The ultimate goal for the treatment of children with cerebral palsy (CP) is an improvement in functionality and increased independence, which will prepare these children for adult life 1 . The prognosis of a child with CP often depends on the type and severity of the palsy and the accompanying medical comorbidities 2 . In hemiplegic cerebral palsy (HCP), different severities and combinations of impairments in sensory function, perception, muscle tone, muscle strength and range of motion contribute to their motor dysfunction. Furthermore, these factors should be evaluated and managed because functionality is a component of overall health, and the appropriate combinations of interventions can improve function 3 .
Spasticity is a prevalent, disabling clinical symptom for children with HCP 4 and develops over time 1 concomitantly with motor development. This symptom influences motor learning and the acquisition of functional skills. Several studies have reported the effectiveness of botulinum neurotoxin type A (BXT-A) in reducing muscle tone and improving function in children with CP 4-6 . This treatment has been thought to facilitate the learning of more normal movement patterns 7 . No studies have focused on the influence of BXT-A on motor learning during the first months of life, which is a critical period for neurological development, or on the effects of this agent on the gradual consolidation of abnormal patterns of movement. However, previous observations describing improved responses in young children without the development of deformities and more structured learning potential 6,8suggest that there is a critical time during growth and development when the management of upper and lower limb spasticity in children with HCP is likely to be optimal.
The objectives of the current study were to describe the functional trajectory of infants subjected to early treatment of spasticity — study group (SG) — and compare their motor and functional performance to a comparison group (CG), composed by children who were not treated with BXT-A.
METHODS
The SG was part of a cohort follow-up from a program that evaluated babies who were at risk at the Hospital de Clínicas of the Federal University of Paraná (UFPR), a tertiary centre for high risk gestations. Infants with the diagnosis of HCP who were treated with BXT-A before two years of age were included in this study. All of the included subjects were at levels I and II, according to the Gross Motor Function Classification System (GMFCS) 9. After approval by the Human Research Ethics Committee of the Hospital de Clínicas of the UFPR, 13 children were consecutively enrolled into this study from November 2001 to November 2003. Two infants were excluded because of a lack of follow-up.
At the end of three years of monitoring, the SG motor and functional performance was assessed and compared to another group in a cross-sectional study. The CG was composed of children with HCP at levels I and II, according to GMFCS 9 . These patients were referred from other clinical services after three years of age and were not exposed to BXT-A or orthopaedic surgery. One HCP child was excluded because he was at level III, according to GMFCS 9 . Informed consent was obtained from the parents/guardians of all participants.
Intervention
The BXT-A injections were administered under general anaesthesia using electro-stimulation guidance (model NS 252J, Fisher & Paykel Electronics, Auckland, New Zealand). Injections were administered to at least two sites per muscle belly with a maximum dose of 50 U/site. Passive and active evaluations of spasticity, passive range of motion in the target joint, muscle strength and gait and hand function observations were performed to determine if the subjects' spasticity caused discomfort, interfered with their ability to function or their acquisition of developmental milestones, or it will lead to musculoskeletal deformity. After this, the author LHCS determined treatment goals and discussed it with caregiver/child. If the family planed vacations or any other impediment for the treatment, the session was postponed 10 . Treatment was individualised with no standardisation of the muscle group, dose, number of sessions or age at the initiation of treatment. The toxin used was BXT-A (BOTOX®, Allergan, Irvine, CA, USA) at a dilution of 100 U in 1 mL of 0.9% NaCl solution. At each assessment with the multidisciplinary team, along with the assessment of the need for intervention with the toxin — and independently of the need for it at that time —, caregivers were instructed on how to train motor skills corresponding to each stage of development. The multidisciplinary team has remained the same throughout follow-up. The patients were revaluated one and three months after application. The next medical reassessments were defined on a case-by-case basis.
Outcomes measures used in monitoring of the study group
The considered data were: initial age and time of attendance, number of medical evaluations, number of blockades with BXT-A, interval between sessions and medical re-evaluation, selected and applied muscles in each session, BXT-A dose per kg and number of sessions. Evaluation of spasticity 11 , range of active and passive extension of the wrist evaluated with a goniometer drive, and gait pattern (Physician's Rating Scale - PRS) 12were performed during each clinical evaluation always by LHCS. A periodic Gross Motor Function Measure (GMFM)-88 13 assessment was used to analyse child's motor capability and allowed to draw the motor development curve (MDC) 14 for each SG child. All GMFM evaluations in this study were performed by the same trained author of this study, MBZ.
Outcomes measures used in comparing the groups
For the cross-sectional study, the data from the final assessment of the SG were considered, after three years of follow-up, compared to the data of the first assessment of the CG, before any kind of intervention in this group. The final evaluation of SG was held in conjunction with the sixth assessment of motor function, not considering a specific period after BTX-A session.
Gender, presence of epilepsy, number of adverse events in the prenatal and perinatal periods, classification according to GMFCS and data from the evaluation of the range of active extension of the wrist were considered, besides the speed of hand movements (Figs 1 and 2), PRS score 12 , spasticity 10 , muscular strength, sensitivity function and the presence of hemineglect, as assessed by the WISC IV subtest 15 . Neuroimage classification 16and intelligence quotient (IQ) 15 were also considered by the authors of this study, ACN and SM, respectively.
The GMFM 13 score allowed comparing the best positioning in relation to the median in the motor development curves (MDC) for CP for CP 14 . The Pediatric Evaluation of Disability Inventory (PEDI) 17 was used to assess the child's actual performance during day-to-day life and the positioning in relation to the third percentile for the Pediatric Physical Functioning Reference Curves (PPFRC) for self-care and mobility 18 . All PEDI 17 evaluations were performed by the same trained author of this study, MP. The assessment tools GMFM 13 , GMFCS 9 , PEDI 17and PRS 12 are considered valid and reliable for assessing functional ability of children with cerebral palsy 19 .
Statistics
For the association between quantitative variables, the Spearman correlation coefficient was estimated. In order to compare the quantitative variables between the two independent subgroups, either Student's t-test or Mann-Whitney non-parametric test was considered appropriate. Fisher's exact test was used for comparisons between dichotomous nominal variables and Student's t-test was used for dependent variables; p<0.05 was considered statistically significant. Statistica/w v.5.1® software was applied for the analyses.
RESULTS
Twenty-four children participated in the study, and detailed data for each child are provided in Table 1.
Table 1. Individual characteristics of children in the study and the comparison groups.
| P | G | Age | Invol Side | Advers events | Epilepsia | Age walking | Wrist extention | Hemineglect | GMFCS | GMFM | Motor curve | Self-care | Mobility | Neuroimage | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study group | 1 | M | 41 | L | No | Yes | 24 | 30 | No | I | 81% | 5%↓Med | 23%↓ | 16%↓ | 1 |
| 2 | M | 41 | L | Yes | Yes | 24 | 20 | No | I | 94.1% | Med | 5% ↓ | 15%↓ | 1 | |
| 3 | M | 41 | R | Yes | No | 32 | -30 | Yes | II | 58.5% | 10%↓- | 16%↓ | 9%↓ | 4 | |
| 4 | M | 55 | R | Yes | No | 23 | 0 | No | I | 98.3% | 2%↑+2 SD | 6%↓ | 7%↓ | 2 | |
| 5 | F | 48 | R | Yes | No | 13 | 30 | Yes | I | 93.8% | Med | 11%↓ | 7%↓ | 2 | |
| 6 | M | 53 | L | Yes | No | 18 | 10 | Yes | I | 97% | 1%↑+2 SD | 17%↓ | 5%↓ | 3 | |
| 7 | M | 45 | L | Yes | No | 19 | 45 | No | I | 94.7% | 5%↑Med | 1%↑ | 5%↓ | 2 | |
| 8 | M | 55 | L | No | No | 17 | 90 | No | I | 93.2% | 5%↑Med | 6%↓ | 13%↓ | 5 | |
| 9 | M | 46 | L | Yes | No | 18 | 90 | No | I | 95% | 2%↑+2 SD | 3 %↑ | 5%↓ | 3 | |
| 10 | F | 38 | L | Yes | No | 18 | 30 | Yes | I | 92% | 5%↑Med | 9%↓ | 3%↓ | 2 | |
| 11 | F | 39 | L | Yes | Yes | 20 | 60 | No | I | 93% | 5%↑Med | 23%↓ | 6%↓ | 1 | |
| Comparison group | 1 | M | 40 | L | Yes | No | 20 | 10 | No | I | 92.5% | 5%↑Med | 11%↓ | 1%↑ | 3 |
| 2 | M | 39 | L | No | No | 15 | 10 | No | II | 92% | 1%↑+2 SD | 13%↓ | 1%↓ | 2 | |
| 3 | M | 51 | L | No | No | 48 | 10 | # | I | 53% | 17%↓-2 SD | 13%↓ | 37%↓ | 4 | |
| 4 | M | 41 | R | No | No | 24 | 10 | No | I | 90.3% | 1%↑Med | 36%↓ | 23%↓ | 2 | |
| 5 | F | 39 | R | No | No | 20 | 45 | No | I | 93% | 5%↑Med | 26%↓ | 11%↓ | 1 | |
| 6 | M | 45 | R | Yes | No | 12 | -30 | Yes | I | 86% | Med | 12%↓ | 10%↓ | 2 | |
| 7 | M | 53 | R | Yes | No | 30 | 90 | No | I | 96% | 1%↑Med | 10%↓ | 14%↓ | 2 | |
| 8 | M | 46 | R | Yes | No | 30 | -60 | Yes | I | 72% | 8%↓-2 SD | 18%↓ | 2%↓ | 3 | |
| 9 | M | 41 | R | Yes | No | 16 | 20 | No | I | 85.6% | 3%↓Med | 10%↓ | 8%↓ | 1 | |
| 10 | M | 58 | R | No | No | 14 | 70 | Yes | I | 95.6% | Med | 10%↓ | 6%↓ | 1 | |
| 11 | F | 50 | L | Yes | No | 36 | 10 | # | I | 80.2% | 1%↓-2 SD | 5%↓ | 20%↓ | 4 | |
| 12 | M | 41 | R | No | No | 12 | 30 | Yes | I | 95% | 7%↑Med | 33%↓ | 12%↓ | 1 | |
| 13 | M | 53 | L | Yes | No | 13 | 0 | No | I | 96% | Med | 3%↓ | 9%↓ | 2 |
P: patient; G: gender; M: masculine; F: feminine; Age: age (months) of evaluation; Invol Side: side of involvement; L: left; R: right; Adverse events: presence of adverse events at birth; Epilepsia: presence of epilepsia; Age Walking: age (months) of acquisition of independent walking; Wrist Extention: range of active extention of the wrist; GMFCS: Gross Motor Function Classification System; GMFM: total score in the Gross Motor Function Measure; MDC: distance to the median in the Motor Development Curve; Self-Care - distance to the 3th percentile in the Pediatric Physical Functioning Reference Curve (PPFRC) for self-care; Mobility - distance to the 3th percentile in the PPFRC for mobility; Neuroimage - neuroimage classification: 1. Maldevelopment, 2. Periventricular Atrophy, 3. Cortical/Subcortical Atrophy, 4. Miscelaneous, 5. Normal; Med: median; #: data not obtained; ↑ above; ↓ below.
Data on spasticity treatment of the study group
The SG was composed of 11 HCP children and included 8 boys and 8 (73%) children with left-side involvement. Treatment of spasticity started at a mean age of 9 months (±3) and ranged from 6 to 15 months. The mean follow-up time was 36.63 months (±6.31). The total number of BXT-A sessions was 41. One patient accomplished only one session, two accomplished three sessions, six accomplished four sessions and two were subjected to five sessions, and adverse effects were not reported. There was an intervention targeting the upper limbs in all sessions and targeting the lower limbs in 34 ones (83%). To compare muscle tone in each child, 11 muscles were evaluated at the beginning and at the end of the study period. In 64 (53%) evaluations, the tonus remained stable, there was a decrease in 40 (33%) cases, and an increase in 17 (14%) ones. Data on the BXT-A treatment for the SG, the frequency of the muscles injections and data on changes in muscle tone from the begining to the end of the study are available in Table 2. The range of passive wrist extention remained at good levels for the duration of the study and the range of active wrist extention increased in six patients (Table 3). The only patient who showed decreased in the active range of wrist extention was patient 3, level II in the GMFCS, and the only in both groups with Large-vessel arterial infarct in the left internal carotid artery.
Table 2. Average dose of botulinum neurotoxin type A used in each year of life in the study group children, number of sessions and frequency of the muscle injections per session, besides the changes in muscle tonus considering the initial and the final tonus evaluation.
| Age (n=11) | BXT-A dose and distribution | |
|---|---|---|
| Dose per kg | Number of sessions (n=41) | |
| Up to 12 months | 10.98 | 12 |
| Between 13 and 24 months | 11.89 | 16 |
| Between 25 and 36 months | 14.07 | 8 |
| Between 37 and 48 months | 11.81 | 4 |
| Above 49 months | 15.2 | 1 |
| Frequency of muscles injections/session | Muscles injected | Percentage |
|---|---|---|
| Upper limb | PM | 84% |
| BR | 87% | |
| PT | 87% | |
| FDS | 84% | |
| FPB | 76% | |
| AP | 76% | |
| Lower limb | GA | 97% |
| Soleus | 82% | |
| Adductors | 29% | |
| Medial HA | 24% |
| Initial and final muscle tonus evaluation (Aswhorth scale) | ||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | |||||||||||
| Muscle | I | F | I | F | I | F | I | F | I | F | I | F | I | F | I | F | I | F | I | F | I | F |
| PM | 2 | 2 | 2 | 1 | 1 | 3 | 2 | 1 | 2 | 2 | 3 | 2 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 2 | 1 | 1 |
| BR | 2 | 2 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 3 | 3 | 2 | 2 | 2 | 1 | 2 | 2 | 2 | 2 | 1 | 1 |
| PT | 2 | 2 | 2 | 1 | 1 | 2 | 2 | 3 | 1 | 1 | 2 | 1 | 3 | 2 | 2 | 1 | 2 | 2 | 2 | 2 | 2 | 1 |
| FCR | 1 | 1 | 1 | 1 | 2 | 3 | 2 | 3 | 2 | 2 | 3 | 2 | 2 | 2 | 1 | 1 | 2 | 1 | 1 | 2 | 1 | 1 |
| FCU | 1 | 1 | 1 | 1 | 2 | 3 | 2 | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 1 | 1 | 2 | 1 | 1 | 2 | 1 | 1 |
| FDS | 2 | 2 | 2 | 1 | 3 | 3 | 2 | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 1 |
| FPB | 2 | 1 | 2 | 1 | 1 | 1 | 2 | 3 | 1 | 2 | 2 | 1 | 2 | 2 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 1 |
| AP | 2 | 1 | 1 | 1 | 1 | 3 | 2 | 2 | 1 | 2 | 1 | 1 | 2 | 1 | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 1 |
| GA | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 2 | 3 | 2 | 3 | 4 | 2 | 4 | 1 | 1 | 2 | 2 | 2 | 2 | 1 | 2 |
| AD | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 2 | 1 | 3 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
| HA | 1 | 1 | 1 | 1 | 3 | 1 | 2 | 2 | 3 | 1 | 3 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
I: initial; F: final; PM: pectoralis major; BR: braquioradialis; PT: pronador teres; FCR: flexor carpi radialis; FCU: flexor carpi ulnaris; FDS: flexor digitorum superficialis; FPB: flexor pollicis brevis; AP: adductor pollicis; GA: gastrocnemius; AD: adductors; HA: hamstrings; BXT-A: botulinum neurotoxin type A.
Table 3. Range of movement at initial and final evaluations of the study group children.
| Patient | Passive extension of the wrist | Active extension of the wrist | ||
|---|---|---|---|---|
| Initial | Final | Initial | Final | |
| 1 | 90 | 90 | 10 | 30 |
| 2 | 90 | 90 | 30 | 20 |
| 3 | 90 | 90 | -30 | |
| 4 | 70 | 75 | 0 | 0 |
| 5 | 90 | 90 | 30 | |
| 6 | 90 | 90 | 10 | |
| 7 | 60 | 90 | 20 | 45 |
| 8 | 90 | 90 | 20 | 90 |
| 9 | 90 | 90 | 30 | 90 |
| 10 | 60 | 90 | 10 | 30 |
| 11 | 90 | 90 | 10 | 60 |
No obtained data by younger age and/or no cooperation of the patient.
The first evaluation using the GMFM was conducted when the BXT-A was first indicated, and there were a total of six evaluations during the study. The total score obtained in each GMFM was compared to the functional level as assessed by the GMFCS and with the MDC for HCP. Improvement in the MDC was observed in seven patients, while three were maintained at good levels and one (patient 3) was below average (-2SD) (Table 4). No adverse reactions were observed or any negative effects of the BTX-A sessions in the functional capacity of any child of the SG.
Table 4. Gross Motor Function Classification System and positioning in the motor development curves for cerebral palsy in each Gross Motor Function Measure evaluation of the study group children.
| Patient | GMFCS | GMFM 1 | GMFM 2 | GMFM 3 | GMFM 4 | GMFM 5 | GMFM 6 |
|---|---|---|---|---|---|---|---|
| 1 | I | 17%↓-2 SD | 8%↓ MED | 20%↓-2 SD | 20%↓ MED | 5%↓MED | |
| 2 | I | 8%↓ MED | 2%↓-2 SD | 1%↓ MED | MED | ||
| 3 | II | 2%↓-2 SD | 2%↓ MED | 3%↓-2 SD | 5%↓-2 SD | 20%↓ MED | 10%↓-2 SD |
| 4 | I | 2%↑ MED | 2%↑ MED | 2%↑MED | 2%↑+2 SD | 2%↑+2 SD | |
| 5 | I | 8%↓ MED | 3%↑ MED | MED | MED | MED | |
| 6 | I | 5%↑+2 SD | 5%↑+2 SD | 2%↑+2 SD | 5%↑ MED | 5%↑ MED | 1%↑+2 SD |
| 7 | I | 12%↓-2 SD | 6%↓ MED | 6%↓ MED | MED | 5%↑ MED | |
| 8 | I | 8%↑ MED | 2%↑ MED | 1%↑ MED | 5%↑ MED | ||
| 9 | I | 20%↑+2 SD | 8%↑+2 SD | 8%↑ MED | 2%↑+2 SD | 2%↑+2 SD | |
| 10 | I | 1%↓ MED | 5%↑ MED | MED | 5%↑ MED | ||
| 11 | I | 2%↓-2 SD | 2%↑+2 SD | 1%↑+2 SD | 4%↑ MED | 5%↑ MED |
GMFCS: Gross Motor Function Classification System; GMFM (1 to 6): position in the curve from the first to the sixth Gross Motor Function Measure; SD: standard deviation; MED: median; ↑ above; ↓ below.
Data regarding the comparison between groups
Twenty-four children with HCP — mean age of 49.3±5.2 months and an age range of 39 to 60 months — participated in the study. CG was composed of 13 HCP children and included 11 boys and 5 (38%) children with left-side involvement.
There was no significant difference between groups regarding the number of adverse events in pre- and perinatal periods (p=0.21), presence of epilepsy (p=0.08), gender (p=0.63) or classification according to the GMFCS (p=1). Due to the sample size and the presence of a variety of neuroimaging classifications, it was not possible to compare the data between the groups.
Children from both groups were referred to physiotherapy. At the time of the cross-sectional assessment, 18 patients had follow-up with physical therapy for over 2 years (75%) and 6 (25%) for less than 2 years. This variable could not be controlled due to the different children's backgrounds and the variety of types, frequency and intensity of the physiotherapy treatment that they received.
There was no statistically significant difference between the groups regarding sensitivity function, spasticity, muscle strength and the presence of hemineglect 19 .
The SG subjects exhibited a higher active extension of the wrist, a higher percentage of balls and rings transferred and a higher PRS score than the CG subjects; however, there was no significant difference (Table 5). The GMFM scores of the SG subjects were higher in four of the five dimensions and were significantly higher for dimension B. The SG subjects presented with higher than average scores and less variation compared to the CG in terms of variation relative to the median in the MDC; nevertheless, there was no significant difference (p=0.53). The SG showed higher scores in five of the six areas evaluated in the PEDI (Table 5) and were closer to the third percentile for both self-care and mobility in the PPFRC, but this difference was not significant.
Table 5. Comparison between groups concerning developmental and functional data.
| Variables | Study group | Comparison group | p-value | ||||
|---|---|---|---|---|---|---|---|
| Mean | SD | Range | Mean | SD | Range | ||
| Age (months) | |||||||
| At evaluation | 45.64 | 6.3 | 38-55 | 45.92 | 6.4 | 39-58 | 0.914 |
| Signs of hemiplegia | 4.36 | 1.43 | 2-6 | 6.5 | 4.8 | 1-16 | 0.566 |
| Head control | 5.36 | 1.86 | 3-9 | 5.5 | 3.23 | 3-12 | 0.566 |
| Sitting control | 9.18 | 2.4 | 6-12 | 10.36 | 5.32 | 6-24 | 0.949 |
| Independent walking | 20.55 | 5.03 | 13-32 | 22.31 | 10.96 | 12-48 | 0.820 |
| Cognitive function | |||||||
| Performance | 71.09 | 19.10 | 47-106 | 77 | 26.29 | 47-126 | 0.833 |
| Verbal | 82.55 | 15.80 | 52-105 | 88.92 | 30.16 | 48-152 | 0.740 |
| Total | 74.55 | 18.27 | 45-101 | 81.83 | 30.94 | 43-141 | 0.833 |
| GMFM (%) | |||||||
| Dimension A | 96 | 10 | 68.6-100 | 98 | 3 | 90-100 | 0.820 |
| Dimension B | 97 | 7 | 76.6-100 | 94 | 6 | 83.3-100 | 0.035 |
| Dimension C | 89 | 26 | 14.2-100 | 83 | 28 | 16.6-100 | 0.361 |
| Dimension D | 89 | 5 | 82-97.4 | 84 | 16 | 33.3-100 | 0.459 |
| Dimension E | 82 | 13 | 49-94 | 74 | 15 | 36.1-90.2 | 0.134 |
| Total score | 91 | 12 | 58.5-98.3 | 87 | 12 | 53-96 | 0.119 |
| PEDI | |||||||
| FS normative score | |||||||
| Self-care | 35.04 | 9,07 | 18-50 | 23.71 | 20,3 | -10-41.4 | 0.277 |
| Mobility | 27.40 | 7.95 | 12.2-35.9 | 22.02 | 25,12 | -10-56 | 0.608 |
| Social function | 27.13 | 15.88 | -10-46.8 | 32.64 | 12.23 | 13.7-52 | 0.424 |
| CA normative score | |||||||
| Self-care | 43.92 | 14.24 | 23.3-68.6 | 31.25 | 21.32 | -10-52 | 0,424 |
| Mobility | 39,95 | 13.70 | 12.7-58.8 | 33.28 | 19.17 | -10-58.3 | 0,494 |
| Social function | 52.47 | 13.62 | 27.5-68.7 | 49.70 | 12.31 | 24-68.9 | 0,569 |
| Distance MDC (cm) | 0.64 | 6.31 | -16-5 | -2.15 | 8.91 | -20-7 | 0.531 |
| Distance in PPFRC | |||||||
| Self-care | 9.09 | 7.71 | -3-23 | 14.85 | 10.61 | 3-36 | 0.252 |
| Mobility | 8.27 | 4.43 | 3-36 | 11.69 | 10.28 | -1-37 | 0.459 |
| Range of moviment | |||||||
| Active wrist extension | 34,09 | 36.25 | -30-90 | 16,54 | 38.48 | -60-90 | 0.228 |
| Hand moviment velocity | |||||||
| Transfer of the ball (%) | 49.53 | 23.14 | 22-100 | 43.20 | 23.49 | 10-95 | 0.566 |
| Transfer of the rings (%) | 50.49 | 24.16 | 22-100 | 50.04 | 12.45 | 35-77 | 0.740 |
| Physician's Rating Scale | 13 | 2 | 10-14 | 11.61 | 2.4 | 7-14 | 0.424 |
SD: standard deviation; GMFM: Gross Motor Function Measure; PEDI: Pediatric Evaluation Disability Inventory; FS: functional skills; CA: caregiver assistance; MDC: Motor Development Curve; PPFRC: Pediatric Physical Functioning Reference Curves.
DISCUSSION
This study was designed to address when BTX-A treatment should be started for CP children with spasticity. In addition to the results relating to the early spasticity treatment offered to a group of CP patients, we also compared the functional results of this group with one that did not receive this treatment. The results allow us to partially answer the question which led to the study when considering the improvement in the motor trajectory of the SG and also the better functional outcomes for this group, compared to the CG.
CP is characterised by a limitation to perform activities that begins with impaired motor development, which is especially exacerbated by a relative deprivation of experience with regard to mobility and learning 20 . Various combinations of sensory impairment, spasticity and/or reduced muscle length associated with spasticity contribute to the patient's difficulties in reaching, pointing, grasping, releasing and manipulating objects 21 . In the lower limbs, spasticity contributes to the difficulty in transferring weight onto the involved side, in the acquisition of standing balance and in independent walking 22 . Rehabilitation therapies are usually started as soon as motor deficits are observed and are aimed to influence motor learning 23 .
Even though authors, such as Pascual-Pascual and Pascual-Castroviejo 24 and Delgado et al. 25 , have demonstrated a good safety profile for BTX-A in infants younger than 2 years and an increase in their responsiveness to physiotherapy treatment, BTX-A is usually initiated around 2 years old 7,26 . We had previously demonstrated that younger patients exhibit a greater reduction in spasticity after intervention than older patients6 . The expected benefit of the intervention is to provide a more appropriate sensorimotor experience at a critical period of neurodevelopment, which may influence subsequent motor learning and improve function 27 .
In this study, spasticity in children of the SG was treated as soon as it affected the child's function. The treatment protocol was guided by observing the target functional status for each individual child. Although all children have the same diagnosis of HCP, there was great variation in dose, location, age, number and range of applications, which reflects the clinical variability, pointing to the need for individualized assessments, very comprehensive and focused on the functional development.
Both the muscle tone and range of motion in the SG remained at good levels, with no structure deformities occurring during evolution. The fact that the final evaluation of this group has not been done in post BTX-A session may be one factor that explains the increased muscle tone in some cases. But from a functional standpoint, the patients had a good outcome. Three infants who had a reduced ability to extend their wrists during the first assessment showed improvement in this measure during treatment and final assessment. Among those that were measured in the beginning, most improved their active range of motion. Beckung et al. 14published the MDC for CP patients, which have been developed to assist in planning treatment and evaluating outcomes after intervention. These curves do not represent the natural course of motor development in CP but consider the trajectory over time for children undergoing treatments considered appropriate in light of current knowledge in developed countries, according to different topographical distributions. From this point of view, the observation, in this study, that seven patients improved their positions in their MDC is even more important and may be associated with the early treatment of spasticity.
Comparing both groups, children from the SG showed higher active extension of the wrist, movement velocity and PRS scores than the CG. They also showed better position in the MDC and higher scores in the GMFM 13 , especially in dimension b. One way to measure the impact of CP is to measure a patient's difficulties in performing daily activities 27 . Information pertaining to the difficulty in carrying out these activities is highly relevant because this is usually the main complaint of affected children, parents and relatives 28 . Children of the SG showed higher scores in the PEDI 17 and a better position in the PPFRC 18 , which, in everyday life, means greater independence in activities related to self-care and mobility and less of a need for caregiver assistance. It should be noted that although the results do not show significance, the SG had better functional outcomes than the CG, especially in the GMFM scores 13 , which is considered the gold standard for the development of motor skills.
The acquisition of developmental milestones was similar in both groups. However, independent walking occurred earlier in the SG, and a lower percentage of these children started walking after 2 years of age. Bleck 29 stated that most children with HCP begin to walk independently between 18 and 21 months of age and that the limiting factors for this acquisition are mental retardation, behaviour disorders and epilepsy. The study by Beckung et al.30 showed that, in children with CP, the variable that was most often associated with the prognosis of walking was intellectual capacity; however, this report was unable to show that intellectual impairment was responsible for the inability to walk. These findings suggest the importance of cognitive ability in the acquisition of functional skills that require auto-perception and adaptation to the environment. Children from the SG had lower IQ scores into both verbal and performance areas than those of the CG. Nevertheless, they presented with better functional results, which could have been related to the treatment. These outcomes were associated with an absence of adverse reactions, thereby indicating the benefit of early treatment with BXT-A.
The study limitations were: no randomisation, HCP clinical heterogeneity, sample size, physiotherapy not controlled and associated comorbidities. Ideally, the CG should have been selected randomly from patients at the same clinic. However, this possibility was abandoned for ethical reasons and because of the unanimous parent concordance for BXT-A use. The randomization of the groups probably would not help to form more homogeneous groups. The heterogeneity of the injury makes it a challenge to compare children with CP. The motor difficulty observed varied considerably within the same topographic and functional classification, confirming the reports in the literature that there are not two children with CP affected in the same way 20 .
The ideal would be controlled physiotherapy, with a targeted approach to the task, so ecological and intensive 23. But in studies like the present one, with evaluation measures for long periods of time in patients coming from different backgrounds, it is impossible to control all the variables that may contribute to functional improvement. Nor only physiotherapy but different therapies may have contributed in the development of motor and cognitive skills in both groups, including environmental enrichment. Different uncontrolled factors such as life situations, child personality and familial styles can also influence the developmental trajectory and are not amenable to change.
The decision to treat spasticity in children with HCP, especially infants, is complicated due to the existence of several factors that may influence treatment outcome, including patient's phase of accelerated growth and level of psychomotor development. Although spasticity is highlighted as the main cause of disability 4 , hemineglect, sensibility and strength impairment also affect the outcome of motor rehabilitation. However, the long-term follow-up of a group who received early spasticity treatment with BXT-A, together with guidelines from a multidisciplinary team, shows that it is possible to change the motor trajectory of these individuals. The reduction of muscle tone in itself is not the most important outcome in this study, but rather the change in trajectory of the functional study subjects. The comparing of this SG with another group of children who did not have access to this management shows that the SG had better functional outcomes. The results of this study, especially the positive development of children in the SG, suggest that further researches with larger populations are needed to determine the optimal timing of early spasticity therapy.