What is the new emerging therapeutic direction for cerebral palsy?
Despite of the broad variety diverse therapeutic means to promote the recovery and rehabilitation of these children none of them are able to facilitate processes of repair, regeneration and recovery of damaged brain.
Recently a new and promising therapeutic approach has emerged, stem cell based therapy which aims to promote the recovery of brain function, by multi-pronged restorative mechanism.
Based on the particular biological features of, the preclinical (laboratory) encouraging outcomes and the results of first clinical trials on safety and feasibility in acquired brain injury, cord blood is prefiguring as a very promising source for stem cell based therapy in pediatric neurology.
The results of an advanced clinical study were published in "Blood" journal in 2015. They represent the outcome of phase II clinical trial1 "designed to assess the efficacy of a single intravenous infusion of autologous cord blood in young children with spastic cerebral palsy".
63 eligible children were enrolled with a median age of 2 years (from 1 to 6 years old).
All of them were evaluated neurologically, cognitively and behaviorally at baseline, prior to infusion of umbilical cord blood by applying standardized measurements and assessment scales. For example: to measure the primary outcome, children were assessed by applying the Gross Motor Function Measure 66 (GMFM-66) Score. "This is a standardized observational instrument designed and validated to measure change in gross motor function over time in children with cerebral palsy"
On the follow up visits scheduled at 1 and 2 year after the infusion all treated children were assessed by applying the same scales, in order to quantify in a measurable way any change occurred in meantime.
In addition a brain MRI (Diffusion Tensor Magnetic Resonance Imaging) was performed at baseline and at 1 year after infusion of own cord blood unit, to highlight any structural change identifiable on the imaging of brain.
From the 63 patients, 32 children were first infused with own cord blood unit and 1 year later with placebo, while the rest of 31 children were infused first with placebo and then with own cord blood unit. Children were randomly selected to be part of the first or second group.
Each cord blood unit had to have at least a pre-cryopreservation concentration of cells of 1 x 107 Total nucleated cells/kg body weight or more, to be sterile, to have negative maternal infectious disease screening results and cord blood unit confirmation identity by HLA confirmation testing.
Results of the study revealed that own cord blood unit may improve motor function of young children with spastic cerebral palsy if meets a minimum criteria of pre-cryopreservation cellularity ≥ 2 - 2,5 x 107 Total nucleated cells/kg body weight.
This study similar with the previous pilot study published in 2010 confirmed the safety of own cord blood infusion, no serious adverse events being reported.
Here you can watch an prof.dr. Joanne Kurtzberg speaking about her experience in treating children with cerebral palsy by infusion of their own umbilical cord blood
The pilot study marked a new exploration direction on the potential of clinical application of cord blood stem cells in the regenerative medicine field.
The medical team lead by prof. dr. Joanne Kurtzberg proposed this phase I clinical study based on the results of preclinical studies, which have been shown to lessen the impact of hypoxic brain injury and stroke in animal models, corroborated with the neurological improvement noticed in children treated for inborn errors of metabolism undergoing unrelated donor umbilical cord blood transplantation.
From March 2004 to December 2009, 184 children received 198 cord blood unit (CBU) infusions, from a total of 2042 referrals, more than half of patients with different acquired neurologic disorders not being eligible for the clinical trial, due to lack of autologous graft (own umbilical cord blood unit)2.
After a clinical and paraclinical evaluation of the referral patients and a quality evaluation of the CBU, the selected eligible children were infused with autologous graft, via peripheral IV over 15 – 30 minutes.
Infusions were generally well tolerated, only 3 children presenting anaphylactic reactions (wheezing with or without urticaria) 2 to 10 minutes after infusion. In the 12 months follow up none of the infused children experienced infections, autoimmune diseases, tumors, or other adverse events confirming the safety and feasibility of this procedure.
The safety and feasibility of autologous cord blood infusion was proved also in a second clinical study conducted in Hanyang University Medical Center, South Korea3.
The study results published in 2012 confirmed the safety and feasibility of autologous cord blood infusion for cerebral palsy. Although 5 patients of the 20 enrolled experienced temporary nausea, hemoglobinuria, or urticaria during intravenous infusion these were easily controlled with medication and IV hydration. No other adverse reaction was reported during the follow up period up to 24 weeks after infusion.
Although this study was limited by the small number of subjects, (20 patients enrolled) the different types of cerebral palsy and underlying causes, 25 % of children showed partial improvements in neurodevelopmental evaluation tests following intravenous autologous cord blood mononucleated cells infusion.
The neurodevelopmental improvements occurred significantly in patients with hemiplegia or diplegia rather than with quadriplegia.
The results of these clinical studies are important arguments supporting the efforts for initiating further clinical research, in multicentric studies on a larger scale.
Getting reliable, proven and statistic significantly results it's very important, especially since this new therapy may have a significant impact on the prognosis of cerebral palsy children, to make a difference in their life.
What is cerebral palsy?
Cerebral palsy is the most common group of neurodevelopmental conditions and the main cause of non progressive physical disability in children. It is caused by damage to or abnormalities inside the developing brain that disrupt the brain’s ability to control movement and maintain posture and balance.
Comorbidities caused by early brain damage, including cognitive, sensory, and behavioural deficits are frequently associated to restricted functional activity of these children.
Its prevalence of 2-3 cases at 1000 living birth remained largely unchanged. 85% -90% are congenital cerebral palsy cases, the brain damage happen before or during birth.
Up to 10 % of the cases are acquired cerebral palsy, the brain damage occurs more than 28 days after birth.
What are the causes of cerebral palsy?
Major improvements have been done in clinical care in the last 4 decades, such as detecting “fetal distress” (abnormal fetal heart rate tracing), reducing complications in labor and delivery, enhancing neonatal supportive treatment (treatment of neonatal jaundice and avoiding kernicterus).
Despite these advances which have contributed to the prevention of cerebral palsy, in developed nations a new category of children affected with cerebral palsy have occurred.
They come from the increasing number of premature and low-birth weight (<1500 g) babies that survive due to introduction of new revolutionary drugs (e.g. postnatal surfactant, antenatal steroids), modern lung protective ventilation methods of premature babies, optimal nutrition and overall progress in neonatal care.
Other causes of cerebral palsy in term infants (representing 50 to 65% of children with CP) and young children (up to 5 years old) include:
- Newborn asphyxia caused by birth complications (e.g.detachment of the placenta, uterine rupture, prolapsed umbilical cord, long or short umbilical cord, true knots of umbilical cord)
- Before or during birth infection (Congenital cytomegalovirus, Rubella, Chickenpox , Chorioamnionitis - bacterial infection of the amniotic fluid, chorion and placenta, most common caused by E. coli, group B streptococci and anaerobic bacteria which ascend into the uterus)
- Infection after birth (such as meningitis)
- Placental abnormalities (e.g. abnormal shape or implantation; circulatory disturbance; placental inflammation; degenerative placental lesions; tumors of the placenta)
- Placenta praevia
- Restricted intrauterine growth of the fetus (IUGR)
- Prolonged severe jaundice of the newborn
- Traumatic brain injury
- What are the current treatment options?
Currently, there is no recognized cure for cerebral palsy. Today there is a wide range of conventional:
- Therapies (e.g. physical therapy and physiotherapy, massage therapy, aqua therapy, behavioral therapy)
- Medications (e.g. Antispasticity medication, Anticonvulsants, Bisphosphonates)
- Surgeries (e.g. surgery to correct anatomical abnormalities: hip surgery, hand surgery)
- Assistive technologies (walking frames, wheelchairs, adapted computer access) and orthotic devices
- Other complementary interventions
All of these are aimed to support and help manage effects on the body, optimize mobility and ability to communicate, promote independence and self care, prevent or treat the possible complications.
If the treatment is initiated in early stage, children with cerebral palsy may overcome developmental disabilities and enjoy near-normal adult lives, prognosis being in accordance with the severity of experienced disabilities.
2. Sun J. et al. Differences in quality between privately and publicly banked umbilical cord blood units: a pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion. 2010, 50
3. Lee YH, Choi KV, Moon JH, et al. “Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy.” J Transl Med., 2012, 23(10), 58