Sensitivity and specificity of the 'Awaji' electrodiagnostic criteria for amyotrophic lateral sclerosis: retrospective comparison of the Awaji and revised El Escorial criteria for ALS.

The Awaji Commission recently proposed a modification of the electrodiagnostic criteria for ALS. We assessed whether the Awaji recommendations improve the sensitivity of the early diagnosis of ALS. In a retrospective study we reviewed clinical and neurophysiological data for 213 patients who visited our motor neuron disease outpatient clinic between October 2006 and December 2008. Using the El Escorial criteria, 51 patients were diagnosed with definite or probable ALS, 14 with probable laboratory-supported ALS, and 28 with possible ALS. An alternative diagnosis was present in 120 patients. Applying the Awaji recommendations, 66 patients were diagnosed with either definite or probable ALS, and 27 with possible ALS. Of the 14 patients diagnosed with probable laboratory-supported ALS, eight switched to probable ALS and six to possible ALS using the Awaji recommendations; none of the patients with an ALS mimic was diagnosed with ALS according to the Awaji recommendations. In conclusion, the new criteria for ALS do not result in a loss of specificity and can potentially improve the sensitivity by 16%. However, this diagnostic improvement appears eliminated if patients with probable laboratory-supported ALS - due to UMN signs in one region - should be categorized as possible ALS.

Prospective, blind study of the triple stimulation technique in the diagnosis of ALS.

OBJECTIVE: To evaluate the diagnostic yield of magnetic cortical stimulation with the triple stimulation technique (TST) to identify upper motor neuron (UMN) involvement in patients suspected of having ALS. METHODS: Fifty-nine patients were recruited to undergo TST in addition to the standard work-up for suspected motor neuron disease. TST combines transcranial magnetic stimulation of the motor cortex with collision studies, which results in a higher sensitivity in detecting UMN involvement. Primary outcome was the number of abnormal TST results in patients with possible ALS. The positivity rate was converted to the number needed to test with TST (NN-TST) for one extra diagnosis of ALS. RESULTS: Fifty patients underwent TST. In the total group (n=59), 18 patients had a motor neuron disorder but did not fulfil criteria for 'probable' or 'definite' ALS. In four of these patients TST was abnormal (NN-TST, 4.5). One TST was erroneously interpreted as abnormal. TST findings were normal in inclusion body myositis and peripheral nerve disorders. CONCLUSION: This prospective and blind study confirms open studies of TST in the evaluation of ALS. We suggest that TST can be used to arrive at a diagnosis of 'probable' or 'definite' ALS in patients lacking UMN signs in the upper extremities.

Prevalence and distribution of fasciculations in healthy adults: Effect of age, caffeine consumption and exercise.

Our objective was to determine the prevalence and distribution of fasciculations in healthy adults and to assess the effect of age, caffeine and exercise. Fasciculations were studied with ultrasonography in 58 healthy adults in various age categories. Questionnaires were used to determine effect of caffeine and regular exercise on the presence of fasciculations. Finally, we tested the effect of strenuous exercise on fasciculations in 10 healthy adults. Twenty-five subjects (43%) showed fasciculations on ultrasonography, mostly in the abductor hallucis longus muscle. Fasciculations were only sporadically encountered in muscle groups above the knee. Subjects with fasciculations were significantly older than those without. Caffeine and regular physical exercise did not influence the prevalence of fasciculations. However, strenuous physical exercise caused a temporary increase in fasciculations, but only in lower leg muscles. Fasciculations above the knee should raise suspicion and may warrant further investigation.

Muscle imaging: mapping responses to transcranial magnetic stimulation with high-density surface electromyography.

Representations of different body parts or muscles in the human primary motor cortex overlap extensively. At the effector level, most muscles are surrounded by and overlap with several neighbours as well. This hampers the assessment of excitability in individual muscles with transcranial magnetic stimulation (TMS), even if so-called "focal" stimulating coils are used. Here we used a novel mapping paradigm based on high-density surface electromyography (HD-sEMG) to investigate the spatial selectivity of TMS in the forearm musculature. In addition, we tested the hypothesis that selective stimulation can be improved by a voluntary background contraction of the target muscle. We mapped and compared the topographies of motor evoked potential (MEP) amplitudes during rest and during background contractions of two forearm muscles (extensor carpi radialis and extensor digitorum communis). The MEP topographies were also compared to the amplitude topography of voluntary EMG. The results indicate that under many conditions a large proportion of the MEP activity recorded at the surface originated from the target muscle's neighbours. There was a systematic relationship between TMS intensity and the topographic distribution of MEP responses during voluntary contraction. With increasing stimulus intensity, the MEP topography deviated increasingly more from the topography of voluntary EMG. We conclude that when standard EMG montages are used, the recorded MEPs are not necessarily evoked in the target muscle alone. Stimulation during a voluntary background contraction of the target muscle may enhance the selectivity of TMS. It however remains essential to use stimulus intensities as low as possible, to minimize the contribution of surrounding non-target muscles to the MEP.

Inter-operator agreement in decomposition of motor unit firings from high-density surface EMG.

High-density surface EMG can be used to obtain a spatially selective representation of several motor unit action potentials. Recently, a decomposition of the signal into the underlying motor neuron firing patterns has been described. The reliability of the algorithm has not yet been tested. Eleven healthy subjects participated. High-density surface EMG was recorded from the vastus lateralis muscle during an isometric knee extension. Two independent operators analyzed the signals. After operator-supervised cluster analysis of spikes, motor unit action potential templates were constructed and an automatic template matching was performed. The decomposition was adjusted by hand. Agreement between operators was calculated for the number of coincident firings. Bland-Altman plots of peak-to-peak amplitude were constructed and limits of agreement were calculated. For completely decomposed motor unit action potential trains the between-operator agreement of firing events was very high. The peak-to-peak amplitude of monopolar motor unit action potentials was 115microV (SD 74microV). The agreement was within 3microV and independent of amplitude. With partial decomposition agreement within 26microV was achieved. For bipolarly derived motor unit action potentials the peak-to-peak amplitude was 54microV (SD 49microV), the agreement was within 3microV. Only for recordings obtained from a force level below 5% of the maximum voluntary contraction full decomposition was possible. It was concluded that when full decomposition is achieved, two independent operators are likely to arrive at nearly identical firing patterns.

Fasciculation potentials in high-density surface EMG.

Fasciculation potentials (FPs) are observed in healthy individuals, but also in patients with neurogenic disorders. The exact site of origin and the clinical relevance in distinguishing, for example, amyotrophic lateral sclerosis (ALS) from other neurogenic diseases based on specific characteristics of the FPs is still a matter of debate and needs further exploration. This report describes the use of high-density surface EMG (HD-sEMG), with multiple electrodes in a compact grid to noninvasively record FPs. The technique provides both temporal and spatial information of fasciculations. Examples of the FPs of a patient diagnosed with definite ALS are presented. FPs are shown in different electrode montages and the unique spatial characteristics of different FPs are presented. During 30-second recordings, 137 FPs were detected that via a decomposition algorithm could be assigned to 11 different underlying sources. It is concluded that HD-sEMG, both because of its noninvasive character and the unique spatiotemporal information, is very suitable to examine fasciculations. It allows long stable recording times and provides quantitative information. This electrophysiologic tool is expected to expand the existing knowledge of FP properties.

Using two-dimensional spatial information in decomposition of surface EMG signals.

Recently, high-density surface EMG electrode grids and multi-channel amplifiers became available for non-invasive recording of human motor units (MUs). We present a way to decompose surface EMG signals into MU firing patterns, whereby we concentrate on the importance of two-dimensional spatial differences between the MU action potentials (MUAPs). Our method is exemplified with high-density EMG data from the vastus lateralis muscle of a single subject. Bipolar and Laplacian spatial filtering was applied to the monopolar raw signals. From the single recording in this subject six different simultaneously active MUs could be distinguished using the spatial differences between MUAPs in the direction perpendicular to the muscle fiber direction. After spike-triggered averaging, 125-channel two-dimensional MUAP templates were obtained. Template-matching allowed tracking of all MU firings. The impact of spatial information was measured by using subsets of the MUAP templates, either in parallel or perpendicular to the muscle fiber direction. The use of one-dimensional spatial information perpendicular to the muscle fiber direction was superior to the use of a linear array electrode in the longitudinal direction. However, to detect the firing events of the MUs with a high accuracy, as needed for instance for estimation of firing synchrony, two-dimensional information from the complete grid electrode appears essential.

Multi-channel EMG of the M. triceps brachii in rats during treadmill locomotion.

OBJECTIVES: The study aims at a precise characterisation of intramuscularly varying recruitment patterns within the triceps brachii muscle (long and lateral head; proximal, medial, distal regions) in the time course of averaged step cycles during locomotion. METHODS: The triceps brachii muscle of 15 Hannover rats was investigated with a supramuscular 16-electrodes grid during treadmill locomotion. Multi-channel electromyogram (EMG) was recorded simultaneously with high-speed videography. The rectified and smoothed EMG was time-normalised. EMG profiles and dynamic EMG-map series were calculated. Differences between EMG distribution patterns were tested by multivariate analysis of variance. RESULTS: In the pre-stance phase EMG activity increased especially in the proximal long head. It most likely propagated from lower muscle layers of the long head. During stance phase the EMG activity of the lateral head rose steeply and exceeded those of the long head in short time. The fastest steps show the highest EMG amplitudes. CONCLUSIONS: EMG registrations with grid electrodes help in the identification of intramuscular co-ordination processes during locomotion. While the EMG profiles characterise the time course, the topographical distribution is better represented in dynamic EMG interference maps. The dynamic changing activation patterns of triceps brachii depend on the phase of the step cycle. This clearly indicates the different functions of the muscle heads.

Fasciculations and their F-response revisited: high-density surface EMG in ALS and benign fasciculations.

OBJECTIVE: To compare the prevalence of fasciculation potentials (FPs) with F-responses between patients with amyotrophic lateral sclerosis (ALS) and patients with benign fasciculations. METHODS: In seven patients with ALS and seven patients with benign fasciculations, high-density surface EMG was recorded for 15 min from the gastrocnemius muscle. Template matching was used to search for pairs of FPs with a repetition within 10-110 ms. RESULTS: Interspike interval (ISI) histograms were constructed from 282 pairs of benign fasciculations and from 337 FP pairs in ALS. Peaks attributable to F-waves were found at latencies of 32 ms (benign) and 35 ms (ALS). Five patients with benign fasciculations and four patients with ALS had FPs with F-waves. CONCLUSIONS: F-waves of FPs occur in both conditions - therefore they are not diagnostically helpful. SIGNIFICANCE: F-waves confirm the distal origin of FPs for an individual axon. The occurrence of these FPs in a benign condition suggests that the generation of ectopic discharges in the distal axons is not specific to progressive neurodegeneration.

Muscle ultrasonography: a diagnostic tool for amyotrophic lateral sclerosis.

OBJECTIVE: In a prospective study we tested whether muscle ultrasonography can differentiate between amyotrophic lateral sclerosis (ALS) and mimics. Furthermore, we assessed the ability of ultrasonography to identify subclinical lower motor neuron involvement. METHODS: In 59 patients, suspected for adult onset motor neuron disease, ultrasound scans were made of 12 different muscle groups. Echo intensity was determined and each muscle was screened for fasciculations. Ultrasonography was considered diagnostic for ALS when echo intensity was 1.5 SD above normal in at least two muscles and fasciculations were present in at least four muscles. RESULTS: Ultrasonography differentiated between ALS and mimics with 96% sensitivity and 84% specificity. In the 27 ALS patients, ultrasonography detected 15 regions with lower motor neuron involvement that were negative using either clinical examination or needle EMG. CONCLUSIONS: Muscle ultrasound can differentiate between amyotrophic lateral sclerosis and mimics with high sensitivity and specificity, and is a sensitive tool to screen for regional lower motor neuron involvement. SIGNIFICANCE: Muscle ultrasonography is a promising tool in the diagnostic work up of ALS.

Enhanced physiological tremor deteriorates plantar flexor torque steadiness after bed rest.

This study evaluated the effectiveness of resistance training to preserve submaximal plantar flexor (PF) torque steadiness following 60 days of bed rest (BR). Twenty-two healthy male subjects underwent either BR only (CTR, n=8), or BR plus resistance training (RT, n=14). The magnitude of torque fluctuations during steady submaximal isometric PF contractions (20%, 40%, 60% and 80% of maximum) were assessed before and after BR. Across contraction intensities, torque fluctuations (coefficient of variation, CV) increased more (P<0.05) after BR for CTR (from 0.31±0.10 to 0.92±0.63; P<0.001), than for RT (from 0.30±0.09 to 0.54±0.27; P<0.01). A shift in the spectral content of torque fluctuations towards increased rhythmic activity between 6.5 and 20Hz was observed in CTR only (P<0.05). H-reflex amplitude (H(max)/M(max) ratio) declined across groups from 0.57±0.18 before BR to 0.44±0.14 following BR (P<0.01) without correlation to CV. The present study showed that increased torque fluctuation after BR resulted from enhanced physiological tremor. Resistance training prevented the spectral shift in isometric PF torque fluctuation and offset ∼50% of the decline in performance associated with long-term BR.

The alpha-motoneuron pool as transmitter of rhythmicities in cortical motor drive.

OBJECTIVE: Investigate the effectiveness and frequency dependence of central drive transmission via the alpha-motoneuron pool to the muscle. METHODS: We describe a model for the simulation of alpha-motoneuron firing and the EMG signal as response to central drive input. The transfer in the frequency domain is investigated. Coherence between stochastical central input and EMG is also evaluated. RESULTS: The transmission of central rhythmicities to the EMG signal relates to the spectral content of the latter. Coherence between central input to the alpha-motoneuron pool and the EMG signal is significant whereby the coupling strength hardly depends on the frequency in a range from 1 to 100 Hz. Common central input to pairs of alpha-motoneurons strongly increases the coherence levels. The often-used rectification of the EMG signal introduces a clear frequency dependence. CONCLUSIONS: Oscillatory phenomena are strongly transmitted via the alpha-motoneuron pool. The motoneuron firing frequencies do play a role in the transmission gain, but do not influence the coherence levels. Rectification of the EMG signal enhances the transmission gain, but lowers coherence and introduces a strong frequency dependency. We think that it should be avoided. SIGNIFICANCE: Our findings show that rhythmicities are translated into alpha-motoneuron activity without strong non-linearities.

Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial.

BACKGROUND: Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone. METHODS: In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236. FINDINGS: Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1.2, 95% CI 0.3-4.4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group. INTERPRETATION: Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed. FUNDING: The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

Interspike interval analysis in a patient with peripheral nerve hyperexcitability and potassium channel antibodies.

Neuromyotonia or Isaacs' syndrome is a rare peripheral nerve hyperexcitability disorder caused by antibodies against potassium channels of myelinated axons. We present the high-density surface electromyographic (EMG) recordings of a patient with fasciculations and cramps due to neuromyotonia. To characterize the time course of hyperexcitability, we analyzed the interspike intervals (ISIs) between fasciculation potentials, doublet, and multiplet discharges. ISI duration increased within each burst. The ISI histograms found can be explained by the recovery cycle of the myelinated axon and its dependency on the slow potassium conductance. We conclude that ISI analysis is a useful tool to understand the membrane dynamics underlying abnormal motor unit activity.

Firing pattern of fasciculations in ALS: evidence for axonal and neuronal origin.

BACKGROUND: In amyotrophic lateral sclerosis (ALS), the origin of fasciculations is disputed. We hypothesized that the discharge pattern of fasciculation potentials (FPs) would be different for FPs arising in the motor axon or in the spinal motor neuron. METHOD: FPs were recorded by high-density surface EMG of the biceps brachii or vastus lateralis muscle for 15 minutes in 10 patients with ALS. Records were decomposed into different FP waveforms and their firing moments. Interspike interval (ISI) histograms were constructed for FPs that fired more than 100 times. RESULTS: Two types of ISI histograms were found. 1) In 23 of 30 different FPs with a total of 8,597 ISIs, the refractory period was 3 to 4 msec. ISIs longer than 15 msec had a Poisson distribution. Five of these 23 FPs discharged doublets with an ISI of approximately 5 msec, indicative of supernormality. This is consistent with the FPs arising in motor axons. 2) In the other 7 FPs, accounting for 11,266 ISIs, the refractory period was 17 to 46 msec. The preferred ISI duration was around 80 msec. Both timing factors are consistent with origin in the spinal motor neuron. CONCLUSIONS: Firing pattern analysis, based on high-density surface EMG, can detect fasciculation potentials (FPs) of axonal and neuronal origin in amyotrophic lateral sclerosis. The two FP types coexist within the same muscle. The recognition that clinically identical fasciculations conceal the existence of two types of FP that can be studied in a noninvasive manner will introduce a new aspect in the research of motor neuron disease.

Expectancy induces dynamic modulation of corticospinal excitability.

Behavioral studies using motor preparation paradigms have revealed that increased expectancy of a response signal shortens reaction times (RTs). Neurophysiological data suggest that in such paradigms, not only RT but also neuronal activity in the motor structures involved is modulated by expectancy of behaviorally relevant events. Here, we directly tested whether expectancy of a response signal modulates excitability of the corticospinal system used in the subsequent movement. We combined single- and paired-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex with a simple RT task with variable preparatory delays. We found that, in line with typical behavioral observations, the subjects' RTs decreased with increasing response signal expectancy. TMS results revealed a modulation of corticospinal excitability in correspondence with response signal expectancy. Besides an increased excitability over the time-course of the preparatory delay, corticospinal excitability transiently increased whenever a response signal was expected. Paired-pulse TMS showed that this modulation is unlikely to be mediated by excitability changes in interneuronal inhibitory or facilitatory networks in the primary motor cortex. Changes in corticospinal synchronization or other mechanisms involving spinal circuits are candidates mediating the modulation of corticospinal excitability by expectancy.