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26 October 2022

AbobotulinumtoxinA Doses in Upper and Lower Limb Spasticity: A Systematic Literature Review

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1
PRM Department, GH St Louis Lariboisière F. Widal, Paris University, 75010 Paris, France
2
Ipsen, 92100 Boulogne-Billancourt, France
3
Evidera, London W6 8BJ, UK
4
Evidera, Waltham, MA 02451, USA
Toxins2022, 14(11), 734;https://doi.org/10.3390/toxins14110734
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Abstract

Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical studies have shown that abobotulinumtoxinA (AboBoNT-A) therapy reduces upper and lower limb spasticity in adults. However, physicians may administer potentially inadequate doses, given the lack of consensus on adjusting dose according to muscle volume, the wide dose ranges in the summary of product characteristics or cited in the published literature, and/or the high quantity of toxin available for injection. Against this background, a systematic literature review based on searches of MEDLINE and Embase (via Ovid SP) and three relevant conferences (2018 to 2020) was conducted in November 2020 to examine AboBoNT-A doses given to adults for upper or lower limb muscles affected by spasticity of any etiology in clinical and real-world evidence studies. From the 1781 unique records identified from the electronic databases and conference proceedings screened, 49 unique studies represented across 56 publications (53 full-text articles, 3 conference abstracts) were eligible for inclusion. Evidence from these studies suggested that AboBoNT-A dose given per muscle in clinical practice varies considerably, with only a slight trend toward a relationship between dose and muscle volume. Expert-based consensus is needed to inform recommendations for standardizing AboBoNT-A treatment initiation doses based on muscle volume.
Keywords:
botulinum toxins; muscle hypertonia; muscle spasticity; injections; intramuscular; central nervous system diseases
Key Contribution:
This research is the first systematic review on AboBoNT-A doses injected in upper and lower limb muscles to treat adults with spasticity and has highlighted wide variation in such practice; the results could prompt the development of standardization of AboBoNT-A treatment based on muscle volume.
Plain Language Summary: People with specific diseases or injuries of their nervous system may develop permanent stiffening of muscles in their arms and/or legs, known as spasticity; this can follow, for example, a stroke, brain damage from head injuries, or certain neurological diseases and impact mobility. Spasticity can be reduced by periodic injections of a drug called abobotulinumtoxinA (AboBoNT-A) into affected muscles; this treatment reduces muscles’ ability to contract, thereby lessening the stiffening. However, there are concerns physicians may give insufficient doses of AboBoNT-A through fears about excessive dosing; this wariness probably reflects the lack of both agreement among medical experts and clear guidance in the product literature about how to adjust doses according to the volume (i.e., bulk) of different muscles. Given this uncertainty, we carried out a systematic review to identify and analyze published information on the doses of AboBoNT-A used to inject different muscles. Specifically, we searched standard databases and websites of three scientific conferences for research on patients with spasticity (from any cause) treated with AboBoNT-A, either as part of a clinical trial or during everyday medical care. Thus, 49 relevant studies were identified for inclusion in the review. Evidence from these studies suggested that the AboBoNT-A dose given per muscle in clinical practice varies greatly, with little or no link between dose and muscle volume. Thus, there is a need for agreement between experts so that clear recommendations can then be drawn up on how best to choose the appropriate starting dose of AboBoNT-A for a particular muscle volume.

1. Introduction

Limb spasticity is a disabling condition characterized by muscle stiffness, pain and occasionally sudden uncontrollable movements (muscle spasms) of the upper or lower limbs [1,2]. Here, spasticity is used as a standard term to refer to the three components of muscle hypertonia: spasticity, spastic dystonia and spastic co-contractions; it develops in the lower limbs of almost half of adults who experience a stroke and can also occur following traumatic brain injury, cerebral palsy or as part of progressive diseases causing upper motor neuron lesions such as multiple sclerosis [1,2]. Clinical studies have shown that treatment with abobotulinumtoxinA (AboBoNT-A), a neurotoxin that causes muscle weakness by blocking the release of acetylcholine at the neuromuscular junction, reduces both upper and lower limb spasticity in adults, with a good tolerance profile [3,4]. However, there are concerns around AboBoNT-A treatment initiation that can prompt clinicians to be over-cautious in using the therapy, so resulting in the administration of doses that are inadequate for patients’ needs; this situation is likely due to the wide dose ranges per muscle described in the summary of product characteristics [5] or cited in the literature, the lack of consensus on adjusting these doses according to several factors (e.g., muscle volume, etiology and severity of spasticity, muscle structure), and/or the high quantity of toxin available for injection; it has been demonstrated that at maximal dose per label, higher toxin quantity (2 to 3 fold) could be injected over a single session with AboBoNT-A in adults, compared with other formulations, allowing treatment of a greater number of target muscles [6]. Current French clinical guidelines for the treatment of spasticity did not provide recommendations about AboBoNT-A dose to be injected per specific muscle [7], while clinical guidelines from the Royal College of Physicians in the United Kingdom reported muscle-specific recommendations with large dose ranges for several muscles (e.g., biceps brachii: 100–300 U) [8]. Recently, consensus guidelines for botulinum toxin therapy from the Interdisciplinary Working Group for Movement Disorders (IAB) did not consider AboBoNT-A because this drug was said to have different potency labeling compared with the other two main botulinum toxins A (onabotulinumtoxinA and incobotulinumtoxinA) [9]; this is keeping with a general acceptance that none of these toxins can be compared directly since they each contain a different quantity of neuroactive toxin and dose units are not interchangeable between them [6].
Given the uncertainties around current clinical practice, this study aimed to gather evidence on intramuscular dosages of AboBoNT-A used by healthcare professionals. Specifically, it involved conducting a systematic review to explore data from published interventional and observational studies of such treatment in adults with upper or lower limb spasticity regardless of the etiology of this condition.

2. Results

2.1. Study Selection

The literature searches identified 1781 unique records from the electronic databases. Of these, 349 abstracts met the criteria for full-text review, which determined that 53 of the publications were eligible for inclusion in the systematic review. In addition, 3 eligible conference abstracts were identified from the grey literature searches of conference proceedings, so resulting in a total of 56 publications (see Figure 1). Most of these (49 of 56) were the primary publications for unique studies, with the rest (7 of 56) being deemed related publications because of a clear overlap with population/patient samples reported in some of the primary publications, based on details of the trial/cohort name, and enrollment years.
Figure 1. Preferred reporting items for systematic reviews and meta-analyses flow diagram. Legend: MA = meta-analysis; N = total number of records in the identified box; n = number of records in each category; NMA = network meta-analysis; SLR = systematic literature review.

2.2. Study Characteristics

Most of the 49 primary studies included in the systematic review were conducted in Europe (n = 30), with the rest being international studies or from the Middle East/Asia (n = 7 each), Oceania (n = 3), Africa (Tunisia; n = 1), and South America (Brazil; n = 1). About half of the studies were randomized controlled trials (RCTs; n = 24), with the rest being observational real-world studies (n = 18), single-arm trials (n = 6) or non-randomized trials (n = 1). Sample sizes across studies ranged from nine to 456 patients, with most studies (36/49; 73%) enrolling fewer than 100 patients each. Most studies (31/49; 63%) reported on patients with upper limb spasticity, while 4 studies reported on patients with upper or lower limb spasticity. Overall study characteristics of the included studies are shown in Table 1.
Table 1. Characteristics of the included studies.
The mean age of patients varied between 41.6 and 69 years. Information on the underlying etiology of spasticity was available for 44 studies. Most included patients with limb spasticity due to stroke or brain injury (38 studies), five studies included patients with multiple sclerosis or other disorders causing upper motor neuron lesions (e.g., degenerative myelopathy, Strümpell–Lorrain disease), and one study included a population with head or spinal cord injuries, or those who had undergone neurosurgery.

2.3. Risk of Bias

The 46 full-text studies included in the systematic review included 23 RCTs, seven quantitative non-randomized studies, and 16 quantitative descriptive studies (Appendix A). The risk-of-bias assessment indicated no concerns regarding study quality across the 23 RCTs, but not all assessment questions could be fully answered for the non-randomized and quantitative descriptive studies. However, these data were not considered to have a material bearing on the findings of the systematic review because the primary focus of the quality-assessment tool was the impact of study quality on treatment outcomes, rather than on assigned treatment dosing (the focus of the review).

2.4. Treatment Information Available from Included Studies

Studies were selected for inclusion in the systematic review on the basis that they reported a mean/median AboBoNT-A dose, a fixed dose (i.e., patients received a specific dose for a specific muscle) or a dose range for a specific muscle. Although some studies also included other treatment arms (e.g., placebo/control or another botulinum toxin A treatment), only data relating to AboBoNT-A were extracted. The data on the administration of AboBoNT-A derived from individual studies for analysis in the systematic review are presented in Appendix B.
The range of concomitant treatments used with AboBoNT-A across the studies included other medications, rehabilitation programs (e.g., physiotherapy and occupational therapy), and electrical stimulation, and one study used robot-assisted gait training to improve patient walking ability [48].

2.5. Dose per Muscle Volume Analysis

The 49 unique clinical trials and real-world practice studies collectively reported AboBoNT-A dose information across 50 specific muscles of both limbs. The relationship between muscle volume and AboBoNT-A dose given in these studies was explored through scatter plots. For these plots, the specific muscles injected in each study were assumed to have the average muscle volume in cm3 that was reported for upper-limb muscles in Holzbaur et al., 2007 [59] and lower-limb muscles in Handsfield et al., 2014 [60]. Accordingly, dose values were plotted only for those muscles for which the muscle volume was available. For example, no information on the volume of the adductor pollicis muscle was available, and therefore AboBoNT-A dose values reported for this muscle were not included in the upper-limb scatter plot. Based on muscle-volume clusters on the volume-dose plots, muscles were grouped into three volume categories (small, medium, and large). In the upper limb, large-, medium-, and small-volume muscles had a volume of ≥100 cm3, 20–99 cm3, and <20 cm3, respectively. In the lower limb, the respective volumes were ≥400 cm3, 100–399 cm3, and <100 cm3.

2.5.1. Upper Limb

In the upper limb, mean, median, or fixed doses were most commonly reported for the flexor digitorum profundus (23 studies), biceps brachii (20), flexor carpi ulnaris (20), flexor digitorum superficialis (20), flexor carpi radialis (19), brachioradialis (15), and pectoralis major (14).
Wide dose ranges were found across studies, even when accounting for average muscle volume. In the small-volume muscle group, AboBoNT-A mean and median doses ranged from 47 U to 150 U, and 25 U to 200 U, respectively (Table 2). In the medium-volume group, mean and median doses ranged from 62.5 U to 200 U, and 50 U to 300 U, respectively. In the large-volume muscle group, mean and median doses ranged from 50 U to 400 U, and 75 U to 300 U, respectively.
Table 2. Range of mean and median doses by muscle-volume categories across the included studies.
A positive correlation between AboBoNT-A dose and average muscle volume was more clearly identified when including only studies that reported the number of patients injected with AboBoNT-A into a specific muscle (Figure 2). The mean/median dose generally ranged from 100 U to 200 U for small- and medium-volume muscles, when considering only values for 50 or more treated patients. A similar trend was observed for the large-volume muscle group, although the mean/median AboBoNT-A dose was more likely to be around 200 U to 250 U, particularly in larger muscles with an average volume of 250 cm3 or more. These findings should, however, be interpreted with caution as some studies reporting on upper limb muscles (6 of 34) were not included in the plot as they did not report the number of patients receiving AboBoNT-A treatment per muscle. Of note, the plots did not provide any evidence to suggest differences between interventional and RWE studies in the relationship between muscle volume and dose.
Figure 2. Mean, median and fixed abobotulinumtoxinA dose (in units) by the average volume of upper limb muscles. Legend: U, unit; n, number of patients injected with abobotulinumtoxinA in a specific muscle at a specific dose.

2.5.2. Lower Limb

In the lower limb, mean, median, or fixed doses were most commonly reported for the tibialis posterior (10 studies), and soleus, lateral and medial gastrocnemius (8 studies each). Data for each of the remaining muscles were mostly available from one or two studies only.
In the small-volume muscle group, only two muscles were included in the scatter plot since the average volume was not available for the three other muscles reported in some studies. The mean dose for the flexor digitorum longus (average muscle volume: 30 cm3) and the flexor hallucis longus (average muscle volume: 78.8 cm3) ranged from 106 U to 233.3 U, and 94.9 U to 164 U, respectively. Relatively consistent mean-dose ranges were reported for medium-volume muscles, averaging 85 U to 372.7 U. In the large-volume muscle group, mean doses ranged from 88 U to 495.3 U (or up to 750 U if fixed doses were included).
When considering only values for groups of more than 50 patients receiving AboBoNT-A, the dose generally ranged between 100 U and 180 U for small-volume muscles, and between 100 U and 300 U for medium-volume muscles (Figure 3). Although data on larger muscles were scarce, larger studies (n > 50) tended to report a general range of 300 U to 500 U. As for the upper limb, these findings should be interpreted with caution given that some studies reporting on lower limb muscles (2 of 19) were not included on the plot as they did not report on the number of patients treated with AboBoNT-A. As for the upper limb, the plots did not provide any evidence to suggest differences between interventional and RWE studies in the relationship between muscle volume and dose.
Figure 3. Mean, median and fixed abobotulinumtoxinA dose (in units) by the average volume of lower limb muscles. Legend: U, unit; n, number of patients injected with abobotulinumtoxinA in a specific muscle at a specific dose.

3. Discussion

AboBoNT-A was approved by the United States Food and Drug Administration in 2015 for adults with upper limb spasticity, and it received label extensions for lower limb spasticity in children and adults in 2016 and 2017, respectively, and for upper limb spasticity in children in 2019. AboBoNT-A is also approved in Europe for upper and lower limb spasticity. However, the establishment of the drug as a recommended treatment option for adults with spasticity has occurred in the absence of published consensus on whether or how dosing should be adjusted in line with the volume of the target muscles, within the broad licensed dose ranges; this is the basis of concerns that treatment of such patients may be suboptimal due to the administration of inadequate doses. Although they should be the reference in terms of dosing, licensed dose ranges have been based on initial evidence from clinical trials, which helps to explain why they are wide. Against this background, the current review aimed to systematically summarize data on AboBoNT-A dose given per specific muscle of the upper and lower limb in adults with limb spasticity irrespective of underlying etiology or country in which the primary study was conducted. The results were intended to explore the extent of variability in AboBoNT-A prescribing in clinical practice, from both a clinical-trial and a real-world perspective.
Overall, there was no evidence of a strong relationship between muscle volume and AboBoNT-A dose, with wide dose ranges being reported for the same muscle or across muscles of a similar volume. For the upper limb, dose ranges were relatively consistent across small- and medium-volume muscles (mean/median 25 U to 300 U), and slightly higher doses were reported for large-volume muscles (mean/median 50 U to 400 U). Slightly higher doses and greater dose ranges were reported for the lower limb, presumably reflecting the larger volume of the muscles and the greater heterogeneity of this muscle-group category with regard to muscle volume.
This systematic review had some key strengths. To our knowledge, it is the first research to analyze potential inter-relationships between AboBoNT-A doses being used for spasticity and the volume of the injected muscles in adults, and so it targets an important gap in the literature. In a recently published systematic review and meta-analysis of clinical trials of the effects of AboBoNT-A on the Modified Ashworth Scale score in patients with stroke-related spasticity, Ojardias and colleagues reported a D50 of 491.7 U for large-volume muscles (arm muscles injected up to the elbow, and leg muscles down to the ankle) and 108 U for small-volume muscles (other muscles) [61]. Crucially, however, no further relationship analysis between muscle volume and the AboBoNT-A dose injected was reported. Other strengths of our review included its assessment of the evidence from both real-world and interventional studies, thereby ensuring the capture of relevant evidence on dosing practice across a broad range of practice settings and clinical scenarios. Moreover, the review included no limitations as to the etiology of spasticity or the specific muscles involved, to help ensure the representativeness and potential generalizability of its findings.
The review also had some limitations. First, there was considerable variability in how AboBoNT-A doses were reported across studies, and several studies did not report on the number of patients receiving an AboBoNT-A injection in a specific muscle. Furthermore, to increase the availability of AboBoNT-A dose data, this review included mean, median, and fixed values (i.e., where all patients received the same dose for the specific muscle). Mean values are, however, prone to outliers, which was evident in their considerably wider dose ranges compared to those for median values. Second, the variability of AboBoNT-A doses per muscle volume across the included studies could be explained by factors not captured by this systematic review (e.g., the severity of hypertonia, type of symptomatology, the dilution of the toxin prior to injection, pennate or fusiform muscle, and different study objectives).

4. Clinical Opinion

Despite the limitations of this systematic review, its findings indicate a pressing need for clear guidance on AboBoNT-A dosing for adults with spasticity. With this in mind and based on our practice, we propose “easy to remember “narrow AboBoNT-A dose ranges to be injected in first intention into muscles of different volume categories, as listed in Table 3. These are for first-intention AboBoNT-A treatment in botulinum toxin-naïve patients. In general, we observed that the suggested dose is 1 to 1.5 times the muscle volume (100 to 150 U for a muscle volume of 100 cm3) for both upper and lower limbs. These rather conservative dose ranges have a well-established safety profile since they are within French SmPC dose ranges (for in-label muscles) [5]. However, doses can be adjusted according to efficacy and the desired effect. Dose increases are possible in the absence of safety concerns and if there is an insufficient effect from a previous dose. These dose ranges are starting-points and the dose to be used may be adjusted based on the following factors:
(1)
etiology of the hypertonia;
(2)
type of hypertonia (i.e., spasticity vs. dystonia);
(3)
severity of hypertonia;
(4)
time post onset of spasticity;
(5)
structure of the muscle (i.e., smaller doses are needed to target the neuromuscular junctions in a long muscle such as the biceps brachii [neuromuscular junctions are all in the same place] whereas in bipennate muscles [e.g., rectus femoris, gastrocnemii] the junctions are much more disseminated such that greater doses may be required);
(6)
individual patient characteristics (e.g., size, weight, presence of fixed contractures, fibrosis);
(7)
whether the function associated with the muscle is impaired or not (e.g., iliac muscle for movement of the lower limb);
(8)
desired duration of action.
Table 3. Proposed abobotulinumtoxinA dose ranges per muscle volume ∆.
Table 3. Proposed abobotulinumtoxinA dose ranges per muscle volume ∆.
Range of AboBoNT-A Doses (U)Muscle Volume (SD) * (cm3)Dose Ranges According to French Label (U) [5]Muscles (Off-Label Use in Italic)
Upper Limb
200–300380.5 (157.7)NADeltoideus **
372.1 (177.3)150–300Triceps brachii†
290.0 (169.0)100–300Pectoralis major
262.3 (147.2)150–300Latissimus dorsi
164.5 (63.9)75–300Subscapularis
143.7 (63.7)50–400Brachialis
143.7 (68.7)50–400Biceps brachii
100–20091.6 (39.3)100–200Flexor digitorum profundus
74.2 (27.4)100–200Flexor digitorum superficialis
65.1 (36.050–200Brachioradialis
50.0 (20.4)NASupraspinatus
38.4 (17.2)45–200Pronator teres
37.1 (13.6)25–200Flexor carpi ulnaris
34.8 (17.1)25–200Flexor carpi radialis
32.7 (16.3)NATeres major
28.0 (13.9)NATeres minor
17.1 (6.3)20–200Flexor pollicis longus
17.0 (7.4)NAExtensor carpi ulnaris
25–10011.9 (5.7)NAAbductor pollicis longus
11.2 (5.8)NAPronator quadratus
6.6 (3.4)NAExtensor pollicis longus
NA25–50Thenar Eminence muscles ‡,§
NANAHypothenar Eminence muscles‡,¥
NANADorsal and Palmar Interossei‡
Lower Limb
200–400849.0 (194.7)100–400Gluteus maximus
830.9 (194.3)NAVastus lateralis
559.8 (129.4)100–300Adductor magnus
438.2 (91.6)300–550Soleus
274.8 (89.9)NAPsoas
270.5 (56,6)NAVastus intermedius
269 (64.3)100–400Rectus femoris
257.4 (61.8)100–450Medial gastrocnemius
245.4 (54.2)NASemimembranosus
206.5 (48.4)NABiceps femoris (long head)
150–200186 (47.0)NASemitendinosus
176.8 (41.6)NAIliacus
163.7 (41.9)NASartorius
162.1 (43.7)50–150Adductor longus
150 (42.2)100–450Lateral gastrocnemius
135.2 (27,5)NATibialis anterior
104.8 (22.3)100–250Tibialis posterior
100–150104 (24.8)100–200Gracilis
104 (25.8)50–150Adductor brevis
100.1 (32.0)NABiceps femoris (short head)
102.3 (21.6)NAEDL + EHL + peroneu tertius
78.8 (23.1)50–200Flexor hallucis longus
30 (8.2)50–200Flexor digitorum longus
25–100NA50–100, 50–200Intrinsic muscles (abductor hallucis, flexor digitorum brevis, flexor hallucis brevis, extensor digitorum brevis) ‡
NANAInterossei‡
∆ These proposals are intended to facilitate first intention AboBoNT-A treatment in botulinum toxin-naïve patients, not to be taken directly as clinical recommendations. * From Holzbaur et al., 2007 [59] for the upper limb and Handsfield et al., 2014 [60] for the lower limb. ** In practice, lower doses are injected in either anterior, medium or posterior deltoid. † In practice, lower doses are injected in either long or medial/lateral head. ‡ The exact volume of this muscle is unknown. Ranking is arbitrary. § Adductor pollicis, opponens pollicis, flexor pollicis brevis, abductor pollicis brevis. ¥ Opponens digiti minimi, abductor digiti minimi, flexor digiti minimi brevis, palmaris brevis. Legend: EDL, Extensor digitorum longus; EHL, Extensor hallucis longus; NA, not available; SD, standard deviation; U, unit.

5. Conclusions

The AboBoNT-A doses used to treat adults with upper or lower limb spasticity reported in the literature varied considerably across muscles, having only a moderate association with muscle volume. Expert-based consensus is needed to inform recommendations for standardizing initial dose ranges of AboBoNT-A treatment based on muscle volume in such patients.

6. Materials and Methods

This systematic review was conducted in accordance with standards of established guidelines (i.e., PRISMA) [62] and the Cochrane Handbook for Systematic Reviews of Interventions [63]).

6.1. Eligibility Criteria

6.1.1. Types of Studies

Clinical trials and real-world evidence studies were of interest; however, articles indexed as case reports, reviews, letters, or news were excluded from the searches and during screening.

6.1.2. Types of Participants

Studies including only adults (age > 18 years) with upper or lower limb spasticity, regardless of etiology were considered eligible for this systematic review.

6.1.3. Types of Interventions

Studies investigating AboBoNT-A treatment and reporting a mean/median dose of AboBoNT-A or a dose range for a specific muscle were considered. Studies that reported doses only for muscle groups, rather than for specific muscles were not eligible.

6.2. Information Sources

Searches were conducted in MEDLINE, MEDLINE In-Process and Embase via Ovid SP (https://ovidsp.ovid.com, accessed on 12 November 2020). The following conferences were also searched for relevant abstracts from 2018 to 2020 meetings: (1) International Society of Physical and Rehabilitation Medicine (2018: Paris, France; 2019: Kobe, Japan; 2020: virtual); (2) World Congress for Neurorehabilitation (2018: Mumbai, India; 2020: virtual); (3) Toxin’s (International Neurotoxin Association; 2019: Copenhagen, Denmark; 2021: virtual). In addition, the bibliographies of relevant systematic reviews published in the past three years and identified during the screening of material retrieved by the searches were cross-checked as a quality-assurance step to identify any relevant studies that were not identified through the electronic database searches.

6.3. Search Strategy

Searches were based on separate search terms for upper and lower limb spasticity and AboBoNT-A as treatment. The search strategy involved a combination of Medical Subjects Headings (extremities/arm/leg/limb/muscle spasticity/muscle hypertonia/dystonia/spasticity/stroke/cerebral palsy/cerebrovascular accident/multiple sclerosis/spinal cord injury/spinal cord injuries) and the keywords “botulinum toxin A,” “dysport,” “abobotulinumtoxinA,” “abobotulinum toxin type A,” “abobotulinum toxin A,” “botulinum a toxin,” “botulinum toxin type a,” “type a botulinum toxin$,” “clostridium botulinum toxin type a,” “clostridium botulinum a toxin botulinum neurotoxin a,” “limb or arm or leg or arms or legs or extremit$,” “spastic$ or hypertonic or hypertonia$ or dystonia$ or dystonic,” “cerebral palsy/stroke or post-stroke or spinal cord injury* or multiple sclerosis” and a combination thereof. No limitations on the publication date were applied, and the searches were limited neither by language nor geography.

6.4. Selection Process

Once the literature searches had been conducted and duplicate records across the databases had been removed, each title and abstract identified was screened by two independent investigators according to the inclusion/exclusion criteria. The full-text articles of studies accepted at the abstract level were retrieved for further review. The full-text screening was conducted by two independent investigators using the same inclusion and exclusion criteria that had been applied during abstract screening. Accepted articles needed to meet all of the inclusion criteria and none of the exclusion criteria. During both rounds of screening, discrepancies were resolved through discussion between investigators, and a third, senior investigator was consulted if necessary.

6.5. Data Collection Process

Extraction of data from the included studies was performed using a Microsoft Excel®-based data extraction template. The data extraction was conducted by one investigator, and reviewed by a second, senior investigator to ensure consistency and accuracy as a validation step. Any discrepancies were resolved in discussion with a third investigator by comparing the collected data with the information provided by the full paper or abstract. Extracted items included baseline characteristics (population and disease etiology), and information related to treatment with AboBoNT-A (dose and type of value [mean, median, fixed, range], upper and/or lower limb, muscle treated). Patient and treatment characteristics were only extracted for the patient group receiving AboBoNT-A; information on comparator treatments or comparative outcome data were not extracted. Data from any study that was represented in multiple articles (including interim and/or final/complete results, post-hoc or subgroup analyses) were extracted as being from a single study.

6.6. Study Risk-of-Bias Assessment

Quality assessment of qualitative research, RCTs, non-randomized studies, quantitative descriptive studies, and/or mixed methods studies included in this systematic review was conducted by using the Mixed Methods Appraisal Tool (MMAT) version 2018, Canadian Intellectual Property Office, Industry Canada. [64]. The MMAT can be used to appraise the quality of various types of empirical studies (i.e., primary research based on experiment, observation or simulation). A single study-design category is selected for each included study and appraised with the respective questions per category. No overall score is assigned with this tool; answers to questions relevant to each category are assigned as “yes,” “no,” or “can’t tell.” Note that, in order to operate the tool, assessment of the quality of the included studies could be conducted only for the objectives and outcomes for which the studies were designed rather than specifically for the dosing data they provided for the systematic review. Conference abstracts were not quality-assessed due to the limited information available in them.

6.7. Data Analysis and Synthesis

The relationship between muscle volume and AboBoNT-A dose given in the included studies was explored through scatter plots. The specific muscles injected in each study were assumed to have the average muscle volume in cm3, as reported in Holzbaur et al., 2007 for upper-limb muscles [59] and Handsfield et al., 2014 for lower-limb muscles [60]. Based on muscle-volume clusters on the volume-dose plots, individual muscles were grouped into three volume categories (small, medium, and large). In the upper limb, large-, medium-, and small-volume muscles had a volume of ≥100 cm3, 20–99 cm3, and <20 cm3, respectively. In the lower limb, the respective volumes were ≥400 cm3, 100–399 cm3, and <100 cm3. Across studies and for muscles for which sample size was reported, average AboBoNT-A doses (mean, median or fixed-dose values, depending on data availability) were plotted against the average muscle volume to explore interrelationships between these two variables. Dose values were plotted only for muscles for which the average muscle volume was available. The dot size on the plot was weighted by sample size for each muscle injected.

Author Contributions

A.S., C.D., A.F. (Andreas Freitag), I.I., K.F., L.L., J.-Y.L., A.F. (Anne Forestier) and D.G. made substantial contributions to the conception and design, data acquisition, or analysis and interpretation of data. A.S., C.D., A.F. (Andreas Freitag), I.I., K.F., L.L., J.-Y.L., A.F. (Anne Forestier) and D.G. participated in drafting the manuscript or revising it critically for important intellectual content. All authors gave final approval of the version to be published. A.S., C.D., A.F. (Andreas Freitag), I.I., K.F., L.L., J.-Y.L., A.F. (Anne Forestier) and D.G. agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Ipsen.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We thank Simin Hua for her help in the data analysis.

Conflicts of Interest

This study was sponsored by Ipsen. AF, II, KF and LL are employees of Evidera, which received funding from Ipsen for performing the SLR and statistical analyses that informed this study. CD, JYL and AFo are employees of Ipsen. DG and AS report personal fees for consultancy from Ipsen, Allergan and Merz.

Appendix A

Table A1. Quality assessment of quantitative randomized controlled trials.
Table A1. Quality assessment of quantitative randomized controlled trials.
First Author,
Year		Is Randomization Appropriately
Performed?		Are the Groups Comparable
at Baseline?		Are There
Complete Outcome Data?		Are Outcome
Assessors Blinded
to the Intervention Provided?		Did the
Participants
Adhere to the
Assigned
Intervention?
Bakheit, 2000 [12]Can’t tellYesYesCan’t tellYes
Bakheit, 2001 [13]YesYesYesYesYes
Baricich, 2008 [17]YesYesYesCan’t tellYes
Bhakta, 2000 [12]YesYesYesYesYes
Burbaud, 1996 [21]Can’t tellYesYesCan’t tellYes
Gracies, 2017 [28]YesYesYesYesYes
Hesse, 1995 [32]Can’t tellYesCan’t tellCan’t tellYes
Hesse, 1998 [33]YesYesYesCan’t tellYes
Johnson, 2002 [35]YesYesYesCan’t tellYes
Kong, 2007 [36]YesYesYesYesYes
Lam, 2012 [37]YesYesYesYesYes
Marco, 2007 [39]YesYesYesYesYes
McCrory, 2009 [40]YesYesYesYesYes
O’Dell, 2018 [43]Can’t tellYesYesCan’t tellYes
Picelli, 2014 [47]YesYesYesYesYes
Picelli, 2016 [48]YesYesYesYesYes
Rekand, 2019 [50]YesYesYesYesYes
Rosales, 2012 [51]YesYesYesYesYes
Shaw, 2010 [52]YesYesYesYesYes
Sun, 2010 [53]YesYesYesYesYes
Suputtitada, 2005 [54]YesYesYesYesYes
Yazdchi, 2013 [57]YesCan’t tellYesCan’t tellCan’t tell
Yelnik, 2007 [58]YesYesYesYesYes
Table A2. Quality assessment of quantitative non-randomized studies.
Table A2. Quality assessment of quantitative non-randomized studies.
First Author,
Year		Are the
Participants
Representative of the Target
Population?		Are Measurements Appropriate
Regarding Both the Outcome and Intervention (or Exposure)?		Are There
Complete Outcome Data?		Are the
Confounders
Accounted for in the Design and Analysis?		During the Study Period, Is the Intervention Administered (or Exposure Occurred) as Intended?
Bakheit, 2002 [14]Can’t tellYesYesCan’t tellYes
Barden, 2014 [16]YesYesYesCan’t tellYes
Carvalho, 2018 [23]YesYesYesCan’t tellYes
de Niet, 2015 [24]NoYesYesYesYes
Frasson, 2005 [26]YesYesYesCan’t tellYes
Ghroubi, 2020 [27]YesYesYesCan’t tellYes
Turner-Stokes, 2013 [55]YesYesYesYesYes
Table A3. Quality assessment of quantitative descriptive studies.
Table A3. Quality assessment of quantitative descriptive studies.
First Author,
Year		Is the Sampling Strategy Relevant to Address the
Research
Question?		Is the Sample
Representative of the Target
Population?		Are the
Measurements Appropriate?		Is the Risk of
Nonresponse Bias Low?		Is the Statistical Analysis
Appropriate to
Answer the
Research
Question?
Alvisi, 2018 [10]YesNoYesCan’t tellCan’t tell
Ashford, 2009 [11]YesYesYesCan’t tellYes
Bakheit, 2004 [15]YesYesYesCan’t tellYes
Beseler, 2012 [18]YesYesYesYesCan’t tell
Bhakta, 1996 [19]YesYesYesCan’t tellYes
Cardoso, 2007 [22]YesYesYesCan’t tellYes
Finsterer, 1997 [25]NoYesYesYesYes
Hecht, 2008 [31]YesNoYesYesNo
Hubble, 2013 [34]YesYesYesNoCan’t tell
Moccia, 2020 [41]YesYesYesCan’t tellYes
Nott, 2014 [42]YesYesYesYesYes
Otom, 2014 [44]YesYesYesYesCan’t tell
Pauri, 2000 [45]YesYesYesYesYes
Picelli, 2012 [46]YesYesYesYesYes
Picelli, 2020 [49]YesYesYesCan’t tellCan’t tell
Woldag, 2003 [56]YesYesYesYesCan’t tell

Appendix B

Table A4. Results of individual studies—upper limb.
Table A4. Results of individual studies—upper limb.
First Author,
Year 		InterventionName of
Muscle 		Volume
Category 		Muscle
Volume (cm3)		Type of AboBoNT-A Dose MeasureDose
Value (U)
Alvisi, 2018 [10]AboBoNT-AAbductor pollicis
longus		Small11.9Fixed value160
AboBoNT-AFlexor pollicis longusSmall17.1Range50–200
AboBoNT-ATeres majorMedium32.7Fixed value100
AboBoNT-ABrachioradialisMedium65.1Range100–200
AboBoNT-AFlexor carpi radialisMedium34.8Range150–200
AboBoNT-AFlexor carpi ulnarisMedium37.1Range100–200
AboBoNT-AFlexor digitorum
profundus		Medium91.6Range100–200
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Range100–300
AboBoNT-APronator teresMedium38.4Range50–350
AboBoNT-ATriceps brachiiLarge372.1Fixed value350
AboBoNT-ABiceps brachiiLarge143.7Range150–300
AboBoNT-ABrachialisLarge143.7Range100–150
AboBoNT-APectoralis majorLarge290.0Range100–400
Ashford, 2009 [11]AboBoNT-ASubscapularisLarge164.5Fixed value400
AboBoNT-ARhomboideus majorLargeNRFixed value250
AboBoNT-ATrapeziusLargeNRFixed value100
AboBoNT-ABiceps brachiiLarge143.7Range150–400
AboBoNT-ABrachialisLarge143.7Range150–250
AboBoNT-ALatissimus dorsiLarge262.3Range400–500
AboBoNT-APectoralis majorLarge290.0Range250–500
Bakheit, 2000 [12]AboBoNT-AFlexor carpi radialisMedium34.8Range75–225
AboBoNT-AFlexor carpi ulnarisMedium37.1Range75–225
AboBoNT-AFlexor digitorum
profundus		Medium91.6Range75–225
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Range75–225
AboBoNT-ABiceps brachiiLarge143.7Range200–600
Bakheit, 2001 [13]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value150
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2RangeNR
AboBoNT-ABiceps brachiiLarge143.7Range300–400
Bakheit, 2002 [14] AboBoNT-ABiceps brachiiLarge143.7Fixed value500
Bakheit, 2004 [15]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value150
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Range150–250
AboBoNT-ABiceps brachiiLarge143.7Range300–400
Barden, 2014 [16]AboBoNT-AFlexor pollicis longusSmall17.1Median75
AboBoNT-APronator quadratusSmall11.2Median87.5
AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-AFlexor carpi radialisMedium34.8Median150
AboBoNT-AFlexor carpi ulnarisMedium37.1Median150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median100
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median190
AboBoNT-APronator teresMedium38.4Median87.5
AboBoNT-ABiceps brachiiLarge143.7Median188
AboBoNT-ABrachialisLarge143.7Median75
AboBoNT-APectoralis majorLarge290.0Median150
AboBoNT-ASubscapularisLarge164.5Median150
Bhakta, 1996 [19]AboBoNT-AFlexor carpi ulnarisMedium37.1Mean117.9
AboBoNT-AFlexor digitorum
profundus		Medium91.6Mean143.2
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Mean134.1
AboBoNT-ABiceps brachiiLarge143.7Mean220
Bhakta, 2000 [20]AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-AFlexor carpi ulnarisMedium37.1Median100
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median200
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median300
AboBoNT-ABiceps brachiiLarge143.7Median300
Cardoso, 2007 [22]AboBoNT-AOpponens pollicisSmallNRMean62.5
AboBoNT-ABrachioradialisMedium65.1Mean187.5
AboBoNT-Flexor carpi radialisMedium34.8Mean170
AboBoNT-AFlexor carpi ulnarisMedium37.1Mean150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Mean150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Mean150
AboBoNT-APronator teresMedium38.4Mean150
AboBoNT-ABiceps brachiiLarge143.7Mean225
AboBoNT-ADeltoideusLarge380.5Mean200
AboBoNT-APectoralis majorLarge290.0Mean250
AboBoNT-ATriceps brachiiLarge372.1Mean200
Carvalho, 2018 [23]AboBoNT-ASupraspinatusMedium50.0Mean124
Teres majorMedium32.7Mean104
AboBoNT-ADeltoideusLarge380.5Mean130
AboBoNT-AInfraspinatusLarge118.6Mean50
AboBoNT-ALatissimus dorsiLarge262.3Mean115
AboBoNT-APectoralis majorLarge290.0Mean120
AboBoNT-ASubscapularisLarge164.5Mean133
AboBoNT-ARhomboideus majorLargeNRMean125
AboBoNT-ATrapeziusLargeNRMean96
Finsterer, 1997 [25]AboBoNT-ABrachioradialisMedium65.1Fixed value60
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value40
AboBoNT-ABiceps brachiiLarge143.7Range100–160
AboBoNT-ATrapeziusLargeNRRange80–100
Ghroubi, 2020 [27]AboBoNT-AAdductor pollicisSmallNRMedian50
AboBoNT-AFlexor pollicis longusSmall17.1Median50
AboBoNT-APronator quadratusSmall11.2Median100
AboBoNT-ADorsal interossei (hand)SmallNRMedian100
AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-AFlexor carpi radialisMedium34.8Median100
AboBoNT-AFlexor carpi ulnarisMedium37.1Median100
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median100
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median150
AboBoNT-APronator teresMedium38.4Median100
AboBoNT-ABiceps brachiiLarge143.7Median200
AboBoNT-ABrachialisLarge143.7Median100
AboBoNT-ADeltoideusLarge380.5Median240
AboBoNT-ALatissimus dorsiLarge262.3Median200
AboBoNT-APectoralis majorLarge290.0Median150
AboBoNT-ASubscapularisLarge164.5Median150
AboBoNT-ATriceps brachiiLarge372.1Median170
Gracies, 2018 [29]AboBoNT-AFlexor pollicis longusSmall17.1Mean106.3
AboBoNT-ABrachioradialisMedium65.1Mean140.7
AboBoNT-AFlexor carpi radialisMedium34.8Mean142.3
AboBoNT-AFlexor carpi ulnarisMedium37.1Mean103.1
AboBoNT-AFlexor digitorum
profundus		Medium91.6Mean155.8
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Mean156.9
AboBoNT-APronator teresMedium38.4Mean144.6
AboBoNT-ABiceps brachiiLarge143.7Mean206.4
AboBoNT-ABrachialisLarge143.7Mean208.3
AboBoNT-APectoralis majorLarge290.0Mean176.8
Gul, 2016 [30]AboBoNT-ALatissimus dorsiLarge262.3Range150–200
AboBoNT-APectoralis majorLarge290.0Range170–290
AboBoNT-ASubscapularisLarge164.5Range100–175
AboBoNT-ATriceps brachiiLarge372.1Range150–200
Hesse, 1998 [33]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value125
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value125
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value125
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Fixed value125
AboBoNT-ABiceps brachiiLarge143.7Fixed value250
AboBoNT-ABrachialisLarge143.7Fixed value250
Hubble, 2013 * [34]AboBoNT-A in UKAdductor pollicisSmallNRMean291
AboBoNT-A in FranceFlexor pollicis longusSmall17.1Mean103
AboBoNT-A in GermanyFlexor pollicis longusSmall17.1Mean87
AboBoNT-A in GreeceFlexor pollicis longusSmall17.1Mean93
AboBoNT-A in SwedenFlexor pollicis longusSmall17.1Mean47
AboBoNT-A in UKFlexor pollicis longusSmall17.1Mean106
AboBoNT-A in FranceBrachioradialisMedium65.1Mean183
AboBoNT-A in GermanyBrachioradialisMedium65.1Mean125
AboBoNT-A in GreeceBrachioradialisMedium65.1Mean183
AboBoNT-A in SwedenBrachioradialisMedium65.1Mean183
AboBoNT-A in the UKBrachioradialisMedium65.1Mean192
AboBoNT-A in FranceFlexor carpi radialisMedium34.8Mean158
AboBoNT-A in GermanyFlexor carpi radialisMedium34.8Mean106
AboBoNT-A in GreeceFlexor carpi radialisMedium34.8Mean152
AboBoNT-A in SwedenFlexor carpi radialisMedium34.8Mean107
AboBoNT-A in UKFlexor carpi radialisMedium34.8Mean134
AboBoNT-A in FranceFlexor carpi ulnarisMedium37.1Mean167
AboBoNT-A in GermanyFlexor carpi ulnarisMedium37.1Mean100
AboBoNT-A in GreeceFlexor carpi ulnarisMedium37.1Mean127
AboBoNT-A in SwedenFlexor carpi ulnarisMedium37.1Mean80
AboBoNT-A in UKFlexor carpi ulnarisMedium37.1Mean142
AboBoNT-A in FranceFlexor digitorum
profundus		Medium91.6Mean137
AboBoNT-A in GermanyFlexor digitorum
profundus		Medium91.6Mean127
AboBoNT-A in GreeceFlexor digitorum
profundus		Medium91.6Mean102
AboBoNT-A in SwedenFlexor digitorum
profundus		Medium91.6Mean74
AboBoNT-A in the UKFlexor digitorum
profundus		Medium91.6Mean146
AboBoNT-A in FranceFlexor digitorum
superficialis		Medium74.2Mean145
AboBoNT-A in GermanyFlexor digitorum
superficialis		Medium74.2Mean130
AboBoNT-A in GreeceFlexor digitorum
superficialis		Medium74.2Mean83
AboBoNT-A in SwedenFlexor digitorum
superficialis		Medium74.2Mean88
AboBoNT-A in UKFlexor digitorum
superficialis		Medium74.2Mean218
AboBoNT-A in FrancePronator teresMedium38.4Mean129
AboBoNT-A in GreecePronator teresMedium38.4Mean96
AboBoNT-A in UKPronator teresMedium38.4Mean136
AboBoNT-A in FranceBiceps brachiiLarge143.7Mean226
AboBoNT-A in GermanyBiceps brachiiLarge143.7Mean188
AboBoNT-A in GreeceBiceps brachiiLarge143.7Mean244
AboBoNT-A in SwedenBiceps brachiiLarge143.7Mean170
AboBoNT-A in the UKBiceps brachiiLarge143.7Mean364
AboBoNT-A in FranceBrachialisLarge143.7Mean218
AboBoNT-A in GermanyBrachialisLarge143.7Mean112
AboBoNT-A in GreeceBrachialisLarge143.7Mean175
AboBoNT-A in SwedenBrachialisLarge143.7Mean218
AboBoNT-A in the UKBrachialisLarge143.7Mean160
AboBoNT-A in FrancePectoralis majorLarge290.0Mean186
AboBoNT-A in GermanyPectoralis majorLarge290.0Mean114
AboBoNT-A in GreecePectoralis majorLarge290.0Mean165
AboBoNT-A in SwedenPectoralis majorLarge290.0Mean233
AboBoNT-A in the UKPectoralis majorLarge290.0Mean271
Kong, 2007 [36]AboBoNT-ABiceps brachiiLarge143.7Fixed value250
AboBoNT-APectoralis majorLarge290.0Fixed value250
Lam, 2012 [37]AboBoNT-AAdductor pollicisSmallNRMedian100
AboBoNT-AFlexor pollicis longusSmall17.1Median100
AboBoNT-AFlexor pollicis brevisSmallNRMedian50
AboBoNT-ABrachioradialisMedium65.1Median150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median150
AboBoNT-ABiceps brachiiLarge143.7Median250
AboBoNT-ABrachialisLarge143.7Median150
AboBoNT-APectoralis majorLarge290.0Median250
Lejeune, 2020 † [38]AboBoNT-A/baselineSupraspinatusMedium50.0Median100
AboBoNT-A/baselineTeres minorMedium28.0Median100
AboBoNT-A/baselineRhomboideus majorLargeNRMedian150
AboBoNT-A/baselineTrapeziusLargeNRMedian100
AboBoNT-A/cycle 1Latissimus dorsiLarge262.3Mean200
AboBoNT-A/cycle 1Pectoralis majorLarge290.0Mean168
AboBoNT-A/cycle 1SubscapularisLarge164.5Mean175
AboBoNT-A/cycle 1Triceps brachiiLarge372.1Mean150
AboBoNT-A/cycle 2Latissimus dorsiLarge262.3Mean194.5
AboBoNT-A/cycle 2Pectoralis majorLarge290.0Mean226
AboBoNT-A/cycle 2SubscapularisLarge164.5Mean147.6
AboBoNT-A/cycle 2Triceps brachiiLarge372.1Mean184.8
AboBoNT-A/cycle 3Latissimus dorsiLarge262.3Mean193.4
AboBoNT-A/cycle 3Pectoralis majorLarge290.0Mean227.7
AboBoNT-A/cycle 3SubscapularisLarge164.5Mean122.8
AboBoNT-A/cycle 3Triceps brachiiLarge372.1Mean186.1
AboBoNT-A/cycle 4Latissimus dorsiLarge262.3Mean175.4
AboBoNT-A/cycle 4Pectoralis majorLarge290.0Mean224
AboBoNT-A/cycle 4SubscapularisLarge164.5Mean130
AboBoNT-A/cycle 4Triceps brachiiLarge372.1Mean194
Marciniak, 2017 ‡ [65]AboBoNT-A 500UAdductor pollicisSmallNRMean25
AboBoNT-A 1000UAdductor pollicisSmallNRMean50
AboBoNT-A 1000UExtensor pollicis
longus		Small6.6Mean150
AboBoNT-A 500UFlexor pollicis longusSmall17.1Mean72.5
AboBoNT-A 500U PTMGBrachioradialisMedium65.1Mean100
AboBoNT-A 500U non-PTMGBrachioradialisMedium65.1Mean81.3
AboBoNT-A 1000U PTMGBrachioradialisMedium65.1Mean200
AboBoNT-A 1000U non-PTMGBrachioradialisMedium65.1Mean105
AboBoNT-A 500U PTMGFlexor carpi radialisMedium34.8Mean100
AboBoNT-A 500U non-PTMGFlexor carpi radialisMedium34.8Mean90.6
AboBoNT-A 1000U PTMGFlexor carpi radialisMedium34.8Mean191.7
AboBoNT-A 1000U non-PTMGFlexor carpi radialisMedium34.8Mean174.7
AboBoNT-A 500U PTMGFlexor carpi ulnarisMedium37.1Mean100
AboBoNT-A 500U non-PTMGFlexor carpi ulnarisMedium37.1Mean94.1
AboBoNT-A 1000U PTMGFlexor carpi ulnarisMedium37.1Mean191.7
AboBoNT-A 1000U non-PTMGFlexor carpi ulnarisMedium37.1Mean156.8
AboBoNT-A 500U PTMGFlexor digitorum
profundus		Medium91.6Mean100
AboBoNT-A 500U non-PTMGFlexor digitorum
profundus		Medium91.6Mean62.5
AboBoNT-A 1000U PTMGFlexor digitorum
profundus		Medium91.6Mean194.4
AboBoNT-A 1000U non-PTMGFlexor digitorum
profundus		Medium91.6Mean181.3
AboBoNT-A 500U PTMGFlexor digitorum
superficialis		Medium74.2Mean100
AboBoNT-A 500U non-PTMGFlexor digitorum
superficialis		Medium74.2Mean82.5
AboBoNT-A 1000U PTMGFlexor digitorum
superficialis		Medium74.2Mean200
AboBoNT-A 1000U non-PTMGFlexor digitorum
superficialis		Medium74.2Mean196.2
AboBoNT-A 500UPronator teresMedium38.4Mean66.7
AboBoNT-A 1000UPronator teresMedium38.4Mean136.7
AboBoNT-A 500UBiceps brachiiLarge143.7Mean103.3
AboBoNT-A 1000UBiceps brachiiLarge143.7Mean228.6
AboBoNT-A 500U PTMGBrachialisLarge143.7Mean187.5
AboBoNT-A 500U non-PTMGBrachialisLarge143.7Mean124
AboBoNT-A 1000U PTMGBrachialisLarge143.7Mean400
AboBoNT-A 1000U non-PTMGBrachialisLarge143.7Mean211.1
AboBoNT-A 500ULatissimus dorsiLarge262.3Mean100
AboBoNT-A 1000ULatissimus dorsiLarge262.3Mean100
AboBoNT-A 500UPectoralis majorLarge290.0Mean100
AboBoNT-A 1000UPectoralis majorLarge290.0Mean250
AboBoNT-A 500USubscapularisLarge164.5Mean100
Marco, 2007 [39]AboBoNT-APectoralis majorLarge290.0Fixed value500
McCrory, 2009 § [40]AboBoNT-A/cycle 1Flexor pollicis longusSmall17.1Median100
AboBoNT-A/cycle 2Extensor carpi ulnarisSmall17Median150
AboBoNT-A/cycle 2Flexor pollicis longusSmall17.1Median200
AboBoNT-A/cycle 1BrachioradialisMedium65.1Median100
AboBoNT-A/cycle 1Flexor carpi radialisMedium34.8Median150
AboBoNT-A/cycle 1Flexor carpi ulnarisMedium37.1Median150
AboBoNT-A/cycle 1Flexor digitorum
profundus		Medium91.6Median150
AboBoNT-A/cycle 1Flexor digitorum
superficialis		Medium74.2Median200
AboBoNT-A/cycle 2BrachioradialisMedium65.1Median100
AboBoNT-A/cycle 2Flexor carpi radialisMedium34.8Median150
AboBoNT-A/cycle 2Flexor digitorum
profundus		Medium91.6Median150
AboBoNT-A/cycle 2Flexor digitorum
superficialis		Medium74.2Median200
AboBoNT-A/cycle 1Biceps brachiiLarge143.7Median300
AboBoNT-A/cycle 1BrachialisLarge143.7Median100
AboBoNT-A/cycle 1Triceps brachiiLarge372.1Median275
AboBoNT-A/cycle 2Biceps brachiiLarge143.7Median300
AboBoNT-A/cycle 2BrachialisLarge143.7Median100
AboBoNT-A/cycle 2Triceps brachiiLarge372.1Median250
Moccia, 2020 [41]AboBoNT-ABrachioradialisMedium65.1Mean169.3
AboBoNT-AFlexor carpi radialisMedium34.8Mean500
AboBoNT-AFlexor carpi ulnarisMedium37.1Mean250
AboBoNT-AFlexor digitorum
profundus		Medium91.6Mean147.1
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Mean153.3
AboBoNT-ABiceps brachiiLarge143.7Mean250.7
AboBoNT-ABrachialisLarge143.7Mean75
AboBoNT-APectoralis majorLarge290.0Mean193.3
AboBoNT-ATriceps brachiiLarge372.1Mean100
Nott, 2014 [42]AboBoNT-AAdductor pollicisSmallNRMedian37.5
AboBoNT-AFlexor pollicis longusSmall17.1Median75
AboBoNT-ALumbricals (hand)SmallNRMedian100
AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-AFlexor carpi radialisMedium34.8Median150
AboBoNT-AFlexor carpi ulnarisMedium37.1Median150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median100
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median190
AboBoNT-APronator teresMedium38.4Median87.5
AboBoNT-ABiceps brachiiLarge143.7Median188
AboBoNT-ABrachialisLarge143.7Median75
AboBoNT-APectoralis majorLarge290.0Median150
AboBoNT-ASubscapularisLarge164.5Median150
O’Dell, 2018 [43]AboBoNT-A 500UAdductor pollicisSmallNRMean30
AboBoNT-A 1000UAdductor pollicisSmallNRMean50.7
AboBoNT-A 500UFlexor pollicis longusSmall17.1Mean64.4
AboBoNT-A 1000UFlexor pollicis longusSmall17.1Mean139.7
AboBoNT-A 500UBrachioradialisMedium65.1Mean88.3
AboBoNT-A 1000UBrachioradialisMedium65.1Mean172.1
AboBoNT-A 500UFlexor carpi radialisMedium34.8Mean92.2
AboBoNT-A 1000UFlexor carpi radialisMedium34.8Mean178.1
AboBoNT-A 500UFlexor carpi ulnarisMedium37.1Mean89.9
AboBoNT-A 1000UFlexor carpi ulnarisMedium37.1Mean171.2
AboBoNT-A 500UFlexor digitorum
profundus		Medium91.6Mean93.5
AboBoNT-A 1000UFlexor digitorum
profundus		Medium91.6Mean195.5
AboBoNT-A 500UFlexor digitorum
superficialis		Medium74.2Mean95.4
AboBoNT-A 1000UFlexor digitorum
superficialis		Medium74.2Mean196.8
AboBoNT-A 500UPronator teresMedium38.4Mean81.8
AboBoNT-A 1000UPronator teresMedium38.4Mean157.3
AboBoNT-A 500UBiceps brachiiLarge143.7Mean106.4
AboBoNT-A 1000UBiceps brachiiLarge143.7Mean207.4
AboBoNT-A 500UBrachialisLarge143.7Mean148.5
AboBoNT-A 1000UBrachialisLarge143.7Mean321.4
AboBoNT-A 500ULatissimus dorsiLarge262.3Mean100
AboBoNT-A 1000ULatissimus dorsiLarge262.3Mean175
AboBoNT-A 500UPectoralis majorLarge290.0Mean100
AboBoNT-A 1000UPectoralis majorLarge290.0Mean200
AboBoNT-A 500USubscapularisLarge164.5Mean100
AboBoNT-A 1000UTriceps brachiiLarge372.1Mean100
AboBoNT-A 500UTriceps brachiiLarge372.1Mean200
Picelli, 2014 [47]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value150
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Fixed value250
Rekand, 2019 [50]AboBoNT-A current practiceBrachioradialisMedium65.1Range30–210
AboBoNT-A NMJ-targetedBrachioradialisMedium65.1Range40–200
AboBoNT-A current practiceFlexor carpi radialisMedium34.8Range30–210
AboBoNT-A NMJ-targetedFlexor carpi radialisMedium34.8Range40–200
AboBoNT-A current practiceFlexor carpi ulnarisMedium37.1Range30–210
AboBoNT-A NMJ-targetedFlexor carpi ulnarisMedium37.1Range40–200
AboBoNT-A current practiceBiceps brachiiLarge143.7Range30–210
AboBoNT-A NMJ-targetedBiceps brachiiLarge143.7Range40–200
AboBoNT-A current practiceBrachialisLarge143.7Range30–210
AboBoNT-A NMJ-targetedBrachialisLarge143.7Range40–200
Rosales, 2012 [51]AboBoNT-AFlexor pollicis longusSmall17.1Median25
AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-AFlexor carpi radialisMedium34.8Median100
AboBoNT-AFlexor carpi ulnarisMedium37.1Median100
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median50
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median50
AboBoNT-ABiceps brachiiLarge143.7Median200
Shaw, 2010 ¥ [52]AboBoNT-A/3, 6, 9 monthsFlexor pollicis longusSmall17.1Median50
AboBoNT-A/baselineFlexor pollicis longusSmall17.1Median100
AboBoNT-ABrachioradialisMedium65.1Median100
AboBoNT-A/3, 6, 9 monthsFlexor carpi radialisMedium34.8Median100
AboBoNT-AFlexor carpi ulnarisMedium37.1Median100
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median100
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median100
AboBoNT-A/baselineFlexor carpi radialisMedium34.8Median50
AboBoNT-ABiceps brachiiLarge143.7Median100
AboBoNT-A/baseline and 3 monthsPectoralis majorLarge290.0Median100
AboBoNT-A/6 monthsPectoralis majorLarge290.0Median200
AboBoNT-A/9 monthsPectoralis majorLarge290.0Median150
Shaw, 2010 [52]AboBoNT-APronator teresMedium38.4Median100
Sun, 2010 [53]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value150
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value150
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Fixed value150
AboBoNT-ABiceps brachiiLarge143.7Fixed value400
Suputtitada, 2005 [54]AboBoNT-A 350UFlexor carpi radialisMedium34.8Fixed value50
AboBoNT-A 500UFlexor carpi radialisMedium34.8Fixed value75
AboBoNT-A 1000UFlexor carpi radialisMedium34.8Fixed value150
AboBoNT-A 350UFlexor carpi ulnarisMedium37.1Fixed value50
AboBoNT-A 500UFlexor carpi ulnarisMedium37.1Fixed value75
AboBoNT-A 1000UFlexor carpi ulnarisMedium37.1Fixed value150
AboBoNT-A 350UFlexor digitorum
profundus		Medium91.6Fixed value50
AboBoNT-A 500UFlexor digitorum
profundus		Medium91.6Fixed value75
AboBoNT-A 1000UFlexor digitorum
profundus		Medium91.6Fixed value150
AboBoNT-A 350UFlexor digitorum
superficialis		Medium74.2Fixed value50
AboBoNT-A 500UFlexor digitorum
superficialis		Medium74.2Fixed value75
AboBoNT-A 1000UFlexor digitorum
superficialis		Medium74.2Fixed value150
AboBoNT-A 350UBiceps brachiiLarge143.7Fixed value150
AboBoNT-A 500UBiceps brachiiLarge143.7Fixed value200
AboBoNT-A 1000UBiceps brachiiLarge143.7Fixed value400
Turner-Stokes, 2013 [55]AboBoNT-AAdductor pollicisSmallNRMedian50
AboBoNT-ADorsal interossei (hand)SmallNRMedian150
AboBoNT-AFlexor pollicis brevisSmallNRMedian50
AboBoNT-ALumbricals (hand)SmallNRMedian100
AboBoNT-AOpponens pollicisSmallNRMedian50
AboBoNT-AFlexor pollicis longusSmall17.1Median100
AboBoNT-ABrachioradialisMedium65.1Median112.5
AboBoNT-AFlexor carpi radialisMedium34.8Median125
AboBoNT-AFlexor digitorum
profundus		Medium91.6Median150
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Median150
AboBoNT-APronator teresMedium38.4Median100
AboBoNT-ATeres majorMedium32.7Median75
AboBoNT-ABiceps brachiiLarge143.7Median200
AboBoNT-ABrachialisLarge143.7Median150
AboBoNT-ADeltoideusLarge380.5Median100
AboBoNT-ALatissimus dorsiLarge262.3Median120
AboBoNT-APectoralis majorLarge290.0Median200
AboBoNT-ASubscapularisLarge164.5Median200
AboBoNT-ATriceps brachiiLarge372.1Median175
Woldag, 2003 [56]AboBoNT-AFlexor carpi radialisMedium34.8Fixed value120
AboBoNT-AFlexor carpi ulnarisMedium37.1Fixed value120
AboBoNT-AFlexor digitorum
profundus		Medium91.6Fixed value120
AboBoNT-AFlexor digitorum
superficialis		Medium74.2Fixed value120
Yazdchi, 2013 [57]AboBoNT-AFlexor carpi radialisMedium34.8Range50–100
AboBoNT-AFlexor carpi ulnarisMedium37.1Range50–100
AboBoNT-AFlexor digitorum
profundus		Medium91.6Range100–150
AboBoNT-ABiceps brachiiLarge143.7Range150–200
Yelnik, 2007 [58]AboBoNT-ASubscapularisLarge164.5Fixed value500
* Survey of AboBoNT-A use by physicians in five European countries. † Study in which patients received up to 4 additional AboBoNT-A treatment cycles at least 12 weeks apart over 1 year. ‡ Study in which doses of AboBoNT-A were reported or not reported for each muscle as part of the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]). § Study in which patients received 2 cycles of treatment, 12 weeks apart. ¥ Study in which participants in the intervention group received AboBoNT-A injections to the upper limb immediately following study entry, plus repeat injections at 3, 6 and 9 months if clinically indicated. Legend: AboBoNT-A, abobotulinumtoxinA; NMJ, neuromuscular junction; NR, not reported; PTMG, primary target muscle group; U, unit; UK, United Kingdom.
Table A5. Results of individual studies—lower limb.
Table A5. Results of individual studies—lower limb.
First Author,
Year 		InterventionName of
Muscle 		Volume
Category 		Muscle
Volume (cm3)		Type of AboBoNT-A Dose MeasureDose
Value (U)
Baricich, 2008 [17]AboBoNT-AGastrocnemius
(medialis)		Medium257.4Range150–250
AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Range150–250
Beseler, 2012 [18]AboBoNT-AFlexor hallucis longusSmall78.8Mean125
AboBoNT-AFlexor digitorum brevisSmallNRMean85
AboBoNT-AExtensor hallucis longusMedium102.3Mean100
AboBoNT-ASartoriusMedium163.7Mean85
AboBoNT-ATibialis posteriorMedium104.8Mean200
AboBoNT-ASoleusLarge438.2Mean150
AboBoNT-ATriceps suraeLarge845.6Mean166
Burbaud, 1996 [21]AboBoNT-AFlexor digitorum longusSmall30.0Range150–300
AboBoNT-ATibialis posteriorMedium104.8Range200–350
AboBoNT-ATriceps suraeLarge845.6Range500–1000
AboBoNT-ASoleusLarge438.2Range200–400
de Niet, 2015 [24]AboBoNT-ATriceps suraeLarge845.6Fixed value500
AboBoNT-ATriceps suraeLarge845.6Fixed value750
Esquenazi, 2020 [66]AboBoNT-A 1000UFlexor digitorum longusSmall30.0Mean139.1
AboBoNT-A 1500UFlexor digitorum longusSmall30.0Mean221.7
AboBoNT-A 1000UFlexor digitorum brevisSmallNRMean77.3
AboBoNT-A 1500UFlexor digitorum brevisSmallNRMean137.5
AboBoNT-A 1000UFlexor hallucis longusSmall78.8Mean94.9
AboBoNT-A 1500UFlexor hallucis longusSmall78.8Mean164
AboBoNT-A 1000UFlexor hallucis brevisSmallNRMean111.1
AboBoNT-A 1500UFlexor hallucis brevisSmallNRMean160
AboBoNT-A 1000UBiceps femorisMedium100.1Mean183.3
AboBoNT-A 1500UBiceps femorisMedium100.1Mean300
AboBoNT-A 1000UGastrocnemius
(lateralis)		Medium150.0Mean88.8
AboBoNT-A 1000UGastrocnemius
(medialis)		Medium257.4Mean141.6
AboBoNT-A 1500UGastrocnemius
(lateralis)		Medium150.0Mean128.8
AboBoNT-A 1500UGastrocnemius
(medialis)		Medium257.4Mean169.6
AboBoNT-A 1000URectus femorisMedium269.0Mean186.9
AboBoNT-A 1500URectus femorisMedium269.0Mean372.7
AboBoNT-A 1000UTibialis posteriorMedium104.8Mean190
AboBoNT-A 1500UTibialis posteriorMedium104.8Mean274.7
AboBoNT-A 1500UAdductor magnusLarge559.8Mean300
AboBoNT-A 1000USoleusLarge438.2Mean333.3
AboBoNT-A 1500USoleusLarge438.2Mean478.6
Finsterer, 1997 [25]AboBoNT-ARectus femorisMedium269.0Range40–80
AboBoNT-AAdductor magnusLarge559.8Range60–240
AboBoNT-AGastrocnemius
(combined)		Large407.4Range60–120
Frasson, 2005 [26]AboBoNT-AExtensor digitorum brevisSmallNRFixed value50
Gracies, 2017 [28]AboBoNT-A 1000UFlexor digitorum brevisSmallNRMean89.4
AboBoNT-A 1500UFlexor digitorum brevisSmallNRMean140.8
AboBoNT-A 1000UFlexor hallucis brevisSmallNRMean93.3
AboBoNT-A 1500UFlexor hallucis brevisSmallNRMean107.9
AboBoNT-A 1000UFlexor digitorum longusSmall30.0Mean136.7
AboBoNT-A 1000UFlexor hallucis longusSmall78.8Mean96.4
AboBoNT-A 1500UFlexor hallucis longusSmall78.8Mean158.6
AboBoNT-A 1000UBiceps femorisMedium100.1Mean195.8
AboBoNT-A 1500UBiceps femorisMedium100.1Mean306.3
AboBoNT-A 1500UExtensor digitorum
longus		Medium102.3Mean220.9
AboBoNT-A 1000UGastrocnemius
(medialis)		Medium257.4Mean122.5
AboBoNT-A 1500UGastrocnemius
(medialis)		Medium257.4Mean183.5
AboBoNT-A 1000UGastrocnemius
(lateralis)		Medium150.0Mean95.2
AboBoNT-A 1500UGastrocnemius
(lateralis)		Medium150.0Mean145.6
AboBoNT-A 1000UGracilisMedium104.0Mean111.1
AboBoNT-A 1500UGracilisMedium104.0Mean183.3
AboBoNT-A 1000URectus femorisMedium269.0Mean210.1
AboBoNT-A 1500URectus femorisMedium269.0Mean350
AboBoNT-A 1000UTibialis posteriorMedium104.8Mean196.8
AboBoNT-A 1500UTibialis posteriorMedium104.8Mean284.3
AboBoNT-A 1000UAdductor magnusLarge559.8Mean183.3
AboBoNT-A 1500UAdductor magnusLarge559.8Mean257.1
AboBoNT-A 1000UGluteus maximusLarge849.0Mean100
AboBoNT-A 1500UGluteus maximusLarge849.0Mean220
AboBoNT-A 1000USoleusLarge438.2Mean333.3
AboBoNT-A 1500USoleusLarge438.2Mean495.3
Gracies, 2018 [29]AboBoNT-AFlexor digitorum longusSmall30.0Mean151.1
AboBoNT-AFlexor hallucis longusSmall78.8Mean125.7
AboBoNT-AGastrocnemius
(medialis)		Medium257.4Mean192.1
AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Mean177.1
AboBoNT-ARectus femorisMedium269.0Mean194.4
AboBoNT-ATibialis posteriorMedium104.8Mean196
AboBoNT-ASoleusLarge438.2Mean299.2
Hecht, 2008 [31]AboBoNT-ATibialis posteriorMedium104.8Range240–480
AboBoNT-AGastrocnemius
(combined)		Large407.4Range150–500
Hesse, 1995 [32]AboBoNT-A 2000UGastrocnemius
(medialis)		Medium257.4Fixed value500
AboBoNT-A 2000UGastrocnemius
(lateralis)		Medium150.0Fixed value500
AboBoNT-A 1500UGastrocnemius
(medialis)		Medium257.4Fixed value250
AboBoNT-A 1500UGastrocnemius
(lateralis)		Medium150.0Fixed value250
AboBoNT-A 2000UTibialis posteriorMedium104.8Fixed value500
AboBoNT-A 1500UTibialis posteriorMedium104.8Fixed value500
AboBoNT-A 2000USoleusLarge438.2Fixed value500
AboBoNT-A 1500USoleusLarge438.2Fixed value500
Hubble, 2013* [34]AboBoNT-A in FranceFlexor digitorum longusSmall30.0Mean150
AboBoNT-A in GermanFlexor digitorum longusSmall30.0Mean106
AboBoNT-A in SwedenFlexor digitorum longusSmall30.0Mean167
AboBoNT-A in UKFlexor digitorum longusSmall30.0Mean212
AboBoNT-A in FranceTibialis posteriorMedium104.8Mean244
AboBoNT-A in GermanyTibialis posteriorMedium104.8Mean200
AboBoNT-A in GreeceTibialis posteriorMedium104.8Mean185
AboBoNT-A in SwedenTibialis posteriorMedium104.8Mean161
AboBoNT-A in UKTibialis posteriorMedium104.8Mean306
AboBoNT-A in FranceAdductor magnusLarge559.8Mean287
AboBoNT-A in GermanyAdductor magnusLarge559.8Mean243
AboBoNT-A in GreeceAdductor magnusLarge559.8Mean385
AboBoNT-A in SwedenAdductor magnusLarge559.8Mean264
AboBoNT-A in UKAdductor magnusLarge559.8Mean416
AboBoNT-A in FranceGastrocnemius
(combined)		Large407.4Mean277
AboBoNT-A in GermanyGastrocnemius
(combined)		Large407.4Mean336
AboBoNT-A in GreeceGastrocnemius
(combined)		Large407.4Mean150
AboBoNT-A in SwedenGastrocnemius
(combined)		Large407.4Mean168
AboBoNT-A in UKGastrocnemius
(combined)		Large407.4Mean367
AboBoNT-A in UKQuadriceps femorisLarge1803.0Mean437
AboBoNT-A in FranceSoleusLarge438.2Mean259
AboBoNT-A in GermanySoleusLarge438.2Mean275
AboBoNT-A in GreeceSoleusLarge438.2Mean100
AboBoNT-A in SwedenSoleusLarge438.2Mean141
AboBoNT-A in UKSoleusLarge438.2Mean267
Johnson, 2002 [35]AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Fixed value200
AboBoNT-AGastrocnemius
(medialis)		Medium257.4Fixed value200
AboBoNT-ATibialis posteriorMedium104.8Fixed value400
Moccia, 2020 [41]AboBoNT-AFlexor digitorum longusSmall30.0Mean233.3
AboBoNT-AAdductor longusMedium162.1Mean323.5
AboBoNT-AExtensor hallucis longusMedium102.3Mean115.6
AboBoNT-ATibialis posteriorMedium104.8Mean271.2
AboBoNT-AIliopsoasLarge451.6Mean220
AboBoNT-AQuadriceps femorisLarge1803Mean310.4
AboBoNT-ATriceps suraeLarge845.6Mean411.3
Otom, 2014 [44]AboBoNT-AGastrocnemius
(combined)		Large407.4Fixed value500
Pauri, 2000 [45]AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Mean123.3
AboBoNT-AGastrocnemius
(medialis)		Medium257.4Mean165.9
AboBoNT-ATibialis posteriorMedium104.8Mean300
AboBoNT-ASoleusLarge438.2Mean88
Picelli, 2012 [46]AboBoNT-AGastrocnemius
(medialis)		Medium257.4Fixed value250
AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Fixed value250
Picelli, 2016 † [48]AboBoNT-AGastrocnemius
(medialis)		Medium257.4Fixed value250
AboBoNT-AGastrocnemius
(lateralis)		Medium150.0Fixed value250
AboBoNT-ASoleusLarge438.2Fixed value250
Picelli, 2020 [49]AboBoNT-AGastrocnemius
(medialis)		Medium257.4Mean188
AboBoNT-AGastrocnemius
(lateralis)		Medium150Mean187
AboBoNT-ATibialis posteriorMedium104.8Mean191
AboBoNT-ASoleusLarge438.2Mean313
* Survey of AboBoNT-A use by physicians in five European countries. † Study in which patients received robot-assisted gait training (RAGT). Legend: AboBoNT-A, abobotulinumtoxinA; NR, not reported; U, unit; UK, United Kingdom.

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