Neurophysiological Study Of Motor Neuron Disease

Part1The significance of F-waves in the diagnosis and differential diagnosis of amyotrophic lateral sclerosis and Kennedy diseaseBackground:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease affecting motor neurons in the cerebral cortex, brainstem and spinal cord. The main cinical manifestations include progressive muscle weakness and atrophy, bulbar palsy and pyramidal signs. The pathogenesis of ALS remains unclear and there is no effective treatment. The prognosis of ALS patients is poor. The diagnosis of ALS requires involvement of both upper and lower motor neurons. The specific biomarkers of ALS are lacking. Disease progression of ALS is occult. Clinical manifestations of ALS are heterogeneous. It’s easy to be misdiagnosed and underdiagnosed in the early disease stage. In some ALS patients, upper motor neuron signs appear later in the disease course or not at all. It is difficult to distinguish ALS from KD clinically. Previous studies have demonstrated differences between ALS and KD in sensory action potential amplitudes, needle electromyography manifestations, cortical excitability testing, serum creatine kinase levels, and clinical presentations. However, differences in the characteristics of F-waves between ALS and KD have not been explored up till now.Objective:The study aimed to investigate the characteristics of F-waves in ALS by comparing F-wave parameters of ulnar nerves between ALS patients and normal participants and by analyzing the effect of dysfunction of upper and lower motor neurons on F-waves. In addition, we compared the parameters of F-waves recorded bilaterally from the median, ulnar, tibial, and deep peroneal nerves in ALS patients and KD patients to investigate the value of F-waves in the diagnosis and differential diagnosis of ALS and KD.Methods:Eighty-two patients with ALS who visited the outpatient department of neurology in our hospital from September 2013 to July 2014 were consecutively enrolled in our study. Medical record databases which contained the name, gender, age, disease duration, disease onset location, symptoms, signs and MRC rating scales of the muscles investigated were established for all patients. Fifty age and gender matched healthy volunteers served as controls. Standard nerve conduction study and F-waves were performed to the ulnar nerves of the patients with ALS and normal controls. F-wave parameters in ulnar nerves between the ALS patients and the normal controls were compared; the associations between F-wave parameters of ulnar nerves and the presence or absence of pyramidal signs in the same upper limbs or the MRC rating scales of abductor digiti minimi were analyzed by using Logistic regression analysis. Thirty-seven lower motor neuron dominant male ALS patients who visited the outpatient department of neurology in our hospital between September 2013 to December 2014 and 32 KD patients who visited the outpatient department of neurology in our hospital during the same period were consecutively enrolled in our study. Thirty healthy male volunteers served as controls. The present study aimed to investigate the differences in F-wave parameters in bilateral median, ulnar, tibial and peroneal nerves between ALS patients, KD patients and normal controls.Results:Compared with the F-wave parameters in the ulnar nerves of the normal controls, the mean (P= 0.040) and maximum (P< 0.001) F-wave amplitudes, mean (P< 0.001) and maximum (P< 0.001) F/M amplitude ratios, index repeating neuron (RN) (P< 0.001), index F-wave repeaters (Freps) (P< 0.001) and frequency of giant F-waves (P< 0.001) in the ulnar nerves of the ALS patients were significantly increased; the F-wave chronodispersion (P< 0.001), minimum F-wave latency were significantly prolonged; the F-wave duration(P= 0.004) were significantly reduced; the F-wave persistence (P< 0.001) was significantly reduced. The minimum F-wave latency (P< 0.001) and F-wave persistence (P< 0.001) significantly correlated with the MRC rating scales of abductor digiti minimi; the mean (P< 0.001) and maximum (P= 0.002) F-wave amplitudes significantly correlated with pyramidal signs in the upper limbs; the mean F/M amplitude ratio (MRC, P< 0.001; pyramidal sign, P< 0.001), maximum F/M amplitude ratio (MRC, P= 0.001; pyramidal sign, P-0.002), F-wave duration (MRC, P< 0.001; pyramidal sign, P= 0.047), index RN (MRC, P< 0.001; pyramidal sign, P= 0.009) and index Freps (MRC, P< 0.001; pyramidal sign, P= 0.002) significantly correlated with both the MRC rating scales of abductor digiti minimi and pyramidal signs in the upper limbs in ALS.We compared the parameters of F-waves between ALS and KD. The maximum F-wave amplitudes, frequencies of giant F-waves, and frequencies of patients with giant F-waves in the median, ulnar, tibial and peroneal nerves were significantly higher in the KD patients than in the ALS patients and the normal controls. Giant F-waves were detected in multiple nerves and were often symmetrical in the KD patients compared with the ALS patients. The number of nerves with giant F-waves seems to be the most robust variable for differentiation of ALS from KD, with an area under the curve of 0.908 (95% CI:0.835-0.982). A cut-off value of the number of nerves with gaint F-waves (≥ 3) for diagnosing KD showed high sensitivity and specificity:85% sensitivity and 81% specificity vs. ALS patients. No significant correlations were found between the pooled frequency of giant F-waves and disease duration in the KD (r= 0.162, P= 0.418) or ALS groups (r= 0.107, P= 0.529).Conclusions:F-wave parameters were related to the function of both upper and lower motor neurons, and could reflect the integrity and excitability of motoneuron pool. F-waves might be used to discriminate ALS from KD, which were not affected by disease durations of patients. A significant increase in the frequency of giant F-waves, especially in the median and peroneal nerves, or giant F-waves recorded from multiple nerves (> 3) or symmetrically between the left and right sides in male patients with lower motor neuron syndromes are highly suggestive of KD. In these cases, genetic testing is recommended.Part 2Electrophysiological study and investigation of pathogenesis of split-hand sign in amyotrophic lateral sclerosisBackground:In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous, with relative preservation of the abductor digiti minimi (ADM). This specific feature of ALS has been termed the "split-hand" sign. Both cortical and peripheral mechanisms have been proposed to underlie the different levels of atrophy among the small hand muscles in ALS in previous studies. However, there are few studies that have directly compared the dysfunction of motoneuron pool innervating the APB and ADM.Objective:This study aimed to determine whether differences in the dysfunction of spinal motoneuron pool innervating the APB and ADM in ALS patients were consistent with the split-hand sign in ALS and contributed to the pathogenesis of ALS based on studying F-waves.Methods:Forty ALS patients who were seen at the Department of Neurology in Peking Union Medical College Hospital between September 2013 and March 2014 were consecutively enrolled in the study. Twenty healthy volunteers served as controls. The ALS patients were assigned to 2 groups based on their physical symptoms. The patients in group 1 (20 patients with ALS) had wasting and weakness of the intrinsic hand muscles. The patients in group 2 (20 patients with ALS) exhibited no wasting or weakness of the intrinsic hand muscles. Motor nerve conduction studies and F-waves were performed to both the median and ulnar nerves of all participants. The F-wave parameters were compared between the APB and ADM, including F-wave latency, F-wave persistence, F-wave amplitude, F/M amplitude ratio, index repeating neuron (RN), and index F-wave repeaters (Freps).Results:The F-wave persistence (P< 0.05), index RN (P< 0.001), and index Freps (P< 0.001) significantly differed between the APB and ADM in the normal control participants. For the hands of the ALS patients that lacked detectable wasting or weakness, significantly reduced F-wave persistence (P< 0.001), increased index RN (P< 0.001), and increased index Freps (P< 0.001) were observed in APB in comparison with the normal participants, with relatively normal ADM F-wave parameters. For the hands of ALS patients that exhibited wasting and weakness, the mean F-wave amplitude (P< 0.05), F/M amplitude ratio (P< 0.05), F-wave persistence (P< 0.001), index RN (P< 0.05), and index Freps(P< 0.05) significantly differed between the APB and ADM. The differences in the dysfunction of motoneuron pool innervating APB and ADM are unique manifestations in ALS patients. The F-wave persistence (P= 0.002), index RN (P< 0.001), and index Freps (P< 0.001) in the APB seemed to differentiate ALS from the normal controls more robustly than the ADM/APB CMAP amplitude ratio.Conclusions:The differences in F-wave characteristics between APB and ADM in the normal participants and ALS patients were consistent with the split-hand sign, which indicated that dysfunction of spinal motoneuron pool may contribute to the pathogenesis of split-hand sign in ALS. F-waves may reveal subclinical alterations in anterior horn cells, and may potentially help to distinguish ALS from mimic disorders.Part 3A comparison of the electrophysiological features between amyotrophic lateral sclerosis and mimic disordersBackground:Amyotrophic lateral sclerosis (ALS) is a relentless progressive devastating disorder. The simultaneous combination of upper motor neuron and lower motor neuron dysfunction in clinical manifestation strongly suggests the clinical diagnosis of ALS. However, early in the course of ALS, weakness and atrophy may be limited to the small hand muscles of ALS patients. Disorders with symptoms mimicking ALS should be excluded to make a clinical diagnosis of ALS, such as distal-type cervical spondylotic amyotrophy (CSA), Hirayama disease (HD), and Kennedy disease (KD).Objective:To investigate the characteristics of nerve conduction study and the patterns of small hand muscle involvement in ALS and some mimic disorders, such as distal-type CSA, HD, and KD.Methods:We reviewed clinical data and findings of nerve conduction studies of the upper limbs in 200 ALS patients,95 patients with distal-type CSA,88 HD patients,43 KD patients who underwent electrodiagnostic examinations in the neurophysiology department of Peking Union Medical College Hospital during 2000 and 2014. One hundred and fifty healthy volunteers served as normal controls.Results:The abductor digiti minimi/abductor pollicis brevis (ADM/APB) compound muscle action potential (CMAP) amplitude ratio was significantly higher in the ALS patients (3.52 ± 0.60, P< 0.001) than that in the normal controls(1.00 ± 0.24). The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA (0.93 ± 0.77, P< 0.001) and the HD patients (0.63 ± 0.52, P< 0.001) compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude (9.91 ± 5.05mV, P= 0.005) than the HD patients (12.07 ± 4.88mV). The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients (P< 0.001) than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the KD patients was similar to that of the normal controls (1.06 ± 0.40, P= 0.862). An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio (≥ 4.5) were observed exclusively in the ALS patients. Sensory nerve action potential (SNAP) amplitudes and sensory conduction velocity (SCV) of median and ulnar nerves were all normal in patients with ALS, distal-type CSA and HD. In KD patients, the percentages with abnormal SNAP amplitude and SCV were 810a nd 9.3% respectively.Conclusions:The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders. Nerve conduction study, especially ADM/APB CMAP amplitude ratio may aid in the diagnosis of ALS and also in distinguishing between ALS and mimic disorders.