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Fasciculations are a major clinical feature, present very early in the natural history of amyotrophic lateral sclerosis (ALS).1 They represent spontaneous discharges of motor units or portions of motor units, that can sometimes also be activated volitionally.2 There is no objective evidence that fasciculation potential (FP) discharges can be modulated by the patient or by the examiner. In this study we have addressed this issue in ALS, spinal muscular atrophy (SMA) and benign fasciculation syndrome (BFS).
Methods
We evaluated fasciculation firing frequency, using surface electromyographic (EMG) recordings from the first dorsal interosseous (DI) muscle in the hand at rest, and randomly after a period of maximal contraction, thus involving upper and lower motor neuron excitation, after radial sensory nerve stimulation and after supramaximal electrical stimulation of the ulnar nerve at the wrist, representing lower motor neuron excitation. We studied 75 patients with definite or probable ALS, excluding patients with polyneuropathy, diabetes or ulnar neuropathy (median age 61 years (range 27–75 years), median disease duration 12 months (range 3–24 months), 48 were men). One hand, in which first DI strength was 4 on the MRC (Medical Research Council) score 4 or 5, was studied in each patient. In each participant, FPs were recorded at rest in the first DI muscle. Six patients with SMA type 3 were studied (median age 45 years; range 28–60 years). All had MRC 4 strength with FPs in the studied first DI muscle. Eleven patients (8 men) with BFS were included (median age 55 years; range 40–63 years). Each had been symptomatic for several years, and all had been followed for more than 3 years without clinical change. In all subjects with BFS the EMG was normal, including motor unit potential analysis in the selected first DI muscle.
An initial baseline, recording was made with the first DI muscle relaxed. Recordings were made with a gain of 0.3 mV/division, filter setting 20–500 Hz and sweep speed of 500 ms/division. The baseline recordings were each of 2 min duration. Spontaneous discharges >100μV amplitude were detected automatically by the EMG machine (KeyPoint-Net, Dantec-Natus) and quantified as frequency at the end of the 2 min period. Recordings with movement artefact were discarded. Following this initial baseline recording, four additional 2 min recordings were carried out in randomised order, after 10 min rest intervals, using the following protocols: (a) a second 2 min baseline to assess reliability; (b) FP frequency following 1 min full contraction of the target muscle; (c) after supramaximal stimulation of the ulnar nerve at the wrist (1 Hz, 40 stimuli) and (d) after sensory branch stimulation of the radial nerve (20 Hz, 600 stimulations), using stimulus intensity 2.5 times greater than the threshold for sensation.3–5
For statistical analyses, percentage change was compared using non-parametric tests (Wilcoxon test for paired observations and Kruskal-Wallis test for multiple comparisons). After correction for multiple comparisons (Benjamini and Hochberg method), p<0.05 was set as significant.
Results
Needle recording of the first DI MRC 5 muscles was normal or showed mild signs of reinnervation. In hands of first DI MRC 4 strength, large motor unit potentials and, generally, fibrillation/positive sharp waves were found.
Results of the fasciculation frequency studies are summarised in table 1. Twenty-one patients with ALS were not included due to poor cooperation or absence of FPs in this muscle. The remaining 54 patients underwent the full protocol (31=MRC 4, 23=MRC 5). The baseline fasciculation frequency was similar in the different patient groups. We normalised the fasciculation frequency in the baseline recordings as 100% for each group. In the ALS MRC 5, hands FP frequency did not change after any intervention (p>0.05). In the ALS MRC 4, hands baseline FP frequency increased to 127.3% (IQR 85.9–207.7; p=0.01) after sensory nerve stimulation. In the group of participants with BFS, no significant change was found in any protocol. In the SMA group, the fasciculation frequency values were stable for all protocols, except for sensory nerve stimulation, which increased FP frequency to 315.2% (IQR 80.3–546.1); however, the small number of patients with SMA studied precluded statistical analysis. In one patient with SMA the study was repeated 3 months after the initial investigation. Sensory nerve stimulation increased the fasciculation frequency by 341% at the first assessment and 272% at the second assessment. In nine additional patients with ALS with first DI strength MRC 4, baseline frequency was compared with threshold and 2.5 times threshold stimulation of the superficial radial sensory nerve. Threshold stimulation did not increase FP frequency, but 2.5 times threshold stimulation increased it by 237% (p<0.05).
Results of fasciculation frequency at baseline and following the experimental protocols (see text)
Discussion
Hjorth et al6 noted that more fasciculations were detected in surface EMG recordings than by clinical assessment. FPs fired at a median interdischarge interval of 4–5 s, corresponding to a median value of 0.25 Hz. Our results show that 2 min recording from the first DI provides a reliable measurement of FP frequency, as no significant difference was found between random baseline recordings in the different groups investigated. In ALS, the mean change between paired observations was 29% (SD 23%).
In observing fasciculation, clinicians are taught to stimulate the skin, percuss the muscle or examine the effect of maximal voluntary contraction, in the belief that these manoeuvres may evoke fasciculations.7 ,8 Studies of the effect of sensory nerve stimulation on motor unit recruitment in normal human participants have revealed that under conditions of increasing input from cutaneous receptors, net excitation of motor neurons is altered such that recruitment of high threshold units can occur earlier, while recruitment of low threshold units may be delayed.5 However, our results do not support muscle contraction or peripheral motor axon stimulation mimicking voluntary contraction as effective in eliciting FPs in ALS. Nonetheless, above-threshold sensory stimulation of the skin overlying the tested muscle can be effective in increasing FP frequency in weak muscles, probably by modulation of lower motor neuron excitability. Spinal segments with reduced lower motor neuron numbers show decreased inhibition in ALS5–9 and studies in animal models of ALS confirm that excitability of spinal interneurons increases with disease progression,10 findings that support our observations.
Footnotes
Contributors All authors have contributed to this paper. MdC was involved in study design, neurophysiological investigation and draft preparation. AT was involved in statistical analysis. SP was involved in patient recruitment and clinical follow-up. MS was involved in study design, data discussion and writing.
Funding This work was partially funded by the SOPHIA project funded by JPND and by “Fundação para a Ciência e Tecnologia” (JPND/0002/2011).
Competing interests None.
Patient consent Obtained.
Ethics approval This protocol was approved by the Centro Hospitalar Lisboa Norte Ethics Commission.
Provenance and peer review Not commissioned; externally peer reviewed.