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Multimodal evoked potentials follow up in multiple sclerosis patients under fingolimod therapy

Journal of the Neurological Sciences, June 2016, Pages 143 - 146

Abstract

Background

Clinical trials have shown the therapeutic effect of fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RR-MS), but its influence on nervous conduction assessed by evoked potentials (EPs) has not been previously investigated.

Methods

EP data of 20 patients examined 12 months prior to initiation of fingolimod (t = − 1), at treatment initiation (t = 0) and 1 year later (t = + 1) were compared. Each EP (VEP, MEP, SEP) and EP sum score, a global evoked potential score as the sum score of the each EP score was evaluated and correlated with Expanded Disability Status Scale (EDSS).

Results

During pre-treatment period (1 year) EDSS worsened while one year after fingolimod treatment EDSS remained stable. From t − 1 to t0 VEP, SEP, MEP and EP sum score worsened while from t0 to t + 1 VEP, SEP and EP sum score improved, and MEP score remain stable. VEP and SEP were related to EDSS at baseline (t = − 1), while MEP and total EP sum score were related to EDSS at all time points.

Conclusion

Fingolimod is able to improve visual and somatosensory evoked potential in RR-MS patients even if clinical disability scale remains stable. VEP and SEP could give eloquent information on pathway underweighted in EDSS. EPs are useful to evaluate fingolimod effects in clinical practice.

Highlights

  • Fingolimod restores evoked potential abnormalities in MS patients.
  • Multimodal evoked potentials are a good marker of MS disability.
  • Evoked potentials might be considered a function biomarker of drug effect.

Keywords: Evoked potential, Fingolimod, Multiple sclerosis, EDSS, VEP, SEP, MEP.

1. Introduction

In multiple sclerosis, demyelination and conduction block or axonal loss lead to evoked potential (EP) abnormalities such as delayed latency, morphological abnormalities, wave cancellation and increased refractory period. The use of EPs in the diagnosis of MS has been greatly reduced by the advent of magnetic resonance imaging (MRI). However there is a general agreement on their advantage in assessing the functional involvement of the central nervous system in MS patients [1]. Growing evidence has shown that EPs are strictly related to function, as demonstrated by correlation between somatosensory [2], pyramidal [3] visual [4] and brainstem [5] symptoms and signs with abnormalities in the corresponding EP. Thus, serial evaluation of EP is widely used for the assessment of disease progression as they correlate with disease disability [6]. Oral fingolimod (FTY720) is a 1-sphingosine-1-phosphate-receptor modulator. Through interaction with sphingosine-1-phosphate receptors on neural cells, fingolimod may have neuroprotective or reparative effects [7]. The remyelination process promoted by fingolimod may be the consequence of the attenuated inflammatory milieu trough its anti-inflammatory effect, preventing egress of lymphocytes from the lymph nodes. However a direct proliferative effect targeting endogenous remyelinating cells such as oligodendrocytes progenitor cells also seems to be plausible [8]. It is currently approved as a monotherapy for relapsing remitting multiple sclerosis (RRMS) patients with high disease activity. In two double-blind, placebo controlled trials [9] and [10], fingolimod has been shown to slow the disability progression in RRMS patients, to reduce the number of new or enlarging T2 hyperintense and gadolinium-enhancing magnetic resonance (MRI) lesions and to reduce brain volume loss. As described above, EP is widely used in monitoring and predicting disability [11] and [12] and to assess the effects of treatment [1]. Landi et al. have already demonstrated neuromodulatory activity of fingolimod on glutamate-mediated excitotoxicity and its effect on membrane polarization. We aimed to evaluate the direct impact of fingolimod on functional parameters as assessed by EP in a long term follow-up [13].

2. Patients and methods

2.1. Patients

Data were collected from patients who referred to the multiple sclerosis center of our department (Clinica Neurologica, University Federico II of Naples) for routine clinical and neurophysiological evaluations. Inclusion criteria were: diagnosis of clinically definite multiple sclerosis according to the McDonald criteria [14], starting fingolimod therapy as clinical practice; who performed a complete neurological exam including Expanded Disability Status Scale (EDSS) [15] and multimodal evoked potential (visual, somatosensory and motor to lower limb) 1 year before. All patients had previously received at least one other immunomodulatory agent. All RRMS patients were seen at Clinica Neurologica, University Federico II of Naples. The study was performed according to the declaration of Helsinki.

2.2. Multimodal evoked potentials

Multimodal EP was obtained according to previously published study [16]. All the evoked potential recordings were performed using a conventional Medtronic electromyography. Recordings were made via surface disc electrodes.

2.3. Visual evoked potential

VEPs were obtained in all patients stimulating each eye in turn with a 30 min of arc checkboard reversed pattern at 1.5 Hz on a video monitor. Cortical responses were recorded at Oz referred to Fz. A total of 100 responses were averaged twice and superimposed Filter bandpass was 0.5–100 Hz. The P1 latency of the negative-positive-negative complex (N1-P1-N2) was measured; the amplitude was calculated peak to peak from N1 to P1. Analysis time was 500 ms.

2.4. Somatosensory evoked potential

Somatosensory evoked potentials (SSEPs) following tibial nerve electrical stimulation at medial malleolus were recorded from the popliteal fossa (popliteal potential), 12th thoracic vertebra (N22 wave) referred to the iliac crest, and the CPz (P37 wave) referred to Fz. The stimulation rate was at 1.5 Hz. One thousand (tibial SSEP) responses were averaged twice and superimposed. The latency and amplitude of popliteal potentials, N22 waves, P37 waves, and N22-P37 intervals (central conduction time = CCT) were measured. Filter bandpass was 10–2000 Hz. Stimulus duration was 0.2 ms and rate of stimulation was 1.5 Hz. A total of 1000 responses were averaged twice and superimposed. Analysis time was 100 ms.

2.5. Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) of motor cortex was performed with a high power magnetic stimulator (MagPro X100, Medtronic, Denmark). MEPs were recorded from abductor hallucis (AH) muscles after TMS with a circular coil applied over the scalp. The shortest onset latency and the largest peak to peak amplitude of four consecutive MEPs, obtained during moderate active muscle contraction, were measured. We measured the shortest F-wave latency among 32 consecutive responses applying an electric stimulation at supramaximal intensity (0.2 ms square wave pulses) of the tibial nerve at ankle. The peripheral conduction time (PCT), excluding the turnaround time at the spinal motor neuron (1 ms), was calculated from the latencies of the CMAPs and F-waves as follows: (latency of CMAPs + latency of F-waves − 1) ∕ 2. The conduction time from the motor cortex to the spinal motor neurons (i.e., the CMCT) was calculated by subtracting the PCT from the onset latency of the MEPs. The signals from the EMG electrodes were amplified, Filter bandpass was 20–3000 Hz. Analysis time was 100 ms.

2.6. Scoring and analysis of EP data

The primary goal of this study was to evaluate the influence of fingolimod treatment on electrophysiological measures in RRMS patients. Furthermore, we correlated alterations in evoked potentials (VEP, SEP, MEP) with the Expanded Disability Status Scale as a general marker for permanent disability. Therefore we used a previous generate ordinal EP score [17] and [18] in which each abnormal result scored one point (e.g. abnormal latency and/or amplitude on either side). Sum scores of each electrophysiological measure were calculated from absolute values. The range of scores was: 0 (no pathological value on both sides), 1 (pathological value on one side, decrease in amplitude or abnormal latency), 2 (pathological value on one side, abnormal amplitude and latency or pathological value on both sides, latency or amplitude), 3 (pathological value on both sides, one side with abnormal latency and amplitude plus one side with abnormal amplitude or latency) and 4 (pathological values on both sides assessed). Than, we calculated the global evoked potential score as the sum of the each EP score (EP sum score). EP sum scores were evaluated before (t = − 1), at baseline (t = 0) and after fingolimod initiation (t = + 1). Afterwards we performed a comparison analysis of EP scores between t = − 1 and t = 0 and between t = 0 and t = + 1. Further, these sum scores were correlated with the Expanded Disability Status Scale and with multiple sclerosis severity score (MSSS) [19] of the patients over time.

2.7. Statistics

All clinical variables have been tested for normality distribution using Shapiro–Wilk test. Two-tailed Student's t-test for paired data and Wilcoxon matched-paired signed-rank test have been used when appropriate. For each EP, proportion of patients that improved, worsened or remained stable has been calculated in the pre-treatment period (t = − 1 to t = 0) and treatment period (t = 0 to t = + 1). Chi-squared test has been applied to compare such proportions. Finally, linear regression has been used to evaluate the relationship between variables at each time. All data are presented as mean ± standard deviation or median with minimum and maximum values following their distribution. Significance was assumed for p < 0.05. All analyses were performed using Stata 13.1 software packages.

3. Results

Twenty patients (12 women and 8 men) aged between 30 and 47 years (mean age, 36.45 ± 4.9) were included. All patients have a diagnosis of RRMS with at least three-years of disease duration (mean 5 ± 1.2 years). All patients had received a previous DMT such as interferon beta-1a (10 out of 20 patients have received Rebif ® 44 mcg; 2 out of 20 patients have received Avonex ®), interferon beta-1b (3 out of 20 patients have received Betaseron®), glatiramer acetate (5 out of 20 patients have received Copaxone®). EDSS at baseline was between 2.5 and 5.5; 3 out of 20 patients have had a history of unilateral acute optic neuritis. All patients were eligible to start a second line therapy (Table 1).

Table 1

Demographic and clinical characteristics of RR-MS patients.

 

Characteristic
N. RR-MS patients 20
Female, N (%) 12 (60)
Age, mean ± SD (years) 36.45 ± 4.9
Disease duration, mean ± SD (years) 5 ± 1.62
EDSS, mean ± SD (range) 2.97 ± 0.65 (2–4.5)
MSSS, mean ± SD (range) 5.68 ± 0.83 (4.25–6.95)

During pre-treatment period (1 year) EDSS worsened (2.75 (2–4.5) vs 3 (2.5–5.5), p = 0.01) while one year after fingolimod treatment EDSS remained stable (p = 0.42) compared to baseline (t = 0).

At baseline 90% of patients had a VEP score of 2 and 10% had a VEP score of 3. Before treatment VEP sum score worsened in 90% and remained stable in 10% of patients while after fingolimod treatment VEP sum score was stable in 95% of patients and 5% worsened (Fig. 1). Change in VEP score over time was shown in Table 2. VEP at baseline was only related to EDSS (coeff. = 0.25, R = 0.28, p = 0.02) while no correlation was found between VEP and age, disease duration and MSSS (p > 0.05). At t = 0 and t = + 1 VEP was not related to EDSS, age, disease duration and MSSS (p > 0.05).

Fig. 1

Fig. 1

Developmental of EP scores before and under fingolimod treatment.

During pre-treatment period (1 year) VEP, SEP and MEP worsened (p = 0.01) while one year after fingolimod treatment VEP and SEP ameliorated (p = 0.01) and MEP remained stable (p = 0.39). VEP = visual evoked potential; SEP = sensory evoked potentials; MEP = motor evoked potentials.

 

Table 2

EP change over time.

 

t = − 1 t = 0 pa t = + 1 pb
VEP score, mean ± SD (range) 2.1 ± 0.31 (2–3) 3 ± 0 (3–3) < 0.01 1.45 ± 0.60 (2–4) < 0.01
SEP score, mean ± SD (range) 2.35 ± 0.49 (2–3) 3.25 ± 0.55 (2–4) < 0.01 2.75 ± 0.72 (2–4) 0.01
MEP score, mean ± SD (range) 2.3 ± 0.86 (1–4) 2.80 ± 0.70 (2–4) < 0.01 2.95 ± 0.76 (1–4) 0.40

a Wilcoxon matched pairs signed ranks test between t = 0 and t = − 1.

b Wilcoxon matched pairs signed ranks test between t = + 1 and t = 0.

At baseline 65% of patients had a SEP score of 2 and 35% had a VEP score of 3. Before treatment SEP sum score worsened in 80% of patients and remained stable in 20% of patients while, after fingolimod treatment, was stable in 50% of patients, 5% worsened and 45% improved (Fig. 1). Change in SEP score over time was showed in Table 2. SEP at baseline was only related to EDSS (coeff = 0.45, R = 0.36, p = 0.01) while no correlation was found between SEP and age, disease duration and MSSS (p > 0.05). At t = 0 and t = + 1 SEP was not related to EDSS, age, disease duration and MSSS (p > 0.05).

At baseline 10% of patients had a MEP score of 1, 65% had a MEP score of 2.10% had a MEP score of 3 and 15% had a MEP score of 4. Before treatment MEP sum score worsened in 50% of patients and remained stable in 50% of patients while, after fingolimod treatment, 70% of patients remained stable, 4% worsened and 26% of patients ameliorated (Fig. 1). Change in MEP score over time was showed in Table 2. At t = − 1, t = 0 and t = + 1 MEP was related to EDSS (coeff. = 0.99, R = 0.57, p = 0.01; coeff. = 0.71, R = 0.45, p = 0.01; coeff. = 0.92, R = 0.44, p = 0.01 respectively). At t = − 1 MEP sum score was also related to MSSS (coeff. = 0.54, R = 0.27, p = 0.02) but was not related to age and disease duration (p > 0.05).

We also evaluated an EP sum score (see methods section). At baseline, EP sum score was related to disease duration (coeff. = 0.40, R = 0.27, p = 0.02), EDSS (coeff. = 1.68, R = 0.79, p = 0.01) and MSSS (coeff. = 0.94, R = 0.39, p = 0.01) but not with age (p = 0.15). EP sum score was also related to EDSS at t = 0 and t = + 1 (coeff. = 0.1, R = 0.36, p = 0.01; coeff. = 1.34, R = 0.42, p = 0.01 respectively).

4. Discussion

Clinical trials and growing evidence from clinical practice have shown the therapeutic effect of fingolimod in reducing clinical and radiological disease activity [9] and [10]. Recently, Landi et al. provided in vivo evidence that fingolimod modifies cortical excitability and resting membrane properties in RRMS patients. We demonstrated its influence on the capability of nervous conduction by means of evoked potentials, providing a good and reliable tool to monitoring disease progression and investigate the mechanisms of action of newly developed drugs [13]. Multimodal evoked potential have already been used to assess the effects of treatments in MS patients [11]. Improved latency of visual EPs after interferon-1b [20] and MEPs amplitude after interferon-β1a [21] were reported. Recently, Meuth et al. [18] demonstrated the effect of natalizumab in stabilizing or ameliorating electrophysiological parameters. In our study we investigated EP changes under fingolimod therapy. Under a previous first line disease modifying drug (DMT) we observed a worsening in clinical and all evoked potentials. Then, we started fingolimod, the first approval oral drug for MS patients, and demonstrated a significative improvement of VEP and SEP after one year of treatment. A stability of EDSS and no progression of MEP were also recorded. It seems reasonable to suggest that treatment effects of fingolimod are caused by its immunomodulatory effect, but maybe also as result of a direct effect on nerve conduction or remyelination. In rat model of experimental autoimmune encephalomyelitis histopathological analysis of brain and spinal cord revealed several key features that distinguish FTY720-treated animals from the positive controls [22] and that would account, at least in part, for improvements seen in both the VEP and SEP recordings. The most obvious amelioration under FTY720 treatment included significantly less demyelination in the spinal cord and no detectable lesions in the brain parenchyma. However, this effect could also be due to a profound anti-inflammatory effect, which results in a restoration of nerve conductance leading to a reversal of clinical symptoms. Re-myelination of primary demyelinated lesions is considered a normal response during the early stages of MS [23] and [24], even in some patients with progressive disease [25], and a consistent feature in experimental models [26] and [27]. The reduced release of immune cells from lymph nodes leads to their decreased infiltration into CNS and protect oligodendrocytes from immune attack. Therefore, FTY has demonstrated to increase oligodendrogenesis and to remyelinate axons, through a direct effect on myelin repair. However molecular events leading to functional restoration of nerve conduction are complex and not fully understood, yet it is becoming increasingly clear that cross talk between neurons and glia plays an essential role. Signals from oligodendrocytes and astrocytes are required for axonal survival and profoundly influence neuronal excitability, axonal transport, clustering of ion channels and synaptic transmission [28]. Experimental evidence suggests that fingolimod could have direct effects on astrocyte and oligodendrocyte lineages including differentiation, migration and survival [29] and [30]. We also found that after treatment period MEP remained stable. The reasons for a less significative effect of fingolimod on motor evoked potentials, however, remain unclear. The efficacy of reparative mechanism on nerve conduction along monosynaptic pathway such as cortico-spinal tract is less than efficacy of same mechanism on a polysynaptic way [31]. This could be due to a more pronounced signal amplification and synchronization at each single level in polysynaptic pathways. Finally, in line with previous studies [4] and [11], we revealed both baseline and follow up correlations of total EP sum score and EDSS. In detail, VEP and SEP were related to EDSS only at baseline, while MEP was related to EDSS at each time points, thus confirming that clinical evaluation of disability in multiple sclerosis through EDSS is mainly based on motor function. In summary, our study demonstrated that fingolimod is able to improve the functional capability of nervous system conductions for VEP and SEP. It's a key information about pathway underweight in EDSS above all, when clinically asymptomatic. Evoked potentials might therefore be considerate useful tool in order to evaluate fingolimod effects in clinical practice. However, the analysis of EPs in a larger group of patients is required.

Funding and conflict of interest

The authors stated that there are no conflicts of interest regarding the publication of this article.

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Footnotes

a Department of Neuroscience, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Italy

b Danish Research Center for Magnetic Resonance (DRCMR), Hvidovre Hospital, Hvidovre, Denmark

Corresponding author at: Department of Neuroscience, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy.


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    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
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