Federica Melillo

Normative Values for Intertrial Variability of Motor Responses to Nerve Root and Transcranial Stimulation: A Condition for Follow-Up Studies in Individual Subjects

Objective Intertrial variability (ITV) of motor responses to peripheral (CMAP) and transcranial (MEP) stimulation prevents their use in follow-up studies. Our purpose was to develop strategies to reduce and measure CMAP and MEP ITV to guide long-term monitoring of conduction slowing and conduction failure of peripheral and central motor pathway in the individual patient. Methods Maximal compound muscle action potentials to High Voltage Electrical Stimulation (HVES) of lumbo-sacral nerve roots (r-CMAP) and activated, averaged motor evoked potentials (MEPs) to Transcranial Magnetic Stimulation (TMS) using double cone coil were recorded from 10 proximal and distal muscle districts of lower limbs. The procedure was repeated twice, 1–2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients, using constant stimulating and recording sites and adopting a standardized procedure of voluntary activation. ITV for latency and area indexes and for the ratio between MEP and r-CMAP areas (a-Ratio) was expressed as Relative Intertrial Variation (RIV, 5th-95th percentile). As an inverse correlation between the size of area and ITV was found, raw ITV values were normalized as a function of area to make them comparable with one another. Results All RIV values for latencies were significantly below the optimum threshold of ± 10%, with the exception of r-CMAP latencies recorded from Vastus Lateralis muscle. RIVs for a-Ratio, the most important index of central conduction failure, ranged from a maximum of -25.3% to +32.2% (Vastus Medialis) to a minimum of -15.0% to + 17.4% (Flexor Hallucis Brevis). Conclusions The described procedure represents an effort to lower as much as possible variability of motor responses in serial recording; the reported ITV normative values are the necessary premise to detect significant changes of motor conduction slowing and failure in the individual patient in follow-up studies.

A new neurophysiological approach to assess central motor conduction damage to proximal and distal muscles of lower limbs

OBJECTIVE To develop a neurophysiological method to explore central motor pathways to proximal and distal muscles of lower limbs. METHODS MEPs to transcranial magnetic stimulation using the double cone coil were bilaterally and simultaneously recorded from vastus medialis, tibialis anterior and flexor hallucis brevis. Voluntary facilitation was controlled using a predefined sequence of movements of constant amplitude. Compound motor action potentials elicited by maximal high voltage electrical stimulation of lumbosacral roots (root-CMAPs) were recorded from the same muscles to obtain the corresponding peripheral conduction times. We studied 28 healthy subjects and 28 multiple sclerosis (MS) patients with no or mild motor impairment. RESULTS The described facilitation procedure and the averaging of 5 MEPs reduced area variability to about 10%. In MS patients conduction slowing and/or MEP area reduction in at least one muscle was found in 91.7% of cases, with significant correlation with individual motor impairment. CONCLUSIONS Combined use of stable MEPs and maximal root-CMAPs was able to detect both conduction slowing and conduction failure in central motor pathways to proximal and distal districts of lower limbs in MS patients. SIGNIFICANCE The proposed method provides an extensive electrophysiological mapping of central motor impairment of lower limbs in clinical application.

Computerized posturography is more sensitive than clinical Romberg Test in detecting postural control impairment in minimally impaired Multiple Sclerosis patients

Balance impairment, frequent in Multiple Sclerosis patients (MS), is difficult to detect promptly with routine clinical examination. Computerized platforms can measure subtle deficit but, given the complexity of postural system, multiple tests should be adopted. To evaluate whether platform was more sensitive than Romberg Test (RT) in detecting balance abnormalities, we 1) chose a battery of posturographic tests, 2) collected normative data from 58 healthy subjects 3) applied the tests to Clinically Isolated Syndrome (n=42) and minimally impaired MS (n=76). Subjects underwent 3 trials of quiet standing with eyes open and closed (modified Clinical Test of Sensory Interaction on Balance, mCTSIB) and 4 trials of voluntary anterior and lateral maximal leaning on right and left sides (Limits of Stability, LOS), giving 10 postural indexes. For every subject, the best trials were selected for subsequent analysis. Normative values were established in a range from 1st to 99th percentile, defining balance impairment by the presence of at least 2 indexes out of range. Even adopting the above mentioned strict definition of balance impairment, the forceplate resulted more sensitive than RT, detecting abnormalities in 25% of patients, while RT was abnormal in 7% only. In RT-negative patients with 1-year follow-up (n =67) the detection of a single abnormal index was able to predict a subsequent onset of symptomatic balance impairment. The proposed procedure is quick, easy to perform and can improve the assessment of the clinical course of MS, from a pre-clinical stage up to medium degree of disability.

T45. Effects of fampridine administration on central motor conduction failure in multiple sclerosis patients

Introduction Fampridine is a slow-release potassium channel blocker that ameliorates the impaired conduction in CNS demyelinated axons. In multiple sclerosis (MS) patients, wide fluctuations in fatigue perception make difficult to assess the highly variable clinical response to treatment. Previous study reported that central motor conduction time (CMCT) improvement may predict fampridine response. Nevertheless, more than conduction slowdown, central motor conduction failure (CMCF), i.e. conduction block and axonal damage, reflects walking impairment in MS patients. Decrease of Motor Evoked Potentials (MEP) area, much more than amplitude, may detect CMCF. Serial MEP area recordings and analysis, according to a protocol that reduces MEP area random variability, may detect CMCF variation. We evaluated the effects of fampridine on CMCT and CMCF by serial recordings of MEPs from several proximal and distal muscle districts of lower limbs in a MS patients cohort and we correlated the obtained data with clinical outcome. Methods In 10 MS patients, MEPs to TMS by double-cone coil and maximal Compound Motor Action Potentials (CMAPs) to High Voltage Electrical Stimulation of lumbosacral roots were recorded from Vastus Medialis and Lateralis, Tibialis Anterior, Peroneus Longus and Flexor Hallucis Brevis of both limbs (T1) according to the published method (Di Sapio et al., 2014). Stimulation and recorded sites were marked. In 3 patients the test was repeated after one week (T1b), as control. After 14 days of fampridine treatment, before stopping therapy (T2), the procedure was repeated, strictly maintaining the same stimulation and recording sites and stimulation intensities. The 25-foot walking test (25FWT), 6-min walking test (6’-WT), the Fatigue Score Scale (FSS) and the Modified Fatigue Inventory Scale (MFIS) were administered at each time point. In each patient CMCT, MEP area and MEP Area/CMAP area ratios (ARs) were compared, and if appropriate their variability normalized according to Troni et al. (2016). Patients were classified as neurophysiological responders when 2 or more area/latency indexes significantly improved, remaining the others stable. Moreover, pooled data from the whole cohort in different time-points were compared using T test (Wilcoxon). Results CMCT, MEP area and AR did not change significantly in patients not receiving fampridine. After fampridine administration 3 patients were classified as responders; the same patients reported fatigue reduction and showed significant improvement in FSS score and 25FWT, while MFIS and 6’WT improved only in 1 patient. By analysing pooled data obtained from responders only, a significant reduction of CMCT (p = 0.0057) and increase in MEP area (p = 0.0014) and AR (p = 0.048) were noted. Conclusion The CMCF evaluation, together with CMCT, both made more sensitive by adopting multiple recording sites, correlate with self-reported and clinical outcome of fampridine treatment and may help to clarify doubt cases.

P141: Motor evoked potentials from multiple recording sites of the lower limbs as a monitoring tool of central motor function

Results: When the interval between 2 consecutive stimuli was 0.5 s, the response to the second sound was about half of the size in comparison to the first one. On the other hand, when the interval was longer than 4 s, the amplitudes of both responses were the same. The responses differ significantly in accordance with the interval of the stimuli. Ketamine suppressed the response to the first auditory stimuli that resulted in the amplitudes of both responses becoming the same even in the smaller interval. Conclusion: We therefore conclude that the auditory gating function in common marmosets is similar to humans. In addition, the deficit induced by ketamine suggests that it could be a model for the study of some psychiatric diseases.

P992: Approaching the mechanisms underlying analgesia induced by high voltage electrical stimulation of lumbosacral nerve roots

Introduction: Idiopathic juvenile arthritis (IJA) can be described as a chronic inflammatory syndrome associated with chronic pain status. Patients with IJA may have a high cardiovascular morbidity and mortality. Changes in heart rate variability (HRV) may be a great marker of less favorable healthy life in all ages. Moreover, low HRV may be an indicator of increase in cardiovascular risks, including sudden death. The aim of this protocol was performed the HRV analyses during sleep in pediatric patients with JIA. Methods: We studied 10 patients with JIA that were compared with 10 healthy subjects matched for age, gender and Tanner stage. All subjects were monitored following one night of habituation in the sleep laboratory. Sleep analysis was performed by international criteria. The HRV Standard Time and Frequency Domain were calculated for 5-minute periods in all sleep stages. The frequency components were subdivided in low and high frequency, and the time domain analyses were calculated by determination of the ratio of the standard deviation of the RR intervals. The U-test for independent samples was used for identifying differences in HRV parameters, with a significance level set at 5%. Results: We found that JIA patients had more arousals than controls. They also presented a reduction in NREM sleep, and they had a significantly longer total sleep time, and wake time after sleep onset (WASO). The analyses of HRV in time and Frequency Domain during sleep demonstrated the presence of significant differences between JIA patients and controls in all stages of sleep. We found changes in the standard deviation of normalto-normal interval (SDNN) during slow wake sleep (SWS) [47.0±38.5 vs 94.6±75.2, p=0.02], and by the total power of spectral analyses. The total power was lower in patients than in healthy controls in all sleep stages (p<0.05). Positive correlation was found between number of joints with impairment and pNN50 parameter (rs=0.45; p<0.05). Conclusion: Patients with JIA showed sleep fragmentation and they had presented changes in their cardiovascular autonomic function during sleep. We found low HRV in patients with JIA during all sleep stages. The treatment of sleep disruption in patients with chronic pain can be a successful strategy to control their cardiovascular risk.

P574: Computerized static posturography: modified clinical test of sensory interaction on balance and limits of stability in multiple sclerosis patients

Background: In the assessment of visual pathway involvement in Multiple Sclerosis-MS, optical coherence tomography-OCT is used to measure retinal nerve fiber layer-RNFL thickness as a marker of axonal loss and visual evoked potentials-VEPs as an indicator of demyelination. However, no clear indications are available on their combined use in MS monitoring. We evaluated cross-sectional and longitudinal correlations and sensitivity of OCT and VEPs and their correlates with clinical and magnetic resonance imaging-MRI evidence of disease activity in a real-world clinical setting. Methods: 80 MS patients (13 clinically isolated syndrome-CIS, 55 relapsingremitting-RR, 9 secondary progressive-SP, 3 primary progressive-PP), age 36.7+9.7 years, disease duration 6.0+6.6 years, underwent neurological and neurophysiological evaluation with OCT and VEPs, with routine clinical and MRI monitoring for a mean period of 1 year. Additional OCT-VEPs follow-up was obtained in 50 patients. Results: While VEPs were more sensitive than OCT in eyes with recent (<3 months) optic neuritis-ON at baseline (80.0% Vs 6.7%, p=0.001), the two sensitivities were similar in chronic ON eyes (78.4%). Comparing eyes with and without previous ON, VEP latency and RNFL thickness were respectively significantly higher (131.2 ms Vs 118.8 ms, p=0.008) and lower (78.15 μm Vs 90.00 μm, p<0.001) in the first subgroup. No significant differences were found between the two subgroups when analyzing VEP latency and RNFL thickness evolution during the follow-up period. However, eyes with baseline recent ON had significant reduction in VEP latency (−15.3 ms) and RNFL thickness (−7,7 μm) at follow-up. No significant correlation was found between OCT-VEPs parameters and disease activity. Similar results were found when considering only RR and CIS patients. Conclusions: These results would exclude recommending OCT and VEPs as surrogate biomarkers in MS phase II clinical trials evaluating disease modifying drugs, even when focusing on relapsing form of MS. The main role for OCT and VEPs in short-to-medium term follow-up programs would consist in monitoring neural damage after acute ON. However, these findings cannot exclude the usefulness of these techniques for longer follow-ups and/or large phase III studies.