Chapter 9
Botulinum Neurotoxin
Chapter objectives
- Explain the proposed mechanism of effect for Botulinum neurotoxin (BoNT).
- Present a narrative review of the research evidence for BoNT.
- Discuss indications and aims for the use of BoNT for children and adults with upper limb spasticity.
- Detail principles and practices of determining client suitability, injection sites, and follow-up.
Abbreviations
| BoNT | Botulinum neurotoxin |
| BoNT-A | Botulinum neurotoxin-A |
| CIMT | Constraint induced movement therapy |
| COPM | Canadian Occupational Performance Measure |
| CRPS | Chronic regional pain syndrome |
| EMG | Electromyography |
| FES | Functional electrical stimulation |
| GAS | Goal attainment scaling |
| GMFCS | Gross Motor Functional Classification Scale |
| HIPM | Hypertonicity Intervention Planning Model |
| ICF | International Classification of Functioning, Disability and Health |
| IP | Interphalangeal (joints) |
| MACS | Manual Ability Classification System |
| MASMS | Modified Ashworth Scale of Muscle Spasticity |
| mCIMT | Modified constraint-induced movement therapy |
| MCP | Metacarpophalangeal (joints) |
| MTS | Modified Tardieu Scale of Muscle Spasticity |
| PROM | Passive range of motion |
| RCT | Randomised controlled trial |
| QUEST | Quality of Upper Extremity Skills Test |
| UMNS | Upper motor neurone syndrome |
| Z&Z | Zancolli & Zancolli Hand Classification |
9.1 Clostridium botulinum
Botulinum toxins are protein neurotoxins that are naturally produced by the bacterium, Clostridium botulinum (C.botulinum), which is commonly found on plants and in soil, water and the intestinal tracts of animals [1]. If consumed, C. botulinum leads to botulism food poisoning which is potentially fatal and causes paralysis that starts in the face and then moves through the body. Botulinum neurotoxins (BoNTs) are produced by different strains of the bacteria that are categorised by serotype, into types A to G, according to the different proteins to which they attach (see Box 9.1). The serotypes differ from one another in terms of the neuromuscular block that they produce and the duration of effect of that block. Serotype A is the most potent with the longest duration of effect. Only serotypes A and B are routinely used in healthcare. Commercially-produced BoNTs each have their own formulation and require different dosages in order to achieve the required outcome, that is, temporary reduction of the level of contraction and, therefore, weakening of the injected muscles [2, 5, 6].
9.1.1 Botulinum neurotoxin: aims and approved uses
Intramuscular injection of Botulinum neurotoxin-A (BoNT-A) has become a common treatment for muscles affected by spasticity, the neural component of hypertonicity (see Section 2.4.2.9) [7, 8], and has been described as the ‘first choice’ intervention for post-stroke upper limb spasticity [9]. Reducing focal spasticity in targeted muscles is intended to provide a ‘therapeutic window of opportunity’ during which other rehabilitation interventions may be used to enhance motor ability and active or passive function, or to address secondary complications and impairment progression [10, 11]. In children with cerebral palsy, an additional aim is to replace or delay the need for surgery, especially for those with more severe upper limb impairment described as Level IV or V on the Manual Ability Classification System (MACS) [12]. The documented reasons for BoNT-A use in relation to upper limb spasticity are presented in Table 9.1. This range of uses illustrates that there is a commonality of purpose between BoNT-A and other interventions, such as casting, that aim to reduce the positive features of UMNS in order to prevent contractures and/or promote function or ease of care.
Table 9.1 Botulinum neurotoxin use for upper limb spasticity.
| Children [8, 10, 11] | Adults [3, 9, 15, 16] |
|
|
BoNT injections provide a means of managing focal spasticity, that is, spasticity which is particularly evident in the muscles affecting a joint or group of joints, such as the internal rotators at the shoulder or the long flexors affecting the finger joints. If a person is severely affected by spasticity throughout the body, and a more generalised reduction in spasticity is required, then another type of pharmacological approach that has a systemic effect (e.g. medication taken orally or via an intrathecal pump mechanism) is recommended as more appropriate than BoNT [13, 14]. Particular benefits of the use of BoNT over systemic muscle relaxants include its targeted action rather than a generalised effect which can exacerbate muscle weakness, and the reduced likelihood of drug interactions [9].
The most commonly available commercially-produced formulations of BoNT-A for intramuscular injection are Botox®, Dysport® and Xeomin®. The only approved BoNT-B is Myobloc®, also marketed as Neurobloc® (see Box 9.2). These formulations are approved for different client groups and characteristics in different continents and countries. For example, in Australia, BoNT-A (Botox® and Dysport®) is licensed for use in adults with moderate to severe upper limb spasticity due to stroke, and for the lower limb in children with cerebral palsy (2 to 17 years of age). However, only Botox® is approved for upper limb use in children if the spasticity is of a moderate to severe level [17]. In contrast, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom has approved Dysport® and Botox® for use with focal spasticity in children with cerebral palsy (two years or older) for either upper or lower limb spasticity [18], while Botox® is approved for use in treating upper limb spasticity in adults with stroke.
Various techniques are used to guide intramuscular neurotoxin injection, including use of palpation, EMG, electrical stimulation and ultrasound guidance [19]. Injection is usually conducted by a medical professional, but in some countries, for example the United Kingdom, occupational and/or physiotherapists may be certified as injectors under specific non-medical prescribing agreements [20].
The use of BoNT-A injection for the management of spasticity in children with cerebral palsy is described as being “well established, safe and effective” [[21], p. 2258]. Similarly, the use of BoNT-A, in particular Botox®, for upper limb spasticity post-stroke is reported to be a safe therapeutic intervention [14, 22]. Nevertheless, relevant literature has also noted that licensing does not reflect clinical need for either adults or children with brain injury, and therefore ‘off-label’ use (that is, use outside of currently licensed uses) is accepted as common practice [11, 16]. One report of off-label use in paediatric outpatient settings found that such prescribing occurs in 62% of visits for children with cerebral palsy [23]. Under such conditions, a high level of practitioner vigilance is recommended to ensure correct dosages and dilutions, as well as the development of new systems of licensing and safety surveillance to address increasing applications of BoNT [11, 16, 24].
9.2 Mechanism of effect
BoNT acts on peripheral nerve endings to produce ‘chemodenervation’ which leads to muscle paresis or paralysis. That is, the neurotoxin chemically interrupts communication between peripheral motor nerves and skeletal muscles at the neuromuscular junction so that the muscle does not receive the usual signals to contract—it is chemically denervated [25]. BoNT affects the alpha motor neuron and related skeletal (extrafusal) muscle fibres, as well as the gamma motor neuron and associated muscle spindle (intrafusal) fibres [26]. As BoNT targets nerves its effect is focused on the neural component of hypertonicity, that is, the hyperactive reflexes that lead to muscle overactivity, including spasticity, spastic clonus, spastic dystonia and cocontraction (see Section 2.4). BoNT does not influence the non-neural (mechanical) aspects of hypertonicity that lead to secondary adaptive changes and contracture [2, 13].
The usual process by which signals move from motor neurons to muscles at the neuromuscular junction involves a neurotransmitter (acetylcholine), contained within a vesicle or sac. The vesicle moves towards the nerve terminal (ending), where it binds to the membrane and releases the neurotransmitter into the synaptic cleft, thus forwarding a signal from the nerve to the muscle. Binding to the nerve terminal and releasing the neurotransmitter involves different proteins (see Box 9.1). BoNTs prevent the vesicles from binding to the presynaptic membrane, by cleaving (breaking) the relevant proteins. For example, BoNT-A cleaves the SNAP-25 protein, and inhibits the release of neurotransmitter at the neuromuscular junction. Therefore, when a muscle is injected with BoNT, synaptic transmission is interrupted and the postsynaptic muscle fibre does not receive signals from the nerve as usual. Functionally, this means that BoNT decreases the muscle overactivity and excessive contractions that occur in people with spasticity by blocking hyperactive nerve impulses [5, 6, 13, 27]. The muscle is weakened because fewer motor units (nerve and muscle fibre elements, see Section 2.1.2.1) are available to drive muscle contraction.
9.2.1 Duration of effect
Clinical effects of BoNT are usually noticeable within two to four days after injection. The duration of effect is temporary and reversible, and may last between 12 and 16 weeks. Maximal effect is reached at about two weeks and remains at the same level for around 2.5 months, after which a gradual decline in effect occurs. Clinical duration of response also depends, however, on the dosage used and the muscles injected. The effect of BoNT is reversed because new axonal ‘sprouts’ develop at the nerve terminal to replace the original synapses. As the nerve terminals recover, sprouts retreat and usual synapses are regenerated [6, 13, 27]. The recommended dosing interval is three months because more frequent use has been described as carrying the risk of developing antibodies which can lead to treatment resistance or reduced effectiveness over time [24, 28].
9.2.2 Treatment resistance and adverse events
Treatment resistance may develop due to the presence of proteins in therapeutic BoNT that can stimulate antibodies which block the biological activity of the neurotoxin, although this is reported to be rare [29]. Risk factors for antibody-induced treatment failure include the amount of antigen (or antibody-causing proteins) introduced in a single injection dose, the interval between injections, total cumulative dose, the antigen–antibody reaction of each person’s immune system, low total body weight and, possibly, being female [2, 4, 27, 30]. The frequency of immunoresistance to BoNTs in people receiving long-term treatment has been reported to range from 3 to 23%, depending on the patient sample, the treatment regimen and the neurotoxin preparation [29]. During the 1990s, up to 30% of children receiving injection were found to develop antibodies, however, reformulated BoNT-A means that this problem is no longer experienced [11]. It is not clear whether people who become resistant to one type of BoNT remain clinically responsive to other types and further research is necessary to understand this interaction [13]. Recently, a BoNT-A formulation has been developed (Xeomin®) that does not contain complexing proteins (groups of proteins to which the neurotoxin is attached for stability and diffusion). It has been found to have equivalent outcomes to Botox® in the management of hypersalivation, hyperhidrosis, dystonia and post-stroke upper limb spasticity [31]. Since this formulation does not contain the proteins that stimulate the development of immunoresistance, it is possible that its use may lead to a reduced incidence of antibody-induced therapy failure after long-term treatment compared with other BoNT-A formulations. However, further comparative research is required [32, 33].
Adverse events are described as local, procedural or systemic [11, 14, 34]. The purpose of BoNT injection is to promote focal (targeted) weakening of muscles affected by spasticity, however, ‘spread’ of neurotoxin may lead to weakening of nearby or distant muscles, and large doses may lead to excessive weakening of the targeted and/or local muscles. Local weakening beyond targeted muscles, as well as distant effects, can occur when dosing and dilution guidelines are not respected, especially for smaller muscles [11]. Procedural effects are those that are related to the injection and associated processes such as sedation or general anaesthesia. Mild procedural effects that have been reported include soreness at the injection site, bruising, skin rash and oedema [2, 11].
Systemic effects that have been reported in both children and adults due to spread of BoNT-A include signs of botulism (such as generalised muscle weakness, difficulties with talking, breathing, swallowing [dysphagia] and drooping eyelids), nausea, vomiting, headache, fatigue and bladder/bowel incontinence [24, 31, 35]. Severe adverse reactions, although infrequent, have included aspiration, aspiration-pneumonia and death [31]. Current information regarding BoNT-A safety is reviewed in 9.2.2.1 and 9.2.2.2 and summarised in Box 9.3.
9.2.2.1 Adverse events in children
Heightened concern regarding the potential for adverse events after the occurrence of several deaths [36], has led to a number of audits of BoNT-A injection practice and outcomes in relation to children with cerebral palsy. In a review of episodes of systemic adverse events across a 15 year period for children aged between 9 months and 23 years, Naidu et al. [34] established that the incidence of serious adverse effects was low. Serious events included 19 incidents of incontinence (1% of injection episodes) which resolved spontaneously within one to six weeks, and 25 unplanned hospital admissions for respiratory symptoms (1.3% of injection episodes). The incidence of adverse effects was found to be associated with children in higher Gross Motor Function Classification Scale levels (that is, GMFCS levels IV and V) who had a history of aspiration and respiratory disease. The authors speculated that alternatives to mask-anaesthesia may be important for such children when receiving BoNT-A injection.
A prospective, pre-post cohort audit of BoNT-A (Botox®) injecting practice investigated the occurrence of adverse effects over a 16 month period in children aged between 1 and 19 years, across all levels of the GMFCS [37]. Adverse effects occurred in 23.2% of children. All were transient, manifesting by 14 days and not lasting more than 20 days, with no deaths occurring. Procedurally-related events (bruising, pain, vomiting) occurred in 4.7% of cases. Episodes of sphincter problems (urinary and bowel incontinence, 2%) occurred following injection into upper leg muscles, indicating a localised, rather than systemic, effect. The audit indicated that the study population was skewed towards greater disability, with 20% of children classified as GMFCS Level IV and 22% as GMFCS Level V. All cases of post-injection respiratory tract infections occurred in these children, who were also found to have experienced a higher rate of such infections in the month prior to injection compared with the month post-injection. The authors concluded that, although the incidence of adverse effects was higher than expected, they were not severe enough to warrant ceasing the provision of BoNT-A injection to children across all levels of GMFCS.
A second practice audit retrospectively reviewed adverse effects of BoNT-A injection (Botox® and Dysport®) across a 13 year period, in children aged between 1.5 and 18 years, of whom 34.5% were categorised within GMFCS levels IV and V [38]. Upper limbs were injected in 31.9% of cases. Five serious cases of adverse effects were found; all were in GMFCS level V and led to a longer period of hospitalisation but not to death. Due to the lack of accompanying botulism symptoms, all were attributed to the medication used for sedation. Other adverse events occurred within one month of injection in 8.7% of participants and included excessive weakness, either generalised or in the injected limb, lethargy, seizure, disturbance of swallowing or speech production, local pain, vomiting, pallor and flu-like symptoms. Logistic regression indicated that the incidence of adverse effects was associated with two factors: GMFCS level (IV and V) and the presence of epilepsy. BoNT-A dose was not associated with adverse effects. The authors concluded that the use of BoNT-A injection was safe and the findings did not warrant changes in practice. Nevertheless, recognition of dosing differences between manufacturers’ formulations is recommended as essential for preventing the occurrence of adverse effects, particularly for children [11, 16, 24].
9.2.2.2 Adverse events in adults
In two recent reviews, few serious adverse effects were reported in adults receiving BoNT-A for treatment of post-stroke upper limb spasticity [15, 39]. These reviews collectively included 27 RCTs, of which they had 11 in common. Overall, reported adverse effects ranged from 6% (Botox®) [40] to 38% (Xeomin®) [41] to 83.1% (Botox®) [42], however, the majority of these were mild and included, for example, pain or bruising at the injection site, nausea, dry mouth and fatigue. Severe treatment-related adverse events included dysphagia [43], significant upper limb weakening in 10 participants related to high BoNT-A dosage [44] and changes in respiratory function [42]. Severe, non-treatment-related adverse effects included epilepsy, appendicitis, hypertension and depression. One study participant in a placebo group died due to an intracranial haematoma which was deemed unrelated to the BoNT-A intervention [33]. The presence of neutralising antibodies, which would render a person resistant to BoNT, was not reported in any study [15, 39]. An earlier systematic review on the safety of BoNT-A across nine studies found that 42.86% of treatment-group participants reported an adverse event compared to 48.18% of control-participants. The difference was not statistically significant and the authors concluded that BoNT-A is a safe treatment for adults with post-stroke spasticity [22].
9.2.3 Additional uses in neurology
In addition to reducing spasticity by weakening muscle contractions, BoNT has been found to have other applications in neurology, including analgesic (antinociceptive) and antisecretory uses [14]. It has been reported to reduce post-operative pain, spasms, analgesic consumption and length of hospital stay in children with cerebral palsy who received injections five to ten days prior to lower limb adductor surgery [45]. Study participants who received BoNT-A (Botox®) injection rather than placebo demonstrated a 74% reduction in mean pain scores, a 50% reduction in mean analgesic consumption, and a 33% reduction in mean length of hospital stay. The researchers concluded that spasms contributed significantly to post-operative pain in children with cerebral palsy and proposed that the same effects may be evident following upper limb surgery [46]. BoNT-A has been found to be effective for reducing the pain and abnormal cocontraction related to dystonia, probably through influencing the intrafusal fibres of the muscle spindle [47, 48]. It is also used to treat clonus, tics, tremors, hyperhidrosis (excessive sweating) and hypersalivation (drooling) in children and adults with neurological conditions through its action on the autonomic nervous system [27].
9.3 Botulinum neurotoxin research: A narrative review
The effectiveness of BoNT in the treatment of upper limb spasticity for children and adults with brain injury is described here through a narrative literature review (see Section 7.2). The search strategy for the review included identifying relevant systematic reviews in the Cochrane Review Database; other pertinent systematic reviews and RCTs, and applicable consensus statements were located using key search terms in Medline, Cinahl and EMBASE. Studies were primarily chosen on the basis of their content in relation to common clinical questions (for example, whether to cast after BoNT-A injection to promote uptake or whether reduced spasticity leads to improvement in upper limb function). Study recency and methodological quality were also considered, with a preference for including more recent studies of moderate to high methodological quality (Cochrane reviews, other systematic reviews and meta-analyses, RCTs).
9.3.1 Enhancing BoNT-A uptake
Enhancing the effect of BoNT-A is proposed to improve intervention outcomes after injection, and increased uptake (or potentiation) of neurotoxin occurs in the nerve terminals that are most active [49]. It has been reported that BoNT-A is rapidly internalised in active, injected muscles, with chemodenervation occurring as quickly as 15 to 20 minutes after injection [50], although effects are suggested to be noticeable within two to three days [27, 51]. Techniques used to increase muscle activity have, therefore, been paired with BoNT-A injection, with positive results. Post-stroke, for example, greater improvement has been noted following periodic electrical stimulation of an injected muscle and its antagonist for three 30-minute sessions per day during the three days after injection [52, 53]. Although electrical stimulation may increase uptake, to date there has been little agreement on the most appropriate protocols, in terms of duration, rate and timing of stimulation. To investigate the most suitable stimulation protocol, a pilot study was undertaken that compared the efficacy of a single 60 minute electrical stimulation session immediately after injection with repeated sessions starting the day after injection (30 minutes of muscle stimulation per day for three consecutive days) [54]. Results suggested improved BoNT-A uptake when electrical muscle stimulation occurred immediately after injection rather than later.
While serial casting of the upper limb is clinically indicated after BoNT-A when organic contracture is present in the limb (see Section 9.4.1.3), there is insufficient evidence to determine whether the provision of low-load, prolonged stretch promotes the uptake of neurotoxin after injection [12]. Serial casting after BoNT-A injection has been studied for the reduction of mild to moderate contracture in the lower limb; results indicated that casting enhanced the benefits of BoNT-A injection [55, 56]. Newman et al. [57] investigated whether serial casting immediately after, or delayed until 4 weeks after, BoNT-A led to improved outcomes. Those who received delayed serial casting demonstrated greater reductions in both spasticity and contracture at three and six months post-injection. The authors theorised that, since muscle activity is reported to enhance BoNT-A uptake, immobilisation in a cast directly after injection reduced the effectiveness of the treatment. Further research is required to determine the effect of serial and/or inhibitory casting post-BoNT-A injection in the upper limb.
9.3.2 BoNT-A for children with spasticity
The effectiveness of BoNT-A as an adjunct to occupational therapy intervention for children with cerebral palsy, aged 0 to 19 years, was investigated in a recent (2010) Cochrane Review [35]. The Review was based on 10 randomised controlled trials (RCTs), with nine determined to be of high methodological quality. Participants were children with spastic hemiplegia, diplegia, quadriplegia and triplegia, aged between 22 months and 16 years. No participants had contracture and some had undergone previous upper limb surgery.
Overall, the Cochrane Review concluded that:
there is high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic cerebral palsy. BoNT-A should not be used in isolation but should be accompanied by [pre-] planned occupational therapy [35, p. 2].
Improvements in the upper limb after receiving a combination of BoNT-A injection and occupational therapy were evident at the body function/structure (reduced spasticity and stiffness) and activity level domains of the International Classification of Functioning, Disability and Health (ICF, see Section 4.1). In relation to body function/structure outcomes, the combination of BoNT-A and occupational therapy was found to significantly reduce spasticity in the elbow flexors, forearm pronators and wrist flexors. This reduction persisted at six months for the elbow flexors and forearm pronators, which is longer than the expected effect of BoNT-A injection. There was strong evidence to indicate that children who received combined BoNT-A and occupational therapy (compared with no treatment), demonstrated greater improvements at the activity level three months post-injection, assessed on the QUEST (Quality of Upper Extremity Skills Test) at three months. Lack of maintenance of these improvements at six months post-injection suggests that, when activity-level improvement is the goal of intervention, children may require re-injection before six months. Positive effects were also noted in activity-level outcomes measured using individualised goal attainment scores on the COPM and the GAS (see Section 4.4.2) that persisted for six months.
The most commonly reported adverse event across the studies included in the Review was excessive grip weakness. This is an interesting finding, since grip strength above 60 mmHg is the one characteristic that has previously been noted to be a predictor of a positive outcome, in terms of improved upper limb function from BoNT-A injection, for children with spastic hemiplegia [58]. This finding suggests that care should be taken with regard to BoNT-A dosage when addressing finger flexor spasticity, bearing in mind that muscles affected by spasticity are typically weak (see Section 2.4.1.1).
In general, BoNT-A is approved for use in children with cerebral palsy who are over two years of age (see Section 9.1.1), although it is reported to be safe for use in children younger than two years old [59]. The use of BoNT-A with younger children in the early stages of development is proposed to be important for promoting the achievement of motor milestones, for preventing the influence of short, stiff muscles on joint and bone development, and for slowing the progression to (lower limb) surgery in children with more severe impairment [21, 60]. A recent systematic review investigated the evidence supporting the efficacy of off-label use of BoNT-A for improving attainment of motor milestones and general motor development in children younger than two years [61]. Three RCTs met the inclusion criteria [62–64], however, only one focused on children under two years [64], and only one (a different study) focused on the upper limb [63]. Inability to specifically determine the proportion of children in the upper limb study that were aged under two years meant that it was not possible to accurately correlate the effect of BoNT-A with age. Nevertheless, results indicated a reduction in spasticity levels in the upper limb, particularly the forearm pronators and wrist flexors, for children aged under four years, two months. Although improvement in general upper limb motor development was not supported by changes on the QUEST, closer analysis of sub-sections of the assessment showed that a progressive improvement in grasp was evident [61, 63]. The measurement of upper limb development in children under two years using the QUEST was considered a limitation of the study because the tool is validated for use with children between 18 months and 8 years [61]. Reported adverse effects of BoNT-A were weakness in the index finger and finger flexors [63].
Related posts:
