Detection of fasciculations in amyotrophic lateral sclerosis: The optimal ultrasound scan time
Funding: This study was supported by National Health and Medical Research Council of Australia grant No. 1037746 (to Forefront, a collaborative research group dedicated to the study of motor neuron disease); International Federation of Clinical Neurophysiology Research Scholarship (to Y.-I.N., K.S., and J.M.M); Nakabayashi Trust for ALS research (to Y.-I.N.); 2015 Australian Endeavour Executive Fellowship (to N.S.); University of Sydney Post-Doctoral Fellowship (to W.H.).
Conflicts of Interest: The authors have no competing financial interests. Prof Kiernan serves as Editor-in-Chief of the Journal of Neurology, Neurosurgery, and Psychiatry.
ABSTRACT
Introduction
This study seeks to elucidate the optimal scan time to detect fasciculations by using ultrasound in the diagnosis of amyotrophic lateral sclerosis (ALS).
Methods
The intervals between fasciculations were recorded from tongue, abdominal, and limb muscles in ALS patients, incorporating assessment of the cumulative probability of 2 fasciculations occurring.
Results
From prospective studies of 228 muscles from 19 ALS patients, fasciculations were detectable in 68% of patients. The longest interfasciculation interval recorded was 81.4 s in the hand muscle. The cumulative probability of 2 fasciculations occurring was calculated as ≥0.9 in all muscles during a period of 60 s.
Discussion
A definition of 2 or more fasciculations occurring during a scan time of 60 s reliably allowed detection of fasciculations in ALS. Muscle Nerve, 2017
Abbreviations
-
- ABD
-
- rectus abdominis
-
- ALS
-
- amyotrophic lateral sclerosis
-
- ALSFRS-R
-
- revised ALS Functional Rating Scale
-
- BB
-
- biceps brachii
-
- EI
-
- echo intensity
-
- EMG
-
- electromyography
-
- FDI
-
- first dorsal interosseous
-
- Int
-
- interval
-
- LMN
-
- lower motor neuron
-
- MRC
-
- Medical Research Council
-
- TA
-
- tibialis anterior
-
- VL
-
- vastas lateralis
Fasciculations are the clinical and electromyographic hallmarks of amyotrophic lateral sclerosis (ALS), particularly when they are widespread and are accompanied by muscle wasting or electromyographic changes of denervation.1 Recently, muscle ultrasound has been incorporated as a simple, noninvasive tool for assessment of muscle structural changes and for detection of fasciculations in ALS patients. The utility of ultrasound for detection of fasciculations began in the 1990s when initial studies suggested that ultrasound was more sensitive than clinical or electromyographic examination for detection of fasciculations in lower motor neuron (LMN) syndromes and peripheral neuropathy.2, 3 For a diagnosis of ALS, Misawa and colleagues4 demonstrated that muscle ultrasound substantially increased diagnostic sensitivity if the presence of fasciculations on ultrasound was incorporated into the Awaji criteria. In addition, muscle ultrasound can reliably differentiate fasciculations from artifacts including voluntary contraction5 with possibly greater sensitivity than electromyography (EMG), whereas reliable relaxation may be difficult to ascertain.
To establish the utility of muscle ultrasound for detection of fasciculations in the clinical setting, it is important to delineate criteria for judging the presence of fasciculations, including the optimal scan time. As a guide, 2 or more focal muscle twitches, present for at least 10 s in each muscle, has been judged as confirmation of the presence of fasciculations in previous studies.3, 6-8 However, clear definitions and guidelines for ultrasound detection of muscle fasciculations in ALS are currently lacking, and definitions were not standardized in previous studies.4, 5, 9 No studies have yet clarified the optimal time for ultrasound scanning necessary to confirm the presence of fasciculations. In terms of EMG, Mills10 suggested that observation for up to 90 s is required to judge the presence of fasciculation. The current study seeks to elucidate the optimal scan time for an ultrasound diagnosis of fasciculations and to clarify ultrasound-specific precautions when identifying fasciculations.
MATERIALS AND METHODS
Ultrasound was prospectively studied in ALS patients recruited from a specialized multidisciplinary ALS clinic in November 2016. All participants provided written informed consent, and the study was approved by the human research ethics committee of the University of Sydney.
Patients
All patients recruited for the study were classified as possible, probable, or definite ALS according to the Awaji criteria.11, 12 Patients with possible ALS included in the study had clinical and electrophysiological findings of sporadic, progressive LMN involvement in the bulbar and 1 or more other (cervical, thoracic, and lumbar) regions with upper motor neuron signs in 1 region and more than 6 months history of disease progression before the ultrasound examination. Extensive clinical, imaging, and laboratory examinations were performed in all patients to exclude other LMN disorders such as multifocal motor neuropathy, spinal muscular atrophy, spinobulbar muscular atrophy, and postpolio syndrome. To determine the diagnostic category accurately, a complete neurological examination and EMG were performed by experienced neurologists for each patient. Muscle strength based on Medical Research Council (MRC) grading was undertaken in limb muscles, and the revised ALS Functional Rating Scale (ALSFRS-R) was calculated.13 Muscle weakness was defined as MRC grade 4 or less.
Ultrasound
Ultrasound was performed by a single examiner (Y.-I.N.) with 5 years experience in neuromuscular ultrasound who was blinded to the clinical history and findings from neurological examination. A MyLab Alpha ultrasound machine (Esaote, Genova, Italy) was used with a 3–11 MHz broadband linear array transducer (AL2442; Esaote). All settings were kept at the preset for muscle imaging in all examinations, with an imaging depth of 40 mm, a width of 40 mm, a gain of 70, and a frame rate of 15 Hz. The tongue, the trapezius bilaterally, the biceps brachii (BB) bilaterally, the first dorsal interosseous (FDI) bilaterally, the rectus abdominis (ABD), the vastus lateralis (VL) bilaterally, and the tibialis anterior (TA) bilaterally muscles were examined in each patient. Ultrasound recording was performed at 1 site (1 cross-sectional muscle image) in each muscle. The methodology employed was based on a previous EMG study by Mills.10 Recording from each muscle continued until 5 or more fasciculations had been observed visually. If a muscle showed no fasciculations on muscle ultrasound for 180 s from the scan start, the examiner stopped the observation, and the muscle was not included in the analysis of fasciculation intervals. Ultrasound videos were recorded in all scans and subsequently examined in detail. In the subsequent review of ultrasound recordings, the occurrence of individual fasciculations detected in the observable area was measured (t1, t2, t3, t4, t5) by using a frame feeding function. The movement of fasciculation was defined as twitching of small parts of the muscle lasting for 0.2–0.5 s, as described in previous studies.14 In the present study, a time period for when the focal area of the muscle had shifted maximally was measured by using a minimum time unit scale of 10 ms. The risk of missing the presence of fasciculations by using a 15 Hz frame rate was low given that the typical fasciculation duration was 0.2–0.5 s. In addition, the cross-sectional area of each muscle was measured with a manual tracking method at the first frame still image to calculate the proportion of muscle cross-sectional area on the whole ultrasound observable area (40 × 40 mm) as a percentage (muscle cross-sectional area [mm2]/1,600 [mm2] × 100). In muscles with a width or depth greater than 40 mm, it was not feasible for the ultrasound image area to include views of the entire muscle, and a representative sample was included for analysis. Echo intensity (EI) of the TA muscle, which was adjusted to the bone, was scored based on the Heckmatt rating scale as follows: 1, normal; 2, slightly increased muscle EI with normal bone reflection; 3, moderately increased muscle EI with reduced bone reflection; and 4, severely increased muscle EI without bone reflection.15
Statistical Analysis
From the time fasciculations were identified, interfasciculation intervals were calculated as described in a previous study.10 For each scan, if t1 … t5 represent the times of occurrence of fasciculations, the intervals (Int) were calculated from the difference between t1 … t5 (Int1, t2 − t1, t3 − t2, t4 − t3, and t5 − t4; Int2, t3 − t1, t4 − t2, and t5 − t3; Int3, t4 − t1 and t5 − t2; Int4, t5 − t1). Consequently, 4 Int1, 3 Int2, 2 Int3, and 1 Int1 were obtained from each scan (Supporting Information Fig. 1). The value of each Intn can be expressed as the estimated duration from the scan start time to the time in which n fasciculations occur. The cumulative probability of 2 fasciculations occurring was calculated by using Int2 in each muscle, given that the detection of 2 or more fasciculations in the scan time was regarded as the gold standard for fasciculation identification in most previous studies. To elucidate the effect of the proportion of muscle cross-sectional area in the whole image on the detection rate of fasciculations, we analyzed the correlation between the proportion of muscle cross-sectional area in the whole observable area and mean Int2 by using pooled data from all muscles. In addition, to test the effect of the muscle EI on the detection rate of fasciculation, we analyzed the correlation between the Heckmatt rating scale and mean Int2 of the TA muscle. Spearman rank correlation was used to test the correlation.
RESULTS
From a cohort of 19 consecutive ALS patients (8 definite, 7 probable, and 4 possible ALS), recordings were made in 228 muscles. Patients consisted of 17 Caucasians and 2 Asians with no family history of ALS. Patient age (60.9 ± 12.1 years, mean ± SD), functional status (ALSFRS-R 37.8 ± 7.2, mean ± SD), and disease duration (median 28 months, range 6–106 months) were representative of a typical ALS patient population. From this cohort, at least 5 fasciculations were extracted in 155 of 228 muscles (68%) included in the subsequent analysis. Assessment of the detection rate of fasciculation in each muscle (Table 1) established that the BB muscle had the highest fasciculation detection rate (84%) among the 7 muscles typically sampled. The proportion of muscles with weakness was highest (82%) and the mean proportion of muscle cross-sectional area on the observable area in muscles with fasciculations was lowest (14%) in the FDI muscle (Table 1). Muscle weakness was present in 66% of BB, 82% of FDI, 46% of VL, and 50% of TA muscles.
| Muscle | Number of muscles included in analysis | Proportion of muscles with fasciculations (%) | Mean proportion of muscle cross-sectional area on the observable area in muscles with fasciculations (%) |
|---|---|---|---|
| Tongue | 19 | 47 | 32 |
| Trapezius | 38 | 45 | 24 |
| BB | 38 | 84 | 35 |
| FDI | 38 | 74 | 14 |
| ABD | 19 | 63 | 19 |
| VL | 38 | 74 | 46 |
| TA | 38 | 76 | 48 |
| All muscles | 228 | 68 | 33 |
- a ABD, rectus abdominis; BB, biceps brachii; FDI, first dorsal interosseous; TA, tibialis anterior; VL, vastas lateralis.
Regarding the frequency of fasciculations in each muscle (Table 2), Int1–4 durations were longest in the FDI muscle. From Int1 in the whole data set, the longest interfasciculation interval was 81.43 s in the FDI. Assessment of the probability of 2 fasciculations occurring (Fig. 1) suggested that the cumulative probability of indentifying 2 fasciculations was ≥ 0.9 in all the muscles by 60 s of observation. By extension, a scan time of 126 s was required to ensure that the probability became 1.0 in the FDI muscle.
The cumulative probability of detecting 2 fasciculations in each muscle. Dots are plotted every 2 s. At 60 s, the probability of detecting 2 fasciculations is greater than 0.9 in all muscles. The probability of the FDI muscle reaches 1.0 at 126 s. ABD, rectus abdominis; BB, biceps brachii; FDI, first dorsal interosseous; TA, tibialis anterior; VL, vastas lateralis.
| Int1 (s) | Int2 (s) | Int3 (s) | Int4 (s) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Muscle | Mean | Range | n | Mean | Range | n | Mean | Range | n | Mean | Range | n |
| Tongue | 7.69 | 0.37–51.53 | 36 | 17.75 | 1.28–69.87 | 27 | 26.63 | 2.79–84.01 | 18 | 30.76 | 5.46–85.59 | 9 |
| Trapezius | 6.99 | 0.42–61.59 | 68 | 12.21 | 1.73–69.17 | 51 | 18.31 | 2.89–83.92 | 34 | 27.95 | 3.99–94.30 | 17 |
| BB | 4.41 | 0.11–50.79 | 128 | 8.21 | 0.74–51.41 | 96 | 12.31 | 1.63–56.11 | 64 | 17.63 | 2.52–85.40 | 32 |
| FDI | 9.50 | 0.17–81.43 | 112 | 18.36 | 1.32–126.03 | 84 | 27.54 | 2.43–143.11 | 56 | 37.99 | 5.22–152.32 | 28 |
| ABD | 7.70 | 0.69–44.42 | 48 | 15.65 | 1.75–47.60 | 36 | 23.48 | 2.73–60.98 | 24 | 30.81 | 3.98–64.59 | 12 |
| VL | 6.36 | 0.21–56.23 | 112 | 13.22 | 0.84–98.15 | 84 | 19.82 | 1.96–131.21 | 56 | 25.43 | 2.63–144.94 | 28 |
| TA | 8.31 | 0.21–71.98 | 116 | 17.25 | 1.56–90.68 | 87 | 25.88 | 2.62–106.82 | 58 | 33.25 | 3.93–119.37 | 29 |
- a ABD, rectus abdominis; BB, biceps brachii; FDI, first dorsal interosseous; Int, interval; TA, tibialis anterior; VL, vastas lateralis.
In the analysis of correlations between the proportion of muscle cross-sectional area in the whole observable area and mean Int2 and between Heckmatt rating scale and mean Int2 in the TA muscles, there were no significant correlations (r = −0.048, P = 0.554 and r = 0.239, P = 0.211, respectively).
DISCUSSION
This study was adopted from electromyographic methodology derived by Mills.10 We have established that a scan time of 60 s may optimally identify the presence of fasciculation in ALS muscles if the observable area is fixed as 40 × 40 mm and the presence of fasciculation is defined as detection of more than 2 fasciculations during scan time. Furthermore, the proportion of muscle cross-sectional area on the whole observable area or echogenicity does not influence the optimal scan time.
Mills showed that 90 s was required to detect more than 2 fasciculation potentials in the EMG assessment of ALS patients. To detect more than 2 fasciculations in most muscles, the required ultrasound scan time is much shorter than that for EMG. The main reason for this apparent discrepancy may be that the observable area of ultrasound (40 × 40 mm in this study) was much larger than that for EMG. The detection of fasciculations by ultrasound within a 60-s scan time could be reasonably regarded as equivalent to the identification of clinical fasciculations or fasciculation potentials in EMG. Such a modification would significantly reduce patient burden resulting from the extended time and discomfort associated with EMG in the diagnostic examination.
Unlike EMG, in which the recordable area is determined inside the muscle, the ultrasound scan area of the muscle varied by muscle because the muscle volume remained dependent on the part of the body undergoing examination. However, the data obtained from this study showed no correlation between the proportion of muscle cross-sectional area and fasciculation intervals when 40 × 40 mm was used as the fixed observable area of ultrasound. Consequently, this area may be appropriate for detecting fasciculations in all muscles. This area seems to be acceptable in most commercially available ultrasound machines, given that most linear transducers have about 40 mm of width.
The FDI muscle had the longest fasciculation interval among all muscle groups that we studied. The proportion of muscle cross-sectional area in the FDI muscle did not differ much from that recorded in the ABD muscle. Regarding muscle strength, approximately 40% of the muscles studied had no clinical weakness in the BB, vastus lateralis, and TA muscles. However, 82% of the FDI muscles had clinical evidence of weakness. This finding may suggest that muscle wasting could be an additional factor that determines whether a longer scan time is required to detect fasciculation.
In terms of limitations, patients who had a definite diagnosis of ALS were included to elucidate the typical characteristics of fasciculations in ALS, although the diagnostic categories of probable and possible ALS were also included.
Detection of fasciculations has clear significance in the diagnosis of ALS. Fasciculation intervals as determined here may provide simple and easy criteria for future ultrasound studies. In addition, the distribution of fasciculations may also be important for distinguishing ALS from mimic conditions.7, 16, 17 Ultrasound is a useful noninvasive tool for understanding the distribution of fasciculations, and it requires a shorter time frame for examination than that required for EMG. We determined the optimal scan time for determining the presence of fasciculations in the tongue, truncal, and limb muscles. This may contribute to establishing muscle ultrasound criteria for fasciculations in the diagnosis of ALS.
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