Occasional essay: upper motor neuron syndrome in amyotrophic lateral sclerosis

The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify in ALS.2 LMN involvement is sensitively detected by electromyography (EMG)3 but, as yet, there are no generally accepted markers for monitoring UMN abnormalities,4 the neurobiology of ALS itself, and disease spread through the brain and spinal cord,.5 Full clinical assessment is therefore necessary to exclude other diagnoses and to monitor disease progression. In part, this difficulty regarding detection of UMN involvement in ALS derives from the definition of ‘the UMN syndrome’. Abnormalities of motor control in ALS require reformulation within an expanded concept of the UMN, together with the neuropathological, neuro-imaging and neurophysiological abnormalities in ALS. We review these issues here

The hydrothermal precipitation of arsenical solids in the Ca-Fe-AsO4-SO4 system at elevated temperatures

Hydrothermal precipitation experiments were carried out in sealed test tubes to investigate the characteristics of solids precipitated from Ca-Fe-As04-S04 solutions at temperatures up to 225°C. The solids precipitated from solutions were examined by studying the individual Fe-AsC>4, Ca-AsCTj and Fe-Ca- As04 systems at low (3). Precipitation of solids in the Fe-AsC>4-SC)4 system at pH1:1. The family of Type-2 compounds show close similarities and are usually produced from starting solutions with Fe:As >1:1 at temperatures >175°C. These compounds are light brown in colour and are composed of crystals up to 50(j.m, they easily accommodate sulphate into their lattice and have compositions which approximate to:- Fe3(As04)2(0H)x(S04)y (where x and y = 0 to 1). The formation of the Type-1 compound is common in the temperature range 150 - 225°C from solutions with ratios of Fe:As of 95% of the contained arsenic from solution. High temperatures are preferable (>175°C) as this promotes the growth of crystalline arsenical compounds. For optimum conditions the Fe:As ratio in the solution must be around 1:1 to satisfy the Fe:As requirements of the precipitated compound (scorodite or the Type-2 compound, 1:1 or ~1.5:1 respectively) and most of the arsenic is removed within 30 minutes. When higher Fe:As ratios are used, the rate at which the compounds are precipitated is reduced. In the Fe-AsC>4 system at pH5 using an Fe:As ratio of ~1:1, a crystalline compound; designated Type-3 (approximating to Fe2(FIAs04)x(As04)y), is precipitated from arsenical-ferrihydrite sludges at temperatures above 125°C. Only at elevated pHs (>3) do calcium arsenate compounds begin to precipitate, and during neutralisation of iron-rich solutions arsenic preferentially combines with iron rather than calcium. In sulphate-rich solutions calcium will precipitate as gypsum rather than combine with arsenate to produce calcium arsenate compounds. From precipitation work carried out in the calcium-arsenate system, it was found that at temperatures below 100°C, the solids are partly hydrated and are usually composed of one of the following:- pharmacolite, haidingerite, or guerinite (CaHAsC>4.2H20, CaHAs04.H20 and CasH2(As04)4.9H20, respectively). In the temperature range 100 - 200°C at pH's4). Solids precipitated at pH's above 8 and at temperatures above 100°C precipitated johnbaumite (Cas(As04)30H). Above 200°C, the predominant solid approaches a Ca3(AsC>4)2 composition which contains only minor amounts of constitutional water. This work has examined a wide range of solution compositions and it has been found that all the hydrothermally prepared calcium arsenate-type compounds have very high apparent solubilities (>1000mg/L). Through experimental observation and consideration of some theoretical concepts a preliminary assessment of the long term behaviour of crystalline arsenic bearing metallurgical wastes in the environment has been made. Through empirical solubility testing and comparison with natural analogues it can be predicted that crystalline scorodite should have a low solubility for prolonged periods of time. Since scorodite is commonly found in many weathering zones and in most climatic regions of the world it is considered to be the most stable arsenate compound formed in nature and may be suitable for arsenic disposal purposes

Levosimendan for amyotrophic lateral sclerosis

© 2021 Elsevier Ltd. All rights reserved.Levosimendan is a drug developed and approved in the EU to treat severe heart failure by intravenous administration. Its principal pharmacological effect is to increase cardiac contractility by calcium sensitisation of troponin C. Because of the positive action of the drug on the neuromechanical efficiency and contractile function of the diaphragm in healthy controls, levosimendan was considered potentially useful for treating amyotrophic lateral sclerosis, a disease characterised by progressive upper and lower motor neuron deficits. This hypothesis was tested in the phase LEVALS 2 trial, in which the drug was given orally.info:eu-repo/semantics/publishedVersio

The cutaneous silent period as a measure of upper motor neuron dysfunction in amyotrophic lateral sclerosis

© 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objectives: We investigated the cutaneous silent period (CutSP) as a measure of upper motor neuron (UMN) dysfunction in amyotrophic lateral sclerosis. Methods: The onset latency, duration, and amount of EMG suppression of the CutSP were compared with clinical UMN signs in 24 patients with amyotrophic lateral sclerosis (ALS). UMN signs were quantified using a clinical index and transcranial magnetic stimulation (TMS). Central motor conduction time (CMCT), cortical motor threshold and motor evoked potential amplitudes were assessed as measures of UMN dysfunction. CutSP was studied in abductor digit minimi (ADM) and tibialis anterior (TA) EMG recordings following stimulation of the 5th finger and sural nerves respectively. Non-parametric tests and binomial logistic regression were applied to evaluate the data. Results: CutSP onset latency was increased in ALS patients, compared to healthy controls, both for ADM and TA muscles. In limbs with clinical UMN signs or abnormal TMS findings, the CutSP onset latency was particularly increased. There was a significant positive correlation between CutSP onset latency and the UMN score in both upper and lower limbs. In TA muscles there was also a negative correlation between CutSP onset latency and EMG suppression. The logistic regression model based on CutSP parameters correctly classified more than 70% of the cases regarding the presence of clinical signs of UMN lesion, in both upper and lower limbs. The results were not significant for TMS. Conclusion: We conclude that upper limb CutSP changes associates with UMN lesion in ALS. This neurophysiological measurement merits further investigation in ALS.This work was funded by the project “Spinal circuitry in Motor Neuron Disease: Changes in Spinal and Corticospinal Mechanisms in Amyotrophic Lateral Sclerosis and its variants” (sponsored by Biogen Inc)info:eu-repo/semantics/publishedVersio

Exploring the split hand phenomenon with the neurophysiological index

© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).In 164 subjects of different age groups, we studied the neurophysiological index (NI) ([CMAP amplitude/Distal motor latency] *[F-wave frequency]; CMAP=compound muscle action potential) for three hand muscles (APB= abductor pollicis brevis; FDI= first dorsal interosseous; ADM= abductor digiti minimi). A split hand index based on CMAP amplitude (SHI_CMAP) and NI (SHI_NI) were calculated ([APB CMAP amplitude or NI * FDI CMAP amplitude or NI]/[ADM CMAP amplitude or NI]). All these neurophysiological measurements differed between age groups (p<0.001). Hand muscle NIs, as well as SHI_NI and SHI_CMAP were age dependent. This may be relevant for diagnostic purposes in motor neuron diseases.info:eu-repo/semantics/publishedVersio

Vulvodynia: a neuroinflammatory pain syndrome originating in pelvic visceral nerve plexuses due to mechanical factors

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.This short opinion aimed to present the evidence to support our hypothesis that vulvodynia is a neuroinflammatory pain syndrome originating in the pelvic visceral nerve plexuses caused by the failure of weakened uterosacral ligaments (USLs) to support the pelvic visceral nerve plexuses, i.e., T11-L2 sympathetic and S2-4 parasympathetic plexuses. These are supported by the USLs, 2 cm from their insertion to the cervix. They innervate the pelvic organs, glands, and muscles. If the USLs are weak or lax, gravitational force or even the muscles may distort and stimulate the unsupported plexuses. Inappropriate afferent signals could then be interpreted as originating from an end-organ site. Activation of sensory visceral nerves causes a neuro-inflammatory response in the affected tissues, leading to neuroproliferation of small peripheral sensory nerve fibers, which may cause hyperalgesia and allodynia in the territory of the damaged innervation. Repair of the primary abnormality of USL laxity, responsible for mechanical stimulation of the pelvic sensory plexus, may lead to resolution of the pain syndrome.info:eu-repo/semantics/publishedVersio

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors

Diaphragmatic Neurophysiology and Respiratory Markers in ALS

The main reason for short survival in amyotrophic lateral sclerosis (ALS) is involvement of respiratory muscles. Severe compromise of diaphragmatic function due to marked loss of motor units causes poor inspiratory strength leading to symptomatic respiratory fatigue, and hypercapnia and hypoxemia, often firstly detected while sleeping supine. Weakness of expiratory muscles leads to cough weakness and poor bronchial clearance, increasing the risk of respiratory infection. Respiratory tests should therefore encompass inspiratory and expiratory function, and include measurements of blood gases during sleep. Non-volitional tests, such as phrenic nerve stimulation, are particularly convenient for investigating respiratory function in patients unable to perform standard respiratory function tests due to poor cooperation or facial weakness. However, SNIP is a sensitive test when patients with bulbar involvement are able to perform the necessary maneuvers. It is likely that central respiratory regulation is disturbed in some ALS patients, but its evaluation is more complex and not regularly implemented. Practical tests should incorporate tolerability, sensitivity, easy application for regular monitoring, and prognostic value. Impending respiratory failure can cause increased circulating inflammatory markers, but molecular assessment of respiratory distress requires further study. In future, home-monitoring of patients with accessible devices should be developed

Mirror movements: a simple algorithm for mirror activity signal processing and normative values

© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Mirror activity is an involuntary activation of a muscle when the respective contralateral muscle is contracting. This phenomenon has been described primarily in children and in disease states, and, more recently, also in healthy adults. Different ways of assessing mirror activity have been described. In this work we propose a simple protocol for quantifying the amount of mirror activity during a brief isolated full force isometric contraction of a given muscle. The signal was analyzed by a custom-built algorithm that detects the beginning and the end of muscle contraction. The amount of EMG signal on the mirror muscle in relation to the amount of EMG signal of the active muscle is then calculated. We studied 57 right-handed healthy subjects. Mirror activity was evaluated in the Abductor digiti minimi (ADM) and Tibialis anterior (TA) muscles during a 2-3 seconds full force isometric contraction. The intensity of mirror movement was represented as a percentage of the signal from maximal voluntary contraction. The performance of the algorithm for the detection of the beginning of muscle contraction was very good, when compared to 2 human operators. Intraclass correlation coefficient was excellent (0.998). The Bland-Altman plots showed similar performances of the algorithm and the human operators. We found a significant correlation of mirror activity with intensity and age. There was significantly more intense mirror activity in the left limbs (non-dominant) when compared to the right limbs. The upper limits of normality for mirror EMG signal was 27.4% for right ADM, 15.4% for left ADM, 10.4% for right TA and 2.1% for left TA. This simple protocol allows for an objective measurement of the amount of mirror activity. We propose this technique for investigation of neurological disorders.This work was funded by the project “Spinal circuitry in Motor Neuron Disease: Changes in Spinal and Corticospinal Mechanisms in Amyotrophic Lateral Sclerosis and its variants” (sponsored by Biogen Inc).info:eu-repo/semantics/publishedVersio

Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies

Dominant mutations in the skeletal muscle ryanodine receptor (RYR1) gene are well-recognized causes of both malignant hyperthermia susceptibility (MHS) and central core disease (CCD). More recently, recessive RYR1 mutations have been described in few congenital myopathy patients with variable pathology, including multi-minicores. Although a clinical overlap between patients with dominant and recessive RYR1 mutations exists, in most cases with recessive mutations the pattern of muscle weakness is remarkably different from that observed in dominant CCD. In order to characterize the spectrum of congenital myopathies associated with RYR1 mutations, we have investigated a cohort of 44 patients from 28 families with clinical and/or histopathological features suggestive of RYR1 involvement. We have identified 25 RYR1 mutations, 9 of them novel, including 12 dominant and 13 recessive mutations. With only one exception, dominant mutations were associated with a CCD phenotype, prominent cores and predominantly occurred in the RYR1 C-terminal exons 101 and 102. In contrast, the 13 recessive RYR1 mutations were distributed evenly along the entire RYR1 gene and were associated with a wide range of clinico-pathological phenotypes. Protein expression studies in nine cases suggested a correlation between specific mutations, RyR1 protein levels and resulting phenotype: in particular, whilst patients with dominant or recessive mutations associated with typical CCD phenotypes appeared to have normal RyR1 expression, individuals with more generalized weakness, multi-minicores and external ophthalmoplegia had a pronounced depletion of the RyR1 protein. The phenomenon of protein depletion was observed in some patients compound heterozygous for recessive mutations at the genomic level and silenced another allele in skeletal muscle, providing additional information on the mechanism of disease in these patients. Our data represent the most extensive study of RYR1-related myopathies and indicate complex genotype-phenotype correlations associated with mutations differentially affecting assembly and function of the RyR1 calcium release channe