Persistent Inflammation in Cerebral Palsy: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
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 researchers' entry 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]. Researchers' findings from this entry 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, researchers' entry 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. Researchers 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, researchers cannot assume that inflammation between two individuals with CP will be the same. Whilst data in this area is still emerging, the findings of researchers' entry suggest that the variability between and within studies might be explained by subgroups of people with CP. Specifically, researchers note that participant age, severity of CP, type/topography and etiology may be important to consider when assessing inflammation. Researchers 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, researchers noted that most included studies of this entry 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 researchers' entry 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 researchers' 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 entry 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 entry 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, researchers 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 researchers to understand responders and non-responders to treatments with an inflammatory mechanism of action.

5. Outstanding Unknowns of Inflammation in CP

This entry 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 entry 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 researchers work to comprehend how inflammation is sustained, it is also important to understand whether blood biomarkers of systemic inflammation (as commonly reported in this entry), remain a direct indicator of central nervous system inflammation in established CP. Whilst researchers 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 entry 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 entry 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

References

  1. Rosenbaum, P.; Paneth, N.; Leviton, A.; Goldstein, M.; Bax, M.; Damiano, D.; Dan, B.; Jacobsson, B.; A report: The definition and classification of cerebral palsy. DMCN 2007, 109, 8-14, .
  2. Hagberg, H.; Gressens, P.; Mallard, C.; Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann. Neurol. 2012, 71, 444-457, 10.1002/ana.22620.
  3. Girard, S.; Kadhim, H.; Roy, M.; Lavoie, K.; Brochu, M.E.; Larouche, A.; Sébire, G.; Role of perinatal inflammation in cerebral palsy. Pediatr. Neurol 2009, 40, 168-174, 10.1016/j.pediatrneurol.2008.09.016.
  4. Magalhães, R.C.; Moreira, J.M.; Lauar, A.O.; da Silva, A.A.S.; Teixeira, A.L.; ACS, E.S.; Inflammatory biomarkers in children with cerebral palsy: A systematic review.. Res. Dev. Disabil. 2019, 95, 103508, .
  5. Lin, C.Y.; Chang, Y.C.; Wang, S.T.; Lee, T.Y.; Lin, C.F.; Huang, C.C.; Altered inflammatory responses in preterm children with cerebral palsy. Ann. Neurol. 2010, 68, 204-212, .
  6. Taher, N.A.B.; Kelly, L.A.; Al-Harbi, A.I.; O’Dea, M.I.; Zareen, Z.; Ryan, E.; Molloy, E.J.; Doherty, D.G.; Altered distributions and functions of natural killer T cells and γδ T cells in neonates with neonatal encephalopathy, in school-age children at follow-up, and in children with cerebral palsy. . J Neuroimmunol 2021, 356, 577-597, .
  7. Upadhyay, J.; Ansari, M.N.; Samad, A.; Sayana, A.; Dysregulation of multiple signaling pathways: A possible cause of cerebral palsy. Exp. Biol. Med. 2022, 247, 779-787, .
  8. Hagberg, H.; Mallard, C.; Ferriero, D.M.; Vannucci, S.J.; Levison, S.W.; Vexler, Z.S.; Gressens, P.; The role of inflammation in perinatal brain injury. . Nat. Rev. Neurol. 2015, 11, 192-208, .
  9. Zareen, Z.; Strickland, T.; Fallah, L.; McEneaney, V.; Kelly, L.; McDonald, D.; Molloy, E.J.; Cytokine dysregulation in children with cerebral palsy. Dev. Med. Child. Neurol. 2021, 63, 407-412, .
  10. Fleiss, B.; Gressens, P.; Tertiary mechanisms of brain damage: A new hope for treatment of cerebral palsy?. Lancet Neurol. 2012, 11, 556-566, .
  11. Schleiss, M.R.; Altered cytokine responses in children with cerebral palsy: Pathogenesis and novel therapies. Dev. Med. Child Neurol. 2021, 63, 365-366, .
  12. Sankowski, R.; Mader, S.; Valdés-Ferrer, S.I.; Systemic inflammation and the brain: Novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front. Cell. Neurosci. 2015, 9, 28, .
  13. Romero, B.; Robinson, K.G.; Batish, M.; Akins, R.E.; An Emerging Role for Epigenetics in Cerebral Palsy. J. Pers. Med 2021, 11, 1187, .
  14. Nelson, K.B.; Grether, J.K.; Dambrosia, J.M.; Walsh, E.; Kohler, S.; Satyanarayana, G.; Nelson, P.G.; Dickens, B.F.; Phillips, T.M.; Neonatal cytokines and cerebral palsy in very preterm infants. Pediatr. Res. 2003, 53, 600-607, .
  15. Wang, B.; Wang, F.; Wu, D.; Xu, X.; Yang, L.; Zhu, J.; Yuan, J.; Tang, J.; Relationship Between TNF-alpha and the Risk of Cerebral Palsy: A Systematic Review and Meta-Analysis. Front. Neurol. 2022, 13, 929280, .
  16. Kitase, Y.; Chin, E.M.; Ramachandra, S.; Burkhardt, C.; Madurai, N.K.; Lenz, C.; Hoon, A.H., Jr.; Robinson, S.; Jantzie, L.L.; Sustained peripheral immune hyper-reactivity (SPIHR): An enduring biomarker of altered inflammatory responses in adult rats after perinatal brain injury. J. Neuroinflammation 2021, 18, 242, .
  17. Sadowska, M.; Sarecka-Hujar, B.; Kopyta, I.; Cerebral Palsy: Current Opinions on Definition, Epidemiology, Risk Factors, Classification and Treatment Options. Neuropsychiatr Dis. Treat. 2020, 16, 1505-1518, .
  18. Hollung, S.J.; Bakken, I.J.; Vik, T.; Lydersen, S.; Wiik, R.; Aaberg, K.M.; Andersen, G.L.; Comorbidities in cerebral palsy: A patient registry study.. Dev. Med. Child. Neurol 2020, 62, 97-103, .
  19. Wu, J.; Li, X.; Plasma Tumor Necrosis Factor-alpha (TNF-alpha) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy. . Med. Sci. Monit. 2015, 21, 3868-3824, .
  20. Xia, L.; Chen, M.; Bi, D.; Song, J.; Zhang, X.; Wang, Y.; Zhu, D.; Shang, Q.; Xu, F.; Wang, X.; et al. Combined Analysis of Interleukin-10 Gene Polymorphisms and Protein Expression in Children With Cerebral Palsy. Front. Neurol. 2018, 9, 182, .
  21. Novak, I.; Badawi, N.; Hunt, R.; Wallace, E.; Walker, K.; Fahey, M.; Stem cell intervention for cerebral palsy: Systematic review with meta-analysis.. Dev. Med. Child Neurol. 2016, 58, 40, .
  22. Sun, J.M.; Case, L.E.; McLaughlin, C.; Burgess, A.; Skergan, N.; Crane, S.; Jasien, J.M.; Mikati, M.A.; Troy, J.; Kurtzberg, J.; et al. Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial. . Dev. Med. Child Neurol. 2022, 64, 1477-1486, .
  23. Stockx, E.M.; Camilleri, P.; Skuza, E.M.; Churchward, T.; Howes, J.M.; Ho, M.; McDonald, T.; Freezer, N.; Hamilton, G.; Wilkinson, M.H.; et al. New acoustic method for detecting upper airway obstruction in patients with sleep apnoea.. Respirology 2010, 15, 326-335, .
  24. McGrath-Morrow, S.A.; Ryan, T.; Riekert, K.; Lefton-Greif, M.A.; Eakin, M.; Collaco, J.M.; The impact of bronchopulmonary dysplasia on caregiver health related quality of life during the first 2 years of life.. Pediatr. Pulmonol. 2013, 48, 579-586, .
  25. Luo, Y.; Cai, X.; Liu, S.; Wang, S.; Nold-Petry, C.A.; Nold, M.F.; Bufler, P.; Norris, D.; Dinarello, C.A.; Fujita, M; et al. Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells.. Proc. Natl. Acad. Sci. 2014, 111, 15178-15183, .
  26. Nold, M.F.; Nold-Petry, C.A.; Zepp, J.A.; Palmer, B.E.; Bufler, P.; Dinarello, C.A.; IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 2010, 11, 1014-1022, .
  27. Woolfenden, S.; Farrar, M.A.; Eapen, V.; Masi, A.; Wakefield, C.E.; Badawi, N.; Novak, I.; Nassar, N.; Lingam, R.; Dale, R.C.; et al. Delivering paediatric precision medicine: Genomic and environmental considerations along the causal pathway of childhood neurodevelopmental disorders. . Dev. Med. Child Neurol. 2022, 64, 1077-1084, .
  28. Sewell, E.; Roberts, J.; Mukhopadhyay, S.; Association of Infection in Neonates and Long-Term Neurodevelopmental Outcome. . Clin. Perinatol. 2021, 48, 251-261, .
  29. Jain, V.G.; Kline, J.E.; He, L.; Kline-Fath, B.M.; Altaye, M.; Muglia, L.J.; DeFranco, E.A.; Ambalavanan, N.; Parikh, N.A.; Cincinnati Infant Neurodevelopment Early Prediction Study Investigators.; et al. Acute histologic chorioamnionitis independently and directly increases the risk for brain abnormalities seen on magnetic resonance imaging in very preterm infants. . Am. J. Obstet. Gynecol. 2022, 227, -, .
  30. Estes, M.L.; McAllister, A.K.; Maternal immune activation: Implications for neuropsychiatric disorders.. Science 2016, 353, 772-777, .
  31. Wienecke, L.M.; Cohen, S.; Bauersachs, J.; Mebazaa, A.; Chousterman, B.G.; Immunity and inflammation: The neglected key players in congenital heart disease?. Hert Fail. Rev. 2022, 27, 1957-1971, .
  32. Saand, A.R.; Yu, F.; Chen, J.; Chou, S.H.; Systemic inflammation in hemorrhagic strokes—A novel neurological sign and therapeutic target?. J. Cereb. Blood Flow Metab. 2019, 39, 959-988, .
  33. Stamatovic, S.M.; Phillips, C.M.; Martinez-Revollar, G.; Keep, R.F.; Andjelkovic, A.V.; Involvement of Epigenetic Mechanisms and Non-coding RNAs in Blood-Brain Barrier and Neurovascular Unit Injury and Recovery After Stroke. . Front. Neurosci. 2019, 13, 864, .
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