Overview of botulinum toxin as a treatment for spasticity in stroke patients

Abstract

Spasticity after the occurrence of stroke induces limb deformity, functional disability and/or pain in patients, which limits their activities of daily living and deteriorates their quality of life. Botulinum toxin (BTX) has recently been reported as an efficacious therapeutic agent for the treatment of spasticity. Systematic review and meta-analysis studies have demonstrated that BTX therapy after stroke reduces spasticity and increases physical activity capacity and performance levels. Moreover, BTX can be used as an adjuvant in physiotherapy. Several studies have confirmed that the combination of BTX therapy and physiotherapy improves motor recovery. However, to date, only a few such combination studies have been conducted and their findings are considered preliminary and controversial. Therefore, future studies are required to determine the appropriate combination of treatment methods that will aid motor recovery.

Key Words: Botulinum toxin, Rehabilitation, Stroke, Spasticity, Neurorehabilitation

Core tip: In this overview, we describe that botulinum toxins (BTXs) were very useful to reduce spasticity in stroke patients. Moreover, we introduce studies on appropriate effective and safe injection methods; pilot studies that evaluated combined rehabilitation and BTX treatment; and adverse events after BTX injection, including risk factors of neutralizing antibodies.

INTRODUCTION

Spasticity is a common complication in patients who have experienced stroke. The incidence of spasticity is reported to be 17%-43% in post-stroke patients[1-3]. Spasticity induces limb deformity, functional disability and/or pain that limits activities of daily living (ADL) and deteriorates the quality of life (QOL). In order to reduce spasticity, clinicians prescribe oral medications, intrathecal baclofen therapy, nerve phenolization, casting or splinting, rehabilitation therapy or a combination of these therapeutic approaches[4-8]. A recent study has shown that botulinum toxin (BTX) is an efficacious therapeutic agent for the treatment of spasticity[9].

BTX is poisonous in nature and is produced by the anaerobic bacterium Clostridium Botulinum[10]. BTX blocks vesicular acetylcholine release at neuromuscular junctions and reduces focal muscle tonus and contracture[11]. Therefore, BTX is used for treating muscular hyperactivity and excessive or inappropriate muscle contraction. Seven types of BTX exist in nature, but two toxin types, type A (BTX-A) and type B (BTX-B), are used in the clinical setting. Most clinical trials have utilized BTX-A because it has a longer lasting effect than BTX-B[12,13]. BTX-B tends to be selected for spasticity treatment when patients have neutralizing antibodies against BTX-A or develop antibodies after repetitive BTX-A injection treatment[14,15].

Many studies have reported that BTX injection treatment reduces spasticity in stroke patients[16-25]. However, a few studies have focused on rehabilitation therapy after BTX treatment for improving motor function[26-28]. This review focuses on the following factors of BTX treatment in post-stroke patients: (1) the effectiveness of spasticity reduction, with regard to ADL and QOL; (2) the appropriate injection method; (3) combined BTX therapy and neurorehabilitation; and (4) adverse events. The purpose of this review is to provide a comprehensive overview of BTX treatment for muscular spasticity in post-stroke patients, to understand its mechanisms of action, and to suggest appropriate treatment approaches.

EFFECTIVENESS FOR SPASTICITY

Several reports clarified the effectiveness of BTX treatment for upper limb spasticity experienced after stroke[16-21]. A recent systematic review and meta-analysis reported that BTX-A reduced spasticity and thereby improved physical activity capacity and performance levels in the upper limb in patients who experienced stroke[29]. BTX-A (Botox^®) injection in the upper limb muscles are recommended at the following doses: 25-100 units for the flexor carpi radialis; 20-70 units for the flexor carpi ulnaris; 20-60 units for the flexor digitorum superficialis; 20-60 units for the flexor digitorum profundus; 10-30 units for the flexor pollicis longus; and 5-25 units for the adductor pollicis[30].

Furthermore, several studies have reported the effectiveness of BTX therapy in stroke-induced lower limb spasticity[22-25]. However, a systematic review and meta-analysis reported that BTX-A treatment for stroke-induced lower limb spasticity was associated with a slight improvement in functional ambulation[19,31]. A multicenter, double-blind trial demonstrated the effectiveness of BTX-A in cases of lower limb spasticity, but improvements in gait pattern scale and speed were not significant, compared to that observed in the placebo group[32]. A previous study suggested that high-dose BTX-A treatment may induce excessive muscle weakening that may deteriorate limb function[25]. BTX-A (Botox^®) injection doses in the lower limb is recommended at the following doses: 50-250 units for the medial and lateral head of the gastrocnemius respectively; 50-200 units for the soleus; and 50-150 units for the tibialis posterior[30]. However, to the best of our knowledge, no study has evaluated the appropriate BTX dose for treatment of upper and lower limb spasticity and therefore, future studies are required to clarify these dosages. Moreover, it is noted that clinicians should consider the maximum dose of BTX per session, which differs in each country (e.g., 360 units in Japan and 600 units in Europe)[32-35].

Treatment of spasticity in patients who experience a stroke with BTX-A may improve ADL and QOL[36,37]. A previous study reported that high-dose BTX-A significantly improved ADL scores for limb position and self-dressing[36]. Furthermore, another study in post-stroke patients reported that BTX-A therapy improved overall QOL scores and muscle tone, reduced disability, and improved the ability to function[37]. However, a recent meta-analysis study revealed that BTX-A did not significantly improve overall health-related QOL[38].

APPROPRIATE INJECTION METHOD

Several studies have reported on BTX-A injection techniques[39-41]. Francisco et al[39] compared the efficacy of high and low volumes of BTX at the same dose for wrist and finger flexor spasticity. They found that modified Ashworth Scale scores were significantly decreased in both high and low-volume injection groups. However, there was no significant difference between the groups[40]. Gracies et al[41] reported that injecting a small volume of BTX-A near the neuromuscular junction was more effective than injecting a similar volume at a greater distance from the neuromuscular junction. However, injecting a large volume at a greater distance from the junction was as effective as a small volume injected near the neuromuscular junction. Mayer et al [40] also reported that a single motor point and multisite low-dose, high-volume BTX-A injections produced a similar impact in spasticity reduction. Therefore, the appropriate injection methods according to BTX-A volume and injection points must be elucidated. Moreover, BTX-A injections are more accurate when the affected muscles are targeted via needle electromyography or under ultrasound guidance. This conventional method is not supported by evidence, but correct muscle selection has been confirmed to be a key feature in the efficacy of BTX treatment[42,43].

COMBINATION OF BTX THERAPY AND NEUROREHABILITATION

As mentioned above, BTX improves motor function by reducing muscular spasticity in post-stroke patients. Therefore, BTX therapy may be a useful adjuvant therapy in combination with neurorehabilitation. In fact, several studies have reported that the combination of BTX therapy and physiotherapy improved motor recovery[26-28]. A recent study reported that BTX injection, followed by home-based functional training, may have the potential to improve active motor function of the affected upper limb in post-stroke patients[26]. Moreover, previous studies have reported that casting and dynamic splinting following BTX-A injection improved range of motion as well as motor function[5,27,28]. Thus, BTX when combined with physiotherapy or casting may be useful for improving motor function in stroke-induced spasticity.

Recently, various neurorehabilitation strategies have been established to improve neural plasticity and motor recovery. These approaches include constraint-induced movement therapy (CIMT), transcutaneous electrical neuromuscular stimulation (TENS) and non-invasive brain stimulation (NIBS)[44-49]. A preliminary study demonstrated that the combination of BTX injection and CIMT may improve functional gains in post-stroke patients[44,45]. Moreover, a recent study reported that combined BTX-A and NIBS improves motor function in patients with stroke-induced upper limb hemiparesis[48]. However, a previous study reported that combining BTX injection with TENS did not have any additional effect on motor recovery[47]. The number of these combination studies remains small and their results are considered preliminary and controversial. Although BTX-A probably enhances the effects of neurorehabilitation strategies in post-stroke patients, future studies are required to determine the appropriate combination of treatments for optimum motor recovery.

ADVERSE EVENTS

In general, pain, rash, edema and muscle weakness have been noted at the injection site and remote muscle weakness, fatigue and allergic reaction have been reported as adverse events related to BTX therapy. To clarify the safety of BTX-A, Turkel et al[50] analyzed 9 double-blind, placebo-controlled studies in more than 500 patients who had experienced a stroke. The most frequent reported adverse events by the patients (> 5% but < 10% in either group) were respiratory infection, seizures, incoordination and injection site pain, none of which occurred at a significantly high rate in the BTX-A group. Nausea alone was reported at a significantly higher rate in the BTX-A group than in the placebo group. In contrast, injection site pain, chest pain and allergic reaction were found at a significantly higher frequency in the placebo group. Other reviews have also reported no serious adverse events after BTX-A administration in adult post-stroke patients[35]. Therefore, BTX has recently been considered a safe and efficacious treatment for spasticity in post-stroke patients.

However, care should be taken to try to avoid producing neutralizing antibodies. A higher dose per treatment, repetitive treatment and shorter intervals between treatments are risk factors for the production of neutralizing antibodies[51-53]. Of these, the interval between treatments is the most important risk factor. Therefore, BTX-A treatment intervals of more than three months and BTX-B treatment intervals of two months are recommended[54].

CONCLUSION

Many reports have shown the usefulness of the BTX treatment for spasticity in stroke patients. However, a few studies have reported the effectiveness of rehabilitation after BTX treatment in stroke patients. Future studies are needed to evaluate the efficacy of BTX after treatment with rehabilitation.