Chun-yu TIAN, Li-ge LENG, Zeng-min TIAN

Department of Neurosurgery, General Hospital of Navy, Beijing 100048, China

Introduction

Cerebral palsy (CP) is a chronic childhood disability with no effective cure, resulting in a significant personal, social, and economical burden. CP was first described in 1862 by William John Little, an orthopedic surgeon, who noted that newborns undergoing asphyxia or mechanical injury before or during childbirth developed rigidity and distortion of limbs later in life [1]. Initially, CP was considered solely to be a movement disorder associated with white matter injury, mainly because the characteristic signs observed in these patients are abnormalities in movement and coordination that include spasticity,rigidity, ataxia, and muscle weakness [2]. However,subsequent studies have shown that apart from white matter injury, grey matter abnormalities in the cortex and subcortical structures contribute to developmental delays, cognitive disturbances,and psychomotor abnormalities in these patients[3,4]. To include these symptoms, CP is now more comprehensively defined as a “group of permanent disorders of the development of movement and posture, causing activity limitation that is attributed to nonprogressive disturbances that occurred in the developing fetus or the infant brain”. These are often accompanied by disturbances of sensation,perception, cognition, communication and behavior[5,6]. In this paper we defined (1) criteria of cerebral palsy; (2) classification of cerebral palsy; (3) etiology,neuroimaging, and epidemiology of cerebral palsy;(4) Different kinds of treatments of cerebral palsy.We summarized the latest literatures in two databases mentioned above, in combination with our own clinical experience and cases.

Data searching strategy and selection criteria

Data were drawn from an international survey of the literature inPUBMED (1994～2014) and CNKI(1994～2014), using the following keywords: ‘‘cerebral palsy’’[Title] and “treatment” ’[Title], or‘‘cerebral palsy’’[Title] and “therapy” ’[Title]. Criteria for including studies of cerebral palsy are that, the method of treatment are discussed and elaborated,and published in a regular scientific article in recent 10 years (exclusion of sole abstracts).

Data extraction and quality assessment

An expert panel used a consensus building technique.Two reviewers independently screened the articles identified in the literature search. そe10-point Jadad scale was used to assess the quality of the trials based on the following items, including allocation sequence generation, randomization concealment, methods of blinding, and descriptions of withdrawals and dropouts.

Data analysis

Our clinical experience is also summarized. We summarized the latest literatures in two databases mentioned above, in combination with our own clinical experience and cases. So we could sum up the clinical patterns of disease in all directions.

Epidemiology

Three hundreds of eighty-five studies met all selection criteria and were identified. The Jadad score was 3～4. そrough reading literatures, we try to elaborate various aspects of this disease. In etiology part, we also give the results in our hospital for reference.

Cerebral palsy is the most common cause of childhood disability. The worldwide prevalence of is 1.5～4.0 per 1 000 live births, with an average lifetime cost of 1 million dollars per person in the United States, while it is 1.8～6.0 per 1 000 live births in China. As the development of perinatal period technology and neonatal intensive care and treatment technology, the survival rate of low birth weight newborn was obviously improved, leading an upward trend in the incidence of cerebral palsy. A study in Danish Cerebral Palsy registration center showed the number of cerebral palsy in premature infant was significantly lower than before, while a slightly higher number in mature infant; the monoplegia incidence with cerebral palsy was significantly elevated, and the diplegia incidence was significantly reduced. そe incidence of cerebral palsy has no obvious change,with a male/female ratio of 1.4:1 [7]. The incidence of CP is strongly associated with gestational age, and prematurity is considered to be a leading risk factor for the development of CP. Even though technological advancements in neonatal intensive care units have resulted in improved survival of premature and very low birth weight infants, the incidence of CP has not decreased [8-10]. Whereas 5%～10% of premature infants develop motor disability, a much larger proportion (40%～50%) develop some form of cognitive and/or behavioral abnormality[11,12].

Etiology

The causes of cerebral palsy are varied, that can be divided into three phases: before delivery, delivery,and after delivery. The causes of cerebral palsy can mainly be divided into six reasons. (1)Preterm birth and low weight. As the gestational age decreases,the incidence of cerebral palsy gradually rises. At 32 weeks, the incidence of cerebral palsy is 4%,while that is 20% at 27 weeks. (2) Hypoxic-ischemic Encephalopathy of newborn (HIE). (3) Intrauterine infection. 5%～10% of total patients with cerebral palsy are caused by intrauterine infection. (4)Hyperbilirubinemia. (5) Twins or multiplets. (6)Genetic metabolic factors. Besides, there are the other possible factors includ hypotension, hypoglycaemia,acidosis, vascular accidents, perinatal seizures,electrolyte disturbance, nutritional deficiencies and other metabolic abnormalities.

There were 472 patients with cerebral palsy treated in Navy General Hospital (Beijing) during 2004～2010. The ages ranged from 3 months to 16 years. The male/female ratio is 2.1:1. The causes of cerebral palsy were as following table 1. Hypoxic Encephalophathy, Preterm birth (low weight) and Hyperbilirubinemia are first three reasons for cerebral palsy.

Tab. 1 The causes of cerebral palsy in our group.

Pathology

Several risk factors, such as very low birth weight,prematurity, intraventricular hemorrhage, multiple pregnancy, chorioamnionitis, hypoxia, neonatal encephalopathy, fetal infections, and genetic factors, have been found to be strongly associated with CP [13-15]. The primary pathophysiological mechanisms that result in CP can be broadly classified as: (1) hypoxia and ischemia that leads to a cascade of excito-oxidative events in the brain;(2) intrauterine infections/inflammation resulting in a fetal inflammatory response syndrome and neuroinflammation; (3) genetic or other congenital causes. These mechanisms may often work in combination. Although CP can have multiple etiologies, neuroinflammation and periventricular leukomalacia (PVL) are common pathological substrates. Inflammation in the central nervous system (CNS) is mediated by immune cells in the brain that include microglia and infiltrating macrophages. Activated microglia and astrocytes are implicated in the development of a number of neurodegenerative disorders both in children and adults. Periventricular leukomalacia, the pathophysiological substrate associated with CP in humans, is characterized by focal necrosis around the ventricles, and diあuse microglial, astrocyte activation in the immature white matter [16,17].

However, there is at present no cure for perinatal and neonatal brain injury and CP. Neuroprotective strategies such as therapeutic hypothermia, which is currently considered to be the most promising approach to improved outcomes, results in only an 11% decrease in risk of death or severe disability.Patient management is primarily confined to methods of rehabilitation for alleviating symptoms and improving quality of life. Despite these advances,decreasing the incidence of CP will not be possible until new treatments for the disorder can be discovered.

The neonatal hypoxic-ischaemic encephalopathy is sometimes associated with haemorrhagic lesions in the neostriatum, globus pallidus and thalamus. Cerebral palsy can be subclassified in several ways. Divisions based on neuropathology are unsatisfactory. The satisfactory clinical subclassification is based on clinical features.Subependymal haemorrhage, infarction and intraventricular haemorrhage are common in premature infants. Some cases of early onset athetotic hemiplegia are due to congenital malformation rather than trauma, hypoxia or ischaemia.

Many neuropathological changes are found in cerebral palsy. The obviously abnormality in dyskinetic cerebral palsy is the status marmoratus or marbelling, aあecting the neostriatum, particularly the putamen. そis is due to irregularly arranged bundles of myelinated fibres with gliosis and cyst formation.Thalamic neuronal loss is secondary to nerostriatal degeneration. There are lack of myelin, loss of axons and degeneration of pallidal and subthalamic neurons.

Clinical features

そe incidence of cerebral palsy is dependent on the condition of obstetric, perinatal and infant care.In developed countries the incidence is 1～3‰ and towards less in recent years. Most studies draw no difference in prevalence between the sexes, but our date noted cerebral palsy was twice as common in males.

The perinatal and infantile disorder does not usually caus permanent brain damage. There may be a neonatal encephalopathy with diminished conscious levels, alteration in tone and seizures.In the initial stages many signs of cerebral palsy are similar. Early signs tend to be non-specific and include irritability or feeding diきculties. そe latter is due to repetitive jaw opening and tongue protrusion.Primitive reflexes persist with overactive startle response.

Abnormal posture is often the first indication to the parents of abnormality. Delayed or impaired head control, sitting, crawling, standing and walking are typical. There is usually associated with diminished eye contact, smiling, comprehension and talking.Hearing diきculties may compound these problems.In the older child abnormalities are more obvious.Dystonic movements may involve the head, limbs and trunk.

Particular attention should be paid to family history. It is important not to miss dopa-responsive dystonia, which sometimes simulate cerebral palsy.Tests may include routine haematology, automated biochemistry, studies of brain imaging, amino acid screening of blood and urine. Inborn errors of metabolism require specialized enzyme analysis or genetic testing, which will depend on the disorder under suspicion.

Keep in mind the possibility of cervical disk disease compromising the cervical cord with dystonic cerebral palsy with severe jerky torticollis.These patients may improve with effective surgical intervention. If gait develops, it is ofen delayed and unsteady. Two thirds of patients over 10 years are still unable to walk, stand or even sit without support.

Gross motor function assessment

Pediatric CNS are still in development stage. Clinical manifestations lack of specificity and show a variety of performance, that can be divided into four parts.(1) Central motor dysfunction and development retardation: gross motor development retardation,fine motor development retardation, lower locomotor activity. (2) Postural dysfunction. (3) Low strength and dystonia. (4) Pathological reflexes. Gross motor function evaluation is the most important project in CP assessment. Gross motor function measure(GMFM), Peabody developmental motor scalegross motor (PDMS-GM) and Neuropsychology developmental scale for children aged 0～6 years old are the mainly 3 measures. Among them, GMFM is the most common used.

Neuroimaging

Most neuroimagings of CP patients were abnormal,and only a few of them were normal. Abnormalities include periventricular white matter abnormalities,deep grey matter abnormalities, malformations, and miscellaneous lesions. Application of MRI brain scan in the first weeks of life has provided useful information. Most children (80%) with cerebral palsy have abnormal neuroradiological findings. 20% other cases have no abnormality detectable by conventional MR or CT imaging. White matter damage is the most common abnormality. Combined gray and white matter abnormalities are more common among children with hemiplegia; isolated white matter abnormalities are more common with bilateral spasticity and ataxia; isolated grey matter damage is the least common finding. Neuroimaging findings could not relate to the presence of birth asphyxia,sex, epilepsy, gestation, type of CP, or microcephaly.

Clinical eきcacy of diあerent treatments

Rehabilitation

High-quality health care for children with CP depends on collaborations among parents, health care provider and community agencies with ongoing monitoring of the child’s health and function.Rehabilitation interventions include speech and language therapy to improve verbal communication,physical therapy for passive stretching of spastic muscles, and sensorimotor integration therapy to promote function. In addition, therapeutic interventions change over time.

Drugs

そe American Academy of Neurology has published guidelines on the pharmacologic treatment of spasticity in children and adolescents with cerebral palsy. Treatments recommended include injections of botulinum toxin into spastic muscles, as well as intrathecal baclofen[17]. Systemic medications,including diazepam, baclofen, tizanidine and dantrolene have been used to diminish spasticity in children with cerebral palsy, although they might cause weakness or excessive sedation. Moreover, few studies have documented functional gains in children who have been treated with systemic medications.Similarly, trihexyphenidyl (Artane) has been used in children with dystonia, but there is no convincing evidence of its effectiveness. Interventions to reduce spasticity and promote function in children with cerebral palsy are usually recommended in a sequence from least to most invasive.

Surgical therapy

Unilateral thalamotomy may relieve involuntary movements in contralateral athetotic hemiplegia.The risks and benefits of the operation should be considered carefully before this procedure.

The internal segment of the globus pallidus is another target for lesioning or deep brain stimulation. Bilateral pallidotomy can produce marked improvement for dystonic cerebral palsy[15].

Cerebellar stimulation shows improvement by one or two out of five grades in spasticity. Addition benefits include improved alertness, behaviour,memory and cognitive functions.

Electrical stimulation of the cervical spinal cord between C2 and C4 segaments via an epidural electrode is eあective in relieving dystonia.

Stem cell transplantation

Experimental clinical and animal studies have begun to elucidate the utility of stem cell-based therapies to prevent or repair perinatal brain injury.Predominantly, these cells have been derived either from neuronal embryonic or adult tissue (neural stem cells), or from non-neural origin such as those isolated from bone marrow and umbilical cord. Neural stem cells are self-renewing and give rise to neurons, astrocytes, and oligodendrocytes.Experimentally, these cells appeared to hold great promise for neural repair after injury, including in perinatal hypoxic ischemic brain injury, however,the therapeutic benefits of transplantation of neural stem cells have not been convincingly shown[18].Neural stem cells are difficult to harvest, lack homogeneity, and are found in very low numbers in the central nervous system [2]. Stem cell therapies oあer promising treatment potential, with the exciting prospect that stem cells may be able to act via a variety of diverse actions at diあerent phases of brain injury progression[19-21]. However, in addition to considering their eきcacy, it is important to reflect on ethical concerns, accessibility, and abundance of stem cells for clinical applications [22-24].

Nanoparticles

Despite the advances in CNS therapies and increasing understanding of disease origin and progression, treatment of CNS diseases remains a significant challenge. There is a paucity of studies exhibiting evidence of a critical correlation between early detection, prognosis, and treatment success. Nanotechnology-based approaches are providing potential platforms for CNS therapy. The physicochemical properties of the nanoparticles can be tailored to overcome the BBB and to improve penetration and diffusion through the brain parenchyma, allowing for controlled, sustained release of a therapeutic medicine[25,26]. These approaches have shown significant promise in preclinical studies for the treatment of many CNS diseases, including cancer, neuroinflammation,and neurodegeneration. Among the different nanoparticle platforms, dendrimers show significant promise as drug delivery vehicles due to their small size, tailorable end groups, and favorable biosafety profile.

The conditions of cerebral palsy are complex, so are the treatments. そe specific therapy schemes are varied from person to person. Treatment process is long, and often needs the combination of various methods. Drugs, surgery and rehabilitation treatment can hardly cure cerebral palsy but can only relieve the symptoms and improve quality of life of the patients.The latter two treatment methods, to some extent,raise a new hope to cure this disease.

In this review, the current advances in different kind of treatments of brain injury are discussed with specific relevance to cerebral palsy. Cerebral palsy has its unique clinical characteristics, which is complex and difficult to cure. The most suitable treatment needs to follow different situation in the patients.Sometimes the combination of various treatments is needed. However there are still some therapies in prospect.

Acknowledgements

そis study was supported by Special Financial Grant from the China Postdoctoral Science Foundation(2012750866).

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