Group A comprised 28 ALS patients showing clinical signs of UMN involvement, whereas 22 ALS patients in group B exhibited no clinical UMN signs in the tested limb. The mean value of TST amplitude ratios was significantly lower in group A compared with group B (Z = −4.827, P < 0.001, Fig. 2). The TST amplitude ratio in group A was abnormal in 25 of 28 patients (89.3%), whereas this parameter was abnormal in 6 of 22 patients (27.3%) in group B. Thus, clinical UMN signs of ALS patients were nearly always accompanied by a corticospinal conduction deficit as measured by the TST amplitude ratio, which are therefore highly significantly associated (χ2 = 14.845, P < 0.001).
The sensitivities to detect these abnormalities using conventional TMS in group A were 18 of 28 (64.3%) for MEP and CMCT and 22 of 28 (78.6%) for RMT, which were markedly lower than the 89.3% detected by TST. Thus, TST was more sensitive than conventional TMS. The comparison between TST and conventional TMS parameters is shown in Table 3.
However, the correlation between clinical and electrophysiological signs of UMN loss was not absolutely consistent. A normal TST amplitude ratio was found in 3 of 28 (10.7%) group A patients with clinical UMN signs. Conversely, an abnormal TST amplitude ratio was found in 6 of 22 (27.3%, group B) patients without UMN signs. Of those, two also showed an increased RMT. Further clinical examination revealed severe proximal weakness in their upper limbs. The consistent abnormality of RMTs and TST amplitude ratios suggested that their UMN was involved despite the lack of clinical UMN signs. These patients ultimately developed definite ALS, which suggests that these two techniques used together had shown a subclinical UMN involvement.
For the 50 ALS patients, a strongly significant negative correlation was found between TST values and RMT (ρ = −0.774, P < 0.001) and between TST and Modified Ashworth Scale (ρ = −0.772, P < 0.001). However, no correlation was detected between TST values and the following parameters: muscle strength of the right abductor digiti minimi (ρ = 0.142, P = 0.324), CMAPwrist (ρ = −0.093, P = 0.522), Revised ALS Functional Rating Scale (ρ = −0.028, P = 0.848), and disease duration (ρ = −0.112, P = 0.437).
Clinical and Electrophysiological Findings in Non-ALS Patients With Central Motor Conduction Disturbances
The 20 patients without ALS were split into 2 groups according to the presence or absence of clinical UMN signs. Group C comprised 12 non-ALS patients with clinical signs of UMN involvement. Eight non-ALS patients with no clinical UMN signs were in group D. The mean value of TST amplitude ratio was also significantly lower in group C compared with group D (Z = −2.086, P = 0.037, Fig. 2), and no significant difference was found between group C and group A (Z = −0.946, P = 0.344). The abnormal TST amplitude ratios found in group C patients (9/12, 75.0%) were significantly more often than those in group D (1/8, 12.5%; χ2 = 7.500, P = 0.006). Thus, the average decrease in the TST amplitude ratio was more marked in non-ALS patients with a pyramidal syndrome than those without a pyramidal syndrome. Clinical UMN signs in non-ALS patients were also accompanied by abnormal TST amplitude ratios.
The main finding obtained in this study was the existence of a significant association between the TST amplitude ratio and UMN dysfunction in both ALS patients and non-ALS patients. Indeed, TST may reveal subclinical UMN impairments in ALS patients.
It is supported by the data presented in this study that an abnormal TST amplitude ratio is a sign for a UMN involvement in ALS. First, 89.3% of ALS patients with clinical UMN signs showed a reduced TST amplitude ratio, which was a much higher proportion than the 27.3% of ALS patients not exhibiting those signs. Second, there was a significant difference in TST amplitude ratios between groups with and without clinical UMN signs. Thus, a significant association was found between clinical and TST assessments of UMN involvement in ALS. In the ALS patients in group A, the frequency of 89.3% for UMN involvement detected by abnormal TST ratios was a little higher than the previously reported 66.7% in ALS patients with clinical UMN signs.17 The frequency of abnormal TST ratios in all ALS patients, i.e., groups A and B, was 62%, which is similar to 55.6% in Attarian et al.,17 but much lower than Komissarow's detection rate of 84% in all ALS patients.18 These discrepancies may be accounted for by a higher incidence of absent MEPs that was observed in our study (without excluding variations caused by different coils such as figure of eight vs. circular coil). To summarize, the frequency of abnormal TST amplitude ratios was significantly increased in ALS patients presenting with clear UMN signs compared with those without.
However, discrepancies between clinical UMN signs and TST amplitude ratios were found in ALS patients with UMN signs. A normal TST amplitude ratio was found in 10.7% of ALS patients showing clinical UMN signs. In theory, the TST ratio should not be affected by the loss of LMNs. However, in a study investigating the effects of heavy LMN loss,19 the TST amplitude ratio was either 0 or 100% for a given patient. Therefore, the TST response is a less reliable measure of UMN loss when accompanied by severe loss of LMNs. Thus, caution may be required in the interpretation of a normal TST result if severe LMN symptoms are present. Another explanation of normal TST ratios in ALS patients might be the occurrence of spinal synaptic reorganization,20 leading to a greater convergence of intact corticomotoneuronal axons onto resident motor neurons. Conversely, abnormal TST amplitude ratios were found in 27.3% of ALS patients without clinical UMN signs. This frequency is not markedly different from the 36% found in Rösler group of ALS patients who also showed abnormal TST ratios without UMN signs.5
Of the six patients with abnormal TST and no UMN signs in our study, two also showed increased RMTs. Although the TST ratios in those patients were relatively close to the normal level, the concurrent abnormality of RMTs and TST amplitude ratios suggested even in the absence of clinical UMN signs that the UMN system was involved. Confounding factors, such as proximal conduction blocks between the anterior horn cell soma and Erb point, were also excluded in ALS.5,21 These results may be explained instead by such a severe loss of proximal LMNs that the clinical examination of the upper arm is unable to detect a UMN involvement. These two patients later developed ALS, which indicates that the subclinical assessment of UMN involvement ultimately proved to be correct. Therefore, the probability of an ALS diagnosis apparently increases when a low TST amplitude ratio is detected. The use of TST is best suited to patients with minor UMN involvement, in whom a clinical neurological examination would have detected no abnormalities.
In contrast to previous studies of TST in ALS, this study included all patients referred to a motor neuron disease clinic. Many were ultimately diagnosed with central and peripheral neurological mimics of ALS, such as peripheral nerve or muscle disorders. A frequency of 12.5% abnormal TST amplitude ratios was found in these patients, which implies a high specificity of the TST test. Thus, most patients with peripheral abnormalities show a normal TST amplitude ratio.
As expected, the groups with various central motor disorders had a high percentage of abnormal TST results. In both ALS and non-ALS patients, an abnormal TST can be interpreted almost in the same way as clinical UMN signs. However, if other pathologies within the corticospinal system, such as cervical spondylotic myelopathy, are excluded by appropriate neuroimaging, then a low TST amplitude ratio increases the probability of ALS. Additional information can be gained from the CMCT that is more often abnormal in the case of compression.22,23 In this sense, TST deviations are not specific for ALS and can be used to find various central motor conduction abnormalities including those in multiple sclerosis and stroke.24
Resting motor threshold in ALS patients has been reported to be initially normal or reduced while increasing gradually with disease progression until the cortical response eventually disappears.25 Resting motor threshold has been studied less systematically. In our study, we found abnormal RMT values in 78.6% of ALS patients with UMN signs. This demonstrates that an abnormal RMT was frequently a measure for UMN dysfunction in our sample of ALS patients. Our results are in line with those of Triggs et al.,26 who found that RMT increases the sensitivity of TMS in ALS. The cause for increased RMT values in ALS is considered to be a progressive loss of functioning UMNs rather than a reduced corticospinal excitability.2 Hence, UMN loss in ALS may be more accurately diagnosed by the combined use of TST and RMT. This may be compared with the ratio of MEP/CMAPerb at rest, which in previous studies changed from one stimulus to the next5,17 and therefore suggests a lack of accuracy in the assessment of cortico-spinal impairments. In this study, the sensitivity of TST was with 89.3% higher than that of CMCT with 64.3%, again suggesting that CMCT is a less sensitive method for detecting UMN dysfunction in ALS.27
Besides its high sensitivity, the TST allows an estimation of the proportional loss of UMNs supplying the target muscle. Alternatively, Modified Ashworth Scale provides a unique clinical measure of spasticity that has been generally used to quantify the UMN involvement in stroke or multiple sclerosis.28,29 In this study, the Modified Ashworth Scale was found to be negatively correlated with the TST amplitude ratio in ALS patients, which suggests that the TST may reflect the severity of the UMN conduction failure. It was also found that decreased TST amplitude ratios are linearly correlated with increasing RMTs but the TST might be more sensitive than the RMT because in our patients with an RMT of 100%, the TST amplitude ratios ranged from 17% to 76%. In conclusion, the evidence discussed above suggests that TST may provide a quantitative electrophysiological measure of central motor conduction failure. This quantitative diagnostic method may therefore contribute to monitoring ALS disease progression in longitudinal studies, for which no alternative test exists to measure central nervous damage.30,31 Although TST is a potentially useful tool for monitoring disease progression in ALS patients, it needs to be further evaluated in follow-up studies.
It has been reported that testing several regions of the body increases the sensitivity of TMS to support an ALS diagnosis. Another study noted that the lower limb TST could improve the examination of corticospinal conduction failures in various diseases.32
We found that TST is neither painful nor time-consuming and is generally accepted by patients. However, there are two drawbacks of TST. First, this method cannot be used to study proximal muscles because the short time intervals of two stimuli prevent forming a clear separation between the first and second main deflection in TST curves. Second, for studying the lower limbs, the use of a monopolar needle electrode is required for gluteal stimulation, which can be explored in the future.33
In conclusion, TST appears to be an accurate and reliable measure for detecting and quantifying UMN conduction failure in ALS. Triple stimulation technique can contribute to an early diagnosis by finding subclinical evidence of UMN abnormality in suspected ALS. As a result, the level of diagnostic certainty in the evaluation of ALS may be increased.
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Keywords:© 2019 by the American Clinical Neurophysiology Society
Amyotrophic lateral sclerosis; Transcranial magnetic stimulation; Triple stimulation technique; Upper motor neuron; Motor evoked potential