OnabotulinumtoxinA Muscle Injection Patterns in Spasticity
OnabotulinumtoxinA Muscle Injection Patterns in Spasticity
A prospective protocol outlining the methodology of this systematic review was developed and followed. A literature search was performed to identify all English-language clinical trials or observational studies (prospective or retrospective) of onabotulinumtoxinA injections used for the treatment of patients with adult spasticity published since 1990. The methods used to perform this review involved both electronic and manual components, and followed established "best practice" guidelines for systematic review research. Searches in MEDLINE and EMBASE were conducted for all studies of BoNT used for treatment of adult spasticity and published between January 1985 and April 2011 to identify any studies of onabotulinumtoxinA. The combination of the following search terms was used: spastic, spasticity, spasm, hyperreflexia, hypertonia, hemiplegia, paralysis. For details of the specific search terms used, please see Additional file 1 . The electronic searches were further supplemented by a manual search of the reference lists of all accepted studies, as well as the reference lists of recent relevant reviews and meta-analyses.
Animal or in vitro studies, studies performed in pediatric populations, and studies reporting treatment with BoNT products other than onabotulinumtoxinA were excluded. The full-text publications of accepted abstracts were reviewed to satisfy all of the following inclusion criteria, regardless of spastic pattern or origin: adult patients with spasticity, treated with onabotulinumtoxinA, and available data on which individual muscles in the upper and/or lower limbs were injected with onabotulinumtoxinA. Included studies were not required to report the number of patients injected or dose parameters for specific muscles, although this data was captured when reported. The agreement of two investigators was required to accept or reject any articles during the review process.
Data elements of interest from each accepted study were extracted to a data extraction form. Extracted information included study-level (e.g., year of publication, geographic region, and study design), patient-level (e.g., sample size, mean age, and gender distribution), and treatment-level (e.g., mean dose and site of onabotulinumtoxinA injection) characteristics. Whenever possible, subgroup data were extracted by spasticity diagnosis from studies enrolling patients with spasticity due to various causes. All injected muscles were considered as reported, regardless of the spastic pattern or origin of spasticity in individuals or patient populations. For studies with patient samples that also included patients treated with other BTX-A formulations, only patients treated with onabotulinumtoxinA were considered. One investigator extracted the data from each study, and a second investigator independently reviewed the extracted data for completeness and accuracy against the original study. Efficacy, safety, and patient-reported outcomes were not assessed in this review and therefore not captured.
Linked studies, which are multiple studies that report outcomes from the same patient sample, in part or in total, were identified during the screening and data extraction phases. When linked studies were identified, only data from the largest, most recent, or most complete report were extracted. However, relevant data from earlier and smaller reports were also used if the report presented pertinent subgroup data not presented in the larger, more complete report. Therefore, all linked studies were considered to be included studies, though each set of linked studies was only counted as one study to avoid double-counting patients.
Descriptive statistics were applied to summarize study-, patient-, and treatment-level data. Information on injected muscles and corresponding onabotulinumtoxinA doses was summarized for individual muscles and muscle groups for upper and lower limbs. Studies reporting on patients treated with onabotulinumtoxinA for both upper- and lower-limb spasticity were included in both respective categories of muscles. Some studies had multiple treatment arms where all patients received onabotulinumtoxinA (with varying doses, patient characteristics, or supplemental treatments such as physiotherapy). All tables include counts of the number of studies (k), the number of onabotulinumtoxinA treatment arms (t), and the number of patients (n) that match a given characteristic, as well as the total number of patients in treatment arms that reported the characteristic (N). To calculate the frequency of injections in individual muscles, the number of all patients/limbs treated with onabotulinumtoxinA in upper limbs or lower limbs, respectively, was used as a denominator, while the numerator for each muscle injected was the number of patients/limbs injected in that particular muscle. Mean doses per muscle were calculated as a mean of all study means, weighted by the number of patients who received injections into each muscle in each study. Note that mean dose may not necessarily account for the full range of doses administered, since dose range was reported in more studies than was mean dose and mean dose could only be tabulated for the subset of studies that explicitly reported it (see semitendinosus, for example). Descriptive summary data, including frequencies of muscles injected, are presented for patients with upper-limb spasticity and lower-limb spasticity, regardless of spasticity origin. Categorical outcomes are presented as proportions, and continuous outcomes are presented using means and ranges.
Information on injected muscles was also analyzed separately by the origin of spasticity (i.e., stroke, traumatic brain injury, spinal cord injury, or multiple sclerosis) using the same methods as described above. These subgroup analyses are presented in Additional files 2, 3, 4 and 5 .
Since the focus of this review was not on efficacy and safety, the risk of bias within individual studies was not assessed.
Methods
Literature Search
A prospective protocol outlining the methodology of this systematic review was developed and followed. A literature search was performed to identify all English-language clinical trials or observational studies (prospective or retrospective) of onabotulinumtoxinA injections used for the treatment of patients with adult spasticity published since 1990. The methods used to perform this review involved both electronic and manual components, and followed established "best practice" guidelines for systematic review research. Searches in MEDLINE and EMBASE were conducted for all studies of BoNT used for treatment of adult spasticity and published between January 1985 and April 2011 to identify any studies of onabotulinumtoxinA. The combination of the following search terms was used: spastic, spasticity, spasm, hyperreflexia, hypertonia, hemiplegia, paralysis. For details of the specific search terms used, please see Additional file 1 . The electronic searches were further supplemented by a manual search of the reference lists of all accepted studies, as well as the reference lists of recent relevant reviews and meta-analyses.
Study Identification
Animal or in vitro studies, studies performed in pediatric populations, and studies reporting treatment with BoNT products other than onabotulinumtoxinA were excluded. The full-text publications of accepted abstracts were reviewed to satisfy all of the following inclusion criteria, regardless of spastic pattern or origin: adult patients with spasticity, treated with onabotulinumtoxinA, and available data on which individual muscles in the upper and/or lower limbs were injected with onabotulinumtoxinA. Included studies were not required to report the number of patients injected or dose parameters for specific muscles, although this data was captured when reported. The agreement of two investigators was required to accept or reject any articles during the review process.
Data Extraction and Synthesis
Data elements of interest from each accepted study were extracted to a data extraction form. Extracted information included study-level (e.g., year of publication, geographic region, and study design), patient-level (e.g., sample size, mean age, and gender distribution), and treatment-level (e.g., mean dose and site of onabotulinumtoxinA injection) characteristics. Whenever possible, subgroup data were extracted by spasticity diagnosis from studies enrolling patients with spasticity due to various causes. All injected muscles were considered as reported, regardless of the spastic pattern or origin of spasticity in individuals or patient populations. For studies with patient samples that also included patients treated with other BTX-A formulations, only patients treated with onabotulinumtoxinA were considered. One investigator extracted the data from each study, and a second investigator independently reviewed the extracted data for completeness and accuracy against the original study. Efficacy, safety, and patient-reported outcomes were not assessed in this review and therefore not captured.
Linked studies, which are multiple studies that report outcomes from the same patient sample, in part or in total, were identified during the screening and data extraction phases. When linked studies were identified, only data from the largest, most recent, or most complete report were extracted. However, relevant data from earlier and smaller reports were also used if the report presented pertinent subgroup data not presented in the larger, more complete report. Therefore, all linked studies were considered to be included studies, though each set of linked studies was only counted as one study to avoid double-counting patients.
Descriptive statistics were applied to summarize study-, patient-, and treatment-level data. Information on injected muscles and corresponding onabotulinumtoxinA doses was summarized for individual muscles and muscle groups for upper and lower limbs. Studies reporting on patients treated with onabotulinumtoxinA for both upper- and lower-limb spasticity were included in both respective categories of muscles. Some studies had multiple treatment arms where all patients received onabotulinumtoxinA (with varying doses, patient characteristics, or supplemental treatments such as physiotherapy). All tables include counts of the number of studies (k), the number of onabotulinumtoxinA treatment arms (t), and the number of patients (n) that match a given characteristic, as well as the total number of patients in treatment arms that reported the characteristic (N). To calculate the frequency of injections in individual muscles, the number of all patients/limbs treated with onabotulinumtoxinA in upper limbs or lower limbs, respectively, was used as a denominator, while the numerator for each muscle injected was the number of patients/limbs injected in that particular muscle. Mean doses per muscle were calculated as a mean of all study means, weighted by the number of patients who received injections into each muscle in each study. Note that mean dose may not necessarily account for the full range of doses administered, since dose range was reported in more studies than was mean dose and mean dose could only be tabulated for the subset of studies that explicitly reported it (see semitendinosus, for example). Descriptive summary data, including frequencies of muscles injected, are presented for patients with upper-limb spasticity and lower-limb spasticity, regardless of spasticity origin. Categorical outcomes are presented as proportions, and continuous outcomes are presented using means and ranges.
Information on injected muscles was also analyzed separately by the origin of spasticity (i.e., stroke, traumatic brain injury, spinal cord injury, or multiple sclerosis) using the same methods as described above. These subgroup analyses are presented in Additional files 2, 3, 4 and 5 .
Since the focus of this review was not on efficacy and safety, the risk of bias within individual studies was not assessed.
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