C50 CONCEPTS AND TECHNIQUES IN CLINICAL ELECTROPHYSIOLOGY: LOWER AND UPPER MOTOR NEURON MEASUREMENT IN ALS
DE CARVALHO M1, PINTO S2, SWASH M3
1Department of Neurology. Hospital de Santa Maria, Lisbon, 2Instituto de Medicina Molecular. Faculty of Medicine. University of Lisbon Portugal, 3Institute of Neuroscience, Barts and The London, Department of Neurology, Royal London Hospital, Queen Mary College, University of London, United Kingdom
E-mail address for correspondence: [email protected]
Keywords: ALS progression, lower motor neuron, upper motor neuron
Background: Lower (LMN) associated with upper motor neuron (UMN) dysfunction defines ALS. Amplitude of the motor response, neurophysiological index (NI) and motor unit number estimation (MUNE) are sensitive methods for detecting LMN loss over time. These measurements are more sensitive than functional scales or forced vital capacity, and the rate of motor unit loss as evaluated by MUNE is a prognostic factor. The main limitations of these measurements are the large standard deviation (SD) of the mean, change overtime and the need of some training to perform the neurophysiological studies, especially MUNE. The large SD has a negative impact on the calculated number need for treatment for testing an estimated effect in clinical trials. The inclusion of a homogenous population would circumvent this inconvenience. Regarding UMN evaluation the conventional transcranial magnetic stimulation (TMS) measurements are considered in sensitive. The new triple stimulation is accepted as a promising tool. Although there are a large number of transversal studies in ALS analyzing the utility of several TMS measurements to detect abnormalities related to UMN dysfunction, only a few studies focused on longitudinal evaluations to find TMS measurements that could show sensitivity to disclose changes. Probably, motor evoked potential amplitude is very variable to be reliable, but corticomotor threshold and central conduction time show progressive increase over time and can be useful. Moreover, cortical silent period has been reported as meaningful, and should be explored further in ALS.
An interesting point is that in spite of many studies evaluating UMN and LMN loss in ALS, none investigated the measurements for LMN and UMN lesion in the same population of patients. This strategy may allow the testing of the interdependency of LMN and UMN degeneration.
Objectives: We review the relevant literature concerning clinical neurophysiology to measure the progressive UMN and LMN dysfunction in ALS. In addition, we aimed to test the sensitivity to change of neurophysiological measurements for UMN and LMN evaluation, in a group of ALS patients suitable for entry into clinical trials.
Methods: We included 28 early affected ALS patients with probable or definite disease (revised El Escorial criteria): ALS-FRS >30, disease duration <24 months, forced vital capacity (FVC) > 70%. All of them had abductor digiti minimi (ADM) strength > 3 on the MRC scale on both hands. We evaluated the following measurements at entry and 6 months later: ALS-FRS, FVC, amplitude of ADM motor response (CMAP); NI, MUNE, cortical silent period before and after ADM fatigue, the ratio motor evoked response by TMS/CMAP; TMS index (TMSi) as previously described-Z score of the cortical threshold + Z score of the central conduction time. A p value < 0.01 was accepted as significant (Friedman and Wilcoxon signed rank tests).
Results: All patients were completely evaluated at both visits. The ratio MEP/CMAP and the increase of the CSP after fatigue did not change significantly. ALS-FRS (18.4%), FVC (15.4%), CMAP (25.5%), NI (41.9%), MUNE (40.4%) decreased significantly in 6 months. TMSi and CSP increased significantly (170.4 and 29.2%, respectively). NI, MUNE and CMAP had a lower coefficient of variability (0.57, 0.61 and 0.65 respectively). This coefficient was very large for TMSi. NI and MUNE changed more than ALS-FRS, FVC and CMAP, but similarly to TMSi and CSP. CMAP was more sensitive than FVC. TMSi and CSP increment was statistically comparable.
Discussion: In addition to confirming that NI and MUNE are sensitive markers of LMN loss, this study shows that conventional TMS can be used to evaluate UMN loss in ALS over time. Both TMSi and CSP increased significantly over 6 months, and the percentage of change was comparable to LMN loss. Although the amplitude of the motor response evoked by TMS is quite variable, cortical threshold and central conduction time increased in this period. In addition, the prolongation of the CSP suggests a progressive dysfunction of inhibitory pathways. Thus, that conventional TMS can be a useful to measure UMN dysfunction in ALS. Its role in ALS should be reconsidered.
C51 MOTOR UNIT NUMBER INDEX (MUNIX): A NOVEL NEUROPHYSIOLOGICAL TECHNIQUE TO FOLLOW DISEASE PROGRESSION IN ALS
NEUWIRTH C1, NANDEDKAR S2, STALBERG E2, WEBER M1
1Muskelzentrum/ALS clinic, Kantonsspital St.Gallen, St.Gallen, Switzerland, 2Department of Neurophysiology, University Hospital, Uppsala, Sweden
E-mail address for correspondence: [email protected]
Keywords: MUNIX, motor unit number, electrophysiology
Background: Several motor unit number estimation (MUNE) techniques have been applied to quantify motoneuron loss in ALS. Disadvantages of the existing methods are that they are time consuming (20–30 min. per muscle) and/or invasive. MUNIX is based on surface-EMG recordings, requiring only a few minutes per muscle Citation[1].
Objective: To evaluate the feasibility of MUNIX as a marker to objectively measure disease progression in ALS.
Methods: As of summer 2007 seven patients (5 males, 2 females, mean age 61, disease duration less than 14 months) were enrolled in a randomized controlled clinical trial (SIRONA) At 2-monthly follow-up visits clinical data, CMAPs and MUNIX from 8 muscles (APB, ADM, AH, EDB bilaterally) were obtained. After measuring one single supramaximal CMAP, surface EMG was recorded during voluntary contraction of muscles at increasing force levels (minimal to maximal, 9 times).
Results: By the end of March data were available over a 6-month-period from each patient. The method was very well tolerated, no participant retired from the trial. Technically no major problems occurred. At study entry mean MUNIX per muscle was 56.5±20.4, mean CMAP per muscle 4.3±1.3 and mean ALSFRSR 43.6±2.4. After 6 months MUNIX had dropped to 53.1±18.0, CMAP to 3.9±1.6 and ALSFRSR to 39.0±5.2. Changes were only significant for the ALSFRSR (p < 0.019 paired t-test).
Discussion: MUNIX analysis is quick to perform and well tolerated, but patient co-operation is necessary. Changes over a 6-month-period were not significant. One-year data and their statistical analysis will show whether MUNIX is superior to standard neurophysiological measures (CMAP) and clinical scores.
C52 FACILITATION OF THE JAW-JERK REFLEX IN BULBAR ONSET ALS PATIENTS
GUTIERREZ J1, ALVARAZ I1, MUSTELIER R1, LESTAYO Z1, LARA G1, ZALDIVAR T1, HARDIMAN O2
1Cuban Institute of Neurology and Neurosurgery,, Havana, Cuba, 2Beaumont Hospital &Trinity College, Dublin, Ireland
E-mail address for correspondence: [email protected]
Keywords: ALS, jaw-jerk reflex
Background: The jaw-jerk Reflex (JJR) is the trigeminal equivalent of monosynaptic myotatic reflexes in limb muscles. JJR excitability is determined by suprasegmental influences on brainstem motor circuits, and could be used as an indirect assessment of upper motor neuron tone. There are no previous studies of JJR in patients with amyotrophic lateral sclerosis (ALS).
Objective: To describe the electrophysiological features of the JJR in patients with early-stage ALS.
Methods: We studied 17 patients with a definitive diagnosis of bulbar onset ALS (<1 year of evolution) and 15 age-matched healthy controls. The reflex was evoked by tapping the subject's chin at rest with a modified neurologist's reflex hammer that also triggered the oscilloscope recordings. The responses were recorded with surface electrodes placed over the masseter muscle. All subjects were stimulated 20 times, at intervals of 30 seconds. Average onset latency and peak to peak amplitude, as well as the percentage of occurrence of the responses, were measured in all subjects.
Results: ALS patients showed significantly increased JJR amplitudes compared to controls (370±65 uv. vs. 250±110 uv.), p < 0.05). The percentage of occurrence was also significantly higher in patients than in normal subjects (75.5±17.3% vs. 55.5±18.2%, p < 0.05) and ALS patients showed a poor habituation of the responses over repeated tapings. Average onset latency was reduced in the ALS group, as compared to controls, but this difference was not statistically significant (6.7±1.5 ms. vs. 7.3±1.3 ms, p > 0.05).
Conclusion: These findings demonstrate that patients with early stage ALS have a facilitated JJR. These enhancement could be explained by two reasons: 1- Increased suprasegmental excitatory influences on brainstem motor circuits. 2- Decreased cortico-bulbar inhibitory influences on brainstem motor neurons, as happen with the other myotatic reflexes. The study of JJR could provide evidence of UMN involvement, independent of cervical spinal cord compression, which could be helpful to support an earlier ALS diagnosis.
C53 QUANTITATIVE MUSCLE ULTRASONOGRAPHY IN AMYOTROPHIC LATERAL SCLEROSIS
ARTS IM1, VAN ROOIJ FG1, OVEREEM S1, PILLEN S2, SCHELHAAS HJ1, ZWARTS MJ2
1Department of Neurology, 2Department of Clinical Neurophysiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
E-mail address for correspondence: [email protected]
Keywords: early diagnosis, muscle ultrasonography, quantitative analysis
Background: Amyotrophic lateral sclerosis (ALS) can be difficult to diagnose, especially in an early stage of the disease. Quantitative muscle ultrasonography can be used to detect structural muscle changes in neuromuscular diseases. Furthermore ultrasonography can detect movements like fasciculations.
Objectives: The primary objective is to examine whether quantitative muscle ultrasonography can detect structural muscle changes in early-stage ALS. In addition a longitudinal study was performed to asses if quantitative muscle ultrasonography can be used to monitor disease progression.
Methods: Bilateral transverse scans were made of five muscles or muscle groups (sternocleidomastoid, biceps brachii/brachialis, forearm flexor group, quadriceps femoris and anterior tibial muscles) in 75 patients suspected of having ALS. Echo intensity and muscle thickness were determined for each muscle. Twenty-five patients were also screened for fasciculations. For the longitudinal study 35 patients were examined five times with an interval of six weeks using the previously described ultrasound protocol. In addition the ALSFRS was administered and muscle strength was tested (manual muscle testing) each time.
Results: Of the 75 patients included, 48 patients received a final diagnosis of ALS and were analyzed further. Quantitative analysis revealed a significant increase in echo intensity in all muscles and a decrease in muscle thickness of the biceps brachii, forearm flexors and quadriceps femoris on both sides. Fasciculations were easy to detect in multiple muscles of all screened patients except one. The results of the follow up study will be presented at the Symposium.
Discussion and Conclusion: Quantitative ultrasound can be used to detect muscle changes, including fasciculations, caused by ALS in an early phase of the disease. Our results suggest that quantitative muscle ultrasonography probably can be used to increase diagnostic certainty by detecting muscle abnormalities in clinically unaffected regions. Particularly now a more prominent role for fasciculations in the electrophysiological diagnosis of ALS is suggested Citation[1].
The results of the longitudinal study are needed to verify if quantitative muscle ultrasonography can also be used to monitor disease progression.
C54 USING THE CLINICAL PHENOTYPE TO PREDICT MRI CHANGES IN ALS: A 4 TESLA STUDY USING FRACTIONAL ANISOTROPY.
KATZ JS1, WOOLLEY-LEVINE S1, ZHANG Y2, CHAMPION S1, WEINER M2
1California Pacific Medical Center, San Francisco, 2University of California San Francisco, San Francisco, CA, United States
E-mail address for correspondence: [email protected]
Keywords: diffusion tensor imaging, corticospinal tracts, phenotypes
Background: Several diffusion tensor imaging (DTI) studies of the corticospinal tracts (CST) in ALS have demonstrated reduced fractional anisotropy compared to controls. Still, exact correlations between the motor disability and the severity of diffusion abnormalities remain uncertain. Several studies have explored the relationship of FA findings to the severity of motor signs and have found correlations, yet it is not clear whether specific patterns of motor involvement can predict these abnormalities.
Objectives: Using DTI and recording fractional anisotropy (FA), we sought to determine if patients with ALS that involved only the limbs differed from those with generalized patterns within the CST or in other frontal regions.
Methods: We created a clinical categorization scheme that divided patients into two basic phenotypes. We defined generalized ALS (GALS) in patients who had upper motor neuron involvement in the bulbar region and at least one limb region, and had lower motor neuron involvement in at least one limb at the time of study. Localized ALS (LALS) was defined as upper motor neuron and lower motor neuron involvement only in the limbs at the time of the study. Eighteen patients and fifteen controls underwent DTI imaging using a 4.0-Tesla (Bruker/Siemens) MRI system, based on EPI sequence (TR/TE = 6000/77ms; field of view 256×224cm; 128×112 matrix size, 2 x 2 x 3 mm3 resolution; b = 0, and b = 1000 with 6 non-collinear directions). Alignment of FA images from all study subjects was performed by SPM2 software. Analyses were performed in ALS versus controls and between generalized and regional ALS voxel-by-voxel accounting for age and gender. Significance level was set at p < 0.005 without controlling for multiple comparison.
Results: The mean age of the ALS cohort was 58 years, mean FVC 91% and mean ALSFRS-R score 35. Patients with GALS had a shorter duration of disease (mean 17.5 months v 32.8), lower FVC (mean 82.5% v. 98.2%) and lower ALS FRS score (33 v. 37). Compared to controls, there was significant FA reduction along motor fibers and across the corpus callosum in GALS, but only minimal change in the motor fibers in LALS versus controls. For the overall cohort, ALSFRS-R positively correlated with FA in bilateral motor fibers, frontal WM, temporal white matter but we did not see strong correlations with duration of disease or FVC.
Discussion and Conclusions: A correlation between FA along the CST and ALS-FRS is established from previous studies. However, our findings also suggest that the clinical pattern can help predict whether CST involvement will be present in the brain by FA. In particular, upper motor neuron bulbar involvement, which was the primary method to differentiate patients in this study, were associated with greater CST and colossal involvement, while limb-only patterns did not show the extent or degree of these central changes. The findings give some indication that the spread and degree of disease centrally differs between the varied phenotypes.
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