CP have problems like stiffness,
weakness of muscles, awkwardness, slowness, difficulty with bal-
ance, and shakiness, ranges from mild to severe. Mild CP in children
is barely noticeable and the child may have a problem in one arm or
leg, whereas in cases of severe CP the child may suffer from various
difficulties in performing day to day tasks.4 CP comprises a group of

Clin Exp Pharmacol Physiol. 2020;00:1–11. wileyonlinelibrary.com/journal/cep© 2020 John Wiley & Sons Australia, Ltd | 1
2 |
disorders which have variable clinical presentations and multiple ae-
tiologies. The pattern of CP is described by several methods. These
methods are performed to characterize children with CP that occurs
for a variety of reasons like future status prediction, clinical descrip-
tion, and monitoring changes in body functions. These methods help
5
in incorporating information from various dimensions.
Some research studies have shown that damage to certain parts
of the brain causes a consistent pattern of impairment. Such obser-
vations lead to the topographical classification of different spastic
forms of CP-like quadriplegia, diplegia, or hemiplegia, caused by
the pyramidal tract injury (Figure 1). In some cases, certain popula-
tions of patients are predisposed to a certain type of CP such as the
cases of spastic diplegia and premature infants. Ataxia, athetoid and
dystonia are an extrapyramidal type of CP that involves the whole
body. Mixed types of CP including both extrapyramidal features
and spastic (pyramidal) CP are present in many children. Several
factors and methods of ascertainment determine the variation in
the frequency of CP. The Lifestyle Assessment Score is included
in population-based study so that children with developmental
impairment are included. Gross Motor Function Classification
System level I determines the type of CP from mild to severe in
children. Some population-based studies have missed this system
of classification of CP. The CP of postnatal aetiology, genetic or
malformation syndrome is also excluded in some studies. Thus, it is
difficult to compare the study results directly. 5 Table 1 represents
the Gross Motor Function Classification System (GMFCS) of CP for
children aged 6–12 years.
FIGURE 1 Topographical classification of cerebral palsy
UPADHYAY et al.
2 | A E TI O LO G Y O F C E R E B R A L PA L S Y
The aetiological factors associated with CP vary according to the
gestational age group and clinical classification of CP. The risk fac-
tors associated with CP are placental abruption, uterine rupture, and
cord prolapse. These are uncommon conditions and collectively ac-
count for a small proportion of CP. Other risk factors associated with
CP are intrauterine exposure to infections, prematurity, congenital
malformations, maternal fever during delivery, ischaemic stroke,
intrauterine growth retardation (excessive gestational age), and
complications of multiple gestations. Severity in cases of any one
of these factors is sufficient to cause CP. The interaction between
genetic vulnerabilities and environmental pollutants is an emerging
aspect in understanding the aetiology of CP.6 Eastman and DeLeon
reported the causative factors in CP in their first controlled stud-
ies.7 Their findings determine the causative factors in CP as shown
in Table 2.
These observations by Eastman and DeLeon clearly defined that
birth asphyxia and birth injury accounts for only for a small per-
centage of CP. Also, they identified the non-asphyxial aetiological
factors of CP. Clinical studies, neuroimaging, and population-based
controlled studies provide the best estimates of the CP caused by
each aetiologic factor.6,7 Table 3 represents the percentage of CP in
population-based studies in term and near term infants attributed to
causative agents involved in CP.8-11
Identification of known aetiological factors is essential because
by knowing these causative agents we can prevent the chances of
UPADHYAY et al. | 3

TA B L E 1 Gross Motor Function

Classification System (GMFCS) of cerebral
palsy for children (6–12 years)
GMFCS level Associated problems
Level I Children's performance skills like running and jumping but coordination,
balance, and speed are impaired.
Level II Children walk indoors and climb stairs by holding railing but walking on
uneven surfaces is limited.
Level III Children walk with an assisted mobility device. Climb stairs by holding the
railing. A wheel chair is required for long distance travelling or outdoors.
Level IV Children walk on a walker for a short distance and rely on wheelchair at home,
school, and community.
Level V Limitations of motor functions, unable to move independently, physical
impairment restricted the voluntary movement of muscles. Ability in
maintaining head and trunk postures antigravity.

TA B L E 2 Causative agents in cerebral

S. No. Causative agents
palsy
1 Preterm infants
2 Placental abruption
3 Birth asphyxia
4 Congenital anomalies
5 Maternal conditions
during labour
Preterm infants are at high risk for CP. Infants
born at term are at high risk for CP.
It is more common in children with CP. Placenta
abruption and cord prolapse are dangerous to
infants.
Conditions like respiratory depression, poor
colour, hypotonia, or abnormal cry. The Apgar
score not determined until 2 years.
Presence of more congenital anomalies in infants
who developed CP.
Women who had a fever during labour had seven
times more CP than non-febrile mothers.

TA B L E 3 Percentage of cerebral palsy

S. No. Causative agents Percentage References
according to causative agents identified in
term and near term infants 1. Clinical studies Exposure to inflammation during 11%–12% [8,9]
based pregnancy
Birth asphyxia 6% [10]
Multiple birth complications 5% [11]
2. Neuroimaging Perinatal ischaemic stroke 22% [8]
studies Congenital malformations 15% [8]
White matter disorder 12% [8]
Hypoxia–ischaemia 5% [8]

CP in children. Some other risk factors associated with CP are given
below.
2.1 | Congenital aetiologies
Multiple congenital developmental deformities in infants lead to
CP. These developmental defects occur during normal growth and
development and follow the pattern that impairs normal function.
Neural tube closure defect during fetal development is the deform-
ity recognized early that leads to motor defects in infants. Neural
tube defect in the brain called encephalocele affects midface, nose
and posterior occiput.12-14 Meningomyelocele is the most common
neural tube defect that occurs in the spine. This defect causes spine
level paralysis but does not cause CP. Schizencephaly is the seg-
mental defects in the brain. There is a cleft present in the brain. It
varies and causes disability and involves a severe quadriplegic pat-
tern, especially spasticity and mental retardation.15 Meckel's syn-
drome includes encephalocele with microcephaly, polydactyly, and
renal dysplasia and occurs due to chromosomal defect on the 17th
chromosome in the homeobox gene (HOXB6). This suggested the
involvement of genes in causing these deformities. Children having
encephalocele have significant motor impairment involving quadri-
plegic pattern with more hypertonia and hypotonia.16 Microcephaly
4 |
is the proliferative defect of the brain caused by infections and
toxins. Enlargement of the brain is called megalencephaly whereas
macrocephaly is a condition in which the head is too large. Cellular
hyper-proliferation causes megalencephaly and microcephaly is
caused by hydrocephalus. During brain development neurons mi-
grate towards the periphery and any impairment in the migration
pattern causes lissencephaly in which there is decreased cerebral
gyri. This condition involves a quadriplegic pattern. Polymicrogyria is
the opposite of lissencephaly in which too many small gyri are found.
Impaired synaptic formation and remodelling has been involved in
Down syndrome, autism, Rett syndrome, and fragile X syndrome,
ataxia, mental retardation, and idiopathic spasticity, as the major
neurologic pathology.12
2.2 | Neonatal aetiologies
The prenatal and neonatal aetiologies associated with prematu-
rity and birth complications causes CP. The use of cranial ultra-
sound helps in a better understanding of brain haemorrhages.
Haemorrhage occurs in the ventricles and periventricular white
matter. Mechanical ventilation and early gestational age are the
major risk factors in causing haemorrhages. Ventricular bleed-
ing is called intraventricular haemorrhage (IVH) and bleeding in
the periventricular area is called germinal matrix haemorrhage
(GMH) and the combination of both intraventricular haemorrhage
(IVH) and periventricular area haemorrhage is called periventricu-
lar–intraventricular haemorrhage (PIVH). Table 4 represents the
classification of haemorrhagic patterns according to the grading
17
system.
These grades reported prognostic significance and vary greatly.
Premature babies with no periventricular–intraventricular haemor-
rhage (PIVH) survived better than those with periventricular–intra-
ventricular haemorrhage (PIVH). The risk of development of CP gets
increases with the severity of the grade. A study reported that the
CP risk was 9% in Grade I, 11% in Grade II, 36% in Grade III and
76% in Grade IV.18 These cerebral haemorrhages originated from
GMH and intraventricular haemorrhage (IVH) develops during the
first 72 hours after birth. Bleeding in the brain occurs and then gets
resolved.
The development of periventricular leukomalacia (PVL) occurs in
the first three weeks after childbirth in some cases. Cyst develop-
ment with periventricular leukomalacia (PVL) is called cystic periven-
tricular leukomalacia. Infants with this type of cystic periventricular
TA B L E 4 Types of haemorrhagic pattern
Grade Type of haemorrhage
Grade I Germinal matrix haemorrhage
Grade II Lateral ventricle haemorrhage
Grade III Ventricular system enlargement
Grade IV Periventricular haemorrhage and
infarctions
UPADHYAY et al.
leukomalacia have a greater risk of CP development.19,20 In general,
premature infants who have severe bleeding are at higher risk of CP
development. Hypoxic–ischaemic encephalopathy (HIE) is the con-
dition when hypoxia occurs during delivery. Its causes vary from
dystocia to anoxia and fewer flow states in the neonates. A severe
form of HIE is cyst formation subcortically and is called multicys-
tic encephalomalacia. Children with this condition develop a severe
quadriplegic pattern of CP with mental retardation. Development
of cysts in the thalamus and basal ganglia of these children causes
dystonia.12
2.3 | Postnatal aetiologies
This group of aetiologies includes postnatal trauma, infections,
metabolic encephalopathy, and toxicities and constitutes 10%–25%
cases of CP. 20,21 Non-accidental traumas in children may be due to
skull fracture or shaken baby syndrome which causes brain injury.
The shaken baby syndrome occurs in a child less than one year by
shaking the baby back and forth. This causes shearing, stretching,
and tearing of long axons and capillaries of the brain especially in
the cortex region. Surviving babies have severe spastic quadriplegic
CP pattern.15 Permanent neurologic deficits occur in children suf-
fering from a wide range of infections. Viral infections during the
prenatal and neonatal period are the most common cause of CP-like
cytomegalovirus leaves 90% of infants with deafness and mental
retardation, 50% develop motor defects or CP. Congenital rubella
infection in children causes mental retardation and CP.12 Congenital
infections including toxoplasmosis, rubella, cytomegalovirus, herpes
virus, and hepatitis B (TORCH) can be transmitted to the fetus from
mothers through the placenta and affects the developing brain pro-
ducing motor defects and CP. Chorioamnionitis or inflammation of
the placental membrane may increase the risk of CP by four-fold in
term infants. The hypothesis includes an elevated level of fetal cy-
tokines due to maternal infections causes fetal brain injury; inflam-
mation of placental membrane causes poor blood flow and gaseous
exchange causing hypoxic–ischaemic brain injury in the fetus; ma-
ternal fever raises the fetal core temperature which is harmful to the
developing brain; maternal infection leads to direct infection of the
fetal brain or meninges. 22
Metabolic disorders like lactic acidosis (pyruvate dehydrogenase
deficiency) cause hypotonia, seizures in children. Due to this disor-
der, some children die during early childhood and those who survive
suffer from severe quadriplegic CP. Urea cycle disorder like ammonia
accumulation causes brain injury and shows quadriplegic pattern CP.
Specific management of these metabolic disorders is required espe-
cially during surgery. An example includes glutaric aciduria type 1
present in normal infants. If the infant experiences childhood illness
like high fever, acidosis occurs which damages brain areas i.e. cau-
date and putamen. This causes movement and spastic disorder in
children with dystonia. 23
Many toxic agents, like alcohol and drugs, cause neurologic
deficits. Alcohol impairs brain development during pregnancy and
UPADHYAY et al.
causes CP of severe malformations called lissencephaly. 24 Drugs like
valproic acid taken by mothers during pregnancy interfere with brain
energy, carbohydrate, and lipid metabolism. It permanently impairs
the neuronal function and causes postnatal neurological disease and
CP. 25 A study reported administration of dexamethasone immedi-
ately after birth in preterm infants suffering from respiratory distress
syndrome is significantly associated with high incidences of develop-
mental delay and CP. 26 Figure 2 represents the aetiological factors of
CP between gestation period 20 weeks and neonatal period.
2.3.1 | Genetic factors
Hemminki et al. observed CP risk in some families in the National
Swedish Database. 27 The aetiology of secondary CP and perinatal
strokes includes genetic factors. 28 The risk of CP is also associated
with genetic polymorphism of genes encoding proteins of vascular
6
endothelium, inflammation or coagulation of the placenta.
2.3.2 | Multiple gestations
A high rate of preterm births and death of co-twin are the risk fac-
tors associated with CP. In case of monozygotic twins, if the death
FIGURE 2 Aetiological factors of cerebral palsy between gestation period weeks and neonatal period
| 5
of one twin occurs, there is a vascular collapse in the surviving twin
and embolism originates from the dead twin circulation and results
in secondary CP or porencephaly or encephalomalacia. 29
2.3.3 | Vascular diseases during pregnancy
Several epidemiological studies demonstrate that preeclampsia and
intrauterine growth restriction factors have been associated with
neonatal encephalopathy and CP in full-term newborns.30
2.3.4 | Preterm and post-term birth and sex
When a fetus gets separated from its natural environment before
the completion of the gestation period, it alters normal growth and
development of the brain of the fetus. 31 Animal studies demon-
strate that maternal and paternal factors like peptide vaso-intes-
tinal act on the neural axis which stimulates the development and
any alteration in these factors affects the growth and develop-
ment of the fetus. 32 In the case of post-term birth, the placental
involution begins during post maturity making the brain more sen-
sitive to damage. 30 Recent studies indicate that sex may influence
the pathogenesis of brain injuries development. CP is much more
6 |
prevalent in males as compared to females. In the premature male,
the white matter of the brain had significantly reduced compared
with the full-term males and females. Intraventricular haemor-
rhage in preterm females showed a reduction in the grey matter
as compared to control. 33
3 | PATH O PH YS I O LO G Y O F C E R E B R A L
PA L S Y
During the first trimester of pregnancy until 24 weeks of gesta-
tion, the development of cortical neurogenesis occurs which is
characterized by organization, migration, and proliferation of pre-
cursor cells of neurons. This can be affected by genetic deficits,
infections, or toxic agents resulting in malformations like lissen-
cephaly, polymicrogyria, cortical dysplasia, and schizencephaly.
In the second phase of pregnancy, growth, and developmental
events like axonal and dendrite growth, myelination, synapse for-
mation takes place. At this stage of brain development environ-
mental factors like ischaemia, hypoxia is involved and causes CP.
The CP is the result of impaired and destructive developmental
26
mechanisms.
3.1 | Neuropathological aspects of cerebral palsy
acquired perinatally in preterm and full-term neonates
The neuropathological aspects involve the understanding of the
development of the immature brain, which leads to the study of
two main distinctive associations i.e. white matter injury in pre-
mature babies and grey matter lesions in basal ganglia presented
with perinatal asphyxia. Hemiplegia is observed in full-term in-
fants. It was seen in the cases of antenatal porencephaly/schizen-
cephaly and arterial ischaemia or haemorrhagic stroke occurring
perinatally. Cystic lesions and larger infarcts developed in fetuses
and neonates than adults. The reason is that in full-term neonate
only one-sixth astrocytein the white matter is present when com-
pared with the adult. Cavitary lesions developed when astrocytic
invasion cannot occur. Quadriplegia occurs as a result of dam-
age to the thalamus and diffuse basal ganglia, watershed pattern
damage, and cortico-subcortical injury. In microcephaly, abnormal
neuronal generation and proliferation were observed. Abnormal
migration of neurons was noted in type I lissencephaly and the
absence of integrity of extracellular matrix were observed in type
II lissencephaly also known as “cobblestone syndrome”. 34 Spastic
diplegiain preterm infants is associated with diffuse white matter
injury with haemorrhages i.e. intraparenchymal haemorrhage and
lesions i.e. periventricular cavitary lesions. These infants have
larger microvascular territories with improperly developed collat-
eral circulation as well as immature cerebral blood flow auto regu-
lation. Impairment of corticospinal tract causes the development
of motor disorders as it is the final step mediating the influence of
motor neurons present in the brain stem and spinal cord.
UPADHYAY et al.
3.2 | Microscopic alterations
3.2.1 | Cerebral lesions (in preterm and full-term
infants)
Gestation period between 24 and 34 weeks shows the enhanced
vulnerability of white matter which is related to the growth of cer-
ebral pathways. During this phase high proliferation, maturation, and
migration of astrocytes and oligodendrocyte precursor i.e. glial cells
and expression of microglial cells.35 The cortical subplate possess
two types of neurons during this phase i.e. “GABAergic” neurons
originating from progenitors which are generated in the subventricu-
lar and ventricular zone of the dorsal forebrain, migrating towards
upper cortical layers and “subplate neurons” serving as a synaptic
contact site for cortico-cortical and thalamocortical tracts.36,37 The
diffuse white matter injury and focal necrotic component shows de-
generation of axons. Death of neurons and gliosis are common in
basal ganglia, subplate, and the cerebellum.
In periventricular leukomalacia, GABAergic neuronal loss in the
subplate has been observed in some studies of preterm infants of
human.38 GABAergic neurons contribute to the upper cortical layer
thickness; the diminution of this neuron in the subplate causes func-
tional and structural consequences. The germinative zones have high
angiogenesis and propensity to haemorrhage because of increased
expression levels of vascular growth factor and cyclo-oxygenase.
Germinative zone gets destroyed by the haemorrhage and intrapa-
renchymal haemorrhage impairs the dorsal telencephalic subventric-
ular zone and cerebral white matter. The final consequences lead to
the destruction of white matter axons, pre-oligodendrocyte losses
and thalamocortical axons interruption and impairment in the devel-
opment of cortical plate. 26
In case of full-term infants’ enhanced vulnerability of grey mat-
ter is observed during brain development, identified by intracortical
fibres rearrangement, columnar circuitry development, destructive
synapses formation, callosal axons retraction and termination of
cortico-cortical pathways.39
3.2.2 | Biochemical aspects (perinatally acquired
cell death, process loss, and developmental disorders)
Interaction of several causal factors causes CP but the pathophysi-
ological mechanism is common in CP. Hypoxic–ischaemic and in-
flammatory conditions are the key factors that cause cell death or
loss of cell processes. They produce pro-inflammatory cytokines in
excess, cause oxidative stress, modification of extracellular matrix,
deprivation of growth factors, and excessive release of glutamate
thus triggering the excitatory cascade reactions. These processes
result in myelination gliosis defects, degeneration of thalamus
involving secondary cortical and maldevelopment of thalamus in
preterm newborns. After any injury, the microglial cells are the
first elements that respond. These cells mediate neurotoxicity
because of the expression of both ionotropic and metabotropic,
UPADHYAY et al.
TA B L E 5 Pathophysiology of unilateral
S. No. Impairment
spastic cerebral palsy (upper extremity
function) 1 Movement
execution
2 Sensory motor
3 Motor planning
4 Bimanual
coordination
adenosine and glutamatergic receptors involved in inflammatory
responses. 40,41
Neuronal injury of primary cortical and basal ganglia oc-
curs in full-term newborns by similar mechanisms. In full-term
neonates, the diffuse hypoxic–ischaemic conditions cause fail-
+ +
ure of cellular energy which in turn induces failure of Na /K
ATPase pump, which leads to neuronal depolarization and causes
+ 2+
an influx of Na and Ca water into cells. Cell oedema occurs
which leads to cell death, necrosis, and apoptosis. 42 Glutamate
the main excitatory neurotransmitter located at the presynaptic
terminal, postsynaptic membranes, and synapses in the brain.
The reuptake of glutamate (energy-dependent process) fails and
results in excitotoxicity. Calcium-mediated excitotoxicity is me-
diated by NMDA glutamate receptor in hypoxic–ischaemic brain
injury in neonates caused by neuronal nitric oxide synthase ac-
tivation. Glutamate mediated excitotoxicity occurs in males
causing poly (ADP-ribose) polymerase-I, PARP-1 activation and
apoptosis-inducing factor AIF transfer into the nucleus trigger-
ing apoptosis whereas in females oxidative stress causes cyto-
chrome-c release from the mitochondria and activates caspase 3
to produce apoptosis. 33
| 7
Description
Damage to the corticospinal tract (CST) and other motor
pathways results in impairments in the upper extremity
movement like difficulty in selective finger movement,
precision grip, slow and clumsy movement.45
Children with CP have the capability of adjusting fingertip
forces to the objects texture and weight, with variable
forces.48
The fingertip force coordination gets impaired during object
release and exacerbated during speed.49,50
During the third trimester, thalamocortical somatosensory
projections approach their cortical destination and do
not get damaged by the periventricular lesions. These
projections circumvent the lesions and terminate them in the
postcentral gyrus. Infarction in the middle cerebral artery
often affects the postcentral gyrus which is most likely to
affect the somatosensory system.43 Therefore, children with
this type of unilateral spastic CP mainly of cerebral artery
origin at the middle generally have sensory impairments that
affect fine motor skills like light touch and discrimination
(tactile perception), proprioception and stereognosis are
often injured. 51,52
Impairment in motor planning occurs in children with
unilateral spastic CP. 53 This can also affect precision
grasping. The children with this type of CP have a
problem during object manipulation, the fingertip forces
development must be planned before doing any activity
as the sensory information related to properties of objects
is not available. Use of objects internal models based on
previous experiences should be used in manipulating a given
object. 51 This provides a base for rehabilitation protocols.
Impairment in the bimanual coordination occurs in children
with unilateral spastic CP beyond the unimanual dexterity
deficits. 54,55 The children show reduced ability to coordinate
their bimanual movements.
3.2.3 | The neural basis of unilateral spastic
cerebral palsy
During human fetal development, the corticospinal tract (CST)
motor pathways from motor areas especially the motor cortex de-
velop in a corticofugal manner and reaches the spinal cord by the
twentieth week of gestation.43 They undergo synaptogenesis at
the spinal-segmental level with the target cells. Bilateral projec-
tions are developed initially by the motor cortices to both ipsilat-
eral and contralateral upper extremities. Continued development
identified by the gradual weakening of the projection i.e. ipsi-
lateral and contralateral projections gets strengthened through
synaptic competition driven by the motor cortex activity.44 This
intricate process is much more susceptible to perinatal and pre-
natal damage of the brain. The upper extremity movement is con-
trolled by the corticospinal tract (CST) which directly innervates
motor neurons. Any impairment in this system can permanently
damage manual dexterity.45 Unilateral spastic CP is caused by an
infarct in the middle cerebral artery, hemi-brain atrophy, brain
malformations, and periventricular lesions.46,47 Table 5 represents
the pathophysiology of unilateral spastic CP.
8 |
4 | TH E R A PEU TI C I NTE RV E NTI O N S
Several therapeutic interventions are used in the management of CP.
The techniques used in the treatment of CP are conventional ap-
proaches (including traditional physiotherapy and occupational ther-
apy, neurodevelopment treatment, hippotherapy, etc.) and recent or
current approaches (including electrical stimulation technique). The
most commonly used therapeutic interventions are occupational
therapy and traditional physiotherapy and have been shown to ben-
efit in the treatment of CP. The preferred techniques used in the CP
treatment are as follows.
4.1 | Conventional approach
4.1.1 | Traditional physiotherapy and
occupational therapy
Physiotherapy improves muscle strength, local muscular endurance,
55
and overall joint mobility. Whereas occupational therapy is based
on fine motor movements, especially the upper extremities, in per-
forming the activity of daily living, These therapies modify the learn-
ing and enhance initiating attention and information processing. 56
4.1.2 | Neurodevelopmental treatment (NDT)
This technique is one of the most popular in the treatment of chil-
dren suffering from CP. The objective of NDT is the progression of
normal motor development and to prevent the development of sec-
ondary impairments due to muscle contractures, joint and limb de-
formities.56 The primary challenge is to improve motor performance
skills, postural behaviour and accomplish nearly normal function.57
4.1.3 | Sensory integration (SI)
The principle of this technique is based upon the hypothesis that in
order to develop and implement a normal adaptive behavioural re-
sponse, the child must be able to optimally receive, adjust, integrate
and process the sensory information. Many children suffering from
CP, learning disabilities, and other neurodevelopmental disabilities
have associated sensory difficulties. A therapeutic environment is
created in which the child learns rich sensory motor experience and
improvement occurs in his ability to process and integrate visual,
58
perceptual, proprioceptive and auditory sensory information.
4.1.4 | Hippotherapy
This technique is based on horseback riding or simulator as a thera-
peutic or rehabilitative treatment to improve the coordination, gait,
motor skills, balance of trunk, pelvic movement, muscle symmetry,
UPADHYAY et al.
posture, and psychosocial parameters. Therefore, changes the over-
all quality of patient.59
4.1.5 | Constraint-induced movement therapy
(CIMT)
Constraint-induced movement therapy is a physical upper extremity
rehabilitation approach to improve daily activities.60 This technique
is mainly used in children with unilateral CP (unilateral early brain
lesions), resulting in weakness, and sensory impairments resulting in
the severity of hand impairments.61,62
4.1.6 | Hyperbaric oxygen therapy (HBO)
This approach is based on improving oxygen demand in the injured area
of the brain cells to improve all the complication associated with it.63
Previous studies reported lack data available to cure CP in children.56
4.1.7 | Acupuncture
This therapy is simple, inexpensive, and safe as compared to other
techniques. Previous studies reported it improves motor activity, sen-
sation, speech, and other neurological functions in children with CP.64
4.1.8 | Body weight support trade mill training
In this technique, the child is supported in a harness on the tread-
mill. The position should be in an upright posture, restricting weight-
bearing. The child walks slowly on the moving treadmill, eliciting
stepping movements. This treadmill training allows the development
of stepping movements needed for ambulation, which helps in im-
provement in gait patterns and lower extremity movements.65,66
4.1.9 | Vojta method
This approach is based on the observation that children suffering
from CP exhibit many of the reflexes seen in normal newly born in-
fants. According to this approach, reflex pattern in the newborn can
be provoked and activated in CP children with the help of appropri-
ate stimulation that facilitates reflex locomotion development.67,68
4.2 | Recent or current approach
4.2.1 | Electrical stimulation
This technique helps in improving muscle strength and motor func-
tion. Stimulation is provided with the help of a transcutaneous
UPADHYAY et al.
electrical nerve stimulation (TENS) unit which is non-invasive, port-
able, and can be used in home settings by the patient. Non-muscular
electrical stimulation (NMES) involves transcutaneous electrical
current resulting in muscle contraction. Muscle strength has been
increased by increasing the cross-sectional area of the muscle and
69
increases the recruitment of muscle fibres (type 2). Functional
electrical stimulation (FES) applies electrical stimulation during a
given task when a specific muscle is contracting.69,70 Another trans-
cutaneous application of threshold electrical stimulation (TES) pro-
vided at low intensity does not elicit actual muscle contraction. It
acts by increasing muscle blood flow and bulk.69,71
4.2.2 | Brain stimulation technique
Deep brain stimulation (DBS)
This innovative technique interplays between externally applied
electrical forces and the central nervous system for therapeutic tar-
gets. The basis of intracellular communication is the electrochemical
grid and chemical reaction for the electrical impulse, which are the
key fundamental elements of DBS. Initially, impulse triggers the re-
lease of neurotransmitters of the cell, either activating or deactivat-
ing neurons at the stimulation site. This direct stimulation modulates
the faulty neurochemical system.72
Transcranial direct current stimulation (TDCS)
Nowadays these types of brain stimulation techniques have at-
tracted much attention. TDCS has some advantages over other
brain stimulation techniques that it is non-invasive, uses only two
electrodes (cathode and anode) for inducing weak direct currents
(1–2 mA) in the scalp surface.73 In this, the stimulation by anode
electrode causes enhancement of cortical excitability whereas the
stimulation of the cathode electrode acts as inhibitory. The TDCS
system is painless, inexpensive, portable, safe, and effective allow-
ing physicians to accomplish exercise therapy and brain stimulation
together in rehabilitation centres. The main aim of this technique is
the induction of synaptic efficacy regionally and modulation of corti-
cal excitability.74
Repetitive transcranial magnetic stimulation (rTMS)
This technique is based on the principle of electromagnetic induc-
tion to produce electrical currents in the brain. Repetitive stimu-
lation with TMS can modulate cortical excitability and generate
permanent changes in brain function. It is used in many neurological
disorders as therapeutic intervention such as stroke, refractory epi-
lepsy, neuropathic pain, schizophrenia, depression, attention deficit
hyperactivity, and autism disorder.74
5 | CO N C LU S I O N
The aetiology behind the development of CP involved a large num-
ber of causal factors including brain injury, infections, inflammations,
| 9
and toxic agents i.e. both prenatal factors as well as postnatal fac-
tors. In this paper, we discuss the aetiology and pathophysiology of
CP as it helps in understanding and preventing the disease. Early
recognition of CP is required as if the treatment is started later the
spastic conditions become stronger, and only limited results can be
achieved. We need to know more about the series of events occur-
ring during brain development and the factors which are responsible
for causing brain injury and impairment of developmental processes.
Currently, there is no effective cure available for CP. Treatment op-
tions like medications, surgery, counselling, and support are avail-
able. A better understanding of aetiology and pathophysiology helps
researchers in preventing and treating CP among children.
C O N FL I C T O F I N T E R E S T
The authors have no conflict of interest.
PEER REVIEW
The peer review history for this article is available at https://publo​
ns.com/publo​n/10.1111/1440-1681.13379.
ORCID
Mohd Nazam Ansari https://orcid.org/0000-0001-8580-3002
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How to cite this article: Upadhyay J, Tiwari N, Ansari MN.
Cerebral palsy: Aetiology, pathophysiology and therapeutic
interventions. Clin Exp Pharmacol Physiol. 2020;00:1–11.
https://doi.org/10.1111/1440-1681.13379