Study on Variation Trend of Repetitive Nerve Stimulation Waveform in Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motor neurons. Despite extensive research, there is currently no effective cure for ALS. Electrophysiological studies have identified decremental responses during low-frequency repetitive nerve stimulation (RNS) in ALS patients, apart from diffuse neurogenic activities. However, the differences in waveform features between ALS and generalized myasthenia gravis (GMG) remain unclear. This study aims to explore the variation trend of the amplitude curve in ALS and GMG patients during low-frequency RNS and to discuss the possible mechanisms underlying these differences.
Introduction ALS, first described by French neurologist Jean-Martin Charcot in 1869, is the most common type of motor neuron disease. It is characterized by an occult onset and a relentlessly progressive course, primarily involving pyramidal cells in the cerebral cortex, motor nuclei in the brainstem, pyramidal tracts, and anterior horn cells of the spinal cord. The annual incidence of ALS ranges from 1.5 to 2.5 cases per 100,000 people, with a median survival of 30 months post-diagnosis. Approximately 10% of patients survive for 10 years or more.
Recent studies have revealed that ALS not only affects upper and lower motor neurons but also involves the neuromuscular junction (NMJ), leading to its dysfunction. The NMJ is crucial for the transmission of impulses between nerves and muscles, and its function is primarily evaluated using RNS. In 1959, Mulder first discovered that ALS patients with muscle fatigue phenomena produced a decremental response during low-frequency RNS, suggesting NMJ involvement in ALS. This decremental pattern can be observed in multiple nerves, with the accessory nerve showing the highest positive rate, while the facial nerve rarely exhibits this pattern.
Methods This study recruited 85 ALS patients and 41 GMG patients from Peking Union Medical College Hospital (PUMCH) between July 1, 2012, and February 28, 2015. The RNS study included stimulation of the ulnar nerve, accessory nerve, and facial nerve at 3Hz and 5Hz. The percentage reduction in the amplitude of the fourth or fifth wave from the first wave was calculated and compared with the normal values established by the hospital. A 15% decrease in amplitude was defined as a decremental response.
Results The study found that the abnormal rate of RNS decline was 54.1% (46/85) in the ALS group. Specifically, the abnormal rates were 54.1% (46/85) for the accessory nerve, 8.2% (7/85) for the ulnar nerve, and 0% (0/85) for the facial nerve. In the GMG group, the abnormal rate of RNS decline was 100% (41/41) for the accessory nerve. However, there was a significant difference between the two groups in the amplitude after the sixth wave.
Discussion Both ALS and GMG patients exhibited a decremental amplitude during low-frequency RNS. However, the recovery trend after the sixth wave showed significant variation between the two groups, implying different pathogeneses of NMJ dysfunction. In GMG patients, the decrement typically dropped to its nadir at the fourth or fifth wave and then significantly recovered by the sixth wave, forming a “U-shaped” curve. In contrast, ALS patients did not show significant recovery after the nadir, resulting in an “L-shaped” curve.
The NMJ is vital for unidirectional impulse conduction between nerves and muscles, consisting of the presynaptic region, synaptic cleft, and postsynaptic region. In GMG, the decremental response is primarily due to the action of acetylcholine receptor antibodies (AchR-Ab) on the postsynaptic membrane, blocking the transmission process. The recovery of calcium levels in the presynaptic membrane and the replenishment of immediate release quanta lead to the “U-shaped” recovery curve observed in GMG patients.
In ALS, the mechanism of NMJ dysfunction is more complex. ALS is characterized by progressive denervation and chronic nerve regeneration. The degeneration and loss of anterior horn motor neurons lead to denervation of corresponding muscle fibers and destruction of NMJ structures. The surviving motor neurons form new NMJ structures through collateral sprouting, but these structures remain immature due to the ongoing degeneration and reinnervation cycle. This immature NMJ structure results in a decreased safety factor of neuromuscular transmission and a reduced release and storage of acetylcholine, leading to the “L-shaped” decremental response observed in ALS patients.
The study also found that the positive rate of low-frequency RNS in ALS was higher in the limb onset group compared to the bulbar onset group, consistent with previous research. Additionally, the positive rate was significantly higher in patients with severe muscle weakness (0–III grade) compared to those with milder weakness (IV–V grade).
Conclusion The variation trend of the decremental curve in low-frequency RNS between ALS and GMG patients highlights the different pathogeneses of NMJ dysfunction in these two diseases. The “U-shaped” recovery curve in GMG patients indicates a specific involvement of the postsynaptic membrane, while the “L-shaped” curve in ALS patients suggests a more complex and widespread involvement of the entire NMJ structure. Understanding these differences can aid in the differential diagnosis and provide insights into the underlying mechanisms of NMJ dysfunction in ALS and GMG.
doi.org/10.1097/CM9.0000000000000117
Was this helpful?
0 / 0