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DOI: 10.1111/1440-1681.13379
REVIEW ARTICLE
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
Clin Exp Pharmacol Physiol. 2020;47:1891–1901. wileyonlinelibrary.com/journal/cep© 2020 John Wiley & Sons Australia, Ltd 1891 |
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1892 UPADHYAY et al.
disorders which have variable clinical presentations and multiple ae- 2 | A E TI O LO G Y O F C E R E B R A L PA L S Y
tiologies. The pattern of CP is described by several methods. These
methods are performed to characterize children with CP that occurs The aetiological factors associated with CP vary according to the
for a variety of reasons like future status prediction, clinical descrip- gestational age group and clinical classification of CP. The risk fac-
tion, and monitoring changes in body functions. These methods help tors associated with CP are placental abruption, uterine rupture, and
5
in incorporating information from various dimensions. cord prolapse. These are uncommon conditions and collectively ac-
Some research studies have shown that damage to certain parts count for a small proportion of CP. Other risk factors associated with
of the brain causes a consistent pattern of impairment. Such obser- CP are intrauterine exposure to infections, prematurity, congenital
vations lead to the topographical classification of different spastic malformations, maternal fever during delivery, ischaemic stroke,
forms of CP-like quadriplegia, diplegia, or hemiplegia, caused by intrauterine growth retardation (excessive gestational age), and
the pyramidal tract injury (Figure 1). In some cases, certain popula- complications of multiple gestations. Severity in cases of any one
tions of patients are predisposed to a certain type of CP such as the of these factors is sufficient to cause CP. The interaction between
cases of spastic diplegia and premature infants. Ataxia, athetoid and genetic vulnerabilities and environmental pollutants is an emerging
dystonia are an extrapyramidal type of CP that involves the whole aspect in understanding the aetiology of CP.6 Eastman and DeLeon
body. Mixed types of CP including both extrapyramidal features reported the causative factors in CP in their first controlled stud-
and spastic (pyramidal) CP are present in many children. Several ies.7 Their findings determine the causative factors in CP as shown
factors and methods of ascertainment determine the variation in in Table 2.
the frequency of CP. The Lifestyle Assessment Score is included These observations by Eastman and DeLeon clearly defined that
in population-based study so that children with developmental birth asphyxia and birth injury accounts for only for a small per-
impairment are included. Gross Motor Function Classification centage of CP. Also, they identified the non-asphyxial aetiological
System level I determines the type of CP from mild to severe in factors of CP. Clinical studies, neuroimaging, and population-based
children. Some population-based studies have missed this system controlled studies provide the best estimates of the CP caused by
of classification of CP. The CP of postnatal aetiology, genetic or each aetiologic factor.6,7 Table 3 represents the percentage of CP in
malformation syndrome is also excluded in some studies. Thus, it is population-based studies in term and near term infants attributed to
difficult to compare the study results directly. 5 Table 1 represents causative agents involved in CP.8-11
the Gross Motor Function Classification System (GMFCS) of CP for Identification of known aetiological factors is essential because
children aged 6–12 years. by knowing these causative agents we can prevent the chances of
CP in children. Some other risk factors associated with CP are given and posterior occiput.12-14 Meningomyelocele is the most common
below. 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
2.1 | Congenital aetiologies varies and causes disability and involves a severe quadriplegic pat-
tern, especially spasticity and mental retardation.15 Meckel's syn-
Multiple congenital developmental deformities in infants lead to drome includes encephalocele with microcephaly, polydactyly, and
CP. These developmental defects occur during normal growth and renal dysplasia and occurs due to chromosomal defect on the 17th
development and follow the pattern that impairs normal function. chromosome in the homeobox gene (HOXB6). This suggested the
Neural tube closure defect during fetal development is the deform- involvement of genes in causing these deformities. Children having
ity recognized early that leads to motor defects in infants. Neural encephalocele have significant motor impairment involving quadri-
tube defect in the brain called encephalocele affects midface, nose plegic pattern with more hypertonia and hypotonia.16 Microcephaly
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1894 UPADHYAY et al.
is the proliferative defect of the brain caused by infections and leukomalacia have a greater risk of CP development.19,20 In general,
toxins. Enlargement of the brain is called megalencephaly whereas premature infants who have severe bleeding are at higher risk of CP
macrocephaly is a condition in which the head is too large. Cellular development. Hypoxic–ischaemic encephalopathy (HIE) is the con-
hyper-proliferation causes megalencephaly and microcephaly is dition when hypoxia occurs during delivery. Its causes vary from
caused by hydrocephalus. During brain development neurons mi- dystocia to anoxia and fewer flow states in the neonates. A severe
grate towards the periphery and any impairment in the migration form of HIE is cyst formation subcortically and is called multicys-
pattern causes lissencephaly in which there is decreased cerebral tic encephalomalacia. Children with this condition develop a severe
gyri. This condition involves a quadriplegic pattern. Polymicrogyria is quadriplegic pattern of CP with mental retardation. Development
the opposite of lissencephaly in which too many small gyri are found. of cysts in the thalamus and basal ganglia of these children causes
Impaired synaptic formation and remodelling has been involved in dystonia.12
Down syndrome, autism, Rett syndrome, and fragile X syndrome,
ataxia, mental retardation, and idiopathic spasticity, as the major
neurologic pathology.12 2.3 | Postnatal aetiologies
causes CP of severe malformations called lissencephaly. 24 Drugs like of one twin occurs, there is a vascular collapse in the surviving twin
valproic acid taken by mothers during pregnancy interfere with brain and embolism originates from the dead twin circulation and results
energy, carbohydrate, and lipid metabolism. It permanently impairs in secondary CP or porencephaly or encephalomalacia. 29
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 2.3.3 | Vascular diseases during pregnancy
syndrome is significantly associated with high incidences of develop-
mental delay and CP. 26 Figure 2 represents the aetiological factors of Several epidemiological studies demonstrate that preeclampsia and
CP between gestation period 20 weeks and neonatal period. intrauterine growth restriction factors have been associated with
neonatal encephalopathy and CP in full-term newborns.30
2.3.1 | Genetic factors
2.3.4 | Preterm and post-term birth and sex
Hemminki et al. observed CP risk in some families in the National
Swedish Database. 27 The aetiology of secondary CP and perinatal When a fetus gets separated from its natural environment before
strokes includes genetic factors. 28 The risk of CP is also associated the completion of the gestation period, it alters normal growth and
with genetic polymorphism of genes encoding proteins of vascular development of the brain of the fetus. 31 Animal studies demon-
6
endothelium, inflammation or coagulation of the placenta. 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-
2.3.2 | Multiple gestations ment of the fetus. 32 In the case of post-term birth, the placental
involution begins during post maturity making the brain more sen-
A high rate of preterm births and death of co-twin are the risk fac- sitive to damage. 30 Recent studies indicate that sex may influence
tors associated with CP. In case of monozygotic twins, if the death the pathogenesis of brain injuries development. CP is much more
F I G U R E 2 Aetiological factors of cerebral palsy between gestation period weeks and neonatal period
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1896 UPADHYAY et al.
TA B L E 5 Pathophysiology of unilateral
S. No. Impairment Description
spastic cerebral palsy (upper extremity
function) 1 Movement Damage to the corticospinal tract (CST) and other motor
execution 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
2 Sensory motor 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
3 Motor planning 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.
4 Bimanual Impairment in the bimanual coordination occurs in children
coordination with unilateral spastic CP beyond the unimanual dexterity
deficits. 54,55 The children show reduced ability to coordinate
their bimanual movements.
adenosine and glutamatergic receptors involved in inflammatory 3.2.3 | The neural basis of unilateral spastic
responses. 40,41
cerebral palsy
Neuronal injury of primary cortical and basal ganglia oc-
curs in full-term newborns by similar mechanisms. In full-term During human fetal development, the corticospinal tract (CST)
neonates, the diffuse hypoxic–ischaemic conditions cause fail- motor pathways from motor areas especially the motor cortex de-
+ +
ure of cellular energy which in turn induces failure of Na /K velop in a corticofugal manner and reaches the spinal cord by the
ATPase pump, which leads to neuronal depolarization and causes twentieth week of gestation.43 They undergo synaptogenesis at
+ 2+
an influx of Na and Ca water into cells. Cell oedema occurs the spinal-segmental level with the target cells. Bilateral projec-
which leads to cell death, necrosis, and apoptosis. 42 Glutamate tions are developed initially by the motor cortices to both ipsilat-
the main excitatory neurotransmitter located at the presynaptic eral and contralateral upper extremities. Continued development
terminal, postsynaptic membranes, and synapses in the brain. identified by the gradual weakening of the projection i.e. ipsi-
The reuptake of glutamate (energy-dependent process) fails and lateral and contralateral projections gets strengthened through
results in excitotoxicity. Calcium-mediated excitotoxicity is me- synaptic competition driven by the motor cortex activity.44 This
diated by NMDA glutamate receptor in hypoxic–ischaemic brain intricate process is much more susceptible to perinatal and pre-
injury in neonates caused by neuronal nitric oxide synthase ac- natal damage of the brain. The upper extremity movement is con-
tivation. Glutamate mediated excitotoxicity occurs in males trolled by the corticospinal tract (CST) which directly innervates
causing poly (ADP-ribose) polymerase-I, PARP-1 activation and motor neurons. Any impairment in this system can permanently
apoptosis-inducing factor AIF transfer into the nucleus trigger- damage manual dexterity.45 Unilateral spastic CP is caused by an
ing apoptosis whereas in females oxidative stress causes cyto- infarct in the middle cerebral artery, hemi-brain atrophy, brain
chrome-c release from the mitochondria and activates caspase 3 malformations, and periventricular lesions.46,47 Table 5 represents
to produce apoptosis. 33 the pathophysiology of unilateral spastic CP.
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1898 UPADHYAY et al.
4 | TH E R A PEU TI C I NTE RV E NTI O N S posture, and psychosocial parameters. Therefore, changes the over-
all quality of patient.59
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- 4.1.5 | Constraint-induced movement therapy
apy, neurodevelopment treatment, hippotherapy, etc.) and recent or (CIMT)
current approaches (including electrical stimulation technique). The
most commonly used therapeutic interventions are occupational Constraint-induced movement therapy is a physical upper extremity
therapy and traditional physiotherapy and have been shown to ben- rehabilitation approach to improve daily activities.60 This technique
efit in the treatment of CP. The preferred techniques used in the CP is mainly used in children with unilateral CP (unilateral early brain
treatment are as follows. lesions), resulting in weakness, and sensory impairments resulting in
the severity of hand impairments.61,62
4.1 | Conventional approach
4.1.6 | Hyperbaric oxygen therapy (HBO)
4.1.1 | Traditional physiotherapy and
occupational therapy 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
Physiotherapy improves muscle strength, local muscular endurance, Previous studies reported lack data available to cure CP in children.56
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- 4.1.7 | Acupuncture
ing and enhance initiating attention and information processing. 56
This therapy is simple, inexpensive, and safe as compared to other
techniques. Previous studies reported it improves motor activity, sen-
4.1.2 | Neurodevelopmental treatment (NDT) sation, speech, and other neurological functions in children with CP.64
electrical nerve stimulation (TENS) unit which is non-invasive, port- and toxic agents i.e. both prenatal factors as well as postnatal fac-
able, and can be used in home settings by the patient. Non-muscular tors. In this paper, we discuss the aetiology and pathophysiology of
electrical stimulation (NMES) involves transcutaneous electrical CP as it helps in understanding and preventing the disease. Early
current resulting in muscle contraction. Muscle strength has been recognition of CP is required as if the treatment is started later the
increased by increasing the cross-sectional area of the muscle and spastic conditions become stronger, and only limited results can be
69
increases the recruitment of muscle fibres (type 2). Functional achieved. We need to know more about the series of events occur-
electrical stimulation (FES) applies electrical stimulation during a ring during brain development and the factors which are responsible
given task when a specific muscle is contracting.69,70 Another trans- for causing brain injury and impairment of developmental processes.
cutaneous application of threshold electrical stimulation (TES) pro- Currently, there is no effective cure available for CP. Treatment op-
vided at low intensity does not elicit actual muscle contraction. It tions like medications, surgery, counselling, and support are avail-
acts by increasing muscle blood flow and bulk.69,71 able. A better understanding of aetiology and pathophysiology helps
researchers in preventing and treating CP among children.
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