Browsing by Subject "Cerebral Palsy"

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    Brain structural connectivity increases concurrent with functional improvement: evidence from diffusion tensor MRI in children with cerebral palsy during therapy.
    (NeuroImage. Clinical, 2015-01-09) Englander, Zoë A; Sun, Jessica; Laura Case; Mikati, Mohamad A; Kurtzberg, Joanne; Song, Allen W
    Cerebral Palsy (CP) refers to a heterogeneous group of permanent but non-progressive movement disorders caused by injury to the developing fetal or infant brain (Bax et al., 2005). Because of its serious long-term consequences, effective interventions that can help improve motor function, independence, and quality of life are critically needed. Our ongoing longitudinal clinical trial to treat children with CP is specifically designed to meet this challenge. To maximize the potential for functional improvement, all children in this trial received autologous cord blood transfusions (with order randomized with a placebo administration over 2 years) in conjunction with more standard physical and occupational therapies. As a part of this trial, magnetic resonance imaging (MRI) is used to improve our understanding of how these interventions affect brain development, and to develop biomarkers of treatment efficacy. In this report, diffusion tensor imaging (DTI) and subsequent brain connectome analyses were performed in a subset of children enrolled in the clinical trial (n = 17), who all exhibited positive but varying degrees of functional improvement over the first 2-year period of the study. Strong correlations between increases in white matter (WM) connectivity and functional improvement were demonstrated; however no significant relationships between either of these factors with the age of the child at time of enrollment were identified. Thus, our data indicate that increases in brain connectivity reflect improved functional abilities in children with CP. In future work, this potential biomarker can be used to help differentiate the underlying mechanisms of functional improvement, as well as to identify treatments that can best facilitate functional improvement upon un-blinding of the timing of autologous cord blood transfusions at the completion of this study.
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    Case 3: Increased Snoring in a 7-year-old Boy.
    (Pediatrics in review, 2017-12) Bhoopalan, Senthil Velan; Das, Samrat
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    Comparative effects of multilevel muscle tendon surgery, osteotomies, and dorsal rhizotomy on functional and gait outcome measures for children with cerebral palsy.
    (PM & R : the journal of injury, function, and rehabilitation, 2015-05) Feger, Mark A; Lunsford, Christopher D; Sauer, Lindsay D; Novicoff, Wendy; Abel, Mark F

    Objective

    To compare the impact of common surgical interventions (selective dorsal rhizotomy, muscle-tendon surgery, and osteotomies) for patients with cerebral palsy (CP) on Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables as assessed via 3-dimensional motion analysis.

    Design

    Retrospective cohort study.

    Setting

    Motion analyses laboratory.

    Participants

    Ninety-four patients with CP, 56 of whom underwent surgery (37, muscle-tendon surgery; 11, osteotomy; and 8, selective dorsal rhizotomy) and 38 of whom did not have surgery; the patients were ages 4-18 years, with a Gross Motor Function Classification System classification of I, II, or III.

    Interventions

    Single-event, multilevel muscle tendon surgery, selective dorsal rhizotomy, and osteotomy.

    Main outcome measures

    Change scores (postintervention - preintervention) in Gross Motor Function Measure and temporal, kinematic, and kinetic gait variables.

    Results

    No statistically significant differences in change scores were found between groups in the Gross Motor Function Measure, velocity, or stride length measures after the observation period. The selective dorsal rhizotomy group had greater improvements in knee extension when compared with the nonsurgical group and greater hip and knee total range of motion during the gait cycle when compared with nonsurgical group and the muscle-tendon surgery and osteotomy cohorts. Lastly, the muscle-tendon surgery group had greater improvements in total knee range of motion compared with the nonsurgical group.

    Conclusions

    Patients who undergo selective dorsal rhizotomy and, to a lesser extent, muscle tendon procedures demonstrate greater improvements in kinematic gait variables compared with nonsurgical interventions in patients with spasticity resulting from CP.
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    Differential developmental trajectories of magnetic susceptibility in human brain gray and white matter over the lifespan.
    (Human Brain Mapping, 2014-06) Li, Wei; Wu, Bing; Batrachenko, Anastasia; Bancroft-Wu, Vivian; Morey, Rajendra A; Shashi, Vandana; Langkammer, Christian; De Bellis, Michael D; Ropele, Stefan; Song, Allen W; Liu, Chunlei
    As indicated by several recent studies, magnetic susceptibility of the brain is influenced mainly by myelin in the white matter and by iron deposits in the deep nuclei. Myelination and iron deposition in the brain evolve both spatially and temporally. This evolution reflects an important characteristic of normal brain development and ageing. In this study, we assessed the changes of regional susceptibility in the human brain in vivo by examining the developmental and ageing process from 1 to 83 years of age. The evolution of magnetic susceptibility over this lifespan was found to display differential trajectories between the gray and the white matter. In both cortical and subcortical white matter, an initial decrease followed by a subsequent increase in magnetic susceptibility was observed, which could be fitted by a Poisson curve. In the gray matter, including the cortical gray matter and the iron-rich deep nuclei, magnetic susceptibility displayed a monotonic increase that can be described by an exponential growth. The rate of change varied according to functional and anatomical regions of the brain. For the brain nuclei, the age-related changes of susceptibility were in good agreement with the findings from R2* measurement. Our results suggest that magnetic susceptibility may provide valuable information regarding the spatial and temporal patterns of brain myelination and iron deposition during brain maturation and ageing.
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    Diffusion Tensor Imaging Biomarkers of Stem Cell Therapy Efficacy in Pediatric Cerebral Palsy
    (2012) Batrachenko, Anastasiya

    Cerebral palsy (CP) is a non-progressive sensory-motor disorder and is one of the most costly and debilitating chronic pediatric conditions, affecting 2-3 out of 1000 children in the United States. To better understand the underlying mechanisms that result in the devastating motor deficits in CP patients, quantitative assessment of brain regions and connectivity with respect to the severity of injury is critical. It is generally known that motor control can be largely influenced by the integrity of the corticospinal tract (CST) connecting the primary motor cortex (pre-central gyrus) to the brainstem and the spinal cord. Thus, we further sought to establish CST volume as a sensitive and reliable biomarker that can reveal functional deficit in individual patients through comprehensive quantitative analyses in 29 consented human subjects (1-6 years of age, mean 2.67±1.36 years) diagnosed with hemiplegic, diplegic, or quadriplegic CP. The proportional reduction of bilateral CST volume with increased disease severity was observed for diplegic and quadriplegic patients (i.e. with bilateral motor deficits). Furthermore, CST volume with respect to disease severity in hemiplegic patients (i.e. with unilateral motor deficits) exhibited more complex patterns of asymmetry, revealing evidence for alternative neuromechanisms of motor control, such as compensation and neuronal plasticity by the unaffected hemisphere. In all cases, other diffusion metrics such as fractional anisotropy (FA) and mean diffusivity (MD) within the CST did not display significant correlation with disease severity. It is thus concluded that individual CST volume, accurately derived from DTI tractography, is one of the strongest non-invasive imaging biomarkers which could potentially help understand the differential causes for motor deficits and compensation in bilateral CP. It could also be further adopted to assess the underlying mechanism for functional recovery in individual patients undergoing cellular therapies. In addition to motor disability, numerous other neurodevelopmental differences are associated with CP and contribute greatly to the disease morbidity. Therefore, we further examined global changes in WM connectivity with respect to CP disease severity with a whole brain connectome analysis in a cohort of 18 pediatric patients with bilateral CP. As expected, reduction in overall and mutual connectivities throughout the motor regions, including the primary and supplemental motor areas, basal ganglia, and brainstem, was associated with the extent of primary motor disability. In addition, our results show diffuse and significant reduction in global inter-regional connectivity, measured as fiber volume, throughout the entire brain in relation to disease severity. This novel finding has not been previously reported in the CP literature and brings CP into line with multiple other pediatric neuropsychiatric disorders that are thought to involve network-level structural and/or functional disruptions early in development.

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    Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial.
    (Stem cells translational medicine, 2017-12) Sun, Jessica M; Song, Allen W; Case, Laura E; Mikati, Mohamad A; Gustafson, Kathryn E; Simmons, Ryan; Goldstein, Ricki; Petry, Jodi; McLaughlin, Colleen; Waters-Pick, Barbara; Chen, Lyon W; Wease, Stephen; Blackwell, Beth; Worley, Gordon; Troy, Jesse; Kurtzberg, Joanne
    Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 107 /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071-2078.
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    Human Umbilical Cord Blood Cells Ameliorate Motor Deficits in Rabbits in a Cerebral Palsy Model.
    (Developmental neuroscience, 2015-01) Drobyshevsky, Alexander; Cotten, C Michael; Shi, Zhongjie; Luo, Kehuan; Jiang, Rugang; Derrick, Matthew; Tracy, Elizabeth T; Gentry, Tracy; Goldberg, Ronald N; Kurtzberg, Joanne; Tan, Sidhartha
    Cerebral palsy (CP) has a significant impact on both patients and society, but therapy is limited. Human umbilical cord blood cells (HUCBC), containing various stem and progenitor cells, have been used to treat various brain genetic conditions. In small animal experiments, HUCBC have improved outcomes after hypoxic-ischemic (HI) injury. Clinical trials using HUCBC are underway, testing feasibility, safety and efficacy for neonatal injury as well as CP. We tested HUCBC therapy in a validated rabbit model of CP after acute changes secondary to HI injury had subsided. Following uterine ischemia at 70% gestation, we infused HUCBC into newborn rabbit kits with either mild or severe neurobehavioral changes. Infusion of high-dose HUCBC (5 × 10(6) cells) dramatically altered the natural history of the injury, alleviating the abnormal phenotype including posture, righting reflex, locomotion, tone, and dystonia. Half the high dose showed lesser but still significant improvement. The swimming test, however, showed that joint function did not restore to naïve control function in either group. Tracing HUCBC with either MRI biomarkers or PCR for human DNA found little penetration of HUCBC in the newborn brain in the immediate newborn period, suggesting that the beneficial effects were not due to cellular integration or direct proliferative effects but rather to paracrine signaling. This is the first study to show that HUCBC improve motor performance in a dose-dependent manner, perhaps by improving compensatory repair processes.
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    Neurodevelopmental outcomes among extremely premature infants with linear growth restriction.
    (Journal of perinatology : official journal of the California Perinatal Association, 2019-02) Meyers, JM; Tan, S; Bell, EF; Duncan, AF; Guillet, R; Stoll, BJ; D'Angio, CT; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

    Objective

    To compare neurodevelopmental outcomes in linear growth-restricted (LGR) infants born <29 weeks with and without weight gain out of proportion to linear growth.

    Study design

    We compared 2-year neurodevelopmental outcomes between infants with and without LGR and between LGR infants with and without weight gain out of proportion to linear growth. The outcomes were Bayley-III cognitive, motor, and language scores, cerebral palsy, Gross Motor Function Classification System (GMFCS) level ≥ 2, and neurodevelopmental impairment.

    Result

    In total, 1227 infants were analyzed. LGR infants were smaller and less mature at birth, had higher BMI, and had lower Bayley-III language scores (82.3 vs. 85.0, p < 0.05). Among infants with LGR, infants with high BMI had lower language scores compared with those with low-to-normal BMI (80.8 vs. 83.3, p < 0.05), and were more likely to have GMFCS level ≥2 and neurodevelopmental impairment.

    Conclusion

    Among infants with LGR, weight gain out of proportion to linear growth was associated with poorer neurodevelopmental outcomes.
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    Stem cell therapies in cerebral palsy and autism spectrum disorder.
    (Developmental medicine and child neurology, 2021-05) Sun, Jessica M; Kurtzberg, Joanne
    Across disciplines, there is great anticipation that evolving cell therapies may finally provide a therapeutic option for conditions in dire need. These conditions are typically complex and their pathophysiology incompletely understood, hindering the development of robust preclinical models and the precise assessment of therapeutic effects in human studies. This article provides an overview of the status of cell therapy investigations in two common neurodevelopmental disorders, cerebral palsy and autism spectrum disorder. Challenges facing this line of study, including inherent heterogeneity, knowledge gaps, and unrealistic expectations, are discussed. Much progress has been made in the past decade, but to definitively determine if cell therapies have a role in the treatment of neurodevelopmental disorders, both fields will need to evolve together. WHAT THIS PAPER ADDS: The safety profile of reported cell therapies in children with neurodevelopmental disorders is encouraging. Efficacy trials in cerebral palsy and autism spectrum disorder are ongoing in the United States and Asia. Unresolved issues pertain to the properties of the cells being studied and the characteristics of the neurodevelopmental conditions themselves.