Hemiparetic gait and changes in functional

Toxicon xxx (2015) 1e5

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Hemiparetic gait and changes in functional performance due to OnabotulinumtoxinA injection to lower limb muscles Alberto Esquenazi*, Daniel Moon, Amanda Wikoff, Patricio Sale MossRehab Gait & Motion Analysis Laboratory and Department of PM&R MossRehab, Elkins Park, PA, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 14 July 2015 Received in revised form 28 July 2015 Accepted 4 August 2015 Available online xxx

Objective: To review gait alterations and evaluate the effects of OnabotulinumtoxinA on spatiotemporal walking parameters of patients with hemiparetic gait. Design: Retrospective pre- and post-intervention analysis. Setting: Gait analysis laboratory in a tertiary level rehabilitation hospital. Participants: 42 patients with hemiparesis. 19 males and 23 females, age 18e78 years were included. Intervention: Spatiotemporal parameters collected before and within 4e10 weeks after OnabotA injection to the ankle muscles. Data was recorded at self-selected velocity on a 12 m instrumented walkway. The most common muscles injected were medial and lateral gastrocnemius, soleus and tibialis posterior. Average total OnabotulinumtoxinA dose was 320 ± 107 units. Main outcome: Spatiotemporal parameters of walking assessed before (T0) and within 4e10 weeks post injection (T1). Paired t-test was used to compare pre- and post-intervention data. A sequential Holm eBonferroni procedure was used to adjust for multiple comparisons and minimize the risk of type I error. Statistical significance was set at p < 0.05. Results: Statistically significant increases were seen for walking velocity (20%) (T0 ¼ 0.40 ± 0.26 m/s and T1 ¼ 0.48 ± 0.29 m/s; p ¼ 0.006), and increased cadence (T0 ¼ 63.48 ± 23.93 steps/min, and T1 ¼ 70.88 ± 23.65 steps/min; p ¼ 0.006) following OnabotulinumtoxinA injections. Conclusion: This study demonstrates that injection of OnabotulinumtoxinA 320 units to ankle muscles selected with the aid of dynamic electromyography can significantly increase gait velocity and enhance functional ambulation in adults with hemiparesis due to upper motor neuron syndrome. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Gait analysis Hemiparesis OnabotulinumtoxinA Spasticity

1. Introduction Many persons with upper motor neuron (UMN) syndrome are able to ambulate, but often with inefficient movement strategies, limb instability, and pain (Mayer et al., 2001). The objective of this paper is to review and discuss the alterations of hemiparetic gait and evaluate the effects of OnabotulinumtoxinA (OnabotA) on temporal spatial walking parameters of patients with hemiparetic gait dysfunction. Supraspinal structures are involved in the control of ambulation, including the brainstem reticular formation, basal ganglia, motor, premotor, and supplementary motor area of the motor cortex, as well as the cerebellum (Dietz, 1997; Duysens and Van De Crommert, 1998). Peripheral nerves located in tendons, muscles,

* Corresponding author. E-mail address: [email protected] (A. Esquenazi).

ligaments, and joints relay information regarding limb position and kinesthesia. Proprioceptive information transmitted to the cortex assists with controlling volitional movements planned by the motor cortex. Proprioceptive information transferred to the cerebellum assists with involuntary modulation of motor control (Schneider et al., 1977). Load information sensed by mechanical receptors in the sole of the feet and from proprioceptive inputs in the extensor muscles of the foot (Dietz and Duysens, 2000), as well as afferents that signal hip-joint position (Pang and Yang, 2000), play a role in muscle activation patterns and stanceeswing phase transitions during ambulation. Ambulation is the end result of a well-choreographed pattern of phasic muscle activation and deactivation that is modulated by complex interactions within and between the central and peripheral nervous system and the gravitational forces. Given the multiple and complex neural pathways involved in producing ambulation, it is not surprising that disorders of the neurologic system result in gait disturbances. The various hemiparetic gait patterns are the

http://dx.doi.org/10.1016/j.toxicon.2015.08.004 0041-0101/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Esquenazi, A., et al., Hemiparetic gait and changes in functional performance due to OnabotulinumtoxinA injection to lower limb muscles, Toxicon (2015), http://dx.doi.org/10.1016/j.toxicon.2015.08.004

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A. Esquenazi et al. / Toxicon xxx (2015) 1e5

result of an upper motor neuron lesion (frequently associated with cerebrovascular disease, tumor, and traumatic brain injuries) which can impair movement through muscle paresis, problems with muscle overactivity (e.g., spasticity, co-contraction, clonus), and increased muscle stiffness. UMN syndrome is an umbrella term encompassing any dysfunction disrupting the sensorimotor pathways of the central nervous system. Normally, a relationship exists between muscle activation and development of muscle tension; however, in UMN syndrome, this relationship is altered and contributes to the movement disorder (O'Dwyer et al., 1996). Dynamic electromyography (EMG) studies of lower limb muscles during ambulation can reveal the presence of abnormal muscle activation patterns that reflect problems with timing and coordination of muscle activity, such as abbreviated, premature, delayed, or prolonged activation patterns, loss of phasic activation, and cocontraction of antagonist muscle groups (Den Otter et al., 2007; Lamontagne et al., 2002). General observation of hemiparetic gait reveals an overall marked loss of symmetry with tendency for decreased stance time on the affected limb. The affected lower limb oftentimes appears stiffer and may exhibit one or more of the following patterns: hip extension/adduction and external or internal rotation; knee extension; and foot plantarflexion and/or inversion of the ankle. Initiation of the swing phase is delayed, prolonged, or effortful, and usually associated with stiff-knee posture and ankle equinus (Fig. 1A). Reciprocal arm motion may be diminished on the affected side and is usually positioned in adduction and/or flexion, which may further impair gait efficiency and stability. As a result, self-selected speed of ambulation and fastest comfortable walking speed is reduced in patients with hemiparesis (Hsu et al., 2003; Beaman et al., 2010). Studies have shown that muscle weakness of the hip flexors, knee extensors, and ankle plantarflexors are a key factor contributing to decreased walking

Fig. 1. (A) Lateral and posterior views of an individual with hemiparetic gait pattern during double support. Note the plantarflexed/inverted attitude of the right ankle and internally rotated, adducted and flexed posture of the right arm. (B) Sample of foot fall pattern collected using the Gait Mat II pre-OnabotA injection. (C) Sample of foot fall pattern from the same subject collected post-OnabotA injection.

speed and the limited capacity to increase speed after stroke (Bohannon, 1989; Nadeau et al., 1999; Jonkers et al., 2009). Furthermore, the temporal spatial parameters of ambulation in patients with post-stroke hemiparesis have been shown to be more asymmetric. Stance time is decreased on the affected side and increased on the unaffected side. Double support time is increased in comparison to normal healthy subjects. Overall, this pattern allows preservation of stability due to increased double support with increased time weight-bearing on the non-affected limb (Brandstater et al., 1983; Wall and Turbull, 1986; Olney and Richards, 1996). Hemiparetic gait has been evaluated via kinematic gait studies (Olney and Richards, 1996). During the stance phase on the affected side, ankle dorsiflexion posture was decreased during stance and swing phases. Increased knee hyperextension in the stance phase was seen in most patients, although in some cases excessive knee flexion was present. During the swing phase on the affected side, knee flexion was decreased with delayed initiation of hip flexion, and compensation with hip hiking or circumduction. Kinetic studies have shown abnormally increased lateral plantar support, abnormal force transfer from hindfoot to forefoot with limited rollover, and reduced or absent push-off in terminal stance (Mayer, 2002). Dynamic electromyographic studies of lower limb muscles during ambulation in this population reveal trends for prolonged total duration of tibialis anterior activity during the swing phase, overactivity in the gastrocnemius and soleus muscles during early stance, and co-activation of the quadriceps and hamstrings during stance phase (Den Otter et al., 2007). Equinovarus foot posture is the most frequent abnormal limb posture seen in those with hemiparetic gait. The foot and ankle are inverted and pointed down into plantar flexion. Curling of the toes is frequently an accompanying feature (Cioni et al., 2006). The muscles that can potentially contribute to the equinovarus deformity include the gastrocnemius, soleus, tibialis posterior, extrinsic toe flexors, extensor hallucis longus, and lack of activation of the peroneus longus (Cioni et al., 2006; Esquenazi et al., 2010). Underactivity or overactivity of the tibialis anterior can also contribute to equinus and/or varus deformity. Compared with stroke, gait dysfunction in traumatic brain injury (TBI) has not been as well studied. The potential zone of neurologic insult in TBI is not well circumscribed and may result in a wider range of potential neurologic deficits. Ochi et al. (Ochi et al., 1999) reported on the temporospatial characteristics of locomotion in a population of patients with ambulation dysfunction after TBI. Decrease in walking velocity with a reduction in the duration of stance phase and impairment of weight bearing on the affected limb with an increase in the duration of stance time of the less affected limb were among the reported findings (Esquenazi et al., 2010). These differences in TBI patients were attributed in part to the age difference (Ochi et al., 1999). Previous large studies have attempted to demonstrate functional walking improvement accompanying the reduction in ankle Ashworth. Time and time again those studies have achieved reduction in Ashworth and improvement in other parameters including increased base of support but none have demonstrated significant improvements in walking velocity (Pittock et al., 2003; Mancini et al., 2005; Kaji et al., 2010). The purpose of this study was to determine if OnabotA injection to muscles selected on the basis of dynamic EMG and when injected under the guidance of electrical stimulation improves the ambulation of patients with hemiparetic gait with regards to temporal spatial parameters. We hypothesize that treatment with OnabotA will result in improved walking velocity in patients with hemiparetic gait due to increased cadence and step length as well



as decreased time in double support. In addition, we hypothesize affected limb stance time will increase and unaffected limb stance time will decrease following treatment with OnabotA due to improved ankle posture and stability of the affected limb. 2. Materials and methods In this retrospective study, 42 patient charts were selected from 287 consecutive records reviewed. These patients were all seen for gait analysis in the Gait and Motion Analysis Laboratory at MossRehab in Elkins Park, PA between January 2006 and November 2013. The selected charts fit the following inclusion and exclusion criteria: 2.1. Inclusion criteria Hemiparesis. Gait dysfunction with unilateral ankle involvement due to UMN syndrome. Between 18 and 80 years of age. Evaluation of temporospatial gait parameters with the Gait Mat II and dynamic EMG of ankle muscles before OnabotA treatment. Evaluation of temporospatial gait parameters with the Gait Mat II at least 4, but no more than 10 weeks after OnabotA treatment. Electrical stimulation guidance for OnabotA injection to the calf muscles (gastrocnemius medialis, gastrocnemius lateralis, soleus and/or tibialis posterior) based on clinical need. 2.2. Exclusion criteria Concomitant treatment with phenol. Changes of the pharmacological or rehabilitative treatment occurring between the time of treatment with OnabotA and gait re-evaluation. Interim hospitalizations. Inability to follow commands. Pre-existing pain that interferes with walking. Pregnancy. Approval was obtained from the institutional human protection committee and all information was kept anonymous. All 42 of these charts were included in the data set for this study. The patient's ages ranged from 18 to 78 years old with an average age of 48 (standard deviation ± 17.5). 19 were male and 23 were female (45.2% male, 54.8% female). 24 patients had hemiparesis on their left side, and 18 were affected on their right side (57.1% left, 42.9% right). The average body weight was 75.8 kg (standard deviation ± 15.6), and ranged from 43 to 113 kg. The patient diagnoses were as follows: 28 stroke (66.6%), 10 traumatic brain injury (23.8%), 2 cerebral palsy (4.8%), 1 acute demyelinating disease (2.4%), and 1 myelopathy (2.4%). The evaluation of subjects entailed a physical examination that included passive range of motion, manual muscle strength, sensation testing, and modified Ashworth scale assessment. Gait Mat II® (E.Q. Inc., Chalfont, PA) was used to collect foot fall pattern data to determine temporal spatial gait parameters. Data was collected at 100 Hz (Taylor, 1980). During data collection, the patient was instructed to walk at self-selected speed on an instrumented 12 m walkway without any additional instrumentation. The Gait Mat II is used on a daily basis in our laboratory for clinical assessment of patients with a variety of neurologic and orthopedic diagnoses that affect walking. It's reliability has been previously published (Barker et al., 2006). Patients were allowed to use an assistive device when walking

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as long as the identical device was used at both baseline and follow up testing. A minimum of 30 strides were recorded for each patient to ensure data consistency and validity. After obtaining this information, patients were weighed, and their standing leg lengths were measured (distance from the greater trochanter to the floor). This data is used in calculating the percentage of the patient's leg length compared to step length, and comparing to normal subjects of similar gender and age. In this study, the focus of the data analysis was on pre- and post-treatment comparison of walking velocity, cadence, stance, double support time, and step length. After baseline data was obtained with the Gait Mat II, dynamic EMG recordings were obtained during walking to determine the muscles that were overactive in the patient's affected lower limb, and to identify muscles for injection. Two types of electrodes are used to record dynamic EMG. For the majority of patients, surface electrodes (Motion Lab Systems, Inc. Baton Rouge, LA) were applied to the skin. When deeper muscles, such as the tibialis posterior and long toe flexors were studied, an intramuscular fine-wire electrode was required (Esquenazi and Mayer, 2004). The same physician that evaluated the patient then selected the muscles to be injected with OnabotA based on the information obtained from the dynamic EMG recordings. After treatment consent was obtained from the patient, he/she was placed in the supine position. Prior to the injection, the OnabotA was diluted 100 units per 2 mL of sterile preservative free saline solution. Their skin was then cleaned with alcohol, and a vapocoolant spray was applied to reduce needle insertion discomfort. Using a teflon-coated open lumen needle (27 gauge), an electrical stimulator sent repetitive square wave pulses 0.25 msec in duration at a frequency of one hertz to ensure targeted muscle localization (Life Tech, Inc. Houston, TX, USA). OnabotA was injected intramuscularly through the same needle. The dosage and muscles selected varied from patient to patient in accordance with their clinical needs. No other interventions were implemented beyond instructing the patient to stretch and practice walking. Within four to ten weeks, patients were asked to return for reassessment. This window of time was selected because it is when the peak effect of OnabotA occurs. They were again instructed to walk across the Gait Mat II with emphasis on maintaining the same upper extremity support and bracing conditions. The foot fall data used from these walking trials was used to determine temporal spatial gait parameters pre- and post-OnabotA injections. Both sets of this data were examined and compared. These parameters included velocity, cadence, step length, stance time, double support time, and base of support. Statistical analysis of this data was performed by comparing pre-injection data to post-injection data using a paired t-test for each variable. Step length, stance time and double support time on the affected limb as well as unaffected limb were compared separately pre- and postinjection. Because nine outcome measures were being tested simultaneously, a sequential HolmeBonferroni procedure was utilized to calculate the adjusted p-values for each comparison to reduce the risk of a type I familywise error. Statistical significance was set at p < 0.05. 3. Results The muscles that were most frequently injected in this study were the gastrocnemius (lateralis and medialis) (79%) and the soleus (67%), which is consistent with previously published large clinical observation studies (Esquenazi et al., 2012). Other muscles frequently selected for injection were the tibialis posterior (49%), and long toe flexors (43%). The average dose used for each patient was 320 units with a range of 100e500 units per patient. Table 1 shows the complete list of muscles injected, and


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Table 1 Muscles injected with OnabotA and frequency. Muscles Ankle musculature Lateral gastrocnemius Medial gastrocnemius Soleus Tibialis posterior Tibialis anterior Toe musculature Flexor digitorum longus Flexor hallucis longus Extensor hallucis longus Flexor digitorum brevis

Frequency N ¼ 42

Percentage of total patients

33 33 28 20 2

78.6% 78.6% 66.7% 48.6% 4.8%

18 8 5 1

42.9% 19.0% 11.9% 2.4%

N ¼ number of patients in study.

the percent of the selected patients that received treatment to these muscles. The average temporal spatial parameters obtained at assessment pre- and post-OnabotA injection are shown in Table 2. A 20% increase in mean walking velocity post treatment is the most significant finding of this study (p ¼ 0.006). Before intervention, the average walking velocity for the studied population was 0.40 m/s. After OnabotA injection, velocity significantly increased to 0.48 m/ s. The second significant post-injection difference was the increase in cadence (p ¼ 0.006). At baseline, average cadence was 63.5 steps/ min. This increased to 70.9 steps/min after treatment. Another change seen was the increase in step length on both the affected and unaffected limbs. Prior to OnabotA injection, the average step length for the affected limb was 46.7% of their leg length, and 35.2% on their unaffected limb. At follow up, the average step length had increased to 49.0% of their leg length on the affected limb (p ¼ 0.1), and increased to 39.7% on the unaffected limb (p ¼ 0.06). However, these differences were not found to be statistically significant. The likely mechanisms for increased velocity were gains in cadence and step length. A slight improvement was seen in stance time duration for the unaffected leg as well. At baseline the average percent of the stride in stance phase was 74.9%. This decreased to 73.1% after the injection, suggesting the patient was more confident in taking the next step on the affected leg, however this again was not significant (p ¼ 0.2). The only reported complication was mild short-lasted injection site discomfort. No adverse effects such as excessive weakness, dysphagia, flu-like symptoms or dry mouth were reported at follow-up. Fig. 1B and C above depict an example of a patient's foot fall pattern improvement after OnabotA injection. This visual

representation is created by the Gait Mat II technology. Note the longer step lengths for this patient post injection (1C). This trend was observed for most patients in this study but was not found to be statistically significant for the overall population. 4. Discussion Over the last 20 years, the therapeutic use of OnabotA for spasticity has opened new, exciting opportunities in the field of clinical rehabilitation. Its use in combination with physical rehabilitation, casting, orthosis, robotics training and other pharmacological treatments has shown the potential to improve the clinical condition of adults with UMN syndrome caused by a wide range of etiologies. Published clinical evidence shows that treatment of spasticity with OnabotA is effective in reducing tone and pain (Pittock et al., 2003; Mancini et al., 2005; Kaji et al., 2010; Pierson et al., 1996). The patients receiving these injections often express a sense of subjective improvement as well. However, there is very limited objective evidence of functional gains particularly in walking velocity and other temporal spatial parameters after injection to address equinovarus deformity in adults with UMN syndrome. In fact, only a few studies of gait analysis have been devoted to this. Hesse (Hesse et al., 1996) showed in a small group of patients some positive change of ankle kinematics, reduction of the premature electromyographic activation of plantar flexor muscles and an increase of gait velocity and stride length in persons with hemiparesis due to cerebrovascular accident. Fock (Fock et al., 2004) reported that after OnabotA injection to 7 patients with equinovarus foot due to traumatic brain injury, a significant improvement of ankle dorsiflexion during the stance phase, velocity, cadence and stride length occurred. To our knowledge, this is the largest (N ¼ 42) quantitative study to date to demonstrate significant improvement in gait velocity and functional outcome of walking as a result of selective OnabotA injection to the ankle plantarflexors in a group of adult patients with residual spasticity/muscle overactivity due to UMN syndrome primarily caused by stroke or TBI. Past studies have demonstrated small sample size improvements in specific aspects of gait in small samples, but this current study shows overall improvement of walking in a larger sample, which is notable. Walking velocity is considered to be an effective indicator of the degree of gait impairment, overall functional status, and clinical progress in affected patients. In fact, walking velocity and kinetics are strictly correlated and the former changes with variations of moments of forces and joint powers (Esquenazi and Talaty, 2001). This could be of particular relevance to the injection of OnabotA, since chemodenervation of ankle plantarflexor muscles, which are the main contributors to the development of the internal ankle joint powers,

Table 2 Average spatiotemporal measures before and after OnabotA injection. Pre-OnabotA injection ± SD Velocity (m/sec) Cadence (steps/min) Step length (% of leg length) Affected leg Unaffected leg Stance time (% of stride) Affected leg Unaffected leg Double support (% of stride) Affected leg Unaffected leg Base of support (m)

Post-OnabotA injection ± SD

p-Value

0.40 ± 0.26 63.5 ± 23.9

0.48 ± 0.29 70.9 ± 23.7

0.006* 0.006*

46.7 ± 12.6 35.2 ± 15.7

49.0 ± 13.8 39.7 ± 17.3

0.1 0.06

63.21 ± 10.16 74.92 ± 9.13

63.5 ± 10.18 73.05 ± 7.72

0.736 0.2

17.38 ± 9.73 20.83 ± 9.37 0.11 ± 0.04

16.36 ± 8.41 20.02 ± 8.56 0.10 ± 0.04

0.4 0.8 0.5

P-values adjusted using HolmeBonferroni sequential approach. Values with asterisk indicate significance at the p-value < 0.05.



could potentially negatively influence walking velocity and step length by excessively weakening these muscles. However increased stiffness at the ankle due to overactivity of the plantarflexor muscles is likely the primary culprit leading to decreased gait performance due to impaired limb stability and limb clearance. OnabotA has been shown to significantly decrease ankle stiffness and allow for improved posture of the foot during the stance phase resulting in improved stability (Hesse et al., 1996; Fock et al., 2004). In this study there was a trend toward reduced stance time on the unaffected limb, likely due to an improved perception of stability in the affected limb by the patients but this did not translate into significantly increased stance time of the affected limb or differences in time of double support. From this more stable position, it is also easier to advance the unaffected limb into swing phase. Findings from our study support this as we show a trend towards increased step length on the unaffected side that approached statistical significance. In addition, reducing overactivity of plantarflexors may result in improved dorsiflexion at the ankle in swing phase of the affected limb and ultimately result in increased step length. Understandably, these differences are much smaller as most of the contributions to swing phase come from more proximal leg muscles which were not addressed in this study. Some limitations that exist for this study include its retrospective nature, the use of various dosing schemes, muscle selection based on dynamic EMG, and the lack of control of physical activity/ modalities during the post injection period. No scale to rate quality of life was used in this study. We encourage all our patients to stretch and walk to get the greatest benefit from their injection, but we cannot verify that each patient actually follows through with these instructions or the intensity to which they did. Ideally a larger randomized double blind placebo controlled study should be considered to further study the measures of gait performance after injection of OnabotA or placebo with muscles selected via dynamic EMG. Another proposal for future studies is to observe walking performance based on continuous activity monitoring, or to incorporate patient satisfaction, such as surveying them about their walking abilities before and after OnabotA injections. Ethics statement This study was approved for retrospective data abstraction and review by the Institutional Review Board. Transparency document Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.toxicon.2015.08.004. References Barker, Susan, et al., 2006. Accuracy, reliability, and validity of a spatiotemporal gait analysis system. Med. Eng. Phys. 28 (5), 460e467. Beaman, C.B., Peterson, C.L., Neptune, R.R., et al., 2010. Differences in self-selected and fastest-comfortable walking in post-stroke hemiparetic persons. Gait Posture 31, 311e316. Bohannon, R.W., 1989. Selected determinants of ambulatory capacity in patients with hemiplegia. Clin. Rehabil. 3, 47e53. Brandstater, M.E., Debruin, H., Gowland, C., et al., 1983. Hemiplegic gait: analysis of temporal variables. Arch. Phys. Med. Rehabil. 64, 583e587.

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