1.Assessment Of The Upper Motor Neuron Lesion In Amyotrophic Lateral Sclerosis With The Triple Stimulation Technique 2.Therapeutic Effect Of Repetitive Transcranial Magnetic Stimulation On Amyotrophic Lateral Sclerosis

Part OneAssessment of the upper motor neuron lesion in amyotrophic lateral sclerosis with the triple stimulation techniqueBackground:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both lower and upper motor neurons (UMN). Clinical and subclinical lower motor neuron (LMN) impairment can be readily detected by regular electromyographies (EMG). However, there have been no objective indices to evaluate UMN lesions. Transcranial magnetic stimulation(TMS) has been expected to assess the functional integrity of the corticospinal tract in ALS by measuring motor-evoked potentials(MEPs) and central motor conduction times(CMCTs), but the value of the technique in its original version is limited in the assessment of UMN dysfunction.Recently Rostler et al. have explored a novel TMS technique involving two collisions, the triple stimulation technique(TST), found it is a useful tool for diagnosing and quantify the UMN dysfunction in ALS.Objective:The current prospective study was undertaken to assess the validity of TST amplitude ratio for detecting UMN impairment in ALS and non-ALS, to compare the sensitivity of the conventional TMS parameters to the TST for detecting UMN impairment in ALS, and to correlate the TST with clinical features of ALS, to quantitatively estimate upper motor neuron (UMN) lesion with the triple stimulation technique (TST) in amyotrophic lateral sclerosis (ALS).Methods:Fifty ALS patients, twenty non-ALS patients, and twenty-two healthy control subjects were enrolled in the study. Patients were examined clinically, with conventional transcranial magnetic stimulation (TMS), and TST. The correlation of TST and compound muscle action potential (CMAP), modified ashworth scale (MAS), medical research council scale (MRC), revised ALS functional rating scale (ALSFRS-R), the progression rate of disease were analysized.Results:The TST amplitude ratio was significantly decreased in ALS with UMN signs, compared with controls and ALS patients without UMN signs(Z=-5.524, P=0.000; Z=-4.827, P=0.000). The abnormal rates of the TST amplitude in ALS with UMN signs, ALS without UMN signs and controls were 89.3%,27.3%,9.1%respectively. The TST amplitude ratio was also significantly decreased in non-ALS with pure UMN signs compared with controls(Z=-3.513, P=0.000), but not in non-ALS with pure LMN signs (Z=-1.346, P=0.178). No significant difference was seen in ALS with UMN signs and non-ALS with pure UMN signs (Z=-0.694, P=0.488). In 6 ALS patients, an abnormal TST amplitude ratio suggested UMN involvement despite lack of clinical UMN signs, whose CMAP was significantly decreased (t=-2.889, P=0.010). The abnormal rates of the TST amplitude in detecting UMN lesions were higher than other TMS parameters. The TST amplitude was significantly correlated with tendon reflex in right arm (r=0.690, P=0.000), with modified ashworth scale (MAS) (r=-0.772, P=0.000), with diagnostic degree (r=0.483, P=0.000), with RMT (r=-0.774, P=0.000), the latency of MEP (r=-0.444, P=0.005), motor evoked potential/compound muscle action potential of erb's (MEP/CMAPerb) (r=0.685, P=0.000), MEP/CMAPerb in facilitation (r=0.770, P=0.000).Conclusion:TST appears to be an accurate and sensitive measure of detecting and quantifying UMN conduction failure in ALS than other parameters. TST may reveal the subclinical UMN impairment in ALS. TST may provide a more accurate diagnosis for UMN loss in ALS and an objective scale for monitoring the progression of disease. Part TwoTherapeutic effect of repetitive transcranial magnetic stimulation on amyotrophic lateral sclerosisBackground:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both lower and upper motor neurons (UMN). Glutamate-mediated excitotoxicity is one of the hypothesized pathogenetic mechanisms of ALS. Riluzole was the only drug accepted by the FDA. Repetitive transcranial magnetic stimulation (rTMS) is a technique for noninvasive stimulation of the adult brain, which can produce changes in cortical excitatory neurotransmission. Low-frequency rTMS (stimulus rates of 1Hz or less) produces a lasting decrease in motor cortex excitability. rTMS has been already used as a therapeutic tool in several neurological and psychiatric disorders, such as Parkinson's disease, chronic pain syndrome, primarily depression and stroke. In a proof of study, low-frequency rTMS was found to cause a slight slowing in the rate of disease progression in ALS patients.The rationale for trying low-frequency rTMS in ALS is based on the evidence that it induces a long-lasting decrease of motor cortex excitability that could theoretically antagonize the glutamate-mediated excitotoxicity.Objective:The current prospective study was to undertaken to investigate whether low-frequency rTMS of motor cortex can have any beneficial effect in a few patients with ALS.Methods:Ten patients with ALS were randomly allocated to active or placebo stimulation. Low-frequency rTMS was performed at an intensity of 110% resting motor threshold (RMT). Over the motor cortex of each side and paracentral lobule totally 1800 stimuli were delivered for 2 consecutive weeks every month for 3 consecutive months. Five Patients were given false stimulations. The primary outcome of the survival rate, ALS Functional Rating Scale-Revised (ALSFRS-R), and secondary outcome of manual muscle testing (MMT), resting motor threshold (RMT), motor evoked potentials (MEP), the latency of motor evoked potentials, compound muscle action potential (CMAP), neurophysiological index (NI), repetitive nerve stimulation (RNS) were evaluated before the treatment, after the treatment of every cycle and 3 months after the end of treatment.Results:No significant difference of above parameter between the active and sham patients were observed after the treatment, including the survival rate, ALSFRS-R, the rate of disease Progression, MMT, RMT, MEP, the latency of MEP, CMAP, NI, RNS(P>0.05). All ALS patients continued to deteriorate.We have found that in active patients RMT at the time shortly after the treatment was slightly increased by 3.45%(P=0.082) compared with that before the treatment, then RMT went back to its baseline one day after the treatment. MEP at the time shortly after the treatment was slightly decreased by 0.11mV (P=0.640), MEP latency was slightly increased by 0.57ms (P=0.001) compared with that before the treatment, and then they went back to baseline.At the end of treatment, slighter changes in RMT and MEP amplitude were observed in active patients than sham patients.Conclusions:The present study shows that rTMS performed monthly over a 3 month period has no beneficial effects on the progression of ALS. Low-frequency rTMS (stimulus rates of 1Hz or less) can produce a decrease in motor cortex excitability, and it lasts at most for one day. It was hypothesized that the slighter change in RMT and MEP amplitude observed in active patients might be related to the slowing rate of loss of cortex motor neurons.Though we cannot be sure whether the effects observed in the patients can be attributed to rTMS, further investigation using low-frequency motor cortex stimulation on a larger group of ALS patients is warranted.The rTMS treatment was well tolerated by the patients, except for one patient has the symptom of tinnitus.