Nathalie L. Maitre

Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy: Advances in Diagnosis and Treatment

Importance Cerebral palsy describes the most common physical disability in childhood and occurs in 1 in 500 live births. Historically, the diagnosis has been made between age 12 and 24 months but now can be made before 6 months’ corrected age. Objectives To systematically review best available evidence for early, accurate diagnosis of cerebral palsy and to summarize best available evidence about cerebral palsy–specific early intervention that should follow early diagnosis to optimize neuroplasticity and function. Evidence Review This study systematically searched the literature about early diagnosis of cerebral palsy in MEDLINE (1956-2016), EMBASE (1980-2016), CINAHL (1983-2016), and the Cochrane Library (1988-2016) and by hand searching. Search terms included cerebral palsy, diagnosis, detection, prediction, identification, predictive validity, accuracy, sensitivity, and specificity. The study included systematic reviews with or without meta-analyses, criteria of diagnostic accuracy, and evidence-based clinical guidelines. Findings are reported according to the PRISMA statement, and recommendations are reported according to the Appraisal of Guidelines, Research and Evaluation (AGREE) II instrument. Findings Six systematic reviews and 2 evidence-based clinical guidelines met inclusion criteria. All included articles had high methodological Quality Assessment of Diagnostic Accuracy Studies (QUADAS) ratings. In infants, clinical signs and symptoms of cerebral palsy emerge and evolve before age 2 years; therefore, a combination of standardized tools should be used to predict risk in conjunction with clinical history. Before 5 months’ corrected age, the most predictive tools for detecting risk are term-age magnetic resonance imaging (86%-89% sensitivity), the Prechtl Qualitative Assessment of General Movements (98% sensitivity), and the Hammersmith Infant Neurological Examination (90% sensitivity). After 5 months’ corrected age, the most predictive tools for detecting risk are magnetic resonance imaging (86%-89% sensitivity) (where safe and feasible), the Hammersmith Infant Neurological Examination (90% sensitivity), and the Developmental Assessment of Young Children (83% C index). Topography and severity of cerebral palsy are more difficult to ascertain in infancy, and magnetic resonance imaging and the Hammersmith Infant Neurological Examination may be helpful in assisting clinical decisions. In high-income countries, 2 in 3 individuals with cerebral palsy will walk, 3 in 4 will talk, and 1 in 2 will have normal intelligence. Conclusions and Relevance Early diagnosis begins with a medical history and involves using neuroimaging, standardized neurological, and standardized motor assessments that indicate congruent abnormal findings indicative of cerebral palsy. Clinicians should understand the importance of prompt referral to diagnostic-specific early intervention to optimize infant motor and cognitive plasticity, prevent secondary complications, and enhance caregiver well-being.

Neurodevelopmental Outcome of Infants With Unilateral or Bilateral Periventricular Hemorrhagic Infarction

OBJECTIVE: Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS: This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS: Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05–0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64–1.00] vs 11% [95% CI: 0.01–0.28]). CONCLUSIONS: Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

Respiratory consequences of prematurity: Evolution of a diagnosis and development of a comprehensive approach

Bronchopulmonary dysplasia (BPD) is the most common respiratory consequence of premature birth and contributes to significant short- and long-term morbidity, mortality and resource utilization. Initially defined as a radiographic, clinical and histopathological entity, the chronic lung disease known as BPD has evolved as obstetrical and neonatal care have improved the survival of lower gestational age infants. Now, definitions based on the need for supplementary oxygen at 28 days and/or 36 weeks provide a useful reference point in the neonatal intensive-care unit (NICU), but are no longer based on histopathological findings, and are neither designed to predict longer term respiratory consequences nor to study the evolution of a multifactorial disease. The aims of this review are to critically examine the evolution of the diagnosis of BPD and the challenges inherent to current classifications. We found that the increasing use of respiratory support strategies that administer ambient air without supplementary oxygen confounds oxygen-based definitions of BPD. Furthermore, lack of reproducible, genetic, biochemical and physiological biomarkers limits the ability to identify an impending BPD for early intervention, quantify disease severity for standardized classification and approaches and reliably predict the long-term outcomes. More comprehensive, multidisciplinary approaches to overcome these challenges involve longitudinal observation of extremely preterm infants, not only those with BPD, using genetic, environmental, physiological and clinical data as well as large databases of patient samples. The Prematurity and Respiratory Outcomes Program (PROP) will provide such a framework to address these challenges through high-resolution characterization of both NICU and post-NICU discharge outcomes.

A Pacifier-Activated Music Player With Mother’s Voice Improves Oral Feeding in Preterm Infants

OBJECTIVES: We conducted a randomized trial to test the hypothesis that mother’s voice played through a pacifier-activated music player (PAM) during nonnutritive sucking would improve the development of sucking ability and promote more effective oral feeding in preterm infants. METHODS: Preterm infants between 34 0/7 and 35 6/7 weeks’ postmenstrual age, including those with brain injury, who were taking at least half their feedings enterally and less than half orally, were randomly assigned to receive 5 daily 15-minute sessions of either PAM with mother’s recorded voice or no PAM, along with routine nonnutritive sucking and maternal care in both groups. Assignment was masked to the clinical team. RESULTS: Ninety-four infants (46 and 48 in the PAM intervention and control groups, respectively) completed the study. The intervention group had significantly increased oral feeding rate (2.0 vs 0.9 mL/min, P < .001), oral volume intake (91.1 vs 48.1 mL/kg/d, P = .001), oral feeds/day (6.5 vs 4.0, P < .001), and faster time-to-full oral feedings (31 vs 38 d, P = .04) compared with controls. Weight gain and cortisol levels during the 5-day protocol were not different between groups. Average hospital stays were 20% shorter in the PAM group, but the difference was not significant (P = .07). CONCLUSIONS: A PAM using mother’s voice improves oral feeding skills in preterm infants without adverse effects on hormonal stress or growth.

Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures

Objective:Compare neurodevelopment after levetiracetam (LEV) and phenobarbital (PB) for neonatal seizures.Study design:Retrospective study of infants who received antiepileptic drugs (AEDs) for neonatal seizures. Effect of cumulative exposure to LEV and PB on outcomes of death, cerebral palsy (CP) and Bayley Scales of Infant Development (BSID) scores were evaluated at 24 months corrected age. Analyses were adjusted for number of electrographic seizures and gestational age.Result:In 280 infants with comparable seizure etiology and cranial imaging results, increased exposure to PB was associated with worse BSID cognitive and motor scores (8.1- and 9-point decrease per 100 mg kg−1; P=0.01). The effect was less with LEV (2.2- and 2.6-point decrease per 300 mg kg−1 LEV (P=0.01)). CP probability increased by 2.3-fold per 100 mg kg−1 PB and was not associated with increasing LEV.Conclusion:Increased exposure to PB is associated with worse neurodevelopmental outcomes than LEV. Prospective studies of outcomes of neonatal exposure to AEDs are essential.

Cortical speech sound differentiation in the neonatal intensive care unit predicts cognitive and language development in the first 2 years of life.

Neurodevelopmental delay in childhood is common in infants born preterm, but is difficult to predict before infants leave the neonatal intensive care unit (NICU). We hypothesized that event‐related potential (ERP) methodology characterizing the cortical differentiation of speech sounds in hospitalized infants would predict cognitive and language outcomes during early childhood.

Early prediction of cerebral palsy after neonatal intensive care using motor development trajectories in infancy

UNLABELLED Neonatal intensive care unit (NICU) patients are at high risk for developmental disabilities such as cerebral palsy (CP). Early identification of CP is essential to effective rehabilitation, but diagnosis is often delayed, especially in preterm infants. We hypothesized that through the longitudinal evaluation of motor trajectories in the NICU follow-up clinic, we could distinguish infants who develop CP by 3 years of age. STUDY DESIGN AND SUBJECTS This was a retrospective study of 606 patients in the NICU Follow-up Clinic at Vanderbilt University with birth weight < 1500g or a diagnosis of hypoxic ischemic encephalopathy. OUTCOMES MEASURES Assessments included neurologic exams, the Developmental Assessment of Young Children (DAYC), the Bayley Scales of Infant Development (BSID) and the Gross Motor Function Classification Scale. RESULTS A decrease in DAYC scores between 6 and 12 months was present in preterm and term infants later diagnosed with CP, but not in children without CP (-23 vs. +1.5, p<0.001). DAYC score decreases in infancy were highly predictive of later CP (p<0.001). BSID scores quantified severe motor delays but did not add to prediction of CP diagnosis. CONCLUSION Standardized assessments of motor milestones quantitatively predict the risk of CP in former NICU patients by 12 months, allowing for timely diagnosis, counseling and therapy in high-risk infants.

Influence of gestational age and postnatal age on speech sound processing in NICU infants

The study examined the effect of gestational (GA) and postnatal (PNA) age on speech sound perception in infants. Auditory event-related potentials (ERPs) were recorded in response to speech sounds (syllables) in 50 infant NICU patients (born at 24-40 weeks gestation) prior to discharge. Efficiency of speech perception was quantified as absolute difference in mean amplitudes of ERPs in response to vowel (/a/-/u/) and consonant (/b/-/g/, /d/-/g/) contrasts within 150-250, 250-400, 400-700 ms after stimulus onset. Results indicated that both GA and PNA affected speech sound processing. These effects were more pronounced for consonant than vowel contrasts. Increasing PNA was associated with greater sound discrimination in infants born at or after 30 weeks GA, while minimal PNA-related changes were observed for infants with GA less than 30 weeks. Our findings suggest that a certain level of brain maturity at birth is necessary to benefit from postnatal experience in the first 4 months of life, and both gestational and postnatal ages need to be considered when evaluating infant brain responses.

Novel assessment of cortical response to somatosensory stimuli in children with hemiparetic cerebral palsy.

The brain’s response to somatosensory stimuli is essential to experience-driven learning in children. It was hypothesized that advances in event-related potential technology could quantify the response to touch in somatosensory cortices and characterize the responses of hemiparetic children. In this prospective study of 8 children (5-8 years old) with hemiparetic cerebral palsy, both event-related potential responses to sham or air puff trials and standard functional assessments were used. Event-related potential technology consistently measured signals reflecting activity in the primary and secondary somatosensory cortices as well as complex cognitive processing of touch. Participants showed typical early responses but less efficient perceptual processes. Significant differences between affected and unaffected extremities correlated with sensorimotor testing, stereognosis, and 2-point discrimination (r > 0.800 and P = .001 for all). For the first time, a novel event-related potential paradigm shows that hemiparetic children have slower and less efficient tactile cortical perception in their affected extremities.

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition

BACKGROUND Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation. OBJECTIVE This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure. DESIGN Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures. RESULTS Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 μg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 μg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R. CONCLUSION A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.