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Purpose: To study seizure manifestations and outcomes in children with cortical versus white matter injury, differences potentially explaining variability of epilepsy in children with cerebral palsy., Methods: In this population-based retrospective cohort study, MRIs of children with cerebral palsy due to ischemia or haemorrhage were classified according to presence or absence of cortical injury. MRI findings were then correlated with history of neonatal seizures, seizures during childhood, epilepsy syndromes, and seizure outcomes., Results: Of 256 children studied, neonatal seizures occurred in 57 and seizures during childhood occurred in 93. Children with neonatal seizures were more likely to develop seizures during childhood, mostly those with cortical injury. Cortical injury was more strongly associated with (1) developing seizures during childhood, (2) more severe epilepsy syndromes (infantile spasms syndrome, focal epilepsy, Lennox-Gastaut syndrome), and (3) less likelihood of reaching > 2 years without seizures at last follow-up, compared to children without cortical injury. Children without cortical injury, mainly those with white matter injury, were less likely to develop neonatal seizures and seizures during childhood, and when they did, epilepsy syndromes were more commonly febrile seizures and self-limited focal epilepsies of childhood, with most achieving > 2 years without seizures at last follow-up. The presence of cortical injury also influenced seizure occurrence, severity, and outcome within the different predominant injury patterns of the MRI Classification System in cerebral palsy, most notably white matter injury., Conclusions: Epileptogenesis is understood with cortical injury but not well with white matter injury, the latter potentially related to altered postnatal white matter development or myelination leading to apoptosis, abnormal synaptogenesis or altered thalamic connectivity of cortical neurons. These findings, and the potential mechanisms discussed, likely explain the variability of epilepsy in children with cerebral palsy and epilepsy following early-life brain injury in general., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cerebral palsy is a clinical descriptor covering a diverse group of permanent, non-degenerative disorders of motor function. Around one-third of cases have now been shown to have an underlying genetic aetiology, with the genetic landscape overlapping with those of neurodevelopmental disorders including intellectual disability, epilepsy, speech and language disorders and autism. Here we review the current state of genomic testing in cerebral palsy, highlighting the benefits for personalized medicine and the imperative to consider aetiology during clinical diagnosis. With earlier clinical diagnosis now possible, we emphasize the opportunity for comprehensive and early genomic testing as a crucial component of the routine diagnostic work-up in people with cerebral palsy., (© 2023. Springer Nature Limited.)

Objective: To determine the frequency of paroxysmal nonepileptic events in children with cerebral palsy due to brain injury who have epilepsy and to describe the factors associated with paroxysmal nonepileptic events. Methods: Retrospective, population-based study of children from the Victorian CP Register born 1999-2006. Neuroimaging, medical records, electroencephalograms (EEG), and EEG requests were analyzed. Results: Of the included 256 children, 87 had epilepsy. EEGs (with video correlation) were available for 82 of 87. Eighteen (18/82, 22%) had epileptic events captured on EEG. Twenty-one (21/82, 26%) had paroxysmal nonepileptic events captured on EEG. The majority (13/18, 77%) of children with epileptic events also had paroxysmal nonepileptic events captured. Ten parents and carers continued to report events as epileptic despite there being no ictal EEG correlate for specific events on multiple EEGs. There were no clear associations to identify which children would have ongoing paroxysmal nonepileptic events reported. Conclusions: Paroxysmal nonepileptic events were captured on EEG in one-fourth of children from this cerebral palsy cohort with epilepsy and available EEG. Half the parents and carers reported previously identified paroxysmal nonepileptic events as epileptic on subsequent EEGs, highlighting the need for clearer counseling so that parents better understand seizure semiology in children with EEG-proven paroxysmal nonepileptic events.

Introduction: Cerebral palsy (CP) is the most common physical disability of childhood worldwide. Historically the diagnosis was made between 12 and 24 months, meaning data about effective early interventions to improve motor outcomes are scant. In high-income countries, two in three children will walk. This evaluator-blinded randomised controlled trial will investigate the efficacy of an early and sustained Goals-Activity-Motor Enrichment approach to improve motor and cognitive skills in infants with suspected or confirmed CP., Methods and Analysis: Participants will be recruited from neonatal intensive care units and the community in Australia across four states. To be eligible for inclusion infants will be aged 3-6.5 months corrected for prematurity and have a diagnosis of CP or 'high risk of CP' according to the International Clinical Practice Guideline criteria. Eligible participants whose caregivers consent will be randomly allocated to receive usual care or weekly sessions at home from a GAME-trained study physiotherapist or occupational therapist, paired with a daily home programme, until age 2. The study requires 150 participants per group to detect a 0.5 SD difference in motor skills at 2 years of age, measured by the Peabody Developmental Motor Scales-2. Secondary outcomes include gross motor function, cognition, functional independence, social-emotional development and quality of life. A within-trial economic evaluation is also planned., Ethics and Dissemination: Ethical approval was obtained from the Sydney Children's Hospital Network Human Ethics Committee in April 2017 (ref number HREC/17/SCHN/37). Outcomes will be disseminated through peer-reviewed journal publications, presentations at international conferences and consumer websites., Trial Registration Number: ACTRN12617000006347., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: School readiness includes cognitive, socio-emotional, language and physical growth and development domains which share strong associations with life-course opportunities. Children with cerebral palsy (CP) are at increased risk of poor school readiness compared with their typically developing peers. Recently, earlier diagnosis of CP has allowed interventions to commence sooner, harnessing neuroplasticity. First, we hypothesise that early referral to intervention for children at-risk of CP will lead to improved school readiness at 4-6 years relative to placebo or care as usual. Second, we hypothesise that receipt of early diagnosis and early intervention will lead to cost-savings in the form of reduced healthcare utilisation., Methods and Analysis: Infants identified as at-risk of CP ≤6 months corrected age (n=425) recruited to four randomised trials of neuroprotectants (n=1), early neurorehabilitation (n=2) or early parenting support (n=1) will be re-recruited to one overarching follow-up study at age 4-6 years 3 months. A comprehensive battery of standardised assessments and questionnaires will be administered to assess all domains of school readiness and associated risk factors. Participants will be compared with a historical control group of children (n=245) who were diagnosed with CP in their second year of life. Mixed-effects regression models will be used to compare school readiness outcomes between those referred for early intervention versus placebo/care-as-usual. We will also compare health-resource use associated with early diagnosis and intervention versus later diagnosis and intervention., Ethics and Dissemination: The Children's Health Queensland Hospital and Health Service, The University of Queensland, University of Sydney, Monash University and Curtin University Human Research Ethics Committees have approved this study. Informed consent will be sought from the parent or legal guardian of every child invited to participate. Results will be disseminated in peer-reviewed journals, scientific conferences and professional organisations, and to people with lived experience of CP and their families., Trial Registration Number: ACTRN12621001253897., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Seizures occur in approximately one-third of children with cerebral palsy. This study aimed to determine epilepsy syndromes in children with seizures and cerebral palsy due to vascular injury, anticipating that this would inform treatment and prognosis. We studied a population-based cohort of children with cerebral palsy due to prenatal or perinatal vascular injuries, born 1999-2006. Each child's MRI was reviewed to characterize patterns of grey and white matter injury. Children with syndromic or likely genetic causes of cerebral palsy were excluded, given their inherent association with epilepsy and our aim to study a homogeneous cohort of classical cerebral palsy. Chart review, parent interview and EEGs were used to determine epilepsy syndromes and seizure outcomes. Of 256 children, 93 (36%) had one or more febrile or afebrile seizures beyond the neonatal period and 87 (34%) had epilepsy. Children with seizures were more likely to have had neonatal seizures, have spastic quadriplegic cerebral palsy and function within Gross Motor Function Classification System level IV or V. Fifty-six (60%) children with seizures had electroclinical features of a self-limited focal epilepsy of childhood; we diagnosed these children with a self-limited focal epilepsy-variant given the current International League Against Epilepsy classification precludes a diagnosis of self-limited focal epilepsy in children with a brain lesion. Other epilepsy syndromes were focal epilepsy-not otherwise specified in 28, infantile spasms syndrome in 11, Lennox-Gastaut syndrome in three, genetic generalized epilepsies in two and febrile seizures in nine. No epilepsy syndrome could be assigned in seven children with no EEG. Twenty-one changed syndrome classification during childhood. Self-limited focal epilepsy-variant usually manifested with a mix of autonomic and brachio-facial motor features, and occipital and/or centro-temporal spikes on EEG. Of those with self-limited focal epilepsy-variant, 42/56 (75%) had not had a seizure for >2 years. Favourable seizure outcomes were also seen in some children with infantile spasms syndrome and focal epilepsy-not otherwise specified. Of the 93 children with seizures, at last follow-up (mean age 15 years), 61/91 (67%) had not had a seizure in >2 years. Children with cerebral palsy and seizures can be assigned specific epilepsy syndrome diagnoses typically reserved for normally developing children, those syndromes commonly being age-dependent and self-limited. Compared to typically developing children with epilepsy, self-limited focal epilepsy-variant occurs much more commonly in children with cerebral palsy and epilepsy. These findings have important implications for treatment and prognosis of epilepsy in cerebral palsy, and research into pathogenesis of self-limited focal epilepsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Neural stem cells (NSCs) have the potential to engraft and replace damaged brain tissue, repairing the damaged neonatal brain that causes cerebral palsy (CP). There are procedures that could increase engraftment of NSCs and may be critical for efficacy, but hold notable risks. Before clinical trials progress, it is important to engage with the CP community to understand their opinions. The aim of this study was to determine the acceptability of NSC therapy for CP in the CP community., Methods: Australian residents with CP and parents/carers of those with CP completed a questionnaire to determine their willingness to use NSCs from three sources (fetal, embryonic and induced pluripotent stem cells) and their willingness to undergo accompanying procedures (neurosurgery, immunosuppression) that carry potential risks. To further explore their views, participants also answered free text questions about their ethical concerns regarding the source of NSCs and their perceptions of meaningful outcomes following NSC treatment., Results: In total, 232 responses were analyzed. Participants were willing to use NSCs from all three cell sources and were willing to undergo NSC therapy despite the need for neurosurgery and immunosuppression. Participants identified a range of outcome domains considered important following NSC treatment including gross motor function, quality of life, independence and cognitive function., Conclusions: Hypothetical NSC therapy was acceptable to the Australian CP community. This study has identified important findings from the CP community which can be used to inform future NSC research, including the design of clinical trials which may help to increase recruitment, compliance and participant satisfaction., (© 2023. The Author(s).)

Aim: To define clinical common data elements (CDEs) and a mandatory minimum data set (MDS) for genomic studies of cerebral palsy (CP)., Method: Candidate data elements were collated following a review of the literature and existing CDEs. An online, three-round Delphi survey was used to rate each data element as either 'core', 'recommended', 'exploratory', or 'not required'. Members of the International Cerebral Palsy Genomics Consortium (ICPGC) rated the core CDEs as either mandatory or not, to form the MDS. For both the CDEs and the MDS, a data element was considered to have reached consensus if more than 75% of respondents agreed., Results: Forty-six individuals from around the world formed the Delphi panel: consumers (n=2), scientists/researchers (n=17), medical (n=19), and allied health professionals (n=8). The CDEs include 107 data elements across six categories: demographics, diagnostics, family history, antenatal and neonatal details, clinical traits, and CP-specific assessments. Of these, 10 are mandatory, 42 core, 41 recommended, and 14 are exploratory., Interpretation: The ICPGC CDEs provide a foundation for the standardization of phenotype data captured in CP genomic studies and will benefit international collaborations and pooling of data, particularly in rare conditions., What This Paper Adds: A set of 107 common data elements (CDEs) for genomics studies in cerebral palsy is provided. The CDEs include standard definitions and data values domains. The CDEs will facilitate international data sharing, collaboration, and improved clinical interpretation of findings., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Cerebral palsy (CP) is a broad diagnosis unbound by aetiology and is based on a clinical examination demonstrating abnormalities of movement or posture. CP represents a static neurological condition, provided that neurodegenerative conditions, leukoencephalopathies and neuromuscular disorders are excluded. In paediatrics, the genetic conditions associated with CP are rapidly increasing, with primary and overlapping neurodevelopmental conditions perhaps better categorised by the predominant clinical feature such as CP, intellectual disability, autism spectrum disorder or epilepsy. Progress in molecular genetics may challenge what constitutes CP, but a genetic diagnosis does not negate the CP diagnosis. As clinicians working in the field, we discuss the changing tide of CP. Neuroimaging provides essential information through pattern recognition and demonstration of static brain changes. We present examples of children where a layered clinical diagnosis or dual aetiologies are appropriate. We also present examples of children with genetic causes of CP to highlight the challenges and limitations of neuroimaging to provide an aetiological diagnosis. In consultation with a geneticist, access to genomic testing (exome or genome sequencing) is now available in Australia under Medicare billing for children under the age of 10 with dysmorphic features, one or more major structural organ anomalies, (an evolving) intellectual disability or global developmental delay. We encourage the uptake of genomic testing in CP, because it can be difficult to tell whether a child has an environmental or genetic cause for CP. A specific genetic diagnosis may change patient management, reduce guilt and enable more distinctive research in the future to assist with understanding disease mechanisms., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

To progress stem cell therapies for cerebral palsy, clinicians need to openly engage with patients about emerging evidence and be willing to refer to relevant clinical trials, if and when appropriate. To assess whether education can change clinicians' confidence in information sharing and willingness to refer to relevant clinical trials, an online questionnaire was distributed at a scientific conference before and after a professional workshop on cell therapies for cerebral palsy. Of the 42 participants who completed the survey, 26 self-identified as clinicians. Of these, 81% had had patients ask about stem cells, yet in the pre-workshop questionnaire indicated they were not confident answering questions about cell therapies. Clinicians were most commonly asked about stem cell treatments provided by private clinics, stem cell research and current evidence. Post-workshop, knowledge and confidence regarding stem cells, as well as likelihood to refer to clinical trials using therapies with a strong evidence base (eg, umbilical cord blood/placental cells), significantly increased (p<0.001). This study highlights that by offering resources and education, clinician confidence and willingness to refer to cell therapy trials can improve; this may help drive the stem cell research landscape and support patient decision-making., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Aim: The early diagnosis of cerebral palsy (CP) allows children timely access to early intervention. In 2018, Monash Children's Hospital established an Early Neurodevelopment Clinic based upon evidence-based guidelines for the early diagnosis of CP in high-risk infants. In this study, we aimed to characterise the infants presenting to the clinic and determine the rate of CP diagnosis., Methods: This study analysed data from infants attending the Early Neurodevelopment Clinic between May 2019 and April 2020. Infants at high-risk for CP attended the clinic at 3 months corrected age. Neuroimaging reports were reviewed, and a Prechtl's General Movement Assessment and Hammersmith Infant Neurological Examination were performed. Infants were diagnosed as having typical development, delayed development, high-risk of CP or CP at the time of clinic attendance and referred on to the appropriate pathway., Results: Ninety-six high-risk infants attended the clinic over the 1 year study period. Sixty-eight (71%) infants were extremely preterm or extremely low birthweight, and 28 (29%) were infants at born at older gestation with evidence of moderate to severe brain injury. Nine (9.6%) infants received a CP diagnosis and 12 (12.5%) were considered high-risk of CP. All infants with CP or high-risk of CP were referred to the Victorian Paediatric Rehabilitation Service., Conclusions: It is feasible to implement the early CP diagnosis guidelines into a high-risk infant follow-up clinic. Implementation of the guidelines allows for early diagnosis of CP and appropriate referral of high-risk infants., (© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Aim: To evaluate pain prevalence and characteristics in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) cerebral palsy (CP) motor types., Method: Seventy-five participants with a diagnosis of CP and confirmed dyskinetic or mixed (dyskinetic/spastic) motor type took part in a multisite cross-sectional study. The primary outcome was carer-reported pain prevalence (preceding 2wks) measured using the Health Utilities Index-3. Secondary outcomes were chronicity, intensity, body locations, quality of life, and activity impact., Results: Mean participant age was 10 years 11 months (SD 4y 2mo, range 5-18y). There were 44 males and 31 females and 37 (49%) had predominant dyskinetic CP. Pain was prevalent in 85% and it was chronic in 77% of participants. Fifty-two per cent experienced moderate-to-high carer-reported pain intensity, which was significantly associated with predominant dyskinetic motor types (p=0.008). Pain occurred at multiple body locations (5 out of 21), with significantly increased numbers of locations at higher Gross Motor Function Classification System levels (p=0.02). Face, jaw, and temple pain was significantly associated with predominant dyskinetic motor types (p=0.005). Poorer carer proxy-reported quality of life was detected in those with chronic pain compared to those without (p=0.03); however, chronic pain did not affect quality of life for self-reporting participants., Interpretation: Pain was highly prevalent in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types, highlighting a population in need of lifespan pain management., What This Paper Adds: Chronic pain prevalence in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types is high. Pain occurs across multiple body locations in predominant dyskinetic and mixed (dyskinetic/spastic) motor types. Less recognized locations of pain include the face, jaw, and temple for predominant dyskinetic motor types., (© 2020 Mac Keith Press.)

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Background: To explore the lived experience of chronic pain and dyskinesia in children and adolescents with cerebral palsy., Methods: A convergent parallel mixed methods design was undertaken. First, a quantitative cross-sectional study of participants able to self-report their quality of life was undertaken. This study characterised pain chronicity, intensity, body locations, and quality of life. Second, semi-structured interviews were undertaken with a subset of children and adolescents experiencing chronic pain., Results: Twenty-five children and adolescents took part in the cross-sectional study, 23 of whom experienced chronic pain and 13 of moderate intensity. Pain was often located in multiple bodily regions (6/21), with no trends in quality of life outcomes detected. Eight participated in semi-structured interviews, which identified three key themes including 'lives embedded with dyskinesia', 'real world challenges of chronic pain', and 'still learning strategies to manage their pain and dyskinesia'., Conclusions: A high proportion of children and adolescents with cerebral palsy and dyskinesia who were able to self-report experienced chronic pain. The physical and emotional impacts of living with chronic pain and dyskinesia existed along a spectrum, from those with lesser to greater extent of their impacts. Children and adolescents may benefit from targeted chronic pain education and management within bio-psychosocial models.

Context: Cerebral palsy (CP) is a motor disorder affecting movement, muscle tone and posture due to damage to the foetal or infant brain. The subsequent lack of ambulation, nutritional deficiencies, anticonvulsant use and hormonal deficiencies have been implicated in the low bone mass associated with this condition., Objective: To assess changes in areal bone mineral density (aBMD) during adolescence and young adulthood in individuals with CP. The effect of ambulation, nutrition, hypogonadism on longitudinal changes in aBMD is also examined., Design: Retrospective longitudinal study., Setting and Participants: Forty-five subjects with CP who had longitudinal dual-energy X-ray absorptiometry (DXA) scans at a single tertiary hospital between 2006 and 2018., Results: Mean age at first DXA was 19.4 years (range: 10-36 years), 57.8% were male and 80% were nonambulatory. The mean Z-scores at baseline were <-2.0 at all sites - lumbar spine (LS), femoral neck (FN), total hip (TH) and total body (TB). The median change in aBMD was +1.2%-1.9% per year in all subjects but in those <20 years of age, the median change was 4%-8% per year. Z-scores across all sites remained stable over time. Reduced functional state as measured by the gross motor functional classification scale (GMFCS) had a small negative effect on aBMD over time., Conclusion: In adolescents with CP, low bone mass was evident from the baseline DXA. However, significant bone accrual occurred during the second decade, followed by bone maintenance in young adulthood. Future studies should focus on optimizing bone health from early childhood., (© 2019 John Wiley & Sons Ltd.)

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic-ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

Context: Bone fragility in cerebral palsy (CP) is secondary to a complex interplay of functional, hormonal, and nutritional factors that affect bone remodelling. A greater understanding of bone microarchitectural changes seen in CP should assist therapeutic decision making., Objective: To examine the relationship between trabecular bone score (TBS), BMD and fractures in adults with CP; the influence of clinical factors and body composition on bone microarchitecture were explored., Design: Retrospective cross-sectional study., Setting and Participants: 43 adults (25 male) with CP of median age 25 years (interquartile range 21.4-33.9) who had evaluable dual-energy X-ray absorptiometry imaging of the lumbar spine from a single tertiary hospital between 2005-March 2018., Results: 24/43 (55.8%) of patients had TBS values indicating intermediate or high risk of fracture (<1.31). TBS correlated with areal BMD at the lumbar spine, femoral neck and total body. TBS was significantly associated with arm and leg lean mass, with adjustment for age, gender and height (adjusted R 2  = 0.18, p = 0.042 for arm lean mass; adjusted R 2  = 0.19, p = 0.036 for leg lean mass). There was no difference in TBS when patients were grouped by fracture status, anticonvulsant use, gonadal status or use of PEG feeding. TBS was lower in non-ambulatory patients compared with ambulatory patients (1.28 vs 1.37, p = 0.019)., Conclusions: Abnormal bone microarchitecture, as measured by TBS, was seen in >50% of young adults with CP. TBS correlated with both areal BMD and appendicular lean mass. Maintaining muscle function is likely to be important for bone health in young adults with CP and needs to be confirmed in further studies., (Copyright © 2018. Published by Elsevier Inc.)

Cerebral palsy is the most common cause of physical disability in children, and there is no cure. Umbilical cord blood (UCB) cell therapy for the treatment of children with cerebral palsy is currently being assessed in clinical trials. Although there is much interest in the use of UCB stem cells for neuroprotection and neuroregeneration, the mechanisms of action are not fully understood. Further, UCB contains many stem and progenitor cells of interest, and we will point out that individual cell types within UCB may elicit specific effects. UCB is a clinically proven source of hemotopoietic stem cells (HSCs). It also contains mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs), and immunosupressive cells such as regulatory T cells (Tregs) and monocyte-derived supressor cells. Each of these cell types may be individual candidates for the prevention of brain injury following hypoxic and inflammatory events in the perinatal period. We will discuss specific properties of cell types in UCB, with respect to their therapeutic potential and the importance of optimal timing of administration. We propose that tailored cell therapy and targeted timing of administration will optimize the results for future clinical trials in the neuroprotective treatment of perinatal brain injury.

Although prematurity and hypoxic-ischaemic injury are well-recognized contributors to the pathogenesis of cerebral palsy (CP), as many as one-third of children with CP may lack traditional risk factors. For many of these children, a genetic basis to their condition is suspected. Recent findings have implicated copy number variants and mutations in single genes in children with CP. Current studies are limited by relatively small patient numbers, the underlying genetic heterogeneity identified, and the paucity of validation studies that have been performed. However, several genes mapping to intersecting pathways controlling neurodevelopment and neuronal connectivity have been identified. Analogous to other neurodevelopmental disorders such as autism and intellectual disability, the genomic architecture of CP is likely to be highly complex. Although we are just beginning to understand genetic contributions to CP, new insights are anticipated to serve as a unique window into the neurobiology of CP and suggest new targets for intervention., (© 2017 Mac Keith Press.)

Context: Cerebral palsy (CP) increases fracture risk through diminished ambulation, nutritional deficiencies, and anticonvulsant medication use. Studies examining bone mineral density (BMD) in adults with CP are limited., Objective: To examine the relationship between body composition, BMD, and fractures in adults with CP. The effect of functional, nutritional, and endocrine factors on BMD and body composition is also explored., Design: Retrospective cross-sectional study., Setting and Participants: Forty-five adults with CP (mean age, 28.3 ± 11.0 years) who had dual-energy x-ray absorptiometry imaging at a single tertiary hospital between 2005 and 2015., Results: Seventeen (38%) had a past history of fragility fracture; 43% had a Z-score of ≤ -2.0 at the lumbar spine (LS) and 41% at the femoral neck (FN). In nonambulatory patients, every one unit decrease in FN Z-score increased the risk of fracture 3.2-fold (95% confidence interval, 1.07-9.70; P = .044). Stepwise linear regression revealed that the Gross Motor Function Classification System was the best predictor of LS Z-score (R(2) = 0.550; β = -0.582; P = .002) and FN Z-score (R(2) = 0.428; β = -0.494; P = .004); 35.7% of the variance in BMD was accounted for by lean tissue mass. Hypogonadism, present in 20% of patients, was associated with reduced lean tissue mass and reduced LS BMD. Lean tissue mass positively correlated with BMD in eugonadal patients, but not in hypogonadal patients., Conclusions: Low BMD and fractures are common in adults with CP. This is the first study to document hypogonadism in adults with CP with detrimental changes in body composition and BMD.

Aim: For the 9% to 16% of children with cerebral palsy (CP) who have normal brain imaging, further testing for metabolic and/or genetic conditions has been recommended. This study aimed to identify a cohort of children with CP with normal magnetic resonance imaging (MRI), clinically review and describe the cases, and assess the value of testing for inherited metabolic disorders in these children., Method: Children with congenital CP born from 1999 to 2005 were selected from a population register. Normal MRI reports were identified and the scans reassessed. Children whose scans were performed before 18 months were excluded, as were children with spastic CP (Gross Motor Function Classification System [GMFCS] level I). The remainder were reviewed clinically and offered investigations., Results: Of 730 children identified, 515 had available imaging and 54 were confirmed as normal. Cases with non-spastic CP and those with milder clinical severity were more likely to have normal imaging. Twenty-three children (17 males, six females; mean age 6 y 11 mo, SD 1 y 10 mo, range 3 y 0 mo to 10 y 0 mo) were reviewed clinically and offered investigations. Twelve children had spasticity (11 with diplegia, one quadriplegia), three had dyskinesia, five ataxia, and three hypotonia. Two children functioned in GMFCS level I, 11 in level II, seven in level III and three in level IV. Four children with spasticity had unusual features. No alternative diagnoses were made., Interpretation: Although important to consider in individual cases, comprehensive metabolic testing failed to clarify the aetiology of CP further in this large cohort of children with normal MRIs, even those with atypical features., (© The Authors. Journal compilation © Mac Keith Press 2011.)