Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial

Abstract

Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development-II (BSID-II) Mental and Motor scales (18). F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at 6 months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. 18F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain.

Copyright © 2012 AlphaMed Press.

Figures

Figure 1

Study flow diagram. Abbreviations: CP, cerebral palsy; DTI, diffusion tensor image; EPO, erythropoietin; FA, fractional anisotropy; pUCB, UCB potentiated by rhEPO; PET, 18F-FDG PET (18F-fluorodeoxyglucose positron emission tomography); rhEPO, recombinant human erythropoietin.

Figure 2

Comparing changes in outcome scores. Panel A shows changes in outcome scores from baseline to 1, 3, and 6 months post-treatment between pUCB, EPO, and Control groups. (a): GMPM total score, (b) BSID-II Mental scale raw score, (c) BSID-II Motor scale raw score, and (d) social cognition scale score of the WeeFIM. The pUCB group (n = 31) received umbilical cord blood potentiated with recombinant human erythropoietin and rehabilitation; the EPO group (n = 33) received rhEPO and rehabilitation; the Control group (n = 32) received rehabilitation only. Bars represent the 95% CI. The p-values compared changes in outcome scores between two groups based on post hoc analyses following ANOVA. Panel B shows changes in outcome scores for the period between baseline and 6 months post-treatment according to HLA mismatching in the pUCB group (n = 31). HLA 1-mismatched (n = 11) and HLA 2-mismatched (n = 20). (a): GMFM total score, (b) “self-care” score in functional skill scale of the PEDI, (c) WeeFIM total score, and (d) summation of MMT scores. Bars represent 95% CI. The p-values compare changes in outcome scores based on Mann-Whitney U test. GMPM scores range from 0 to 100, with higher scores indicating better motor performance. BSID-II scores range from 0 to 112 for Motor scale raw score and from 0 to 178 for Mental scale raw score, with higher scores indicating better motor and mental function, respectively. GMFM scores range from 0 to 100, with higher scores indicating better motor function. Scores on the social cognition scale of the WeeFIM range from 3 to 21, with higher scores indicating better social cognition. Total WeeFIM scores range from 18 to 126, with higher scores indicating greater functional independence. Self-care scores in functional skill scale of the PEDI range from 0 to 100, with higher scores indicating better function in self-care items. MMT summation scores range from 0 to 160, with higher scores indicating better muscle strength. Abbreviations: BSID-II, Korean version of the Bayley scales of infant development, second edition; GMFM, gross motor function measure; GMPM, gross motor performance measure; HLA, human leukocyte antigen; MMT, manual muscle strength test; PEDI, pediatric evaluation of disability inventory; rhEPO, recombinant human erythropoietin; WeeFIM, functional independence measure for children.

Figure 3

Correlation between changes of GMPM total score and changes of FA during the interval between baseline and 6 months post-treatment in pUCB (UCB potentiated by rhEPO) group (n = 30). The pUCB group received umbilical cord blood potentiated with recombinant human erythropoietin and rehabilitation. For FA, PLIC at three loci were measured. (A): Posterior portion, right side 95% CI of Pearson r = 0.094–0.691. (B): Anterior portion, left side 95% CI of Pearson r = 0.147–0.717. (C): Posterior portion, left side 95% CI of Pearson r = 0.125–0.707. Abbreviations: FA, fractional anisotropy; GMPM, gross motor performance measure; PLIC, posterior limb of the internal capsule.

Figure 4

Changes in 18F-fluorodeoxyglucose positron emission tomography glucose metabolism during the period between baseline and 2 weeks post-treatment. The pUCB group (n = 31) received umbilical cord blood potentiated with recombinant human erythropoietin and rehabilitation; the EPO group (n = 33) received recombinant human erythropoietin and rehabilitation; the Control group (n = 32) received rehabilitation only. The template brain image was provided by SPM8.0. (A): Areas of increased glucose metabolism in the three groups (p-value < .05). Red and yellow denote areas with increased glucose metabolism. The pUCB group exhibited increased activity in the bilateral basal ganglia, thalami, and small areas in the bilateral frontal, right parietal, and left temporal lobes, whereas the EPO group showed increases in a large area in the bilateral frontal lobes and basal ganglia, and the Control group showed increases only in the bilateral cerebelli. (B): Areas of decreased glucose metabolism in the three groups (p-value < .05). Blue denotes areas with decreased glucose metabolism. The pUCB group exhibited decreased activity in the right occipital lobe and the bilateral parahippocampal gyri, whereas the EPO group showed decreased activity in the bilateral cerebelli, and the Control group showed decreased activity in the bilateral frontal and temporal lobes. Abbreviations: EPO, erythropoietin; pUCB, UCB potentiated by rhEPO.