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Review

Spotlight on botulinum toxin and its potential in the treatment of stroke-related spasticity

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Pages 1085-1099 | Published online: 08 Mar 2016

Abstract

Poststroke spasticity affects up to one-half of stroke patients and has debilitating effects, contributing to diminished activities of daily living, quality of life, pain, and functional impairments. Botulinum toxin (BoNT) is proven to be safe and effective in the treatment of focal poststroke spasticity. The aim of this review is to highlight BoNT and its potential in the treatment of upper and lower limb poststroke spasticity. We review evidence for the efficacy of BoNT type A and B formulations and address considerations of optimal injection technique, patient and caregiver satisfaction, and potential adverse effects of BoNT.

Introduction

Spasticity is a velocity-dependent increase in muscle tone as a part of the upper motor neuron syndrome and is seen in a wide variety of neurologic diseases including stroke.Citation1 Poststroke spasticity can develop as early as 1 week after stroke,Citation2 and it is estimated to occur in up to one-half of stroke survivors.Citation3 The most frequent predictors of spasticity include weakness and reduced motor control.Citation2 Long-term spasticity may lead to tendon contractures and limb deformities that can cause significant pain and functional impairment. Depending on the location of the spasticity, this can impact mobility, activities of daily living such as toileting, dressing, and transferring, and quality of life (QoL) and increase the dependence on caregivers.Citation4

The aim of the treatment in poststroke spasticity is focused on muscle limb overactivity reduction. Treatment modalities are used to alleviate spasticity including physical therapy, systemic and intrathecal medications, and surgery. Systemic medications can be helpful if spasticity is generalized. Agents such as baclofen (gamma-aminobutyric acid [GABA]-B receptor agonist) diazepam (GABA-A receptor agonist), dantrolene (decreases calcium release from skeletal muscle sarcoplasmic reticulum), or tizanidine (TZD; alpha-2 adrenergic receptor agonist) often have systemic side effects such as dry mouth, dizziness, sedation, or generalized weakness.Citation5 After several months of treatment, tolerance may develop to systemic medications.

Chemodenervation and neurolytic procedures with alcohol or phenol may be utilized as second-line management. These techniques are more localized and are injected perineurally to destroy the nerve causing spasticity. The effect may be limited by partial nerve regeneration and adverse effects such as bladder, bowel, and sexual dysfunction.Citation6 Intrathecal baclofen acts on GABA receptors in the lumbar spinal cord and may improve walking speed and functional mobility in poststroke spasticity. However, this therapy is invasive and limited by side effects including nausea, vomiting, and urinary retention. Overdosing may lead to death.Citation7,Citation8

The aim of this review is to highlight botulinum toxin (BoNT) and its potential in the treatment of upper and lower limb poststroke spasticity. Optimal treatment may include BoNT injections into focal muscles in conjunction with an integrated multidisciplinary team approach and intensive rehabilitation programs or to help utilize affected muscles.Citation9 Higher-intensity rehabilitation programs (≥3 1-hour weekly session for ∼10 weeks) may help patients achieve more upper limb goals following BoNT injections for spasticity when compared with usual care programs (≤2 1-hour weekly sessions).Citation10 A recent consensus panel of 44 neurologists and physiatrists with experience in BoNT therapy recommended starting a rehabilitation program during the first week after BoNT injection therapy.Citation11

Pharmacology

There have been major advances in synthesizing BoNT for therapeutic use since the German physician Justinus Kerner first proposed using it clinically in the early 19th century and coined the term “sausage poison.”Citation12 BoNT is synthesized by the anaerobic bacteria Clostridium botulinum, Clostridium baratii, and Clostridium butyricum.Citation13 Serotypes A through G are produced by C. botulinum, serotypes F and C are produced by C. baratii, and serotype E is produced by C. butyricum. Each serotype has a different neurotoxin complex protein structure and is synthesized as polypeptides. All serotypes exert their mechanism of action by inhibiting the release of acetylcholine from nerve endings at the neuromuscular junction.Citation14,Citation15 However, each exerts its effects via different protein structures and intracellular targets and, therefore, has different potencies and length of effect.Citation16 There are currently two serotypes of BoNT, serotypes A and B, that are widely available on the market. The US Food and Drug Administration (FDA) has approved four preparations in the USA. The serotype A (BoNT-A): abobotulinumtoxinA (Dysport; Ipsen, Paris, France), onabotulinumtoxinA (Botox; Allergan, Inc., Irvine, CA, USA), and incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH, Frankfurt, Germany) and serotype B (BoNT-B): rimabotulinumtoxinB (Myobloc/Neurobloc; Solstice Neurosciences, Inc., San Francisco, CA, USA). OnabotulinumtoxinA and more recently abobotulinumtoxinA are currently the only approved treatments for upper limb spasticity in adults approved by the FDA.

Each toxin serotype consists of a light chain (50 kDa) and a heavy chain (100 kDa) that is linked by a disulfide bond. This forms a protein with a total molecular weight of 150 kDa. Of the BoNT-A formulations, abobotulinumtoxinA and onabotulinumtoxinA contain the 150 kDa neurotoxin as part of a larger complexing protein, whereas incobotulinumtoxinA contains only the 150 kDa neurotoxin.Citation17 In order to become active, the neurotoxin must be nicked by proteases into two fragments.Citation18 Under normal circumstances, a nerve action potential causes acetylcholine to be released by vesicles from the presynaptic membrane. This requires a complex set of proteins called soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins to help to mediate fusion of synaptic vesicles. The light chains of BoNT cleave SNARE proteins, thereby preventing vesicle fusion of acetylcholine and inhibiting its release into the neuromuscular junction. BoNT-A and BoNT-E work by removing amino acids from a SNARE protein called synaptosomal-associated protein 25. BoNT B, D, F, and G work by cleaving vesicle-associated membrane protein/synaptobrevin, and BoNT-C cleaves syntaxin and synaptosomal-associated protein 25.Citation19,Citation20 Proposed mechanisms of axonal sprouting play a role in nerve regeneration and eventual repair of paralyzed endplatesCitation21 and may play a role in the wearing-off effect after ∼3 months.

The potency of each preparation of BoNT is measured by mouse units, which is the dose that is lethal in 50% of mice tested.Citation17 Although studies comparing dosage equivalencies between different toxin types have been published, the conversion ratios are not clear, and the FDA specifies that dose conversions should not be performed.

BoNT for upper limb spasticity

The goals of the current review are to highlight the use of BoNT in the treatment of upper and lower limb spasticity. The current review combines class I and II studies addressing the efficacy and safety of BoNT for the treatment of poststroke spasticity ( and ) by assigning levels of evidence according to the American Academy of Neurology guidelines. A broader search was used for the rest of the article. Studies were reviewed from the 2008 Report of Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology,Citation22 and additional literature search was conducted using the PubMed, OvidSP, and Medline databases from January 2008 to October 2015 with the search items “post stroke spasticity,” “upper-limb post stroke spasticity,” “lower limb post stroke spasticity,” “botulinum toxin,” “botulinum neurotoxin,” “abobotulinumtoxinA,” “onabotulinumtoxinA,” “incobotulinumtoxinA,” and “rimabotulinumtoxinB.” Most studies utilized the Modified Ashworth Scale (MAS) as the primary outcome measure for spasticity reduction.

Table 1 Botulinum toxin for poststroke upper limb spasticity

Table 2 Botulinum toxin for poststroke lower limb spasticity

AbobotulinumtoxinA

AbobotulinumtoxinA was approved by the FDA in 2015 for the treatment of upper limb poststroke spasticity. Eleven class I trials have found that abobotulinumtoxinA is effective and safe for the reduction in upper limb poststroke spasticity.Citation23Citation33 Studies assessing both active and passive functional outcomes have demonstrated a significant improvement in passive function (improved range of motion, etc), while failing to show substantial improvement in active muscle function.Citation24,Citation25,Citation27

A trial conducted at 34 neurology and rehabilitation clinics in the USA and in Europe randomized 243 patients to placebo, abobotulinumtoxinA (500 U), or abobotulinumtoxinA (1,000 U). The primary endpoint of mean change in muscle tone of hypertonic muscle groups of the upper limb was significant in both abobotulinumtoxinA groups vs placebo. The secondary endpoint of mean change in the Physician Global Assessment, clinician-rated clinical benefit independent of the MAS, was significantly different after 4 weeks, although the perceived function Disability Assessment Scale (DAS) was not significantly different.Citation34

A study in Australia which assessed 96 patients comparing abobotulinumtoxinA (500–1,000 U) with placebo reported no significant difference in their primary outcome of QoL. However, there was a significant improvement in secondary outcomes including greater reduction in spasticity (P<0.001) and Goal Attainment Scale, pain, mood, global benefit, disability, and carer burden.Citation24 Further analysis of these data suggested significantly higher levels of goal attainment in the treatment group and a cumulative effect over two cycles of treatment.Citation30

Another study randomized 333 patients from 12 stroke services in the UK and found no significant difference in the primary outcome of improved arm function at 1 month, 3 months, or 12 months. Muscle tone and spasticity at the elbow were decreased at 1 month as a secondary outcome measure.Citation25 A final study enrolled 163 patients and randomized them to abobotulinumtoxinA (500 U) vs placebo and found improved scores in the treatment group but failed to find a clinically significant difference in the Functional Motor Assessment Scale.Citation27

Further studies that found improvement in spasticity and passive range of movement in spastic upper limbs have noted improvement in disability with caregiver assistance such as helping dressing and cleaning of the affected limb and decreased caregiver burden.Citation26,Citation31,Citation33,Citation35

OnabotulinumtoxinA

OnabotulinumtoxinA has been studied extensively and found to be safe, and to significantly reduce upper limb spasticity after stroke.Citation28,Citation36Citation40 Studies also used the MAS and found dose-dependent improvements with sustained benefits at 3 months; however, the reduction in pain measurements was not demonstrated.Citation28,Citation37,Citation39Citation42 Although some studies have found improvements in functional disability on the DASCitation28 and the Global Assessment of Response to Treatment,Citation38 others failed to demonstrate gains in functional activity.Citation37,Citation40,Citation43 For example, a class II trial in Malaysia found improvement in flexor tone of the wrist and finger muscles at 1 month and 3 months. Although there were improvements in measures of global function and QoL in the onabotulinumtoxinA group, there were no significant differences between the onabotulinumtoxinA group and placebo.Citation37 The Botox Economic Spasticity Trial randomized onabotulinumtoxinA plus standard of care to placebo plus standard of care and was assessed for passive and active functional goals (as defined by both the patient and the investigator) at 12 weeks followed by an open-label period of 52 weeks. Although more patients in the treatment group achieved their secondary passive goal, there was no difference between groups in the principal and secondary active functional goals.Citation43

Three class I studies assessing the effects of onabotulinumtoxinA vs placebo have found improvements in spasticity but not in pain. The first study randomized 109 patients to receive a lower- (120–150 U) or higher-dose (200–240 U) onabotulinumtoxinA or placebo in spastic upper limbs after stroke and found significant improvements in spasticity with the higher-dose onabotulinumtoxinA. No significant differences were found with the lower-dose onabotulinumtoxinA and placebo. Secondary outcome measures of functional disability showed a significant decrease in the DAS score for limb position and dressing in the higher-dose onabotulinumtoxinA group, but not for hygiene and pain.Citation42 The second study randomized 91 stroke patients to two treatments of placebo and 90 U, 180 U, or 360 U of onabotulinumtoxinA for upper limb spasticity. A dose-dependent response was observed in tone reduction but not in functional disability, pain, or QoL.Citation40 The third study (only 21 patients) assessed the efficacy of onabotulinumtoxinA in reducing pain, impairment, and disability in patients with shoulder pain and spasticity. They found no significant differences in pain scores on the McGill Pain Questionnaire between those injected with BoNT and those injected with placebo (P>0.05), although they did find improvements in hygiene on the DAS (P<0.05) with a similar trend toward significance for improvement on the DAS dressing scale (P=0.061).Citation41

There are few trials comparing BoNT serotypes. Our group reported differences between onabotulinumtoxinA and TZD. This class I study compared injections of onabotulinumtoxinA with TZD vs placebo in 60 patients with upper limb spasticity from either stroke or traumatic brain injury. Patients were randomized to intramuscular onabotulinumtoxinA plus oral placebo, oral TZD plus intramuscular placebo, and intramuscular placebo plus oral placebo. OnabotulinumtoxinA elicited greater reduction in tone than TZD or placebo in finger and wrist flexors at 3 weeks (P<0.001 vs TZD; P<0.02 vs placebo) and 6 weeks (P=0.001 vs TZD; P=0.08 vs placebo). Dressing, hygiene, cosmesis, and pain demonstrated a nonsignificant trend to a greater reduction in the primary therapeutic target 6 weeks after injection in the onabotulinumtoxinA group.Citation36

IncobotulinumtoxinA

Two class I trials have demonstrated reduction in tone with incobotulinumtoxinA. The first study assessed incobotulinumtoxinA by randomizing 148 upper limb poststroke spasticity patients to 400 U of incobotulinumtoxinA vs placebo who were then followed for 20 weeks. At 4 weeks, there was a >1-point improvement in the Ashworth scale score in the finger flexor muscles compared with patients who received placebo (odds ratio 3.91, 95% confidence interval: 1.9–9.3).Citation44 Subsequent open-label extension of the study continued to show benefit, with most investigators, patients, and caregivers rating positive benefit and efficacy throughout the open-label period of 69 weeks.Citation45 The second study randomized 349 patients to incobotulinumtoxinA (400 U) or placebo at 46 international sites. There was a reduction in the Ashworth scale score in the primary target clinical pattern (−0.9 incobotulinumtoxinA vs −0.5 placebo; P<0.001) with >1-point improvement (69.6% incobotulinumtoxinA vs 37.5% placebo) when compared with placebo.Citation46 Both studies demonstrated significant improvements in DAS scores from baseline across domains of dressing, limb position, hygiene, and pain.Citation45,Citation46

RimabotulinumtoxinB

Two smaller class I trials on rimabotulinumtoxinB (BoNT-B) have been completed. The first study randomized 15 patients to 10,000 U of rimabotulinumtoxinB or placebo in elbow, wrist, and fingers and found a significant decrease in wrist tone 2 weeks after injection, but it did not find a decrease in tone at the finger flexors or elbow at 10,000 U of rimabotulinumtoxinB over a 16-week period.Citation47 The second trial randomized 24 patients with elbow flexor spasticity after stroke or traumatic brain injury to 10,000 U or 15,000 U of rimabotulinumtoxinB or placebo and followed for 3 months. Patients who had received either dose of rimabotulinumtoxinB had significantly improved active elbow extension compared with placebo.Citation48

BoNT for lower limb spasticity

There are fewer studies assessing the effects of BoNT in the treatment of lower limb poststroke spasticity compared with upper limb poststroke spasticity (). Most class I studies have assessed the efficacy and safety of abobotulinumtoxinA and onabotulinumtoxinA.

There are three class I studies of onabotulinumtoxinA which have established significant reduction in muscle tone in poststroke lower limb spasticity. In the first study, 85 subjects received 200 U or 300 U of onabotulinumtoxinA or saline injections with the primary measure being plantar flexor Ashworth scores at 12 weeks. Subjects noted significantly greater decrease in spasm frequency (P=0.01), pain reduction (P=0.02), active dorsiflexion (P=0.03), and gait quality (P=0.02).Citation49 In the second study, Kaji et al randomized 120 patients with lower limb spasticity to BoNT-A (300 U) or placebo. Although a significant improvement in spasticity was seen, no change in the speed of gait was found between groups.Citation50 In the third study, Richardson et al assessed onabotulinumtoxinA vs placebo with assessments at 3-week intervals after injection until 12 weeks in patients with either upper or lower limb spasticity from a variety of injuries including stroke. Among 52 people, 20 of which had lower limb spasticity; onabotulinumtoxinA had an effect on focal disability and impairment in lower limbs.Citation39

There is one class I study of abobotulinumtoxinA. In this study, the effects of three doses of abobotulinumtoxinA at 500 U, 1,000 U or 1,500 U in 234 stroke patients were assessed. The primary outcome measure of 2-minute walking distance and stepping rate increased significantly in both groups, but no significant difference was found between groups including placebo. Significant improvements in calf spasticity, limb pain, and reduction in the reuse of walking aids were found with abobotulinumtoxinA compared with placebo, with the greatest benefits found in patients receiving 1,500 U.Citation51

Technical considerations

Optimal dosing and time of administration

Minor differences exist between storing and preparing the various BoNT serotypes, and care should be taken to read the package insert to ensure optimal preparation. For example, onabotulinumtoxinA and abobotulinumtoxinA are both available as powders for reconstitution which must be refrigerated at 2°C–8°C, whereas incobotulinumtoxinA does not need to be refrigerated. RimabotulinumtoxinB does not require reconstitution and is stable for 21 months in refrigerator storage.

Better outcomes may be obtained if BoNT is injected after a shorter duration of onset to spasticity.Citation52,Citation53 This may be attributed to the fact that contractures begin to develop as early as 2 weeks after stroke.Citation2 There are currently no well-defined guidelines regarding optimal BoNT dosing, although several strategies have been implemented. The European Consensus data on BoNT-A for adult spasticity recommend 600 U of onabotulinumtoxinA and incobotulinumtoxinA and up to 1,500 U of abobotulinumtoxinA per injection session.Citation54 More recent literature suggests using higher doses for poststroke spasticity. Baricich et al recently recommended dosing of up to 600–800 U of onabotulinumtoxinA in upper and lower poststroke spasticity.Citation55 A recent review article of eight selected studies suggests that higher doses of BoNT-A are efficacious in reducing upper and lower limb poststroke spasticity, with mild adverse effects.Citation56

Another study aimed at characterizing the dose–response relationships between muscle tone and onabotulinumtoxinA tone pooled data from seven trials. A total of 544 patients were randomized to receive onabotulinumtoxinA or placebo. Dose–response relationships demonstrated greater improvements in muscle tone with increasing doses of onabotulinumtoxinA. Doses estimated to cause a decreased muscle tone were 22.5 U, 18.4 U, 66.3 U, and 42.5 U in the flexor carpi radialis, flexor carpi ulnaris, flexor digitorum superficialis, and flexor digitorum profundus, respectively, and not determinable in the biceps brachii.Citation57

Injection patterns and optimal targeting

The most frequently injected upper and lower limb muscles were reported in a meta-analysis of 70 randomized, nonrandomized, and single-arm studies evaluating onabotulinumtoxinA muscle injection patterns in 2,163 adult spasticity patients. The upper limbs included the flexor carpi radialis (64.0%), flexor carpi ulnaris (59.1%), flexor digitorum superficialis (57.2%), flexor digitorum profundus (52.5%), and biceps brachii (38.8%). The most commonly injected lower limb muscles included the gastrocnemius (66.1%), soleus (54.7%), and tibialis posterior (50.5%).Citation58 A modified Delphi panel of ten clinical experts identified a treatment paradigm for muscle selection, dose for each muscle and for each posture, and use of localization techniques for injecting onabotulinumtoxinA in poststroke upper limb spasticity. The authors identified three common aggregating upper limb postures in poststroke spasticity including 1) adducted shoulder, flexed elbow, pronated forearm, flexed wrist, and clenched fist; 2) flexed elbow, pronated forearm, flexed wrist, and clenched fist; and 3) flexed wrist and clenched fist. They recommended a dilution of onabotulinumtoxinA of 50 U/mL (2:1 dilution ratio) and starting doses for each aggregate were 300 U, 300 U, and 200 U with total maximum doses of 400 U, 400 U, and 300 U, respectively. They also concluded that localization techniques were needed to identify muscles.Citation59

Practitioners commonly used landmark localization, electrical stimulation, electromyography guidance, and ultrasound to identify targeted muscles for injection. The knowledge of high-density endplate areas can maximize yield when using anatomic landmarks for injection. Although some muscles have well-defined motor endplates, other muscles may require a more even spread of injection across the muscleCitation54 or higher dilutions.Citation60 Optimal targeting based on anatomic knowledge of highest endplate density may yield the highest results. Amirali et al histologically mapped end-plate bands in relation to external landmarks in human biceps brachii muscles. The study found that the area of highest endplate density is an inverted V-shaped band 1 cm in width between the lower third and upper two-thirds of the muscle belly.Citation61 In an attempt to determine the effects of onabotulinumtoxinA dilution and endplate targeting in elbow flexors, Gracies et al randomized 21 patients in four groups, 4 months after a 160 U injection of BoNT-A into spastic biceps brachii muscles. These four groups included 1) 100 U/mL dilution, 0.4 cc/site, four-quadrant injection; 2) 100 U/mL dilution, 0.4 cc/site, four sites along endplate band; and 3) 20 U/mL dilution, 2 cc/site, four-quadrant injection. They found that a high-volume dilution (20 U/mL) and an endplate-targeted injection are superior to a low-volume, endplate nontargeted injection, when injecting biceps brachii.Citation60

Although anatomic knowledge of surface landmarks and endplate densities may be important while injecting, electrical stimulation and ultrasound have been shown to be important tools for ensuring accurate injection into the targeted muscles. One study found that only 37% of needle placement attempts reached target muscle fascicles, suggesting that further guidance tools may be needed for correct localization, particularly for small or deep muscles.Citation62 Picelli et al randomized 60 poststroke spasticity patients to manual needle placement, electrical stimulation, and ultrasound techniques using abobotulinumtoxinA. They found that patients injected using electrical stimulation and ultrasound guidance had improved MAS scores, Tardieu angle, and passive range of motion when compared with the manual needle placement group. They found no differences between the ultrasound and electrical stimulation groups.Citation63

Two additional studies have found the benefit of ultrasound over surface landmark techniques and manual needle placement. One study compared surface landmark technique with ultrasound guidance when injecting spastic muscles of the upper extremity with abobotulinumtoxinA and found significant differences between methods, concluding that ultrasound guidance can help avoid injection into nerve and vascular structures and ensure the injection remains within the fascicle borders.Citation64 Another randomized study compared ultrasound guidance with surface landmark techniques by measuring MAS and finger position in poststroke patients with upper limb spasticity treated with incobotulinumtoxinA. After 1 month of follow-up, MAS and finger position at rest were significantly improved in both groups, although they were significantly better in patients treated with ultrasound guidance than those with manual needle placement.Citation65

Adverse events associated with BoNT

Adverse short-term issues related to BoNT include local pain at the site of injection and spread, or the diffusion of toxin from the injected muscle into neighboring muscles causing undesirable weakness. Depending on the location, spread can be dangerous and adverse events that have been reported include dysphagia, dysarthria, dysphonia, respiratory compromise, and rarely death.Citation66 A solid knowledge of the muscle anatomy can help decrease this risk. The long-term effects include anatomic denervation and muscle atrophy, as well as immunoresistance. However, more recent studies demonstrate that a relatively small group of patients actually develop immunoresistance. One study measured 207 patients’ posttreatment serum samples for neutralizing antibodies who received onabotulinumtoxinA with poststroke spasticity and found that one patient who had received four treatments tested positive to neutralizing antibodies after the first injection and did not respond to treatment.Citation67 A meta-analysis assessing rates of neutralizing antibody conversion with onabotulinumtoxinA found that only one subject out of 317 (0.32%) of poststroke spasticity subjects converted from a baseline status of antibody negative to antibody positive after treatment.Citation68 Given the relatively low rate of antibody formation, authors suggest considering other factors when faced with a patient with nonresponsiveness such as technical issues. Several ways of minimizing these effects include increasing doses of BoNTCitation69 and switching serotypes of BoNT.Citation70 IncobotulinumtoxinA theoretically may have less immunoresistance given that it is free of complexing proteins, although no study has confirmed this.

Satisfaction

No significant differences were found in caregiver dependency in a small study of 39 patients randomized to onabotulinumtoxinA vs placebo. Two recent cross-sectional surveys conducted in the USA, Canada, France, and Germany of 79 patients found that 40.5% of patients were very satisfied, 48.1% were somewhat satisfied, and 11.4% were not satisfied with at least two treatment sessions of any of the BoNT-A formulations. Interestingly, patient satisfaction was the lowest right before injection and the highest at the time-of-peak effect. Most of the participating physicians were moderately (57.7%) or very (36.5%) satisfied with the BoNT-A treatment.Citation71 AbobotulinumtoxinA decreases caregiver burden in the long-term care patients who are treated for upper limb spasticity. In this study, 55 patients randomized to abobotulinumtoxinA vs placebo noted a four-point reduction in carer burden (P<0.001) when treated with abobotulinumtoxinA.Citation35 Another study randomized 40 patients with poststroke spasticity to receive abobotulinumtoxinA vs placebo and found a reduction in carer burden at week 6 after injection with abobotulinumtoxinA. This benefit was extended for at least 12 weeks.Citation33

Cost analysis

The cost of BoNT may be prohibitive to patients without insurance coverage, and even for those with insurance coverage that cannot get approval for treatments such as booster injections within 3 months. The BoNT for Upper Limb after Stroke trial assessed the cost-effectiveness of BoNT-A plus an upper limb therapy program in the treatment of poststroke upper limb spasticity in England and Wales. They found that the addition of BoNT-A was not estimated to be cost-effective and in fact two-and-a-half times the cost-effectiveness threshold as set by the National Institute for Health and Clinical Excellence.Citation72 Another study evaluated the cost per patient per injection of two types of BoNT-A, onabotulinumtoxinA (100 U) and abobotulinumtoxinA (500 U), using the recommended dosing of 300 U and 1,000 U for upper limb spasticity, respectively. The cost per patient per injection for upper limb spasticity was less for abobotulinumtoxinA than for onabotulinumtoxinA in 18 of the 19 countries assessed, while allowing for different prices per vial in each country. Ultimately, the authors suggested that substantial savings could be made by using abobotulinumtoxinA in the treatment of upper limb spasticity.Citation73

Conclusion

Poststroke spasticity can be a major source of morbidity and has an impact on activities of daily living, hygiene, caregiver burden, and QoL. The mainstays of conventional treatment include a multifaceted approach that may include incorporating a structured rehabilitation program and/or multidisciplinary team approach, although more data are needed in this area. Based on current class I and II studies, we suggest that BoNT is used as part of a dynamic approach to treating poststroke spasticity. The current data on BoNT demonstrate that it effectively decreases muscle tone in poststroke spasticity of the upper and lower limbs. However, studies assessing both improvements in active function as well as pain reduction have not had as robust a response.

The lack of strong active functional outcomes when compared with passive functional outcomes may reflect the need for more sensitive assessment scales that assess more than just muscle tone. Most studies currently utilize the MAS, while more flexible and patient-centered approaches may be considered, including the Goal Attainment Scale that allows for the use of individualized functional treatment goals.Citation74 Investigators from the BoNT for Upper Limb after Stroke trial who demonstrated reduction in spasticity but not in active function of the upper limb suggest that weakness is more important than spasticity in reduced upper limb function.Citation25 The cumulative data on pain reduction are mixed in post-stroke spasticity, but interestingly there have been some data suggesting a role for BoNT in the reduction of pain including diabetic neuropathic pain,Citation75,Citation76 occipital neuralgia,Citation77 trigeminal neuralgia,Citation78 and complex region pain syndrome.Citation79

Strategies to reduce adverse effects on BoNT injections include having a solid knowledge of anatomy of muscles to be injected before injection, using additional methods such as electromyography, electrical stimulation, or ultrasound guidance. It is important to identify and exclude populations who may have hypersensitivity to BoNT including neuromuscular junction disorders and anterior horn cell disorders prior to injection. In addition, as botulinum serotypes can differ, reading the packaging label before use and being familiar with proper storage techniques, planning out dosing, and knowing reconstitution techniques may be prudent.Citation66

Thus far, there have been only few comparator trials comparing different BoNT formulations, and one study comparing BoNT with an oral therapy, TZD.Citation36 Future head-to-head trials are needed to determine the efficacy of one BoNT serotype and formulation when compared with another in addition to BoNT in comparison with other treatments. Determining which muscles to inject should be tailored to each patient individually. Further research is needed to identify standard muscles in the upper and lower extremity, and further recommendations are needed to identify the number and location of injection sites. As the usage of the other formulations continues to grow, we expect to acquire more information on safety, dosing, efficacy, and potential uses for particular muscles in upper and lower limb spasticity. Given the differences in formulation, mechanism of action, dosing and potential adverse effect profile, we recommend that future studies address formulations individually.

Disclosure

Dr David M Simpson receives consulting fees and research grant support from Allergan, Inc., Merz, and Ipsen. Dr Michelle Kaku reports no conflicts of interest in this work.

References

  • LanceJWThe control of muscle tone, reflexes, and movement: Robert Wartenberg lectureNeurology19813012130313137192811
  • AllisonRShentonLBamforthKKilbrideCRichardsDIncidence, time course and predictors of impairments relating to caring for the profoundly affected arm after stroke: a systematic reviewPhysiother Res Int Epub2015525
  • UrbanPPWolfTUebeleMOccurrence and clinical predictors of spasticity after ischemic strokeStroke2010412016202020705930
  • BraininMNorrvingBSunnerhagenKSPoststroke chronic disease management: towards improved identification and interventions for poststroke spasticity-related complicationsInt J Stroke20116424621205240
  • ChouRPetersonKHelfandMComparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic reviewJ Pain Symptom Manage20042814017515276195
  • StevensonVRehabilitation in practice: spasticity managementClin Rehabil20102429330420360150
  • FranciscoGEBoakeCImprovement in walking speed in poststroke spastic hemiplegia after intrathecal baclofen therapy: a preliminary studyArch Phys Med Rehabil2003841194119912917859
  • MeythalerJMGuin-RenfroeSBrunnerRCHadleyMNIntrathecal baclofen for spastic hypertonia from strokeStroke2001322099210911546903
  • EsquenaziANovakISheeanGSingerBWardAInternational consensus statement for the use of botulinum toxin treatment in adults and children with neurological impairments–introductionEur J Neurol2010171820633176
  • DemetriosMGorelikALouieJBrandCBaguleyIJKhanFOutcomes of ambulatory rehabilitation programmes following botulinum toxin for spasticity in adults with strokeJ Rehabil Med20144673073725073939
  • FranceschiniMIoccoMMolteniFSantamatoASmaniaNManagement of stroke patients submitted to botulinum toxin type A therapy: a Delphi survey of an Italian expert panel of specialist injectorsEur J Phys Rehabil Med20145052553224963604
  • ErbguthFJNaumannMHistorical aspects of botulinum toxin Justinus Kerner (1786–1862) and the “sausage poison”Neurology1999531850185010563638
  • GimenezDFGiménezJASerological Subtypes of Botulinal Neurotoxins. Botulinum and Tetanus NeurotoxinsNew YorkSpringer1993421431
  • SimpsonLLThe origin, structure, and pharmacological activity of botulinum toxinPharmacol Rev1981331551886119708
  • SimpsonLLIdentification of the major steps in botulinum toxin actionAnnu Rev Pharmacol Toxicol20044416719314744243
  • AokiKGuyerBBotulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actionsEur J Neurol20018212911851731
  • FrevertJContent of botulinum neurotoxin in botox®/vistabel®, dysport®/azzalure®, and xeomin®/bocouture®Drugs R D201010677320698714
  • GuptaBRDSugiyamaHRole of a protease in natural activation of Clostridium botulinum neurotoxinInfect Immun197265875904564288
  • BlasiJChapmanERLinkEBotulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25Nature19933651601638103915
  • SchiavoGGBenfenatiFPoulainBTetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevinNature19923598328351331807
  • de PaivaAMeunierFAMolgóJAokiKRDollyJOFunctional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminalsProc Natl Acad Sci U S A1999963200320510077661
  • SimpsonDGraciesJGrahamHAssessment: botulinum neurotoxin for the treatment of spasticity (an evidence-based review) Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of NeurologyNeurology2008701691169818458229
  • HesseSReiterFKonradMJahnkeMTBotulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trialClin Rehabil1998123813889796928
  • McCroryPTurner-StokesLBaguleyIJBotulinum toxin A for treatment of upper limb spasticity following stroke: a multi-centre randomized placebo-controlled study of the effects on quality of life and other person-centred outcomesJ Rehabil Med20094153654419543664
  • ShawLCPriceCIvan WijckFMBotulinum toxin for the upper limb after stroke (BoTULS) trial effect on impairment, activity limitation, and painStroke2011421371137921415398
  • SmithSEllisEWhiteSMooreAA double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injuryClin Rehabil20001451310688339
  • RosalesRLKongKHGohKJBotulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke a randomized controlled trialNeurorehabil Neural Repair20122681282122371239
  • BrashearAGordonMFElovicEIntramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a strokeN Engl J Med200234739540012167681
  • SuputtitadaASuwanwelaNThe lowest effective dose of botulinum A toxin in adult patients with upper limb spasticityDisabil Rehabil20052717618415824048
  • Turner-StokesLBaguleyIJDe GraaffSGoal attainment scaling in the evaluation of treatment of upper limb spasticity with botulinum toxin: a secondary analysis from a double-blind placebo-controlled randomized clinical trialJ Rehabil Med201042818920111849
  • BakheitAPittockSMooreAA randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with strokeEur J Neurol2001855956511784339
  • BakheitAThilmannAWardAA randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after strokeStroke2000312402240611022071
  • BhaktaBBCozensJAChamberlainMABamfordJMImpact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: a randomised double blind placebo controlled trialJ Neurol Neurosurg Psychiatry20006921722110896696
  • GraciesJ-MBrashearAJechRSafety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trialLancet Neurol201514992100126318836
  • LamKLauKKSoKKCan botulinum toxin decrease carer burden in long term care residents with upper limb spasticity? A randomized controlled studyJ Am Med Dir Assoc20121347748422521630
  • SimpsonDMGraciesJ-MYablonSABarbanoRBrashearABotulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled studyJ Neurol Neurosurg Psychiatry20098038038518977811
  • JahangirATanHNorlinahMIntramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after strokeMed J Malaysia20076231918551937
  • SimpsonDAlexanderDO’brienCBotulinum toxin type A in the treatment of upper extremity spasticity A randomized, double-blind, placebo-controlled trialNeurology199646130613068628472
  • RichardsonDSheeanGWerringDEvaluating the role of botulinum toxin in the management of focal hypertonia in adultsJ Neurol Neurosurg Psychiatry20006949950610990511
  • ChildersMKBrashearAJozefczykPDose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a strokeArch Phys Med Rehabil2004851063106915241751
  • MarciniakCMHarveyRLGagnonCMDoes botulinum toxin type A decrease pain and lessen disability in hemiplegic survivors of stroke with shoulder pain and spasticity?: a randomized, double-blind, placebo-controlled trialAm J Phys Med Rehabil2012911007101923064478
  • KajiROsakoYSuyamaKMaedaTUechiYIwasakiMBotulinum toxin type A in post-stroke upper limb spasticityCurr Med Res Opin2010261983199220569068
  • WardABWisselJBorgJFunctional goal achievement in post-stroke spasticity patients: the BOTOX® economic spasticity trial (BEST)J Rehabil Med20144650451324715249
  • KanovskýPSlawekJDenesZEfficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticityClin Neuropharmacol20093225926519644361
  • KaňovskýPSlawekJDenesZEfficacy and safety of treatment with incobotulinum toxin A (botulinum neurotoxin type A free from complexing proteins; NT 201) in post-stroke upper limb spasticityJ Rehabil Med20114348649221533328
  • ElovicEPMuninMCKaňovskýPHanschmannAHiersemenzelRMarciniakCRandomized, placebo-controlled trial of incobotulinumtoxinA for upper-limb post-stroke spasticityMuscle Nerve Epub2015722
  • BrashearAMcAfeeALKuhnERFyffeJBotulinum toxin type B in upper-limb poststroke spasticity: a double-blind, placebo-controlled trialArch Phys Med Rehabil20048570570915129392
  • GraciesJ-MBayleNGoldbergSSimpsonDMBotulinum toxin type B in the spastic arm: a randomized, double-blind, placebo-controlled, preliminary studyArch Phys Med Rehabil2014951303131124709034
  • DunneJWGraciesJ-MHayesMZemanBSingerBJGroupMSA prospective, multicentre, randomized, double-blind, placebo-controlled trial of onabotulinumtoxinA to treat plantarflexor/invertor overactivity after strokeClin Rehabil20122678779722308557
  • KajiROsakoYSuyamaKMaedaTUechiYIwasakiMBotulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trialJ Neurol20102571330133720358216
  • PittockSMooreAHardimanOA double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport®) in the treatment of spastic equinovarus deformity after strokeCerebrovasc Dis20031528930012686794
  • MohammadiBAbdoulrahmani BalouchSDenglerRKolleweKLong-term treatment of spasticity with botulinum toxin type A: an analysis of 1221 treatments in 137 patientsNeurol Res20103230931319726016
  • BurbaudPWiartLDubosJA randomised, double blind, placebo controlled trial of botulinum toxin in the treatment of spastic foot in hemiparetic patientsJ Neurol Neurosurg Psychiatry1996612652698795597
  • WisselJWardABErztgaardPEuropean consensus table on the use of botulinum toxin type A in adult spasticityJ Rehabil Med200941132519197564
  • BaricichAGranaECardaSSantamatoACisariCInvernizziMHigh doses of onabotulinumtoxinA in post-stroke spasticity: a retrospective analysisJ Neural Transm (Vienna)201512291283128725724294
  • SantamatoAMicelloMFRanieriMEmployment of higher doses of botulinum toxin type A to reduce spasticity after strokeJ Neurol Sci20153501625684341
  • YablonSABrinMFVanDenburghAMDose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysisMov Disord20112620921520960474
  • NalysnykLPapapetropoulosSRotellaPSimeoneJCAlterKEEsquenaziAOnabotulinumtoxinA muscle injection patterns in adult spasticity: a systematic literature reviewBMC Neurol20131311824011236
  • SimpsonDPatelAAlfaroAUsing a Delphi panel to identify a treatment paradigm for injecting botulinum toxin to treat common postures in post-stroke upper limb spasticity (P5. 167)Neurology201584P516725480912
  • GraciesJ-MLugassyMWeiszDJVecchioMFlanaganSSimpsonDMBotulinum toxin dilution and endplate targeting in spasticity: a double-blind controlled studyArch Phys Med Rehabil2009909.e16.e19154823
  • AmiraliAMuLGraciesJ-MSimpsonDMAnatomical localization of motor endplate bands in the human biceps brachiiJ Clin Neuromuscul Dis2007930631218090684
  • MolloyFShillHKaelin-LangAKarpBAccuracy of muscle localization without EMG: implications for treatment of limb dystoniaNeurology20025880580711889247
  • PicelliALobbaDMidiriABotulinum toxin injection into the forearm muscles for wrist and fingers spastic overactivity in adults with chronic stroke: a randomized controlled trial comparing three injection techniquesClin Rehabil20142823224223945164
  • HenzelMKMuninMCNiyonkuruCSkidmoreERWeberDJZafonteRDComparison of surface and ultrasound localization to identify forearm flexor muscles for botulinum toxin injectionsPM R2010264264620659720
  • SantamatoAMicelloMFPanzaFCan botulinum toxin type A injection technique influence the clinical outcome of patients with post-stroke upper limb spasticity? A randomized controlled trial comparing manual needle placement and ultrasound-guided injection techniquesJ Neurol Sci2014347394325263601
  • YiannakopoulouESerious and long-term adverse events associated with the therapeutic and cosmetic use of botulinum toxinPharmacology201595656925613637
  • GordonMBrashearAElovicERepeated dosing of botulinum toxin type A for upper limb spasticity following strokeNeurology2004631971197315557529
  • NaumannMCarruthersACarruthersJMeta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indicationsMov Disord2010252211221820737546
  • DresslerDMünchauABhatiaKPQuinnNPBigalkeHAntibody-induced botulinum toxin therapy failure: can it be overcome by increased botulinum toxin doses?Eur Neurol20014711812111844901
  • BarnesMBestDKiddLThe use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A-initial experiencesEur J Neurol20051294795516324088
  • BensmailDHanschmannAWisselJSatisfaction with botulinum toxin treatment in post-stroke spasticity: results from two cross-sectional surveys (patients and physicians)J Med Econ20141761862524841450
  • ShawLRodgersHPriceCBoTULS: a multicentre randomised controlled trial to evaluate the clinical effectiveness and cost-effectiveness of treating upper limb spasticity due to stroke with botulinum toxin type AHealth Technol Assess201014261113iiiiv20515600
  • RozeSKurthHHuntBValentineWMartyREvaluation of the cost per patient per injection of botulinum toxin A in upper limb spasticity: comparison of two preparations in 19 countriesMed Devices (Auckl)201259723204875
  • RosalesRLKanovskyPFernandezHHWhat’s the “catch” in upper-limb post-stroke spasticity: expanding the role of botulinum toxin applicationsParkinsonism Relat Disord201117S3S1021999894
  • GhasemiMAnsariMBasiriKShaigannejadVThe effects of intra-dermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathyJ Res Med Sci20141910624778662
  • YuanRSheuJYuJBotulinum toxin for diabetic neuropathic pain A randomized double-blind crossover trialNeurology2009721473147819246421
  • TaylorMSilvaSCottrellCBotulinum toxin type-A (BOTOX®) in the treatment of occipital neuralgia: a pilot studyHeadache2008481476148119076646
  • WuC-JLianY-JZhengY-KBotulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trialCephalalgia20123244345022492424
  • CarrollIClarkJDMackeySSympathetic block with botulinum toxin to treat complex regional pain syndromeAnn Neurol20096534835119334078