Stem Cell Transplantation Efficacy in Cerebral Palsy: A Case Report from a Physical Therapist Perspective

 Background and Purpose 
Children with spastic cerebral palsy usually display elevation in muscle tone, a decline in gross motor functional abilities , feeding problems and sometimes it may accompanied by visual problems. Studies on stem cell treatment are in their early stages concerning their effect on cerebral palsy.   
Methods  
A child with spastic cerebral palsy on level v on gross motor function classification system was selected for autologous bone marrow derived mononuclear transplantation cell. Muscle tone, gross, fine motor abilities, feeding abilities and visual abilities were assessed on 4 occasions, prior the transplantation, immediately after the transplantation, after 6 months and after 1 year. 
 Results No effect of stem cell transplantation was shown on the child. 
Conclusion Further research studies should be done on the subject but using different population rather than children on level V Gross motor function classification system


INTRODUCTION
Cerebral palsy (CP) is a neurodevelopmental disorder that caused by an injury in immature cerebrum. It leads to motor impairments which includes reduction in muscle strength, cardiorespiratory function and motor functional activities (1). In addition to motor dysfunction , CP may also associated with impairments of vision, behavior, cognition, communication, hearing , behavior and or/ epilepsy (2) .
Cerebral visual impairment (CVI) previously known as cortical visual impairment is defined as subnormal visual acuity -despite normal ocular examination -due to damage or injury in the posterior brain lobe or posterior visual pathways (3); that's clarify the association of CVI with CP(4).
Spasticity is a velocity dependent increase in stretch reflex , and it is a common disorder among children with CP affecting the whole body (5) leading to decrease in gross motor function and activity participation (6).
Children with CP usually have feeding and swallowing disorders that put them to aspiration and malnutrition risks, especially in children with spastic quadriplegia (7).
Stem cells (SCs) are very small cells having no phenotype characteristics of any known adult cells such as epithelial, connective, muscle and neural cells. SCs are able to generate new differentiated cells of the previously mentioned cell types (8) (9).
Sources of SCs are adult body tissues, embryos, mesenchymal and induced pluripotent stem cells (IPS). Adult SCs or somatic SCs exist in the body since the existence of embryo, they are in non-specific state until the body need them such as in repairing in bone marrow, liver, blood etc.
There is two main types of SCs transplants that based on who gives the SCs : autologous where the SCs came from the same person who gets the transplant and allogenic where SCs came from a matched donor (10).
Autologous SC transplant uses healthy blood SCs extracted from the same body that will receive the transplant (11). Recent researches showed some potential of using the autologous SCs transplant to overcome the tremendous effect of CP on children via transplanting bone marrow derived mononuclear cell (BMMNCs) (12) as previous research work concluded that BMMNCs could develop into neural cell tissues (13).
The purpose of this case study was to detect the efficacy of intrathecal infusion of autologous BMMNCs in 3 years and 6 months child with CP on gross motor abilities, fine motor function, vision, feeding and muscle tone. It was hypothesized that using autologous bone marrow derived stem cells will have no effect on gross motor function, fine motor function, vision, feeding and muscle tone on a child with spastic CP.

Design
This is a single case study, repeated measure on four occasions 1. before the transplant, 2.
immediately after the transplantation, 3. after six months of the transplantation and after 1 year of the transplantation.
Informed assent was obtained from the Child's caregivers according to the Principles stated in the Declaration of Helsinki(14).

Materials of Evaluation
Visual Classification Scale (VCS) was used to determine the CVI level(15) , Peabody developmental motor scales-second edition (PDMS-2) was used to determine gross motor and fine motor function (16) , Modified Ashworth Scale (MAS) was used to determine muscle tone (17) and finally Behavioral Pediatrics Feeding Assessment Scale (BPFAS)(18) was used to evaluate feeding behavior. The assessment took place in four occasions, the first time prior the transplant when the child was 43 months old, the second time immediately after the transplant, the child aged 44 months. The third time was after 6months where the child was 48 months and finally after 1 year of the transplant, the child then was 55 months.

Materials of Management:
BMMNCs was transplanted to the child via several steps, the first step was procurement of Autologous Bone Marrow Cells. The child went under general anesthesia and the bone marrow was extracted from the posterior superior iliac crest. The second step was SCs isolation. This step was done by an accredited laboratory party in Wadi El Neel Hospital, the final step was SC's infusion to the child intrathecally (L4-L5).

Results
The BMMNCs was extracted from posterior superior iliac spine and infused intrathecally (L4-L5) and transplanted to a spastic CP child The CVI, gross motor functions, fine motor functions, muscle tone and feeding behavior were assessed in four occasions (before the transplant, immediately after the transplant, after 6 months of the transplant and after 1 year of the transplant).
Visual Classification Scale (VCS) was used to assess the CVI. There was no difference in the CVI level as it was level 3 in the 4 occasions (Table1). Level 3 indicates that the child eye can Fix and gaze shift to a target(15).    The muscle tone was assessed using Modified Ashworth Scale (19), assessing the muscle tone of the 4 limbs in the four previously mentioned assessment occasions (Table 5), it shows that the muscle tone only inhibited immediately post transplantation , but it returned back to the initial degree in the third and fourth assessments. Finally, the feeding behavior was assessed using the BPFAS (20); there was no difference in both total frequency score and total problem score in the 4 assessment occasions. The child showed normal feeding behavior, but higher problems score than the normative means (Table 6).

DISCUSSION
The current case study was performed to detect the efficacy of intrathecal infusion of autologous BMMNCs in a 3 years and 6 months child with CP on gross motor abilities, fine motor function, vision, and feeding and muscle tone. We accepted the null hypothesis which stated that using autologous bone marrow derived stem cells will have no effect on gross motor function, fine motor function, vision, feeding and muscle tone on a child with spastic CP.
The VCS was selected to evaluate the visual function level as she had CVI. The VCS characterizes the performance specifically during the visual examination and it is considered to define each level by indicating a higher degree of visual performance than the previous level(15), so it is considered more specified than other scales as Huo Criteria (21) .
PDMS-2 was chosen for assessing the gross and fine motor functions to our case for its accuracy, high reliability and high validity. That was supported by Walting (22)  Although the H reflex and Hoffman to muscle response (H/M) ratio was the most reliable choice in evaluating the degree of spasticity(23), we went to choose the MAS for an ethical reason.
As a clinical note, during previous interventions with the same child, whenever a muscle electric stimulation was used on the child, it was followed by an epileptic seizure; although -as far as we know -no research evidence revealed that muscular electric stimulation may induce epileptic seizure in epilepsy patients, but we didn't want to take any risks by using electrophysiologic evaluation method as H-reflex and H/M ratio. However MAS was proved to have strong positive relationship with H/M ratio (24) , so the results wouldn't be affected ; in addition to the high reliability and validity of MAS in evaluating spasticity in children with CP (25).
Finally the BPFAS was selected to assess the feeding behavior of the child as it was proven to be an effective measure in assessing feeding behavior(26).
Researches studies on the effect stem cell therapy on CP patients had been started in the last decade, but still there is lack of research studies on different populations of CP. Our case study showed that there was no effect Autologous BMMNCs transplant to CVI, gross motor and fine motor functions, muscle tone and feeding behavior in child with spastic CP.
The current case study's results was supported by Carroll and Mays(27) who stated that although stem cell may be effective in treating acute brain injuries, there is no evidence that it may improve a chronic illness such as CP, even in animal models there was no clear evidence of its beneficial.
It was also supported by a research that was taken place mainly to investigate the safety of BMMNCs transplant in children with CP. Despite that, the trial proved that BMMNCs transplantation was a safe procedure, but the MRI evaluation 6 months post transplantation showed no difference in the brain cells (28), that indicated that no further improvement on CP's associated symptoms.
Our results were confirmed by Steiner et al. (29) who examined the effect of stem cells on animal model, they revealed that no difference between the study and control groups' MRI of the brain and revealed that there was a weak neurogenic effect.
In a systematic review by Novak et al. (30) that was conducted to determine the efficacy and safety of stem cells for improving motor and cognitive function of patients with CP; it was concluded that there was a limited improvement concerning gross motor functions, that somehow support our case study results.
The current study results and recommendations was also supported by Faulkner et al. (31) who mentioned that the evidence of the benefits of stem cell therapy on CP is still need more investigation and more studies.
In contrary , our case study results was contradicted to a systematic review (32) which concluded that stem cell therapy improves associated symptoms in patients with CP and improves motor development, however it supported our recommendations of the need of further researches on the topic as the systematic review mention only one randomized control trial and only other six researches of different types.
This results was also disagree with a case report by Purandare et al. (33) which reported that intrathecal infusion of autologous BMMNCs seems to effective, safe and may have promising functional outcome improvements in patient with CP and also it disagree with another randomized control study which used autologous marrow mesenchymal SCs as a novel treatment for 30 patients with moderate to severe CP (study group), it showed gross motor improvement in the third and sixth month compared to the another 30 patients with CP (control group) (34).

Conclusion
There is no effect to Autologous BMMNCs transplant to CVI, gross motor and fine motor functions, muscle tone and feeding behavior in child with spastic cerebral palsy. Several trials concerning the topic should be studied considering to involve randomized control trials instead of case studies also should consider studying different population rather than children with level V GMFCS.