Chetan P. Phadke

Assessing the neurophysiological effects of botulinum toxin treatment for adults with focal limb spasticity: a systematic review

To examine effectiveness of botulinum toxin therapy (BoNT), accurate quantification of the neurological component of underlying spasticity is needed. Purpose: Systematically identify and summarize literature on neurophysiological methods to test the effectiveness of BoNT, discuss methodological aspects, and recommend best techniques for clinical and research settings. Methods: Electronic databases were searched using specific keywords. Reviews and reference lists were hand-checked to find relevant studies. Studies in adults with focal limb spasticity were included. Results: Over 300 articles were scanned for relevance, and a list of 90 relevant articles was made. After excluding reviews and studies in healthy controls or non-spasticity related BoNT, 22 articles were reviewed. Neurophysiological techniques included electromyography (EMG; n = 11), electrical nerve stimulation (n = 13), transcranial magnetic stimulation (TMS; n = 1), functional magnetic resonance imaging (fMRI; n = 1), reflex threshold (n = 4), Achilles tendon reflex (n = 1), reflex latency (n = 1). Discussion: Maximum M-wave amplitude (M-max) and stretch reflex threshold techniques were successfully used to measure the neurophysiological effects of BoNT and have high test-retest reliability. EMG techniques require effective magnitude normalization techniques and establishing test-retest reliability. Conclusion: Serial electrical nerve stimulation can be incorporated into clinical practice to assist in follow-up. We recommend using M-max and stretch reflex threshold techniques to assess the neurophysiological effects. Implications for Rehabilitation Botulinum toxin decreases muscle tone and is widely used to manage focal limb spasticity. Peripheral nerve electrical stimulation to assess the maximal muscle response and stretch reflex threshold are useful ways of assessing the onset and duration of the neurophysiological effect of botulinum toxin.

Relationship Between Botulinum Toxin, Spasticity, and Pain: a Survey of Patient Perception

OBJECTIVE To assess the prevalence of pain in adults with spasticity and to assess the association between the subjective experience of pain and spasticity. DESIGN Cross-sectional study. SETTING outpatient spasticity management clinic of a rehabilitation centre. PATIENTS Patients with upper motor neuron lesions and spasticity (n=131) were recruited. METHODS We assessed pain intensity and location, relationship between spasticity and pain perception, and perception of pain relief from botulinum toxin type-A (BoNTA) injections. MAIN OUTCOME MEASURES Pain perception rated on a 10-point numerical rating scale and pain quality. RESULTS 65% of the patients with spasticity reported presence of pain and 60% described it as an aching pain. More patients reported pain with movement (34%) compared to rest (21%). There was a statistically poor correlation between the severity of pain and spasticity (r=0.16; p>0.05). Most patients (80%) believed that their pain was related to spasticity and 62% reported that BoNTA injections decreased their pain. CONCLUSIONS The high incidence of pain noted within our sample suggests that physicians may have to consider pain management as part of spasticity treatment. Participants reported that their pain was related to their spasticity, and that it decreased after BoNTA treatment. Further study is needed to explore the relationships between objective measures of spasticity and pain.

Intrafusal effects of botulinum toxin injections for spasticity: revisiting a previous paper.

Botulinum toxin, frequently used to manage focal limb spasticity, has been reported to affect both extrafusal and intrafusal fibers of the injected muscle. Since most studies have used spinal reflexes, it is difficult to isolate the intrafusal effects from extrafusal and central effects. In a paper by On et al. [7], both stretch and H-reflexes were used to examine the intrafusal effects of botulinum toxin injections. Revisiting the data from On et al. [7] presented a unique opportunity to describe a novel method of measuring the effect of botulinum toxin-A on muscle spindle activity in patients with spasticity. H-reflex, maximum M-wave, and Achilles tendon reflex were serially assessed in ten patients with stroke pre-, 2, 4, and 12 weeks post-botulinum. In order to assess the intrafusal effects, we subtracted the %change in H-reflex amplitude from baseline (representing extrafusal and central effects) from the %change in Achilles tendon reflex amplitude from baseline (representing intrafusal, extrafusal and central effects). Using this formula, our results suggest that botulinum induces significant chemodenervation of the intrafusal muscle fibers (33% decreases). Intrafusal effects were greatest at 2 weeks, but tapered off by 12 weeks post-botulinum (p<0.017). We found a significant positive correlation between the intrafusal effects of botulinum toxin and changes in modified Ashworth scale. Our method of assessing the effects of botulinum toxin shows significant effect on intrafusal fibers, which correlates with clinical manifestation of spasticity. Future studies need to investigate ways to maximize intrafusal effects and minimize extrafusal effects of botulinum therapy.

Effect of topical anesthetics on needle insertion pain during botulinum toxin type A injections for limb spasticity.

OBJECTIVE To compare pain perception using 3 anesthetics (eutectic mixture of local anesthetics [EMLA], vapocoolant spray, and ice) compared with a control (no anesthetic) during botulinum toxin type A (BTX-A) injections for lower limb spasticity. DESIGN A placebo-controlled, single-blinded study where each study patient served as their own control. SETTING Spasticity clinic. PARTICIPANTS Subjects (N=30) with ankle spasticity who visited the clinic for BTX-A injections in the gastrocnemius muscle were consecutively sampled. INTERVENTION The gastrocnemius muscle was divided into 4 quadrants and 1 of the 3 different anesthetic agents was applied to each quadrant with 1 quadrant using no anesthetic, control. MAIN OUTCOME MEASURES Numerical Rating Scale (NRS) and the Wong-Baker FACES scale. RESULTS Pain perception using the NRS and FACES scale was significantly lower using ice and EMLA compared with control and spray conditions (P<.05). Pain perception using EMLA and ice was similar. These results indicate that patients experience minimal to moderate pain during BTX-A injections. CONCLUSIONS Pain relief offered by EMLA and ice was comparable, suggesting that ice is a more convenient option because of brief application time (compared with EMLA). Spray may have made the patients more sensitive to pain and alternative approaches for using vapocoolant should be considered.

Effects of Treadmill Incline and Speed on Ankle Muscle Activity in Subjects After a Stroke

OBJECTIVES To examine the effects of walking on a treadmill at varying gradients and speeds on ankle muscle activation in stroke survivors, and to compare the effect of increasing speed on plantarflexor muscle activity in participants grouped according to spasticity severity. DESIGN Within-subject and cross-sectional design. Participants walked on a standard treadmill at 3 different inclines (0°, 3°, 6°) and speeds (self-selected, self-selected+20%, self selected+40%). SETTING University laboratory. PARTICIPANTS A convenience sample of stroke survivors (N=19; 13 men, 6 women) available in university clinics. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Electromyographic activity of medial gastrocnemius (MG) and tibialis anterior (TA) muscles at push-off phase of the gait. RESULTS Paretic MG muscle activity increased (but TA did not change) at faster speeds irrespective of the incline (P<.05). In contrast, MG muscle activity increased at a higher incline in the nonparetic side (P<.05), but not in the paretic side (P>.05). In the high-spasticity subgroup (Tardieu Scale ≥ 2), paretic MG activity increased as walking speed increased (P=.004). CONCLUSIONS Stroke survivors appear to use distinct muscle activation strategies on the paretic and nonparetic sides in response to different walking speeds and inclines. Our data indicates that individuals with stroke can be safely trained on a treadmill to walk 20% to 40% above the self-selected pace to improve MG output without adversely affecting TA output. The speed-dependent characteristic of spasticity may help generate greater MG activity during push-off.

Adverse Clinical Effects of Botulinum Toxin Intramuscular Injections for Spasticity.

OBJECTIVE The adverse events (AEs) with botulinum toxin type-A (BoNTA), used for indications other than spasticity, are widely reported in the literature. However, the site, dose, and frequency of injections are different for spasticity when compared to the treatment for other conditions and hence the AEs may be different as well. The objective of this study was to summarize the AEs reported in Canada and systematically review the AEs with intramuscular botulinum toxin injections to treat focal spasticity. METHODS Data were gathered from Health Canada (2009-2013) and major electronic databases. RESULTS In a 4 year period, 285 AEs were reported. OnabotulinumtoxinA (n=272 events): 68% females, 53% serious, 18% hospitalization, and 8% fatalities. The type of AEs reported were - muscle weakness (19%), oropharyngeal (14%), respiratory (14%), eye related (8%), bowel/bladder related (8%), and infection (5%). IncobotulinumtoxinA (n=13): 38% females, 62% serious, and 54% hospitalization. The type of AEs reported were - muscle weakness (15%), oropharyngeal (15%), respiratory (38%), eye related (23%), bowel/bladder related (15%), and infection (15%). Commonly reported AEs in the literature were muscle weakness, pain, oropharyngeal, bowel/bladder, blood circulation, neurological, gait, and respiratory problems. CONCLUSION While BoNTA is useful in managing spasticity, future studies need to investigate the factors that can minimize AEs. A better understanding of the underlying mechanisms of the AEs can also improve guidelines for BoNTA administration and enhance outcomes.

Patterns of botulinum toxin treatment for spasticity and bleeding complications in patients with thrombotic risk

&NA; The purpose of this study was to assess the prevalence of compartment syndrome or major bleeding episodes and compare compartment syndrome, patient and intervention characteristics in 110 patients with stroke (treated with Warfarin, new oral anticoagulants, antiplatelet, or no anticoagulants) treated for spasticity in deep leg compartment muscles with botulinum toxin injections [onabotulinumtoxinA (n = 77); incobotulinumtoxinA (n = 33)]. We reviewed 674 injection cycles (range 1–25 cycles per patient) and found no cases of compartment syndrome in any patient groups. HighlightsWe found no major bleeding in the deep compartment muscles with spasticity in anticoagulated patients on Warfarin.We found no major bleeding in the deep compartment muscles with spasticity in patients on new anticoagulants.Botulinum injection characteristics were not significantly different in patients with different types of anticoagulants.We found no major bleeding in the deep compartment muscles with spasticity in non‐anticoagulated patients.We found no major bleeding in the deep compartment muscles with spasticity in patients receiving antiplatelet medications.

Phase dependent modulation of soleus H-reflex in healthy, non-injured individuals while walking with an ankle foot orthosis.

OBJECTIVE To examine the dynamic modulation of the soleus H-reflex while walking with a posterior leaf spring ankle foot orthosis (PAFO). METHODS Soleus H-reflexes were evoked on randomly chosen lower limb of fourteen healthy individuals (age range of 22-36 years, 7 women) while walking on a treadmill with and without a PAFO. In order to capture excitability across the duration of the gait cycle, H-reflexes were evoked at heel strike (HS), HS+100ms, HS+200ms, HS+300ms, HS+400ms in the stance phase and at toe-off (TO), TO+100ms, TO+200ms, TO+300ms, TO+400ms in the swing phase respectively. RESULTS H-reflex excitability was significantly higher in the form of greater slope of the rise in H-reflex amplitude across the swing phase (p=0.024) and greater mean H-reflex amplitude (p=0.014) in the swing phase of walking with a PAFO. There was no change in the slope (p=0.25) or the mean amplitude of H-reflexes (p=0.22) in the stance phase of walking with a PAFO. Mean background EMG activity between the two walking conditions was not significantly different for both the tibialis anterior (p=0.69) and soleus muscles (p=0.59). CONCLUSION PAFO increased reflex excitability in the swing phase of walking in healthy individuals. Altered sensory input originating from joint, muscle and cutaneous receptors may be the underlying mechanism for greater reflex excitability. The neurophysiological effect of PAFOs on reflex modulation during walking needs to be tested in persons with neurological injury. The relationship between the sensory input and the reflex output during walking may assist in determining if there exists a neurological disadvantage of using a compensatory device such as a PAFO.

Effects of treadmill incline and speed on peroneus longus muscle activity in persons with chronic stroke and healthy subjects

OBJECTIVE To examine the effects of walking at different inclines and speeds on Peroneus Longus (PL) muscle activation and medial gastrocnemius (MG) coactivation with PL in healthy controls and subjects with stroke. DESIGN Nineteen persons post-stroke (13M/6F) and fifteen healthy controls (10M/5F) walked on a treadmill at different inclines (0°, 3°, and 6°) and speeds (self-selected, self-selected+20%, self-selected+40%). The electromyographic activity of the PL and MG muscles in the stance phase of gait cycle was measured. RESULTS The paretic PL muscle activity did not change with incline, but increased at +40% speed only (p<0.05). The nonparetic PL increased at 6° incline and at faster speeds (p<0.05). In the healthy group, PL muscle activity increased only on the right side at 6° incline, but increased bilaterally at +40% faster speed (p<0.05). The timing of PL muscle activity did not change with incline (p>0.05), but was significantly delayed at +40% faster speed on the paretic side only (p<0.05). In healthy controls, PL muscle activation timing was unchanged with incline (p>0.05), but was significantly delayed at +40% speed only on the left side (p<0.05). The MG/PL amplitude and timing ratios were not significantly different between various walking conditions (p>0.05). CONCLUSION An increase in PL activity occurs to provide ankle stability at walking speeds up to 40% faster than the self-selected speed. Important interlimb differences which may be related to leg dominance and motor control were observed in both stroke and healthy control groups in both PL muscle timing and their clinical impact should be investigated in future studies.

Effect of Botulinum Toxin on Clonus: A Systematic Review

OBJECTIVE To conduct a systematic review of the literature that examined the effect of botulinum toxin type A on clonus. DATA SOURCES A literature search of multiple databases (PubMed, Cochrane, Google Scholar, Embase) was performed to identify articles published in English in the past 30 years (1986-2016). STUDY SELECTION Two reviewers independently applied the following inclusion criteria: (1) any adult patients older than 18 years with upper motor lesion; (2) any location and duration of clonus; and (3) subjective and objective measurements of clonus tested at least 2 weeks after botulinum toxin injection. DATA EXTRACTION Two reviewers independently extracted the data and assessed the methodological quality. A consensus method was used to solve disagreements. DATA SYNTHESIS The systematic review resulted in 164 articles, of which 14 met the inclusion criteria: 3 were randomized controlled trials, 1 was nonrandomized, and 6 were case series and 3 case studies. All studies (181 patients) showed improvement in clonus: 6 of 14 results were statistically significant. Different scales were used for clonus measurement, such as clonus score, patient diaries, clonus spasm score, and electromyogram duration. CONCLUSIONS Overall, there was preliminary evidence indicating improvement in clonus after botulinum injection. The major drawback with studies reviewed here was a large variation in the type of clonus assessment tools, which also lacked validity, reliability, and sensitivity to small changes in clonus.