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National Guideline Alliance (UK). Cerebral palsy in under 25s: assessment and management. London: National Institute for Health and Care Excellence (NICE); 2017 Jan. (NICE Guideline, No. 62.)
Review question: What are the most common causes of cerebral palsy in resource-rich countries with a view to informing relevant investigation and change in management?
5.1. Introduction
When parents are given a diagnosis of cerebral palsy for their child, it is natural that they wish to know the cause. Many children, as they grow older, wish to know what caused their problems with walking or talking or eating and drinking; hence, this is an important part of the initial discussions with parents and/or carers.
Overall, the number of children diagnosed with cerebral palsy in resource-rich countries has not significantly decreased in the last 30 years despite the introduction of investigations and interventions that have changed obstetric and neonatal practice. To be able to prevent cerebral palsy, it is essential to first understand the causes.
Understanding the difference between ‘cause’ and ‘risk’ is key. When looking for causation the clinician is working with the child or young person who has cerebral palsy and is looking back. When looking at risk, the clinician is dealing with a child without diagnosis and is recognising potential factors that, looking forward, may lead to cerebral palsy in that child.
When reflecting on a child or young person’s history there are many factors found in the antenatal, perinatal and postnatal stages of children who are diagnosed with cerebral palsy. As such the individual child may have more than 1 factor that ultimately causes the non-progressive impairment of the brain. This lends strength to the concept of there being ‘causal pathways to cerebral palsy’. Various risk factors acting at different times in the development of the fetal and neonatal brain may lead to similar pathologies resulting in brain damage and thereby a diagnosis of cerebral palsy.
There have been causes of cerebral palsy, in resource-rich countries, that have almost been eradicated over the last 20 years. With increasing mobility and population migration, these causes may re-appear within society as well as emergent new disease processes that can lead to cerebral palsy.
The aim of this evidence review was to identify the most common causes for cerebral palsy with the view to providing information for parents and/or carers and when appropriate to inform the need for further investigation and any change in management. The Committee prioritised the following as possible causes of cerebral palsy to be searched for in this review:
- congenital brain malformations
- congenital and acquired infection
- intraventricular haemorrhage
- periventricular leukomalacia (PVL)/ damage of the white matter/ white matter injury
- hypoxic-ischaemic injury (including perinatal and antenatal injury, stroke or focal infarcts)
- neonatal hypoglycaemia
- neonatal encephalopathy
- kernicterus
- postnatal acquired traumatic brain injury.
5.2. Description of clinical evidence
Seven studies have been included in this review that reported on the prevalence of causes of cerebral palsy in resource-rich countries (Bax 2006, Cans 2004, Garne 2007, Ipek 2007, McIntyre 2013, O’Callaghan 2011, Reid 2014).
The sample sizes ranged from 347 to 4,584.
One study included children with cerebral palsy from 8 European study centres (Bax 2006); 1 study looked at cerebral palsy of postnatal origin from the surveillance of cerebral palsy in a European (SCPE) cohort (Cans 2004); 1 study used 11 cerebral palsy registries contributing to the SCPE cohort (Garne 2007); 1 study was a retrospective investigation of hospital cases of cerebral palsy (Ipek 2007); 1 study collected data by linkage to state-based perinatal repositories and cerebral palsy registries, and by using a maternal questionnaire (O’Callaghan 2011); 1 study used the western Australian births register (McIntyre 2013); and finally, 1 study included publications from 1995 to 2012 reporting imaging findings in cerebral palsy population cohorts (Reid 2014).
The following causes of cerebral palsy were covered by the included studies: white matter damage, basal ganglia lesions, focal infarcts, congenital malformations, infections, head injury, encephalopathy and kernicterus.
In the selection process of papers, priority was given to studies that used registry data from a developed country.
The quality of the evidence was appraised by using the methodological tool validated by Munn 2014, which assesses critical issues of internal and external validity that must be considered when addressing the validity of prevalence data. The criteria address the following issues:
- ensuring a representative sample
- ensuring appropriate recruitment
- ensuring an adequate sample size
- ensuring appropriate description and reporting of study subjects and setting
- ensuring data coverage of the identified sample is adequate
- ensuring the condition was measured reliably and objectively
- ensuring appropriate statistical analysis
- ensuring confounding factors, subgroups and/or differences are identified and counted for.
For full details see the review protocol in Appendix D. See also the study selection flow chart in Appendix F, study evidence tables in Appendix J and the exclusion list in Appendix K.
5.2.1. Summary of included studies
A summary of the studies that were included in this review is presented in Table 16.
Table 16
Summary of included studies.
5.2.2. Summary of results
5.2.2.1. White matter damage
Table 17
Prevalence of white matter damage (including PVL).
5.2.2.2. Basal ganglia lesions
Table 18
Prevalence of basal ganglia lesions.
5.2.2.3. Focal infarcts
Table 19
Prevalence of focal infarcts.
5.2.2.4. Congenital malformations
Table 20
Prevalence of cerebral malformations.
5.2.2.5. Infections
Table 21
Prevalence of infections.
5.2.2.6. Head injury
Table 22
Prevalence of head iinjury.
5.2.2.7. Encephalopathy
Table 23
Prevalence of encephalopathy.
5.2.2.8. Kernicterus
Table 24
prevalence of kernicterus.
5.3. Economic evidence
This review question is not relevant for economic analysis because it does not involve a decision between alternative courses of action.
No economic evaluations on the most common causes of cerebral palsy in resource-rich countries with a view to informing relevant investigation and change in management were identified in the literature search conducted for this guideline. Full details of the search and economic article selection flow chart can be found in Appendix E and Appendix F, respectively.
5.4. Evidence statements
5.4.1. White matter damage
High-quality evidence from two studies with 1,784 infants and children with cerebral palsy found that the prevalence of white matter damage (including PVL) ranged between 19.2% and 45.3%. Evidence showed that the prevalence was higher in children born preterm, and varied depending on GMFCS level. Prevalence of white matter damage also varied depending on cerebral palsy subtypes, being higher in children with spastic cerebral palsy.
5.4.2. Basal ganglia lesions
High-quality evidence from 1 study with 585 infants and children with cerebral palsy found that the prevalence of basal ganglia lesions was 12.8%. These damages were mainly associated with dystonic cerebral palsy, which accounted for 75.6% of the basal ganglia group.
5.4.3. Focal infarcts
High-quality evidence from 1 study with 585 infants and children with cerebral palsy found that prevalence of focal infarcts was 7.4%. These infarcts were mainly associated with hemiplegia (unilateral spastic).
5.4.4. Congenital malformations
High-quality evidence from 3 studies with 6,368 infants and children with cerebral palsy found that the prevalence of congenital malformations ranged between 9.1% and 12%. Evidence showed that the prevalence was higher in children born at term compared to those born preterm, and varied depending on GMFCS level (higher prevalence with worse severity). Prevalence of malformations also varied depending on cerebral palsy subtypes, being 15.7% and 14 to 18% in children with spastic quadriplegia (bilateral spastic LL+UL) and ataxia, respectively.
5.4.5. Infections
High- to moderate-quality evidence from 2 studies with 932 infants and children with post-neonatal cerebral palsy (cases with an age of onset above 24 months) found that the prevalence of maternal infections ranged between 39.5% and 39.9%, with UTI and upper respiratory tract infections being the most frequent.
Moderate-quality evidence from 1 study with 587 infants and children with post-neonatal cerebral palsy found that the prevalence of infections in children was 50%, and it varied with the type of cerebral palsy (higher prevalence in spastic cerebral palsy).
5.4.6. Head injuries
Moderate-quality evidence from 1 study with 587 infants and children with post-neonatal cerebral palsy (cases with an age of onset above 24 months) found that the prevalence of head injuries was 12%, and it varied with the type of cerebral palsy (higher prevalence in spastic cerebral palsy).
5.4.7. Encephalopathy
Moderate-quality evidence from 1 study with 494 infants and children with cerebral palsy found that the prevalence of neonatal encephalopathy and hypoxic-ischaemic encephalopathy was 12.4% and 21.2%, respectively. The evidence also showed that both neonatal encephalopathy and hypoxic-ischaemic encephalopathy were more frequent in children with quadriplegia (bilateral spastic LL+UL).
5.4.8. Kernicterus
Low-quality evidence from 1 study with 371 infants and children with cerebral palsy found that the prevalence of kernicterus was 4.6%.
5.5. Evidence to recommendations
5.5.1. Relative value placed on the outcomes considered
The aim of this review was to identify the most common causes for cerebral palsy with the view to providing information for parents and/or carers and to inform the need for further investigation and changes in management.
5.5.2. Consideration of clinical benefits and harms
The Committee agreed that when parents are given a diagnosis of cerebral palsy for their child, it is natural that they wish to know the cause. Causation of the brain impairment is therefore an important part of the initial clinical discussions with parents and carers. A full reflection on causation can also help young people as they become increasingly independent through adolescence, transition and young adulthood.
The Committee in particular recognised the importance of informing parents about antenatal, perinatal and postnatal factors associated with cerebral palsy, and agreed that it is often about a combination of ‘causes’ that leads to the overall diagnosis.
There was a long discussion about the clinical importance of differentiating cause as a reflective practice and consideration of potential risk as a forward thought process.
A recommendation for each possible cause was drafted based on the prevalence of evidence presented. The Committee considered it important to highlight the prevalence for white matter damage, deep grey matter/ basal ganglia damage, congenital malformation and focal infarcts.
The Committee was aware that the prevalence given by the papers was approximate, and therefore decided to supplement the evidence with their clinical knowledge and judgement. Most of the evidence base was from very large registries with loose definitions of potential causation.
For white matter damage, the Committee formulated a recommendation about its distribution in preterm versus term babies, as well as in different motor presentation, i.e. spastic and dyskinetic cerebral palsy types. The Committee agreed that the information had been provided without confidence intervals and therefore should be used as a guide to the frequency rather than as accurate rates. The Committee recognised that, in particular, the ataxic form of cerebral palsy was the most difficult to identify for clinicians, and it was considerably rarer, hence it was a problem to be represented by the data.
When reviewing the evidence on cerebral malformations as possible causes of cerebral palsy, the Committee agreed the evidence showed a link with gestational age and motor distribution types.
The Committee referred to qualitative evidence in the literature, not reviewed within this protocol, which addressed the cumulative impact of pathological factors that in turn leads to causation of cerebral palsy. Based on their experience and knowledge of such additional evidence, they unanimously agreed it was important to develop a consensus recommendation to that effect. Neonatal encephalopathy was specifically noted as a clinical syndrome or endpoint resulting from a number of different pathological pathways. This highlights that it is not in its own right the cause but is often the manifestation. It may be a symptom of brain damage that has already occurred as well as a symptom of ongoing brain damage from causes such as neonatal infection or hypoglycaemia. The initial encephalopathic event can impact on the grade of severity of any hypoxic-ischaemic event to the brain. It is usually more associated with a dyskinetic type of cerebral palsy.
The Committee considered the role of infection in causation of cerebral palsy. They agreed that there are specific viral infections of the fetal brain and infections of the neonate, such as meningitis, that can be direct causes of cerebral palsy. The Committee agreed that the role of maternal infections as risk factors and as a possible cause should also be explored in more detail. The prevalence of mothers of children with cerebral palsy reporting having background infection was not different from the general population, although the place of recurrent urinary tract infection and link to chorioamnioniitis and local inflammatory factors on the fetal environment in particular needs to be looked at carefully. The Committee considered that, without a clarity of evidence base, it was important to stress that maternal infections are commonly observed in every pregnancy and that specific linkage to an outcome of cerebral palsy in the child is limited. There are, however, a number of congenital viral infections that can lead to non-progressive impairment of the developing brain. Based on their clinical knowledge and although not presented by the evidence in the parameters of the review process, the Committee recommended that certain congenital infections have been associated with neurodevelopmental disorders.
The Committee decided not to comment specifically on kernicterus as a possible cause of cerebral palsy. The evidence base presented was limited as it used a hospital-based population, without clear details on how cerebral palsy was diagnosed and on how the causes of cerebral palsy were ascertained. Historically very high levels of neonatal bilirubin are linked in particular to the development of a bilateral dystonic cerebral palsy. However, routine screening for bilirubin levels in neonates and clear agreed pathways of management limits the impact in the wider population. It is, however, important to think about this as a potential cause particularly in migrant populations, where delivery has happened outside the UK. Further guidance on this is seen in other NICE guidelines on intrapartum care and postnatal care up to 8 weeks after birth.
Finally, based on the evidence provided, the Committee drafted a specific evidence-based recommendation on the prevalence of postnatal causes of cerebral palsy, and mentioned specifically meningitis as the most reported among infective cause of non-progressive brain impairment.
In terms of minimising the impact of impairment to the development brain, thereby reducing risk, there are a number of interventions that the Committee is aware of, but they have not been reviewed specifically in this guideline. These include:
- antenatal steroids in threatened preterm delivery
- minimising fluctuation to cerebral blood flow and oxygenation in preterm infants
- minimising use of postnatal steroids
- neuroprotective approaches post neonatal encephalopathy, such as therapeutic hypothermia, xenon inhalation and the use of medicines that prevent secondary neuronal degeneration such as allopurinol
- magnesium sulfate given to mother in preterm labour.
5.5.3. Consideration of economic benefits and harms
Knowing the most common causes of cerebral palsy may lead to better identification (and thus more timely management) and has therefore, indirectly, potentially important resource implications. However, this is an epidemiological review question and economic analysis is not applicable.
5.5.4. Quality of evidence
The quality of the evidence has been assessed by using the tool developed and published by Munn 2014.
Prevalence data can be sourced from various study designs. Therefore, studies have been assigned high quality and downgraded based on the limitations identified. Quality of the included evidence ranged between high and low; main reasons for downgrading were incomplete data reporting and unclear definitions used to identify either cerebral palsy or the cause.
5.5.5. Other considerations
The Committee considered the evidence for common causes of cerebral palsy as individual causes as well as sequences of interlinked factors termed ‘causal pathways to cerebral palsy’. This is important as there is a need for preventing the triggering factor, such as premature labour, as well as preventing and managing the downstream risk factor such as intraventricular haemorrhage. In addition, and for the same reason, the Committee examined the evidence presented together with the recommendations drafted and evidence presented for the magnetic resource imaging (MRI) causation review.
The recommendations related to this evidence review were based on the evidence and the Committee’s clinical experience.
5.5.6. Key conclusions
The Committee concluded that a number of brain abnormalities are reported in the evidence as possible causes of cerebral palsy, including white matter damage, basal ganglia damage, congenital malformations, and focal infarcts. The prevalence of such causes varies with the type and severity of cerebral palsy as well as the level of prematurity of the child.
5.6. Recommendations
- 3.
When assessing the likely cause of cerebral palsy in a child, recognise that a number of MRI-identified brain abnormalities have been reported at the following approximate prevalences in children with cerebral palsy:
- white matter damage: 45%
- basal ganglia or deep grey matter damage: 13%
- congenital malformation: 10%
- focal infarcts: 7%.
- 4.
When assessing the likely cause of cerebral palsy, recognise that white matter damage, including periventricular leukomalacia shown on neuroimaging:
- is more common in children born preterm than in those born at term
- may occur in children with any functional level or motor subtype, but is more common in spastic than in dyskinetic cerebral palsy
- 5.
When assessing the likely cause of cerebral palsy, recognise that basal ganglia or deep grey matter damage is mostly associated with dyskinetic cerebral palsy.
- 6.
When assessing the likely cause of cerebral palsy, recognise that congenital malformations as a cause of cerebral palsy:
- are more common in children born at term than in those born preterm
- may occur in children with any functional level or motor subtype
- are associated with higher levels of functional impairment than other causes.
- 7.
Recognise that the clinical syndrome of neonatal encephalopathy can result from various pathological events, such as a hypoxic–ischaemic brain injury or sepsis, and if there has been more than one such event they may interact to damage the developing brain.
- 8.
When assessing the likely cause of cerebral palsy, recognise that neonatal encephalopathy has been reported at the following approximate prevalences in children with cerebral palsy born after 35 weeks:
- attributed to a perinatal hypoxic–ischaemic injury: 20%
- not attributed to a perinatal hypoxic–ischaemic injury: 12%.
- 9.
Recognise that for cerebral palsy associated with a perinatal hypoxic–ischaemic injury:
- the extent of long-term functional impairment is often related to the severity of the initial encephalopathy
- the dyskinetic motor subtype is more common than other subtypes.
- 10.
Recognise that for cerebral palsy acquired after the neonatal period, the following causes and approximate prevalences have been reported:
- meningitis: 20%
- other infections: 30%
- head injury: 12%.
- 11.
When assessing the likely cause of cerebral palsy, recognise that independent risk factors:
- can have a cumulative impact, adversely affecting the developing brain and resulting in cerebral palsy
- may have an impact at any stage of development, including the antenatal, perinatal and postnatal periods.
5.7. Research recommendations
None prioritised for this topic.
- Causes of cerebral palsy - Cerebral palsy in under 25s: assessment and managemen...Causes of cerebral palsy - Cerebral palsy in under 25s: assessment and management
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