Nerve stimulation boosts botulinum toxin action in spasticity.

Spasticity leads to functional and structural changes in nerves and muscles, which alter skeletal muscle function. To evaluate whether short-term electrical nerve stimulation (NS) improves the effect of botulinum toxin in spastic skeletal muscle, we studied changes in the amplitude of the compound muscle action potential (CMAP) recorded from the extensor digitorum brevis (EDB) muscle in response to peroneal nerve stimulation at the ankle after injection of botulinum toxin type A (BTXA) alone or combined with short-term NS. In paraparetic patients, both EDB muscles were injected with BTXA; and NS was applied to one EDB muscle alone. All patients received a 30-minute session of electrical NS once a day for 5 consecutive days after BTXA injection. We used two different stimulation frequencies (low-frequency, 4 Hz; and high-frequency, 25 Hz). EDB-CMAP amplitudes were evaluated before BTXA injection (day 0) and changes in CMAP amplitude, expressed as a percentage (CMAP%), were measured at various time points over a 30-day period after BTXA injection. We compared changes in the CMAP% amplitude on the stimulated and contralateral nonstimulated sides. We also studied the electromyographic activity recorded from EDB muscles over a 30-day period. CMAP% amplitudes measured at all time points after BTXA injections were significantly reduced in both EDB muscles. On days 4, 10, and 15, the CMAP% amplitude reduction was significantly greater for the low-frequency stimulated EDB than for the contralateral nonstimulated EDB. No significant differences in CMAP% were observed for the high-frequency stimulated and nonstimulated EDB. After BTXA injection, spontaneous activity appeared in both EDB muscles; but it appeared earlier and involved larger areas in the stimulated than in the nonstimulated EDB. In conclusion, short-term NS accelerates the effectiveness of intramuscular BTXA injections on the neuromuscular blockade in patients with spastic paraparesis and could induce a rapid and persistent improvement in spasticity. Its action probably arises mainly from low-frequency NS.     

Comparison of botulinum toxin injection and neurotomy in patients with distal lower limb spasticity

Background and purpose:  We compared the efficacy of botulinum toxin injection (BTI) and tibial nerve neurotomy (TNN) in an open-label study of 34 post-stroke hemiplegic patients with distal lower limb deformation.
Methods:  The dose of BT was 300 U (Botox). TNN was performed with a 6–12 month delay on the motor branches of the tibial nerve. Muscles to be treated were selected according to the distal deformity (equinus, varus and clawing toes). Patients were assessed following each treatment for spasticity, motor control, range of movements, balance, gait and the Rivermead Motor Assessment.
Results:  TNN (M3, M6 and Y1) resulted in a more significant effect than BTI (D15, M2 and M5) on most of the measures: ankle plantar flexor spasticity, range of movement in dorsiflexion and eversion, foot position in upright situation, Functional Ambulation Categories (barefoot), RMA, gait velocity (comfortable condition), subjective benefit and use of walking aids. Patients treated for tibialis posterior or flexor digitorum longus spasticity often complained of subjective sensory disorders at the plantar sole over a period of 4–6 weeks.
Conclusion:  In conclusion, TNN is more effective than BTI on most of the functional parameters. The interest of BTI lies in the preliminary testing of the efficacy of a technique for reducing spasticity on lower limb function.     

Intrafusal effects of botulinum toxin in post-stroke upper limb spasticity

A previous study in subjects with focal dystonia suggested that the greater and longer-lasting effect induced by botulinum toxin type A (BoNT-A) on the tonic vibration reflex (TVR) than on the maximal M-wave (M-max) might be the physiological marker of the toxin's action at the level of intrafusal muscle fibres. With this approach, we investigated the possible effect of BoNT-A on fusimotor synapses in eight patients with post-stroke spasticity (four with no residual motor capacity before treatment and four with partially spared muscle strength and residual motor capacity). TVR and M-max were recorded from the wrist and finger flexor muscles before treatment and at 1, 4 and 7 months afterwards. The TVR reduction was greater than the M-max reduction and remained fairly constant over time only in the subjects with a residual motor capacity before the treatment. This pilot study suggests that some degree of strength and active movement is necessary for the action of BoNT-A on intrafusal fibres.     

Botulinum toxin in the management of childhood muscle spasticity: comparison of clinical practice of 17 treatment centres

At least two randomized controlled trials (RCTs) have shown botulinum toxin type A (BtxA) to be efficacious and safe when used in the management of muscle spasticity in children. However, the need to use standard treatment protocols in these studies obscures some aspects of routine clinical practice that may have important effect on clinical outcomes. The purpose of this study was to seek additional information on the use of BtxA that is not usually captured by RCTs. This was performed by reviewing the clinical practice of practitioners in 17 treatment centres in Europe. The details of treatment with BtxA, including the dose, site and frequency of injections and the use of anaesthesia or sedation, were abstracted from the patient's records. Information was also obtained on the response to treatment and the occurrence and severity of adverse events. The data on 758 children who received a total of 1,594 treatments in 17 different clinics in Europe were analysed. Ninety-four per cent of patients had cerebral palsy. There was a general agreement on the indications for treatment but the average dose of BtxA used varied between centres. One treatment centre used general anaesthesia (GA) prior to injections in most patients. The reported efficacy and adverse events profile was similar for all centres. The evidence from routine clinical practice for the efficacy and safety of BtxA in the management of muscle spasticity in children, as described in this study, is in agreement with that of most of the open-label and RCTs published to date. The present study also demonstrates the disagreement between clinicians on the optimal dose of BtxA for individual muscles and confirms that the injections can be carried out without GA in almost all cases.     

Clinical value of botulinum toxin in neurological indications

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3–4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.     

A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke

OBJECTIVE: To study the efficacy and safety of botulinum toxin type A (BtxA) in the treatment of upper limb muscle spasticity, caused by stroke. METHODS: This was a randomized, controlled trial. Patients received either placebo injections or a total of 1000 IU of BtxA (Dysport) into five muscles of the affected arm. Muscle tone was assessed using the Modified Ashworth Scale (MAS). Other outcome measures were the change in the joint range of motion (ROM), the Barthel index, pain score, goal attainment and the subjective evaluation of benefit by patients and investigators. The patients were assessed blind to randomization at baseline and 4, 8, 12 and 16 weeks after treatment. RESULTS: Fifty nine patients were recruited and received treatment. One patient was lost to follow-up before the last scheduled visit of the study. The group of patients who received BtxA had a significant reduction in the summed MAS score at week 4 compared with the placebo group (P=0.004). The magnitude of benefit over the 16 week follow-up period was significantly reduced for the BtxA group in the wrist (P=0.004) and the finger joints (P=0.001) when compared with the placebo. There was no statistically significant difference between the groups in the joint ROM, muscle pain, goal-attainment or the Barthel index scores at week 4 of the study. At week 16, the BtxA group showed significantly greater improvement in the passive ROM at the elbow (P=0.036). The patients' global assessment of benefit at the end of the study showed that 16 (50%) patients in the placebo group had 'much improved' or had 'some improvement' compared with 24 (92.3%) patients in the BtxA group (P=0.007). The investigators' rating for the same item was 16 (50%) and 23 (88.4%) patients, respectively (P=0.002). Sixteen and twenty patients in the BtxA and placebo groups, respectively, had an adverse event. The most frequently reported adverse events were accidental injury, respiratory and urinary tract infections and muscle pain. CONCLUSION: The findings of the present study suggest that treatment with BtxA in a dose of 1000 units reduces muscle tone in patients with post-stroke upper limb spasticity. This effect is sustained for at least 16 weeks. BtxA is safe in the dose used in this study. IMPORTANT NOTE: The authors wish to emphasize that the botulinum toxin preparation used in this study was Dysport (Ipsen Ltd) which has a different therapeutic equivalence from other commercially available product, Botox (Allergan Inc.).     

Management of spasticity and dystonia in children with acquired brain injury with rehabilitation and botulinum toxin A

Objective: To investigate the effect of a combination of botulinum toxin A (BTX-A) and rehabilitation on spasticity, pain and motor functioning in children with acquired brain injury (ABI).

Methods: All children and adolescents with ABI, aged 2–20 years, consecutively treated in the department over a 22-month period, were prospectively followed-up and clinically assessed pre- and post-treatment. They had spasticity and/or dystonia leading to impairment in activities of daily living, orthopaedic deformations and/or pain. Injections were performed using electro-stimulation. Doses of BTX-A (Botox®) were administered using recent recommendations.

Results: Twenty-five children (mean age 6.3 years) participated in the study (51 injection sessions). All patients received BTX-A injections, followed with physical and/or occupational therapy. Significant improvement was achieved for spasticity reduction (p < 0.0001), command on antagonist muscles (p = 0.03 for the tibialis anterior) and goniometry assessment (p < 0.05). Pain relief was achieved in patients in a minimally responsive state. Functional goals were achieved, such as improving transfers or gait, grasping and releasing abilities, with significant transfer in activities of daily living (p < 0.0001).

Conclusion: A combination of BTX-A injection with rehabilitation is an interesting option for treatment of muscle tone disorders in children with ABI.     

Use of spasmography to assess the effects of botulinum toxin type A in patients with lower-limb spasticity

Lower-limb spasticity is one of the main features of advanced multiple sclerosis (MS), and botulinum toxin type A (BTX-A) is known to be effective in the treatment of lower-limb spasticity. Two hundred randomly selected MS outpatients were analysed for spasticity using clinical scores. Of the 200 randomly selected MS outpatients, 23% had marked or severe spasticity. Hence, the aims of this study were to investigate the effect of BTX-A injections in MS patients with lower-limb spasticity refractory to conventional treatment, and to evaluate the new method of spasmography for analysing muscle tone. Fifteen MS patients (mean MS duration, 11.2 years) with spasticity of the lower limbs were injected with BTX-A (BOTOX®) into the affected muscles. A control group of 15 healthy volunteers was analysed by spasmography. In the 15 MS patients, the Modified Ashworth Scale scores for the left and right legs were significantly lower than baseline values ( P < 0.05) at 3 and 6 weeks post-treatment. At 6 weeks post-treatment, the spasmography measures ( n = 12) of mean muscle tone and mean maximum muscle tone of both legs in passive mode were significantly reduced ( P < 0.05) compared with baseline. The time to walk 10 m (n = 9) was significantly reduced compared with baseline ( P < 0.05) at 3 and 6 weeks post-treatment. No adverse events were reported for any patients treated with BTX-A. These data indicate that BTX-A is effective and safe in the treatment of lower-limb spasticity, and that spasmography is a useful method for assessing therapeutic intervention in Spasticity.     

Spastic cocontraction in hemiparesis: Effects of botulinum toxin

Introduction: In this study of spastic hemiparesis we evaluated cocontraction during sustained agonist/antagonist efforts, before and after botulinum toxin (BoNT) injection in 1 agonist. Methods: Nineteen hemiparetic subjects performed maximal isometric elbow flexion/extension efforts with the elbow at 100° (extensors stretched). Using flexor and extensor surface electromyography we calculated agonist recruitment/cocontraction indices from 500‐ms peak voluntary agonist recruitment, before and 1 month after onabotulinumtoxinA injection (160 U) into biceps brachii. Results: Before injection, agonist recruitment and cocontraction indices were higher in extensors than flexors [0.74 ± 0.15 vs. 0.59 ± 0.10 (P < 0.01) and 0.43 ± 0.25 vs. 0.25 ± 0.13 (P < 0.05), respectively]. Biceps injection decreased extensor cocontraction index (?35%, P < 0.05) while increasing flexor agonist recruitment and cocontraction indices. Conclusions: In spastic hemiparesis, stretch may facilitate agonist recruitment and spastic cocontraction. In the non‐injected antagonist, cocontraction may be reduced by enhanced reciprocal inhibition from a more relaxed, and therefore stretched, agonist, or through decreased recurrent inhibition from the injected muscle. Muscle Nerve, 2012     

The pathophysiology of spasticity

Spasticity is only one of several components of the upper motor neurone (UMN) syndrome, known collectively as the `positive' phenomena, that are characterized by muscle overactivity. Other components include tendon hyper-reflexia, clonus, the clasp-knife phenomenon, flexor and extensor spasms, a Babinski sign, and spastic dystonia. Spasticity is a form of hypertonia due to hyperexcitable tonic stretch reflexes. It is distinguished from rigidity by its dependence upon the speed of the muscle stretch and by the presence of other positive UMN signs. Hyperactive spinal reflexes mediate most of these positive phenomena, while others are due to disordered control of voluntary movement or abnormal efferent drive. An UMN lesion disturbs the balance of supraspinal inhibitory and excitatory inputs, producing a state of net disinhibition of the spinal reflexes. These include proprioceptive (stretch) and nociceptive (flexor withdrawal and extensor) reflexes. The clinical syndrome resulting from an UMN lesion depends more upon its location and extent, and the time since it occurred, than on the pathology of the lesion. However, the change in spinal reflex excitability cannot simply be due to an imbalance in supraspinal control. The delayed onset after the lesion and the frequent reduction in reflex excitability over time, suggests plasticity in the central nervous system. Knowledge of the electrophysiology and neurochemistry of spinal reflexes, together with the action of antispasticity drugs, helps us to understand the pathophysiology of spasticity.     

The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A -- initial experiences.

The increasing use of botulinum toxin type-A, especially for focal dystonia and spasticity has highlighted the issue of secondary non-responsiveness. Within the last few years botulinum toxin type-B (Myobloc/Neurobloc) has become commercially available as an alternative to type-A. This paper discusses our initial experience of botulinum toxin type-B in a total of 63 individuals who attended our botulinum clinic. Thirty-six patients had cervical dystonia and a secondary non-response to type-A toxin. Thirteen of these patients (36%) had a reasonable clinical response to Neurobloc and continue to have injections. The other 23 patients either had no response, or a poor response, or had unacceptable side effects and ceased treatment. A small number of people with blepharospasm, hemifacial spasm and foot dystonia also had a disappointing response to injection. Twenty patients with spasticity were also type-A resistant. Seven of these show some continuing response to type-B, without unacceptable side effects. These findings demonstrate that botulinum toxin type-B has a place in the management of patients who have become non-responsive to type-A, but overall the responses to type-B toxin were disappointing.     

Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents' view of functional outcome

Botulinum toxin type A (BTX-A) has been used successfully to manage spasticity in children with cerebral palsy. Little has been done to evaluate treatment outcome and satisfaction from the patients' and parents' points of view. The aim of this study was to investigate the parents' perceptions of the benefits of BTX-A on movement disorders in children with cerebral palsy. Twenty-six children with adductor spasticity were enrolled into an open-label, prospective study. Patients received intramuscular injections of BTX-A, and assessments of joint mobility (passive range of motion), degree of spasticity (Modified Ashworth Scale) and functional benefit (Gross Motor Function Measure) were made before and 12–18 weeks after treatment. Parents' assessment of treatment outcomes were evaluated using a standardised questionnaire. BTX-A was shown to be effective in reducing muscular hyperactivity and functional limitations. Parents' satisfaction with the treatment outcome was high. For non-ambulatory patients, the reported benefits included facilitation of daily care, ease of positioning and reduction of pain. For patients who were disabled to a lesser extent, improvements in gait and posture included sitting with improved comfort, standing for longer periods of time and/or walking longer distances. The parents' responses supported the impressions of the therapists, demonstrating that BTX-A produced beneficial effects on daily activities, according to both objective measures and parents' observation.     

Management of spasticity with botulinum toxin type A: implementing the treatment algorithm

Intramuscular injections of botulinum toxin type A (BTX-A) may successfully treat spasticity resulting from focal muscle overactivity. However, BTX-A should not be considered as a monotherapy. Physical interventions such as strengthening programmes, range-of-motion exercises or serial casting should be implemented following BTX-A injections. The likelihood of treatment success relies heavily on tailoring the treatment protocol to an individual's needs. This paper presents five case studies which describe patient management problems that have been addressed by applying an algorithm for the management of spasticity with botulinum toxin type A. The case studies are representative of patients with hand, arm, hip, leg and/or foot spasticity who have received BTX-A injections. The potential pitfalls of BTX-A treatment are presented and possible reasons for treatment failure are discussed. The case studies highlight the importance of reassessing functional objectives for each individual after treatment. The objectives of BTX-A treatment vary considerably between patients. If the treatment goals are not achieved, modification of the injection procedure and/or dose may be required. A continued failure of treatment suggests either poor patient selection or inappropriate treatment goals. Successful treatment does not obviate the need for routine re-evaluation of the goals at treatment follow-up.     

A multilevel approach to botulinum toxin type A treatment of the (ilio)psoas in spasticity in cerebral palsy

In spasticity, flexion deformity of the hip is frequently associated with contracture or hyper-reflexia of the psoas muscle. Botulinum toxin type A (BTX-A) has been used for some considerable time in the management of paediatric gait disorders. We have been using a multilevel approach to manage spasticity in cerebral palsy for several years, the combination of gait analysis and clinical evaluation being important for the selection of target muscles for BTX-A injections. Twenty cerebral palsy children (12 female) with spasticity were treated with BTX-A injections (BOTOX® mean dose, 2 U/kg body weight) into the psoas muscle. Patients were monitored using range of motion measurements of maximal hip extension, clinical estimates of hypertonia in the hip flexors, gait analysis (three-dimensional kinematics and kinetics) and surface electromyography of major lower limb muscles. Full gait analysis was carried out on 12 of the patients. Significant clinical improvements were observed following 15 of the 21 psoas treatments. Furthermore, the kinematics results of gait analysis showed improvement in one or more parameters in nine of the 12 patients. In conclusion, we have demonstrated the value of a multilevel approach to BTX-A treatment in the management of spasticity in children with cerebral palsy.     

Management of spasticity in adults: practical application of botulinum toxin

Spasticity, characterized by increased muscle tone, exaggerated stretch reflexes, and abnormal limb posture, is a common sequel of central nervous system pathology. Historically, medicinal treatments have been of limited efficacy. This review discusses the clinical features of spasticity, the functional and pathological consequences, and treatment. It reviews the most common patterns of spasticity encountered in the upper and lower limbs and focuses on focal treatment of spastic muscles with the three commercially available botulinum toxins Botox®, Dysport®, and Myobloc®/NeuroBloc®. It addresses practical details such as muscle selection and identification, drug dilution, and doses.     

The effects of isotonic and isokinetic muscle stretch on the excitability of the spinal alpha motor neurones in patients with muscle spasticity

To examine the effect of isotonic (with and without weight bearing) and isokinetic muscle stretch on the excitability of the spinal alpha motor neurones (alphaMN) in patients with spasticity and to establish whether this effect is maintained for at least 24 h after the intervention. A single 20-min session of isotonic muscle stretch (with or without weight bearing) or isokinetic stretch was delivered to the ankle plantar flexors in patients with post-stroke lower limb spasticity and healthy control subjects. The effect of these types of muscle stretch on the excitability of alphaMN was assessed by measuring the latency of the Hoffmann reflex (H-reflex) and the ratio of the amplitude of the maximum H-reflex (H(max)) to that of the maximum action motor potential of the soleus muscle (M(max)). Sixty-six hemiplegic stroke patients and 21 healthy control subjects were recruited and completed the trial. The H(max):M(max) ratio was significantly higher in patients with spasticity than in healthy control subjects. However, there were no statistically significant differences in the H-reflex latency or the change in H(max):M(max) ratio between the baseline values and those recorded immediately after the therapy intervention or 24 h later for each type of muscle stretch. Similarly, there were no significant differences in these variables between the interventions. In the present study neither isotonic muscle stretch (with or without weight bearing) or isokinetic stretch had a statistically significant effect on the excitability of the alphaMN in patients with muscle spasticity. This suggests that the previously reported reduction in spasticity after muscle stretch is because of mechanisms other than the direct effect on alphaMN. However, the lack of a demonstrable benefit of treatment may be due the fact that we examined the effects of a single, rather than repeated treatment cycles.     

Effects of botulinum toxin A therapy and multidisciplinary rehabilitation on lower limb spasticity classified by spastic muscle echo intensity in post-stroke patients

Objectives: The purpose of the present study was to investigate retrospectively the relationship between botulinum toxin type A plus multidisciplinary rehabilitation and muscle echo intensity in post-stroke patients with spasticity. The primary aim was to investigate whether the effects of the intervention on the improvement of spasticity depend on muscle echo intensity, and the secondary aim was to investigate whether the motor function of the lower limbs depends on muscle echo intensity.

Methods: A 12-day inpatient protocol was designed for 102 post-stroke patients with spasticity due to lower limb paralysis. Muscle echo intensity of the triceps surae muscle was measured by ultrasonography, and the patients were categorized into four groups based on Heckmatt scale grades (Grades I–IV).

Results: All four groups classified by the Heckmatt scale showed significant pre-to-post-intervention differences in the knee and ankle modified Ashworth scale scores (p < 0.05). Grades I–III patient groups showed a significant improvement in lower limb motor function following intervention. Grade IV patients did not show a significant improvement in lower limb motor function.

Conclusions: We observed significant improvements in the modified Ashworth scale scores after botulinum toxin type A and multidisciplinary rehabilitation therapy on post-stroke patients with spasticity. Although patients with lower muscle echo intensity demonstrated improvements in motor function, the improvement was poor in those with higher muscle echo intensity.