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Improving the Motor Skill of Children With Posterior Fossa Syndrome: A Case Series Regina Harbourne, PT, PhD; Katherine Becker, BS; David J. Arpin, MS; Tony W. Wilson, PhD; Max J. Kurz, PhD Department of Physical Therapy, Munroe-Meyer Institute (Drs Harbourne and Kurz and Mr Arpin), Center for Magnetoencephalography (Ms Becker), and Department of Pharmacology and Experimental Medicine, College of Medicine (Dr Wilson), University of Nebraska Medical Center, Omaha, Nebraska. Children who receive treatment for medulloblastoma have a high survival rate, but also a high likelihood of developing posterior fossa syndrome, a condition that includes devastating balance and motor problems. This case series used 2 novel neuromodulation devices in conjunction with an intensive physical therapy intervention for 2 children who were 5 years post tumor treatment with a diagnosis of posterior fossa syndrome. Preand postclinical measures, in addition to magnetoencephalography brain imaging, describe positive behavioral and neuroplastic changes resulting from the intervention. The positive outcomes in these cases suggest that further study is needed using neuromodulatory devices and long-term rehabilitation in children with balance and movement disorders resulting from cancer treatment. (Pediatr Phys Ther 2014;26:462–468) Key words: brain/physiopathology, cancer, child, electric stimulation, female, humans, magnetic resonance imaging, medulloblastoma, models/neurological, motor skills, neuropathways/physiopathology, physical therapy, posterior fossa syndrome, postural balance/physiology, rehabilitation, sensation disorders/physiopathology INTRODUCTION Of all childhood cancers, leukemia and tumors of the brain and central nervous system account for about half of all cases.1 The most common type of solid tumor is the medulloblastoma, a brain tumor that occurs in rostral regions of the fourth ventricle in 80% of patients.2 Although survival rates are excellent and the children have a high likelihood of remaining cancer free,3 nearly 25% of survivors exhibit lingering after effects, including ataxia, balance problems, functional motor deficits, emotional la0898-5669/110/2604-0462 Pediatric Physical Therapy C 2014 Wolters Kluwer Health | Lippincott Williams & Copyright Wilkins and Section on Pediatrics of the American Physical Therapy Association
Correspondence: Regina Harbourne, PT, PhD, Department of Physical Therapy, Rangos School of Health Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282 ([email protected]). At the time this article was written David Arpin was a student at the University of Nebraska Medical Center, and Katherine Becker was a student at the University of Nebraska at Omaha, Omaha, Nebraska. Grant Support: Funding for this project was provided by the Hattie B. Munroe Foundation, Omaha, Nebraska. The authors declare no conflict of interest. DOI: 10.1097/PEP.0000000000000092
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bility, and speech dysfunction.4-7 These signs appear approximately 24 to 48 hours after surgery8-10 and are collectively identified as posterior fossa syndrome (PFS). This syndrome has been associated with invasion of the brainstem by the tumor and damage to the cerebello-thalamiccerebral pathway,9,11 a pathway critical to the transmission of sensory information from the cerebellum to the cortex.11 Thus, the disruption of vestibular, tactile, and visual information may account for a variety of coordination and balance problems, which have proven to be difficult to treat in children with PFS. It should be emphasized that although much attention has been focused on preventing the long-term effects of the cancer treatment by refining the surgical technique and radiation therapies, the syndrome of motor, speech, and cognitive problems remains intractable and effective remediation of the impairments remains elusive.12 For these reasons, therapies that focus on the cerebello-thalamic-cerebral network may be able to address the array of deficits seen in PFS and improve motor function and long-term outcome. Thus, the focus of this case report is to describe an innovative motor learning intervention using neuromodulation devices that focus on the cerebello-thalamic-cerebral network and vestibular system, used as part of an intervention for 2 children with a diagnosis of PFS. Pediatric Physical Therapy
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The 2 electrical neuromodulatory devices used in this intervention were developed to modify or enhance sensory information, using the tongue as an alternate pathway to the central nervous system. One device, the Brainport (Wicab, Middleton, Wisconsin), indicates head position to the central nervous system and uses sensory substitution to promote neuroplastic change in the service of balance improvement.13,14 The other device, a cranial nerve noninvasive neuromodulation (CN-NINM) unit, uses nondirectional electrical input to the tongue to modulate neural oscillatory circuits, similar to the mechanism of deep brain stimulation.15 These devices originated from the idea that the tongue is an effective interface for sending signals to the central nervous system due to its low electrical impedance and dense concentration of sensory receptors.13,14,16 In addition, the anterior portion of the tongue is innervated by the mandibular nerve that projects to the trigeminal ganglion and ultimately to the pons of the brainstem.17 Thus, stimulation of the tongue is thought to propagate to several brain areas to affect the integration of a diverse range of sensory input.16 Because the area of damage for children with PFS lies within the brainstem/cerebellar area postulated to be affected by these devices, we hypothesized that the devices may have potential to improve motor skills and reduce symptoms in children with PFS. Preliminary experimental evidence from adults with balance problems indicates long-term behavioral changes related to the use of these neuromodulation devices plus motor therapy.16,17 The long-lasting effects on postural control after removal of the electrotactile sensory information suggest neural adaptation. The Brainport device has been shown to improve the balance of patients with vestibular dysfunction13,14 and stroke.18 The CN-NINM device has been shown to improve postural reactions in adults with balance deficits.16 Thus we used both in combination with motor therapy for the 2 children in this study. This case report series describes a short-term, innovative motor-learning intervention using augmentation from neuromodulation devices for 2 children with a diagnosis of PFS. We used 2 neuromodulation devices originally developed for adults with neurologic deficits,18 balance disorders,16 and balance deficits secondary to vestibular dysfunction.14 The primary objective of this investigation was to determine if neuromodulation devices, combined with a motor learning program, were feasible and could improve the balance and motor function of children with PFS. The secondary objective of this investigation was to evaluate if the changes in the children’s balance and motor control were accompanied by neuroplastic changes in the activity of the sensorimotor cortices.
METHODS Participants/Case Description Our Institutional Review Board approved this study, and parental consent and child assent was obtained. ParPediatric Physical Therapy
ticipant 1 was a female fraternal twin, 14 years old, who had a normal developmental course until the diagnosis of a cerebellar tumor at 6 years of age. Posterior fossa syndrome followed the successful removal and treatment of the medulloblastoma. Extensive rehabilitation took place for 2 years to regain speech and walking skills. Physical therapy consisted of inpatient rehabilitation with progression to outpatient therapy and gradual reduction in therapy as skills plateaued. Specific interventions, consistent with the standard of care generally provided after brain injury, included provision of assistive devices (walker), strengthening, balance activities, gait training, and functional skill training.19 Ataxia, balance difficulties, and gross motor delay continued to limit function. At the start of this intervention, she was able to walk independently without any device, but could not safely walk while holding her lunch tray or a glass of liquid, and needed a railing to ascend and descend stairs. She frequently fell when walking on uneven terrain or when negotiating a novel and busy environment. Participant 2, a young girl, was diagnosed with a cerebellar tumor at the age of 5 months. After removal of the tumor, chemotherapy was initiated and completed by 1 year of age. Thus, her motor development milestones were delayed, and the diagnosis of PFS was given because of her ataxia and disordered movement and speech. She was able to walk by the age of 4 years using either her parent’s hand for balance assist, or a posterior walker to prevent falls. She participated in a variety of therapeutic interventions, ranging from consultation for home-based services at 1 year of age, to daily therapy at a rehabilitation center at 2 years of age, and then a reduction in services progressively until school age. She was 6 years old at the start of this intervention, and able to walk independently in familiar environments, such as her home. She also exhibited ataxia, balance difficulties, and gross and fine motor delays. She used a posterior rolling walker at school to prevent falls due to her ataxia and poor balance and the unpredictability of the kindergarten environment and held her parents’ hand for balance assist outside the home. She was engaged in many activities to promote motor skill development in a supervised environment with adaptations and adult assistance including swimming, gymnastics, and t-ball; however, adults guarded her closely to avoid falls during these activities. Her skills at the start of the intervention included independent walking without a device at home, walking with a posterior rollater walker outside the home, ascending and descending stairs using a railing, and light support from an assisting adult for balance in her outside activities (t-ball, dance class.) Falls were infrequent because of close assistance by family members in all standing/walking activities. Both children were currently ineligible for intensive rehabilitation services because they had already completed recommended rehabilitation programs. Thus, their current motor skills were considered their “new normal.” Both children had extensive family support and busy schedules with their families in an attempt to improve balance and motor skills via recreational means. Motor Skill Training in Posterior Fossa Syndrome 463
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Instruments
Intervention
The first device used during the static balance training was the Brainport device that provides feedback about postural orientation via electrotactile stimulation of the tongue. Essentially, the Brainport device has 2 main components: a Controller and an Intraoral device (Fig. 1A and B). The Intraoral device is made up of a 10 × 10 electrode array, a tether, and a micro-electro mechanical system (MEMS) accelerometer (Fig. 1B). The MEMS accelerometer senses head position in both the anterior/posterior and medial/lateral directions and is mounted beneath the electrode array, facing the roof of the mouth. The Intraoral device is positioned on the anterior portion of the tongue and held in place by pressing the tongue against the roof of the mouth. A small tether transmits head-position information measured by the MEMS accelerometer to a small controller worn around the user’s neck, where orientation information is converted into a dynamic pattern of stimulation activating the electrode array in the direction of movement instantaneously. The subject felt the positional information as a pattern of electrotactile stimulation on the tongue. For example, if the child leaned to the left, the stimulus moved to the left side of the patient’s tongue; a forward lean moved the stimulus to the front of the tongue (Fig. 1C). The second device was CN-NINM (Tactile Communication and Neurorehabilitation Laboratory, University of Wisconsin-Madison), which was used during movement (vs postural) activities. Stimulation to the tongue was delivered by a small, flexible polyester-base printed circuit containing 144 electrodes placed on the anterior portion of the tongue, similar to the grid in Fig. 1. The array was held in place by pressure of the tongue to the roof of the mouth.13 The array is in a tongue-shaped matrix. The circular gold-plated electrodes are 1.55 mm in diameter with an on-center spacing of 2.32 mm. The maximal output voltage of the device was 24 volts. Stimulation of CN-NINM consists of 3 square-pulse bursts with an intraburst frequency of 200 Hz and an interburst frequency of 50 Hz that does not vary throughout the stimulation session. This signal was delivered to all 144 electrodes of the array and did not vary with time or movement of the subject.16
Intervention began with 3 days of intensive therapy (1.5 hours in the morning and 1.5 hours in the afternoon) to train the child and family in the use of the neuromodulation devices and motor learning activities. These activities were individually tailored to each child depending on the child’s age, developmental level, and specific functional and balance deficit, and goals identified by the child and family. General guiding principles for the exercise activities included 20 minutes of static balance activities with reduced vision (eyes closed, performed with the Brainport device for postural steadiness feedback), 20 minutes of dynamic balance activities including walking on and off a treadmill and moving through space, and 20 minutes of coordination activities. The movement activities were done using the CNNINM device. Families were instructed to work slowly to gain control, rather than focusing on speed. After the initial 3 days of intensive training, the child received a home program modified to specific individual needs. The children performed activities under parental supervision at home 5 days per week for 8 weeks, and then returned for testing. A weekly Skype (Skype Technologies) visit to the therapist allowed updating, modification, and progression of the individualized programs. Tongue Stimulation Stimulation to the tongue by the Brainport device was delivered by a small, flexible polyester-base printed circuit placed on the anterior portion of the tongue.13 The child was shown how to adjust the sensation to tolerance, by taking the intensity to a point at which the stimulation could be felt strongly, then notching the intensity slightly lower, until the stimulation felt comfortable. Each time the device was taken out of the mouth and put back in, the device would have to be readjusted and centered so feedback received was accurate. Stimulation of CN-NINM consists of 3 square-pulse bursts with an intraburst frequency of 200 Hz and a consistent interburst frequency of 50 Hz. The electrical signal
Fig. 1. (A) BrainPort device, (B) Electric grid array that sits on the tongue, and (C) Tactostimulation of the tongue corresponds to the position of the head. Reprinted from http://tcnl.bme.wisc.edu/projects/completed/bss with permission of Yuri Danilov, PhD. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad. 464
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did not vary over time or contain any external environmental cues, to eliminate unnecessary information to the subject.16 The children also adjusted this device to their tolerance as they did the Brainport, but the device did not need to be centered because the stimulation was uniform across the grid.
variables using an AMTI force plate (Advanced Medical Technology Inc, Watertown, Massachusetts) embedded in the floor of the laboratory as the children stood in place with their feet together and their eyes open for 30 seconds. We calculated velocity and excursion from 2 trials and evaluated the average performance.
Magnetoencephalography Brain Imaging Procedures
Outcomes
The children were cued with an audible tone to perform a simple knee extension movement to a physical target as the neuromagnetic responses of the somatosensory cortices were sampled continuously at 1 kHz using a whole brain magnetoencephalography (MEG) machine that was equipped with 306 sensors (Elekta Neuromag, Helsinki, Finland). Each child performed approximately 115 knee extension movements per session with the more affected leg, and the total recording time was approximately 8.5 minutes. The data analyses epochs were a total duration of 4 seconds (−1.5 to 2.5 seconds), with the auditory cue defined as time 0.0 seconds, and the baseline defined as −0.7 to −0.2 seconds. The artifact-free epochs for each MEG sensor were transformed into the time-frequency domain and averaged over the respective trials. The power within each time-frequency bin was normalized by dividing by the amount of power present in the specific frequency bin during the baseline. This normalization procedure allowed for the visual inspection of power changes that were present in the MEG sensors. We identified the time-frequency band containing the largest movementrelated power change in the MEG sensors near sensorimotor cortices in each child following the intervention. These frequency bands were then imaged to determine if the activation patterns of the sensorimotor cortices might have changed after therapy. A minimum variance vector beamforming algorithm was employed for the entire brain to determine the cortical areas that were responsible for largest power changes noted through the MEG sensors.20 The source power in these images were normalized by the averaged prestimulus period and computed at a 4.0 × 4.0 × 4.0 mm3 voxel resolution.21,22 All MEG calculations were performed with BESA software (BESA version 5.3.2).
MEG Outcomes. Participant 1 moved her right knee during the MEG recording. Before the intervention, the child activated a larger cortical network to perform the knee movement. The largest amount of activity was found in the supplementary motor area and medial parietal regions (Fig. 2, left image). Additional weaker activations were also located in the medial pre- and postcentral gyri. After the intervention, considerable changes were noted in the activated cortical network (Fig 2, right image). The activity previously seen in the supplementary motor area and parietal regions was completely diminished, and the activity was strongly localized in the pre- and postcentral gyri. Participant 2 moved her left knee during the MEG recording. At baseline, this child exhibited a weak amount of activity in the ipsilateral medial areas of the precentral gyrus (Fig. 3, left image). Once again, we noted considerable changes after the therapeutic intervention. A strong and more prominent activation in the contralateral medial areas of the precentral gyrus was observed. Secondary weaker responses were also present in the ispsilateral preand postcentral gyri (Fig. 3, right image). Clinical Outcomes. Both participants showed improvements in balance. On the BBT-P, both children improved beyond the minimal clinically important difference of 3.66 to 5.83 total point change.25 Participant 1 achieved a 6-point gain, and participant 2 achieved a 14-point gain from pre to posttesting. Both children improved in the ability to stand on a dynamic surface (foam), with participant 1 increasing from 1 minute to 10 minutes, and participant 2 increasing from 9 to 18 seconds. Because no reference values have been reported for this task, it is difficult to say whether the change was a clinically important difference; however, other balance skills reported by the children indicated a carryover of improved balance to daily tasks. Gait
Clinical Measures Both participants performed all items on the Berg Balance Test for Pediatrics (BBT-P).23 Although the test challenged the 6-year-old child (participant 2), the older child (participant 1) needed an additional test to assure enough postural challenge. Therefore, the Bruininks-Oseretsky Test of Motor Skill, balance section,24 was also given preand postintervention to participant 1. A Gait-Rite mat and software system (CIR Systems Inc, Sparta, New Jersey) measured overall gait velocity and step length. We report here the changes in “fast” walking because that was the more challenging task for the participants. We additionally measured center of pressure (COP) Pediatric Physical Therapy
Fig. 2. Left image shows preintervention for participant 1; right image shows postintervention. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad. Motor Skill Training in Posterior Fossa Syndrome 465
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tered first grade without a need for her walker. She also played T-ball without the assistance of an adult and was able to walk on the diving board and jump into the pool independently. Her mother noted more changes in motor skill and balance during the 8-week intervention than in the previous 3 years. DISCUSSION
Fig. 3. Left image shows preintervention for participant 2; right image shows postintervention. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad.
velocity and step length increased for both participants, although the increase could not be considered important clinically. More noticeable to the families were balance improvements, which may be reflected in the COP variables, including increases in velocity and excursion. These 2 variables may indicate that the children could more easily recover from larger displacements of the center of mass over the base of support without falling. In addition to the clinical measures detailed in the Table, participant 1 accomplished additional functional goals related to daily skills, set by the child and family. These included the following: running up stairs without holding the railing, riding a bike on level surfaces, carrying groceries and glasses of liquid, and standing on uneven/wobbly surfaces in her exercise sessions at the gym. Participant 2 also reported changes in areas not directly a focus of the study, but that were important to the family. The most unexpected result was an improvement in bladder control such that leaking was eliminated. She en-
Clinically, both patients exhibited improved balance and motor skills after the 8-week intervention. In addition to the measures reported in the Table, the families reported several changes that they attributed to the intervention. These changes were unexpected by either the families or the therapists but are reported here for completeness. The increases in velocity and excursion for the COP measures in standing indicate that the children could more quickly adjust their postural sway and increased the distance they could sway without losing balance. In addition, the increased time of standing on an unstable surface (foam) indicates an improved ability to adjust quickly to unexpected perturbations of the standing surface. Several factors may influence change in motor skill acquisition in children. One is maturation, which is unlikely to be driving the changes noted because 8 weeks is a relatively short amount of time in these older children. Another factor is environmental change; in these 2 cases, posture and movement activities were not different from the usual family engagement, and the home environment remained the same. Musculoskeletal changes due to exercise and visual perceptual changes due to refocusing balance feedback to proprioceptive systems may also factor into the changes measured in these children. The final factors are increased skill practice, which is a different kind of practice, and the input provided by the neuromodulation devices. Regarding skill practice, evidence for
TABLE 1 Pre and Post Clinical Outcome Measures
Participant 1
Participant 2
Test
Pre
Post
Berg-Pediatric Bruininks-Oseretsky-Balance Stand on foam Gait velocity (fast) Step length (fast) COP Velocity AP COP Velocity ML COP Excursion AP COP Excursion ML Berg-Pediatric Stand on foam Gait velocity (fast) Step length (fast) COP Velocity AP COP Velocity ML COP Excursion AP COP Excursion ML
50 (89% of total possible points) 13 (35% of total) 1 min 144 cm/s 66 cm 27 mm/s 20 mm/s 805 mm 598 mm 38 (68% of total) 9s 122 cm/s 43 cm 43 mm/s 33 mm/s 1300 mm 993 mm
56 (100%) 19 (51% of total) 10 min 146 cm/s 68 cm 28 mm/s 24 mm/s 822 mm 723 mm 52 (93% of total) 18 s 124 cm/s 47 cm 51 mm/s 39 mm/s 1540 mm 1170 mm
Abbreviations: AP, anterior posterior; COP, center of pressure; ML, medial lateral.
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functional task training is generally positive in individuals with neurologic deficits, including those with stroke and cerebral palsy.26,27 Thus, the postural tasks were of a functional nature and generally useful to the children during daily activities. The Brainport device may have served to augment information for postural orientation, and the CN-NINM device may have increased the neural receptivity or connectivity to support learning and neuroplastic change. Brainport is thought to work through the reweighting of sensory inputs to increase reliance on the alternative sensory input over the affected modality.17 Brainport augments sensory information and has been used to improve ocular motor control in the blind,27 and improve balance,13 postural sway,13 and gait14 in those with vestibular damage. In addition, Brainport has been used to improve ankle force following muscle fatigue in healthy young adults.17 Whereas the Brainport device augments or substitutes for a lack of sensory information from the usual modality, the CN-NINM device provides nonspecific stimulation. In theory, the CN-NINM unit provides stimulation to the central nervous system, similar to more invasive techniques such as vagal nerve stimulation.15 Thus, the signal from the device “drives” the processing of information, rather than augmenting information as in the Brainport device. This nonspecific stimulation on the tongue has been shown to improve behavioral motor responses in people with balance deficits, and these behavioral findings are accompanied by brain changes.16 The MEG brain imaging results suggest that the noted clinical improvements and reports by the family are most likely related to beneficial neuroplastic changes in the activation of the somatosensory cortices. At baseline, participant 1 required a larger cortical network to perform the knee movement task, which suggests that compensatory networks were used to control the knee joint movements. However, after the therapy, there was a remarkable reduction in the size and localization of the activated cortical network. This implies that the activated cortical network was refined after therapy. For participant 2, the activation of the sensorimotor cortices that were responsible for controlling the knee joint was in the ipsilateral hemisphere at baseline. However, after therapy, the activation was strong and more prominent in the contralateral somatosensory cortices. This suggests that the therapy may have partially normalized the activation of the cortices that should be involved in the control of the knee joint. Although weaker, this child also recruited compensatory networks in the ipsilateral somatosensory cortices for controlling the knee joint movements after therapy. We suspect that these compensatory networks may be pruned with further therapy. In addition, child 2 was only 6 years old, and younger children may show different responses to training because they may still be establishing the connectivity networks for optimal efficiency of function.28 An important component in evaluating the efficacy of these treatments will be in monitoring the longitudinal effects of these therapies. Because these neuromodulatory devices are relatively new and no studies have identified Pediatric Physical Therapy
their long-term effects,16,29,30 longitudinal studies should be undertaken to monitor the long-term therapeutic benefits of using these devices. In addition, because of the novelty of these therapies, larger sample sizes are needed from healthy populations, as well as assessment of the effects in a variety of clinical populations. Notably the differences in the ages of these 2 children may account for differences in their neural activity patterns and the way in which these patterns changed after therapy. Thus study of children with a larger representation of ages is needed as the brain becomes more structurally and functionally specialized with age.31 Moreover, other clinical variables should be taken into consideration (age, postoperative residual tumor status, type of radiation, or chemotherapy), as cancer treatment is characterized by a great deal of heterogeneity.32 Because few researchers have used this technology, and to date no studies have been reported which investigate long-term effects, determining the costs of this technology is difficult. However, one can see the immediate behavioral improvements when using this technology and the absence reports of negative effects. These technologies should be assessed in randomized clinical trials to compare with “traditional” physical therapy (PT) alone, to PT with each device, and to PT with the combined devices, to truly contrast the benefits of each therapy. Summary The clinical improvements in the 2 participants appeared to be supported by the impressions of the families. Extensive and variable practice for posture and movement learning, with augmented feedback and cranial nerve modulation for an intensive 8-week intervention, may allow significant changes to take place in the brain for long-term functional improvements. The information from these case studies should inform further investigations of the longterm rehabilitation potential for children with PFS and add to the body of evidence for the use of neuromodulation devices in rehabilitation.
ACKNOWLEDGMENTS The authors thank the children and families who gave tireless effort in participating in this project.
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19. Ylvisaker M, Adelson PD, Braga LW, et al. Rehabilitation and ongoing support after pediatric TBI: twenty years of progress. J Head Trauma Rehabil. 2005;20:95-109. 20. Gross J, Kujala J, Hamalainen M, Timmermann L, Schnitzler A, Salmelin R. Dynamic imaging of coherent sources: Studying neural interactions in the human brain. Proc Nat Acad Sci. 2001;98:694-699. 21. van Veen BD, van Drongelen W, Yuchtman M, Suzuki A. Localization of brain electrical activity via linearly constrained minimum variance spatial filtering. IEEE Trans Biomed Eng. 1997;44:867-880. 22. Hillebrand A, Singh KD, Holliday IE, Furlong PL, Barnes GR. A new approach to neuroimaging with magnetoencephalography. Hum Brain Mapp. 2005; 25:199-211. 23. Franjoine MR, Gunther JS, Taylor MJ. Pediatric balance scale: a modified version of the berg balance scale for the school-age child with mild to moderate motor impairment. Ped Phys Ther. 2002;15(2):114128. 24. Bruininks RH, Bruininks BD. Bruininks Oseretsky Test of Motor Proficiency: Examiners Manual. 2nd ed. Circle Pines, MN: AGS Publishing; 2005. 25. Chen CL, Shen IH, Chen CY, Wu CY, Liu WY, Chung CY. Validity, responsiveness, minimal detectable change, and minimal clinically important change of Pediatric Balance Scale in children with cerebral palsy. Res Dev Disabil. 2013;34(3):916-922. 26. French B, Thomas LH, Leathley MJ, Repetitive task training for improving functional ability after stroke. Stroke. 2009;40(4): e98-e99. 27. Ketelaar M, Vermeer A, Hart HT, van Petegem-van Beek E, Helders PJ. Effects of a functional therapy program on motor abilities of children with cerebral palsy. Phys Ther. 2001;81(9):15341545. 28. Supekar K, Musen M, Menon V. Development of large-scale functional brain networks in children. PLoS Biol. 2009;7(7): e1000157. 29. Nau A, Hertle RW, Yang D. Effect of tongue stimulation on nystagmus eye movements in blind patients. Brain Struct Funct. 2012;217:761765. 30. Vuillerme N, Boisgontier M. Effectiveness of a tongue-placed electrotactile biofeedback to improve ankle force sense following plantarflexor muscles fatigue. Gait Posture. 2009;30(4):556-559. 31. Johnson MH. Functional brain development in humans. Nat Rev Neurosci. 2001;2:475-483. 32. Packer RJ, Gurney JG, Punyko JA, et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor Study. J Clin Oncol. 2003;21:32553261.
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R E P O R T
Improving the Motor Skill of Children With Posterior Fossa Syndrome: A Case Series Regina Harbourne, PT, PhD; Katherine Becker, BS; David J. Arpin, MS; Tony W. Wilson, PhD; Max J. Kurz, PhD Department of Physical Therapy, Munroe-Meyer Institute (Drs Harbourne and Kurz and Mr Arpin), Center for Magnetoencephalography (Ms Becker), and Department of Pharmacology and Experimental Medicine, College of Medicine (Dr Wilson), University of Nebraska Medical Center, Omaha, Nebraska. Children who receive treatment for medulloblastoma have a high survival rate, but also a high likelihood of developing posterior fossa syndrome, a condition that includes devastating balance and motor problems. This case series used 2 novel neuromodulation devices in conjunction with an intensive physical therapy intervention for 2 children who were 5 years post tumor treatment with a diagnosis of posterior fossa syndrome. Preand postclinical measures, in addition to magnetoencephalography brain imaging, describe positive behavioral and neuroplastic changes resulting from the intervention. The positive outcomes in these cases suggest that further study is needed using neuromodulatory devices and long-term rehabilitation in children with balance and movement disorders resulting from cancer treatment. (Pediatr Phys Ther 2014;26:462–468) Key words: brain/physiopathology, cancer, child, electric stimulation, female, humans, magnetic resonance imaging, medulloblastoma, models/neurological, motor skills, neuropathways/physiopathology, physical therapy, posterior fossa syndrome, postural balance/physiology, rehabilitation, sensation disorders/physiopathology INTRODUCTION Of all childhood cancers, leukemia and tumors of the brain and central nervous system account for about half of all cases.1 The most common type of solid tumor is the medulloblastoma, a brain tumor that occurs in rostral regions of the fourth ventricle in 80% of patients.2 Although survival rates are excellent and the children have a high likelihood of remaining cancer free,3 nearly 25% of survivors exhibit lingering after effects, including ataxia, balance problems, functional motor deficits, emotional la0898-5669/110/2604-0462 Pediatric Physical Therapy C 2014 Wolters Kluwer Health | Lippincott Williams & Copyright Wilkins and Section on Pediatrics of the American Physical Therapy Association
Correspondence: Regina Harbourne, PT, PhD, Department of Physical Therapy, Rangos School of Health Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, PA 15282 ([email protected]). At the time this article was written David Arpin was a student at the University of Nebraska Medical Center, and Katherine Becker was a student at the University of Nebraska at Omaha, Omaha, Nebraska. Grant Support: Funding for this project was provided by the Hattie B. Munroe Foundation, Omaha, Nebraska. The authors declare no conflict of interest. DOI: 10.1097/PEP.0000000000000092
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bility, and speech dysfunction.4-7 These signs appear approximately 24 to 48 hours after surgery8-10 and are collectively identified as posterior fossa syndrome (PFS). This syndrome has been associated with invasion of the brainstem by the tumor and damage to the cerebello-thalamiccerebral pathway,9,11 a pathway critical to the transmission of sensory information from the cerebellum to the cortex.11 Thus, the disruption of vestibular, tactile, and visual information may account for a variety of coordination and balance problems, which have proven to be difficult to treat in children with PFS. It should be emphasized that although much attention has been focused on preventing the long-term effects of the cancer treatment by refining the surgical technique and radiation therapies, the syndrome of motor, speech, and cognitive problems remains intractable and effective remediation of the impairments remains elusive.12 For these reasons, therapies that focus on the cerebello-thalamic-cerebral network may be able to address the array of deficits seen in PFS and improve motor function and long-term outcome. Thus, the focus of this case report is to describe an innovative motor learning intervention using neuromodulation devices that focus on the cerebello-thalamic-cerebral network and vestibular system, used as part of an intervention for 2 children with a diagnosis of PFS. Pediatric Physical Therapy
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The 2 electrical neuromodulatory devices used in this intervention were developed to modify or enhance sensory information, using the tongue as an alternate pathway to the central nervous system. One device, the Brainport (Wicab, Middleton, Wisconsin), indicates head position to the central nervous system and uses sensory substitution to promote neuroplastic change in the service of balance improvement.13,14 The other device, a cranial nerve noninvasive neuromodulation (CN-NINM) unit, uses nondirectional electrical input to the tongue to modulate neural oscillatory circuits, similar to the mechanism of deep brain stimulation.15 These devices originated from the idea that the tongue is an effective interface for sending signals to the central nervous system due to its low electrical impedance and dense concentration of sensory receptors.13,14,16 In addition, the anterior portion of the tongue is innervated by the mandibular nerve that projects to the trigeminal ganglion and ultimately to the pons of the brainstem.17 Thus, stimulation of the tongue is thought to propagate to several brain areas to affect the integration of a diverse range of sensory input.16 Because the area of damage for children with PFS lies within the brainstem/cerebellar area postulated to be affected by these devices, we hypothesized that the devices may have potential to improve motor skills and reduce symptoms in children with PFS. Preliminary experimental evidence from adults with balance problems indicates long-term behavioral changes related to the use of these neuromodulation devices plus motor therapy.16,17 The long-lasting effects on postural control after removal of the electrotactile sensory information suggest neural adaptation. The Brainport device has been shown to improve the balance of patients with vestibular dysfunction13,14 and stroke.18 The CN-NINM device has been shown to improve postural reactions in adults with balance deficits.16 Thus we used both in combination with motor therapy for the 2 children in this study. This case report series describes a short-term, innovative motor-learning intervention using augmentation from neuromodulation devices for 2 children with a diagnosis of PFS. We used 2 neuromodulation devices originally developed for adults with neurologic deficits,18 balance disorders,16 and balance deficits secondary to vestibular dysfunction.14 The primary objective of this investigation was to determine if neuromodulation devices, combined with a motor learning program, were feasible and could improve the balance and motor function of children with PFS. The secondary objective of this investigation was to evaluate if the changes in the children’s balance and motor control were accompanied by neuroplastic changes in the activity of the sensorimotor cortices.
METHODS Participants/Case Description Our Institutional Review Board approved this study, and parental consent and child assent was obtained. ParPediatric Physical Therapy
ticipant 1 was a female fraternal twin, 14 years old, who had a normal developmental course until the diagnosis of a cerebellar tumor at 6 years of age. Posterior fossa syndrome followed the successful removal and treatment of the medulloblastoma. Extensive rehabilitation took place for 2 years to regain speech and walking skills. Physical therapy consisted of inpatient rehabilitation with progression to outpatient therapy and gradual reduction in therapy as skills plateaued. Specific interventions, consistent with the standard of care generally provided after brain injury, included provision of assistive devices (walker), strengthening, balance activities, gait training, and functional skill training.19 Ataxia, balance difficulties, and gross motor delay continued to limit function. At the start of this intervention, she was able to walk independently without any device, but could not safely walk while holding her lunch tray or a glass of liquid, and needed a railing to ascend and descend stairs. She frequently fell when walking on uneven terrain or when negotiating a novel and busy environment. Participant 2, a young girl, was diagnosed with a cerebellar tumor at the age of 5 months. After removal of the tumor, chemotherapy was initiated and completed by 1 year of age. Thus, her motor development milestones were delayed, and the diagnosis of PFS was given because of her ataxia and disordered movement and speech. She was able to walk by the age of 4 years using either her parent’s hand for balance assist, or a posterior walker to prevent falls. She participated in a variety of therapeutic interventions, ranging from consultation for home-based services at 1 year of age, to daily therapy at a rehabilitation center at 2 years of age, and then a reduction in services progressively until school age. She was 6 years old at the start of this intervention, and able to walk independently in familiar environments, such as her home. She also exhibited ataxia, balance difficulties, and gross and fine motor delays. She used a posterior rolling walker at school to prevent falls due to her ataxia and poor balance and the unpredictability of the kindergarten environment and held her parents’ hand for balance assist outside the home. She was engaged in many activities to promote motor skill development in a supervised environment with adaptations and adult assistance including swimming, gymnastics, and t-ball; however, adults guarded her closely to avoid falls during these activities. Her skills at the start of the intervention included independent walking without a device at home, walking with a posterior rollater walker outside the home, ascending and descending stairs using a railing, and light support from an assisting adult for balance in her outside activities (t-ball, dance class.) Falls were infrequent because of close assistance by family members in all standing/walking activities. Both children were currently ineligible for intensive rehabilitation services because they had already completed recommended rehabilitation programs. Thus, their current motor skills were considered their “new normal.” Both children had extensive family support and busy schedules with their families in an attempt to improve balance and motor skills via recreational means. Motor Skill Training in Posterior Fossa Syndrome 463
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Instruments
Intervention
The first device used during the static balance training was the Brainport device that provides feedback about postural orientation via electrotactile stimulation of the tongue. Essentially, the Brainport device has 2 main components: a Controller and an Intraoral device (Fig. 1A and B). The Intraoral device is made up of a 10 × 10 electrode array, a tether, and a micro-electro mechanical system (MEMS) accelerometer (Fig. 1B). The MEMS accelerometer senses head position in both the anterior/posterior and medial/lateral directions and is mounted beneath the electrode array, facing the roof of the mouth. The Intraoral device is positioned on the anterior portion of the tongue and held in place by pressing the tongue against the roof of the mouth. A small tether transmits head-position information measured by the MEMS accelerometer to a small controller worn around the user’s neck, where orientation information is converted into a dynamic pattern of stimulation activating the electrode array in the direction of movement instantaneously. The subject felt the positional information as a pattern of electrotactile stimulation on the tongue. For example, if the child leaned to the left, the stimulus moved to the left side of the patient’s tongue; a forward lean moved the stimulus to the front of the tongue (Fig. 1C). The second device was CN-NINM (Tactile Communication and Neurorehabilitation Laboratory, University of Wisconsin-Madison), which was used during movement (vs postural) activities. Stimulation to the tongue was delivered by a small, flexible polyester-base printed circuit containing 144 electrodes placed on the anterior portion of the tongue, similar to the grid in Fig. 1. The array was held in place by pressure of the tongue to the roof of the mouth.13 The array is in a tongue-shaped matrix. The circular gold-plated electrodes are 1.55 mm in diameter with an on-center spacing of 2.32 mm. The maximal output voltage of the device was 24 volts. Stimulation of CN-NINM consists of 3 square-pulse bursts with an intraburst frequency of 200 Hz and an interburst frequency of 50 Hz that does not vary throughout the stimulation session. This signal was delivered to all 144 electrodes of the array and did not vary with time or movement of the subject.16
Intervention began with 3 days of intensive therapy (1.5 hours in the morning and 1.5 hours in the afternoon) to train the child and family in the use of the neuromodulation devices and motor learning activities. These activities were individually tailored to each child depending on the child’s age, developmental level, and specific functional and balance deficit, and goals identified by the child and family. General guiding principles for the exercise activities included 20 minutes of static balance activities with reduced vision (eyes closed, performed with the Brainport device for postural steadiness feedback), 20 minutes of dynamic balance activities including walking on and off a treadmill and moving through space, and 20 minutes of coordination activities. The movement activities were done using the CNNINM device. Families were instructed to work slowly to gain control, rather than focusing on speed. After the initial 3 days of intensive training, the child received a home program modified to specific individual needs. The children performed activities under parental supervision at home 5 days per week for 8 weeks, and then returned for testing. A weekly Skype (Skype Technologies) visit to the therapist allowed updating, modification, and progression of the individualized programs. Tongue Stimulation Stimulation to the tongue by the Brainport device was delivered by a small, flexible polyester-base printed circuit placed on the anterior portion of the tongue.13 The child was shown how to adjust the sensation to tolerance, by taking the intensity to a point at which the stimulation could be felt strongly, then notching the intensity slightly lower, until the stimulation felt comfortable. Each time the device was taken out of the mouth and put back in, the device would have to be readjusted and centered so feedback received was accurate. Stimulation of CN-NINM consists of 3 square-pulse bursts with an intraburst frequency of 200 Hz and a consistent interburst frequency of 50 Hz. The electrical signal
Fig. 1. (A) BrainPort device, (B) Electric grid array that sits on the tongue, and (C) Tactostimulation of the tongue corresponds to the position of the head. Reprinted from http://tcnl.bme.wisc.edu/projects/completed/bss with permission of Yuri Danilov, PhD. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad. 464
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did not vary over time or contain any external environmental cues, to eliminate unnecessary information to the subject.16 The children also adjusted this device to their tolerance as they did the Brainport, but the device did not need to be centered because the stimulation was uniform across the grid.
variables using an AMTI force plate (Advanced Medical Technology Inc, Watertown, Massachusetts) embedded in the floor of the laboratory as the children stood in place with their feet together and their eyes open for 30 seconds. We calculated velocity and excursion from 2 trials and evaluated the average performance.
Magnetoencephalography Brain Imaging Procedures
Outcomes
The children were cued with an audible tone to perform a simple knee extension movement to a physical target as the neuromagnetic responses of the somatosensory cortices were sampled continuously at 1 kHz using a whole brain magnetoencephalography (MEG) machine that was equipped with 306 sensors (Elekta Neuromag, Helsinki, Finland). Each child performed approximately 115 knee extension movements per session with the more affected leg, and the total recording time was approximately 8.5 minutes. The data analyses epochs were a total duration of 4 seconds (−1.5 to 2.5 seconds), with the auditory cue defined as time 0.0 seconds, and the baseline defined as −0.7 to −0.2 seconds. The artifact-free epochs for each MEG sensor were transformed into the time-frequency domain and averaged over the respective trials. The power within each time-frequency bin was normalized by dividing by the amount of power present in the specific frequency bin during the baseline. This normalization procedure allowed for the visual inspection of power changes that were present in the MEG sensors. We identified the time-frequency band containing the largest movementrelated power change in the MEG sensors near sensorimotor cortices in each child following the intervention. These frequency bands were then imaged to determine if the activation patterns of the sensorimotor cortices might have changed after therapy. A minimum variance vector beamforming algorithm was employed for the entire brain to determine the cortical areas that were responsible for largest power changes noted through the MEG sensors.20 The source power in these images were normalized by the averaged prestimulus period and computed at a 4.0 × 4.0 × 4.0 mm3 voxel resolution.21,22 All MEG calculations were performed with BESA software (BESA version 5.3.2).
MEG Outcomes. Participant 1 moved her right knee during the MEG recording. Before the intervention, the child activated a larger cortical network to perform the knee movement. The largest amount of activity was found in the supplementary motor area and medial parietal regions (Fig. 2, left image). Additional weaker activations were also located in the medial pre- and postcentral gyri. After the intervention, considerable changes were noted in the activated cortical network (Fig 2, right image). The activity previously seen in the supplementary motor area and parietal regions was completely diminished, and the activity was strongly localized in the pre- and postcentral gyri. Participant 2 moved her left knee during the MEG recording. At baseline, this child exhibited a weak amount of activity in the ipsilateral medial areas of the precentral gyrus (Fig. 3, left image). Once again, we noted considerable changes after the therapeutic intervention. A strong and more prominent activation in the contralateral medial areas of the precentral gyrus was observed. Secondary weaker responses were also present in the ispsilateral preand postcentral gyri (Fig. 3, right image). Clinical Outcomes. Both participants showed improvements in balance. On the BBT-P, both children improved beyond the minimal clinically important difference of 3.66 to 5.83 total point change.25 Participant 1 achieved a 6-point gain, and participant 2 achieved a 14-point gain from pre to posttesting. Both children improved in the ability to stand on a dynamic surface (foam), with participant 1 increasing from 1 minute to 10 minutes, and participant 2 increasing from 9 to 18 seconds. Because no reference values have been reported for this task, it is difficult to say whether the change was a clinically important difference; however, other balance skills reported by the children indicated a carryover of improved balance to daily tasks. Gait
Clinical Measures Both participants performed all items on the Berg Balance Test for Pediatrics (BBT-P).23 Although the test challenged the 6-year-old child (participant 2), the older child (participant 1) needed an additional test to assure enough postural challenge. Therefore, the Bruininks-Oseretsky Test of Motor Skill, balance section,24 was also given preand postintervention to participant 1. A Gait-Rite mat and software system (CIR Systems Inc, Sparta, New Jersey) measured overall gait velocity and step length. We report here the changes in “fast” walking because that was the more challenging task for the participants. We additionally measured center of pressure (COP) Pediatric Physical Therapy
Fig. 2. Left image shows preintervention for participant 1; right image shows postintervention. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad. Motor Skill Training in Posterior Fossa Syndrome 465
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tered first grade without a need for her walker. She also played T-ball without the assistance of an adult and was able to walk on the diving board and jump into the pool independently. Her mother noted more changes in motor skill and balance during the 8-week intervention than in the previous 3 years. DISCUSSION
Fig. 3. Left image shows preintervention for participant 2; right image shows postintervention. This figure is available in color in the article on the journal website, www.pedpt.com, and the iPad.
velocity and step length increased for both participants, although the increase could not be considered important clinically. More noticeable to the families were balance improvements, which may be reflected in the COP variables, including increases in velocity and excursion. These 2 variables may indicate that the children could more easily recover from larger displacements of the center of mass over the base of support without falling. In addition to the clinical measures detailed in the Table, participant 1 accomplished additional functional goals related to daily skills, set by the child and family. These included the following: running up stairs without holding the railing, riding a bike on level surfaces, carrying groceries and glasses of liquid, and standing on uneven/wobbly surfaces in her exercise sessions at the gym. Participant 2 also reported changes in areas not directly a focus of the study, but that were important to the family. The most unexpected result was an improvement in bladder control such that leaking was eliminated. She en-
Clinically, both patients exhibited improved balance and motor skills after the 8-week intervention. In addition to the measures reported in the Table, the families reported several changes that they attributed to the intervention. These changes were unexpected by either the families or the therapists but are reported here for completeness. The increases in velocity and excursion for the COP measures in standing indicate that the children could more quickly adjust their postural sway and increased the distance they could sway without losing balance. In addition, the increased time of standing on an unstable surface (foam) indicates an improved ability to adjust quickly to unexpected perturbations of the standing surface. Several factors may influence change in motor skill acquisition in children. One is maturation, which is unlikely to be driving the changes noted because 8 weeks is a relatively short amount of time in these older children. Another factor is environmental change; in these 2 cases, posture and movement activities were not different from the usual family engagement, and the home environment remained the same. Musculoskeletal changes due to exercise and visual perceptual changes due to refocusing balance feedback to proprioceptive systems may also factor into the changes measured in these children. The final factors are increased skill practice, which is a different kind of practice, and the input provided by the neuromodulation devices. Regarding skill practice, evidence for
TABLE 1 Pre and Post Clinical Outcome Measures
Participant 1
Participant 2
Test
Pre
Post
Berg-Pediatric Bruininks-Oseretsky-Balance Stand on foam Gait velocity (fast) Step length (fast) COP Velocity AP COP Velocity ML COP Excursion AP COP Excursion ML Berg-Pediatric Stand on foam Gait velocity (fast) Step length (fast) COP Velocity AP COP Velocity ML COP Excursion AP COP Excursion ML
50 (89% of total possible points) 13 (35% of total) 1 min 144 cm/s 66 cm 27 mm/s 20 mm/s 805 mm 598 mm 38 (68% of total) 9s 122 cm/s 43 cm 43 mm/s 33 mm/s 1300 mm 993 mm
56 (100%) 19 (51% of total) 10 min 146 cm/s 68 cm 28 mm/s 24 mm/s 822 mm 723 mm 52 (93% of total) 18 s 124 cm/s 47 cm 51 mm/s 39 mm/s 1540 mm 1170 mm
Abbreviations: AP, anterior posterior; COP, center of pressure; ML, medial lateral.
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functional task training is generally positive in individuals with neurologic deficits, including those with stroke and cerebral palsy.26,27 Thus, the postural tasks were of a functional nature and generally useful to the children during daily activities. The Brainport device may have served to augment information for postural orientation, and the CN-NINM device may have increased the neural receptivity or connectivity to support learning and neuroplastic change. Brainport is thought to work through the reweighting of sensory inputs to increase reliance on the alternative sensory input over the affected modality.17 Brainport augments sensory information and has been used to improve ocular motor control in the blind,27 and improve balance,13 postural sway,13 and gait14 in those with vestibular damage. In addition, Brainport has been used to improve ankle force following muscle fatigue in healthy young adults.17 Whereas the Brainport device augments or substitutes for a lack of sensory information from the usual modality, the CN-NINM device provides nonspecific stimulation. In theory, the CN-NINM unit provides stimulation to the central nervous system, similar to more invasive techniques such as vagal nerve stimulation.15 Thus, the signal from the device “drives” the processing of information, rather than augmenting information as in the Brainport device. This nonspecific stimulation on the tongue has been shown to improve behavioral motor responses in people with balance deficits, and these behavioral findings are accompanied by brain changes.16 The MEG brain imaging results suggest that the noted clinical improvements and reports by the family are most likely related to beneficial neuroplastic changes in the activation of the somatosensory cortices. At baseline, participant 1 required a larger cortical network to perform the knee movement task, which suggests that compensatory networks were used to control the knee joint movements. However, after the therapy, there was a remarkable reduction in the size and localization of the activated cortical network. This implies that the activated cortical network was refined after therapy. For participant 2, the activation of the sensorimotor cortices that were responsible for controlling the knee joint was in the ipsilateral hemisphere at baseline. However, after therapy, the activation was strong and more prominent in the contralateral somatosensory cortices. This suggests that the therapy may have partially normalized the activation of the cortices that should be involved in the control of the knee joint. Although weaker, this child also recruited compensatory networks in the ipsilateral somatosensory cortices for controlling the knee joint movements after therapy. We suspect that these compensatory networks may be pruned with further therapy. In addition, child 2 was only 6 years old, and younger children may show different responses to training because they may still be establishing the connectivity networks for optimal efficiency of function.28 An important component in evaluating the efficacy of these treatments will be in monitoring the longitudinal effects of these therapies. Because these neuromodulatory devices are relatively new and no studies have identified Pediatric Physical Therapy
their long-term effects,16,29,30 longitudinal studies should be undertaken to monitor the long-term therapeutic benefits of using these devices. In addition, because of the novelty of these therapies, larger sample sizes are needed from healthy populations, as well as assessment of the effects in a variety of clinical populations. Notably the differences in the ages of these 2 children may account for differences in their neural activity patterns and the way in which these patterns changed after therapy. Thus study of children with a larger representation of ages is needed as the brain becomes more structurally and functionally specialized with age.31 Moreover, other clinical variables should be taken into consideration (age, postoperative residual tumor status, type of radiation, or chemotherapy), as cancer treatment is characterized by a great deal of heterogeneity.32 Because few researchers have used this technology, and to date no studies have been reported which investigate long-term effects, determining the costs of this technology is difficult. However, one can see the immediate behavioral improvements when using this technology and the absence reports of negative effects. These technologies should be assessed in randomized clinical trials to compare with “traditional” physical therapy (PT) alone, to PT with each device, and to PT with the combined devices, to truly contrast the benefits of each therapy. Summary The clinical improvements in the 2 participants appeared to be supported by the impressions of the families. Extensive and variable practice for posture and movement learning, with augmented feedback and cranial nerve modulation for an intensive 8-week intervention, may allow significant changes to take place in the brain for long-term functional improvements. The information from these case studies should inform further investigations of the longterm rehabilitation potential for children with PFS and add to the body of evidence for the use of neuromodulation devices in rehabilitation.
ACKNOWLEDGMENTS The authors thank the children and families who gave tireless effort in participating in this project.
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