Pediatric Neurology

Background and ObjectivesCerebral 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. MethodsWe 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. ResultsOf 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? DiscussionWe 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.

AimTo determine the interrater reliability and stability of the Gross Motor Function Classification System (GMFCS), mini-Manual Ability Classification System (mini-MACS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) in individuals with STXBP1-Related Disorder (STXBP1-RD) and SYNGAP1-Related Disorder (SYNGAP1-RD). MethodsData were collected from 83 individuals with STXBP1-RD (mean age = 9.8 years) and 101 individuals with SYNGAP1-RD (mean age = 10.9 years). Two raters completed the GMFCS, MACS/MiniMACS, and CFCS assessments on the same day, and test-retest stability was evaluated for participants with two longitudinal assessments. ResultsInterrater agreement varied from 73.8% to 77.3% for the STXBP1-RD cohort and from 60.5% to 83.3% for the SYNGAP1-RD cohort. Interrater reliability weighted kappa scores for the STXBP1-RD cohort varied from 0.83 to 0.93 while the SYNGAP1-RD cohort ranged from 0.66-0.81. Test-retest stability scores for the STXBP1-RD group varied from 0.62 to 0.94 while the SYNGAP1-RD group ranged from 0.38 to 0.78. Significant correlations were found between all assessment scales for both STXBP1-RD (Kendalls Tau range from 0.25-0.42) and SYNGAP1-RD (Kendalls Tau range from 0.19-0.45). InterpretationThe GMFCS, MACS/MiniMACS, and CFCS demonstrate appropriate levels of interrater reliability and stability for individuals with STXBP1-RD and SYNGAP1-RD. What this paper addsO_LIClassification tools are reliable and stable in individuals with STXBP1-RD and SYNGAP1-RD. C_LIO_LIGross motor function is least affected for both conditions. C_LIO_LILanguage function is most affected for both conditions. C_LIO_LICorrelations are decreased compared to children with cerebral palsy due to phenotype differences. C_LI

Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.

IntroductionPontocerebellar hypoplasia type 2A (PCH2A) is a rare autosomal recessive neurodegenerative disease caused by a specific pathogenic variant in the TSEN54 gene (p.A307S). Affected children show early but initially unspecific symptoms, diagnosed primarily through postnatal MRI, with confirmation by genetic testing. This study examines the diagnostic process and key considerations for accurate diagnosis. Patients and MethodsWe retrospectively collected data from 65 children (33 female, 32 male) with genetically confirmed PCH2A as part of a Natural History Study. Data were gathered via parental questionnaires, interviews, and medical reports. The cohort was divided into two groups based on year of birth: children born before (n=30) and after (n=35) the identification of the pathogenic variant in 2008. ResultsPrenatally, in 4 of 21 cases with specialized ultrasound (gestational weeks 12-32), only unspecific cerebebellar abnormalities were reported. One fetal MRI (week 31) revealed clear cerebellar hypoplasia, in two others (week 21 and 31), slight cerebellar abnormalities were reported. Postnatal neurosonography often indicated disease features (26/54), later confirmed by MRI (62/63). Clinical symptoms appeared at a median age of 0 months (range 0-6 months), often initially suggesting acute rather than congenital issues. In the group born after 2008, median time from first symptoms to genetic confirmation was 5 months. ConclusionPCH2A presents early with nonspecific symptoms. Prenatal and postnatal ultrasound imaging can fail to detect the condition, with MRI being the gold standard for diagnosis. Over time, the diagnostic process, including genetic confirmation, has become faster. Highlights- Diagnostic Challenges: Prenatal imaging fails to detect PCH2A - Postnatal Imaging: MRI 92% diagnostic sensitive, ultrasound misinterpretations - Genetic testing impact: Earlier PCH2A diagnosis in children born after 2008

Mutations in the X-linked endosomal Na+/H+ Exchanger 6 (NHE6) causes Christianson Syndrome (CS). In the largest study to date, we examine genetic diversity and clinical progression, including cerebellar degeneration, in CS into adulthood. Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. Forty-four individuals with 31 unique NHE6 mutations, age 2 to 32 years, were followed prospectively, herein reporting baseline, 1-year follow-up, and retrospective natural history. We present data on the CS phenotype with regard to physical growth, adaptive and motor regression, and across the lifespan, including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model: the rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined: a majority of adult (18+ years) participants lost gross and fine motor skills over a 1-year follow-up. Previously defined core diagnostic criteria for CS (present in >85%) - namely nonverbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia - were universally present in age 6 to 16; however, an additional core feature of high pain tolerance was added (present in 91%), and furthermore, evolution of symptoms were noted across the lifespan, such that postnatal microcephaly, ataxia and high pain threshold were often not apparent prior to age 6, and hyperkinesis decreased after age 16. While neurologic exams were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study. In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype, thereby identifying critical targets for treatment.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

ObjectiveCerebral palsy (CP) affects approximately 1 million Americans and 18 million individuals worldwide, yet contemporary US epidemiologic data remains limited. We aimed to use Cerebral Palsy Research Network (CPRN) clinical registry to describe demographics and clinical characteristics of individuals with CP across the US and determine associations with gross motor function and genetic etiology. MethodsRegistry subjects were included if they had clinician-confirmed CP and prospectively entered data for Gross Motor Function Classification System (GMFCS) Level, gestational age, genetic etiology, CP distribution, and tone/movement types. Logistic regression was used to determine which of these variables plus race, sex, ethnicity, and age were associated with GMFCS level and genetic etiology. ResultsA total of 9,756 children and adults with CP from 22 CPRN sites met inclusion criteria. Participants were predominantly White (73.0%), male (57.3%), non-Hispanic (87.8%), and younger than 18 years (73.7%). Most were classified as GMFCS levels I-III (55.6%), born preterm (52.8%), had spasticity (83.8%), and had quadriplegia (41.9%); 12.2% were identified as having a genetic etiology. Tone/movement types, CP distribution, and gestational age were significantly associated with both GMFCS level and genetic etiology (p<0.001). Compared to White individuals, Black individuals were more likely to have greater gross motor impairment (p<0.001). ConclusionIn this large US cohort, clinical and demographic factors, including race, were associated with gross motor function and genetic etiology in CP. These findings highlight persistent disparities and demonstrate the value of a national clinical registry for informing prognostication, quality improvement efforts, and targeted genetic testing strategies.

Background and ObjectiveTourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/MethodsData from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. ResultsFemales with TS (25.5% of the sample) had a later age of symptom onset (6.5{+/-}2.8 vs. 6.0{+/-}2.7; p=0.001), later age at diagnosis (13.3{+/-}11.2 vs. 10.7{+/-}8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4{+/-}9.1 vs. 30.7{+/-}8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9{+/-}3.3 vs. 8.9{+/-}3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). ConclusionFemales with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.

ObjectiveTo describe a standardized methodology for capturing clinically valuable information on young people with cerebral palsy (CP) from caregivers and clinicians during routine clinical care. MethodsWe developed a caregiver-facing intake form and clinician-facing standardized note template and integrated both into routine clinical care at a tertiary care CP center (https://bit.ly/CP-Intake-Methodology). We extracted this caregiver and clinician-entered data on people with an ICD10 diagnosis of CP seen between 3/22/23 and 12/28/23. We used this data to describe how CP manifests in this group and which medical features affected the odds of walking, oral feeding, and speech by age 5. ResultsOf 686 visits, 663 (97%) had caregiver- and clinician-entered data and 633 had a clinician-confirmed CP diagnosis (mean age 9.1, 53.4% Male, 78.5% White). It was common to have quadriplegia (288/613, 47.0%), both spasticity and dystonia (257/632, 40.7%), walk independently (368/633, 58.1%), eat all food and drink safely by mouth (288/578, 55.9%), and produce understandable speech (249/584, 42.6%). Cortical grey matter injury and duration of initial critical care unit stay affected the odds of walking, oral feeding, and speech (binary logistic regression, p<0.001). ConclusionsWe comprehensively captured caregiver and clinician-entered data on 97% of people seen in a tertiary care CP Center and used this data to determine medical features affecting the odds of three functional outcomes. By sharing our methodology, we aim to facilitate replication of this dataset at other sites and grow our understanding of how CP manifests in the US. Article summaryUsing caregiver and clinician-entered data on people seen in a tertiary-care CP center, we determined medical features affecting the odds of three functional outcomes. Whats known on this subjectDetailed CP characterization can be limited if using population-based registries and retrospective chart review alone, including limited data on recently validated functional classification systems for CP. What this study addsWe comprehensively captured caregiver and clinician-entered data on 97% of people seen in our CP Center to describe how CP manifests and show that cortical injury and initial ICU stay duration affect the odds of walking, oral feeding, and speech. Contributors StatementSusie Kim helped design the study, aggregated data, carried out data analyses, and critically reviewed and revised the manuscript. Kelsey Steffen helped conceptualize and design the study and critically reviewed and revised the manuscript. Lauren Gottschalk, Jennifer Miros, Katie Leger, Amy Viehoever, and Karen Taca helped design the study and critically reviewed and revised the manuscript. Bhooma Aravamuthan conceptualized and designed the study, supervised data collection and analysis, drafted the initial manuscript, and critically reviewed and revised the manuscript.

AimTo determine the specific movement features in children with cerebral palsy (CP) that prompt expert identification of dystonia MethodsDystonia identification in CP, particularly when co-morbid with spasticity, can be difficult. For this retrospective case-control study, we conducted a qualitative thematic analysis of consensus-building discussions between three pediatric movement disorders physicians as they attempted to identify the presence or absence of dystonia in gait videos of 40 subjects with spastic CP and periventricular leukomalacia. ResultsInitial unanimous consensus regarding the presence or absence of dystonia was achieved in 12 videos (30%). Following consensus building discussion, 22 additional videos (55%) yielded unanimous consensus. Two main themes were generated: 1) Unilateral leg or foot adduction that was variable over time, and 2) Difficulty in identifying dystonia. Codes contributing to Theme 1 were more likely to appear when a discussant was favoring the presence of dystonia in a video (Chi-square, p=0.004). DiscussionThese results provide specific movement features that could aid dystonia diagnosis in ambulatory children with CP. However, these results also suggest that, even amongst putative motor phenotyping experts, visual dystonia diagnosis in CP remains difficult, highlighting the need for developing and using objective dystonia diagnosis measures. What this paper adds- Dystonia identification is visually difficult, even for experts - Unilateral lower extremity variable adduction could represent gait dystonia in cerebral palsy - Qualitative thematic analysis objectively identifies expert-cited dystonia features in cerebral palsy

BackgroundThe prevalence of symptomatic COVID-19 in children remains low to date. In just a few months, COVID-19 has affected millions of people worldwide, and as of the date of this publication, the pandemic continues. Based on the current available evidence, children do not appear to be at higher risk of contracting COVID-19 than adults. However, children with neurological and neuromuscular conditions are vulnerable to the respiratory complications of other viral infections. ObjectivesTo assess whether children with brain-based developmental disabilities were more likely to develop COVID-19 and have complications or poorer outcomes following infection. MethodsWe conducted a two-week rapid review on studies with primary data regarding children aged between zero and 18 years old with brain-based developmental disabilities, or who were at risk of developing such disabilities, with confirmed or suspected COVID-19. We performed our literature searches on April 18, 2020. ResultsOur search strategy identified 538 individual records, of which four were included in our review. Of the 50 COVID-19 pediatric patients reported in the included studies, a total of seven children were at risk of developing brain-based disabilities. Symptoms ranged in severity. However, generally, patients were discharged or saw improvements in their symptoms by the end of the study period. No deaths were reported. DiscussionOur study highlights a knowledge gap regarding the impact of COVID-19 in children with brain-based developmental disabilities.

BackgroundThe trio Rho guanine nucleotide exchange factor gene (TRIO) is highly expressed in the developing brain and contributes to neuronal development, specifically axon guidance, synaptogenesis, and cytoskeleton organization. Pathogenic TRIO variants are associated with a neurodevelopmental disorder with substantial phenotypic heterogeneity. Prior case series suggested genotype-phenotype associations related to variant type and location in the protein. However, these results need validation in a larger sample. The objectives of this research were to examine associations between phenotype, variant location and variant type among previously reported TRIO-related neurodevelopmental disorder cases, and identify recurrent TRIO variants. MethodsEighty-seven previously published studies annotated in the Human Gene Mutation Database reporting at least one TRIO variant were identified. Thirty-two additional cases were ascertained from the Simons Searchlight Study. A total of 699 individual case records were reviewed. After removing redundant cases, 449 unique records remained with available genotype data, of which 228 also had available phenotype information. Along with descriptive statistics, Chi-square analysis was used to test associations between variant and head size. ResultsIn a meta-analysis of reported TRIO variants, categorically-defined head size is associated with variant type (missense vs truncating) and protein domain location ({chi}2 = 39.20; p = <0.001). Specifically, missense variants in the spectrin repeat domain are associated with macrocephaly whereas missense variants outside the spectrin domain and truncating variants are associated with microcephaly. The most prevalent phenotypic features were intellectual disability/developmental delay followed by autism spectrum disorder (ASD) or ASD-like behaviors. Seven recurrent TRIO variants were identified, with head size consistent across cases with the same variant. ConclusionsTRIO variant type and location exhibit unique phenotypic associations. This observation may help clinicians and families to anticipate neurodevelopmental outcomes. Furthermore, identified recurrent variants may serve as targets for future translational and pharmacological research.

AIM: To evaluate whether selective motor control quantified from spontaneous infant movement recordings provides diagnostic and prognostic information for cerebral palsy (CP) beyond established movement-based assessments. METHOD: This multicenter diagnostic and prognostic accuracy study included 302 infants (151 with CP) with spontaneous movement recordings obtained between 10 and 20 weeks corrected age from cohorts in Australia and the United States. All eligible infants with CP were included, and a comparison sample without CP was randomly selected. Recordings were scored using the Baby Observational Selective Control Appraisal (BabyOSCAR), Motor Optimality Score Revised (MOS-R), and General Movements Assessment (GMA). Outcomes at 2 years or older included CP diagnosis, Gross Motor Function Classification System (GMFCS) level, and motor distribution. RESULTS: BabyOSCAR discriminated CP diagnosis (area under the curve [AUC] 0.98), including children later classified in GMFCS level I. Among infants with CP, BabyOSCAR discriminated GMFCS levels I - II from III - V (AUC 0.89). BabyOSCAR absolute asymmetry also discriminated unilateral CP from all other infants (AUC 0.90). Diagnostic discrimination was also observed for MOS-R (AUC 0.94) and GMA (AUC 0.86). INTERPRETATION: Quantifying selective motor control from brief infant movement recordings may provide complementary early information about CP diagnosis, functional level, and motor distribution.

Dystonia treatment evaluation in cerebral palsy (CP) is limited by the lack of clinician-assessed scales linking dystonia severity to functional impact. We asked 7 pediatric movement disorder specialists to review videos of 27 children with CP while performing an upper extremity task and while walking. Experts rated arm and leg dystonia severity using the Global Dystonia Severity Rating Scale (GDRS) and task-specific functional impact on a five-point scale adapted from the Dyskinetic Cerebral Palsy Functional Impact Scale. Arm GDRS scores correlated with functional impact on the upper extremity task (linear regression R2=0.48, p=0.0005). Leg GDRS scores correlated with gait impact (R2=0.43, p=0.001). A four-point increase in total GDRS corresponded to a one-point worsening in combined functional impact. By demonstrating how expert-rated limb dystonia severity correlates with task-specific functional impact in children with CP, these results could help clinically identify functionally-meaningful differences in dystonia severity.

Background and objectivesSex chromosome trisomy (SCT) is a common chromosomal abnormality associated with increased risks for early developmental delays and neurodevelopmental disorders later in childhood. Our objective was to quantify the spectrum of early developmental milestones in SCT. We hypothesized later milestone achievement in SCT than the general population. MethodsData were collected as part of the eXtraordinarY Babies Study, a prospective natural history of developmental and health trajectories in a prenatally identified sample of infants with SCT. Parent reported, clinician-validated, early motor and language milestones were collected at 2, 6, 12, 18, 24, and 36-months. Age distributions of milestone achievement were compared with normative data. ResultsIn all SCT conditions, compared with normative data, there was increased variability and a later median age of skill development across multiple gross motor and expressive language milestones. Results also show a significant amount of overlap with the general pediatric population, suggesting that for many children with prenatally identified SCT, early milestones present within, or close to, the expected timeline. ConclusionsAs increasing numbers of infants with prenatal SCT diagnoses present at pediatric practices, we provide an evidence-based schedule of milestone achievement in SCT as a tool for pediatricians and families. Detailed data on SCT milestones can support clinical interpretation of milestone achievement. Increased variability and later median age of milestone acquisition in SCT compared to norms support consideration of all infants with SCT as high risk.

AIM: STXBP1-related disorder (STXBP1-RD) is a severe developmental and epileptic encephalopathy characterized by early-onset seizures and persistent cognitive and motor impairments. With disease-modifying trials emerging, a disorder-specific severity scale is needed. To address this, we adapted a validated clinician-reported measure from CDKL5 Deficiency Disorder to develop the STXBP1 Clinical Severity Assessment (S-CSA) and evaluated its psychometric properties. METHOD: The S-CSA was adapted from the CDKL5 Clinical Severity Assessment through expert consensus sessions with STXBP1 clinicians. Revisions addressed gaps in motor and vision domains, adding tremor and vision items. The measure was administered to 123 individuals with STXBP1-RD. Psychometric evaluation included confirmatory factor analysis, internal consistency, composite reliability, average variance extracted, and distinctiveness, compared with recommended thresholds. RESULTS: Analyses supported a three-domain structure (motor, communication, vision) with factor loadings >0.5 and strong internal consistency (Cronbachs alpha >0.7; composite reliability >0.88). Model fit and variance metrics met recommended standards, and domains demonstrated distinctiveness. No ceiling or floor effects were observed. Minimal skew was seen in motor (0.34) and communication (0.16) domains; positive skew in vision (2.2) was seen, identifying patients with and without cortical visual impairment. INTERPRETATION: The S-CSA demonstrates strong validity and reliability in STXBP1-RD and may show utility in clinical trials for STXBP1-RD and potentially other severe DEEs. Key Words: STXBP1-Related Disorder, Developmental and Epileptic Encephalopathies, Clinical Outcome Assessments

AbstractO_ST_ABSBackgroundC_ST_ABSThe increasing clinical use of combining structural MRI (sMRI) with General Movements Assessment (GMA) or Hammersmith Infant Neurological Exam (HINE) before five months corrected age (CA) for early diagnosis of cerebral palsy (CP) lacks sufficient prognostic data for children with CP, especially those with Gross Motor Function Classification System (GMFCS) I. ObjectiveEvaluate the predictive value of sMRI, GMA, and HINE individually and in combination for early CP diagnosis and assess accuracy across varying GMFCS levels in a regional cohort of preterm infants. MethodsWe performed sMRI between 39-44 weeks postmenstrual age and GMA and HINE between 12-18 weeks CA in 395 preterm infants born at [&le;]32 weeks gestation across five NICUs in Greater Cincinnati. Brain abnormalities on sMRI included white matter injuries, cortical and deep gray matter lesions, or extensive cerebellar hemorrhage. Absent fidgety movements constituted abnormal GMA; abnormal HINEs were scores <56. The primary outcome was CP diagnosis at 22-26 months CA, classified by the GMFCS. We calculated sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios for individual tests and combinations. ResultsOf 338 (86%) infants with complete follow-up, 48 (14.2%) showed sMRI abnormalities, 15 (4.6%) had abnormal GMA, and 69 (20.9%) had abnormal HINE. Thirty-nine children (11.5%) developed CP at age 2, of which 28 had GMFCS level I and 11 had GMFCS >II. The combination of sMRI and GMA achieved 100% specificity but only 22% sensitivity while the combination of abnormal sMRI and HINE demonstrated sensitivity of 32% and specificity of 98% for prediction of CP. Individual or combined tests showed far higher sensitivity (78-100%) for predicting CP in children with GMFCS levels II-V. ConclusionsThe combination of sMRI with GMA or HINE demonstrated high specificity but low sensitivity for early CP diagnosis in a regional cohort of preterm infants. This approach appears effective for early detection of CP levels II-V but not for level I cases, the most prevalent type, underscoring the need for continued developmental follow-up for all very preterm infants and need for more sensitive diagnostic tools for early detection of CP. Key PointsO_ST_ABSQuestionsC_ST_ABSWhat is the individual and combined prognostic accuracy of sMRI, GMA, and HINE for early diagnosis of CP in preterm infants? FindingsIn our prospective, regional study of preterm infants born at [&le;]32 weeks gestation, we found that combining brain abnormalities on sMRI with abnormal GMA achieved 100% specificity but 22% sensitivity for diagnosing CP. Individual or combined tests showed far higher sensitivity (78-100%) for predicting CP in children with GMFCS levels II-V. Both individual and combined tests were poor predictors of GMFCS level I CP, the most common type. MeaningWhile sMRI combined with GMA or HINE is effective for diagnosing CP with GMFCS levels II-V, this approach falls short for children with GMFCS level I.

Background and ObjectivesTraumatic brain injury (TBI) is the leading cause of acquired disability in children. Children with TBI are at risk of persistent deficits in neurocognitive functioning that affect daily life. However, neurocognitive outcomes are highly heterogenous and this heterogeneity is poorly understood. This study aims to investigate whether the heterogeneity in neurocognitive outcome can be reduced by distinguishing subgroups of children with distinct profiles of neurocognitive functioning, and to investigate whether these subgroups differ in demographic, premorbid and clinical characteristics. MethodsThis multicenter study included a consecutive cohort of children with mild to severe TBI and demographically matched neurologically healthy (NH) children. Seven neurocognitive domains were assessed six months post-TBI using computerized tests. The TBI and NH group were compared on the neurocognitive domains using t-tests. Results of the TBI group were subjected to cluster analysis to derive subgroups with distinct profiles of neurocognitive functioning. Resulting subgroups were compared on demographic, premorbid and clinical characteristics available at time of hospital visit. ResultsA total of 113 children with TBI and 113 NH children were included. The TBI group had lower performance than NH children on the neurocognitive domains Speed, Stability, Attention & Control, Verbal Working Memory and Visual Working Memory (.009[&le;]ps[&le;].047, -.42[&le;]ds[&le;]-.29). Cluster analysis revealed four subgroups of patients with diverging neurocognitive outcome profiles. One subgroup was characterized by good outcome, whereas three subgroups had adverse outcome characterized by weak global outcome, weak visual-processing outcome or weak executive functioning outcome. The subgroups did not differ in clinical characteristics but did differ in demographic and premorbid characteristics. The weak global outcome subgroup had more premorbid behavioral problems, while the good outcome subgroup had higher socio-economic status than the other subgroups. DiscussionThis study indicates that children with mild to severe TBI exhibit neurocognitive deficits compared to matched controls at six months post TBI, among which subgroups of children with distinct neurocognitive outcome profiles exist. The neurocognitive outcome subgroups represent children with diverging severity and configuration of neurocognitive weaknesses. The subgroups with the diverging neurocognitive outcome profiles did not differ in clinical characteristics, highlighting the importance to consider other factors for the prognosis of neurocognitive outcome.

Background and ObjectivesApproximately 25% of pediatric patients who undergo cerebellar tumor resection develop cerebellar mutism syndrome (CMS). Our group recently showed that damage to the cerebellar outflow pathway is associated with increased risk of CMS. Here, we tested whether these findings replicate in an independent cohort. MethodsWe evaluated the relationship between lesion location and the development of CMS in an observational study of 56 pediatric patients who underwent cerebellar tumor resection. We hypothesized that individuals that developed CMS after surgery (CMS+), relative to those that did not (CMS-) would have lesions that preferentially intersected with: 1) the cerebellar outflow pathway, and 2) a previously generated lesion-symptom map of CMS. Analyses were conducted in accordance with pre-registered hypotheses and analytic methods (https://osf.io/r8yjv/). ResultsWe found supporting evidence for both hypotheses. Compared with CMS-patients, CMS+ patients (n=10) had lesions with greater overlap with the cerebellar outflow pathway (Cohens d=.73, p=.05), and the CMS lesion-symptom map (Cohens d=1.1, p=.004). DiscussionThese results strengthen the association of lesion location with risk of developing CMS and demonstrate generalizability across cohorts. These findings may help to inform the optimal surgical approach to pediatric cerebellar tumors.

ObjectiveTo investigate clinical, social, and systems-level determinants predictive of genetics clinic referral and completion of genetics clinic visits among child neurology patients. MethodsElectronic health record data were extracted from patients 0-18 years old who were evaluated in child neurology clinics at a single tertiary care institution between July 2018 to January 2020. Variables aligned with the Health Equity Implementation Framework. Referral and referral completion rates to genetics and cardiology clinics were compared among Black vs White patients using bivariate analysis. Demographic variables associated with genetics clinic referral and visit completion were identified using logistic regressions. ResultsIn a cohort of 11,371 child neurology patients, 304 genetics clinic referrals and 82 cardiology clinic referrals were placed. In multivariate analysis of patients with Black or White ethnoracial identity (n=10,601), genetics clinic referral rates did not differ by race, but were significantly associated with younger age, rural address, neurodevelopmental disorder diagnosis, number of neurology clinic visits, and provider type. The only predictors of genetics clinic visit completion number of neurology clinic visits and race/ethnicity, with White patients being twice as likely as Black patients to complete the visit. Cardiology clinic referrals and visit completion did not differ by race/ethnicity. InterpretationAlthough race/ethnicity was not associated with differences in genetics clinic referral rates, White patients were twice as likely as Black patients to complete a genetics clinic visit after referral. Further work is needed to determine whether this is due to systemic/structural racism, differences in attitudes toward genetic testing, or other factors.