Cerebral palsy characteristics in term-born children with and without detectable perinatal risk factors: A cross-sectional study.

AIM: To compare, in term-born children with cerebral palsy (CP), the characteristics of those who exhibit detectable risk factors for CP at birth with those who do not. METHOD: This was a cross-sectional study of term-born children using the Canadian Cerebral Palsy Registry comparing those with and without perinatal risk factors and/or neonatal symptoms for pregnancy, birth and neonatal characteristics, magnetic resonance imaging (MRI) findings, CP subtype, and impairment severity. Risk factors were quantified with a CP risk calculator. Multivariable and multinomial regressions were expressed as odds ratios (OR) and relative risk ratios. RESULTS: Of 1333 term-born children, 781 (58.6%) had complete variables for the CP risk calculator, of whom 195 (25%) had 'undetectable' newborn infant CP risk, and they did not have greater postneonatal brain injury. Focal injury on MRI was more common (OR 2.0, 95% confidence interval [CI] 1.3-3.1) than in the 'detectable' group. The 'undetectable' group had more unilateral CP (OR 1.8, 95% CI 1.3-2.6), less severe motor impairment (OR 0.76, 95% CI 0.67-0.86), and were more verbal (OR 2.3, 95% CI 1.5-3.6). INTERPRETATION: In the Canadian CP Registry, one-quarter of term-born children lacked neonatal encephalopathy, seizures, or perinatal risk factors. They were more likely to have unilateral CP, focal MRI findings, and communicate with words than children with risk factors or neonatal symptoms.

Early Biomarkers in the Prediction of Later Functional Impairment in Preterm Children With Cerebral Palsy.

BACKGROUND: To identify early biomarkers that could predict later functional capabilities in preterm children with later cerebral palsy (CP). METHODS: Data from 968 preterm children with later CP were extracted from the Canadian Cerebral Palsy Registry. One hundred eighty-two infants were born before 27 weeks of gestation, 461 infants were born between 27 and 33 weeks, and 325 infants were born between 34 and 37 weeks. Univariate and chi-square analyses were conducted to measure the association between early objective biomarkers and later mobility status defined as Gross Motor Function Classification System (GMFCS) levels IV and V as well as tube feeding dependence. RESULTS: Univariate analysis suggested no significant association between GMFCS levels IV and V or impaired feeding status and bilateral white matter injury on magnetic resonance imaging, high-grade intraventricular hemorrhage on head ultrasound, chorioamnionitis, a birth weight of 1000 to 1500 g or <1000 g, as well as an Apgar score of ≤5 at five minutes of life. Similar results were found for gestational age <28 weeks at birth. Only a significant association between GMFCS levels IV and V and a cord or first hour of life pH of ≤7 was reported (mobility status: odds ratio [OR] 1.95, 95% confidence interval [CI] 1.09 to 3.57) and feeding status: OR 2.23, CI 0.97 to 4.65)]. CONCLUSIONS: Prediction of functional outcomes based on specific early biomarkers appears hard to obtain in children with CP born preterm in contrast to those born at term. The complications and causal pathways inherent to prematurity may contribute to making prognostication less determinant.

Uncertainties Regarding Cerebral Palsy Diagnosis: Opportunities to Clarify the Consensus Definition.

Background and Objectives: We have established that physicians, including neurologists, variably diagnose cerebral palsy (CP) when using the most recent CP definition from 2006. We also know that child neurologists and neurodevelopmentalists view themselves to be optimally suited to diagnose CP based on their training backgrounds. Therefore, to reduce variability in CP diagnosis, our objective was to elucidate uncertainties child neurologists and neurodevelopmentalists may have regarding practical application of the 2006 definition. Methods: We conducted a cross-sectional survey of child neurologists and neurodevelopmentalists built into a discussion seminar at the 2022 Child Neurology Society (CNS) Annual Meeting, the largest professional meeting of these specialists in North America. Seminar attendees were provided the 2006 definition and asked whether they had any uncertainties about the practical application of the definition across 4 hypothetical clinical vignettes. A group of national and international CP leaders then processed these data through iterative discussions to develop recommendations for clarifying the 2006 definition. Results: The seminar was attended by 50% of all conference attendees claiming CME (202/401). Of the 164 closing survey respondents, 145 (88%) expressed uncertainty regarding the clinical application of the 2006 definition. These uncertainties focused on 1) age, both regarding the minimum and maximum ages of brain disturbance or motor symptom onset (67/164, 41%), and 2) interpretation of the term "nonprogressive" (48/164, 29%). Almost all respondents (157/164, 96%) felt that we should revise the 2006 consensus definition of CP. Discussion: To address the most common CP diagnostic uncertainties we identified, we collectively propose 4 points of clarification to the 2006 definition: 1) motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible; 3) the clinical motor disability phenotype should be nonprogressive through 5 years old; and 4) a CP diagnosis should be re-evaluated if motor disability is progressive or absent by 5 years old. We anticipate that clarifying the 2006 definition of CP in this manner could address the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.

Association of Gestational Age at Birth and Changes on MRI With Prevalence and Spectrum of Comorbidities in Children With Cerebral Palsy.

BACKGROUND AND OBJECTIVES: For individuals with cerebral palsy (CP) and caregivers, comorbidities may be a greater challenge than neuromotor impairment. Clinicians may make assumptions regarding risk of comorbidities based simply on term vs preterm birth, but this has not been well examined. To better understand factors affecting comorbidity pattern, we investigated the relationship between gestational age (GA) and imaging pattern on the presence of specific comorbidities. METHODS: This is a cross-sectional study of data extracted from the Canadian Cerebral Palsy Registry of children with CP. Multivariable analysis was used to evaluate the relationship between brain injury, GA, and comorbidities. Comorbidities included in the analysis were communication, cognitive, visual, and auditory impairment, seizures in the past year, and gavage feeding. Each comorbidity was assessed as a separate nonexclusive outcome, with GA, MRI pattern, birth weight, postneonatal insult, 5-minute Apgar score, and male sex considered as potential modifiers. RESULTS: The only comorbidity affected by GA on multivariable analysis was seizures within the past year that were more prevalent in term children (odds ratio [OR] 1.1 95% CI 1.0-1.2) and was also affected by Apgar score (OR 0.9 95% CI 0.85-0.94), but not MRI pattern. MRI pattern appeared important for communication impairment (deep gray OR 4.2 95% CI 1.8-10.0; total brain injury OR 8.5, 95% CI 3.2-22.6; malformation OR 2.7, 95% CI 1.3-5.7) and cognitive impairment (deep gray OR 5.6, 95% CI 2.4-13.2; total brain injury OR 10.1, 95% CI 4.0-25.3; malformation OR 3.3, 95% CI 1.6-6.8; watershed OR 3.6, 95% CI 1.4-8.9). Focal injury compared with normal MRI was associated with reduced odds of visual impairment (OR 0.24, 95% CI 0.12-0.48), auditory impairment (OR 0.2195% CI 0.10-0.46) and communication impairment (OR 0.46, 95% CI 0.26-0.82), and overall number of comorbidities (coefficient -0.73, 95% CI -1.2 to -0.31). The number of comorbidities was increased by total brain injury pattern (coefficient 0.65, 95% CI 0.15-1.13) and reduced by focal brain injury (coefficient -0.73, 95% CI -1.2 to -0.31) and increasing 5-minute Apgar score (coefficient -0.11, 95% CI -0.16 to -0.07). DISCUSSION: In those with brain injuries sufficient to cause CP, development of additional comorbidities is less affected by GA at birth and more related to the underlying cause of CP as reflected by MRI patterns.

Risk Factors for Perinatal Arterial Ischemic Stroke: A Machine Learning Approach.

BACKGROUND AND OBJECTIVES: Perinatal arterial ischemic stroke (PAIS) is a focal vascular brain injury presumed to occur between the fetal period and the first 28 days of life. It is the leading cause of hemiparetic cerebral palsy. Multiple maternal, intrapartum, delivery, and fetal factors have been associated with PAIS, but studies are limited by modest sample sizes and complex interactions between factors. Machine learning approaches use large and complex data sets to enable unbiased identification of clinical predictors but have not yet been applied to PAIS. We combined large PAIS data sets and used machine learning methods to identify clinical PAIS factors and compare this data-driven approach with previously described literature-driven clinical prediction models. METHODS: Common data elements from 3 registries with patients with PAIS, the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and a longitudinal cohort of healthy controls (Alberta Pregnancy Outcomes and Nutrition Study), were used to identify potential predictors of PAIS. Inclusion criteria were term birth and idiopathic PAIS (absence of primary causative medical condition). Data including maternal/pregnancy, intrapartum, and neonatal factors were collected between January 2003 and March 2020. Common data elements were entered into a validated random forest machine learning pipeline to identify the highest predictive features and develop a predictive model. Univariable analyses were completed post hoc to assess the relationship between each predictor and outcome. RESULTS: A machine learning model was developed using data from 2,571 neonates, including 527 cases (20%) and 2,044 controls (80%). With a mean of 21 features selected, the random forest machine learning approach predicted the outcome with approximately 86.5% balanced accuracy. Factors that were selected a priori through literature-driven variable selection that were also identified as most important by the machine learning model were maternal age, recreational substance exposure, tobacco exposure, intrapartum maternal fever, and low Apgar score at 5 minutes. Additional variables identified through machine learning included in utero alcohol exposure, infertility, miscarriage, primigravida, meconium, spontaneous vaginal delivery, neonatal head circumference, and 1-minute Apgar score. Overall, the machine learning model performed better (area under the curve [AUC] 0.93) than the literature-driven model (AUC 0.73). DISCUSSION: Machine learning may be an alternative, unbiased method to identify clinical predictors associated with PAIS. Identification of previously suggested and novel clinical factors requires cautious interpretation but supports the multifactorial nature of PAIS pathophysiology. Our results suggest that identification of neonates at risk of PAIS is possible.

Risk Factors for Term-Born Spastic Diplegic Cerebral Palsy: A Case-Control Study.

BACKGROUND: To identify if a predetermined set of potential risk factors are associated with spastic diplegic cerebral palsy (SDCP) in term-born children. METHODS: This is a case-control study with cases (n = 134) extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls (n = 1950) from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Our primary variable was the SDCP phenotype in term-born children. Possible risk factors were selected a priori and include extreme maternal age (<19 or >35 years), pregnancy complications, maternal disease, substance use, perinatal infection, mode of delivery, perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia), sex, and birth weight. Multivariable analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Multivariable analysis revealed associations between term-born SDCP and pregnancy complications (OR = 4.73; 95% CI = 1.91 to 10.56), maternal disease (OR = 2.52; 95% CI = 1.57 to 3.93), substance use (OR = 3.11; 95% CI = 2.10 to 4.55), perinatal infection (OR = 2.72; 95% CI 1.32 to 5.10), Caesarean section (OR = 2.35; 95% CI = 1.62 to 3.40), and perinatal adversity (OR = 2.91; 95% CI = 1.94 to 4.50). Multiple regression analysis revealed associations between SDCP and pregnancy complications (OR = 3.28; 95% CI 1.20 to 8.15), maternal disease (OR = 2.52; 95% CI 1.50 to 4.12), substance use (OR = 3.59; 95% CI 2.37 to 5.40), perinatal infection (OR = 3.78, 95% CI 1.71 to 7.72), Caesarean section (OR = 2.72; 95% CI 1.82 to 4.03), and perinatal adversity (OR = 4.16; 95% CI 2.67 to 6.70). INTERPRETATION: Antenatal (pregnancy complications, maternal disease, substance use) and perinatal (infections, Caesarean section, and perinatal adversity) risk factors are associated with an increased risk of SDCP in term-born children, suggesting variable interactions between risk factors to provide a clinicopathologic framework that is different from SDCP observed in preterm-born children.

Risk Factors and Outcomes for Cerebral Palsy With Hypoxic-Ischemic Brain Injury Patterns Without Documented Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Perinatal hypoxic-ischemic brain injury is a leading cause of term-born cerebral palsy, the most common lifelong physical disability. Diagnosis is commonly made in the neonatal period by the combination of neonatal encephalopathy (NE) and typical neuroimaging findings. However, children without a history of neonatal encephalopathy may present later in childhood with motor disability and neuroimaging findings consistent with perinatal hypoxic-ischemic injury. We sought to determine the prevalence of such presentations using the retrospective viewpoint of a large multiregional cerebral palsy registry. METHODS: Patient cases were extracted from the Canadian Cerebral Palsy Registry with gestational age >36 weeks, an MRI pattern consistent with hypoxic-ischemic injury (HII, acute total, partial prolonged, or combined), and an absence of postnatal cause for HII. Documentation of NE was noted. Maternal-fetal risk factors, labor and delivery, neonatal course, and clinical outcome were extracted. Comparisons were performed using χ2 tests and multivariable logistic regression with multiple imputation. Propensity scores were used to assess for bias. RESULTS: Of the 170 children with MRI findings typical for HII, 140 (82.4%, 95% confidence interval [CI] 75.7%-87.7%) had documented NE and 29 (17.0%, 95% CI 11.7%-23.6%) did not. The group without NE had more abnormalities of amniotic fluid volume (odds ratio [OR] 15.8, 95% CI 1.2-835), had fetal growth restriction (OR 4.7, 95% CI 1.0-19.9), had less resuscitation (OR 0.03, 95% CI 0.007-0.08), had higher 5-minute Apgar scores (OR 2.2, 95% CI 1.6-3.0), were less likely to have neonatal seizures (OR 0.004, 95% CI 0.00009-0.03), and did not receive therapeutic hypothermia. MRI was performed at a median 1.1 months (interquartile range [IQR] 0.67-12.8 months) for those with NE and 12.2 months (IQR 6.6-25.9) for those without (p = 0.011). Patterns of injury on MRI were seen in similar proportions. Hemiplegia was more common in those without documented NE (OR 5.1, 95% CI 1.5-16.1); rates of preserved ambulatory function were similar. DISCUSSION: Approximately one-sixth of term-born children with an eventual diagnosis of cerebral palsy and MRI findings consistent with perinatal hypoxic-ischemic brain injury do not have documented neonatal encephalopathy, which was associated with abnormalities of fetal growth and amniotic fluid volume, and a less complex neonatal course. Long-term outcomes seem comparable with their peers with encephalopathy. The absence of documented neonatal encephalopathy does not exclude perinatal hypoxic-ischemic injury, which may have occurred antenatally and must be carefully evaluated with MRI.

SIGnature Libraries: A roadmap for the formation of special interest group libraries.

Objective: "SIGnature Libraries" channel the dynamism of academic society-based special interest groups (SIG) to systematically identify and provide user-oriented access to essential literature for a subspecialty field in a manner that keeps pace with the field's continuing evolution. The libraries include literature beyond clinical trial data to encompass historical context, diagnostic conceptualization, and community organization materials to foster a holistic understanding of how neurologic conditions affect individuals, their community, and their lived experience. Methods: Utilizing a modified-Delphi approach, Child Neurology Society's Cerebral Palsy (CP) SIG (n = 75) administered two rounds of literature submissions and ratings. A final review by an 11-member international advisory group determined threshold ratings for resource inclusion and the library's final structure. Results: Seventy-nine articles were submitted for the first Delphi round and 22 articles for the second Delphi round. Survey response rates among SIG members were 29/75 for the first round and 24/75 for the second round. The advisory board added additional articles in the final review process in view of the overall project goal. A total of 60 articles were included in the final library, and articles were divided into seven sections and stratified by rating scores. A process for ongoing revisions of the library was determined. The library will be published on the Child Neurology Society website and made publicly accessible. Conclusions: The CP SIGnature Library offers learners an unprecedented resource that provides equitable access to latest consensus guidelines, existing seminal datasets, up-to-date review articles, and other patient care tools. A distinctive feature of the library is its intentional large scope and depth, presented in a stratified fashion relative to the consensus-determined importance of each article. Learners can efficiently navigate the library based on individual interests and goals, and the library can be used as core curriculum for CP education.

Uncertainties regarding cerebral palsy diagnosis: opportunities to operationalize the consensus definition.

Background and Objectives: Cerebral palsy (CP), the most common motor disability of childhood, is variably diagnosed. We hypothesized that child neurologists and neurodevelopmentalists, often on the frontlines of CP diagnosis in North America, harbor uncertainties regarding the practical application of the most recent CP consensus definition from 2006. Methods: We conducted a cross-sectional survey of child neurologists and neurodevelopmentalists at the 2022 Child Neurology Society Annual Meeting. Attendees were provided the 2006 CP consensus definition and asked whether they had any uncertainties about the practical application of the definition across four hypothetical clinical vignettes. Results: Of 230 attendees, 164 responded to the closing survey questions (71%). 145/164 (88%) expressed at least one uncertainty regarding the clinical application of the 2006 definition. Overwhelmingly, these areas of uncertainty focused on: 1) Age, both with regards to the minimum age of diagnosis and the maximum age of brain disturbance or motor symptom onset, (67/164, 41%), and 2) Interpretation of the term "non-progressive" (48/164, 29%). The vast majority of respondents (157/164, 96%) answered 'Yes' to the question: Do you think we should revise the 2006 consensus definition of CP? Discussion: We propose that the uncertainties we identified could be addressed by operationalizing the 2006 consensus definition to support a more uniform CP diagnosis. To address the most common CP diagnostic uncertainties we identified, we propose 3 points of clarification based on the available literature: 1) Motor symptoms/signs should be present by 2 years old; 2) CP can and should be diagnosed as early as possible, even if activity limitation is not yet present, if motor symptoms/signs can be reasonably predicted to yield activity limitation (e.g. by using standardized examination instruments, Brain MRI, and a suggestive clinical history); and 3) The clinical motor disability phenotype should be non-progressive through 5 years old. We anticipate that operationalizing the 2006 definition of CP in this manner could clarify the uncertainties we identified among child neurologists and neurodevelopmentalists and reduce the diagnostic variability that currently exists.

Characteristics of Children With Cerebral Palsy in the Post-Therapeutic Hypothermia Era.

Objectives: To explore the profile of children with cerebral palsy secondary to intrapartum asphyxia treated with therapeutic hypothermia after birth and to compare characteristics of children treated with therapeutic hypothermia with mild vs severe cerebral palsy outcome. Study Design: We identified all children treated with therapeutic hypothermia for intrapartum asphyxia in a single-center tertiary-level neonatal intensive care unit from 2008 to 2018 with a cerebral palsy outcome. We collected perinatal and outcome measures from patient charts. We searched the literature for characteristics of children with cerebral palsy prior to therapeutic hypothermia (historical cohort) to compare to our cohort. We subdivided our cohort into mild vs severe cerebral palsy and compared neonatal characteristics to identify predictors of severe phenotype. Results: Thirty of 355 cooled neonates (8%) developed cerebral palsy. More children had spastic quadriparesis and epilepsy, and fewer had visual impairment in the post-therapeutic hypothermia era compared to the historical cohort, but had similar Gross Motor Function Classification System scores. In our cohort, more children had severe (19 of 30, 63%) compared to mild cerebral palsy (11 of 30, 37%). The severe group had higher mean birth weight, lower 5- and 10-minute Apgar scores, and more often white matter injury with associated deep gray matter injury or near-total injury pattern (P < .05). Conclusions: Our data demonstrated more infants with severe rather than mild cerebral palsy in our cohort treated with therapeutic hypothermia. Birthweight, 5- and 10-minute Apgar scores, and magnetic resonance imaging (MRI) findings were significantly different between mild and severe phenotype groups. Our findings can guide clinicians how to better weigh these factors, when counseling parents in the neonatal period.

Evaluation of Individuals with Non-Syndromic Global Developmental Delay and Intellectual Disability.

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID.

Physicians' attitudes towards ethical issues and end-of-life decision-making for pediatric patients with unresponsive wakefulness syndrome: An international survey.

AIM: We examined physicians' perspectives on the mental capabilities of pediatric patients with unresponsive wakefulness syndrome (UWS) and their attitudes towards limiting life-sustaining treatment (LST) in an international context. METHOD: A questionnaire survey was conducted among 267 neuropediatricians, practicing in 65 countries. Comparisons were made according to the Human Development Index (HDI) of the countries. The Idler Index of Religiosity was applied to determine religiosity. RESULTS: Participants from countries with a very high HDI were generally more favorable to limiting LST (p < 0.001), specifically cardiopulmonary resuscitation (p = 0.021), intubation/ventilation (p = 0.014), hemodialysis/hemofiltration (p < 0.001), and antibiotic therapy (p < 0.001). Treatment costs that were too high had a weaker influence on their decisions (p < 0.001). Participants who found it never ethically justifiable to limit LST had a higher mean Idler Index of private (p = 0.001) and general (p = 0.020) religiosity and were less satisfied with treatment decisions (p < 0.001) and the communication during the process (p = 0.016). INTERPRETATION: The perspectives towards limiting LST for pediatric patients with UWS are markedly different between physicians from countries with very high and lower HDIs.

Early Biomarkers in the Prediction of Later Functional Impairment in Term Children with Cerebral Palsy.

AIM: To identify possible early biomarkers that could predict later functional capabilities in children at risk for cerebral palsy (CP). METHODS: Data from 869 term children with CP were extracted from the Canadian Cerebral Palsy Registry. Univariate analyses were conducted to measure the association between readily available objective early biomarkers (neonatal encephalopathy [NE], cord or first hour of life pH, magnetic resonance imaging [MRI]) and functional outcomes such as mobility and feeding status. Multivariable regressions were then modeled to study whether adding predictors would affect the strength of the observed association. RESULTS: Patients with NE have higher odds of having an assigned Gross Motor Function Classification Score level of IV to V (prevalence ratio [PR], 2.87; 95% confidence interval [CI], 2.07 to 3.97) and are more likely to require dependent tube feeding (PR, 2.09; 95% CI, 1.12 to 3.88); this was similarly seen in patients with MRI findings of deep gray matter injury, watershed injury, near-total brain injury, and/or cortical malformation (mobility status [PR, 5.13; 95% CI, 3.73 to 7.11] and feeding status [PR, 4.87; 95% CI, 2.57 to 9.75]). Patients with cord or first hour of life pH <7 were also more likely to predict dependent mobility status (PR, 2.86; 95% CI, 1.76 to 4.69), however, not significantly more likely to predict eventual dependent feeding status (PR, 1.47; 95% CI, 0.58 to 3.32). CONCLUSIONS: This retrospective cohort study demonstrates that NE, MRI findings and cord or first hour of life pH can reliably predict later CP related functioning. These associations can be used to inform and clarify early prognosis discussions between caregivers and health professionals.

Development of a Bedside Tool to Predict the Diagnosis of Cerebral Palsy in Term-Born Neonates.

Importance: Cerebral palsy (CP) is the most common abnormality of motor development and causes lifelong impairment. Early diagnosis and therapy can improve outcomes, but early identification of infants at risk remains challenging. Objective: To develop a CP prognostic tool that can be applied to all term neonates to identify those at increased risk of developing CP. Design, Setting, and Participants: This case-control study used data from the Canadian Cerebral Palsy Registry (data collected from January 2003 to December 2019) for children with CP and the Alberta Pregnancy Outcomes and Nutrition study (mothers enrolled from May 2009 to September 2012; data extracted in 2020) for controls. There were 2771 children with CP and 2131 controls evaluated; 941 and 144, respectively, were removed for gestational age less than 37 weeks at birth, 565 with CP removed for incomplete data, and 2 controls removed for a diagnosis of CP. Data were analyzed from April to August 2022. Exposures: Potential risk factors were selected a priori based on the literature, including maternal, intrapartum, and infant characteristics. Main Outcomes and Measures: Diagnosis of CP, defined as a disorder of motor function due to a nonprogressive brain abnormality before age 1 year and classified by Gross Motor Function Classification System levels I to V. Results: Of 3250 included individuals, 1752 (53.9%) were male, and the median (IQR) gestational age at birth was 39 (38-40) weeks. Encephalopathy was present in 335 of 1184 infants with CP (28%) and 0 controls. The final prediction model included 12 variables and correctly classified 75% of infants, with a sensitivity of 56% (95% CI, 52-60) and specificity of 82% (95% CI, 81-84). The C statistic was 0.74 (95% CI, 71-76). Risk factors were found to be additive. A proposed threshold for screening is probability greater than 0.3, with a sensitivity of 65% (95% CI, 61-68) and specificity of 71% (95% CI, 69-73). The prognostic tool identified 2.4-fold more children with CP than would have presented with encephalopathy (odds ratio, 13.8; 95% CI, 8.87-22.65; P < .001). Conclusions and Relevance: In this case-control study, a prognostic model using 12 clinical variables improved the prediction of CP compared with clinical presentation with encephalopathy. This tool can be applied to all term newborns to help select infants for closer surveillance or further diagnostic tests, which could improve outcomes through early intervention.

Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Stability of the Gross Motor Function Classification System over time in children with cerebral palsy.

AIM: To assess the stability of the Gross Motor Functional Classification System (GMFCS) in children with cerebral palsy (CP) from time of preliminary diagnosis (~2 years of age) to time of diagnosis (~5 years of age), and to examine factors associated with reclassification. METHOD: We conducted a longitudinal study using a sample from the Canadian CP Registry. Stability was analysed by using the percentage of agreement between timepoints and a weighted prevalence and bias adjusted kappa statistic. Univariate and multivariate logistic regressions were performed to identify variables associated with reclassification. RESULTS: The study included 1670 children (857 males, 713 females) with a mean age of 11 years 4 months (SD 4 years, range 3 years 5 months-20 years 1 month) at time of data extraction (3rd September 2019), of which 1435 (85.9%) maintained a stable GMFCS, with a weighted kappa of 0.91 (95% confidence interval 0.89-0.92). Univariate logistic regression showed that initial GMFCS level, CP subtype, and the presence of cognitive impairment were associated with the likelihood of change in the GMFCS level (p < 0.1). In the multivariate analysis, however, the likelihood was associated with initial GMFCS level only (odds ratio 7.10-8.88, p < 0.00). INTERPRETATION: The GMFCS has good stability in early childhood. For the majority of children, it is predictive of their long-term motor function. WHAT THIS PAPER ADDS: The Gross Motor Function Classification System (GMFCS) rating in early childhood is stable over time. There is no directionality in the reclassification of the GMFCS. The initial GMFCS level was related to the likelihood of change in follow-up GMFCS level.

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy: A Case-Control Study.

OBJECTIVE: The aim of this study was to identify possible risk factors associated with term-born children with cerebral palsy (CP) and periventricular white matter injury (PVWMI) on imaging. METHODS: This is a case-controlled study restricted to term-born children with CP with the cases extracted from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition (APrON) study. A diagnosis of PVWMI was performed based on expert categorization of MRI reports. Risk factor variables were selected a priori; these included pregnancy complications, antenatal toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia). We used multivariable analyses to calculate odds ratios (ORs) and their 95% CIs. RESULTS: A total of 160 cases (7.06% of the registry sample) were compared with 1,950 controls. Of the term-born PVWMI participants, 59.4% were male and 13.5% were born to mothers of extreme maternal age. Multivariable analysis of each risk factor controlled for weight showed PVWMI is associated with pregnancy complications (OR = 3.35; 95% CI = 2.23-4.94), antenatal toxin exposure (OR = 2.45; 95% CI = 1.67-3.55), perinatal infection (OR = 3.61; 95% CI = 1.96-6.29), and perinatal adversity (OR = 2.03; 95% CI = 1.42-2.94). Term-born male participants were not more likely to experience PVWMI compared with female participants (OR = 1.37; 95% CI = 0.98-1.93). Multiple regression analyses suggested independent associations between PVWMI and pregnancy complications (OR = 3.75; 95% CI 2.46-5.62), antenatal toxin exposure (OR = 2.80; 95% CI 1.88-4.12), perinatal infection (OR = 4.62; 95% CI 2.46-8.42), and perinatal adversity (OR = 2.49; 95% CI = 1.71-3.69). DISCUSSION: Risk factors such as pregnancy complications, antenatal toxin exposure, perinatal infection, and perinatal adversity are associated with PVWMI in term-born children, suggesting perhaps variable interactions between antenatal and perinatal factors to yield this under-recognized CP phenotype.

Development and Validation of a Prediction Model for Perinatal Arterial Ischemic Stroke in Term Neonates.

Importance: Perinatal arterial ischemic stroke (PAIS) is a focal brain injury in term neonates that is identified postnatally but is presumed to occur near the time of birth. Many pregnancy, delivery, and fetal factors have been associated with PAIS, but early risk detection is lacking; thus, targeted treatment and prevention efforts are currently limited. Objective: To develop and validate a diagnostic risk prediction model that uses common clinical factors to predict the probability of PAIS in a term neonate. Design, Setting, and Participants: In this diagnostic study, a prediction model was developed using multivariable logistic regression with registry-based case data collected between January 2003, and March 2020, from the Alberta Perinatal Stroke Project, Canadian Cerebral Palsy Registry, International Pediatric Stroke Study, and Alberta Pregnancy Outcomes and Nutrition study. Criteria for inclusion were term birth and no underlying medical conditions associated with stroke diagnosis. Records with more than 20% missing data were excluded. Variable selection was based on peer-reviewed literature. Data were analyzed in September 2021. Exposures: Clinical pregnancy, delivery, and neonatal factors associated with PAIS as common data elements across the 4 registries. Main Outcomes and Measures: The primary outcome was the discriminative accuracy of the model predicting PAIS, measured by the concordance statistic (C statistic). Results: Of 2571 term neonates in the initial analysis (527 [20%] case and 2044 [80%] control individuals; gestational age range, 37-42 weeks), 1389 (54%) were male, with a greater proportion of males among cases compared with controls (318 [60%] vs 1071 [52%]). The final model was developed using 1924 neonates, including 321 cases (17%) and 1603 controls (83%), and 9 clinical factors associated with risk of PAIS in term neonates: maternal age, tobacco exposure, recreational drug exposure, preeclampsia, chorioamnionitis, intrapartum maternal fever, emergency cesarean delivery, low 5-minute Apgar score, and male sex. The model demonstrated good discrimination between cases and controls (C statistic, 0.73; 95% CI, 0.69-0.76) and good model fit (Hosmer-Lemeshow P = .20). Internal validation techniques yielded similar C statistics (0.73 [95% CI, 0.69-0.77] with bootstrap resampling, 10-fold cross-validated area under the curve, 0.72 [bootstrap bias-corrected 95% CI, 0.69-0.76]), as did a sensitivity analysis using cases and controls from Alberta, Canada, only (C statistic, 0.71; 95% CI, 0.65-0.77). Conclusions and Relevance: The findings suggest that clinical variables can be used to develop and internally validate a model to predict the risk of PAIS in term neonates, with good predictive performance and strong internal validity. Identifying neonates with a high probability of PAIS who could then be screened for early diagnosis and treatment may be associated with reductions in lifelong morbidity for affected individuals and their families.