Monitoring the short-term effect of intravenous immunoglobulins in multifocal motor neuropathy using motor unit number index

Clinical Neurophysiology 128 (2017) 235–240

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Monitoring the short-term effect of intravenous immunoglobulins in multifocal motor neuropathy using motor unit number index Manon Philibert a,1, Aude-Marie Grapperon a,1, Emilien Delmont a,b, Shahram Attarian a,b,c,⇑ a

Neuromuscular Disease and ALS Reference Center, Timone University Hospital, Marseille, France Aix-Marseille University, UMR 7286, Faculty of Medicine, Marseille, France c Aix-Marseille University – Inserm UMR 910 Medical Genetics and Functional Genomics, Marseille, France b

a r t i c l e

i n f o

Article history: Accepted 12 November 2016 Available online 01 December 2016 Keywords: Multifocal motor neuropathy Motor unit number index Dysimmune neuropathy Intravenous immunoglobulins

h i g h l i g h t s  MUNIX was used to test therapeutic response to intravenous immunoglobulins (IVIg) in multifocal

motor neuropathy (MMN) patients.  MUNIX sum-score was lower in MMN patients than in healthy controls.  MUNIX sum-score improved quickly after intravenous immunoglobulin treatment in MMN.

a b s t r a c t Objective: To determine whether motor unit number index (MUNIX) is pertinent to monitor the effect of intravenous immunoglobulins (IVIg) in multifocal motor neuropathy (MMN). Methods: MUNIX was assessed longitudinally in 7 MMN patients and 17 healthy controls in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. A MUNIX sum-score and a compound muscle action potential (CMAP) sum-score were calculated by summing up the scores of APB and ADM. MMN patients were evaluated on the first day of IVIg infusion, 5 MMN patients were evaluated 22 days after IVIg infusion, and 3 MMN patients were evaluated 1 month after two IVIg infusions. Results: Intraclass correlation coefficient of the MUNIX sum-score in healthy controls was 0.85, showing good test–retest reproducibility. MUNIX and CMAP sum-scores were lower in MMN patients than in healthy controls (p < 0.01 and 0.02, respectively). MUNIX sum-score improved in three of the five patients 22 days after IVIg infusion and in two of the three patients 1 month after 2 IVIg infusions, whereas CMAP sum-score improved in only one patient in both evaluations. Conclusions: In this preliminary study, MUNIX seems to be a reliable and sensitive tool to monitor the short-term efficiency of IVIg in MMN. Significance: MUNIX can help monitor IVIg treatment in MMN. Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Multifocal motor neuropathy (MMN) is an immune-mediated, purely motor neuropathy, characterized by an asymmetrical, progressive, and primarily distal muscle weakness, which generally starts and predominates in the upper limbs (Nobile-Orazio et al., 2005; Léger et al., 2015). Electrophysiological studies show persis⇑ Corresponding author at: Reference Center for Neuromuscular Disease and ALS, Timone University Hospital, 264 rue Saint Pierre, 13005 Marseille, France. Fax: +33 4 91 42 68 55. E-mail address: [email protected] (S. Attarian). 1 These authors contributed equally to this work.

tent multifocal conduction blocks on motor nerves, with normal sensory nerve conduction study. First-line treatment is intravenous immunoglobulins (IVIg), with a success rate of approximately 80% (Azulay et al., 1994; Van den Berg et al., 1995; Federico et al., 2000; Léger et al., 2001; Hahn et al., 2013). Most patients need repeated IVIg infusions for a long term. Maintenance IVIg therapy should be tailored based on the clinical response of the patients (Berg-Vos et al., 2002; Slee et al., 2007). Nevertheless, clinical assessment may not be sensitive enough to monitor the response to IVIg; therefore, clinicians need more sensitive markers to measure disease progression.

http://dx.doi.org/10.1016/j.clinph.2016.11.012 1388-2457/Ó 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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Electromyography is mandatory to diagnose MMN and is considered as quantitative data; however, it is uncommonly applied as outcome measures in the monitoring of MMN patients. Motor unit number index (MUNIX) (Nandedkar et al., 2004, 2010) is a new electrophysiological technique that estimates the number of functional motor units for each analyzed muscle. MUNIX has the advantage over the currently available motor unit number estimation techniques of being a rapid and easy-to-perform method which only requires measurable compound muscle action potentials (CMAP). MUNIX was reported to be useful in measuring motor unit loss in patients with amyotrophic lateral sclerosis (Nandedkar et al., 2010; Boekestein et al., 2012; Furtula et al., 2013; Neuwirth et al., 2015) and axonal loss in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Paramanathan et al., 2016). MUNIX demonstrated proper reproducibility in ALS and healthy controls (Ahn et al., 2010; Nandedkar et al., 2011; Neuwirth et al., 2011, 2016; Fathi et al., 2016). We have recently demonstrated that MUNIX has a good reproducibility and is related to the disability in CIDP (Delmont et al., 2016). In this study, we assessed whether MUNIX was modified after IVIg treatment in MMN patients. Our aim was to determine if MUNIX was relevant to monitor the response to treatment in MMN. 2. Methods 2.1. Subjects Seven MMN patients fulfilling the Joint Task Force of the EFNS and the PNS 2010 criteria (Joint Task Force of the EFNS and the PNS, 2010) were enrolled at the Department of Neuromuscular Disorders in the University Hospital of Marseille, France, between February and August 2015. All patients presented MMN with conduction blocks evidenced by nerve conduction studies. Clinical and electrophysiological characteristics of the MMN patients are summarized in Table 1. Seventeen healthy controls were included. All patients and controls gave informed consent prior to the study enrolment. 2.2. Clinical assessment Clinical assessment was performed by the same trained rater at every visit. Disability was evaluated by overall neuropathy limitation scale (ONLS) (Graham and Hughes, 2006). Muscle strength was measured by the Medical Research Council (MRC) scale in the two muscles of interest: abductor pollicis brevis (APB) and abductor digiti minimi (ADM). MRC sum-score was calculated by summing up the APB and ADM scores. 2.3. MUNIX procedure MUNIX was performed on APB and ADM muscles for all patients and controls. Studies were performed on the most affected side for each patient. Records were made using commercially available Keypoint machine (Medtronic, Copenhagen, Denmark), disposable pregelled surface 10-mm2 electrodes, and handheld bipolar stimulator with saline-soaked electrodes. Subjects were positioned in a comfortable supine position during measurements. The bandpass filter setting was 3–3000 Hz. Skin temperature was >32 °C. Points of stimulation, placement of recording electrodes, and distances between active and reference electrodes were standardized as described in the original technique (Nandedkar et al., 2004; Neuwirth et al., 2010). Flat baseline was controlled before the examination. The first step consisted of recording the CMAP

amplitude by supramaximal stimulation. The position of the active recording electrode was adjusted so as to achieve the highest possible CMAP amplitude (van Dijk et al., 1995; Bromberg and Spiegelberg, 1997) to optimize the reliability of the technique (Ahn et al., 2010; Nandedkar et al., 2010; Neuwirth et al., 2010; Sandberg et al., 2011). The size of the negative phase was used to calculate the CMAP amplitude. Then, the surface electromyography interference pattern (SIP) was recorded with a time analysis of 300 ms epochs, 10 times for each muscle, at five different force levels. The patient was asked to give a voluntary contraction against the resistance provided by the operator at increasing isometric force levels (10%, 25%, 50%, 75%, and then 100% of the maximal force) with 15 s of rest between 75% and 100% and 30 s between the two series. Maximum contraction was performed initially as a reference for the patient to estimate his/her strength. SIP area, SIP power, and ideal case motor unit count (ICMUC) were calculated for each SIP recording. The criteria to accept SIP epochs, previously described, to avoid interference with volume-conducted activity of neighboring muscles that could influence MUNIX calculation, were SIP area >20 mVms, ICMUC <100, SIP area/CMAP area >1 (Nandedkar et al., 2010) and CMAP >0.5 mV. Finally, electromyography measures were used to calculate MUNIX and motor unit size index (MUSIX) by means of an Excel file. Ten valid ICMUC-SIP area combinations were required for a reliable regression analysis for MUNIX computation. MUNIX tests lasted approximately 15 min. We added the MUNIX, MUSIX and CMAP amplitude scores of the APB and ADM muscles to compute MUNIX sum-score, MUSIX sum-score, and CMAP sum-score. 2.4. Study design Patients were examined at two different time points. Five patients were evaluated on the first day of IVIg infusion (day 1), considered as the worst clinical state, and 22 days after the infusion (day 22) (interquartile range 20–23) corresponding to the beginning of the third week after the end of the infusion. The action of IVIg lasts at least 3 weeks after the infusion (half-life of IgG is 21 days). Hence, in the recommendations of EFNS PNS the interval of IVIg infusion is every 2–4 weeks (EFNS 2010 MMN). We therefore used the comparison between days 1 and 22 to evaluate the short-term efficiency of IVIg infusion. Three recently diagnosed patients received their first IVIg infusion during the inclusion period and were investigated on the first day of the first infusion (Infusion 1) and also on the first day of the third infusion (Infusion 3). The median interval between two infusions was 6 weeks. The comparison between Infusion 1 and Infusion 3 was used to evaluate the response to treatment at a longer term. All patients were treated with the same dose of IVIg of 2 g/kg. All the evaluations included a clinical and an electrophysiological examination that were performed by the same investigator trained for this technique, with the same electrode placement. MUNIX was assessed twice in 17 healthy controls, with a median interval of 10 days (7–14 days). 2.5. Statistical analysis The intra rater variability of MUNIX in the control group was determined with an intraclass correlation coefficient (ICC). The best reproducibility is achieved if ICC is equal to 1. In previous studies MUNIX reproducibility was considered good if ICC >0.75 (Futurla et al., 2013). To assess normative data, we calculated the coefficient of variation (COV) between the two measures of MUNIX sum-score, MUSIX sum-score, and CMAP sum-score in the control group. COV was calculated as the absolute difference between test

133 48 8.9 4.5 R

L +

A B 10 6 51 71 MMN 6 MMN 7

M F

1.3 4

+

4 0

5 6

R R

None Thenar Hypothenar

3/5 3/5

+ + +

+ +

L L +

B A B 6 7 7

A 6

2/5 1/5 2/5

L

L L L 6 8 6

5 >50

45 8 3 +

+ 8

16 2.7 16 F M M

45

81 77 80

MMN 2

MMN 3 MMN 4 MMN 5

M

Thenar Dorsal inter-osseous Dorsal inter-osseous

2/5

+ B 4 2/5

Thenar Hypothenar Hypothenar L 5 16 + 2.3 M 35 MMN 1

M: male, F: female, +: present, : absent, L: left, R: right, A: complete efficiency, B: partial efficiency. Data is expressed for each patient, and then by adding the results of every patient, in median with interquartile range. ONLS median value is obtained by adding the results for upper and lower limbs. MRC sum is calculated by adding the MRC score for APB and ADM muscles of the weakness hand side.

135 73 11.5 4.2

88 6 20

27 3.3

9.9 1.6 3.0

69

121 54 17

10.3

41 38 92 46 41 85 90 48 40 Forearm Forearm Forearm Forearm Erb point Erb point Forearm Forearm Forearm Ulnar L Median Median Ulnar L Ulnar L Median Ulnar R Ulnar R Median

5.7 7.3 1.7

8 2.5 48 40 Forearm Ulnar L

2.6

CMAP amplitude drop (%) Evaluation protocol day1 day22 Subjective efficiency MRC sum ONLS upper limb Site of muscle atrophy Weakness hand side Inter-infusion time (weeks) Infusion number IgM anti-GM1 Disease duration (years) Sex Age (YO) Patient

Table 1 Demographic, clinical and electrophysiological characteristics of patients at the first time of evaluation.

Evaluation protocol Infusion1 Infusion3

Nerve with conduction block

Conduction block location

CMAP APB (mV)

MUNIX APB

CMAP ADM (mV)

MUNIX ADM

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and retest values divided by their mean value. As there is no normal value of the COV in MMN patients, we used the COV in healthy controls as normal value to determine if the COV in MMN patients was statistically significant. The 95th percentile of the COV of the healthy control group was determined as the upper limit of the normal range of the COV, and the results of COV above this value were determined as statistically significant. Continuous data was expressed in median with interquartile range. We used the nonparametric Mann–Whitney test or the nonparametric Wilcoxon test (for paired data) to compare them. Categorical data was compared using the nonparametric Fisher’s exact test. Statistical analysis, including Spearman’s correlation analysis, linear regression, COV, and ICC, were performed using GraphPad Prism 5 and IBM SPSS statistics (version 20). A two-sided p value <0.05 was considered as statistically significant. 3. Results 3.1. Healthy controls The group of healthy controls included eight males and nine females and was sex and age matched with patient group (p > 0.5). The median age was 42 years (interquartile range 32– 45 years). The results of the MUNIX test are given in Table 2. The MUNIX sum-score was correlated with the CMAP sum-score (r = 0.82, p < 0.001) but not with the MUSIX sum-score. Test–retest reliability was good in healthy controls (Fig. 1): ICC MUNIX sum-score was 0.85; ICC MUSIX sum-score was 0.85; ICC CMAP sum-score was 0.77. The median COVs of the MUNIX, MUSIX, and CMAP were 12%, 12%, and 7%, respectively. The 95th percentile of the COVs of the MUNIX, MUSIX, and CMAP were 27%, 24%, and 20%, respectively. 3.2. MMN patients Five male and two female MMN patients were recruited. Patients’ median age was 71 years (range 48–79 years). The median disease duration at first evaluation was 4 years (range 2.5– 12 years). Among the three patients evaluated at Infusion 1 and Infusion 3, one patient (MMN 7) had never been previously treated, whereas for two patients (MMN 5 and MMN 6), the treatment had been stopped for several years but had to be restarted because of a relapse of the neuropathy. Patient MMN 5 was included in both protocols and evaluated at day 1 and day 22 as well as at Infusion 1 and Infusion 3. The two other patients evaluated at Infusion 1 and Infusion 3 (MMN6, MMN7) could not be included in both protocols because they disagreed to come back to hospital at day 22 due to their advanced age and the long geographical distance separating their home from the hospital. There were conduction blocks in most of the nerves tested. The localization of the conduction blocks is given in the Table 1. The results of the MUNIX tests at first evaluation are shown in Table 2. MUNIX sum-score was correlated with the CMAP sumscore (r = 0.86, p = 0.01) and MUSIX sum-score (r = 0.96, p < 0.001). MUNIX procedure was well tolerated, and all patients completed the study. Compared to healthy controls, MUNIX and CMAP sum-scores were significantly lower in MMN patients than in healthy controls, whereas MUSIX sum-score was higher in MMN patients than in healthy controls (p < 0.05) (Table 2). MUNIX sum-score was correlated with CMAP sum-score (r = 0.86; p = 0.01) and MUSIX sum-score (r = 0.96; p < 0.0001) and with ONLS score (r = 0.78; p = 0.04). CMAP sum-score was correlated with MUNIX sum-score (r = 0.86; p = 0.01).

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Table 2 Results of MUNIX first evaluation in MMN patients and healthy controls. Data is expressed in median with interquartile range. Muscle

MMN patients (n = 7)Median (interquartile range)

Healthy controls (n = 17)Median (interquartile range)

p value

MUNIX

APB ADM Sum-score

57 (48–95) 27 (14–80.5) 96 (59–165)

185 (154–216) 161 (130–183) 333 (288–376)

p = 0.001 p = 0.001 p = 0.0006

MUSIX

APB ADM Sum-score

93.3 (51.4–114) 121.9 (98.9–197.9) 271 (155.2–384.5)

59.4 (52.5–71.6) 63.7 (59.5–82.7) 127.3 (119.5–145.8)

p = 0.5 p = 0.02 p = 0.01

CMAP (mV)

APB ADM Sum-score

4.5 (2.4–6.5) 3.3 (2.8–7.1) 8.9 (7.2–14.6)

11.3 (9.5–12.5) 10.9 (9–12.1) 20.3 (19.8–23.4)

p = 0.001 p = 0.01 p = 0.002

Sum-scores are obtained by summing up the corresponding results of APB and ADM muscles. MUNIX: motor unit number index, MUSIX: motor unit size index, CMAP: compound muscle action potential, APB: abductor pollicis brevis, ADM: abductor digiti minimi.

Fig. 1. Intra-rater reliability of MUNIX in healthy controls. Linear regression of MUNIX sum-score (APB + ADM) between both evaluation times in 17 healthy controls (R2 = 0.79, r = 0.85, p < 0.0001). MUNIX sum-score is obtained by summing up the results of APB MUNIX and ADM MUNIX. MUNIX: motor unit number index.

3.3. Variation of MUNIX in MMN patients at short-term evaluation (Fig. 2) MUNIX was assessed in five patients before (day 1) and 22 days (day 22) (20–25) after the IVIg infusion. The variation of the MRC sum-score and the variation of ONLS were not significant between day 1 and day 22 evaluations (p > 0.05). MRC sum-score improved in three patients (MMN 1, MMN 2, and MMN 5), although upper limb ONLS score improved in only one patient (MMN 2). Two patients (MMN 3 and MMN 4) had stable MRC sum-score and ONLS upper limb score. The results of the CMAP sum-score and MUNIX sum-score at day 1 and day 22 are represented in Fig. 2. MUNIX sum-score increased significantly in three patients (COV superior to the 95th percentile of the COV of the MUNIX in controls that is 27%), one with improved MRC sum-score (MMN 2) and two with stable MRC sum-score (MMN 3 and MMN 4), whereas CMAP sumscore increased significantly in only one patient who had no change in his MRC nor in upper limb ONLS scores (MMN 4).

3.4. Variation of MUNIX in MMN patients at longer term (Fig. 3) MUNIX was assessed in three patients before (Infusion 1) and 1 month after two IVIg infusions (Infusion 3). Median interval between the two evaluations was 15 weeks (range 15–20 weeks). One patient improved his MRC sum-score (MMN 5), one patient improved his upper limb ONLS scores (MMN 7), and one patient was stable at both evaluations (MMN 6). CMAP sum-score significantly increased in only one patient (MMN 7) who was clinically stable, whereas MUNIX sum-score significantly increased in two patients (MMN 5 and MMN 7), among

Fig. 2. Results and evaluation of MUNIX sum-score and CMAP sum-score between day 1 and day 22 after IVIg infusion in MMN patients and corresponding coefficients of variation. MUNIX sum-score is obtained by summing up the results of APB MUNIX and ADM MUNIX. CMAP sum-score is obtained by summing up the results of APB CMAP and ADM CMAP amplitudes. MUNIX: motor unit number index, CMAP: compound muscle action potential, COV: coefficient of variation, *: significant.

whom only one patient showed MRC sum-score improvement (MMN 5). 4. Discussion We report here the results of our study evaluating the contribution of MUNIX in MMN patients. We showed that MUNIX is altered

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et al., 2010). In CIDP, COVs were 21% for ADM and 28% for APB muscles (Delmont et al., 2016; Paramanathan et al., 2016), and in ALS patients, the COV was 24% for ADM muscle, but it was higher when MUNIX was low (Ahn et al., 2010). Yet, in that study the test– retest reproducibility in ALS patients was inferior to the significant threshold of variation used in our study. Furthermore, the CMAP amplitudes of our patients were not much decreased (Table 1). Thus, we think this COV range can be applied to consider that a variation of MUNIX is due to the efficiency of a treatment or the progression of the disease. The COV and reproducibility of MUNIX should be confirmed in future studies in larger cohorts in normal subjects and specific diseases such as MMN. In our study, MUNIX sum-score increased after IVIg infusions more often than CMAP sum-score. We assumed that MUNIX is more sensitive than CMAP to detect change due to treatment in MMN. MUNIX improvement at short-term evaluation could reflect the removal of conduction blocks, whereas MUNIX improvement at long-term evaluation could encompass both removal of conduction blocks and a part of axonal regeneration. This pilot study of MUNIX in MMN, focusing on few patients, shows encouraging findings but they need to be confirmed by future studies including a larger population of patients. Furthermore, longitudinal studies of MUNIX are needed to assess the long-term effect of IVIg in MMN. MUNIX seems to be a sensitive technique to detect improvement due to IVIg treatment in MMN. This technique may be a useful technique to follow-up MMN patients and monitor IVIg treatment in addition to the usual clinical and electrophysiological evaluations. Our results need to be confirmed by larger studies and longitudinal follow-up to support if the initial variation of MUNIX in first infusions is sustained by long-term clinical improvement. Conflicts of interest Fig. 3. Results and evaluation of MUNIX sum-score and CMAP sum-score between IVIg infusion 1 and infusion 3 (15-week interval) in MMN patients and corresponding coefficients of variation. MUNIX sum-score is obtained by summing up the results of APB MUNIX and ADM MUNIX. CMAP sum-score is obtained by summing up the results of APB CMAP and ADM CMAP amplitudes. MUNIX: motor unit number index, CMAP: compound muscle action potential, COV: coefficient of variation, *: significant.

in MMN patients compared to healthy controls and MUNIX is modified by IVIg treatment. MMN patients had lower MUNIX and CMAP values than healthy controls, which can be due to either axonal destruction or functional loss caused by conduction blocks. MUSIX is higher in MMN patients probably through chronic re-innervation process inducing an increase of the size of the motor units. In a previous study, we showed that MUNIX had good intrarater reproducibility, permitting to use it in the follow-up of chronic inflammatory neuropathies (Delmont et al., 2016). Test– retest reliability is influenced by electrode placement (Bromberg and Spiegelberg, 1997). MUNIX needs to be performed by a trained operator to obtain the maximal CMAP amplitude by meticulous search of motor point and supramaximal stimulation (Ahn et al., 2010; Nandedkar et al., 2010; Neuwirth et al., 2010, 2011). Intra-rater reliability in healthy controls was also strong in this study for MUNIX, MUSIX, and CMAP. Hence, we assumed that MUNIX variation under IVIg treatment in MMN patients was significant if it was above the 95th percentile of the COV of the healthy controls. Median MUNIX sum-score COV in healthy controls was 12% with a 95th percentile of 27%. These results are consistent with previous studies that found a COV in healthy controls of 25% and 29.6% for the ADM muscle (Nandedkar et al., 2004; Ahn

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