Persistent Inflammation in Cerebral Palsy: History
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Subjects: Pediatrics
Contributor:
Madison C. B. Paton
,
Megan Finch-Edmondson
,
Russell C. Dale
,
Michael C. Fahey
,
Claudia A. Nold-Petry
,
Marcel F. Nold
,
Alexandra R. Griffin
,
Iona Novak

Research has established inflammation in the pathogenesis of brain injury and the risk of developing cerebral palsy (CP). However, it is unclear if inflammation is solely pathogenic and primarily contributes to the acute phase of injury, or if inflammation persists with consequence in CP and may therefore be considered a comorbidity. 

  • inflammation
  • biomarker
  • cerebral palsy
  • comorbidity

1. Introduction

Cerebral palsy (CP) describes a group of permanent motor and postural disorders, causing activity limitations, that are attributed to non-progressive disturbances in the developing brain[1]. The motor disorders of CP are commonly accompanied by sensation, perception, cognition, behavior and communication disturbances, with epilepsy and secondary musculoskeletal issues. Inflammation is detailed in the pathogenesis of most perinatal brain injury that contributes to the risk of developing CP, including neonatal stroke, preterm birth, birth asphyxia and infection [2][3]. Systematic reviews of the clinical literature now support an association between higher circulating levels of pro-inflammatory mediators and the diagnosis of CP, particularly in the setting of prematurity [4]. However, the duration and extent of this inflammation, as well as the implications in people with CP, remain unclear.
Inflammation in CP may comprise changes in cytokines [4]; altered immune response with a dysregulated response to stimuli (e.g., lipopolysaccharide (LPS)) [5]; adaptive immune changes including T- and B- cell distribution and function [6], and other genetic and non-genetic changes to signaling pathways [7]. It is commonly reported that inflammation following perinatal brain injury changes over time, between the acute to chronic phases of injury [8]. However, persistent inflammation (i.e., inflammation extending months-to-years after the primary injury phase) has been postulated to have detrimental effects on the brain and may contribute to ongoing sequelae of CP [9][10]. This is supported by the sustained inflammation hypothesis, also known as programming effects, whereby prenatal, antenatal or neonatal pro-inflammatory cytokines induce inflammation that contributes to long-term cytokine dysregulation [11]. Whilst it has been discussed that persistent inflammation may be present in people with CP [5][7], there is ongoing debate about the strength of this evidence and its implications. There are currently two main streams of thought:
(1)
 Inflammation persists well after the original brain injury with long-term consequence in CP. If inflammation persists, other commonly characterized symptoms of CP, including pain and cognition may be confounded or exacerbated. For example, systemic immune disturbances in innate and cellular immunity increase brain glial cell responsiveness, which may worsen neurological deficits [12]. In this context, inflammation may be viewed as a contributing factor to the symptoms experienced by people with CP, and present with the motor and movement impairments, in other terms be a “comorbidity” of CP.
(2)
 Inflammation persists in CP without long-term consequence or indeed, does not persist at all. If inflammation is not a comorbidity of CP, it may instead standalone as a pathogenic feature of CP; meaning that the original inflammatory insult that causes the motor and postural impairment exists with no other long-term implications on health or outcomes. Alternatively, that inflammation does not persist.
When considering either stream of thought, there are many unknowns around how and why inflammation may or may not persist. Crosstalk between inflammation arising from the central nervous and systemic immune system are also unclear, along with the possible contribution of epigenetic programming from the initial insult [13].
Interestingly, the role of inflammation in the pathogenesis of CP is frequently investigated; many publications report on inflammatory biomarkers either collected close to the time of birth (e.g., umbilical cord blood) or during the neonatal period up to 4 weeks of age, or study a mixed at-risk population which are then correlated with outcomes such as CP [14][15]. Early inflammatory biomarkers and associations with neurodevelopmental outcome can be seen as indirect measures that allude to the impact of inflammation, genetic and immune changes in the pathogenesis of brain injury. However, direct measures of inflammation in children and adults with CP is lacking and the extent and duration of inflammation is not understood. The need for more research in this space has been previously stated [7]. The information presented below summarises the findings from our scoping review that can be read in full here: https://doi.org/10.3390/jcm11247368.

2. The Evidence of Persistent Inflammation in CP

There is ample evidence to support the role of inflammation in the pathogenesis of brain injury and its detrimental role in neurodevelopment. Preclinical and clinical research has demonstrated that inflammation prevents endogenous brain repair and regeneration following injury [9][16] and persistent inflammation has been postulated to predispose people with CP to further cognitive dysfunction and brain injury [10]. Specifically, published research supports that aberrant glial activation contributes to ongoing injurious brain processes, with advances in neuroimaging supporting this hypothesis [10]. Our findings from this scoping review indicate that some biomarkers of inflammation are altered in people with CP. This has been investigated mostly via alterations in systemic inflammation, commonly assayed from peripheral blood serum and plasma. Changes were detected across markers of inflammatory status measured via cytokine analysis, immune function or genetic changes. Twelve published studies (10 controlled) demonstrate significant changes or associations in one or more inflammatory biomarkers compared to a relevant comparator or within subgroups of those with CP. The most commonly reported changes in inflammation in CP were noted for IL-6, TNF and IL-10. This is consistent with the current literature in infants, with previous systematic reviews indicating that higher circulating levels of cytokines including TNF and IL-6 are associated with abnormal neurological findings, including CP [4].
Importantly, our scoping review highlights that inflammation can persist in CP well beyond the acute brain injury period, with significantly higher systemic inflammation from childhood, through to adolescence compared to relevant controls. Some differences in gene function were found in participant groups aged up to 18 years. We also note that some studies report differences in inflammatory status related to age; two studies showed that younger children have greater systemic inflammation compared to older children and adults. Interestingly, in the one study that identified no significant inflammatory differences in plasma CRP between those with CP and controls, all participants were adults. This may indicate that inflammatory status and immune function change over time and may become less pronounced with increasing age, however more research is required to elucidate this hypothesis.
Whilst there are several common biomarkers under investigation including IL-6, TNF and IL-10, there remains high heterogeneity between studies. A total of 30 biomarkers of inflammation as well as a number of additional genes were examined and studies included varied sample types, analysis methods, controls, and age ranges and presentations of participants. Even across the most commonly investigated cytokines of IL-6, TNF and IL-10, studies reported mixed significant and non-significant findings. Remarkably, the majority of studies conclude that there are differences in inflammation in CP, spanning more than 38 significant findings. These primarily include alterations in systemic inflammatory and immune function, and more research should be prioritized to investigate these changes in more detail and in larger cohorts with harmonized biomarker panels.

3. Differences in Persistent Inflammation in CP and within Subgroups

CP is a multifactorial and heterogeneous condition, stemming from diverse etiologies and patterns of brain injury, with varied severity and subtype [17]. As such, we cannot assume that inflammation between two individuals with CP will be the same. Whilst data in this area is still emerging, the findings of our scoping review suggest that the variability between and within studies might be explained by subgroups of people with CP. Specifically, we note that participant age, severity of CP, type/topography and etiology may be important to consider when assessing inflammation. We present that those with more severe CP may have higher levels of inflammation, as well as those with spastic quadriplegia. One included study also supports that those with CP born preterm have distinct inflammatory biomarkers, complementing the previously established literature showing unique biomarker profiles in those born preterm and the risk of developing CP [4]. Whilst this data may indicate that there are differences in inflammation both in CP and within subgroups, there may also be contributing factors to persistent inflammation that are not controlled for. For instance, in more severe CP, individuals may have reoccurring infections, micro-aspirations and more extensive muscle contractures [18]. These factors could ultimately explain the higher levels of systemic inflammation observed in both inflammatory and anti-inflammatory cytokines [19][20]. Moreover, the one study that found higher plasma IL-10 in those with spastic quadriplegia may suggest that increased muscle tone alters inflammation [20]. However, interpretation of this finding is limited as other types of CP are not commonly studied. There remains a notable bias towards participants with spastic CP, likely due to prevalence of spastic CP over other CP types. Additionally, we noted that most included studies of this review had a modest sample size (n ≤ 150 total) with a mixed participant demographic. Only one study had a large sample size of n = 479 [20] in order to analyze genetic polymorphisms with subgroup analyses of CP subtypes. Future studies will require larger sample sizes to ensure that further subgroup analyses can be conducted, are adequately powered to detect differences and control for subgroup and comorbidity diversity, especially in this heterogenous and complex condition.

4. Targeting Inflammation as a Comorbidity of CP

It has been previously proposed that understanding “persistent inflammatory mechanism could lead to safe and effective therapies to treat brains that have experienced developmental disruption long after the initial insult” [9]. This is an interesting concept, and our scoping review demonstrates that inflammation should be recognized as a comorbidity of CP, that is, a factor that coexists alongside the movement and postural impairments experienced by people with CP. Given the remaining uncertainties highlighted above, more research to improve our understanding of the extent of inflammation, its mechanisms in CP, as well as who are most likely to have inflammation and require treatment, will be important next-steps.
Importantly, whilst this review has highlighted a number of inflammatory biomarkers of interest (e.g., IL-6, TNF and IL-10), it is unlikely that any one given cytokine alone will be implicated in the pathogenesis and long-term inflammatory status associated with CP. Instead, a broad immunomodulatory and anti-inflammatory strategy may have its place and are now under investigation in CP. For instance, cell therapies including umbilical cord blood have been demonstrated to improve motor function in children with CP [21] [22] primarily working via immunomodulation. Results from this scoping review support the hypothesis that there is persistent inflammation to be targeted. Uncovering the role, extent and impact of this inflammation may also enable research into more treatments that target inflammation.
Alternatively, given the variability in inflammatory biomarkers and likely heterogeneity in any given person with CP, personalized medicine may also be appropriate approach for targeting inflammation in this condition. For instance, we have demonstrated that levels of systemic inflammatory TNF are higher in three studies with a CP sample of n = 117. If this finding is confirmed in more participants with CP compared to controls, TNF may prove a future target for personalized medicine. There are now success stories from clinical translation of inflammatory cytokine drug targets for neonatal conditions including white matter injury and bronchopulmonary dysplasia. These include the use of IL-1 receptor antagonist (anakinra) [23][24] and IL-37 as an endogenous regulator of inflammation that broadly suppresses innate and adaptive immunity [25] [26]. A similar approach may be developed in CP if researchers can establish the importance of any one given cytokine for the condition. Additionally, identifying those with persistent inflammation may also help us to understand responders and non-responders to treatments with an inflammatory mechanism of action.

5. Outstanding Unknowns of Inflammation in CP

This review highlights that inflammation has a number of dimensions; there are multiple contributors to inflammation spanning the transcriptome that contains the genome, proteome, metabolome, leading to phenotypic changes [27]. However, the majority of results in this scoping review are only reflective of changes at the protein level mainly from peripheral blood serum and plasma. To continue establishing inflammation as a comorbidity of CP, more research should be done to elucidate the contribution of upstream and downstream inflammatory factors. This may also help to uncover novel targets. Additionally, the origins of inflammation associated with early brain injury and resulting CP are yet to be fully understood. For instance, is inflammation programmed during the brain injury? If this inflammation remains sustained, why and how? The causes of inflammation may be cellular or from epigenetic programming from the initiating insult  [13]. Not to mention, the confounding role of aberrant inflammation following perinatal infection and neonatal sepsis in CP [28][29], as well as maternal immune activation [30] and congenital abnormalities [31]. Current evidence also suggests that more than 30% of all CP may have a genetic cause, with four main types of DNA variations contributing to the pathogenesis of the condition [7]. Genetic and epigenetic changes may not only increase the risk of developing CP, but may also have a role in ongoing signaling pathway dysregulation like Wnt and glycogen synthase kinase-3. These signaling pathways are critical for brain development and neurogenesis in early life but also support regeneration, synaptic plasticity and homeostasis in adults. Information regarding these changes in CP, such as how inflammation is sustained and the implications of persistent inflammation are only just becoming apparent from research findings.
As we work to comprehend how inflammation is sustained, it is also important to understand whether blood biomarkers of systemic inflammation (as commonly reported in this scoping review), remain a direct indicator of central nervous system inflammation in established CP. Whilst we saw one study that analyzed CSF, more should be done to contrast and compare systemic and central inflammation. Research into neurological conditions including stroke has demonstrated that there is strong peripheral immune-brain crosstalk following injury [32][33]. This crosstalk can be bidirectional and therefore systemic immune responses to stimuli may exacerbate brain inflammation, and vice versa. Not to mention, this review has primarily focused on the detrimental effects of inflammation, however the protective and reparative functions of inflammation in the setting of CP have yet to be considered.
This review also highlights that different causal pathways and etiologies of CP, as well as subtypes, may contribute to persistent inflammation. However, evidence is still emerging and most studies did not provide details of CP etiology or investigate subgroup analyses of participants in relation to inflammation. As stated above, powering for this type of investigation is necessary but will be challenging.

This entry is adapted from the peer-reviewed paper 10.3390/jcm11247368

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