Ectopic Motor Unit Activity in Motor Neuron Disease

__Abstract__ Motor neuron disease (MND) is characterized by the progressive loss of motor neurons that control voluntary muscles. Due to its progressive nature, the muscles gradually lose their function leading to paralysis and, ultimately, death. The most common variant of MND is amyotrophic lateral sclerosis (ALS). Of all the people diagnosed with ALS, 50% die within approximately two to three years after their first symptoms arise and only about 20% live longer than 5 years [1]. Onset is typically around 50 - 70 years of age, but in some patients the onset may be much earlier, around the age of 20 - 30 years. Incidence is higher among men than women, estimated at 2:1 [2-4]. The first symptoms usually occur in the limbs, but muscle weakness may also begin in the bulbar region. Progressive weakness of the respiratory muscles leading to respiratory failure is the most common cause of death. Before the first clinical signs of muscle weakness become apparent, more than 50% of the motor neurons innervating a muscle may already be lost [5]. In the Netherlands, approximately 1,700 people (prevalence 10.3 per 100,000) suffer from ALS [2]. Every year, approximately 500 people (incidence 2.8 per 100,000) in the Netherlands are diagnosed with ALS [2], and about the same number of persons dies every year. In comparison, approximately 570 people in the Netherlands died in traffic accidents in 2013 [6]. The term ALS was first described in 1874 by Jean-Martin Charcot [7]. Despite the tremendous technological progress that has been made in the last 140 years and despite numerous studies that have been conducted to unravel the mechanisms that may cause this deadly disease, relatively little is known about the mechanisms that cause ALS and the progressive degeneration of motor neurons is often unpredictable. The great majority of patients is classified as having sporadic ALS, and only 5 - 10% of the patients have a familial history of this disease. A complex interaction between genetic and environmental factors is believed to contribute to the development of the disease. Several genes have been identified and their discovery gave new insights into the underlying pathophysiological mechanisms. At present, no cure is available, and the only approved and widely used medication (Riluzole) can only marginally slow down the progression of the disease by approximately 3 months [8]. In this section, first the concept of a motor unit as a crucial component being affected by MND will be introduced, together with some basics on how motor units are affected in this condition. Next, one of the most obvious clinical signs, fasciculations, will be discussed, followed by the varying clinical phenotypes. Subsequently, the difficulties in the diagnostic process and the prognosis will be described. Currently, both can be very difficult, especially in the early stages of the disease, even with a thorough clinical and electrodiagnostic examination

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Perioperative Medicine: Efficacy, Safety and Outcom

Acute retigabine-induced effects on myelinated motor axons in amyotrophic lateral sclerosis

Altered motor neuron excitability in patients with amyotrophic lateral sclerosis (ALS) has been suggested to be an early pathophysiological mechanism associated with motor neuron death. Compounds that affect membrane excitability may therefore have disease-modifying effects. Through which mechanism(s), these compounds modulate membrane excitability is mostly provided by preclinical studies, yet remains challenging to verify in clinical studies. Here, we investigated how retigabine affects human myelinated motor axons by applying computational modeling to interpret the complex excitability changes in a recent trial involving 18 ALS patients. Compared to baseline, the post-dose excitability differences were modeled well by a hyperpolarizing shift of the half-activation potential of slow potassium (K+)-channels (till 2 mV). These findings verify that retigabine targets slow K+-channel gating and highlight the usefulness of computational models. Further developments of this approach may facilitate the identification of early target engagement and ultimately aid selecting responders leading to more personalized treatment strategies

The reliability of continuous measurement of mixed venous oxygen saturation during exercise in patients with chronic heart failure

Continuous assessment of mixed venous oxygen saturation (cSvO2) during exercise using a fiber optic pulmonary artery catheter can provide valuable information on the physiological determinants of the exercise capacity in patients with chronic heart failure (CHF). Since its accuracy is not well established during exercise, this study evaluated the reliability of a fiber optic pulmonary artery catheter for measuring SvO2 during exercise in CHF patients. Ten patients with stable CHF performed steady-state exercise tests at 30 and 80% of the ventilatory threshold and consequently a symptom-limited incremental exercise test. During the tests, SvO2 was monitored continuously using a fiber optic pulmonary artery catheter (CCOmbo, Edwards Lifesciences, Irvine, CA, USA) and by oximetric analysis of mixed venous blood samples obtained at rest (n = 26), steady state (n = 17) and peak exercise (n = 8). There was a significant correlation between oximetrically determined SvO2 and cSvO2 values (r = 0.97). The bias between both methods was 0.6% with limits of agreement from -8 to 9%. The limits of agreement for SvO2 values 30% (n = 35) (from -10 to 12% and from -7 to 8%, respectively). In conclusion, continuous measurement of SvO2 during exercise using a fiber optic pulmonary catheter is reliable in patients with CHF, with somewhat less accurate measurements of SvO2 below 30%

CMAP scan discontinuities: Automated detection and relation to motor unit loss

Objective: To evaluate an automated method that extracts motor unit (MU) information from the CMAP scan, a high-detail stimulus-response curve recorded with surface EMG. Discontinuities in the CMAP scan are hypothesized to result from MU loss and reinnervation. Methods: We introduce the parameter D50 to quantify CMAP scan discontinuities. D50 was compared with a previously developed manual score in 253 CMAP scans and with a simultaneously obtained motor unit number estimate (MUNE) in 173 CMAP scans. The effect of MU loss on D50 was determined with a simulation model. Results: We found a high agreement (sensitivity = 86.8%, specificity = 96.6%) between D50 and the manual score. D50 and MUNE were significantly correlated below 80 MUs (r = 0.65, n = 68, p < 0.001), but not when MUNE was larger than 120 MUs (r = 0.23, n = 59, p = 0.08). Conclusions: Discontinuities in the CMAP scan as expressed by a decreased D50 are related to significant MU loss. The determination of D50 is objective, quantitative, and less time-consuming than both manual scoring and many existing MUNE methods. Significance: D50 is potentially useful to monitor neurogenic disorders and moderate to severe MU loss. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved