Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy

Clinical Neurophysiology xxx (2015) xxx–xxx

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Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy q Kneis Sarah a,b,⇑, Wehrle Anja b,c, Freyler Kathrin b, Lehmann Katrin b, Rudolphi Britta d, Hildenbrand Bernd d, Bartsch Hans Helge d, Bertz Hartmut a, Gollhofer Albert b, Ritzmann Ramona b a

Department Medicine I, Haematology, Oncology and Stem Cell Transplantation, University Medical Centre Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany Institute of Sport and Sport Science, University of Freiburg, Schwarzwaldstr. 175, 79117 Freiburg, Germany Institute for Exercise- and Occupational Medicine, Department of Internal Medicine, University Medical Centre Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany d Tumour Biology Centre Freiburg, Breisacher Str. 117, 79106 Freiburg, Germany b c

a r t i c l e

i n f o

Article history: Accepted 26 July 2015 Available online xxxx Keywords: H-reflex Postural stability Co-contraction Latency Motor control

q

h i g h l i g h t s  Breast cancer patients with symptoms of chemotherapy-induced peripheral neuropathy (CIPN) suffer

from balance impairments and neuromuscular dysfunction.  Balance impairment is associated with a higher antagonistic co-contraction of lower-leg muscles.  CIPN is related to a prolonged H-reflex latency and an impaired capability to inhibit spinal excitability

(H-reflex).

a b s t r a c t Objective: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment. Resulting sensory and motor dysfunctions often lead to functional impairments like gait or balance disorders. As the underlying neuromuscular mechanisms are not fully understood, we compared balance performance of CIPN patients with healthy controls (CON) to specify differences responsible for postural instability. Methods: 20 breast cancer patients with CIPN (PAT) and 16 matched CONs were monitored regarding centre of pressure displacement (COP) and electromyographic activity of M. soleus, gastrocnemius, tibialis anterior, rectus femoris and biceps femoris. We calculated antagonistic co-contraction indices (CCI) and elicited soleus H-reflexes to evaluate changes in the elicitability and sensitivity of spinal reflex circuitry. Results: PAT’s COP displacement was greater than CON’s (p = .013) and correlated significantly with the level of CCIs and self-reported CIPN symptoms. PAT revealed prolonged H-wave latency (p = .021), decreased H-reflex elicitability (p = .001), and increased H-reflex sensitivity from bi- to monopedal stance (p = .004). Conclusions: We summarise that CIPN causes balance impairments and leads to changes in elicitability and sensitivity of spinal reflex circuitry associated with postural instability. We assume that increased simultaneous antagonistic muscle activation may be used as a safety strategy for joint stiffness to compensate for neuromuscular degradation. Significance: Sensorimotor training has the potential to influence neuromuscular mechanisms in order to improve balance performance. Therefore, this training modality should be evaluated as a possible treatment strategy for CIPN. Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Place where the work was done: Tumour Biology Centre Freiburg, Germany.

⇑ Corresponding author at: University Medical Centre, Department Medicine I, Haematology, Oncology and Stem Cell Transplantation, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel.: +49 761 270 73240; fax: +49 761 270 36640. E-mail address: [email protected] (S. Kneis). http://dx.doi.org/10.1016/j.clinph.2015.07.022 1388-2457/Ó 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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S. Kneis et al. / Clinical Neurophysiology xxx (2015) xxx–xxx

1. Introduction As screening measures and treatment options improve, the number of cancer survivors increases (Siegel et al., 2012). Many must deal with long-term physical health effects (Rowland and Bellizzi, 2014), including functional impairments due to chemotherapy-induced peripheral neuropathy (CIPN) (Stubblefield et al., 2009). CIPN occurs with an estimated incidence of 30–70% depending on factors such as substance class or cumulative dose (Mantyh, 2006). Taxanes (i.e. paclitaxel), mainly used in breast cancer treatment, cause CIPN in 57–83% of patients (Stubblefield et al., 2009). About 12% of US women will develop breast cancer during their lifetime (Siegel et al., 2015). Most women with late stage breast cancer and nearly a third with early-stage undergo taxane-based chemotherapy (Siegel et al., 2012). CIPN symptoms occur with paraesthesia like numbness and/or pain in a stocking-and-glove distribution (Argyriou et al., 2012). It is well known that neuropathy correlates with a loss of proprioception that causes postural and functional impairments (Resnick et al., 2000; Simoneau et al., 1995; van Schie, 2008). In CIPN patients, these impairments are often described as gait or balance disorders (Grisold et al., 2012; Visovsky and Daly, 2004; Wampler et al., 2007), most probably linked to a higher risk of falling (Tofthagen et al., 2012; Stubblefield et al., 2009), accompanied by significant limitations in daily life activities (Quasthoff and Hartung, 2002; Stubblefield et al., 2009; Windebank and Grisold, 2008). However, the consequences for patients’ daily life are often underestimated (Grisold et al., 2012) and little is known about the specific impairments of postural instability in CIPN (Wampler et al., 2007) or compensation strategies for functional deficits. In view of the lack of evidence-based treatment methods to manage functional impairments (Hershman et al., 2014), investigations need to address the underlying mechanisms of CIPN-induced postural instability. Reports in the literature indicate that enhanced postural skills (e.g. small sway paths in challenging postural tasks, quick balance recovery after perturbation) are accompanied by neuromuscular adaptations (Bruhn et al., 2004; Taube et al., 2007; Zech et al., 2010) and emphasise that changes on spinal and supraspinal levels are associated with alterations in postural control mechanisms (Gruber et al., 2007; Schubert et al., 2008; Taube et al., 2007; Yaggie and Campbell, 2006). Studies analysing spinal reflex circuitries via H-reflex measurements have shown that good balance skills correlate with diminished excitability of spinal reflexes (Taube et al., 2007). The inhibition of spinal excitability, such as for example from a simple to a difficult postural task or after a balance training intervention, apparently reduces involuntary postural oscillations and is thus assumed to lead to distinctly enhanced balance performance (Taube et al., 2008). This inhibitory mechanism allows the execution of controlled muscle activation programs on supraspinal levels (Taube et al., 2008), while facilitated spinal excitability is associated with exaggerated postural oscillations and thus stronger postural sway in a balance task (Taube et al., 2008). In cancer patients suffering from CIPN, proprioceptive feedback and central nervous system (CNS) function at the spinal level are strongly affected (Mantyh, 2006). In particular, large myelinated afferent fibres such as Ia fibres are injured by neurotoxic agents, i.e. taxanes (Mantyh, 2006). Furthermore, injuries to peripheral nerves interfere with proprioceptive cues, known to be essential for a quiet stance (Fitzpatrick and McCloskey, 1994; Peterka and Benolken, 1995). Taxanes among other chemotherapeutic agents are well known to cause selective injuries to the peripheral nervous system, inflammation in the dorsal root ganglion and peripheral nerves, destabilisation of microtubules essential for axonal

transport and neurochemical reorganisation in areas of the spinal cord involved in processing somatosensory information (Mantyh, 2006). These cellular and molecular neurotoxic mechanisms are associated with significant impairments in nerve function related to a reduced or even absent reliability of afferent feedback transmitted via sensory axons (Mantyh, 2006; Stubblefield et al., 2009). It can be emphasised that changes in Ia afferent transmission at the spinal level identifiable in H-reflex sensitivity may be responsible for gait and balance disorders (Wampler et al., 2007) and may cause overall changes in sensorimotor performance in these patient groups (Streckmann et al., 2014). Regarding sensorimotor interaction, there is evidence that an enhanced balance performance is accompanied by less simultaneous contraction of antagonistic muscles, while reduced balance skills are associated with increased co-contractions (Hu and Woollacott, 1994; Nagai et al., 2011). Reduced co-contraction is a key factor when accurate balance regulation is required during demanding postural tasks and consequently is associated with less postural sway (Nagai et al., 2012). In contrast, when upright equilibrium is threatened based on poor balance skills, supraspinal control mechanisms are believed to be responsible for higher co-contraction targeting joint stiffness as a safety strategy for keeping equilibrium (Bruhn et al., 2004; Hortobágyi et al., 2009; Nagai et al., 2011). Thus we speculate that greater postural sway in CIPN patients (Wampler et al., 2007) is accompanied by higher co-contraction. Taken together, these neuromuscular adaptations (i.e. changes in H-reflex sensitivity and co-contraction of antagonistic muscles) are known to affect balance control substantially (Bruhn et al., 2004; Heitkamp et al., 2001; Sayenko et al., 2012; Zech et al., 2010). We also know that neuropathy-induced loss of somatosensory information and/or processing leads to postural instability (Bonnet et al., 2009). However, the neuromuscular mechanisms underlying functional impairment especially in CIPN have been inadequately investigated. This study’s aim was therefore to compare the balance performance of CIPN patients and healthy controls and to detect differences in the underlying neuromuscular mechanisms responsible for CIPN-induced balance impairments.

2. Materials and methods 2.1. Experimental design We applied a repeated-measures matched-subject study design. Thus, we compared a group of breast cancer patients suffering from CIPN (PAT) with one of healthy controls (CON) to assess differences in their balance performance and associated neuromuscular mechanisms. We assessed the centre of pressure (COP) displacement, electromyographic (EMG) activity and spinal excitability in bi- and monopedal stance. Bipedal stance was used as a reference for normalisation.

2.2. Subjects 36 females (mean age 48, range 39–55 years) at the Tumour Biology Centre Freiburg participated in this study – 20 non-bed rest breast cancer patients after taxane-based chemotherapy reporting neuropathy symptoms due to chemotherapy, and 16 healthy controls matched by sex, age, height and weight (Table 1). All participants gave written informed consent to the study, which was approved by the Ethics Committee of the University of Freiburg and conducted according to the Declaration of Helsinki.

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

S. Kneis et al. / Clinical Neurophysiology xxx (2015) xxx–xxx Table 1 Subjects’ characteristics.

Female [n] Diagnosis breast cancer [n] Age [years] (mean ± SD) Height [cm] (mean ± SD) Weight [kg] (mean ± SD) Physical activity Frequency [times per week] (mean ± SD) Activity amount [minutes/ week] (mean ± SD) Cycles of neurotoxic drugs [n] Months [n] since administration of last neurotoxic drug (mean ± SD) Comorbidities [n] Diabetes mellitus Vestibular disorder Spinal injuries* Injuries to lower extremities# H-reflex elicitability [n] Hmax < 20% of Mmax [n] H-wave rises after the M-wave [n] PNP-symptoms NDS [score] (mean ± SD) Normal Achilles tendon reflex [n] Normal patella tendon reflex [n] Vibration sense [0–8] (mean ± SD) FACT/GOG-Ntx [%] (mean ± SD)

PAT

CON

Differences PAT vs. CON [%]

20 20 48.8 ± 4.5 169.5 ± 5.0 75.7 ± 21.7

16 0 46.5 ± 5.4 168.3 ± 6.1 76.6 ± 18.3

3.7 ± 2.9

4.1 ± 2.7

187 ± 109

172 ± 132

+8

4.3 ± 2.2 5.2 ± 4.4

0 –

+100 –

1 2 7 11 18 (20) 13 (18) 10 (18)

0 0 5 7 16 (16) 6 (16) 5 (16)

+5 +10 +4 +12 10 +40 +24

PAT 3.7 ± 1.9 3 (20)

CON 1.1 ± 1.7 11 (16)

p value 0.000 –

3 (20)

10 (16)

–

4.9 ± 1,8

6.9 ± 1.1

–

59.0 ± 14.8

98.0 ± 3.6

0.000

+100 +4 +1 1 9

SD, standard deviation; PNP, peripheral neuropathy; Hmax, maximum H-wave; Mmax, maximum M-wave; NDS, neuropathy deficit score; FACT/GOG-Ntx, Functional Assessment of Cancer Therapy/Gynaecology Oncology Group – Neurotoxity. * Prior to cancer diagnosis and without clinical symptoms. # Injuries to knee, ankle or Achilles tendon, calcaneal spur, Hallux valgus.

2.3. Procedures The PATs’ inclusion criteria were breast cancer diagnosis, completed chemotherapy, CIPN symptoms and age 655 years to exclude age-related degeneration of the neuromuscular system or the bias of inactivity. Participants were in outpatient treatment; none of our patients was in an inpatient clinic or experiencing bed rest. We also assessed comorbidities to ensure that they not worsen neuropathy symptoms. Exclusion criteria for matched CONs were exposition to chemotherapy and any neurological or metabolic disorders causing neuropathic symptoms. After a detailed anamnesis (cancer and CIPN treatment, comorbidities, lifestyle factors like physical activity, alcohol and nicotine consumption and CIPN-caused limitations in daily routine), CIPN was quantified objectively and subjectively: The neuropathy deficit score (NDS) includes objective neurological clinical testing such as reflexes, vibration, pain and temperature sensation, scored from 0 (no symptoms) to 10 (serious symptoms) (Onde et al., 2008; Young et al., 1993). Nerve conduction velocity was determined via latency measures by electrophysiology. To assess subjective CIPN symptoms, all subjects completed a particular sector in the FACT&GOG-Ntx (Functional Assessment of Cancer Therapy/ Gynaecology Oncology Group – Neurotoxicity) (Richardson et al., 2006) containing 11 items (Calhoun et al., 2003). A higher score (max. 100%) represents fewer symptoms and a higher quality of life than a lower score. Table 1 summarises all subjects’ clinical information.

3

Prior to data assessment, the subjects’ right leg was prepared for EMG measurements and peripheral nerve stimulation. Isometric maximum voluntary contractions (MVC) were performed for all recorded muscles according to Roelants et al. (2006). To reduce learning effects, each subject had a five-minute practice session to get used to the monopedal stance. For postural sway measurements, subjects stood over 30 s in bior monopedal stance, respectively, each followed by electrical stimulation over a period of three times 30 s for electrophysiological measurements according to Freyler et al. (2014). Between measurements subjects had at least a 1-min break. 2.4. Outcome measures 2.4.1. Postural sway COP displacement in total was determined during bi- and monopedal stance on a force plate (AMTI, Watertown, USA). The participants were barefoot, standing with arms hanging down, directing their head and eyes forward; they were asked to stand as still as possible. Each measurement entailed one trial lasting 30 s. Signals were recorded as three-dimensional (3D) ground reaction forces sampled at 50 Hz. 2.4.2. EMG recording Bipolar Ag/AgCl surface electrodes (Ambu Blue Sensor P, Ballerup, Denmark, diameter 9 mm, centre-to-centre distance 34 mm) were placed over the right leg’s soleus (SOL), medial gastrocnemius (GM), tibialis anterior (TA), rectus femoris (RF) and biceps femoris (BF) muscles (Horstmann et al., 1988). The electrodes’ longitudinal axes were in line with the presumed direction of the underlying muscle fibres. The reference electrode was placed on the patella. Inter-electrode resistance was kept below 5 k X by shaving, lightly abrading and degreasing the skin with a disinfectant. EMG signals were transmitted via shielded cables to the amplifier (band-pass filter 10 Hz to 1 kHz, 200 amplified) and recorded at 1 kHz (A/D-conversion via a National Instruments PCI-6229 DAQ-card, 16bit resolution). 2.4.3. Electrophysiology Modulation in the SOL’s H-reflex sensitivity and changes in nerve conduction velocity were assessed by measuring the Hreflex; H-reflexes were elicited via percutaneous peripheral nerve stimulation during a period of three times 30 s in bi- and monopedal stance, respectively. We used an electrical stimulator (Digitimer DS7, Digitimer, Welwyn Garden City, UK) to generate single rectangular pulses lasting 1 ms. The cathode (2 cm in diameter) was placed in the popliteal fossa and moved until the best position was found for eliciting an H-reflex in the SOL. The anode (10 * 5 cm dispersal pad) was fixed just below the patella on the anterior knee. H-reflexes were elicited by electrically stimulating the posterior tibial nerve at a 4-s interstimulus interval. The stimulation current was successively augmented, ranging from subthreshold stimulation intensities to those sufficient to elicit Hreflexes to supramaximum intensities for the maximum M-wave (Taube et al., 2008). Hmax/Mmax-recruitment curves were recorded in bi- and monopedal stance (Fig. 1) if H-reflexes could be elicited (elicitability; Pal, 1999). H-reflexes were not evoked in a phase dependent manner; subjects’ forward and backward movements were not considered. 2.4.4. Kinematics Ankle (dorsal flexion and plantar flexion) and knee kinematics (knee flexion and extension) were recorded on electrogoniometers (BiometricsÒ, Gwent, UK). One goniometer was placed over the femur’s lateral epicondyle with one endplate attached to the shank and aligned to the fibula’s lateral malleolus and the other to the

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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Fig. 1. H/M recruitment curves during (a) bipedal (BS) and (b) monopedal stance (MS) of one representative subject of CON (top) and PAT (bottom). H-reflexes and M-waves are normalised to Mmax. While CON showed no change in Hmax/Mmax-ratios from BS to MS, PAT showed first a lower Hmax/Mmax-ratio compared to CON and second an increase in Hmax/Mmax-ratio from BS to MS.

thigh aligned to the greater trochanter. The knee’s flexion angle was set to zero at 0° angle between the femur and fibula. The second goniometer was fixed at the lateral aspect of the right ankle with its ends attached parallel to the foot’s major axis in line with the fifth metatarsal and fibula. A 90° angle between the fifth metatarsal and fibula was defined as 90° ankle angle, whereas a plantar flexion was reflected by an ankle angle exceeding 90°. All signals were filtered (band-pass filter 10 Hz to 1 kHz) and recorded with a sampling frequency of 1 kHz.

2.5. Data processing For bi- and monopedal stances, total COP displacement (COPtotal) was calculated according to the Pythagoras theorem (COPtotal = R Di, i = [0;1200] with Di = [(Displacement in anteriorposterior axis)2 + (Displacement in medio-laterlal)2]½ for each sample point (Taube et al., 2008). EMG signals were rectified, integrated and time-normalised (iEMG [mVs]). For SOL, the background activity 100 ms prior to nerve stimulation was determined and expressed as iEMG [mVs]) to control for any changes in the background EMG concerning the H-reflex recordings’ validity. In addition, to assess simultaneous activation of antagonistic muscles encompassing the ankle, knee and hip joint, we calculated the co-contraction indices (CCI) for TA_SOL, TA_GM and BF_RF with the rectified and normalised EMG via the following equation: CCIi = R(lower EMGi/higher

EMGi)  (lower EMGi + higherEMGi) for each sample point, CCI = R CCIi (Lewek et al., 2004). Prior to calculation, each sample point was expressed as a percentage of the maximum MVC amplitude. CCI calculations allow to quantify voluntary changes in simultaneous antagonistic muscle activation (Hortobágyi et al., 2009; Nagai et al., 2011), being independent of forward or backward leaning (Tokuno et al., 2009) and thus, estimating articular stiffening of posture (Hortobágyi et al., 2009; Nagai et al., 2011; Sayenko et al., 2012): the higher the CCI, the higher antagonistic coactivation and the higher articular stiffening of the respective joint. Furthermore, peak-to-peak amplitudes of the H-reflexes and Mwaves were calculated and maximum H-reflex (Hmax) was expressed relative to the maximum M-wave (Mmax), defined as Hmax/Mmax-ratios to assess H-reflex sensitivity. H-wave latency was determined by the time between stimulus artefact till first slope of the averaged H-reflex and normalised to subjects’ body height (Soudmand et al., 1982). Ankle and knee kinematics were expressed as mean ankle and knee angles.

2.6. Statistics and graphics The variables COPtotal, Hmax/Mmax –ratios, H-wave latencies, all CCIs and scores of NDS and FACT&GOG-Ntx were used for statistical analysis. Differences between our two subject subpopulations were assessed by non-parametric analysis (Mann–Whitney-U-

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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3.2. CCI

test) as the assumption of normal distribution (Shapiro–Wilk test) was not satisfied. The level of significance was set to p = 0.05, and statistically significant differences marked with a (⁄) symbol in all figures. Bivariate correlations were calculated according to Spearman-Rho to display the relationship between variables of both groups, and PAT only for cancer relevant variables. All statistical analyses were conducted using IBM SPSS Version 22 software (SPSS Inc., Chicago, Illinois, USA). Group data are presented as median and 95% confidence interval (95% CI). All graphics were created by using Prism 5 Version 5.03 (GraphPad Software, Inc., La Jolla, CA, USA).

We noted a significant difference between groups in SOL_TA during monopedal stance (+33% in PAT). Moreover, there was a tendency toward augmented CCI for GM_TA in PAT compared to CON. These results reveal an increased level of simultaneouslyactivated antagonistic muscles in the lower leg in PAT compared to CON, being more pronounced in monopedal stance, whilst the agonist–antagonist activation of upper leg muscles revealed no significant changes between groups in both stance conditions (Table 2). 3.3. H-reflex

3. Results

We elicited an H-reflex in 18 of 20 PATs (Table 1). A very small Hreflex was visible in one PAT, but without a recognisable rise, making it impossible to calculate the Hmax/Mmax-ratio. Thus, H-reflexes of 18 subjects of PAT and of all subjects of CON were analysed. Fig. 1 illustrates the Hmax/Mmax-recruitment curves for one exemplary subject from PAT and CON depicting the H-wave modulation from bi- to monopedal stance. Medians and 95% CIs are shown in Table 2 and illustrated in Fig. 3b. Significant group differences appeared revealing a distinctly smaller Hmax/Mmax-ratio in PAT than CON. Furthermore, we observed a significant difference in H-reflex modulation from bi- to monopedal stance: PATs’ Hmax/Mmax–ratio has increased from bi- to monopedal stance (+45%), whereas the CONs’ was unchanged ( 5%). In ten of 18 PATs the H-wave begins to rise after the M-wave (see Table 1: H-wave rises after the M-wave). M-wave amplitudes show no group or condition differences.

PAT to CON comparison revealed significant differences in NDS and FACT/GOG-Ntx scores with an increase in objective (+2.7 points) and subjective ( 39 points) signs of neuropathy (Table 1). In addition, the PATs’ H-wave latency was significantly increased in bi- and monopedal stance (Table 2), indicating a slower nerve conduction velocity than the one in CONs’.

3.1. Postural sway COP displacements in bi- and monopedal stance in one exemplary subject from each group are illustrated in Fig. 2. Two PAT subjects and one CON were unable to stand unassisted on one leg for over 30 sc. Thus they were excluded from analyses. We observed significant differences in monopedal stance in terms of an augmented sway path for PAT compared to CON (+12%). Bipedal stance revealed no group differences. Medians and 95% CIs are shown in Table 2 and illustrated in Fig. 3a.

3.4. SOL background activity We identified no significant group differences in either bi- or monopedal stance (Table 2).

Table 2 Medians, 95% CI and p-values of the kinematic and neuromuscular parameters. Condition

Bipedal stance (BS)

Monopedal stance (MS)

Group by condition differences

Subjects

PAT

CON

PAT

CON

MS/BS

Median 95% CI n = 18 63.1 55.9–65.8 n = 20 102.3 94.1–159.6 106.7 94.1–147.8 96.4 71.4–168.2 n = 17 0.11 0.10–0.27 0.020 0.019–0.023 n = 15 1

Median 95% CI n = 15 63.3 55.8–66.1 n = 15 88.5 76.3–97.3 84.0 72.1–93.3 75.6 59.9–143.2 n = 16 0.37 0.26–0.44 0.019 0.017–0.023 n = 16 1

Median 95% CI n = 18 115.6 110.3–129.9 n = 20 859.8 712.3–1102.7 947.5 691.5–1082.9 203.9 166.1–657.1 n = 17 0.20 0.18–0.31 0.020 0.019–0.023 n = 15 1.01 0.99–1.03 n = 19 6.38 4.24–8.30 2.47 1.96–4.51

Median 95% CI n = 15 102.1 95.9–116.5 n = 15 577.4 482.0–918.9 483.10 454.5–861.5 200.6 156.4–444.5 n = 16 0.35 0.29–0.45 0.019 0.017–0.023 n = 16 1.0 1.01–1.04 n = 15 6.62 4.70–8.55 2.74 1.74–4.70

Postural sway [cm] COPtotal CCI [mV] SOL_TA GM_TA BF_RF H-reflex Hmax/Mmax ratios H-wave latency* normalised to body height [s/m] Background activity SOLnorm

D joint angle [°] Knee Ankle

p value

.383

.138 .058 .291

.001 .001 –

p value

p value

.013

.059

.047 .280 .066 .066 .428 .304 .001 .004 .021 – .470 .758

.732

PAT, CIPN-patients; CON, healthy controls; p, p-value (Mann–Whitney-U-test); CI, confidence interval; COP, centre of pressure; CCI, co-contraction index; SOL_TB, soleus_tibialis anterior; GM_TB, gastrocnemius_tibialis anterior; BF_RF, biceps femoris_rectus femoris; Hmax, maximum H-wave; Mmax, maximum M-wave; BF, biceps femoris_rectus femoris; norm, normalised to BS; D, delta. * H-wave latency normalised to individual body height.

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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Fig. 2. COP displacements during (a) bipedal (BS) and (b) monopedal stance (MS) of one representative subject of CON (top) and PAT (bottom). Both subjects showed an increase in COP displacement from BS to MS, more pronounced in PAT.

3.5. Kinematics In Table 2, medians and 95% CIs of the difference in knee and ankle angles for the two stance conditions are displayed for PAT and CON. No significant differences appeared between the groups for bi- and monopedal stance. 3.6. Correlations Concerning balance performance and co-contraction of antagonistic muscles in monopedal stance: we detected a significant correlation between COPtotal and CCIs of SOL_TA (r = .683; p = .000), GM_TA (r = .682; p = .000) and RF_BF (r = .488; p = .004), indicating

that augmented postural sway is associated with higher antagonistic co-contraction (Fig. 3c). Furthermore, COP displacement in monopedal stance correlates significantly negatively with the FACT&GOG-Ntx score (r = .379; p < .030), meaning that augmented neuropathy symptoms are associated with higher postural sway for PAT. The number of applied cycles of neurotoxic drugs also correlates weakly with PATs’ COP displacement in monopedal stance for PAT (r = .483; p = .042). We noted weak correlations for the Hmax/Mmax-ratio and CCI or COP displacement. However, other findings show that (i) a decreased Hmax/Mmax-ratio and (ii) increased H-reflex latency in monopedal stance are significantly associated with stronger objective (higher score in NDS; (i) r = .346; p = .050; (ii) r = .511;

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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Fig. 3. Results of PAT and CON of (a) the COP displacement and (b) Hmax/Mmax-ratio in bipedal (BS) and monopedal stance (MS). Box-and-whisker plots show the lower quartile (25th percentile), the median (50th percentile), the upper quartile (75th percentile) and the degree of dispersion as 95% confidence interval (95% CI). *Indicates a significant difference (*p < 0.05, Mann–Whithney-U-test). The scatterplot in (c) graphically represents the relationship between centre of pressure displacements (x-axis COPtotal) vs. co-contraction indices (CCIs) of the antagonistic muscles of the shank SOL_TA and GM_TA (y-axis) of PAT and CON.

p = .002) and subjective (lower score in FACT&GOG-Ntx; (i) r = .430; p = .013 (ii) r = .403; p = .020) neuropathy symptoms for PAT. These findings are strengthened by the significant negative correlation we observed between the Hmax/Mmax-ratio and H-wave latency in monopedal stance (r = .346; p = .049).

4. Discussion Our investigation revealed two major findings: first, in the balance condition with greater task difficulty postural sway was increased in the balance condition with greater task difficulty in breast cancer patients suffering from CIPN compared to a matched control group of healthy subjects. This balance impairment correlates with CIPN symptoms, moderately with chemotherapy cycles and higher antagonistic co-contraction of lower-leg muscles. Second, a prolonged H-reflex latency and changes in H-reflex sensitivity related to a modulated spinal excitability reflect CIPNassociated damage to the nervous system. The electrophysiological findings correlate with CIPN symptoms, which were determined by clinical tests (NDS) and a questionnaire (FACT&GOG-Ntx). These outcomes provide evidence of the interrelationship between balance performance, neuromuscular functions and neuropathy symptoms in breast cancer patients suffering from CIPN.

Our postural sway findings are in line with those of Wampler et al. (2007) and Bonnet et al. (2009) evaluating sensorimotor behaviour in breast cancer patients after taxane-based therapy and patients with diabetes-induced neuropathy, respectively. Other authors detected augmented postural sways in challenging balance tasks, which is associated with a higher incidence of falling (Rubenstein and Josephson, 2002). We know that the neuropathycaused loss of somatosensory information affects postural strategies considerably and triggers increased postural instability (Bonnet et al., 2009; Dickstein et al., 2001; Horak and Hlavacka, 2001). Functional consequences are manifold, ranging from physical impairments (Rubenstein and Josephson, 2002; Winter, 1995), higher accident propensity and injury incidence (Karaminidis and Arampatzis, 2007; van Dieën et al., 2005) causing reduced mobility, morbidity and a loss of independence in daily life (Heinrich et al., 2010; Rubenstein and Josephson, 2002; Tinetti, 1994). Our results further suggest that more cycles of taxane-based therapy and more severe CIPN symptoms correlate negatively with body equilibrium and postural stability. Apparently, PAT was a homogenous subpopulation that suffer from a mild-moderate form of CIPN as the NDS score reveals a difference of only 2.6 points compared to CON. Based on literature we expect that an advanced disease stage accompanied by a more distinct and patchy sensory loss may have led to explicitly augmented balance deficits and

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diminished sensorimotor capacities (Mauritz and Dietz, 1980; Nardone et al., 2007). Consequently, we suppose that underlying mechanisms, compensatory postural regulations and functional consequences for affected patients can be classified as follows. 4.1. Underlying mechanisms Our electrophysiological results indicate chemotherapyinduced changes in H-reflex elicitability, sensitivity and latency. Chemotherapeutic agents such as taxanes elicit cellular and molecular neurotoxic dysfunctions in large afferent fibres such as Ia fibres and the dorsal root ganglion (Mantyh, 2006; Stubblefield et al., 2009). We assume that due to persistent damage, sensory feedback from muscle spindles transmitted via the Ia pathway is slower and less reliable after taxane-based therapy as indicated by abnormalities in the clinical assessment of the Achilles and Patellar tendon stretch reflexes (see Table 1). The afferent muscle spindle signals are a major source of information when balance is perturbed, delivering a stretch reflex response via the monosynaptic circuitry immediately compensating perturbations and counteracting postural degradation (Granacher et al., 2006; Nardone et al., 2007). Moreover, sensory muscle spindle input is processed in supraspinal areas, influences motor programs, and considerably contributes to balance strategies via long loop reflexes transmitted via supraspinal areas (Mauritz and Dietz, 1980; Taube et al., 2007). We detected that prolonged H-reflex latency and a high symptom score characterised CIPN patients in this study. Prolonged Hreflex latency and its correlation to sensory symptoms have been reported in conjunction with other types of neuropathy (Bertelsmann et al., 1986; Guo et al., 2014; Marya et al., 1986; Millán-Guerrero et al., 2012). There is evidence that decelerated nerve conduction velocity preferentially represents demyelinating lesions (Chen et al., 2013) and may lead to a delayed response to a postural task, i.e. postural instability. In our study, this may be represented by the PATs augmented COP sway path. Unfortunately, we could not show this relationship on the basis of our correlation results due to small, but significant, group differences in H-reflex latency and the relatively small sample size. Furthermore, we observed marked differences in regard to the Hmax/Mmax-recruitment curves and the corresponding Hmax/Mmax-ratios in our patients compared to healthy controls. Differences are characterised as: first, a significantly smaller Hmax/Mmax-ratio was observed which persisted regardless of the stance condition and was not influenced by changes in kinematics, SOL M-waves or background activity. Second, a later rise in the H-wave compared to the M-wave in contrast to normal Hmax/Mmax-recruitment curves has been demonstrated (Zehr, 2002). Significant differences were detected although H-reflexes were not elicited in a phase dependent manner considering subjects’ forward and backward movements (Tokuno et al., 2009). These findings are in line with observations made in CIPN patients after Vincristin-based chemotherapy (Freund et al., 1969; Pal, 1999). We suspect that this H-reflex delay compared to M-wave, coupled with diminished H-reflex elicitation reveals primarily afferent damage (Argyriou et al., 2012; Mantyh, 2006) that causes an elevated stimulation threshold for the depolarisation of afferent compared to the efferent nerves to evoke an action potential (Mauritz and Dietz, 1980; Taube et al., 2007). Such damage might be responsible for insufficient conduction of afferent information and may disturb spinal reflex circuitries. 4.2. Compensatory postural strategy PAT showed an increase in H-reflex sensitivity from bi- to monopedal stance, pointing towards an increase in spinal

excitability via a facilitation of the SOL H-reflex, or even more probably a reduced capability to inhibit the SOL H-reflex (Taube et al., 2008). Increased H-reflex sensitivity during monopedal stance indicates augmented Ia afferent transmission and consequently, an elevated level of spinal excitability (Zehr, 2002). This is associated with the abnormal and exaggerated occurrence of short loop reflexes transmitted via the Ia afferent pathway in the lower leg’s distal muscles (Chen and Zhou, 2011; Taube et al., 2008). We assume that patients facilitate reflexes because of unreliable muscle spindle cues to stabilise posture during challenging postural tasks accepting enhanced oscillation. In manuscripts addressing adaptations in spinal excitability via peripheral nerve stimulation in longitudinal studies, investigators describe that reduced level of spinal excitability led to an improvement in balance control (Gruber et al., 2007; Taube et al., 2007). On the other hand, authors emphasised that increased excitability of spinal reflexes may cause rapid changes in direction (Cabeza-Ruiz et al., 2011), thus disturbing postural stabilisation by inducing significantly augmented COP displacements (Taube et al., 2008). We assume that patients try to maintain posture despite the aforementioned neuronal dysfunctions and enhanced oscillation by augmenting the activation of simultaneously activated antagonistic muscles (Bruhn et al., 2004; Hortobágyi et al., 2009; Sayenko et al., 2012). This strategy targets joint stiffness for safety reasons (Bruhn et al., 2004; Hortobágyi et al., 2009; Nagai et al., 2011). However, such rigid joint stiffening limits one’s ability to react precisely to sudden perturbation resulting in augmented COP displacement (Allum et al., 2002; Tucker et al., 2008). We know that people with reduced mobility and/or a fall history (e.g. the elderly) display greater antagonistic-muscle co-contraction coupled with increased postural sway and higher fall incidence than younger persons or athletes (Nagai et al., 2011). The less somatosensory information there is available, the more supraspinal control is required to maintain posture (Mauritz and Dietz, 1980). As a result, joints become increasingly stiff by enhancing co-contraction (Bruhn et al., 2004; Hortobágyi et al., 2009; Nagai et al., 2011). This observation is reflected by our findings, even if there are no significant changes but strong tendencies pointing towards group differences. Particularly in the shank muscles, PAT compared to CON showed a more pronounced co-contraction, indicating that increased demand on the postural system reduces patients’ capacity to compensate for the loss of somatosensory information (Bruhn et al., 2004; Hortobágyi et al., 2009; Nagai et al., 2011; Sayenko et al., 2012). 4.3. Limitations and prospective In this context, we considered it necessary to mention that physical inactivity, muscle weakness and chemotherapy-induced side effects within or beyond peripheral neuropathy can also interfere with postural stability (Kiers et al., 2013). As we asked all participants for the amount and frequency of habitual physical activity and found no group differences in their stated data, we can exclude inactivity as a major factor (Table 1). However, animal experiments demonstrated ototoxicity and mild histopathologic changes in the mouse cochlea in response to cytostatic medication (Dong et al., 2015). Upright stance is organised by the CNS using sensory information from the visual, vestibular and proprioceptive afferents to maintain equilibrium and thus, chemotherapy-induced vestibular impairments may have interfered with postural control in this study as well (Fitzpatrick and McCloskey, 1994; Peterka and Benolken, 1995). Although vestibular disorders in PAT did not differ compared to CON (Table 1), in future investigations executed with the aim of gaining a deeper understanding of CIPN methodological distinctions regarding vestibular and proprioceptive feedback as well as dynamic perturbation, paradigms should be considered to simulate the fall situation itself.

Please cite this article in press as: Kneis S et al. Balance impairments and neuromuscular changes in breast cancer patients with chemotherapy-induced peripheral neuropathy. Clin Neurophysiol (2015), http://dx.doi.org/10.1016/j.clinph.2015.07.022

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4.4. Consequences and conclusion In conclusion, we observed an interrelationship among neuropathy symptoms, postural instability and neuromuscular mechanisms in breast cancer patients suffering from CIPN after taxane-based therapy. Disturbed stimulus conduction due to neuropathy-induced CNS damage lead to changes in the Ia afferent reflex circuit relevant for posture control. CIPN patients compensate for this sensory dysfunction associated with unreliable Ia afferent spindle information by intensified co-contraction and involve simultaneously activated antagonistic muscle groups resulting in worse rigidity and postural instability. Furthermore, patients may facilitate afferent input to amplify sensory information considerably declined in CIPN. Evidence from recent research indicates that physical exercise may reduce postural instability in CIPN patients (Streckmann et al., 2014a,b). Research addressing exercise as a means to prevent falls identified regimes including balance training to counteract postural degradation and to reduce co-contraction and hence compensate sensory deficits (Granacher et al., 2006; Karlsson et al., 2013; Streckmann et al., 2014a; Ungar et al., 2013). Balance training delivered in clinical settings could also have the potential to enhance neuromuscular function, to shift neuronal control to subcortical areas, and to induce changes in sensorimotor behaviour (Gruber et al., 2007; Taube et al., 2007, 2008). However, further evidence is required to underline its positive effects on CIPN and further assess it as a treatment option to manage CIPN. Acknowledgements We acknowledge the cooperation of and patients’ recruitment at the Tumour Biology Centre Freiburg. We thank the patients and control individuals for their collaboration. Conflict of interest: None. References Allum JHJ, Carpenter MG, Honegger F, Adkin AL, Bloem BR. Age-dependent variations in the directional sensitivity of balance corrections and compensatory arm movements in man. J Physiol 2002;542:643–63. Argyriou AA, Bruna J, Marmiroli P, Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Crit Rev Oncol Hematol 2012;82:51–77. Bertelsmann F, Heimans J, van Rooy J, Visser S. Comparison of Hoffmann reflex with quantitative assessment of cutaneous sensation in diabetic neuropathy. Acta Neurol Scand 1986;74:121–7. Bonnet C, Carello C, Turvey MT. Diabetes and postural stability: review and hypotheses. J Mot Behav 2009;41:172–92. Bruhn S, Kullmann N, Gollhofer A. The effects of a sensorimotor training and a strength training on postural stabilisation, maximum isometric contraction and jump performance. Int J Sports Med 2004;25:56–60. Cabeza-Ruiz R, García-Massó X, Centeno-Prada RA, Beas-Jiménez JD, Colado JC, González L-M. Time and frequency analysis of the static balance in young adults with Down syndrome. Gait Posture 2011;33:23–8. Calhoun EA, Welshman EE, Chang C-H, Lurain JR, Fishman DA, Hunt TL, Cella D. Psychometric evaluation of the Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group—Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003;13:741–8. Chen X, Stubblefield MD, Custodio CM, Hudis CA, Seidman AD, DeAngelis LM. Electrophysiological features of taxane-induced polyneuropathy in patients with breast cancer. J Clin Neurophysiol 2013;30:199–203. Chen Y-S, Zhou S. Soleus H-reflex and its relation to static postural control. Gait Posture 2011;33:169–78. Dickstein R, Shupert CL, Horak FB. Fingertip touch improves postural stability in patients with peripheral neuropathy. Gait Posture 2001;14:238–47. Dong Y, Ding D, Jiang H, Shi JR, Salvi R, Roth JA. Ototoxicity of paclitaxel in rat cochlear organotypic cultures. Toxicol Appl Pharmacol 2015;280:526–33. Fitzpatrick R, McCloskey DI. Proprioceptive, visual and vestibular thresholds for the perception of sway during standing in humans. J Physiol 1994;478:173–86. Freund H, Kendel K, Obrecht P. Zur Klinik und Pathophysiologie der Vincristinwirkungen am Nervensystem. Dtsch Z Für Nervenheilkd 1969;196: 319–30. Freyler K, Weltin E, Gollhofer A, Ritzmann R. Improved postural control in response to a 4-week balance training with partially unloaded bodyweight. Gait Posture 2014;40:291–6.

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