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A double determination of central motor conduction time in the assessment of Hirayama disease
Accepted Manuscript A double determination of central motor conduction time in the assessment of Hirayama disease Chaojun Zheng, Dongqing Zhu, Feizhou Lu, Yu Zhu, Xiaosheng Ma, Xinlei Xia M.D, Jianyuan Jiang PII: DOI: Reference:
S1388-2457(17)30881-7 http://dx.doi.org/10.1016/j.clinph.2017.07.394 CLINPH 2008206
To appear in:
Clinical Neurophysiology
Received Date: Revised Date: Accepted Date:
23 April 2017 29 June 2017 3 July 2017
Please cite this article as: Zheng, C., Zhu, D., Lu, F., Zhu, Y., Ma, X., Xia M.D, X., Jiang, J., A double determination of central motor conduction time in the assessment of Hirayama disease, Clinical Neurophysiology (2017), doi: http://dx.doi.org/10.1016/j.clinph.2017.07.394
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A double determination of central motor conduction time in the assessment of Hirayama disease CHAOJUN ZHENG, M.D.1#, DONGQING ZHU, M.D. 3#, FEIZHOU LU, M.D.1, 4, YU ZHU, M.D.2, XIAOSHENG MA, M.D.1, XINLEI XIA, M.D.1, JIANYUAN JIANG, M.D.1*
1
Department of Orthopedics, Huashan Hospital, Fudan University. Shanghai 200040. China
2
Department of Physical Medicine and Rehabilitation, Upstate Medical University, State
University of New York at Syracuse, Syracuse, NY 10212, USA 3
Department of Neurology, Huashan Hospital, Fudan University. Shanghai 200040. China
4
Department of Orthopedics, The Fifth People's Hospital, Fudan University. Shanghai
200240. China
Corresponding author: JIANYUAN JIANG, M.D. Department of Orthopedics, Huashan Hospital, Fudan University 12 Mid- Wulumuqi Road, Shanghai 200040, China Tel.: +86 021-5288-7126 Fax: +86 021-6248-9191 E-mail: [email protected]
# These authors contributed equally to this work and should be considered co-first authors.
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Abstract Objective: To investigate central motor conduction time (CMCT) in patients with Hirayama disease (HD) and to analyse the role of motor nerve root lesions in the pathogenesis of HD. Methods: CMCT measured by F-wave (CMCT-F) and by paravertebral magnetic stimulation (CMCT-M) was performed on both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) in 41 HD patients and 22 controls. All patients underwent neck-flexion magnetic resonance imaging evaluation. Results: Prolonged CMCT (CMCT-F and/or CMCT-M) was recorded in at least one tested muscle from 7/41 (17.1%) HD patients, and 4 cases presented significant prolonged CMCT-M with normal CMCT-F on the side with significant cervical cord forward-shifting. This asymmetric forward-shifting was identified in 13 HD patients, and forward-shifting on the symptomatic side was more obvious. Compared to the controls (ADM: 0.9±0.3 ms; APB: 0.8±0.3 ms) and the other 28 HD patients (symptomatic side: ADM: 0.8±0.2 ms, APB: 0.8±0.3 ms), increased nerve root conduction times were demonstrated in these symptomatic sides (ADM: 1.5±0.7 ms; APB: 1.2±0.6 ms) (P<0.05). Conclusions: Motor nerve root may be main lesion site in some HD patients, especially on the symptomatic side of patients with asymmetric neck-flexion cervical cord forward-shifting. Significance:
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Compared to spinal motor neuron lesions, damage to motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD.
Abnormally increased forward traction in shorter nerve roots may be the cause for the main damage in motor nerve root.
Keywords: Hirayama disease; Central motor conduction time; Dynamic magnetic resonance imaging; Motor nerve root; Spinal motor neuron.
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Highlights 1. Motor nerve root damage may play an equally important role as spinal motorneuron lesion in the pathogenesis of Hirayama disease (HD). 2. A double determination of CMCT can effectively locate main lesion site in motor nerve root in HD. 3. Increased forward traction in imperfectly developed nerve root cause the damage of motor nerve root.
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1 Introduction: Hirayama disease (HD) is a benign neurological disease associated with unilateral or asymmetric weakness and/or amyotrophy in the muscles supplied by the C7-T1 myotomes, without significant sensory involvement and myelopathy (Hirayama, 2000; Zhou et al., 2010; Wang et al., 2012). The aetiology of HD remains unclear. Due to the extreme vulnerability of the anterior horn cells to ischaemia and abnormal crescent-shaped signals behind the dural sac in neck-flexion magnetic resonance imaging (MRI) that is consistent with congestion of the epidural venous plexus (Hirayama, 2008; Vargas and Castillo, 2011), HD is mainly ascribed to chronic ischaemic injury of the cervical anterior horn cells (Hirayama, 2000; Hirayama, 2008). However, compared to the imbalance between the development of the cervical cord and the spine (Kohno et al., 1998), a recent study demonstrated that strain on the shortened nerve roots may be the main cause for the forward-shifting of the cervical cord during neck flexion (Toma and Shiozawa, 1995). This hypothesis implies that abnormal increased tension in both intra- and extra-medullary motor nerve roots may be involved in the pathogenesis of HD, and the previous necropsied case report also found significant thinning in both intra- and extra-medullary portions of motor nerve roots in a HD patient (Hirayama et al., 1987).Therefore, the pathophysiology in some patients may mainly involve motor nerve roots (e.g. intra- and/or extra-medullary nerve roots) rather than anterior horn motoneurons. Unfortunately, although identifying the main lesion site is important for investigating the true pathogenesis or causative mechanism of HD, it is not possible to establish the exact lesion site between motor nerve roots and anterior horns by relying on
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conventional neurophysiological tests (e.g., needle EMG and nerve conduction study) and dynamic MRI. Transcranial magnetic stimulation (TMS) is a neurophysiologic method used to evaluate the function of central motor pathways (Groppa et al., 2012; Rossini et al., 2015) method has been widely used in the patients with amyotrophy of upper limb (e.g. amyotrophic lateral sclerosis) for over 20 years (Miscio et al., 1999; Floyd et al., 2009; Udupa and Chen, 2013), and central motor conduction time (CMCT) was demonstrated to be one of the useful measures of single-pulse TMS (Floyd et al., 2009). The recently published study demonstrated the measurement of CMCT using both the F-wave method and paravertebral nerve root magnetic stimulation can provide a non-invasive and painless functional exploration of delay in the proximal motor nerve root including intra- and extra-medullary motor roots (Groppa et al., 2012; Rossini et al., 2015), and both Bischoff et al.
and Di Lazzaro et al. identified the utility of this method in the diagnosis of both lumbosacral and cervical ventral nerve root injury (Bischoff et al., 1993; Di Lazzaro et al., 2004). The aim of the current study was to analyse the findings of CMCT measured by two different methods in HD patients, to identify whether the motor nerve root may be the main lesion site in some patients with HD compared to spinal motor neurons, and to investigate the role of motor nerve root lesions in the pathogenesis of HD.
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2 Methods: 2.1 Subjects: Forty-one patients with HD and 22 healthy control subjects were included in this study. All patients were recruited at the Huashan Hospital between May 2013 and February 2017. The Human Ethics Committee of Huashan Hospital at Fudan University in China granted ethical committee approval, and each subject provided informed consent. The subjects in the control group and in HD patient groups were selected according to the inclusion and exclusion criteria described previously (Zheng et al., 2016; Zheng et al., 2017). Additionally, HD patients with clinical manifestation of upper motor neuron (UMN) lesions (e.g., hyperreflexia of the deep reflexes and pyramidal signs) and/or intramedullary MRI signal abnormalities were excluded from this study to eliminate the disturbance of UMN lesions to the results.
2.2 Testing methods: 2.2.1 Motor evoked potentials: The procedures for both transcranial (TMS) and paravertebral (PMS) magnetic stimulation have been described in a previous report (Gain: 0.5-1.0 mV; Sweep: 5-10 ms; Filters: 10 Hz-10 KHz) (Groppa et al., 2012). In brief, motor evoked potentials (MEPs) from bilateral abductor digiti minimi (ADM) and abductor pollicis brevis (APB) were recorded by surface electrodes using a belly-tendon method at rest (de Carvalho et al., 2003). TMS was performed on the contralateral muscle-tested motor cortex using a figure-8 coil (Yiruide CCY-I, Wuhan, China). The coil was adjusted to find the optimal stimulation site where TMS elicits the largest single-trial MEP with initial negative deviation. Then, the
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resting motor threshold (RMT) was defined at the optimal point as the minimal stimulus intensity required to produce MEPs of 50 µV in at least five out of 10 consecutive stimulations. At the optimal stimulation point, stimulus pulses of a pre-determined supra-threshold intensity (maximum intensity: 170% of RMT) were administered to each subject (Groppa et al., 2012). Then, the onset-latency of the MEP was obtained and defined as the shortest latency from the MEP out of 3-6 trials. PMS was performed with the same figure-8 coil. The coil is place flat on the skin and the centre was initially placed slightly lateral (1-2 cm) to the C7 spinous processes, with the technical direction of current flow in the coil pointing towards the tested side. Then, it was subsequently moved slightly up and down to obtain a consistent and maximal MEP. Just supra-threshold stimulus intensity that gave rise to a small response in the tested muscle was used to elicit the MEP; then, the shortest onset-latency of the MEP was recorded. 2.2.2 F -wave: F-waves were recorded from the ADM and APB using surface electrodes in a belly-tendon montage, stimulating at the wrist according to a previous study (Nihon Kohden MEB-9400, Tokyo, Japan) (Stimuli Duration: 0.2 ms; Resistance < 5 kΩ; Gain: 200-500 µV; Filters: 20 Hz-10 KHz; Sweep: 5-10 ms; Frequency: 0.5 Hz) (Zheng et al., 2016). The minimum amplitude used to identify the F-waves was 20 µV or 1% of the compound muscle action potential (CMAP) amplitude. A series of 20 F-waves were recorded, and the minimal latency of the F-waves was measured. All tests were conducted with the skin temperature higher than 32°C. To exclude the influence of inter-rater variability, all tests were performed by the same experienced
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neurophysiologists blinded to whether the subjects had HD or were healthy.
2.2.3 Measurement of the CMCT: CMCT was calculated by subtracting the peripheral motor latency (PML) from the corticomotor latency (CML). The PML can be measured by both F-wave methods [PML-F = (F-latency + M-latency-1)/2] and PMS methods (PML-M). Thus, CMCT was measured by two different formulas as follows: (1) CMCT-F = CML – (F-latency + M-latency-1)/2; (2) CMCT-M= CML – PML-M. The proximal nerve root conduction time (PNRCT) was measured as follows: PNRCT = CMCT-M - CMCT-F. The measurements of each HD patient were considered abnormal if the responses were 2 standard deviations (SDs) above the mean values for the controls in terms of PML-F, PML-M, CMCT-M, CMCT-F, PNRCT and side-to-side differences of these measurements. 2.2.4 Dynamic MRI: All patients with HD underwent further dynamic MRI evaluation (cervical-standard MRI and cervical-flexion MRI), and the cases with asymmetric forward shifting of the cervical cord during neck flexion were identified by visual inspection. 2.3 Statistical methods All data were analysed using SPSS version 12.0 (IBM, USA). The measurements in HD patients were compared with those of controls by Welch's t-test, and the same tests were also used to compare CMCT-F, CMCT-M and PNRCT between HD patients with and without asymmetric forward shifting of the cervical cord. In the HD patient group, the measurements on the symptomatic side were also compared with those on the less-symptomatic side by paired t-test. Pearson correlation tests were used to analyse the correlation between age or
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height and CMCT in the control group. In all instances, a P-value<0.05 was considered statistically significant.
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3 Results: The measurements of both CMCT (CMCT-F and -M) and PML (PML-F and -M) in 41 HD patients and 22 controls are presented in Table 1. In the control group, there was a significant correlation between height and both CMCT of bilateral ADM (Left-hand CMCT-M: r = 0.68, CMCT-F: r = 0.70; Right-hand CMCT-M: r = 0.64, CMCT-F: r = 0.68) and CMCT of right-hand APB (CMCT-M: r = 0.45; CMCT-F: r = 0.52) (P < 0.05). In contrast, no relationships were found between the age and the CMCT in all tested muscles (P > 0.05). In HD patients, 5 muscles in 3 patients showed no response to either TMS or PMS on the symptomatic side (both APB and ADM in 2 subjects, and ADM in one subject), and CMCT-F could not be calculated in 8 ADM and 3 APB on the symptomatic side and in 2 ADM on the less-symptomatic side because no F-waves were obtained in these muscles. A prolonged CMCT was recorded in at least one tested muscle from 7/41 (17.1%) HD patients in this study, and a significant prolonged CMCT-M with normal CMCT-F (one patient in ADM and three cases in APB) was found on the symptomatic side in 4 of these 7 patients (Supplementary Table S1) (Fig. 1). Furthermore, abnormally increased PMLs were identified in at least one tested muscle in 16/41 (39.0%) HD patients. During neck flexion, asymmetric forward shifting of the cervical cord was identified in 13 patients with HD, and all these patients showed more significant anterolateral displacement on the symptomatic side (Fig. 2). Compared with the less-symptomatic side (ADM: 0.9±0.5 ms; APB: 0.8±0.2 ms), significant prolonged PNRCT was found on the symptomatic side in these 13 patients (ADM: 1.5±0.7 ms; APB: 1.2±0.6 ms) (P < 0.05).
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Furthermore, there were significant differences on the symptomatic-side PNRCT of both ADM and APB between these 13 HD patients and other 28 HD patients (symptomatic side: ADM: 0.8±0.2 ms, APB: 0.8±0.3 ms; less-symptomatic side: ADM: 0.9±0.4 ms, APB: 0.7±0.3 ms) in this study (P < 0.05).
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4 Discussion: The results of this study demonstrated that compared to lesions of spinal motor neurons, damage to the cervical motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD, especially in patients with obvious asymmetric anterior displacement of the cervical cord during neck flexion. In this study, approximately one-eighth of the HD patients had an obvious abnormality of both CMCT-M and -F in at least one tested muscle. This phenomenon may be ascribed to the spinal motor neuron damage in these patients. Impairment of the spinal motor neurons may play an important role directly (loss of spinal motor neurons with faster conduction velocity) and/or indirectly (insufficiency of the synapse from the corticospinal tract to the spinal motor neurons) in the physiology of prolonged CMCT (Kaneko et al., 2001). Both mechanisms were supported by a previous necropsied case report that demonstrated lesions of grey matter in the cervical cord anterior horn innervating tested muscles in a patient with HD (Hirayama et al., 1987). Another possibility for the prolongation of both CMCT-F and -M is a lesion of the descending corticospinal tract, and previous studies have demonstrated that some HD patients may develop dysfunction of UMN with disease progression (Sakai et al., 2011; Li and Remmel, 2012). However, there was no long tract signs, exaggeration of deep tendon reflex or intramedullary MRI signal abnormality in all of these HD patients with prolonged CMCT-F and -M in this study, and significant prolonged PNRCT in all tested muscles with abnormal CMCT also supported the loss of spinal motor neurons with faster conduction velocity in these HD patients. Although previous studies demonstrated that central
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conduction determination using the F-wave method can effectively reduce the disturbance of lower motor neuron lesions (Di Lazzaro et al., 1999), the findings from this study suggest such a determination is easily confused when CMCT-F is used to evaluate the function of UMN in patients with spinal motor neuron lesions. Furthermore, absent F-waves are common in the atrophied muscles of patients with spinal motor neuron lesions, which also affects the application values of CMCT in evaluating UMN. More importantly, using double determination of CMCT, we found in this study that some HD patients present prolonged CMCT-M with a normal CMCT-F. Previous studies have demonstrated that CMCT measured by F-wave methods and by PMS are fundamentally different (Groppa et al., 2012; Rossini et al., 2015). PMS activates cervical nerve roots at the intervertebral foramina and does not measure the time taken for the stimulus to reach the intervertebral foramina from the anterior horn cell, and the total peripheral conduction time from the anterior horn cells to muscles can be evaluated by F-wave methods using the Kimura formula (Groppa et al., 2012; Bischoff et al., 1993). Thus, this pattern of abnormalities may suggest the main lesion in the proximal motor nerve roots (e.g., intra- and/or extra-medullary nerve roots) of the tested muscle in these HD patients compared to the commonly considered main damage site, namely, the anterior horn motor neurons. In the present study, all the latter abnormal patterns occurred on the side with more significant neck-flexion anterior displacement of the cervical cord. According to a previous study, asymmetric forward shifting of the cervical cord may be ascribed to the disproportionate shortening of the nerve roots during the juvenile growth spurt (Toma and
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Shiozawa, 1995). Therefore, one possible reason for this condition is that incomplete development, shorter intra- and extra-medullary motor nerve roots may be more sensitive to damage than the corresponding spinal motor neurons. Furthermore, increased forward traction force on the shorter intra- and extra-medullary motor nerve root during neck flexion has been mentioned in a previous study (Toma and Shiozawa, 1995), which may be a more probable cause of more severe damage in motor nerve roots than in spinal motor neurons. All asymmetric anterior displacements of the cervical cord were more obvious on the symptomatic side, along with significantly prolonged PNRCT in these symptomatic sides, which further supports the vital role of abnormally increased tension of shorter nerve roots in the pathogenesis of HD. There are several limitations to this study. The average ages between the controls and the HD patients were difficult to match because of the age susceptibilities of HD. However, we found no correlation between age and CMCT, and a similar condition was also demonstrated in previous studies (Mano et al., 1992; Mills, 1999). Another clinical limitation of this study is that other measurements such as RMT, MEP amplitude and silent period duration were not analysed in this study. However, for localization of lesions in the motor neve root, the double determination of CMCT has been demonstrated a better method (Udupa and Chen, 2013). Furthermore, compared to the magnetic stimulation methods used in this study, collision technique (e.g. Triple-stimulation technique) may increase the probability of abnormal detection and reduce the interference of the volume conduction from other muscles, as the collision technique can obtain a more synchronized TMS-evoked excitation of the target muscle. Therefore, future investigations might study the clinical
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values of these measurements and compare the application of collision techniques in evaluating HD.
5 Conclusions: In this study, our data strongly support that the cervical motor nerve root (intra- and/or extra-medullary motor nerve) may be the main lesion site in some HD patients, especially on
the symptomatic side of patients with obvious asymmetric forward shifting of the cervical cord during neck flexion. In addition, an abnormally increased forward traction force in shorter nerve roots may be the cause of the main damage in the motor nerve root.
Conflict of interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.
Acknowledgements Financial support from Shanghai City Health System of the Second Batch of Important Diseases Combined Project (2014ZYJ0008) and the National Natural Science Foundation of China Youth Science Foundation Project (81501909) is gratefully acknowledged.
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References Bischoff C, Meyer BU, Machetanz J, Conrad B. The value of magnetic stimulation in the diagnosis of radiculopathies. Muscle Nerve. 1993; 16:154-61.
de Carvalho M, Turkman A, Swash M. Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci. 2003; 210:83-9.
Di Lazzaro V, Oliviero A, Profice P, Ferrara L, Saturno E, Pilato F, Tonali P. The diagnostic value of motor evoked potentials.Clin Neurophysiol. 1999; 110:1297-307.
Di Lazzaro V, Pilato F, Oliviero A, Saturno E, Dileone M, Tonali PA. Role of motor evoked potentials in diagnosis of cauda equina and lumbosacral cord lesions. Neurology. 2004; 63:2266-71.
Floyd AG, Yu QP, Piboolnurak P, Tang MX, Fang Y, Smith WA, Yim J, Rowland LP, Mitsumoto H, Pullman SL. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology. 2009; 72:498-504.
Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, Kaelin-Lang A, Mima T, Rossi S, Thickbroom GW, Rossini PM, Ziemann U, Valls-Solé J, Siebner HR. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin
17
Neurophysiol. 2012; 123:858-82.
Hirayama K, Tomonaga M, Kitano K, Yamada T, Kojima S, Arai K. Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry. 1987; 50:285-90.
Hirayama K. Juvenile muscular atrophy of distal upper extremity (Hirayama disease). Internal medicine (Tokyo, Japan), 2000; 39: 283-290.
Hirayama K. Juvenile muscular atrophy of unilateral upper extremity (Hirayama disease)--half-century progress and establishment since its discovery [in Japanese]. Brain Nerve. 2008; 60:17-29.
Kohno M, Takahashi H, Yagishita A, Tanabe H. "Disproportion theory" of the cervical spine and spinal cord in patients with juvenile cervical flexion myelopathy. A study comparing cervical magnetic resonance images with those of normal controls. Surg Neurol. 1998; 50:421-30.
Kaneko K, Taguchi T, Morita H, Yonemura H, Fujimoto H, Kawai S. Mechanism of prolonged central motor conduction time in compressive cervical myelopathy. Clin Neurophysiol. 2001; 112:1035-40.
18
Li Y, Remmel K. A case of monomelic amyotrophy of the upper limb: MRI findings and the implication on its pathogenesis. J Clin Neuromuscul Dis. 2012; 13: 234-9.
Mano Y, Nakamuro T, Ikoma K, Sugata T, Morimoto S, Takayanagi T, Mayer RF. Central motor conductivity in aged people.Intern Med. 1992; 31:1084-7.
Mills KR. Magnetic Stimulation of the Human Nervous System. Oxford: Oxford University Press; 1999.
Miscio G, Pisano F, Mora G, Mazzini L. Motor neuron disease: usefulness of transcranial magnetic stimulation in improving the diagnosis. Clin Neurophysiol. 1999; 110:975-81.
Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015; 126:1071-107.
Sakai K, Ono K, Okamoto Y, Murakami H, Yamada M. Cervical flexion myelopathy in a patient showing apparent long tract signs: a severe form of Hirayama disease. Joint Bone
19
Spine. 2011; 78:316-8.
Toma S, Shiozawa Z. Amyotrophic cervical myelopathy in adolescence. J Neurol Neurosurg Psychiatry. 1995; 58:56-64.
Udupa K, Chen R. Central motor conduction time. Handb Clin Neurol. 2013; 116:375-86.
Vargas MC, Castillo M. Magnetic resonance imaging in Hirayama disease. J Radiol Case Rep. 2011; 5:17-23.
Wang XN, Cui LY, Liu MS, Guan YZ, Li BH, DU H. A clinical neurophysiology study of Hirayama disease. Chin Med J (Engl). 2012; 125:1115-20.
Zhou B, Chen L, Fan D, Zhou D. Clinical features of Hirayama disease in mainland China. Amyotroph Lateral Scler. 2010; 11:133-9.
Zheng C, Zhu Y, Yang S, Lu F, Jin X, Weber R, Jiang J. A study of dynamic F-waves in juvenile spinal muscular atrophy of the distal upper extremity (Hirayama disease). J Neurol Sci. 2016; 367:298-304.
Zheng C, Zhu D, Lu F, Zhu Y, Ma X, Xia X, Weber R, Jiang J. Compound Muscle Action Potential Decrement to Repetitive Nerve Stimulation Between Hirayama Disease and
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Amyotrophic Lateral Sclerosis. J Clin Neurophysiol. 2017; 34:119-125.
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FIGURE LEGENDS
Fig. 1: A 17-year-old male patient with Hirayama disease. Significant prolonged CMCT-M with a normal CMCT-F was found in ADM on the symptomatic side. The right panel shows 4 MEPs from transcranial magnetic stimulation (1-4) and 3 MEPs from paravertebral magnetic stimulation (5-7), with the left panel showing the F-wave of ADM on the symptomatic side. CML: corticomotor latency; PML-F: peripheral motor latency measured by the F-wave method; PML-M: peripheral motor latency measured by paravertebral magnetic stimulation; CMCT-F: central motor conduction time measured by the F-wave method; CMCT-M: central motor conduction time measured by paravertebral magnetic stimulation; MEPs: motor evoked potentials; ADM: abductor digiti minimi.
Fig. 2: A 17-year-old male patient with Hirayama disease. A: Significant amyotrophy of the intrinsic hand and forearm muscles on the left side; B: On neck-standard position, cervical magnetic resonance imaging (MRI); C: On neck-flexion position, more significant anterior displacement of the cervical cord on the symptomatic side (arrows).
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Table 1：The measurements of MEP in both HD patients and the controls Patients with Hirayama diseases
Healthy subjects
Number of cases
41
22
Age range (years)
19.0±3.6 (14-29)
30.9±8.9 (18-45)
Height range (cm)
172.6±4.1 (162-180)
172.2±4.6 (165-182)
Disease duration (months)
25.0±16.5 (5-72) S side
Less-S side
P
P’
23.0±3.1
21.8±2.8
< 0.01* 20.3±0.9 < 0.01* / < 0.01*
PML-F
15.8±1.7
15.1±1.8
< 0.01* 14.0±0.8 < 0.01* / < 0.01*
CMCT-F
6.9±1.4
6.5±1.3
Abductor digiti minimi CML F-wave methods
S-to-S difference
0.01*
0.9±0.6
Paravertebral magnetic stimulation methods PML-M 15.0±1.9 14.3±1.7 CMCT-M 8.1±1.7 7.5±1.5 S-to-S difference 1.0±0.9 1.1±0.5 0.9±0.4 PNRCT S-to-S difference 0.4±0.5
6.3±1.0
0.07 / 0.36
0.5±0.4
0.01*
0.01*
13.1±0.8 < 0.01* / < 0.01*
0.01*
7.2±1.0
0.01* / 0.36
0.6±0.4
0.01*
0.9±0.3
0.17 / 0.77
0.4±0.3
0.58
0.08
Abductor pollicis brevis CML
21.9±2.7
21.1±1.7
0.03*
20.5±1.6
0.01* / 0.15
15.3±1.8*
14.9±1.3
0.05
14.7±1.1
0.10 / 0.44
6.3±0.9
6.1±0.7
0.01*
5.8±1.0
0.02* / 0.17
0.6±0.4
0.98
0.26
14.0±1.2
0.11 / 0.36
0.03*
6.6±0.9
< 0.01* / 0.19
0.7±0.5
0.47
0.8±0.3
0.09 / 0.86
0.3±0.2
0.03*
F-wave methods PML-F CMCT-F S-to-S difference
0.6±0.5
Paravertebral magnetic stimulation methods PML-M 14.5±1.7 14.2±1.3 CMCT-M 7.3±1.1 6.8±0.8 S-to-S difference 0.8±0.6 0.9±0.4 0.7±0.2 PNRCT S-to-S difference 0.4±0.4
0.06
CMCT-F: central motor conduction time measured by F-wave method; CMCT-M: central motor conduction time measured by paravertebral magnetic stimuli PML: peripheral motor latency; CML: corticomotor latency; PNRCT: proximal nerve root conduction time HD: hirayama disease; MEP: motor evoked potentials; S-to-S difference: side-to-side difference S side: symptomatic side; Less-S side: less-symptomatic side P: P-values between the symptomatic side and less-symptomatic side in HD patients. P’: P-values between the measurements of controls and those of HD patients. a / b: where a is P-values between the measurements of controls and those of S side in HD patients, and b is P-values between the measurements of controls and those of Less-S side in HD patients. *: Statistical significance (P < 0.05)
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S1388-2457(17)30881-7 http://dx.doi.org/10.1016/j.clinph.2017.07.394 CLINPH 2008206
To appear in:
Clinical Neurophysiology
Received Date: Revised Date: Accepted Date:
23 April 2017 29 June 2017 3 July 2017
Please cite this article as: Zheng, C., Zhu, D., Lu, F., Zhu, Y., Ma, X., Xia M.D, X., Jiang, J., A double determination of central motor conduction time in the assessment of Hirayama disease, Clinical Neurophysiology (2017), doi: http://dx.doi.org/10.1016/j.clinph.2017.07.394
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A double determination of central motor conduction time in the assessment of Hirayama disease CHAOJUN ZHENG, M.D.1#, DONGQING ZHU, M.D. 3#, FEIZHOU LU, M.D.1, 4, YU ZHU, M.D.2, XIAOSHENG MA, M.D.1, XINLEI XIA, M.D.1, JIANYUAN JIANG, M.D.1*
1
Department of Orthopedics, Huashan Hospital, Fudan University. Shanghai 200040. China
2
Department of Physical Medicine and Rehabilitation, Upstate Medical University, State
University of New York at Syracuse, Syracuse, NY 10212, USA 3
Department of Neurology, Huashan Hospital, Fudan University. Shanghai 200040. China
4
Department of Orthopedics, The Fifth People's Hospital, Fudan University. Shanghai
200240. China
Corresponding author: JIANYUAN JIANG, M.D. Department of Orthopedics, Huashan Hospital, Fudan University 12 Mid- Wulumuqi Road, Shanghai 200040, China Tel.: +86 021-5288-7126 Fax: +86 021-6248-9191 E-mail: [email protected]
# These authors contributed equally to this work and should be considered co-first authors.
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Abstract Objective: To investigate central motor conduction time (CMCT) in patients with Hirayama disease (HD) and to analyse the role of motor nerve root lesions in the pathogenesis of HD. Methods: CMCT measured by F-wave (CMCT-F) and by paravertebral magnetic stimulation (CMCT-M) was performed on both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) in 41 HD patients and 22 controls. All patients underwent neck-flexion magnetic resonance imaging evaluation. Results: Prolonged CMCT (CMCT-F and/or CMCT-M) was recorded in at least one tested muscle from 7/41 (17.1%) HD patients, and 4 cases presented significant prolonged CMCT-M with normal CMCT-F on the side with significant cervical cord forward-shifting. This asymmetric forward-shifting was identified in 13 HD patients, and forward-shifting on the symptomatic side was more obvious. Compared to the controls (ADM: 0.9±0.3 ms; APB: 0.8±0.3 ms) and the other 28 HD patients (symptomatic side: ADM: 0.8±0.2 ms, APB: 0.8±0.3 ms), increased nerve root conduction times were demonstrated in these symptomatic sides (ADM: 1.5±0.7 ms; APB: 1.2±0.6 ms) (P<0.05). Conclusions: Motor nerve root may be main lesion site in some HD patients, especially on the symptomatic side of patients with asymmetric neck-flexion cervical cord forward-shifting. Significance:
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Compared to spinal motor neuron lesions, damage to motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD.
Abnormally increased forward traction in shorter nerve roots may be the cause for the main damage in motor nerve root.
Keywords: Hirayama disease; Central motor conduction time; Dynamic magnetic resonance imaging; Motor nerve root; Spinal motor neuron.
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Highlights 1. Motor nerve root damage may play an equally important role as spinal motorneuron lesion in the pathogenesis of Hirayama disease (HD). 2. A double determination of CMCT can effectively locate main lesion site in motor nerve root in HD. 3. Increased forward traction in imperfectly developed nerve root cause the damage of motor nerve root.
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1 Introduction: Hirayama disease (HD) is a benign neurological disease associated with unilateral or asymmetric weakness and/or amyotrophy in the muscles supplied by the C7-T1 myotomes, without significant sensory involvement and myelopathy (Hirayama, 2000; Zhou et al., 2010; Wang et al., 2012). The aetiology of HD remains unclear. Due to the extreme vulnerability of the anterior horn cells to ischaemia and abnormal crescent-shaped signals behind the dural sac in neck-flexion magnetic resonance imaging (MRI) that is consistent with congestion of the epidural venous plexus (Hirayama, 2008; Vargas and Castillo, 2011), HD is mainly ascribed to chronic ischaemic injury of the cervical anterior horn cells (Hirayama, 2000; Hirayama, 2008). However, compared to the imbalance between the development of the cervical cord and the spine (Kohno et al., 1998), a recent study demonstrated that strain on the shortened nerve roots may be the main cause for the forward-shifting of the cervical cord during neck flexion (Toma and Shiozawa, 1995). This hypothesis implies that abnormal increased tension in both intra- and extra-medullary motor nerve roots may be involved in the pathogenesis of HD, and the previous necropsied case report also found significant thinning in both intra- and extra-medullary portions of motor nerve roots in a HD patient (Hirayama et al., 1987).Therefore, the pathophysiology in some patients may mainly involve motor nerve roots (e.g. intra- and/or extra-medullary nerve roots) rather than anterior horn motoneurons. Unfortunately, although identifying the main lesion site is important for investigating the true pathogenesis or causative mechanism of HD, it is not possible to establish the exact lesion site between motor nerve roots and anterior horns by relying on
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conventional neurophysiological tests (e.g., needle EMG and nerve conduction study) and dynamic MRI. Transcranial magnetic stimulation (TMS) is a neurophysiologic method used to evaluate the function of central motor pathways (Groppa et al., 2012; Rossini et al., 2015) method has been widely used in the patients with amyotrophy of upper limb (e.g. amyotrophic lateral sclerosis) for over 20 years (Miscio et al., 1999; Floyd et al., 2009; Udupa and Chen, 2013), and central motor conduction time (CMCT) was demonstrated to be one of the useful measures of single-pulse TMS (Floyd et al., 2009). The recently published study demonstrated the measurement of CMCT using both the F-wave method and paravertebral nerve root magnetic stimulation can provide a non-invasive and painless functional exploration of delay in the proximal motor nerve root including intra- and extra-medullary motor roots (Groppa et al., 2012; Rossini et al., 2015), and both Bischoff et al.
and Di Lazzaro et al. identified the utility of this method in the diagnosis of both lumbosacral and cervical ventral nerve root injury (Bischoff et al., 1993; Di Lazzaro et al., 2004). The aim of the current study was to analyse the findings of CMCT measured by two different methods in HD patients, to identify whether the motor nerve root may be the main lesion site in some patients with HD compared to spinal motor neurons, and to investigate the role of motor nerve root lesions in the pathogenesis of HD.
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2 Methods: 2.1 Subjects: Forty-one patients with HD and 22 healthy control subjects were included in this study. All patients were recruited at the Huashan Hospital between May 2013 and February 2017. The Human Ethics Committee of Huashan Hospital at Fudan University in China granted ethical committee approval, and each subject provided informed consent. The subjects in the control group and in HD patient groups were selected according to the inclusion and exclusion criteria described previously (Zheng et al., 2016; Zheng et al., 2017). Additionally, HD patients with clinical manifestation of upper motor neuron (UMN) lesions (e.g., hyperreflexia of the deep reflexes and pyramidal signs) and/or intramedullary MRI signal abnormalities were excluded from this study to eliminate the disturbance of UMN lesions to the results.
2.2 Testing methods: 2.2.1 Motor evoked potentials: The procedures for both transcranial (TMS) and paravertebral (PMS) magnetic stimulation have been described in a previous report (Gain: 0.5-1.0 mV; Sweep: 5-10 ms; Filters: 10 Hz-10 KHz) (Groppa et al., 2012). In brief, motor evoked potentials (MEPs) from bilateral abductor digiti minimi (ADM) and abductor pollicis brevis (APB) were recorded by surface electrodes using a belly-tendon method at rest (de Carvalho et al., 2003). TMS was performed on the contralateral muscle-tested motor cortex using a figure-8 coil (Yiruide CCY-I, Wuhan, China). The coil was adjusted to find the optimal stimulation site where TMS elicits the largest single-trial MEP with initial negative deviation. Then, the
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resting motor threshold (RMT) was defined at the optimal point as the minimal stimulus intensity required to produce MEPs of 50 µV in at least five out of 10 consecutive stimulations. At the optimal stimulation point, stimulus pulses of a pre-determined supra-threshold intensity (maximum intensity: 170% of RMT) were administered to each subject (Groppa et al., 2012). Then, the onset-latency of the MEP was obtained and defined as the shortest latency from the MEP out of 3-6 trials. PMS was performed with the same figure-8 coil. The coil is place flat on the skin and the centre was initially placed slightly lateral (1-2 cm) to the C7 spinous processes, with the technical direction of current flow in the coil pointing towards the tested side. Then, it was subsequently moved slightly up and down to obtain a consistent and maximal MEP. Just supra-threshold stimulus intensity that gave rise to a small response in the tested muscle was used to elicit the MEP; then, the shortest onset-latency of the MEP was recorded. 2.2.2 F -wave: F-waves were recorded from the ADM and APB using surface electrodes in a belly-tendon montage, stimulating at the wrist according to a previous study (Nihon Kohden MEB-9400, Tokyo, Japan) (Stimuli Duration: 0.2 ms; Resistance < 5 kΩ; Gain: 200-500 µV; Filters: 20 Hz-10 KHz; Sweep: 5-10 ms; Frequency: 0.5 Hz) (Zheng et al., 2016). The minimum amplitude used to identify the F-waves was 20 µV or 1% of the compound muscle action potential (CMAP) amplitude. A series of 20 F-waves were recorded, and the minimal latency of the F-waves was measured. All tests were conducted with the skin temperature higher than 32°C. To exclude the influence of inter-rater variability, all tests were performed by the same experienced
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neurophysiologists blinded to whether the subjects had HD or were healthy.
2.2.3 Measurement of the CMCT: CMCT was calculated by subtracting the peripheral motor latency (PML) from the corticomotor latency (CML). The PML can be measured by both F-wave methods [PML-F = (F-latency + M-latency-1)/2] and PMS methods (PML-M). Thus, CMCT was measured by two different formulas as follows: (1) CMCT-F = CML – (F-latency + M-latency-1)/2; (2) CMCT-M= CML – PML-M. The proximal nerve root conduction time (PNRCT) was measured as follows: PNRCT = CMCT-M - CMCT-F. The measurements of each HD patient were considered abnormal if the responses were 2 standard deviations (SDs) above the mean values for the controls in terms of PML-F, PML-M, CMCT-M, CMCT-F, PNRCT and side-to-side differences of these measurements. 2.2.4 Dynamic MRI: All patients with HD underwent further dynamic MRI evaluation (cervical-standard MRI and cervical-flexion MRI), and the cases with asymmetric forward shifting of the cervical cord during neck flexion were identified by visual inspection. 2.3 Statistical methods All data were analysed using SPSS version 12.0 (IBM, USA). The measurements in HD patients were compared with those of controls by Welch's t-test, and the same tests were also used to compare CMCT-F, CMCT-M and PNRCT between HD patients with and without asymmetric forward shifting of the cervical cord. In the HD patient group, the measurements on the symptomatic side were also compared with those on the less-symptomatic side by paired t-test. Pearson correlation tests were used to analyse the correlation between age or
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height and CMCT in the control group. In all instances, a P-value<0.05 was considered statistically significant.
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3 Results: The measurements of both CMCT (CMCT-F and -M) and PML (PML-F and -M) in 41 HD patients and 22 controls are presented in Table 1. In the control group, there was a significant correlation between height and both CMCT of bilateral ADM (Left-hand CMCT-M: r = 0.68, CMCT-F: r = 0.70; Right-hand CMCT-M: r = 0.64, CMCT-F: r = 0.68) and CMCT of right-hand APB (CMCT-M: r = 0.45; CMCT-F: r = 0.52) (P < 0.05). In contrast, no relationships were found between the age and the CMCT in all tested muscles (P > 0.05). In HD patients, 5 muscles in 3 patients showed no response to either TMS or PMS on the symptomatic side (both APB and ADM in 2 subjects, and ADM in one subject), and CMCT-F could not be calculated in 8 ADM and 3 APB on the symptomatic side and in 2 ADM on the less-symptomatic side because no F-waves were obtained in these muscles. A prolonged CMCT was recorded in at least one tested muscle from 7/41 (17.1%) HD patients in this study, and a significant prolonged CMCT-M with normal CMCT-F (one patient in ADM and three cases in APB) was found on the symptomatic side in 4 of these 7 patients (Supplementary Table S1) (Fig. 1). Furthermore, abnormally increased PMLs were identified in at least one tested muscle in 16/41 (39.0%) HD patients. During neck flexion, asymmetric forward shifting of the cervical cord was identified in 13 patients with HD, and all these patients showed more significant anterolateral displacement on the symptomatic side (Fig. 2). Compared with the less-symptomatic side (ADM: 0.9±0.5 ms; APB: 0.8±0.2 ms), significant prolonged PNRCT was found on the symptomatic side in these 13 patients (ADM: 1.5±0.7 ms; APB: 1.2±0.6 ms) (P < 0.05).
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Furthermore, there were significant differences on the symptomatic-side PNRCT of both ADM and APB between these 13 HD patients and other 28 HD patients (symptomatic side: ADM: 0.8±0.2 ms, APB: 0.8±0.3 ms; less-symptomatic side: ADM: 0.9±0.4 ms, APB: 0.7±0.3 ms) in this study (P < 0.05).
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4 Discussion: The results of this study demonstrated that compared to lesions of spinal motor neurons, damage to the cervical motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD, especially in patients with obvious asymmetric anterior displacement of the cervical cord during neck flexion. In this study, approximately one-eighth of the HD patients had an obvious abnormality of both CMCT-M and -F in at least one tested muscle. This phenomenon may be ascribed to the spinal motor neuron damage in these patients. Impairment of the spinal motor neurons may play an important role directly (loss of spinal motor neurons with faster conduction velocity) and/or indirectly (insufficiency of the synapse from the corticospinal tract to the spinal motor neurons) in the physiology of prolonged CMCT (Kaneko et al., 2001). Both mechanisms were supported by a previous necropsied case report that demonstrated lesions of grey matter in the cervical cord anterior horn innervating tested muscles in a patient with HD (Hirayama et al., 1987). Another possibility for the prolongation of both CMCT-F and -M is a lesion of the descending corticospinal tract, and previous studies have demonstrated that some HD patients may develop dysfunction of UMN with disease progression (Sakai et al., 2011; Li and Remmel, 2012). However, there was no long tract signs, exaggeration of deep tendon reflex or intramedullary MRI signal abnormality in all of these HD patients with prolonged CMCT-F and -M in this study, and significant prolonged PNRCT in all tested muscles with abnormal CMCT also supported the loss of spinal motor neurons with faster conduction velocity in these HD patients. Although previous studies demonstrated that central
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conduction determination using the F-wave method can effectively reduce the disturbance of lower motor neuron lesions (Di Lazzaro et al., 1999), the findings from this study suggest such a determination is easily confused when CMCT-F is used to evaluate the function of UMN in patients with spinal motor neuron lesions. Furthermore, absent F-waves are common in the atrophied muscles of patients with spinal motor neuron lesions, which also affects the application values of CMCT in evaluating UMN. More importantly, using double determination of CMCT, we found in this study that some HD patients present prolonged CMCT-M with a normal CMCT-F. Previous studies have demonstrated that CMCT measured by F-wave methods and by PMS are fundamentally different (Groppa et al., 2012; Rossini et al., 2015). PMS activates cervical nerve roots at the intervertebral foramina and does not measure the time taken for the stimulus to reach the intervertebral foramina from the anterior horn cell, and the total peripheral conduction time from the anterior horn cells to muscles can be evaluated by F-wave methods using the Kimura formula (Groppa et al., 2012; Bischoff et al., 1993). Thus, this pattern of abnormalities may suggest the main lesion in the proximal motor nerve roots (e.g., intra- and/or extra-medullary nerve roots) of the tested muscle in these HD patients compared to the commonly considered main damage site, namely, the anterior horn motor neurons. In the present study, all the latter abnormal patterns occurred on the side with more significant neck-flexion anterior displacement of the cervical cord. According to a previous study, asymmetric forward shifting of the cervical cord may be ascribed to the disproportionate shortening of the nerve roots during the juvenile growth spurt (Toma and
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Shiozawa, 1995). Therefore, one possible reason for this condition is that incomplete development, shorter intra- and extra-medullary motor nerve roots may be more sensitive to damage than the corresponding spinal motor neurons. Furthermore, increased forward traction force on the shorter intra- and extra-medullary motor nerve root during neck flexion has been mentioned in a previous study (Toma and Shiozawa, 1995), which may be a more probable cause of more severe damage in motor nerve roots than in spinal motor neurons. All asymmetric anterior displacements of the cervical cord were more obvious on the symptomatic side, along with significantly prolonged PNRCT in these symptomatic sides, which further supports the vital role of abnormally increased tension of shorter nerve roots in the pathogenesis of HD. There are several limitations to this study. The average ages between the controls and the HD patients were difficult to match because of the age susceptibilities of HD. However, we found no correlation between age and CMCT, and a similar condition was also demonstrated in previous studies (Mano et al., 1992; Mills, 1999). Another clinical limitation of this study is that other measurements such as RMT, MEP amplitude and silent period duration were not analysed in this study. However, for localization of lesions in the motor neve root, the double determination of CMCT has been demonstrated a better method (Udupa and Chen, 2013). Furthermore, compared to the magnetic stimulation methods used in this study, collision technique (e.g. Triple-stimulation technique) may increase the probability of abnormal detection and reduce the interference of the volume conduction from other muscles, as the collision technique can obtain a more synchronized TMS-evoked excitation of the target muscle. Therefore, future investigations might study the clinical
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values of these measurements and compare the application of collision techniques in evaluating HD.
5 Conclusions: In this study, our data strongly support that the cervical motor nerve root (intra- and/or extra-medullary motor nerve) may be the main lesion site in some HD patients, especially on
the symptomatic side of patients with obvious asymmetric forward shifting of the cervical cord during neck flexion. In addition, an abnormally increased forward traction force in shorter nerve roots may be the cause of the main damage in the motor nerve root.
Conflict of interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of this paper.
Acknowledgements Financial support from Shanghai City Health System of the Second Batch of Important Diseases Combined Project (2014ZYJ0008) and the National Natural Science Foundation of China Youth Science Foundation Project (81501909) is gratefully acknowledged.
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References Bischoff C, Meyer BU, Machetanz J, Conrad B. The value of magnetic stimulation in the diagnosis of radiculopathies. Muscle Nerve. 1993; 16:154-61.
de Carvalho M, Turkman A, Swash M. Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci. 2003; 210:83-9.
Di Lazzaro V, Oliviero A, Profice P, Ferrara L, Saturno E, Pilato F, Tonali P. The diagnostic value of motor evoked potentials.Clin Neurophysiol. 1999; 110:1297-307.
Di Lazzaro V, Pilato F, Oliviero A, Saturno E, Dileone M, Tonali PA. Role of motor evoked potentials in diagnosis of cauda equina and lumbosacral cord lesions. Neurology. 2004; 63:2266-71.
Floyd AG, Yu QP, Piboolnurak P, Tang MX, Fang Y, Smith WA, Yim J, Rowland LP, Mitsumoto H, Pullman SL. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology. 2009; 72:498-504.
Groppa S, Oliviero A, Eisen A, Quartarone A, Cohen LG, Mall V, Kaelin-Lang A, Mima T, Rossi S, Thickbroom GW, Rossini PM, Ziemann U, Valls-Solé J, Siebner HR. A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee. Clin
17
Neurophysiol. 2012; 123:858-82.
Hirayama K, Tomonaga M, Kitano K, Yamada T, Kojima S, Arai K. Focal cervical poliopathy causing juvenile muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg Psychiatry. 1987; 50:285-90.
Hirayama K. Juvenile muscular atrophy of distal upper extremity (Hirayama disease). Internal medicine (Tokyo, Japan), 2000; 39: 283-290.
Hirayama K. Juvenile muscular atrophy of unilateral upper extremity (Hirayama disease)--half-century progress and establishment since its discovery [in Japanese]. Brain Nerve. 2008; 60:17-29.
Kohno M, Takahashi H, Yagishita A, Tanabe H. "Disproportion theory" of the cervical spine and spinal cord in patients with juvenile cervical flexion myelopathy. A study comparing cervical magnetic resonance images with those of normal controls. Surg Neurol. 1998; 50:421-30.
Kaneko K, Taguchi T, Morita H, Yonemura H, Fujimoto H, Kawai S. Mechanism of prolonged central motor conduction time in compressive cervical myelopathy. Clin Neurophysiol. 2001; 112:1035-40.
18
Li Y, Remmel K. A case of monomelic amyotrophy of the upper limb: MRI findings and the implication on its pathogenesis. J Clin Neuromuscul Dis. 2012; 13: 234-9.
Mano Y, Nakamuro T, Ikoma K, Sugata T, Morimoto S, Takayanagi T, Mayer RF. Central motor conductivity in aged people.Intern Med. 1992; 31:1084-7.
Mills KR. Magnetic Stimulation of the Human Nervous System. Oxford: Oxford University Press; 1999.
Miscio G, Pisano F, Mora G, Mazzini L. Motor neuron disease: usefulness of transcranial magnetic stimulation in improving the diagnosis. Clin Neurophysiol. 1999; 110:975-81.
Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner HR, Ugawa Y, Walsh V, Ziemann U. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015; 126:1071-107.
Sakai K, Ono K, Okamoto Y, Murakami H, Yamada M. Cervical flexion myelopathy in a patient showing apparent long tract signs: a severe form of Hirayama disease. Joint Bone
19
Spine. 2011; 78:316-8.
Toma S, Shiozawa Z. Amyotrophic cervical myelopathy in adolescence. J Neurol Neurosurg Psychiatry. 1995; 58:56-64.
Udupa K, Chen R. Central motor conduction time. Handb Clin Neurol. 2013; 116:375-86.
Vargas MC, Castillo M. Magnetic resonance imaging in Hirayama disease. J Radiol Case Rep. 2011; 5:17-23.
Wang XN, Cui LY, Liu MS, Guan YZ, Li BH, DU H. A clinical neurophysiology study of Hirayama disease. Chin Med J (Engl). 2012; 125:1115-20.
Zhou B, Chen L, Fan D, Zhou D. Clinical features of Hirayama disease in mainland China. Amyotroph Lateral Scler. 2010; 11:133-9.
Zheng C, Zhu Y, Yang S, Lu F, Jin X, Weber R, Jiang J. A study of dynamic F-waves in juvenile spinal muscular atrophy of the distal upper extremity (Hirayama disease). J Neurol Sci. 2016; 367:298-304.
Zheng C, Zhu D, Lu F, Zhu Y, Ma X, Xia X, Weber R, Jiang J. Compound Muscle Action Potential Decrement to Repetitive Nerve Stimulation Between Hirayama Disease and
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Amyotrophic Lateral Sclerosis. J Clin Neurophysiol. 2017; 34:119-125.
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FIGURE LEGENDS
Fig. 1: A 17-year-old male patient with Hirayama disease. Significant prolonged CMCT-M with a normal CMCT-F was found in ADM on the symptomatic side. The right panel shows 4 MEPs from transcranial magnetic stimulation (1-4) and 3 MEPs from paravertebral magnetic stimulation (5-7), with the left panel showing the F-wave of ADM on the symptomatic side. CML: corticomotor latency; PML-F: peripheral motor latency measured by the F-wave method; PML-M: peripheral motor latency measured by paravertebral magnetic stimulation; CMCT-F: central motor conduction time measured by the F-wave method; CMCT-M: central motor conduction time measured by paravertebral magnetic stimulation; MEPs: motor evoked potentials; ADM: abductor digiti minimi.
Fig. 2: A 17-year-old male patient with Hirayama disease. A: Significant amyotrophy of the intrinsic hand and forearm muscles on the left side; B: On neck-standard position, cervical magnetic resonance imaging (MRI); C: On neck-flexion position, more significant anterior displacement of the cervical cord on the symptomatic side (arrows).
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Table 1：The measurements of MEP in both HD patients and the controls Patients with Hirayama diseases
Healthy subjects
Number of cases
41
22
Age range (years)
19.0±3.6 (14-29)
30.9±8.9 (18-45)
Height range (cm)
172.6±4.1 (162-180)
172.2±4.6 (165-182)
Disease duration (months)
25.0±16.5 (5-72) S side
Less-S side
P
P’
23.0±3.1
21.8±2.8
< 0.01* 20.3±0.9 < 0.01* / < 0.01*
PML-F
15.8±1.7
15.1±1.8
< 0.01* 14.0±0.8 < 0.01* / < 0.01*
CMCT-F
6.9±1.4
6.5±1.3
Abductor digiti minimi CML F-wave methods
S-to-S difference
0.01*
0.9±0.6
Paravertebral magnetic stimulation methods PML-M 15.0±1.9 14.3±1.7 CMCT-M 8.1±1.7 7.5±1.5 S-to-S difference 1.0±0.9 1.1±0.5 0.9±0.4 PNRCT S-to-S difference 0.4±0.5
6.3±1.0
0.07 / 0.36
0.5±0.4
0.01*
0.01*
13.1±0.8 < 0.01* / < 0.01*
0.01*
7.2±1.0
0.01* / 0.36
0.6±0.4
0.01*
0.9±0.3
0.17 / 0.77
0.4±0.3
0.58
0.08
Abductor pollicis brevis CML
21.9±2.7
21.1±1.7
0.03*
20.5±1.6
0.01* / 0.15
15.3±1.8*
14.9±1.3
0.05
14.7±1.1
0.10 / 0.44
6.3±0.9
6.1±0.7
0.01*
5.8±1.0
0.02* / 0.17
0.6±0.4
0.98
0.26
14.0±1.2
0.11 / 0.36
0.03*
6.6±0.9
< 0.01* / 0.19
0.7±0.5
0.47
0.8±0.3
0.09 / 0.86
0.3±0.2
0.03*
F-wave methods PML-F CMCT-F S-to-S difference
0.6±0.5
Paravertebral magnetic stimulation methods PML-M 14.5±1.7 14.2±1.3 CMCT-M 7.3±1.1 6.8±0.8 S-to-S difference 0.8±0.6 0.9±0.4 0.7±0.2 PNRCT S-to-S difference 0.4±0.4
0.06
CMCT-F: central motor conduction time measured by F-wave method; CMCT-M: central motor conduction time measured by paravertebral magnetic stimuli PML: peripheral motor latency; CML: corticomotor latency; PNRCT: proximal nerve root conduction time HD: hirayama disease; MEP: motor evoked potentials; S-to-S difference: side-to-side difference S side: symptomatic side; Less-S side: less-symptomatic side P: P-values between the symptomatic side and less-symptomatic side in HD patients. P’: P-values between the measurements of controls and those of HD patients. a / b: where a is P-values between the measurements of controls and those of S side in HD patients, and b is P-values between the measurements of controls and those of Less-S side in HD patients. *: Statistical significance (P < 0.05)
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