Study design:
This retrospective study included database of 849 children with spastic diplegia who underwent BoNT injection for management of lower limb spasticity. They were recruited from the multidisciplinary cerebral palsy clinic of the pediatric neurology, neurosurgery department and physical medicine and rehabilitation department in Ain Shams University Hospitals during the period between December 2020 and December 2022. Further classification of children according to the confirmed diagnosis of the cause of cerebral palsy was done. Children with confirmed genetic mutations were subjected to a more focused analysis regarding the efficacy and safety of BoNT injection in both lower limbs.
Intended study population:
Of the 849 children included from the database, children between 2-18 years of age diagnosed with genetic mutations and having lower limb spasticity were selected in our study. Recruited children received pharmacological treatment of spasticity and regular physical therapy sessions but with limited improvement of their condition.
The patient’s diagnosis, clinical presentation, spasticity patterns, deformities, and brain magnetic resonance imaging (MRI) findings were reviewed. The list below is the inclusion and exclusion criteria of the study:-
Inclusion criteria:
- Genetic diagnosis for the developmental delay
- Age 2-18 years
- Mild to moderate spasticity (MAS I+/II)
- Medications failed to control spasticity.
- Regular physiotherapy sessions
- Informed consent for procedure
Exclusion criteria:
- Movement disorders (Involuntary movements)
- Absolute contraindications to BoNT
- Contraindications to intramuscular injections
- Previous spasticity surgical interventions
- Non-compliance to physical therapy of follow-up visits
- Bleeding disorders
Demographic data including gender, parental consanguinity (referring to first cousins and double first cousins' marriages), perinatal history, age at presentation, diagnosis and BoNT injection were registered. Family history for similar cases was recorded. The details of patient demographics are listed in table 1 below .
Sample size:
A variety of spasticity etiologies are indicated for treatment with BoNT. The effect of BoNT is well-established in the literature, however very limited studies in the literature address the effect of BoNT on genetic diseases only, with very few sample sizes. For example this study on HSP with 18 cases. (Paparella, G., 2020)
In our registry of cases injected with BoNT for spasticity, only 20 genetic cases were selected given the rarity and variability of genetic disorders.
Assessments, procedure & outcome measures:
According to our spasticity clinic protocol, all the patients who will receive BoNT injection underwent a thorough neurological examination, videotaping, and functional status assessment before the procedure. The pre-injection assessment included the following measures:
- Gross Motor Function Classification system for CP (GMFCS) is used for functional grading (Palisano et al., 2008).
- The modified Ashworth scale (MAS) is considered a clinically relevant tool for grading the resistance of a relaxed limb to rapid passive stretch with a grading score ranging from 0 (which indicates normal or lowered muscle tone), up to 4 (which indicates a state in which passive movement of the affected limb is unfeasible)(Bohannon & Smith, 1987) (I just removed the quotations). It was used for tone assessment for each muscle group (hip flexors, hip adductors, knee flexors, extensors, calf planters, and dorsiflexion), and the mean of the scores for the whole limb is calculated. For the statistical analysis purpose of the study, the grade of 1+ was considered as 2, and 1 was added to the remaining grades, so the grades ranged from 2 to 5. To check the response and outcome after Bo injection MAS mean differences were documented initially in the charts for each patient and at 1, 3, and 6 months post BoNT injection.
- Goal attainment scaling (GAS) is used as an outcome measure to evaluate the progress toward targeted functional goals. These goals will be set with the caregivers before BoNT injection to ease the patient care “pain, positioning, mobility” and help in tone reduction guided by the MAS and GMFCS. This allows the caregivers to decide their own personalized preset goals (Krasny-Pacini et al., 2013).
Our BoNT injection protocol follows the standard injection guidelines for a multilevel approach, where the BoNT dose is decided according to the muscle volume, the degree of spasticity, and muscle involvement in the pathological pattern (Heinen et al., 2010; R. & Graham, 1997). The selection of the group of muscles injected depends on the pathological spasticity pattern, deformity, and the functional goals set for each patient. We use anatomic landmarks; electromyogram and ultrasound guidance for accurate localization of the injection site under sedation using isoflurane. This will be followed by intensive rehabilitation and the use of orthotics whenever it’s indicated.
Follow-up post-injection:
Post-injection assessment was recorded at specified intervals to detect functional improvement by measurement of the difference between the initial and follow-up means as follows:
- GMFCS initial and at 6 months.
- MAS initial, at 1, 3, and 6 months.
GAS goals achievement was determined at 4-6 months post-injection with scores ranging from a “no change’’ to a ‘‘much better than the expected outcome". For the statistical analysis to decide the level of achievement, a five-point scale was used: ‘‘-2’’ is the initial pre-injection (initial) level, ‘‘-1’’ constitutes advancement towards the goal without goal attainment, ‘‘0’’ is the anticipated goal post-injection, ‘‘+1’’ constitutes a better outcome than anticipated, and ‘‘+2’’ is the best possible outcome that could have been anticipated for this goal. The patient was defined as a responder if a GAS score of at least 0 was achieved at 4-6 months. Since there are several post-injection goals, we chose the GMFCS level as a guide for goal achievement to detect improvement in mobility.
Statistical analysis:
The IBM SPSS version 19 has been used as the statistical methodology. Descriptive analysis was applied for continuous variables. The statistical hypothesis was the presence or absence of significant differences between the variables before and after treatment. Because of a small-sized sample, the ANOVA test was used to evaluate the treatment effect on all objective variables with an alpha value of 0.05 with Bonferroni correction.
Ethics:
Ethical committee approval for the study design and statistical methodology was obtained by the Ethical Committee of the Faculty of Medicine, Ain Shams University. All research was performed in accordance with relevant guidelines and in accordance with the Declaration of Helsinski. Informed consent was obtained from all participants’ legal guardians.