Our study found that CMAP-12 amplitudes in patients with ALS had remarkable divergences. Eighty patients (53.7%) had CMAP-12 amplitudes decreased by more than 50%, suggesting that approximately half of the patients had obvious motor axon dysfunction in the early stage of the disease. From the ALSFRS and ALSFRS-R scores, we can see that the severity of the disease in the moderately and severely decreased, but not the mildly decreased, groups was significantly worse than that of the normal group. This confirms that motor axonal dysfunction could occur in the relatively early stage of ALS and that a greater decrease in CMAP amplitude is associated with a more deterioration in clinical function.
The univariate survival analysis showed that the reduction in the CMAP-12 amplitude was significantly correlated with survival. A further decrease in the CMAP-12 amplitude was associated with a further shorter survival. Multivariate analysis, after adjusting the influence of multiple confounding factors, further found that the CMAP-12 amplitude remained closely related to survival. The survival time of patients with moderately and severely decreased CMAP-12 amplitude was significantly shorter than that of the normal group, with the severely decreased CMAP-12 amplitude to be associated with the shortest survival. The results indicated that the decrement in CMAP amplitude within 12 months of onset can be used as an independent prognostic factor. Furthermore, our subgroup analysis showed that the survival period was shorter in the patients with moderately and severely decreased CMAP amplitudes within 6 months than in patients with similar decreases within 12 months, suggesting that the earlier the amplitude of CMAP decreased, the worse the prognosis.
There have been studies evaluating CMAP amplitude, neurophysiological index (NI), motor unit number estimation, and motor unit number index as electrophysiological markers for the prognosis of the disease [12, 19–26]. Our present study differs from previous studies in defining the assessment time for CMAP changes in patients to within 12 months of onset, based on the fact that the median survival time of patients with ALS is generally 2 to 4 years, and 12 months may be regarded as a relatively early stage of the disease [27–29]. We believe that it is more meaningful to study the changes of CMAP amplitude in ALS patients in the early stages of the disease than the whole course of the disease. We speculate that the mechanism of the decline in CMAP-12 amplitude may be consist of two components: 1) hyperexcitblity of peripheral motor axons, and 2) motor axonal damage associated with earlier motor neuronal death [6–8]. Using a computerised program for multiple excitability measurements in the median nerve at the wrist, Kanai et al. proved that motor axonal excitability properties are strong predictors for survival in patients with ALS . Besides concerning the early stage (within 12 months of onset), we used a much more routine electrophysiological method as well as selected the most obvious changeable nerve, making the highlights of our study.
Fischer et al. found that denervated synapses of IIb/x muscle fibers in ALS SOD1 mice (47 days old) and axonal loss of the ventral peripheral nerve (80 days old) occurred before neuronal cell body loss (100 days old) . It was found that proximal axonopathy in ALS is associated with the loss of neurofilament (NF) protein in the terminal neuromuscular junction as well, and the progressive loss of NFs may evolve from distal to proximal . In recent years, a dying-back hypothesis has attracted much attention [10, 30, 32, 33]. According to this hypothesis, motor nerves and nerve endings exhibit pathophysiological changes before degeneration of motor neurons and clinical symptom onset in some patients. In particular, the hypothesis suggests that ALS could be a distal axonopathy and that NMJ function may change first and then the pathophysiological changes progress proximal to the cell body . Evidence of dying-back was found in an autopsy of an ALS patient with denervation and innervation of the muscles, while no pathological changes occurred in the motor neurons themselves . Recent studies have found that stimulated Raman scattering microimaging can sensitively detect peripheral nerve degeneration in ALS mice and pathological specimens from ALS patients. It was also found that clear degeneration of the peripheral nerve appeared at the same time as denervated muscle in an early clinical mouse model, and that these changes occurred earlier than hypofunction of the motor nerve .
Nardo et al. found that, compared with C57SOD1G93A mice with slow disease progression, 129SvSOD1G93A mice with rapid disease progression had significant peripheral axonal loss during the onset of the disease, which suggested that PNS damage rather than motor neuron loss itself was related to the rapid progression of the disease [11, 12]. Grouping CMAP amplitudes as determined within 12 months and comparing the differences among groups could help to sort out patients with different patterns of disease progression and to study the underlying mechanism of this progression and even apply drug trials in the future. Our study supported that peripheral motor axonal dysfunction can occur in the early stage of ALS, and that the degree of the axonal injury was related to disease progression and survival. Maintaining peripheral nerve integrity is essential to slow down the progression of the disease , which may provide a clue to future drug development.
In this study, the percentage of bulbar-onset patients was lower; yet, this result is consistent with our previous study . It showed a higher proportion of bulbar-onset patients in the normal CMAP-12 amplitude group compared to the other ones, which seems to contradict to the common belief that this type of patients usually has a poor prognosis. However, it is noteworthy that in 14 patients with bulbar-onset of ALS, there are five patients (35.7%) conformed to the isolated bulbar phenotype of ALS [35–36]. This may partly explain why the median survival of the patients with bulbar-onset of ALS was no difference compared with those with limb-onset in this study (Table 2). On the other hand, although Kanai et al. showed the motor axonal excitability properties were strong and independent predictors for shorter survival in ALS patients, they did not find differences of the prognosis by multivariate analysis between the bulbar-onset and non-bulbar-onset patients in their study .
In addition, we noticed that the median survival of the patients with FAS-type ALS was shorter (Table 2). Consistent with it, we recently proved that 12-month duration was an important criterion for FAS, otherwise the prognosis of FAS-type ALS was significantly worse than that of FAS .
This study has several limitations. First, the sample size of patients was limited, especially patients in the moderately decreased CMAP-12 amplitude group. Second, important data on the use of noninvasive ventilation, riluzole or gastrostomy were absent in this study. Third, we studied only the CMAP amplitude of motor nerves. Recently, Miyaji et al. showed that the attenuation rate of repetitive nerve stimulation (RNS) was negatively correlated with the CMAP amplitude of the first wave. The higher the RNS attenuation rate was, the lower the CMAP amplitude, which probably indicates that there was a correlation between terminal axonal dysfunction and NMJ injury . In future, we might need to combine the measurements of the CMAP-12 amplitude with NMJ changes in patients with ALS to better understand the origin and mechanisms of ALS.