Clinical Neurophysiology xxx (2014) xxx–xxx

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Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations Immacolata Magnano a, Giovanni Mario Pes a, Giovanna Pilurzi a, Maria Paola Cabboi a, Francesca Ginatempo b, Elena Giaconi b, Eusebio Tolu b, Antonio Achene a, Antonio Salis a, John C. Rothwell c, Maurizio Conti a, Franca Deriu b,⇑ a b c

Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy Department of Biomedical Sciences, University of Sassari, Italy Sobell Department of Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK

a r t i c l e

i n f o

Article history: Accepted 9 March 2014 Available online xxxx Keywords: Vestibular-evoked myogenic potentials (VEMPs) Vestibulo-masseteric reflex (VMR) Acoustic-masseteric reflex (AMR) Vestibulo-collic reflex (VCR) Trigemino-collic reflex (TCR) Multiple sclerosis

h i g h l i g h t s  Vestibular and trigeminal reflexes showed a sensitivity similar to that of evoked potentials and

revealed a brainstem dysfunction in patients with multiple sclerosis without associated clinical or MRI findings.  The combined use of these brainstem reflexes and evoked potentials proved to be significantly superior to clinical and MRI assessments, in the first few years after onset.  Brainstem reflexes can effectively complement standard neurophysiological tests in early detection of clinically and radiologically silent lesions.

a b s t r a c t Objective: To investigate vestibulo-masseteric (VMR), acoustic-masseteric (AMR), vestibulo-collic (VCR) and trigemino-collic (TCR) reflexes in patients with multiple sclerosis (MS); to relate abnormalities of brainstem reflexes (BSRs) to multimodal evoked potentials (EPs), clinical and Magnetic Resonance Imaging (MRI) findings. Methods: Click-evoked VMR, AMR and VCR were recorded from active masseter and sternocleidomastoid muscles, respectively; TCR was recorded from active sternocleidomastoid muscles, following electrical stimulation of the infraorbital nerve. EPs and MRI were performed with standard techniques. Results: Frequencies of abnormal BSRs were: VMR 62.1%, AMR 55.1%, VCR 25.9%, TCR 58.6%. Brainstem dysfunction was identified by these tests, combined into a four-reflex battery, in 86.9% of cases, by EPs in 82.7%, MRI in 71.7% and clinical examination in 37.7% of cases. The sensitivity of paired BSRs/EPs (93.3%) was significantly higher than combined MRI/clinical testing (70%) in patients with disease duration 66.4 years. BSR alterations significantly correlated with clinical, EP and MRI findings. Conclusions: The four-BSR battery effectively increases the performance of standard EPs in early detection of brainstem impairment, otherwise undetected by clinical examination and neuroimaging. Significance: Multiple BSR assessment usefully supplements conventional testing and monitoring of brainstem function in MS, especially in newly diagnosed patients. Ó 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

1. Introduction

⇑ Corresponding author. Address: Department Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100 Sassari, Italy. Tel.: +39 079228294; fax: +39 079228156. E-mail address: [email protected] (F. Deriu).

Magnetic Resonance Imaging (MRI) is the standard test in the diagnosis of multiple sclerosis (MS) (Polman et al., 2005). However, imaging of the brainstem is challenging because of its complex anatomy and, despite a good correlation between brainstem impairment and brainstem lesion load detected by MRI, the

http://dx.doi.org/10.1016/j.clinph.2014.03.016 1388-2457/Ó 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

Please cite this article in press as: Magnano I et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.016

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List of abbreviations AMR BAEPs BSRs EDSS EPs FLAIR FS MRI MS

acoustic-masseteric reflex brainstem auditory evoked potentials brainstem reflexes Expanded Disability Status Scale evoked potentials Fluid Attenuated Inversion-Recovery sequences Kurtzke’s functional system Magnetic Resonance Imaging multiple sclerosis

association between clinical and radiological findings is generally poor, raising the so-called ‘‘clinicoradiological paradox’’ (Barkhof, 2002). Although evidence-based knowledge and diagnostic guidelines have highlighted the contribution of MRI over neurophysiological tests, multimodal evoked potentials (EPs) are still useful for disclosing clinically and radiologically undetected lesions (Beer et al., 1995; Comi et al., 1998; Fukutake et al., 1998; O’Connor et al., 1998; Leocani et al., 2003) and for predicting the evolution of disability (Kallmann et al., 2006; Leocani et al., 2006; Margaritella et al., 2012). Unlike the evidence provided by MRI, which is related to anatomy, the information provided by EPs relates to function. Thus, we should not limit the use of EPs in diagnosis and monitoring of the disease since they complement MRI data (Comi et al., 1999). Nevertheless, as with the clinicoradiological paradox, it is necessary to be aware that there may also be discrepancies between clinical and neurophysiological findings (‘‘cliniconeurophysiological paradox’’) (Comi et al., 1998). Brainstem dysfunctions are very common in MS, some of them are not expressed clinically, whereas others manifest as part of a relapse (Nakashima et al., 1999). Evidence suggests that brainstem involvement in MS is one of the major predictive factors for future disability and that detection of infratentorial lesions may help to identify patients with clinically isolated syndrome with higher risk for earlier occurrence of clinically relevant disability (Filippi et al., 1994; Sailer et al., 1999; Minneboo et al., 2004; Tintore et al., 2010). Hence, more accurate tests are needed to identify brainstem involvement in the earliest stage of the disease and to provide neurologists with additional tools for detecting clinically and radiologically silent lesions (Habek, 2013). Indeed, several brainstem reflexes (BSRs) have been investigated in MS and their distinctive alterations have been shown to reflect areas of brainstem damage. In particular, trigeminal reflexes such as jaw, blink, corneal reflexes (Sanders et al., 1985; Nazliel et al., 2002; Klissurski et al., 2009) and trigeminal somatosensory evoked potentials (Soustiel et al., 1996; de Pablos and Agirre, 2006; Gabelic´ et al., 2013b) were reported to provide valuable additional information. Yet despite this, they have not achieved widespread acceptance. In the last decade cervical vestibular-evoked myogenic potentials (Colebatch et al., 1994), which are manifestations of the vestibulo-collic reflex (VCR), have been used to assess the vestibulospinal pathway in MS patients (Sartucci and Logi, 2002; Welgampola, 2008; Gazioglu and Boz, 2012; Güven et al., 2014). Although less sensitive than visual evoked potentials (Bandini et al., 2004), VCR abnormalities have been reported to be very similar to those observed in the brainstem using other neurophysiological techniques (Versino et al., 2002; Ivankovic´ et al., 2013) and a combined evaluation of VCR and brainstem acoustic evoked potentials (BAEP) provides good information about the longitudinal spread of brainstem lesions (Itoh et al., 2001). Furthermore, changes in VCR correlate with disability and disease duration (Alpini et al., 2005; Patkó et al., 2007) and may be able to detect

mSEPs STIR TCR tSEPs VCR VEMP VEPs VMR

median nerve somatosensory evoked potentials Short-Tau Inversion-Recovery sequences trigemino-collic reflex tibial nerve somatosensory evoked potentials vestibulo-collic reflex vestibular-evoked myogenic potential visual evoked potentials vestibulo-masseteric reflex

clinically silent lesions localized in the medulla oblongata and caudal pons (Versino et al., 2002; Alpini et al., 2005; Eleftheriadou et al., 2009). More recently, the ocular vestibular-evoked myogenic potentials (Todd et al., 2007), which are manifestations of the vestibulo-ocular reflex (VOR) (Rosengren et al., 2010), have been used in association with VCR (Rosengren et al., 2007; Rosengren and Colebatch, 2011; Su and Young, 2011; Gabelic´ et al., 2013a; Gazioglu and Boz, 2012). Although the VOR has not been systematically investigated in MS, a combination of VCR and VOR was shown to detect brainstem impairment in nearly 80% of MS patients (Gabelic´ et al., 2013a). While it has been suggested that a combination of such vestibular-evoked myogenic potentials (VEMP) can detect both clinically and radiologically silent brainstem lesions (Habek, 2013), studies on large cohorts of patients are needed. There have been several recent additions to the methods available to test brainstem function. The trigemino-cervical reflex (TCR) tests a presumed pathway between the rostral portion of the spinal trigeminal nucleus and the spinal nucleus of the accessory nerve bilaterally (Di Lazzaro et al., 1995). It has never been investigated systematically in MS, although in a small sample it has been shown to be more sensitive in detecting brainstem involvement in MS patients than the R2 component of the blink reflex (Di Lazzaro et al., 1996). More recently, the vestibulo-masseteric reflex (VMR) and the acoustic-masseteric reflex (AMR) have been characterized in healthy humans but, to the best of our knowledge, neither reflex has been studied so far in any neurological disease. VMR and AMR are myogenic potentials induced in active masseter muscles by stimulation of vestibular and cochlear receptors, respectively (Meier-Ewert et al., 1974; Deriu et al., 2003, 2005, 2007, 2010). They appear as biphasic positive/negative potentials (p11/n15 and p16/n21 waves, respectively) which partially overlap in the averaged unrectified masseter EMG; neurophysiologic criteria to distinguish them have been recently defined (Deriu et al., 2005, 2007, 2010). The VMR shares many physiological features as well as the end organ with the VCR, except that the VMR is bilateral and symmetric whereas the VCR is ipsilateral. Here, we examined whether the diagnostic sensitivity of clinical examination, EPs and MRI can be improved by adding the assessment of VMR, AMR, TCR and VCR either as single reflexes or in a four-reflex battery. We conclude that they are a quick and easy way to supplement standard imaging and clinical evaluation to detect otherwise ‘‘silent’’ lesions in the brainstem. 2. Methods 2.1. Subjects Sixty patients with a diagnosis of definite relapsing remitting MS according to McDonald criteria (Polman et al., 2005), were selected for the study from those referred to the Multiple Sclerosis

Please cite this article in press as: Magnano I et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.016

I. Magnano et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

Centre and to the Magnetic Resonance Imaging (MRI) section of the University of Sassari for periodic check-ups. Only patients with EDSS (Expanded Disability Status Scale, Kurtzke, 1983) score 65 were enrolled. Sixty age- and sex-matched healthy volunteers with no past or current neurological, otological or stomatognathic disorders also participated in the study as controls. For all participants exclusion criteria were: age >55, on-going corticosteroid therapy or its use within the three months preceding the study, past or current cerebello-pontine angle lesions, middle ear disorders, peripheral vestibulopathy and/or section of the eighth nerve, sensorineural deafness, lesions of the labyrinthine segment of the facial nerve, severe stomatognathic disorders and pathologies of sternocleidomastoid muscles. The local ethical committee approved the study (prot. 693/L/ 2008) and written informed consent was obtained from each subject prior to participation in the study. Patients underwent clinical, neurophysiological and MRI evaluation within two weeks. Controls underwent clinical examination and recording of BSRs. Testing procedures and data analysis were carried out independently by two different expert operators who were blinded to the other findings. Discordant data (if >5%) were reassessed in a consensus reading. 2.2. Clinical examination Neurological status was quantified with the EDSS and Kurtzke’s functional system (FS) scores (Kurtzke, 1983). Past and/or present signs/symptoms of brainstem involvement, with particular regard to trigeminal and vestibular systems, were also recorded. Symptoms and signs were considered as current when detected at the time of neurological examination or had occurred within the six months preceding assessment. According to the level of total disability, patients were assigned to three categories as follows: normal, without clinical impairment (EDSS = 0); minimal (EDSS = 1–2.5) and moderate (EDSS = 3–5) disability. Beside the total EDSS score, the following FS scores were considered for the statistical analysis: brainstem, pyramidal, cerebellar and sensory. 2.3. MRI examination MRI scans were acquired with a 1.5 T Superconducting system (Philips-Intera Nova Achieva) using a standard 8-channel head coil as supplied by the manufacturer. Turbo Spin-Echo and Turbo Inversion Recovery T1, T2, Fluid Attenuated Inversion-Recovery (FLAIR) and Short-Tau Inversion-Recovery (STIR) sequences were used. Using a T1-weighted sagittal plane pilot acquisition, planned on a standard 3-plane scout, stacks of axial slices (5 mm thicknessgap 1 mm) parallel to the bicommissural line were collected from all patients, using FLAIR and T1-weighted sequences before and after intravenous injection of gadolinium. In addition, to detect and localize the maximum number of brain and brainstem lesions, 2.5 mm axial 3D T2 and 1.5 mm coronal 3D FLAIR images, were acquired. To improve contrast between lesion and brainstem parenchyma, contiguous 2.5 mm axial STIR images focused and perpendicular to the brainstem were also obtained. Global and regional FLAIR, T2, STIR, T1 and T1-gadolinium enhancing lesion load was evaluated, with a semiquantitative method, both for supratentorial-cerebellar compartments and brainstem, with specific regard to the three brainstem regions (midbrain, pons and medulla). 2.4. Multimodal evoked potentials Multimodal EPs of the visual (VEPs), brainstem auditory (BAEPs) and somatosensory (median nerve stimulation: mSEPs; tibial nerve stimulation: tSEPs) pathways were recorded using a

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Neuropack M1 EP/EMG system (Nihon Kohden Corporation) according to recommended standard protocols (Deuschl and Eisen, 1999). The following major EP components were analysed: VEP: P100 latency and N75-P100 amplitude; BAEP: wave I, III, and V latencies, I/V amplitude ratio and I–III, III–V and I–V interpeak intervals; mSEP: N9, N13, P14 and N20 latencies, P14–N18 and N20–P25 amplitudes, N9–N13, N13–N20, P14–N20 interpeak intervals; tSEP: N8, N22, and P37 latencies, and P37–N45 amplitude For each EP component peak latency and peak-to-peak amplitude were measured. The N13, P14, N20 and P37 latency values were corrected for the height of the subject. Data were compared to the normative data-set of our own laboratory and those exceeding the normal mean value by 2.5 SD were regarded as abnormal. Wave amplitude was considered reduced if smaller than 50% of the corresponding wave following contralateral stimulation. Each EP was categorized according to a conventional 3-point graded ordinal score modified according to Fukutake et al. (1998) as follows: normal EP; right or left latency prolongation and/or amplitude reduction of a main component; right or left absence of a main wave. Since VEPs are integrated outside the brainstem, although considered for the descriptive analysis they were excluded from cumulative score and correlation analysis, which was then limited to a 3-EP battery consisting of BAEPs (III and V main peaks and III–V interpeak interval), mSEPs (P14 and N20 latencies, P14–N18 and N20–P25 amplitudes, P14–N20 interpeak interval) and tSEPs (P37 latency and P37–N45 amplitude). The frequency of alterations in each single and cumulative EPs as well as the percentage of patients with 0–3 altered EPs was also calculated. 2.5. Brainstem reflexes BSR evaluation consisted in recording VMR and AMR from masseter muscles and VCR and TCR from sternocleidomastoid muscles through surface electrodes placed in a belly-to-tendon configuration described in details elsewhere (Deriu et al., 2003, 2005, 2007; Colebatch et al., 1994; Di Lazzaro et al., 1995). Participants were assessed while seating on a comfortable chair with support for neck and head, in a quiet, semi-darkened room. They were instructed to voluntarily activate the target muscles at 30–50% of maximal voluntary contraction to be kept steady during data collection, with the aid of a visual feedback of the filtered and rectified EMG activity. Both rectified and unrectified EMG activity were recorded bilaterally (1902 quad system amplifier, Cambridge Electronic Design LTD, Cambridge, UK), amplified (5000), filtered (bandwidth 5–5000 Hz) and sampled (10 KHz) within a 200 ms window (50 ms pre-stimulus and 150 ms post-stimulus) using an analog/digital converter (1401 power, Cambridge Electronic Design LTD, Cambridge, UK) and Signal 5.0 software on a PC. VMR, AMR and VCR were elicited by means of 0.1 ms click stimuli, generated by a 3505 HP attenuator driven by a Signal 5.0 script for VEMP (Cambridge Electronic Design LTD, Cambridge, UK) and delivered through TDH-49P earphones (Telephonics, Huntington, NY) either to the right or left ear at a frequency of 5 Hz. Click intensities were always the same in each ear and were equal to either 143 dB SPL (i.e. to a suprathreshold intensity for both VMR and VCR) or 108 dB SPL (which is a subthreshold intensity for VMR and VCR, but suprathreshold for the AMR (Deriu et al., 2007). The TCR was evoked using rectangular electrical stimuli (DS7A constant current stimulator, Digitimer Ltd, Hertfordshire, England, UK) of 0.1 ms, which were applied at a frequency of 5 Hz to either the right or left infraorbital nerve via bipolar surface electrodes placed over the infraorbital notch. Stimulus intensity was adjusted to be 4–6 times the perceptual threshold, which was regarded by subjects as strong but not painful.

Please cite this article in press as: Magnano I et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.016

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I. Magnano et al. / Clinical Neurophysiology xxx (2014) xxx–xxx

For each BSR the following parameters were measured on averaged (n = 300–500) unrectified EMG: onset and peak latency of the first positive wave or p1 (i.e. p11 for the VMR, p16 for the AMR, p13 for the VCR and p19 for the TCR); peak latency of the first negative wave or n1 (i.e. n21 for the AMR, n23 for the VCR and n31 for the TCR). The n15 wave of the VMR was not evaluated as it is undetectable in normal hearing people (Deriu et al., 2007). Absolute response amplitudes in the unrectified EMG were measured either for a single peak or peak-to-peak. The rectified averages were also evaluated and used to quantify the level of background muscle activation. Since the amplitude of the myogenic potentials under study scales with the level of tonic muscle activation, absolute peak (for the VMR) or peak-to peak amplitude values were divided by the mean pre-stimulus rectified EMG activity, to obtain an amplitude ratio relative to the level of background muscle activation (corrected amplitude). Finally, p1 inter-side latency difference was measured and amplitude asymmetry ratio was calculated as reported by Rosengren et al. (2010). Each BSR was regarded either as normal or altered according to normative values (expressed as mean ± SD) previously standardized in healthy controls. In such a cohort of subjects, the p1 peak latency proved to be more consistent and reliable than all the other measured parameters, the easiest to measure and the variable with the lowest coefficient of variation. For these reasons, p1 latencies exceeding the upper limits of normal values (i.e. the mean value plus 2.5 SD) and/or absent p1 responses were used as condition of abnormality, regardless the stimulation/recording side. Prolongations of the n1 wave or amplitude reduction of both the p1/n1 wave as well as latency or amplitude asymmetries were not used as criteria for BSR abnormality on their own. The choice of the p1 delay and/or absence as a criterion for abnormality is in line with that reported in the available literature dealing with the use of VEMPs for investigation in patients with MS (Murofushi et al., 2001; Sartucci and Logi, 2002; Bandini et al., 2004; Alpini et al., 2004, 2005; Gazioglu and Boz, 2012). Thus, patients were attributed to a ‘‘normal’’ or ‘‘altered’’ group according to this criterion and, within the abnormal group, the pattern of alteration (latency prolongation and/or absence of the response) was estimated for ipsi- and contralateral responses. Finally, the cumulative frequency of abnormalities in the four BSRs was measured and the proportion of subjects with none or 1 to 4 altered BSR was calculated. 2.6. Statistical analysis Statistical analysis was performed by using the SPSS software for Windows, version 16.0 (Chicago, IL). Results were expressed as means ± SD for scalar variables, or frequencies for categorical variables. Differences between groups of scalar variables were tested using the Mann–Whitney U-test. Differences in frequencies were tested by the v2 test or McNemar test, whenever appropriate. Based on the results obtained various scores of severity of the clinical/radiologic variables were calculated and their correlation was assessed using Spearman’s rho (q) correlation coefficient. A hierarchical cluster analysis procedure was used to outline similarity or dissimilarity between BSR variables. Results were considered to be statistically significant for p-values equal or lower than 0.05. 3. Results 3.1. Clinical data and MRI findings All patients had a diagnosis of relapsing remitting MS with mean disease duration of 8.2 ± 6.4 years (range 1.0–32.2 years, median 6.4 years). Neurological examination revealed clinical

abnormalities in 84.7% of patients. In particular, EDSS score was 0, 1.0–2.5 and 3.0–5.0 in 15.3%, 69.4%, and 15.3% of patients, respectively, with a distribution of altered FS scores as follows: pyramidal system 83.1%, cerebellum 40.7%, somatosensory system 37.3%, brainstem 37.3%. Among the 22 patients with brainstem involvement, 59.0% showed current trigeminal and/or vestibular signs/symptoms, whereas, within the whole sample, 47.5% experienced trigeminal and/or vestibular dysfunction, with a total of 57.6% of patients with current and/or past brainstem involvement. Demographic and clinical features of patients are reported in Table 1. MRI investigation detected monolateral and/or bilateral lesions in the supratentorial/cerebellar compartments and in the brainstem in 98.3% and 71.7% of patients, respectively. Within the brainstem, the distribution of lesions across its three regions was as follows: midbrain 38.3%, pons 68.3% and medulla 43.3%. 3.2. Multimodal evoked potentials The whole EP battery was completed by 58 out of 60 patients. The recording of the P14 wave of the mSEP was available in 49/60 (81.6%) patients. All patients showed normal latency and amplitude of peripheral EP components (i.e. the I wave of BAEPs, the N9 wave of mSEP and the N8 wave of tSEP) as well as of the cervical N13 wave of the mSEP and the lumbar N22 wave of the tSEP. Abnormalities of the P14 wave of the mSEP were recorded in 21/49 (42.9%) of patients. A summary of EP findings is reported in Table 2, which shows the distribution of single and cumulated EP abnormalities in patients. The pattern of EP alterations mainly consisted of absence of a major component, which was more frequent than its delay (p < 0.01). 3.3. Brainstem reflexes Complete VMR, VCR and TCR recordings were available in 58 out of 60 patients, while AMR was obtained in 49/60 patients (due to unavailability of the patients to complete the BSR battery or to technical problems). The 4-BSR set was incomplete in at least one component in 14 patients and thus data for cumulative analysis were available in 46/60 (76.7%) patients. Fig. 1 shows the battery of the four BSRs recorded in a representative control subject and in a patient with MS. For both patient and control groups, averaged values for each measured parameter are shown in Table 3. Values of p1 peak latency are also presented as boxplot in Fig. 2. In comparison with controls, both onset and peak latencies were significantly prolonged in patients, who also showed a significantly larger latency side-asymmetry. Corrected amplitudes of the responses were not significantly different in the two groups, with the exception of the VCR which was significantly smaller among patients.

Table 1 Clinical characteristics of 60 patients with relapsing remitting multiple sclerosis (mean ± SD and range). Sex (females/males) Age (years) Disease duration (years) Total EDSS Brainstem FS Pyramidal FS Sensory FS Cerebellar FS

44/16 33.3 ± 8.3 (20–50) 8.2 yrs ± 6.4 (1–32) 1.78 ± 1.1 (0–4.5) 0.54 ± 0.79 (0–3) 1.19 ± 0.82 (0–3) 0.63 ± 0.89 (0–3) 0.64 ± 0.86 (0–3)

Abbreviations: EDSS, Expanded Disability Status Scale; FS, Functional System (part of EDSS score).

Please cite this article in press as: Magnano I et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.016

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I. Magnano et al. / Clinical Neurophysiology xxx (2014) xxx–xxx Table 2 Distribution of single and cumulated EP alterations in patients with relapsing remitting multiple sclerosis.

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Abnormalities of single EP

VEP

BAEP

mSEP

tSEP

Total number of patients Number (%) of patients with normal EP Number (%) of patients with abnormal EP

58 33 (56.8) 25 (43.1)

59 37 (62.7) 22 (37.3)

58 23 (39.6) 35 (60.3)

58 24 (41.3) 34 (58.6)

Combined number of abnormal EPs1 Number (%) of patients2

0 10 (17.2)

1 18 (30.5)

2 16 (27.5)

3 14 (24.1)

Combined EP alterations include BAEPs, mSEPs and tSEPs. Out of 58 patients who competed the three-EP battery.

Fig. 1. Vestibulo-masseteric reflex (VMR), acoustic-masseteric reflex (AMR), vestibulo-collic reflex (VCR) and trigemino-collic reflex (TCR) recorded in a representative control subject and in a patient with relapsing remitting multiple sclerosis. Averaged (n = 300) unrectified EMG responses to the right and left stimulation were recorded bilaterally from active masseter muscles (MM) for the VMR and AMR and from active sternocleidomastoid muscles (SCM) for the VCR and TCR. In the control subject, the VMR and the AMR appear as a bilateral and symmetric p11/n21 and p16/n21 wave, respectively. In the patient, the AMR is bilaterally absent for both right and left stimulations while the p11 wave of the VMR is bilaterally present but delayed. Note that the bilateral absence of the cochlear response allows clear detection of the vestibular n15 bilaterally. In the patient, the VCR is bilaterally delayed, while the TCR shows composite abnormalities consisting mainly of absence of the response bilaterally, except for a small p19/n31 wave appearing in the left SCM following ipsilateral stimulation. Arrows indicate the time of stimulus delivery.

As specified in the method section, only prolonged peak latency and/or absence of the p1 wave were considered as criteria of abnormality for statistical analysis. On this base, the frequency of altered BSR was significantly different (p = 0.00001) between patients and controls. In particular, all BSRs were detectable bilaterally in controls and they were within the upper limit of normal values (i.e. mean plus 2.5 S.D.), with the exception of one subject who exhibited a bilaterally delayed VCR. The frequency and the

distribution of single and combined BSR abnormalities, as well as the pattern of alterations observed in patients are detailed in Table 4. The VCR was significantly less impaired than the other three reflexes (p < 0.01). When the whole battery of the four BSRs was considered, regardless of any specific reflex and pattern of alteration, 40 out of the total of 46 patients had BSR abnormalities (86.9%). VMR and AMR clustered together but displayed a different pattern from VCR and TCR. As for the pattern of alteration, ranked

Please cite this article in press as: Magnano I et al. Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/j.clinph.2014.03.016

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Table 3 BSR values (mean ± SD) in controls and in patients with relapsing remitting multiple sclerosis (MS). BSR

p1/n1 parameters

CONTROLS

MS PATIENTS

p value1

VMR

p11 onset (ms) p11 peak (ms) p11 interside peak difference (ms) p11 corrected amplitude Amplitude ratio asymmetry

8.7 ± 1.1 11.4 ± 0.8 0.6 ± 0.5 0.4 ± 0.2 16.8 ± 13.4

9.8 ± 1.8 12.6 ± 1.8 1.2 ± 1.1 0.3 ± 0.2 25.8 ± 18.1

Exploring brainstem function in multiple sclerosis by combining brainstem reflexes, evoked potentials, clinical and MRI investigations.

To investigate vestibulo-masseteric (VMR), acoustic-masseteric (AMR), vestibulo-collic (VCR) and trigemino-collic (TCR) reflexes in patients with mult...
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