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NeuroRehabilitation 35 (2014) 25–30 DOI:10.3233/NRE-141093 IOS Press
Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients Marc Rousseaux∗ , Walter Daveluy, Odile Kozlowski and Etienne Allart Neurological Rehabilitation Unit, Hˆopital Swynghedauw, CHRU of Lille, Lille, France
Abstract. BACKGROUND: Hemiplegic patients with supraspinal spasticity can present with a flexor pattern at the hip and knee that hampers both passive and active functions. OBJECTIVE: To investigate the efficacy of OnabotulinumtoxinA injections on this flexor scheme. METHODS: This open-label observational study included eleven patients who had suffered a unilateral stroke or traumatic brain injury. All had impairment in the activities of daily living caused by severe hip and knee flexion. OnabotulinumtoxinA injections of 300–400U (total dose) were administered to the iliopsoas (iliacus) and knee flexors and, when necessary, to other muscles of the hip and knee. Evaluations were performed pre-treatment (weeks −4 to −8, and day 1) and post-treatment (week 10 and week 21): spasticity, range of motion, limb positioning, passive functions and pain. RESULTS: A modest improvement in hip and knee extension was observed, as evidenced by the Modified Ashworth Score and range of passive extension movements. Limb positioning was also improved. Clear benefits were found on passive functioning, including toileting, dressing and bed facilities, as well as pain levels. Active functions remained unchanged. More definite improvement was found in patients with severe difficulties. CONCLUSIONS: OnabotulinumtoxinA injection can contribute to reducing the consequences of disabling lower limb flexion. Keywords: Botulinum toxin type-A, lower limb, muscle spasticity, onabotulinumtoxinA
1. Introduction Hemispheric lesions frequently result in a contralateral hemiplegia comprising a lower limb motor deficit. The supraspinal spasticity, when present, usually affects hip and knee extensors, and ankle plantar flexors (Urban, Wolf, Uebele, Marx, Vogt, Stoeter, Bauermann, Weibrich, Vucurevic, Schneider, & Wissel, 2010). Conversely though, some patients with supraspinal injury can present with a general pattern of severe hip and knee flexion, as well as flexor spasms. This pattern is more commonly observed in spinal lesions and is elicited by a flexor reflex that can be exacerbated by the ∗ Address
for correspondence: Marc Rousseaux, Neurological Rehabilitation Unit, Hˆopital Swynghedauw, University Hospital Center, and University of Lille Nord de la France, 59037 Lille, France. Tel.: +33 320 444872; Fax: +33 320 445832; E-mail: marc. [email protected].
lack of supraspinal inhibition and/or increased activity of afferent nerves coming from the periphery, especially in the case of local lesions of the hip joint or skin (Sheean, 2002). In these cases, pressing the foot on the ground is difficult or even impossible, and this compromises transfers, upright standing and walking. As a result of hip stiffness, passive functions such as toileting and dressing the lower body are compromised, and performing passive movements frequently results in increased pain that further contributes to patient discomfort. The flexor pattern usually accompanies severe motor deficits in hemiplegic patients who are dependent upon carers for the activities of daily living. The flexor pattern is caused by muscle hypertonia and contractures of the hip flexor muscles (including the iliopsoas, rectus femoris, tensor fasciae latae) and the knee flexors (including the internal hamstrings, biceps femoris and gastrocnemius) (Kahle, Leonhardt,
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
& Platzer, 1984). Frequently, hypertonia also involves the hip adductors and the distal muscles, especially the ankle plantar flexors. There are a variety of different treatments that can be offered to such patients. Oral anti-spasticity agents have limited efficacy and give rise to use-limiting adverse effects (Montan´e, Vallano, & Laporte, 2004). Intrathecal baclofen is a much more effective agent and improves passive movements (Meythaler, GuinRenfroe, Brunner, & Hadley, 2001; Dvorak, Ketchum, & McGuire, 2011), but this treatment is relatively invasive and expensive. Neurolysis of the obturator nerve with alcohol or phenol is possible, but its effects are only beneficial for the hip adductors (Viel, Perennou, Ripart, Pelissier, & Eledjam, 2002). Selective neurotomy can also be performed on the motor branches of the sciatic nerve running to the hamstring muscles (Mertens & Sindou, 1991; Decq, Filipetti, Feve, & Saraoui, 1996), but this carries the usual risks associated with surgery. A more recent treatment for muscle hypertonia and spasticity comprises intramuscular injection of botulinum toxin type-A (BoNTA). BoNTA has been used successfully in patients with infantile paralysis in order to reduce hypertonia of the ilio-psoas (Garcia Ruiz, Perez Higueras, Escorihuela, & Castillo, 2002) and hamstring muscles. In patients with multiple sclerosis, it has also been used to reduce the spasticity of the hip adductors (Hyman, Barnes, Bhakta, Cozens, Bakheit, Kreczy-Kleedorfer, Poewe, Wissel, Bain, Glickman, Sayer, Richardson, & Dott, 2000) and knee flexors (Borg-Stein, Pine, Miller, & Brin, 1993; Konstanzer, Ceballos-Baumann, Dressnandt, & Conrad, 1993). Even if injections on the proximal part of the lower limb are commonly used in clinical practice on the hip adductors and knee extensors, their effectiveness on the pathological flexion pattern has never been evaluated in adult patients presenting with severe hemiplegia. We conducted an open-label study to analyse the potential benefit of OnabotulinumtoxinA injections on the hip and knee flexors in patients suffering a stroke or a traumatic brain injury.
2. Participants and methods 2.1. Participants Eligible patients were recruited from the outpatient department or the inpatient rehabilitation unit of the
University Hospital of Lille, France. All patients (or relatives) provided written informed consent prior to participation to this open-label observational study, which was conducted in accordance with the principles of the Declaration of Helsinki. Inclusion criteria comprised those patients who had suffered a stroke or a traumatic brain injury presenting a severe hemiplegia with flexor hip and knee deformity associated with muscle hypertonia and possibly spasms of corresponding muscles. This hypertonia was required to be sufficiently severe as to cause difficulties in daily life, including pain on mobilisation, and/or problems in toileting, dressing and positioning the limb. A total of 11 hemiplegic patients were recruited (5 males, 6 females), with a mean age of 57.6 years (standard deviation [SD]: 14.0 years). The origin of hemiplegia was commonly a unilateral stroke, i.e. an infarction in the middle cerebral artery territory (7 patients) or a subcortical haemorrhage (2 patients), and rarely a traumatic brain injury (2 cases). The mean time since lesion onset was 43.5 months (SD: 88.2 months). All the patients received physical therapy, most often five times a week. 2.2. Assessments Patients were assessed twice before beginning treatment. Initially, an examination was performed to evaluate the situation and to prepare an individualised treatment plan (session 1: week −4 to −8). A second assessment was made on the day of injection (session 2: day 1). Patients were also evaluated twice after treatment (session 3: week 10 ± 2 and session 4: week 21 ± 3). Resistance to passive motion was assessed using the Modified Ashworth Score (scored from 0 to 5) (Bohannon & Smith, 1987) on the hip (flexors, abductors, adductors), knee (flexors, extensors) and ankle (plantar flexors) muscles. The passive range of motion (RoM) was measured using a goniometer at the hip (extension, abduction and adduction), knee (extension) and ankle (dorsiflexion). Motor control was evaluated using the Medical Research Council (MRC) scale (scored from 0 to 5) (British Medical Research Council, 1943) at the hip (flexion, extension, adduction and abduction) and knee (extension). There was also an evaluation of spontaneous joint positioning at the hip (flexion and adduction/abduction), at the knee (flexion), and at the ankle (plantar flexion) in a supine position and, when possible, in a standing position with support.
M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
The level of difficulties encountered during toileting and dressing the lower body, bed positioning and passive transfers was measured using a visual analogue scale (VAS from 0 = no difficulty to 10 = severe difficulties) via an interview with both the patient and caregiver. Similarly, pain levels suffered when lying in bed and during passive mobilisation were also quantified using a VAS (0 = no pain to 10 = unbearable pain). 2.3. OnabotulinumtoxinA injections Target injection sites and doses of OnabotulinumtoxinA (Botox® . Allergan Inc, Irvine, USA) were adapted for each individual patient. Injections were performed using electrical stimulation guiding. OnabotulinumtoxinA injections were systematically performed on the hip flexors (especially the iliopsoas) and knee flexors (the medial hamstrings, i.e. the semi-tendinosus and semi-membranosus, and the biceps femoris). The illiacus part of the illiopsoas was injected using a tefloncoated electro-stimulation needle (Locoplex 100 mm, Vygon, Ecouen, France). The needle insertion point was 2 cm below and 1 cm inside the iliac spine anteriorsuperior and the orientation of the needle was directed vertically whilst the patient was placed in a supine position. The length of the needle (10 cm) permitted injection in the central part of the muscle. Depending on the pattern of spasticity, injections could also be administered to the hip adductors, abductors and rotators and on the ankle plantar flexors, especially for those patients who were able to place the foot on the ground. The total dose was 300U or 400U OnabotulinumtoxinA and the dilution was 4 mL saline for 100U. 2.4. Statistical analysis Repeated measure variance analyses (nonparametric Friedman test) were used with the session (1 to 4) as within-subject factor. For the analysis of spasticity, RoM and joint positions, only patients who received an injection into the target muscles that were specifically involved in the resistance, limitation of RoM and/or pathological positioning were included. No statistical analyses were performed when the number of patients was less than 6. Post-hoc comparisons used the Wilcoxon test. Correlation analyses were performed with the Spearman test. The alpha risk was p ≤ 0.05.
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3. Results 3.1. Population and injection sites Prior to injection, the pathological flexion in a lying position of the hip and knee was found to be relatively severe (hip flexion: 20–55◦ at session 1; 15–60◦ at session 2; knee flexion: 20–120◦ at session 1; 15–124◦ at session 2). Some patients showed a severe adduction (≥10◦ : 5 and 4 patients at sessions 1 and 2, respectively) or abduction (≥10◦ : 4 and 5 patients at sessions 1 and 2, respectively), and/or internal (≥10◦ : 4 and 3 patients at sessions 1 and 2, respectively) or external rotation (≥20◦ : 2 and 3 patients at sessions 1 and 2, respectively). The motor deficit was always important, with hip extension being absent (0-1 on the MRC scale) in 7 cases and severely reduced (2–2.5) in the other, and knee extension being absent in 5 patients (0-1) and limited (2–3.5) in the other. Patients were dependent on carers for the personal activities of daily living (mean Barthel’s index: 16.0/100; SD: 18.2). Onabotulinumtoxin A injections were performed on the iliacus region of the iliopsoas (mean dose: 91.4U; SD: 12.1U [11 patients]), rectus femoris (mean: 50U [1 patient]), internal hamstrings (mean: 89.5U; SD: 15.7U [11 patients]), biceps femoris (mean: 32.8U; SD: 18.2U [9 patients]), hip adductors (mean: 102.1U; SD: 30.7U [7 patients]), hip rotators (i.e. anterior or posterior regions of the gluteus medius) (mean: 70.0U; SD: 32.8U [3 patients]) and gastrocnemius and soleus (mean: 110.0U; SD = 20.0U [4 patients]). Mean total OnabotulinumtoxinA dose was 333.3U (SD: 49.2). 3.2. Treatment effect The effect of OnabotulinumtoxinA injections on hypertonia was modest, with a reduction of approximately 0.5 on the MAS for the hip flexors and 0.3 on the knee flexors at session 3; this difference was significant for the hip flexors (Table 1). A small but non-significant benefit was found for the hip adductors, but there were no definite effects on the hip abductors or ankle plantar flexors. Passive RoM increased for hip extension, with a tendency to statistical significance, whereas there was a greater statistical significance for knee extension. Motor control of the antagonist muscles which were injected was not influenced by the injection procedure. In the supine position, examination showed a significant reduction in hip flexion and a relatively important but non-significant effect on knee flexion. Hip adduction was not obviously affected, but abduction, when
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
Table 1 Presentation of the effect of OnabotulinumtoxinA on spasticity, RoM, motor control and passive functions. The number of patients receiving the treatment is indicated at each level Session 1 W −4 to −8 Spasticity
Range of movement, passive
Motricity, active
Limb position, supine
Limb position, standing (8)
Passive functions
Pain Satisfaction
Hip flexors (11) Hip adductors (7) Hip abductors (3) Knee flexors (11) Ankle plantar-flexors (3) Spasms (11) Hip extension (11) Hip adduction (3) Hip abduction (7) Knee extension (11) Ankle dorsiflexion (3) Hip extension (11) Hip flexion (11) Hip adduction (3) Hip abduction (7) Knee extension (11) Hip flexion (11) Hip adduction (7) Hip abduction (3) Knee flexion (11) Ankle plantar flexion (3) Hip flexion (8) Hip adduction (4) Hip abduction (3) Knee flexion (8) Toileting and dressing (11) Bed positioning (11) Transfers (11) Spontaneous (11) Mobilisation (11) Patient or caregiver (11)
4.8 (0.4) 4.3 (1.2) 2.7 (0.6) 4.8 (0.6) 4.3 (0.6) 0.8 (1.4) −16.7 (7.7) 14.7 (6.8) 16.6 (14.9) −23.7 (23.1) −10.1 (0.4) 0.8 (1.1) 1.1 (1.4) 0.5 (0.9) 0.8 (1.1) 1.2 (1.3) 37.1 (11.2) 6.7 (12.2) 28.0 (12.8) 56.7 (29.7) 37.7 (2.5) 51.0 (14.0) 7.0 (11.9) 11.7 (12.6) 51.9 (19.3) 7.9 (1.6) 7.9 (2.2) 9.3 (1.4) 1.1 (1.9) 7.0 (2.8)
Session 2 D1 4.8 (0.4) 4.3 (1.2) 2.0 (0.0) 4.8 (0.6) 4.7 (0.6) 1.1 (1.5) −17.4 (8.0) 13.3 (7.6) 16.0 (14.0) 26.5 (25.4) 13.3 (4.7) 0.8 (1.1) 1.1 (1.4) 0.5 (0.9) 0.8 (1.1) 1.2 (1.3) 38.2 (13.6) 8.3 (13.3) 27.3 (15.4) 58.4 (31.2) 38.3 (2.9) 50.0 (13.4) 6.2 (11.1) 12.3 (12.5) 52.0 (18.7) 8.0 (1.7) 8.0 (1.9) 9.4 (1.2) 1.3 (2.2) 7.3 (2.8)
Session 3 W 10 ± 4.3 (1.0)∗ 4.1 (1.5) 2.0 (0.0) 4.5 (1.2) 4.3 (1.1) 0.4 (0.8)t −10.3 (9.5)∗ 18.3 (5.7) 22.7 (10.6) −18.7 (9.7) −10.0 (3.0) 0.8 (1.2) 1.1 (1.4) 0.8 (0.8) 0.8 (1.1) 1.2 (1.3) 25.3 (10.1) 6.0 (9.1) 11.7 (12.6) 39.6 (20.7) 33.3 (5.8) 40.1 (17.2) 6.7 (7.9) 10.0 (10.0) 43.6 (22.9) 4.0 (1.7)* 4.3 (2.0)* 6.3 (2.9)* 0.3 (0.9) 4.6 (2.1)* 6.2 (1.9)
Session 4 W 21 ± 3
p
4.5 (0.9) 4.1 (1.5) 2.0 (0.0) 4.6 (1.2) 4.3 (1.1) 0.4 (0.9) −13.3 (11.2)∗ 15.0 (5.0) 21.6 (9.1) −19.4 (18.6) −10.0 (7.0) 0.8 (1.2) 1.0 (1.3) 1.2 (1.0) 0.7 (1.0) 1.3 (1.4) 26.7 (12.3) 6.4 (6.7) 7.7 (9.3) 38.5 (21.6) 39.0 (6.6) 45.9 (15.8) 5.5 (9.0) 14.3 (12.5) 46.2 (21.3) 4.7 (2.5)* 4.8 (2.7)* 6.9 (2.3)* 0.5 (1.6) 4.8 (2.5)* 6.6 (1.8)
0.029 0.392 0.112 0.047 0.061 0.105 0.020 0.392 0.392 0.392 0.261 0.001 0.858 0.088 0.095
0.172 0.0001 0.0001 0.0001 0.067 0.0001
Mean (SD) values pre- (sessions 1 and 2) and post- (sessions 3 and 4) injections. Statistically significant (*p ≤ 0.05) differences and tendencies (t: 0.05≤ p ≤ 0.07) between session 2 and session 3 or session 4 (post-hoc Wilcoxon test).
present (3 patients), was more clearly improved. For the 8 patients assessed in the standing position, hip and knee flexion were non-significantly improved. Difficulties in patient management, especially regarding toileting and dressing, bed positioning and transfers, and pain level during mobilisation, were more clearly influenced by treatment, and a partial benefit was still present at session 4. Spontaneous pain was relatively modest at pre-injection and its reduction was not significant. Active functions remained severely limited. But it is of note that two patients showed improvements in these activities, and one patient regained the ability to walk with assistance using a tripod cane after repeated OnabotulinumtoxinA injections. Treatment satisfaction, as assessed by patients or relatives was judged as positive with a mean score of 6.2/10 at session 3 and 6.6/10 at session 4. All patients received at least one additional Onabotulinumtoxin A injection 4–6 months post-treatment.
3.3. Safety OnabotulinumtoxinA injections were the source of transient pain, especially during the injection of the iliacus muscle for 6 out of 11 patients. However, no patient reported lasting pain, haematoma, muscle weakness or any other side effect. 3.4. Prediction of efficacy We did not find any correlation of the reduction of hypertonia of hip and ankle flexors, passive RoM in extension at the hip and knee, hip and knee positioning in supine position and difficulties in patient management with the time since stroke and Barthel’s index. At session 3, the improvement in patient management significantly correlated with the age (toileting r = 0.653; bed positioning r = 0.689) and difficulties in performing the same activities before injection (toileting r = 0.765;
M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
bed positioning r = 0.592). The improvement in the hip and knee flexor positioning (in supine position), spasms, and RoM for knee extension correlated with the severity of difficulties before injection (r = 0.974; r = 0.765; r = 0.666; r = 0.975; r = 0.936, respectively). Similar results were found at session 4 for the improvement in spontaneous pain, knee flexor positioning, spasms, and RoM of hip extension (r = 0.723; r = 0.815; r = 0.801; r = −0.613, respectively).
4. Discussion The results of this open-label observational study showed that OnabotulinumtoxinA injections on hip and knee flexor muscle resulted in (i) a moderate effect hypertonia, and on passive RoM (ii) a more definite improvement of passive functions and comfort with good levels of satisfaction, with (iii) greater improvement in those with more severe difficulties. The flexor pattern of the hemiplegic lower limb is relatively rare, but its consequences are always disabling for both active and passive functioning. Most patients in this study had severe motor deficits, impairment in passive functions and comfort, and pain elicited by passive mobilisation. In order to reduce hip flexion, we injected in the illiacus muscle, with relatively fair influence on hip flexion. The technique is easier to perform than the anterior (Molenaers, Eyssen, Desloovere, Jonkers, & De Cock, 1999) and posterior approaches to the psoas muscle. In addition, the inferior approach of the psoas is distant from the motor endplates (Van Campenhout & Molenaers, 2011). The rectus femoris was considered in one patient at first injection, but this muscle was injected more frequently (in three cases) at the second injection. At the knee, the injection was preferentially performed on the internal hamstrings, which were the most severely hypertonic muscles. The gastrocnemius is a knee flexor muscle, but its participation in the pathological knee flexion in the supine position is usually modest. In fact, this muscle was preferentially injected in these patients who were able to actively participate in transfers. From the perspective of patients and caregivers, the greatest benefits of OnabotulinumtoxinA injections concerned lower limb positioning, as well as passive movements and comfort, including pain. The beneficial effects of BoNTA treatment on passive RoM have been reported in many studies, including injections into the proximal region of the lower limbs, especially the hip
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adductors in patients with multiple sclerosis (Hyman, Barnes, Bhakta, Cozens, Bakheit, Kreczy-Kleedorfer, Poewe, Wissel, Bain, Glickman, Sayer, Richardson, & Dott; Borg-Stein, Pine, Miller, & Brin, 1993). However, in hemiplegic patients, the possibility of improving passive function and comfort has only been described for the upper limb (Brashear, Gordon, Elovic, Kassicieh, Marciniak, Do, Lee, Jenkins, & Turkel, 2002; Elovic, Brashear, Kaelin, Liu, Millis, Barron, & Turkel, 2008). With respect to the lower limb, most published studies have considered distal deformation (i.e. equinovarus) and, more rarely, knee deformation (or stiff knee) (Gracies, Singer, & Dunne, 2007; Bleyenheuft, Cockx, Caty, Stoquart, Lejeune, & Detrembleur, 2009). The overall effect on muscle hypertonia was relatively modest. But the MAS showed a clear ceiling effect due to the presence of RoM limitations and a score often being rated at its highest level (5/5). Although there was no overall benefit found on active functioning, especially locomotion, it should be noted that baseline activity limitations were high, and that partial improvements were observed in two patients. There was relatively fair tolerance to the injections (Rosales & Chua-Yap, 2008), with the possibility of transient pain during injection of the iliacus muscle, when the needle made contact with the medial surface of the pelvic bone. As detailed in the introduction, other techniques are available for improving passive functioning. Nevertheless, nerve blocks and neurotomies are not possible on hip flexors (except the rectus femoris), and only one study has reported a positive effect for knee flexors (Decq, Filipetti, Feve, & Saraoui, 1996). Intrathecal baclofen has proved effective for hemiplegic patients with severe lower limb hypertonia (Meythaler, GuinRenfroe, Brunner, & Hadley, 2001), and it also improves patient management at home with regard to hygiene and assisted transfers. However, this technique is difficult to implement in severely affected and fragile patients. Several criticisms can be presented for this study. First, it was an open-label study. But stroke patients presenting with a disabling flexor scheme are relatively rare. In order to counterbalance this problem, we performed two successive examinations pre-injection and the patient difficulties were relatively stable. Second, the population was somewhat heterogeneous in terms of time since lesion onset. However, the benefit was independent of this time. Furthermore, the fact that a benefit was observed in a relatively heterogeneous population was an indication that such a treatment can be offered in similar patients, i.e. without restricted indications.
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
In conclusion, our results support the use of OnabotulinumtoxinA injections to the proximal region of the lower limb in patients presenting with severe hemiplegia and an abnormal hypertonic flexor pattern, in order to improve passive functions and comfort.
Declaration of interest Dr. Marc Rousseaux has been a medical consultant and has received honoraria for organizing training and teaching courses from Allergan, Ipsen, and Merz. Other authors have no conflict of interest.
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NeuroRehabilitation 35 (2014) 25–30 DOI:10.3233/NRE-141093 IOS Press
Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients Marc Rousseaux∗ , Walter Daveluy, Odile Kozlowski and Etienne Allart Neurological Rehabilitation Unit, Hˆopital Swynghedauw, CHRU of Lille, Lille, France
Abstract. BACKGROUND: Hemiplegic patients with supraspinal spasticity can present with a flexor pattern at the hip and knee that hampers both passive and active functions. OBJECTIVE: To investigate the efficacy of OnabotulinumtoxinA injections on this flexor scheme. METHODS: This open-label observational study included eleven patients who had suffered a unilateral stroke or traumatic brain injury. All had impairment in the activities of daily living caused by severe hip and knee flexion. OnabotulinumtoxinA injections of 300–400U (total dose) were administered to the iliopsoas (iliacus) and knee flexors and, when necessary, to other muscles of the hip and knee. Evaluations were performed pre-treatment (weeks −4 to −8, and day 1) and post-treatment (week 10 and week 21): spasticity, range of motion, limb positioning, passive functions and pain. RESULTS: A modest improvement in hip and knee extension was observed, as evidenced by the Modified Ashworth Score and range of passive extension movements. Limb positioning was also improved. Clear benefits were found on passive functioning, including toileting, dressing and bed facilities, as well as pain levels. Active functions remained unchanged. More definite improvement was found in patients with severe difficulties. CONCLUSIONS: OnabotulinumtoxinA injection can contribute to reducing the consequences of disabling lower limb flexion. Keywords: Botulinum toxin type-A, lower limb, muscle spasticity, onabotulinumtoxinA
1. Introduction Hemispheric lesions frequently result in a contralateral hemiplegia comprising a lower limb motor deficit. The supraspinal spasticity, when present, usually affects hip and knee extensors, and ankle plantar flexors (Urban, Wolf, Uebele, Marx, Vogt, Stoeter, Bauermann, Weibrich, Vucurevic, Schneider, & Wissel, 2010). Conversely though, some patients with supraspinal injury can present with a general pattern of severe hip and knee flexion, as well as flexor spasms. This pattern is more commonly observed in spinal lesions and is elicited by a flexor reflex that can be exacerbated by the ∗ Address
for correspondence: Marc Rousseaux, Neurological Rehabilitation Unit, Hˆopital Swynghedauw, University Hospital Center, and University of Lille Nord de la France, 59037 Lille, France. Tel.: +33 320 444872; Fax: +33 320 445832; E-mail: marc. [email protected].
lack of supraspinal inhibition and/or increased activity of afferent nerves coming from the periphery, especially in the case of local lesions of the hip joint or skin (Sheean, 2002). In these cases, pressing the foot on the ground is difficult or even impossible, and this compromises transfers, upright standing and walking. As a result of hip stiffness, passive functions such as toileting and dressing the lower body are compromised, and performing passive movements frequently results in increased pain that further contributes to patient discomfort. The flexor pattern usually accompanies severe motor deficits in hemiplegic patients who are dependent upon carers for the activities of daily living. The flexor pattern is caused by muscle hypertonia and contractures of the hip flexor muscles (including the iliopsoas, rectus femoris, tensor fasciae latae) and the knee flexors (including the internal hamstrings, biceps femoris and gastrocnemius) (Kahle, Leonhardt,
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
& Platzer, 1984). Frequently, hypertonia also involves the hip adductors and the distal muscles, especially the ankle plantar flexors. There are a variety of different treatments that can be offered to such patients. Oral anti-spasticity agents have limited efficacy and give rise to use-limiting adverse effects (Montan´e, Vallano, & Laporte, 2004). Intrathecal baclofen is a much more effective agent and improves passive movements (Meythaler, GuinRenfroe, Brunner, & Hadley, 2001; Dvorak, Ketchum, & McGuire, 2011), but this treatment is relatively invasive and expensive. Neurolysis of the obturator nerve with alcohol or phenol is possible, but its effects are only beneficial for the hip adductors (Viel, Perennou, Ripart, Pelissier, & Eledjam, 2002). Selective neurotomy can also be performed on the motor branches of the sciatic nerve running to the hamstring muscles (Mertens & Sindou, 1991; Decq, Filipetti, Feve, & Saraoui, 1996), but this carries the usual risks associated with surgery. A more recent treatment for muscle hypertonia and spasticity comprises intramuscular injection of botulinum toxin type-A (BoNTA). BoNTA has been used successfully in patients with infantile paralysis in order to reduce hypertonia of the ilio-psoas (Garcia Ruiz, Perez Higueras, Escorihuela, & Castillo, 2002) and hamstring muscles. In patients with multiple sclerosis, it has also been used to reduce the spasticity of the hip adductors (Hyman, Barnes, Bhakta, Cozens, Bakheit, Kreczy-Kleedorfer, Poewe, Wissel, Bain, Glickman, Sayer, Richardson, & Dott, 2000) and knee flexors (Borg-Stein, Pine, Miller, & Brin, 1993; Konstanzer, Ceballos-Baumann, Dressnandt, & Conrad, 1993). Even if injections on the proximal part of the lower limb are commonly used in clinical practice on the hip adductors and knee extensors, their effectiveness on the pathological flexion pattern has never been evaluated in adult patients presenting with severe hemiplegia. We conducted an open-label study to analyse the potential benefit of OnabotulinumtoxinA injections on the hip and knee flexors in patients suffering a stroke or a traumatic brain injury.
2. Participants and methods 2.1. Participants Eligible patients were recruited from the outpatient department or the inpatient rehabilitation unit of the
University Hospital of Lille, France. All patients (or relatives) provided written informed consent prior to participation to this open-label observational study, which was conducted in accordance with the principles of the Declaration of Helsinki. Inclusion criteria comprised those patients who had suffered a stroke or a traumatic brain injury presenting a severe hemiplegia with flexor hip and knee deformity associated with muscle hypertonia and possibly spasms of corresponding muscles. This hypertonia was required to be sufficiently severe as to cause difficulties in daily life, including pain on mobilisation, and/or problems in toileting, dressing and positioning the limb. A total of 11 hemiplegic patients were recruited (5 males, 6 females), with a mean age of 57.6 years (standard deviation [SD]: 14.0 years). The origin of hemiplegia was commonly a unilateral stroke, i.e. an infarction in the middle cerebral artery territory (7 patients) or a subcortical haemorrhage (2 patients), and rarely a traumatic brain injury (2 cases). The mean time since lesion onset was 43.5 months (SD: 88.2 months). All the patients received physical therapy, most often five times a week. 2.2. Assessments Patients were assessed twice before beginning treatment. Initially, an examination was performed to evaluate the situation and to prepare an individualised treatment plan (session 1: week −4 to −8). A second assessment was made on the day of injection (session 2: day 1). Patients were also evaluated twice after treatment (session 3: week 10 ± 2 and session 4: week 21 ± 3). Resistance to passive motion was assessed using the Modified Ashworth Score (scored from 0 to 5) (Bohannon & Smith, 1987) on the hip (flexors, abductors, adductors), knee (flexors, extensors) and ankle (plantar flexors) muscles. The passive range of motion (RoM) was measured using a goniometer at the hip (extension, abduction and adduction), knee (extension) and ankle (dorsiflexion). Motor control was evaluated using the Medical Research Council (MRC) scale (scored from 0 to 5) (British Medical Research Council, 1943) at the hip (flexion, extension, adduction and abduction) and knee (extension). There was also an evaluation of spontaneous joint positioning at the hip (flexion and adduction/abduction), at the knee (flexion), and at the ankle (plantar flexion) in a supine position and, when possible, in a standing position with support.
M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
The level of difficulties encountered during toileting and dressing the lower body, bed positioning and passive transfers was measured using a visual analogue scale (VAS from 0 = no difficulty to 10 = severe difficulties) via an interview with both the patient and caregiver. Similarly, pain levels suffered when lying in bed and during passive mobilisation were also quantified using a VAS (0 = no pain to 10 = unbearable pain). 2.3. OnabotulinumtoxinA injections Target injection sites and doses of OnabotulinumtoxinA (Botox® . Allergan Inc, Irvine, USA) were adapted for each individual patient. Injections were performed using electrical stimulation guiding. OnabotulinumtoxinA injections were systematically performed on the hip flexors (especially the iliopsoas) and knee flexors (the medial hamstrings, i.e. the semi-tendinosus and semi-membranosus, and the biceps femoris). The illiacus part of the illiopsoas was injected using a tefloncoated electro-stimulation needle (Locoplex 100 mm, Vygon, Ecouen, France). The needle insertion point was 2 cm below and 1 cm inside the iliac spine anteriorsuperior and the orientation of the needle was directed vertically whilst the patient was placed in a supine position. The length of the needle (10 cm) permitted injection in the central part of the muscle. Depending on the pattern of spasticity, injections could also be administered to the hip adductors, abductors and rotators and on the ankle plantar flexors, especially for those patients who were able to place the foot on the ground. The total dose was 300U or 400U OnabotulinumtoxinA and the dilution was 4 mL saline for 100U. 2.4. Statistical analysis Repeated measure variance analyses (nonparametric Friedman test) were used with the session (1 to 4) as within-subject factor. For the analysis of spasticity, RoM and joint positions, only patients who received an injection into the target muscles that were specifically involved in the resistance, limitation of RoM and/or pathological positioning were included. No statistical analyses were performed when the number of patients was less than 6. Post-hoc comparisons used the Wilcoxon test. Correlation analyses were performed with the Spearman test. The alpha risk was p ≤ 0.05.
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3. Results 3.1. Population and injection sites Prior to injection, the pathological flexion in a lying position of the hip and knee was found to be relatively severe (hip flexion: 20–55◦ at session 1; 15–60◦ at session 2; knee flexion: 20–120◦ at session 1; 15–124◦ at session 2). Some patients showed a severe adduction (≥10◦ : 5 and 4 patients at sessions 1 and 2, respectively) or abduction (≥10◦ : 4 and 5 patients at sessions 1 and 2, respectively), and/or internal (≥10◦ : 4 and 3 patients at sessions 1 and 2, respectively) or external rotation (≥20◦ : 2 and 3 patients at sessions 1 and 2, respectively). The motor deficit was always important, with hip extension being absent (0-1 on the MRC scale) in 7 cases and severely reduced (2–2.5) in the other, and knee extension being absent in 5 patients (0-1) and limited (2–3.5) in the other. Patients were dependent on carers for the personal activities of daily living (mean Barthel’s index: 16.0/100; SD: 18.2). Onabotulinumtoxin A injections were performed on the iliacus region of the iliopsoas (mean dose: 91.4U; SD: 12.1U [11 patients]), rectus femoris (mean: 50U [1 patient]), internal hamstrings (mean: 89.5U; SD: 15.7U [11 patients]), biceps femoris (mean: 32.8U; SD: 18.2U [9 patients]), hip adductors (mean: 102.1U; SD: 30.7U [7 patients]), hip rotators (i.e. anterior or posterior regions of the gluteus medius) (mean: 70.0U; SD: 32.8U [3 patients]) and gastrocnemius and soleus (mean: 110.0U; SD = 20.0U [4 patients]). Mean total OnabotulinumtoxinA dose was 333.3U (SD: 49.2). 3.2. Treatment effect The effect of OnabotulinumtoxinA injections on hypertonia was modest, with a reduction of approximately 0.5 on the MAS for the hip flexors and 0.3 on the knee flexors at session 3; this difference was significant for the hip flexors (Table 1). A small but non-significant benefit was found for the hip adductors, but there were no definite effects on the hip abductors or ankle plantar flexors. Passive RoM increased for hip extension, with a tendency to statistical significance, whereas there was a greater statistical significance for knee extension. Motor control of the antagonist muscles which were injected was not influenced by the injection procedure. In the supine position, examination showed a significant reduction in hip flexion and a relatively important but non-significant effect on knee flexion. Hip adduction was not obviously affected, but abduction, when
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
Table 1 Presentation of the effect of OnabotulinumtoxinA on spasticity, RoM, motor control and passive functions. The number of patients receiving the treatment is indicated at each level Session 1 W −4 to −8 Spasticity
Range of movement, passive
Motricity, active
Limb position, supine
Limb position, standing (8)
Passive functions
Pain Satisfaction
Hip flexors (11) Hip adductors (7) Hip abductors (3) Knee flexors (11) Ankle plantar-flexors (3) Spasms (11) Hip extension (11) Hip adduction (3) Hip abduction (7) Knee extension (11) Ankle dorsiflexion (3) Hip extension (11) Hip flexion (11) Hip adduction (3) Hip abduction (7) Knee extension (11) Hip flexion (11) Hip adduction (7) Hip abduction (3) Knee flexion (11) Ankle plantar flexion (3) Hip flexion (8) Hip adduction (4) Hip abduction (3) Knee flexion (8) Toileting and dressing (11) Bed positioning (11) Transfers (11) Spontaneous (11) Mobilisation (11) Patient or caregiver (11)
4.8 (0.4) 4.3 (1.2) 2.7 (0.6) 4.8 (0.6) 4.3 (0.6) 0.8 (1.4) −16.7 (7.7) 14.7 (6.8) 16.6 (14.9) −23.7 (23.1) −10.1 (0.4) 0.8 (1.1) 1.1 (1.4) 0.5 (0.9) 0.8 (1.1) 1.2 (1.3) 37.1 (11.2) 6.7 (12.2) 28.0 (12.8) 56.7 (29.7) 37.7 (2.5) 51.0 (14.0) 7.0 (11.9) 11.7 (12.6) 51.9 (19.3) 7.9 (1.6) 7.9 (2.2) 9.3 (1.4) 1.1 (1.9) 7.0 (2.8)
Session 2 D1 4.8 (0.4) 4.3 (1.2) 2.0 (0.0) 4.8 (0.6) 4.7 (0.6) 1.1 (1.5) −17.4 (8.0) 13.3 (7.6) 16.0 (14.0) 26.5 (25.4) 13.3 (4.7) 0.8 (1.1) 1.1 (1.4) 0.5 (0.9) 0.8 (1.1) 1.2 (1.3) 38.2 (13.6) 8.3 (13.3) 27.3 (15.4) 58.4 (31.2) 38.3 (2.9) 50.0 (13.4) 6.2 (11.1) 12.3 (12.5) 52.0 (18.7) 8.0 (1.7) 8.0 (1.9) 9.4 (1.2) 1.3 (2.2) 7.3 (2.8)
Session 3 W 10 ± 4.3 (1.0)∗ 4.1 (1.5) 2.0 (0.0) 4.5 (1.2) 4.3 (1.1) 0.4 (0.8)t −10.3 (9.5)∗ 18.3 (5.7) 22.7 (10.6) −18.7 (9.7) −10.0 (3.0) 0.8 (1.2) 1.1 (1.4) 0.8 (0.8) 0.8 (1.1) 1.2 (1.3) 25.3 (10.1) 6.0 (9.1) 11.7 (12.6) 39.6 (20.7) 33.3 (5.8) 40.1 (17.2) 6.7 (7.9) 10.0 (10.0) 43.6 (22.9) 4.0 (1.7)* 4.3 (2.0)* 6.3 (2.9)* 0.3 (0.9) 4.6 (2.1)* 6.2 (1.9)
Session 4 W 21 ± 3
p
4.5 (0.9) 4.1 (1.5) 2.0 (0.0) 4.6 (1.2) 4.3 (1.1) 0.4 (0.9) −13.3 (11.2)∗ 15.0 (5.0) 21.6 (9.1) −19.4 (18.6) −10.0 (7.0) 0.8 (1.2) 1.0 (1.3) 1.2 (1.0) 0.7 (1.0) 1.3 (1.4) 26.7 (12.3) 6.4 (6.7) 7.7 (9.3) 38.5 (21.6) 39.0 (6.6) 45.9 (15.8) 5.5 (9.0) 14.3 (12.5) 46.2 (21.3) 4.7 (2.5)* 4.8 (2.7)* 6.9 (2.3)* 0.5 (1.6) 4.8 (2.5)* 6.6 (1.8)
0.029 0.392 0.112 0.047 0.061 0.105 0.020 0.392 0.392 0.392 0.261 0.001 0.858 0.088 0.095
0.172 0.0001 0.0001 0.0001 0.067 0.0001
Mean (SD) values pre- (sessions 1 and 2) and post- (sessions 3 and 4) injections. Statistically significant (*p ≤ 0.05) differences and tendencies (t: 0.05≤ p ≤ 0.07) between session 2 and session 3 or session 4 (post-hoc Wilcoxon test).
present (3 patients), was more clearly improved. For the 8 patients assessed in the standing position, hip and knee flexion were non-significantly improved. Difficulties in patient management, especially regarding toileting and dressing, bed positioning and transfers, and pain level during mobilisation, were more clearly influenced by treatment, and a partial benefit was still present at session 4. Spontaneous pain was relatively modest at pre-injection and its reduction was not significant. Active functions remained severely limited. But it is of note that two patients showed improvements in these activities, and one patient regained the ability to walk with assistance using a tripod cane after repeated OnabotulinumtoxinA injections. Treatment satisfaction, as assessed by patients or relatives was judged as positive with a mean score of 6.2/10 at session 3 and 6.6/10 at session 4. All patients received at least one additional Onabotulinumtoxin A injection 4–6 months post-treatment.
3.3. Safety OnabotulinumtoxinA injections were the source of transient pain, especially during the injection of the iliacus muscle for 6 out of 11 patients. However, no patient reported lasting pain, haematoma, muscle weakness or any other side effect. 3.4. Prediction of efficacy We did not find any correlation of the reduction of hypertonia of hip and ankle flexors, passive RoM in extension at the hip and knee, hip and knee positioning in supine position and difficulties in patient management with the time since stroke and Barthel’s index. At session 3, the improvement in patient management significantly correlated with the age (toileting r = 0.653; bed positioning r = 0.689) and difficulties in performing the same activities before injection (toileting r = 0.765;
M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
bed positioning r = 0.592). The improvement in the hip and knee flexor positioning (in supine position), spasms, and RoM for knee extension correlated with the severity of difficulties before injection (r = 0.974; r = 0.765; r = 0.666; r = 0.975; r = 0.936, respectively). Similar results were found at session 4 for the improvement in spontaneous pain, knee flexor positioning, spasms, and RoM of hip extension (r = 0.723; r = 0.815; r = 0.801; r = −0.613, respectively).
4. Discussion The results of this open-label observational study showed that OnabotulinumtoxinA injections on hip and knee flexor muscle resulted in (i) a moderate effect hypertonia, and on passive RoM (ii) a more definite improvement of passive functions and comfort with good levels of satisfaction, with (iii) greater improvement in those with more severe difficulties. The flexor pattern of the hemiplegic lower limb is relatively rare, but its consequences are always disabling for both active and passive functioning. Most patients in this study had severe motor deficits, impairment in passive functions and comfort, and pain elicited by passive mobilisation. In order to reduce hip flexion, we injected in the illiacus muscle, with relatively fair influence on hip flexion. The technique is easier to perform than the anterior (Molenaers, Eyssen, Desloovere, Jonkers, & De Cock, 1999) and posterior approaches to the psoas muscle. In addition, the inferior approach of the psoas is distant from the motor endplates (Van Campenhout & Molenaers, 2011). The rectus femoris was considered in one patient at first injection, but this muscle was injected more frequently (in three cases) at the second injection. At the knee, the injection was preferentially performed on the internal hamstrings, which were the most severely hypertonic muscles. The gastrocnemius is a knee flexor muscle, but its participation in the pathological knee flexion in the supine position is usually modest. In fact, this muscle was preferentially injected in these patients who were able to actively participate in transfers. From the perspective of patients and caregivers, the greatest benefits of OnabotulinumtoxinA injections concerned lower limb positioning, as well as passive movements and comfort, including pain. The beneficial effects of BoNTA treatment on passive RoM have been reported in many studies, including injections into the proximal region of the lower limbs, especially the hip
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adductors in patients with multiple sclerosis (Hyman, Barnes, Bhakta, Cozens, Bakheit, Kreczy-Kleedorfer, Poewe, Wissel, Bain, Glickman, Sayer, Richardson, & Dott; Borg-Stein, Pine, Miller, & Brin, 1993). However, in hemiplegic patients, the possibility of improving passive function and comfort has only been described for the upper limb (Brashear, Gordon, Elovic, Kassicieh, Marciniak, Do, Lee, Jenkins, & Turkel, 2002; Elovic, Brashear, Kaelin, Liu, Millis, Barron, & Turkel, 2008). With respect to the lower limb, most published studies have considered distal deformation (i.e. equinovarus) and, more rarely, knee deformation (or stiff knee) (Gracies, Singer, & Dunne, 2007; Bleyenheuft, Cockx, Caty, Stoquart, Lejeune, & Detrembleur, 2009). The overall effect on muscle hypertonia was relatively modest. But the MAS showed a clear ceiling effect due to the presence of RoM limitations and a score often being rated at its highest level (5/5). Although there was no overall benefit found on active functioning, especially locomotion, it should be noted that baseline activity limitations were high, and that partial improvements were observed in two patients. There was relatively fair tolerance to the injections (Rosales & Chua-Yap, 2008), with the possibility of transient pain during injection of the iliacus muscle, when the needle made contact with the medial surface of the pelvic bone. As detailed in the introduction, other techniques are available for improving passive functioning. Nevertheless, nerve blocks and neurotomies are not possible on hip flexors (except the rectus femoris), and only one study has reported a positive effect for knee flexors (Decq, Filipetti, Feve, & Saraoui, 1996). Intrathecal baclofen has proved effective for hemiplegic patients with severe lower limb hypertonia (Meythaler, GuinRenfroe, Brunner, & Hadley, 2001), and it also improves patient management at home with regard to hygiene and assisted transfers. However, this technique is difficult to implement in severely affected and fragile patients. Several criticisms can be presented for this study. First, it was an open-label study. But stroke patients presenting with a disabling flexor scheme are relatively rare. In order to counterbalance this problem, we performed two successive examinations pre-injection and the patient difficulties were relatively stable. Second, the population was somewhat heterogeneous in terms of time since lesion onset. However, the benefit was independent of this time. Furthermore, the fact that a benefit was observed in a relatively heterogeneous population was an indication that such a treatment can be offered in similar patients, i.e. without restricted indications.
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M. Rousseaux et al. / Onabotulinumtoxin-A injection for disabling lower limb flexion in hemiplegic patients
In conclusion, our results support the use of OnabotulinumtoxinA injections to the proximal region of the lower limb in patients presenting with severe hemiplegia and an abnormal hypertonic flexor pattern, in order to improve passive functions and comfort.
Declaration of interest Dr. Marc Rousseaux has been a medical consultant and has received honoraria for organizing training and teaching courses from Allergan, Ipsen, and Merz. Other authors have no conflict of interest.
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