Archives of Physical Medicine and Rehabilitation
Volume 90, Issue 1 , Pages 9-16.e2, January 2009

Botulinum Toxin Dilution and Endplate Targeting in Spasticity: A Double-Blind Controlled Study

Presented as an abstract to the American Neurological Association, October 14, 2002, New York.

  • Jean-Michel Gracies, MD

      Affiliations

    • Department of Neurology, Mount Sinai Medical Center, New York, NY
    • Corresponding Author InformationCorrespondence to Jean-Michel Gracies, MD, Service de Médecine Physique et de Réadaptation, CHU Henri Mondor, 51, av du Maréchal De Lattre De Tassigny, 94010 Créteil, France
    • ,
  • Mara Lugassy, MD

      Affiliations

    • Department of Neurology, Columbia Presbyterian Hospital, New York, NY
    • ,
  • Donald J. Weisz, PhD

      Affiliations

    • Department of Neurosurgery, Mount Sinai Medical Center, New York, NY
    • ,
  • Michele Vecchio, MD

      Affiliations

    • U.O. Physical Medicine and Rehabilitation, Vittorio Emanuele Hospital, Catania, Italy
    • ,
  • Steve Flanagan, MD

      Affiliations

    • Department of Rehabilitation Medicine, Mount Sinai Medical Center, New York, NY
    • ,
  • David M. Simpson, MD

      Affiliations

    • Department of Neurology, Mount Sinai Medical Center, New York, NY

Article Outline

Abstract 

Gracies J-M, Lugassy M, Weisz DJ, Vecchio M, Flanagan S, Simpson DM. Botulinum toxin dilution and endplate targeting in spasticity: a double-blind controlled study.

Objective

To determine the effects of botulinum neurotoxin type A (BTX-A) dilution and endplate-targeting in spastic elbow flexors.

Design

Double blind randomized controlled trial; 4-month follow-up after a 160-unit injection of BTX-A into spastic biceps brachii (4 sites). Randomization into: group 1: 100 mouse units (MU)/mL dilution, 0.4cc/site, 4-quadrant injection; group 2: 100MU/mL dilution, 0.4cc/site, 4 sites along endplate band; group 3: 20MU/mL dilution, 2cc/site, 4-quadrant injection (n=7 per group).

Setting

Institutional tertiary care ambulatory clinic.

Participants

Referred sample of 21 adults with spastic hemiparesis. No participant withdrew due to adverse effects.

Intervention

A 160-unit injection of BTX-A of different dilutions and locations into biceps brachii.

Main Outcome Measures

Primary: agonist and antagonist (cocontraction) mean rectified voltage (MRV) of elbow flexors/extensors during maximal isometric flexion/extension; secondary: maximal voluntary power of elbow flexion/extension; spasticity angle and grade in elbow flexors/extensors (Tardieu Scale); active range of elbow extension/flexion.

Results

BTX-A injection overall reduced agonist flexor MRV (–47.5%, P<0.0001), antagonist flexor MRV (–12%, P=.037), antagonist extensor MRV (–19%, P<.01), flexion maximal voluntary power (–33%, P<.001), elbow flexor spasticity angle (–30%, P<.001) and grade (–17%, P=.03), and increased extension maximal voluntary power (24%, P=.037) and active range of elbow extension (5.5%, 8°, P=.002). Agonist and antagonist flexor MRV reductions in group 3 (–81% and –31%) were greater than in groups 1 and 2, whereas increase in active range of elbow extension was greater in group 2 (10%) than in groups 1 and 3 (P<.05, analysis of covariance [ANCOVA]). Elbow flexor spasticity was significantly reduced in groups 2 and 3 only (P<.05, ANCOVA).

Conclusions

In spastic biceps, high-volume or endplate-targeted BTX-A injections achieve greater neuromuscular blockade, cocontraction and spasticity reduction, and active range of elbow extension improvement, than low volume, nontargeted injections.

Key Words: Botulinum toxin, Muscle spasticity, Rehabilitation

List of Abbreviations: ANCOVA, analysis of covariance, ANOVA, analysis of variance, AROM, active range of motion, BTX-A, botulinum neurotoxin type A, MRV, mean rectified voltage, MU, mouse units

 

MUSCLE OVERACTIVITY (eg, spastic dystonia, spastic cocontraction) is 1 of the 3 cardinal disabling features in patients with spasticity, accompanying motor weakness and muscle shortening.1 However, muscle overactivity is not evenly distributed throughout muscles. Thus therapy targeting overactivity in specific muscles (ie, focal treatment) may be preferable to systemic approaches. BTX-A is the most promising blocking agent used for focal treatment. When injected intramuscularly BTX-A works at the endplate level by blocking the release of acetylcholine into the synaptic cleft. One may anticipate that the blocking efficiency of a given injection of BTX-A will parallel the number of endplates blocked by the injection, (ie, the number of endplates effectively reached by the BTX-A molecules).

To maximize the number of endplates blocked in a given muscle, one may highly dilute BTX-A, in the hope that the large volume of fluid administered into the muscle will carry the BTX-A molecules to endplates remote from the injection site. However, there are currently no data to support the optimal dilution for BTX-A for any indication. Studies in healthy animal and human muscles demonstrate that the degree of paralysis increases with the injected volume, for a given dose of BTX-A.2, 3, 4 In studies of treatment of human spasticity, dilutions of BTX-A have varied widely, from highly concentrated (100U/mL, eg, 1mL of saline per vial of BTX-A) to highly diluted (20U/mL, eg, 5mL of saline per vials of BTX-A).5 However, the few dilution studies in human spasticity published to date have not detected differences in therapeutic efficacy between high and low volume preparations.6, 7

Another strategy to improve efficiency entails specific targeting of injection to areas known to be particularly dense in endplates, if there are such areas and their anatomic distribution is known. Animal studies indicate that targeting BTX-A injection into the endplate areas improves neuromuscular blockade.2, 8 Motor endplates often cluster at characteristic muscle areas (the innervation band), because the endplate generally lies near the midpoint of a given muscle fiber.9, 10, 11, 12 However, muscles may have different morphologic organizations (uni-, bi- or multi-pennate), and innervation bands may be scattered throughout muscles as is the case in human sartorius, gracilis, and gastrocnemius.10, 13, 14 Dissection studies have documented specific areas rich in endplates in human cadaver forearm and calf muscles.15, 16, 17 In a prior study, we mapped endplates histologically in human biceps brachii and demonstrated that the area richest in endplates is an inverted V-shaped band located at the junction between the lower third and the upper two thirds of the muscle belly.18 The goal of the current study was to use the model of elbow flexion-extension in spastic hemiparesis and our knowledge of endplate location in biceps brachii to compare an endplate-targeted injection technique and a high volume of BTX-A with a nontargeted, and low volume technique for a given dose injected.

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Methods 

This was a double-blind parallel group design, with 3 groups corresponding to the 3 tested injection techniques (fig 1).

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  • Fig 1. 

    Flow diagram from screening to study completion. Of the 21 patients screened, 21 were randomized into the trial and all were treated and followed up until study completion.

Study Subjects 

All subjects signed informed consent for this study, which was approved by the Institutional Review Board of Mount Sinai School of Medicine. Twenty-one patients with hemiparesis due to stroke or traumatic brain injury were enrolled in this study (see fig 1). Study participants met the following inclusion criteria: 18 to 80 years of age; spasticity in the elbow flexor muscles (ie, spasticity angle greater than 0 in the Tardieu Scale; see appendix) due to a brain injury that occurred at least 4 weeks before recruitment; impaired upper limb function due to elbow flexor overactivity as clinically determined by the investigator, by palpation of active elbow flexor cocontraction during efforts of elbow extension; and active shoulder flexion greater than 45°. The latter criterion was implemented in an attempt to optimize chances of meaningful improvement of active function after elbow flexor BTX-A injection. Exclusion criteria included: major elbow flexor contracture, defined as maximal passive elbow extension less than 120°; cognitive impairment interfering with the ability to provide informed consent or to cooperate in the study; significant cutaneous or joint inflammation in the affected upper limb; hypersensitivity to BTX-A or its components; ongoing neuromuscular disease (eg, myasthenia gravis) or use of agents interfering with neuromuscular transmission (eg, aminoglycosides); pregnancy or women not taking contraception; anticoagulant treatment with current international normalized ratio higher than 2.5; and serious uncontrolled systemic disease that would, in the opinion of the investigator, interfere with the conduct of the study.

Study Treatment 

Study participants were evaluated at 2 baseline visits (preinjection) followed by 4 monthly visits postinjection. Each subject received an injection of 160MU of BTX-A (Botoxa) distributed to 4 sites of the biceps brachii in the affected arm at the second baseline visit. Participants' previously established regimens of other drug treatments for muscle overactivity, and physical and occupational therapy, remained unchanged during the study. Patients were randomized into 3 groups, with the following pattern of BTX-A injection into the biceps brachii: group 1: Low volume/nontargeted, using a 4-quadrant technique, with 1 injection site into each of the superior and inferior portions of the medial and lateral biceps brachii (quadrants of the muscle belly) as indicated in figure 2, and 0.4cc injected per site (100MU/mL); group 2: Low volume/targeted, using a motor endplate targeting technique consisting of 4 equidistant locations spaced horizontally across the endplate band (see fig 2), and 0.4cc injected per site (100MU/mL); group 3: High volume/nontargeted, using the 4-quadrant technique, with 1 injection site per quadrant and 2cc injected per site (20MU/mL). The endplate targeting technique used for the group 2 patients is based on our previous study in which we localized the motor endplate bands within human cadaver biceps brachii muscles in relation to external landmarks.18 Our findings showed that the ratio of motor endplate location to total olecranon-acromion length is 0.25 at the lateral edge, 0.39 in the midline, and 0.28 at the medial edge.18 We used these landmarks to target the motor endplate band in group 2 patients (see fig 2). To reduce variability and maximize protocol blindedness, all injections were performed by 1 of the investigators (D.M.S., unblinded) and all assessments were made by another, blinded to the injection technique (J.M.G.).

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  • Fig 2. 

    Schematic diagram from a previous human cadaver study showing the inverted V-shaped area dense in endplates at the junction between the lower third and the upper two thirds of the biceps.

Muscle Localization Technique for Injection 

We used the stimulation technique as the optimal means to ensure localization of the needle in the biceps brachii as opposed to neighboring muscles or surrounding nonmuscular tissue.19, 20, 21 The same needle that injects the drug is used to transmit repetitive monopolar stimulation of the targeted muscle, to guide needle position. The needle lies selectively in the targeted muscle when the largest bulk of biceps twitch, as assessed clinically by bicipital tendon palpation, is obtained in isolation using the minimal possible stimulation. Injection was given via a 37mm × 27G, injection needle electrode.b Stimulation was delivered from a constant voltage stimulator, with a pulse duration of 0.2ms and a current intensity ranging from 0.5 to 1mAmp to obtain twitch.

Study Assessments 

Clinical assessments of spasticity and range of active motion were collected at each monthly visit. Physiologic assessments were performed once before and 1 month following injection. The primary outcome measure was change in flexor agonist MRV obtained by surface recording of the elbow flexors during maximal isometric effort of elbow flexion. MRV is an objective and validated method for quantifying the degree of neuromuscular blocking effect due to the toxin after intramuscular injection.22, 23 This measurement was performed using a strain gauge connected to a fixed vertical bar with its horizontal base attached to a table (see supplemental fig 1). The patient sat in a reproducible manner with the elbow flexed at 90°, resting on a precise area at the base of the bar, with the forearm along the vertical bar rotated in full supination, so that the dorsal aspect of the hand was applied against the bar. The wrist was solidly strapped to the bar. After a brief rehearsal and warm-up period, the patient was asked to alternately pull backwards (flexion effort) and push forward (extension effort) as hard as possible in a series of three 5-second duration maximal isometric contractions, each time separated by another 5 seconds of rest. Flexion always preceded extension. The flexor agonist MRV was calculated by averaging the rectified voltage over the 500ms that surrounded the peak rectified voltage of the flexors during a maximal voluntary flexion effort (see supplemental fig 2). The average of 3 consecutive isometric efforts was calculated. This measure served as a quantification of the magnitude of the neuromuscular blocking effect of the injection.

Secondary outcome assessments included: (1) change in maximal voluntary power (in kg) of the elbow flexors and extensors, using dynamometry; (2) change in spasticity in the elbow flexors and extensors, using the 2 measures of the Tardieu Scale (ie, the spasticity angle and the spasticity grade [see appendix 1])24; (3) change in AROM in elbow extension and flexion using goniometry. For analysis of spasticity and AROM before and after injection over time, the mean of the 2 baseline visits (preassessment) was compared with the mean of the 2 visits 1 and 2 months postinjection (early follow-up assessment) and the mean of the 2 visits 3 and 4 months postinjection (late follow-up assessment); (4) change in agonist extensor MRV: the agonist extensor MRV was measured over the 500ms that surrounded the peak of rectified voltage of the extensors during a maximal voluntary effort of elbow extension, taking the average of 3 consecutive efforts (supplemental fig 2B); (5) change in antagonist flexor MRV (ie, the MRV of the coactivated flexors during a maximal isometric effort of elbow extension), measured as the MRV of the flexors during the 500ms that surrounded the peak of rectified voltage of the extensors during a maximal voluntary effort of elbow extension, taking the average of 3 consecutive efforts (supplemental fig 2D); this represents a measure of flexor cocontraction during isometric extensor efforts; (6) change in antagonist extensor MRV (ie, MRV of the coactivated extensors during a maximal isometric effort of elbow), measured as the MRV of the extensors during the 500ms that surrounded the peak of rectified voltage of the flexors during a maximal voluntary effort of elbow flexion, taking the average of 3 consecutive efforts (supplemental fig 2C); this represents a measure of extensor cocontraction during isometric flexor efforts.

Statistical Analysis 

Chi-square tests and 1-way ANOVA were used to determine whether groups differed in terms of preinjection characteristics (ie, demographics, clinical features). Repeated measures ANCOVA using visit (before or 1 month after injection) and group as predictors and baseline values as covariates, were used to measure the overall effects of the injection, and to compare the effects of the 3 injection techniques on the outcome measures. The Sidak method was used to adjust for multiple comparisons. All statistical analyses were conducted with SPSS 13.0 software package.c A P value of .05 was used for statistical significance.

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Results 

The demographic characteristics of the subjects recruited in each group are shown in table 1. All patients had chronic and stable brain injury, due to stroke (15) or trauma (6). All were enrolled over 1 year postinjury (mean ± SD, 65±97mo). Clinical characteristics at baseline, including sex, age, and sensory involvement, passive range of elbow extension (ie, degree of elbow flexor contracture), and spasticity grade and angle in the elbow flexors (data not shown), did not differ between groups (chi-square, 1-way ANOVA).

Table 1. Patient Characteristics
CharacteristicsGroup 1Group 2Group 3Statistics
Low Volume NontargetedLow Volume TargetedHigh Volume Nontargeted
Number777
Men553(NS,chi-square)
Age46±2752±1447±21(NS,ANOVA)
Range (min–max)19–8026–6822–75
Months poststroke84±11932±2279±123(NS,ANOVA)
Range (min–max)16–35118–7817–355
Paretic side left453(NS,chi-square)
Significant sensory deficit554(NS,chi-square)

NOTE. Mean ± SD unless otherwise noted.

Abbreviations: min, minimum; max, maximum, NS, nonsignificant.

Overall Results 

Isometric effort 

In the pooled groups analysis, 1 month after injection of 160U of BTX-A into biceps, there was a 47.5% reduction in agonist MRV of the elbow flexors during a maximal isometric effort of elbow flexion (P<.0001) (fig 3A). There was no change in agonist MRV of the elbow extensors during a maximal isometric effort of elbow extension (fig 3B). However, MRV of flexor and extensor antagonist were both reduced, by 12% (P=.037) and 19.3% (P<.01), respectively (see figs 3A, 3B). Overall, the maximal voluntary power was reduced by 33% (P<.001) in flexion and was increased by 24% (P=.037) in extension.

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  • Fig 3. 

    Overall effects of the injection of 160U of BTX-A into biceps brachii on isometric efforts: Open columns, preinjection; hatched columns, 1 month postinjection. (A) Flexion, (B) extension. The 4 columns on the left of each graph represent the changes in MRV of the agonist and antagonist muscle group for each isometric effort. The last 2 columns on the right represent the corresponding changes in MVP (kg). Error bars, standard error of the mean. Abbreviations: MRV, mean rectified voltage (in volts in the figure); MVP, maximal voluntary power (in kg in the figure). Y-axis is scaled for both V and kg. *P<.05; **P<.01.

Clinical assessment of spasticity and active range of motion 

In the pooled groups analysis, BTX-A injection reduced the spasticity angle (Tardieu Scale) in the elbow flexors by 30% (P=.01) and the spasticity grade by 17% (P<.003) (fig 4). These changes were associated with an 8° increase (5.5%, P=.002) in the range of active elbow extension. There were no significant changes in elbow extensor spasticity and in active range of elbow flexion (data not shown).

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  • Fig 4. 

    Overall effects of the injection of 160U of BTX-A into biceps brachii on spasticity and active range of elbow extension. (A) Spasticity grade, (B) spasticity angle, (C) active range of motion. Open columns, preinjection; hatched columns, 1 month postinjection. Note the reduction in flexor spasticity angle and the increase in active range of elbow extension. Error bars, standard error of the mean. *P<.05; **P<.01.

Results by Group 

Baseline values were equivalent among the 3 injection groups (1-way ANOVA), including agonist flexor MRV, maximal voluntary power in flexion and extension, elbow flexor and extensor spasticity, AROM in flexion and extension, agonist extensor MRV and antagonist flexor and extensor MRV.

Agonist MRV 

The effect of BTX-A injection differed between groups (P=0.039 for interaction visit × group, overall ANCOVA) for reduction in MRV of the flexors as agonists (fig 5A). There was an 81% reduction of agonist flexor MRV in group 3 (high volume/nontargeted; P<.05 for pre- vs postinjection comparison) versus 32% reduction in group 1 (low-volume/non-targeted) and 24% reduction in group 2 (low volume/targeted). Pairwise comparisons showed a nonsignificant trend for a difference between groups 1 and 3 only (P=.07). In contrast, the changes in agonist extensor MRV were similar across the 3 groups (fig 5C), with no effect of visit overall and no pairwise differences between groups.

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  • Fig 5. 

    Effects of dilution and endplate targeting on isometric efforts. (A) Flexor agonist MRV, (B) flexor antagonist MRV, (C) extensor agonist MRV, (D) extensor antagonist MRV. Open columns, preinjection; hatched columns, 1 month postinjection. Error bars, standard error of the mean. MRV (in volts). *P<.05. Non-targ, nontargeted 4-quadrants injection technique. The elbow flexors are significantly more blocked in the highly diluted group (ANCOVA), including when recruited as cocontracting antagonist, while there is no difference between groups in the effects on the noninjected extensors.

Antagonist MRV 

The effect of BTX-A injection on elbow flexor cocontraction during maximal extensor effort differed between groups (P=.032; overall ANCOVA) (fig 5B), with a significant 31% reduction of antagonist flexor MRV in group 3 only (high volume/nontargeted; P<0.05 for pre- vs postinjection comparison). Pairwise comparisons showed a difference between groups 1 and 3 (P=.03). In contrast, the change in antagonist extensor MRV during maximal flexor efforts was similar across groups with no pairwise differences between groups (see fig 5D).

Maximal voluntary power (kg) 

The overall significant decrease in flexion maximal voluntary power and increase in extension maximal voluntary power were similar across groups (data not shown).

Spasticity and active range of motion 

There was a similar 25° (40%) reduction in elbow flexor spasticity angle at 1 month in the endplate-targeted and high-volume groups only (P<.05; pairwise comparisons with group 1, ANCOVA) (fig 6). The overall significant increase in active range of elbow extension was different across groups (P=.04, ANCOVA) with a significant pairwise difference between groups 1 (low volume, nontargeted) and 2 (low volume, targeted).

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  • Fig 6. 

    Effects of dilution and endplate targeting on the changes in spasticity and active range of elbow extension. (A) Flexor spasticity grade, (B) flexor spasticity angle, (C) active range of extension. Post 1-2, mean of the values at 1 month and 2 months postinjection; Post 3-4, mean of the values 3 and 4 months postinjection; Open circles, non-diluted nontargeted group; filled squares, endplate-targeted group; filled triangles, diluted nontargeted group. Error bars, standard error of the mean. *P<.05. Overall ANCOVA was significant only for range of motion (P=.045). Pairwise comparisons Post 1-2 versus baseline were significant only in the targeted and diluted groups for spasticity angle and in the targeted group for AROM.

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Discussion 

When injecting biceps brachii with BTX-A in patients with spastic hemiparesis, a high-volume dilution (20U/mL, ie, 5mL per 100U vial of BTX-A) and an endplate-targeted injection (with a low-volume dilution, 100U/mL, ie, 1mL per vial) are superior to a low volume, and nonendplate-targeted injection. Superior efficacy was demonstrated by greater neuromuscular block of the elbow flexors, greater reduction of elbow flexor spasticity and cocontraction, and greater improvement in active range of elbow extension. High volume dilution in particular achieved the greatest neuromuscular block of injected muscles.

This study also provides a physiologic representation of the overall effect of BTX-A injection into a single muscle (biceps brachii) around a relatively simple joint (elbow), using electromyographic measures of agonist and antagonist (ie, cocontraction) recruitment. The BTX-A-induced blockade of the injected muscle is greater on its maximal function as a voluntarily recruited agonist during an isometric effort (MRV: –47.5%) than on its antagonist cocontraction during a maximal opposite effort (MRV: –12%) or its spasticity (grade: –17%, angle: –30%). Still, the decrease in elbow flexor cocontraction during isometric effort was paralleled by a 24% increase in maximal voluntary power in extension, and a 5% (8°) increase in active range of elbow extension. It is possible that the differential block on agonist and antagonist recruitment of the injected muscle might involve a greater action of BTX-A on large motor units, which are recruited only during maximal voluntary effort as an agonist (size principle).

There was an opposite pattern of effects in the non-injected antagonist muscle (triceps brachii). That muscle was not blocked when recruited maximally as an agonist, but there was 19% reduction of cocontraction in triceps during maximal isometric flexor effort. There was a relatively limited 33% decrease in maximal voluntary power in flexion despite a 47.5% decrease in maximal flexor MRV. The absence of direct block of the triceps suggests that there was no significant physical spread (ie, by diffusion) of BTX-A across the arm. Thus the isolated reduction of triceps cocontraction may suggest a neurophysiologic effect at a central level.25 One hypothesis is that intramuscular BTX-A results in blockade of the Renshaw recurrent inhibition interneuron, which has been suggested in human experiments.25, 26 A Renshaw block on biceps motor neurons after injection of that muscle would release reciprocal inhibition from biceps to triceps motor neurons during flexor contractions, thus decreasing triceps coactivation during flexor efforts.27

There is considerable variability of BTX-A dilution, as reported in the literature and used in practice. For example, BTX-A dilutions in prior reports range from 20U/mL to 100U/mL.23, 25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 Two published controlled studies failed to show differences in therapeutic efficacy between high and low volume preparations.6, 7 However, this may be due in part to insufficient statistical power, because of low subject numbers and lack of sensitivity in the assessments. Both studies used the Ashworth scale as the primary outcome measure, and global calf muscle compound motor action potential for injections limited to gastrocnemius muscles.6, 7 The current study shows that, for a given dose of BTX-A, a higher dilution (higher volume) results in greater neuromuscular block and greater reduction of cocontraction during isometric efforts. This finding is likely due to the ability of higher volume of BTX-A to spread to neuromuscular endplates remote from the injection site.

Although the current study also shows the superior efficacy of BTX-A in a spastic muscle when injected using an endplate targeting technique, the precise location of endplate zones is known in only few human muscles.15, 16, 17, 18 One recent study used an approach similar to our anatomic biceps study,18 by correlating the location of motor endplate bands, assumed from fiber orientation, to external anatomic landmarks in commonly injected muscles.14 Still, precise anatomic targeting of endplates in the majority of muscles is generally not realistic in current clinical practice. Another study proposed a technique of injection as close as possible to endplate areas, looking for characteristic electric potentials in the muscle at rest.43, 44, 45, 46 However, this electromyographic exploring technique of endplate targeting is difficult and time consuming. Furthermore, contact of the needle with endplate zones is painful, even with slow movements of the exploring electrode.

Study Limitations 

The limitations of this preliminary study include the low number of subjects. Furthermore, the differences between the groups seem small, raising questions of their clinical significance. However, when considering the changes, nonadjusted for baseline with respect to active range of elbow extension, this range actually increased by a mean of 15° in group 2 (endplate targeted), by a mean of 8° in group 3 (diluted), versus only 2° in group 1 (4 quadrants nondiluted). We believe that these differences are of clinical significance, especially if they can be increased over time with repeated injections.

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Conclusions 

A high-volume dilution and an endplate-targeted injection are superior to a low-volume, and endplate nontargeted injection, when injecting biceps brachii with BTX-A in patients with spastic hemiparesis. Based on these results, we recommend high volume, endplate-targeted BTX-A injections in human biceps brachii. While not examined in the current study, it is possible that these results may be extrapolated to other large muscles in spastic paresis. Thus, in the absence of further studies mapping endplates in other human muscles, we recommend the use of high volume injections (eg, 20U/mL of BTX-A) to achieve greatest efficacy and potentially allow dose reduction for injection of large spastic muscles, such as those in the lower limb or the upper limb above the elbow. Similar studies could be undertaken to clarify the optimal dilutions for injection into small muscles, such as upper limb muscles below the elbow.

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Appendix 1: Tardieu Scale 

Spasticity Angle (X)

Angle of arrest at slow speed (XV1) minus Angle of catch as fast speed (XV3).

Spasticity Grade (Y)

0.No resistance throughout passive movement.

1.Slight resistance throughout passive movement.

2.Clear catch at precise angle, interrupting passive movement, followed by release.

3.Fatigable clonus (less than 10s when maintaining pressure) occurring at a precise angle, followed by release.

4.Unfatigable clonus (more than 10s when maintaining pressure) occurring at a precise angle.


•Catch without release: graded 0 if XV1=XV3; ‘unratable’ spasticity otherwise.

•Angle 0 = position of minimal stretch of the tested muscle.

•For grades 0 and 1, Spasticity Angle = 0 by definition.

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  • Supplemental Fig 1. 

    Isometric set up. An angular strain gauge measures the flexor and extensor force exerted around the elbow during isometric efforts, while 2 pairs of surface electrodes monitor the activity of the flexors and extensors of the elbow. EMG, electromyography.

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  • Supplemental Fig 2. 

    Methodology of measuring mean rectified voltage. Bottom trace, force transducer signal in volts during a maximal isometric effort of elbow flexion and a maximal isometric effort of elbow extension; Second and third trace from the bottom, raw surface flexor and extensor electromyogram in volts; Top 2 traces, flexor and extensor electromyogram rectified and smoothed (time constant 40ms).

  • NOTE. The area under the curve that measures (A) maximal agonist flexor activity, (B) maximal agonist extensor activity, (C) corresponding extensor cocontraction, and (D) corresponding flexor cocontraction. The MRV over each of these areas is used to represent the (A) flexor agonist MRV, (B) flexor antagonist MRV, (C) extensor antagonist MRV, and (D) flexor antagonist MRV.

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References 

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  • a Botox; Allergan Inc, 2525 Dupont Dr, Irvine, CA 92612.
  • b VIASYS Healthcare, Manor Way, Old Woking, Woking, Surry, GU22 9JU UK.
  • c SPSS 13.0 software package; SPSS Inc, 233 S Wacker Dr, 11th fl, Chicago, IL 60606.

 Supported by a research grant from Allergan, Inc.

 A commercial party having a direct financial interest in the results of the research supporting this article has conferred or will confer a financial benefit on the author or one or more of the authors.

 Reprints are not available from the author.

PII: S0003-9993(08)01499-8

doi:10.1016/j.apmr.2008.04.030

Archives of Physical Medicine and Rehabilitation
Volume 90, Issue 1 , Pages 9-16.e2, January 2009

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