Oxidative Medicine and Cellular Longevity Volume 2022, Article ID 2622310, 20 pages https://doi.org/10.1155/2022/2622310 Review Article A Review on Recent Advances of Cerebral Palsy Sudip Paul,1 Anjuman Nahar,1 Mrinalini Bhagawati,1 and Ajaya Jang Kunwar 2,3 1 Department of Biomedical Engineering, North-Eastern Hill University, Shillong 793022, India Department of Anatomy, Nepalese Army Institute of Health Sciences, College of Medicine, Kathmandu, Nepal 3 Kathmandu Center for Genomics and Research Laboratory, Kathmandu, Nepal 2 Correspondence should be addressed to Ajaya Jang Kunwar; ajayakunwar@gmail.com Received 19 May 2022; Revised 27 June 2022; Accepted 2 July 2022; Published 30 July 2022 Academic Editor: Gaurav Kumar Copyright © 2022 Sudip Paul et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This narrative review summarizes the latest advances in cerebral palsy and identifies where more research is required. Several studies on cerebral palsy were analyzed to generate a general idea of the prevalence of, risk factors associated with, and classification of cerebral palsy (CP). Different classification systems used for the classification of CP on a functional basis were also analyzed. Diagnosis systems used along with the prevention techniques were discussed. State-of-the-art treatment strategies for CP were also analyzed. Statistical distribution was performed based on the selected studies. Prevalence was found to be 2-3/1000 lives; the factors that can be correlated are gestational age and birth weight. The risk factors identified were preconception, prenatal, perinatal, and postnatal categories. According to the evidence, CP is classified into spastic (80%), dyskinetic (15%), and ataxic (5%) forms. Diagnosis approaches were based on clinical investigation and neurological examinations that include magnetic resonance imaging (MRI), biomarkers, and cranial ultrasound. The treatment procedures found were medical and surgical interventions, physiotherapy, occupational therapy, umbilical milking, nanomedicine, and stem cell therapy. Technological advancements in CP were also discussed. CP is the most common neuromotor disability with a prevalence of 2-3/1000 lives. The highest contributing risk factor is prematurity and being underweight. Several preventions and diagnostic techniques like MRI and ultrasound were being used. Treatment like cord blood treatment nanomedicine and stem cell therapy needs to be investigated further in the future to apply in clinical practice. Future studies are indicated in the context of technological advancements among cerebral palsy children. 1. Introduction Cerebral palsy is the most common disability of childhood that affects motor function as a result of injury to the developing brain [1]. It is also known as Little’s disease as the term was first described by William John Little in the year 1843 in which he mentioned spasticity occurs due to damage to the brain during infancy, preterm birth, or birth asphyxia. This was followed by extensive contributions of Osler, Sach, and Peterson, Sigmund Frued, Mac Keith and Polani, and many others until 2006 when an expert executive panel defined CP as a group of permanent disorders of the development of movement and posture, causing activity limitation, which is attributed to nonprogressive disturbances occurring in the developing fetal or infant brain. CP symptoms are heterogeneous, a child having limited brain injury may find difficulty in just one component of the musculoskeletal system, and another child with a broad range of symptoms may suffer from activities that hamper the activities of daily living of the child along with other lifethreatening comorbidities; however, its symptom may improve in due course of time owing to the maturity of the nervous system with age. Damage to the developing brain before, during, or just after delivery affects both neurological and musculoskeletal systems of the body producing symptoms such as abnormal contraction of muscles, postural changes, and movement and activity limitation which are accompanied by sensory disturbances along with perceptual disorders, cognitive issues, inability to communicate, behavioral issues, epilepsy, and secondary musculoskeletal problems. Previously, it was thought that lack of oxygen at birth is responsible for cerebral palsy; however, with emergent
causes and risk factors responsible for the development of cerebral palsy. It is now believed that CP results from a series of events that combines to cause injury to the brain during the developmental period [2, 3]. The epidemiology of CP has changed over time. It occurs in 2-3 in every 1000 live births; however, it is relatively stable over decades [1]. The prevalence of CP was found to be in increasing trend in studies done before 1990 as there was better survival of preterm infants due to advances in medical technology; however, the prevalence decreased subsequently as there was an improvement in prenatal care too after that. The prevalence has remained the same from 1990 to 2003 and was found to be between 2.2 and 2.3; however, it has decreased now [2, 4]. According to another study, the prevalence of CP has decreased from 2.1 to 1.4 in Australian children since 1995; apart from these, various studies show that due to the financial burden of the developing countries, children cannot get the best service for prevention and management of CP which has led to its increased severity; these population trends indicate that changes in preventive and management studies are successful; however, more research is required in these areas. Increasing evidence of various low-cost novel treatment techniques that can be made easily available to the population promises to deliver better outcomes [5, 6]. The incidence of CP is found to be stable in worldwide epidemiological studies, but the management of premature birth complications is still a contributory factor in increasing the incidence of this disease [7]. In the last decade, various prevention and management strategies have been identified in the literature that helped in decreasing the occurrence of this disease. Prescribing magnesium sulfate, progesterone, and corticosteroids to pregnant women for their neuroprotective nature and application of therapeutic hypothermia are some of the evident methods of preventing prematurity which is a major causative factor of CP [5, 6]. This review is aimed at summarizing the strategies that will improve the status of children with CP. The review will begin by compiling research done on the risk factors and etiologies of CP in the last 5 years including efforts to standardize diagnostic criteria along with classification and clinical features of CP. The prevention and management strategies will then be focused on in detail. 2. Methodology The study is aimed at throwing light on recent developments in cerebral palsy and showing new paths for future research in this field. For this purpose, various types of published articles including original research, review articles, and systematic reviews that we consider relevant to our study were selected. A search in Medline via PubMed, Google Scholar, and manually extracted relevant publications by cross-referencing was done to find publications made in the English language. Search terms included cerebral palsy or early brain lesion or perinatal stroke along with management and prevention techniques. We focused on publications of the last five years, i.e., 2017 to 2021, to provide an updated overview. Oxidative Medicine and Cellular Longevity 3. Results 3.1. Risk Factors for and Etiology of Cerebral Palsy. It is now well known that the prime risk factors for CP are delivery before 37 weeks and birth weight of less than 2.5 kg; however, there are some other problems evident in the literature which are found to be some of the prominent reasons for brain damage, some of which includes malformation of the brain in the developmental period, genetic causes, in utero mother and fetus infections, and various other issues [8]. Factors that may put the developing brain prone to injury were divided into risk factors that develop during preconception, during pregnancy, and after birth [2]. A study confirmed that the health of the mother before conception is one of the reasons that affect the central nervous system of the fetus later during the gestational period which might lead to CP. According to this study, preconception is defined as the health conditions of the mother before conception, prenatal is defined as the period of gestation, perinatal is during delivery, and postnatal is after delivery [2]. A study in 2021 also found that the risk factors for cerebral palsy were 21%, 30.5%, 17.1%, and 31.4% when grouped under prenatal, perinatal, postnatal, and unidentified categories [9]. Preconception risk factors include the mother’s systemic illness, substance abuse, maternal undernutrition, swallowing harmful substances, fertility issues, and previous spontaneous termination of pregnancy [7]. Factors that may lead to brain damage during gestation include maternal abnormalities of the central nervous system, gestational diabetes, excessive bleeding per vagina, and preeclampsia. Multiple gestations, cotwin death, genetic contributions, and encephalopathy of prematurity are also strong risk factors for CP [7]. Risk factors during delivery are premature birth, C-section, vacuum-assisted delivery, forceps delivery, delivery after the due date, labor induction, prolonged labor, asphyxia, and meconium aspiration syndrome [10]. Various other risk factors before, during, and after delivery that may lead to brain damage are summed up in Table 1 and Figure 1. Multiple etiologies are responsible for various developmental defects in the fetal brain that results in brain injury which affects the physical functioning of the body [11]. Nearly 75% of CP occurs due to prenatal etiologies whereas 92% of causes are perinatal [2, 12]. It is now well known that CP results from various reasons during pregnancy or during delivery, but in various studies, it is found that it occurs due to brain injury in the postneonatal period also [8, 12]. Postnatal CP is defined as any trauma or disease in the brain after a neonatal period and before 5 years of age [13]. Immediately after delivery, CP may occur in 10-18% of cases due to conditions like hypoglycemia, jaundice, and infections [2, 12, 14, 15]. Though preterm is considered an important benchmark in the etiology of CP, term babies are also high in percentage; this might serve as an indication of a genetic basis associated with CP [2]. For term-birth children, pieces of evidence also suggest that sudden genetic mutations in genes may also be responsible for the development of CP without any other probable causes [16]. Placenta abruption, prolapsed cord, birth asphyxia, congenital anomalies, and maternal conditions during labor like high fever are 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2
Table 1: Risk factors for cerebral palsy [2, 7, 10]. Preconception Before birth During birth After birth Systemic illness of the mother Premature birth Premature birth Use of drugs and stimulants Immune system disorders preceding pregnancy Low birth weight C-section Hypoxic ischemic encephalopathy Infection CNS malformation Vacuum-assisted delivery Hyperbilirubinemia Maternal DM Delivery after the due date Cerebrovascular accidents Prolonged labor Intracranial hemorrhage Asphyxia Meconium aspiration Breech vaginal delivery A high fever during delivery CNS infection Respiratory distress syndrome Artificial respiratory support Hypoglycemia neonatal convulsions Traumatic brain injury Near drowning Spontaneous abortions Prolonged rupture of membrane Maternal hemorrhage Multiple gestations Cotwin death Socioeconomic factors Poisoning Infections Impaired fertility Treatment of fertility Genetic factors Encephalopathy of prematurity Congenital malformation Hypoxic ischemic encephalopathy In utero stroke In vitro fertilization Kernicterus Maternal disorder of clotting Meconium aspiration Fetal growth restriction Preeclampsia Genetic factor 3.40% 21% 17.10% 30.50% Antenatal Natal Postnatal Unidentified Figure 1: Risk factors for cerebral palsy [2, 7, 10]. common causative agents that may lead to brain damage in the fetus. Congenital etiologies such as failure of closure of the neural tube, schizencephaly, chromosomal defects, and microcephaly are also some of the causes [8]. In children born in less than 32 weeks, white matter injury in 84.6% of children was evident which was found to increase with decreasing gestational age [13, 16]. Grey matter injury was seen in moderately preterm infants. Bilateral CP was found to be in a higher percentage than unilateral CP with a Meningitis Sepsis Perinatal stroke Neonatal encephalopathy decrease in gestational age [15]. A study in 2019 among 215-year-old children in Nigeria revealed that most cases were due to birth asphyxia, hyperbilirubinemia, and rubella [2]. An SCPE collaborative study in 2021 referred to the common causes of various types of CP as PVL, congenital infections, asphyxia, hyperbilirubinemia, genetic, neonatal stroke, etc. [15]. Various other causes of CP are listed in Table 2 and Figure 2. Apart from this, events that lead to CP are demonstrated in Figure 3. 3.2. Classification of Cerebral Palsy. As injury to the developing brain occurs due to numerous causes and manifests in different clinical presentations and severity, it has been described under various headings based on the type of movement disorder, area of involvement, and level of damage. According to the type of movement disorder, CP is classified as spastic, dyskinetic, and ataxic. Based on the area of presentation, it can be classified into involvement in one side or both sides of the body, i.e., quadriplegic, hemiplegic, diplegic, and monoplegic, diplegic being most common followed by hemiplegic (20–30%) and quadriplegic (10–15%) (Figure 4). In quadriplegic CP, all four limbs are affected. In this condition, the hands are more affected than the legs, and this occurs due to acute hypoxic asphyxia during the perinatal period, excessive cystic degeneration of the brain, and developmental abnormalities such as polymicrogyria and schizencephaly. The condition presents with 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Oxidative Medicine and Cellular Longevity
Table 2: Etiologies of cerebral palsy [2, 8, 11–13, 15]. Prenatal Perinatal Postnatal Obstructed labor Cord prolapses Antepartum hemorrhage Metabolic acidosis Use of assisted reproductive technology Infection and fever during pregnancy Metabolic disorders Intrauterine infection Chorioamnionitis Maternal ingestion of toxins Preeclampsia Maternal trauma in pregnancy Exposure to methylmercury Genetic syndromes Multiple pregnancies IUGR Fetal growth restriction Placenta abruption Failure of closure of the neural tube Schizencephaly Chromosomal defects Microcephaly Hypoglycemia Jaundice Neonatal meningitis Septicemia Malaria Malaria with seizures Malaria with coma Meningitis Intrapartum hypoxia Rubella 10% 75% 92% Prenatal Perinatal Postnatal Figure 2: Causes of cerebral palsy [2, 8, 11–13, 15]. limited voluntary movements of all the extremities, pseudobulbar signs, accidental food entry in the airways, difficulty in swallowing, optic atrophy, seizures, and severe intellectual abnormality. In hemiplegic CP, hand functions are mostly affected. Dorsiflexion and aversion of the foot are severely impaired in the lower limb. Increased spasticity in flexor muscles, sensory abnormalities, seizures, and visual problems are common findings. In diplegic, CP cystic periventricular leukomalacia is the most common neurological feature seen in premature infants. In the case of hemiplegic CP, only one side of the body is affected with a high tone in flexor muscles and sensory loss. Apart from this, hand function is severely impaired when compared to legs. In the foot, dorsiflexion and eversion are affected. Both matured and premature-born children are at risk of hemiplegic CP [14]. Tuberculosis Sickle cell disease HIV PVL Congenital infections Asphyxia Hyperbilirubinemia Genetic causes Neonatal stroke Popularly, CP was classified according to the Ingram and Hagbergs classification; however, surveillance of cerebral palsy in Europe (SCPE) has simplified the classification of CP as spastic, ataxic, and dyskinetic (Table 3) [2]. Ingram classified CP based on location and severity of neurological symptoms. He classified cerebral palsy into diplegic, hemiplegic, tetraplegic, ataxic, dyskinetic, and mixed [21]. Hagberg however classified CP into spasticity, dyskinetic syndromes, and ataxia. The spastic syndrome occurs due to damage to the brain and tracks controlling movement. It can be divided into monoparesis, hemiparesis, triparesis, tetraparesis, and spastic diplegia. Dyskinetic symptoms are seen due to injury to the subcortical structure, and ataxic symptoms are seen due to cerebellar injuries dividing CP into spastic, affecting one or both sides of the body, dyskinetic involving involuntary movements with altered tone or choreoathetosis movements, and ataxic. Around 80% of CP cases are found to be spastic [22]. Spastic CP in this context is characterized by increased muscle tone and increased reflexes. It has been subcategorized into unilateral or bilateral along with the area of involvement. SCPE refers to dyskinetic CP accounting for 10 to 20% of CP cases and presents as having involuntary, uncontrolled, repetitive, and sometimes stereotypical movements with a fluctuating muscle tone. A faulty posture with enhanced muscle tone is defined as dystonic; a quick, uncontrolled, and twisting movement with hypotonia is called choreoathetosis. On the other hand, ataxic CP consists of 5-10% of CP cases and presents with loss of coordination with hypotonia. In some children, damage may occur in different parts of the developing brain which causes them to develop symptoms of having a combination of two or more types of cerebral palsy. This type is called mixed CP which accounts for 15.4 percent 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4
Risk factors Causes Preconception Spastic 70 – 80% Prenatal • 75% Prenatal [21.5%] Dyskinetic Perinatal 6% Ataxic 6% Postnatal • 92% Perinata [30.5%] Postnatal [19.1%] • 10% Cerebral palsy Spastic Dyskinetic Ataxic Figure 3: Events leading to cerebral palsy [2, 8, 11–13, 15]. 15.40% 35% 30% 20% 5% 15% Spastic diaplegia Spastic quadriplegia Dyskinetic Ataxic Hemiplegic Mixed Figure 4: Different types of cerebral palsy [2, 14]. of all cases. The most common presenting symptoms of mixed type are a combination of spastic and athetoid features [13]. Evaluating the severity of motor disorders is important for predicting the functioning of the affected limbs and the outcome of the treatments. For this purpose, four systems are used for functional classification of CP which include GMFCS, MACS, CFCS, and EDACS [2, 11, 12, 23]. GMFCS developed by Palisano et al. in 1997 is used worldwide for the functional classification of CP (Table 4) [2, 11, 12, 23]. It is easy to use and describes gross motor function. It has levels that describe voluntary movement and the use of aid for movement. It was first designed to measure gross movements in children of 2–12 years of age, but in 2007, it was revised and ages 12–18 were included. According to the new revised version of GMFCS, a child is considered to be in GMFCS level 1 if the individual can walk without any aids. However, there are considerations and limitations according to the age of the child. In level 2, the child can do all these activities, but limitations are present in the form of speed, balance, and endurance. The child finds difficulty walking long distances and requires a handheld or wheeled device for long distances. Gross motor skills are minimal. Level 3 children walk with handheld mobility devices in indoor settings, need supervision during stair climbing, and require wheeled devices for long distances. In level 4, the child lacks self-mobility. The child can sit with support, but transportation requires a manual or powered wheelchair. In level 5, children are dependent on all settings and have limitations to maintain antigravity posture. They strictly require wheelchair transportation. Another classification system, namely, the manual ability classification system (MACS), is a five-level scale used for 4–18 years old which was developed by Eliasson et al. in 2006, to evaluate the functions of the upper limb. In level I, the child can handle objects with ease, there are some limitations with accuracy, but that does not hamper activities of daily living. In level II, the child’s activities are slower and of reduced quality. A different way to perform the activity can be used by the child, but it does not affect the daily activities performed by the child. The child in MACS III has reduced speed while performing hand activities and often with limited success. Some activities need help, but others can be done without any help. A child in MACS IV performs various simple activities with lots of effort. They require constant help and adapted types of equipment for performing simple activities. Individuals in MACS V are dependent [24]. A classification system, namely, the communication function classification system (CFCS), is also a five-level scale that is used to evaluate everyday communication. At an individual level, level I can communicate at a comfortable pace. The person can send and receive information from different people in different individuals. In level II, the pace of communication is slow; however, they can communicate properly. In level III, communication is effective only with a familiar partner. In level IV, the person is not always 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Oxidative Medicine and Cellular Longevity
Table 3: SCPE classification of cerebral palsy [2, 13]. Type of CP Spastic Dyskinetic Ataxic Description Presents with hypertonicity and hyperreflexia May be unilateral or bilateral Presents with involuntary, uncontrolled, repetitive, and sometimes stereotype movements with altered muscle tone Abnormal posture with hypertonicity is termed dystonic A quick, uncontrolled, and twisting movement with hypotonia is called choreoathetosis In coordination with a decreased muscle tone Table 4: Functional classification of children with cerebral palsy [2, 11, 12, 23]. Classification type GMFCS MACS CFCS EDACS consistent in communication with known people, whereas in level V, the individual cannot communicate affectively and consistently with unknown people. The eating and drinking ability classification system is again a five-level classification system used to assess how efficiently a CP child eats and drinks. It is used for more than 3-year-old children. It has extra three levels that help to find out how much help is required while performing these activities. In EDACS level I, an individual can eat and drink safely without any help, but hard food can cause difficulty swallowing. In level II, the individual can eat and drink safely but has very less speed. The child may present with a cough when food is given at an increased speed. In level III, the child cannot eat hard food; he/she needs very soft and mashed food. However, an individual in EDACS IV or V cannot swallow food and drink safely. Tube feeding is required to provide nutrition [24]. 3.3. Clinical Presentations of Cerebral Palsy. The presenting signs and symptoms of CP are diverse and mainly consist of motor disorders, sensory deficits, and associated comorbidities which occur due to a static lesion to the developing brain. These signs and symptoms change as the child ages and new features are added to the list. Thus, with advanced age, there is a worsening of the neuromuscular system and functional capability of the child even though the damage in the brain is static [25]. Injury to the fetal brain can be generally diagnosed by its presenting features; however, often, some of these symptoms resolve after 2 years in many infants owing to the maturation of the CNS [12]. A recent study revealed that the most common symptoms seen were using one hand before 2 years of age, inability to reach normal milestones within the appropriate time, and presence of primitive reflexes after a definite period (Table 5) [22]. Some comorbidities are also associated with cerebral palsy which are summarized in Table 6 [11, 17–20] and demonstrated in Figure 5 [11, 17–20]. Hypertonicity of the muscles owing to brain injury is the most common symptom seen in CP Description Evaluates the gross motor function of the individual with CP Evaluates functions of upper limb Evaluates everyday communication Evaluates the ability to eat for children with CP after 3 years patients along with other motor issues such as impaired balance, coordination, hand function, etc. [10]. A recent study found that this may be due to three causes, i.e., more muscle fibers are required to perform a certain task than healthy individuals, excessive level of collagen deposition in myofibers decreases the efficiency of the muscles by making them stiff, and a disturbance in the neuromuscular junction causes a problem in muscle contraction. The study also revealed that collagen accumulation occurs due to damage to CNS in the developing brain, and this causes issues in the motor abilities of the child as mentioned above. However, there is scarce evidence on the prevention and treatment of this finding [25]. Spastic diplegia is the most common type that accounts for 35% of cases and occurs due to damage to the immature oligodendroglia in the second trimester. In 3- to 6-monthold babies, some of the features seen are decreased neck control, stiffness, floppiness, arching of the back, lower extremity stiffness, and leg crossing while raising from the bed, and in babies older than 6 months of age, there is no rolling. Incoordination of the upper extremities is also evident. Babies older than 10 months of age depict abnormal crawling. Periventricular leukomalacia is the most common neurological finding seen in such cases. Another type of spastic CP apart from diplegic is spastic quadriplegia which accounts for 20% of CP children; the most common reason is premature birth. The child has severe motor and sensory problems, cognitive deficit, seizures, vision problems, and other associated problems which make the child completely dependent. Term infants who are at risk of in utero or perinatal stroke suffer from spastic hemiplegia. They have good cognition and can maintain independent mobility. 15% of CP results from extrapyramidal lesions in term babies. They consist of involuntary movements termed choreoathetosis, dystonic, or dyskinetic clinical features. Hemiplegic CP cases are mostly term babies having causes like brain injury due to lack of oxygen, kernicterus, and neurometabolic or genetic disorders [2]. A high mortality rate is seen in CP children due to respiratory problems [26]. 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. 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Table 5: Early signs of cerebral palsy [22]. Early signs of CP Early hand dominance Delayed motor milestones Persistent primitive reflexes Scissored legs below 6 months Floppiness Stiffness Table 6: Comorbidities associated with cerebral palsy [11, 17–20]. Comorbidities present in CP children Pain Intellectual disability Gait disorders Hip displacement Speech problems Epilepsy Incontinence Behavior disorders Sleep disorders Hearing impairment Vision impairment Cognitive impairment Thyroid dysfunction G.I. disturbances 75% 50% 33% 33% 25% 25% 85% 25% 40% 9% 10% 77% 3% 2% 3% 10% 77% 9% 2% 75% 50% 40% 33% 25% 33% 85% 25% 25% Pain Epilepsy Intellectual disability Incontinence Gait disoders Behaviour disorders Hip displacement Sleep disorders Speech problems Hearing impairment Figure 5: Comorbidities associated with cerebral palsy [11, 17–20]. 3.4. Diagnosis. Early diagnosis is necessary as it helps to provide early intervention during the earliest period of development. It is a special service to prevent developmental delay which optimizes the impact of the interventions on the developing brain’s neuroplasticity [4, 27]. Diagnosis of cerebral palsy is based on the combined use of clinical presenta- tions along with physical assessments and neuroimaging, which can provide various implications for this disease. Assessment of maternal history including the child’s performance of motor functions brings out important points of diagnosis. Owing to the complexity of the condition, psychological tests, vision evaluation, audiometric tests, and electroencephalography are carried out [2]. Close monitoring of early signs in the form of neurobehavioral signs, presence of developmental reflexes that did not disappear with time, abnormal tone and posture, and delayed milestones along with associated comorbidities is essential to screen risk infants. The history of early diagnosis started in the 1800s when William Little urged that the earliest diagnosis will lead to early intervention. It is very important to find out the cause of CP and give the required treatment so that the disease process can be minimized along with increased neuroplasticity and functional outcome. In the 1970s, the idea of risk factors, retaining of abnormal primitive reflexes, and the cranial US in neonatal intensive care units were introduced which helped to identify children who were at risk for CP. In high-income countries, diagnosis of CP was previously done after 1 year, but now, it can be done before 6 months [4]. In 2017, a systematic review was published which inferred that certain tools can be used to diagnose highrisk infants for the development of CP as early as 6 months. A list of such tools is given in Table 7. Prechtl’s Qualitative Assessment of General Movements and the Hammersmith Infant Neurological Examination can also be used as predictive tools along with clinical examination in infants below 5 months of age. After 5 months, magnetic resonance imaging, the Hammersmith Infant Neurological Examination, and the Developmental Assessment of Young Children are used to predict CP in extremely low birth weight infants [4]. A combination of two MRI biomarkers fractional anisotropy of superior thalamic radiations and radial diffusivity of the corticospinal tract was used to evaluate the brain’s sensory and motor tracts, respectively [5]. In 2011 a study named “cerebral palsy—don’t delay” summed up the call for early detection and accurate prediction of CP in the earliest months of life by referring to general movement assessment (GMA), first introduced in 1990 which is an assessment of the spontaneous movement of an infant along with another standardized neurological examination called the Hammersmith Infant Neurological Examination (HINE) [4]. In 2019, a paper was published on the topic of international expert recommendations of clinical features to prompt referral for diagnostic assessment of cerebral palsy where a survey was conducted among 51 international experts in Asia, USA, Australia, Canada, and Europe to find out agreement upon early motor signs and diagnosis of CP and their referral to other health professionals under a project called PROMPT (primary care referral of motor impaired children). The international experts provided a strong agreement on six clinical features and two warning signs along with five referral recommendations based on which a child should be immediately referred for diagnosis to other health care professionals or specialized health services [28]. The American Academy of Neurology recommends a stepwise protocol to help diagnose a cerebral palsy child. The first step is the 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Oxidative Medicine and Cellular Longevity
Table 7: Tools for early diagnosis of CP [4, 13]. Below 5 months GMA MRI HINE Prechtl’s Qualitative Assessment of General Movements The Hammersmith Infant Neurological Examination recognition of the disease by clinical history taking and physical examinations followed by screening for associated comorbidities. This is followed by studying perinatal histories such as fetal anatomy surveys and newborn transcranial ultrasounds. If no abnormalities are detected, MRI is recommended for finding out intracranial abnormalities. Further, if the test is nondiagnostic, then screening for inborn errors of metabolism or genetic abnormality is followed [13]. The entire process is described in Figure 6 [13]. Based on some studies done on dead CP children, Little found that there is some venous and capillary congestion in the brain and spinal cord which led him to refer to this disease as a cerebrospinal disorder. However, William Osler was the person who gave the name cerebral palsy to this condition. Though modern definitions of CP are refined to the context of the cerebral cortex, a critical evaluation study on the concept of CP urges that more studies should be done on the original concept of CP as a “cerebrospinal” disorder, both in clinical work and in animal models [29]. 3.5. Prevention. Based on the time of insult to the brain, CP can be divided into individuals whose brain injury occurred during the gestational period, during delivery, and postdelivery. Thus, prevention strategies can depend on the prevention of factors that will decrease the risk of CP in the antenatal, perinatal, and postnatal periods [30]. Prevention strategies include prevention of risk factors, treatments that affect the disease process, and treatment of neonates who are exposed to risk. Various techniques in the literature are present for the prevention of brain injury during the gestational period and delivery. Administration of magnesium sulfate is an important preventive measure for high-risk mothers [28, 31]. There is moderate quality evidence of an increased rate of CP in mothers who used prophylactic antibiotics during pregnancy. Latest reports show that prenatal and perinatal causes of CP have decreased. This has occurred due to various strategies that are used for the early treatment of neonates [30]. The worldwide incidence of birth before 37 weeks is 12% and is one of the main causes of death and illness in neonates. Various studies infer that prophylactic use of progesterone decreases early birth in women with previous birth complications. Universal cervix screening is recommended by midtrimester transvaginal ultrasonography. Management of IUGR, administration of magnesium support, and corticosteroids for fetal lung maturity are equally important strategies [7, 32]. Decreasing the rate of early birth and low weight in neonates is the most significant consideration in reducing the overall incidence Above 5 months Magnetic resonance imaging The Hammersmith Infant Neurological Examination The Developmental Assessment of Young Children of CP. Therapeutic cooling or hypothermia is helpful in cases of brain injury due to a lack of oxygen. It decreases the risk of CP in term and late preterm infants in such cases. It is started within 6 hours after birth which helps to decrease the temperature by 2°C for 48 hours [28, 32, 33]. Prevention of preeclampsia is done by screening and administration of acetylsalicylic acid along with aspirin which should be started before 16 weeks of gestation, with a daily dose higher than 100 mg in high-risk patients. This issue, however, requires further prospective research. Antenatal steroid therapy is evident in newborns in preventing perinatal death of newborns and preventing the risk of disability and development of sepsis in the initial days of birth. Delayed cord clamping is another intervention used in preterm babies that lowers the risk of bleeding, necrotizing enterocolitis, and anemia that requires blood transfusion and late onset of sepsis which has an impact on the neurological development of the baby. Preventive techniques during pregnancy also include corticosteroids for the mother for accelerating lung maturation in the case of early-birth infants. The literature also has evidence of caffeine for apnea of prematurity. Apart from preterm infants, those who are born at the expected time and suffer from a lack of oxygen during delivery have also benefitted from therapeutic hypothermia. Factors that can prevent postnatal CP that are evident from the literature include finding hidden cases of group B streptococcus, administration of antibiotics and vaccines during and after delivery, safe car seating, safety measures in swimming pools, and preventing shaking of the baby [30]. As CP is seen to occur mostly due to prenatal causes (45%), preventing strategies during this period can decrease the overall incidence of CP. To implement this, a recent study in 2018 advised certain interventions to reduce preterm birth: midwife-led continuity models of care, finding and treating urinary tract infections, augmenting zinc supplementation among pregnant women, and cervical cerclage for high-risk mothers [30, 34]. A schematic diagram for the prevention of cerebral palsy is given in Figure 7. 3.6. Management. Cerebral palsy management is aimed at improving functional ability and independency and managing secondary complications. Physical and occupational therapies, mechanical aids, orthopedic surgery to address patients’ motor problems, and optimal medical and surgical treatment of medical comorbidities are the main management strategies [35]. An increase in neonatal care and decreased prevalence showed a promising impact on early diagnosis [4]. Early intervention programs are the most 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8
CP DIAGNOSIS 1. CLINICAL FEATURES 2. HISTORYTAKING 3. PHYSICALEXA MINATION 4. NEUROIMAGING ABNORMALTONE NEUBORN TRANSCRANIAL ULTRASOUND MATERNAL HISTORY ABNORMAL POSTURE NEONATALANDINFANTILE HISTORY PRIMITIVEREFLEXES DEL AYED SENSORY AND MOTOR EXAMINATIONS MRI DIAGNOSTIC CP NONDIAGNOSTIC SCREENING FOR INBORN ERRORS Figure 6: Diagnostic criteria for detecting cerebral palsy [2, 13]. Therapeutic hypohermia Treatment of neonates who are exposed to risk factors Antenatal steroid therapy in RDS Delayed cord champing Prevention of risk factors Prevention of brain damage Prevention of prematuriy Prevention of low birth wegiht Treatments that affects the disease process Early intervention medications physiotherapy occupational therapy speech therapy surgical procedures treatment of associated problems Prevention of preeclampscia Figure 7: Prevention and management of cerebral palsy [28, 30, 31]. essential component of the management of CP as it addresses the disease process at the earliest and helps in early neuroplasticity of the brain [36]. Two trials, namely, GAME (goals, activity, and motor enrichment) and REACH (rehabilitation early for congenital hemiplegia), are under investigation in Australia to establish evidence for early intervention in children with CP [37]. Addressing functions like physical issues, cognition, communication, eating and drinking, vision, and sleep helps in improving the overall health of the child, and cooperation of the family and environment modification are the major factors for improve- ment [38]. Management of CP children requires a team approach which includes a list of multidisciplinary team members such as an audiologist, medical social worker, nurse, nutritionist, occupational therapist, pediatric gastroenterologist, pediatric neurologist, pediatric orthopedic, surgeon, pediatric pulmonologist, pediatric surgeon, pediatrician, physiatrist, physiotherapist, psychologist, speechlanguage therapist, and special educator [10]. Many recent advances in the management of CP have come up including intrathecal baclofen, selective dorsal rhizotomy, and sensory integration [14]. Various medical managements are effective 2572, 2022, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1155/2022/2622310 by Cochrane Greece, Wiley Online Library on [10/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Oxidative Medicine and Cellular Longevity
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