French National Protocol for genetic of amyotrophic lateral sclerosis.

Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.

Primary Lateral Sclerosis: Clinical, radiological and molecular features.

Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category 'probable' PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.

Adaptive functional reorganization in amyotrophic lateral sclerosis: coexisting degenerative and compensatory changes.

BACKGROUND AND PURPOSE: Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction. METHODS: Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study-group-specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures. RESULTS: Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self-initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato-cerebellar connectivity. CONCLUSIONS: Our findings indicate that, despite the dysfunction of SMA-striatal and SMA-cerebellar networks, cerebello-striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.

Botulinum toxin therapy improves masseter spasticity in Amyotrophic Lateral Sclerosis.

Fifteen ALS patients, with troublesome symptoms linked to masseter spasticity, benefited from BoNT-A injections in each masseter. Based on the medical records of patients, the effect of the first injection was assessed one month later. We retrospectively collected information for 12 patients. Eight of them reported a beneficial effect after the injection for the following symptoms: trismus, tongue, lip and cheek biting, and jaw clonus. Five patients indicated that dental care was easier after injection. Our study showed that injections of BoNT-A unequivocally reduced masseter spasticity in ALS patients who subsequently enjoyed greater comfort in their daily living.

Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy.

Kennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by expansion of a CAG repeat sequence in exon 1 of the androgen receptor gene (AR) encoding a polyglutamine (polyQ) tract. The polyQ-expanded AR accumulates in nuclei, and initiates degeneration and loss of motor neurons and dorsal root ganglia. While the disease has long been considered a pure lower motor neuron disease, recently, the presence of major hyper-creatine-kinase (CK)-emia and myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide range of clinical manifestations. The disease, which affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs, and bulbar involvement. Sensory disturbances are associated with the motor phenotype, but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats taken as pathogenic. Despite several therapeutic attempts made in mouse models, no effective disease-modifying therapy is yet available, although symptomatic therapy is beneficial for the management of the weakness, fatigue and bulbar symptoms.

Biomarkers in amyotrophic lateral sclerosis: combining metabolomic and clinical parameters to define disease progression.

BACKGROUND AND PURPOSE: The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined clinical and metabolomic parameters and independently to validate predictive models. METHODS: In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with (1)H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1-year prospective follow-up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort. RESULTS: The best-fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS. CONCLUSION: Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug's clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers. METHODS: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking. RESULTS: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected. CONCLUSION: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.

Comparative analysis of targeted metabolomics: dominance-based rough set approach versus orthogonal partial least square-discriminant analysis.

BACKGROUND: Metabolomics is an emerging field that includes ascertaining a metabolic profile from a combination of small molecules, and which has health applications. Metabolomic methods are currently applied to discover diagnostic biomarkers and to identify pathophysiological pathways involved in pathology. However, metabolomic data are complex and are usually analyzed by statistical methods. Although the methods have been widely described, most have not been either standardized or validated. Data analysis is the foundation of a robust methodology, so new mathematical methods need to be developed to assess and complement current methods. We therefore applied, for the first time, the dominance-based rough set approach (DRSA) to metabolomics data; we also assessed the complementarity of this method with standard statistical methods. Some attributes were transformed in a way allowing us to discover global and local monotonic relationships between condition and decision attributes. We used previously published metabolomics data (18 variables) for amyotrophic lateral sclerosis (ALS) and non-ALS patients. RESULTS: Principal Component Analysis (PCA) and Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA) allowed satisfactory discrimination (72.7%) between ALS and non-ALS patients. Some discriminant metabolites were identified: acetate, acetone, pyruvate and glutamine. The concentrations of acetate and pyruvate were also identified by univariate analysis as significantly different between ALS and non-ALS patients. DRSA correctly classified 68.7% of the cases and established rules involving some of the metabolites highlighted by OPLS-DA (acetate and acetone). Some rules identified potential biomarkers not revealed by OPLS-DA (beta-hydroxybutyrate). We also found a large number of common discriminating metabolites after Bayesian confirmation measures, particularly acetate, pyruvate, acetone and ascorbate, consistent with the pathophysiological pathways involved in ALS. CONCLUSION: DRSA provides a complementary method for improving the predictive performance of the multivariate data analysis usually used in metabolomics. This method could help in the identification of metabolites involved in disease pathogenesis. Interestingly, these different strategies mostly identified the same metabolites as being discriminant. The selection of strong decision rules with high value of Bayesian confirmation provides useful information about relevant condition-decision relationships not otherwise revealed in metabolomics data.

Framework for integrated MRI average of the spinal cord white and gray matter: the MNI-Poly-AMU template.

The field of spinal cord MRI is lacking a common template, as existing for the brain, which would allow extraction of multi-parametric data (diffusion-weighted, magnetization transfer, etc.) without user bias, thereby facilitating group analysis and multi-center studies. This paper describes a framework to produce an unbiased average anatomical template of the human spinal cord. The template was created by co-registering T2-weighted images (N = 16 healthy volunteers) using a series of pre-processing steps followed by non-linear registration. A white and gray matter probabilistic template was then merged to the average anatomical template, yielding the MNI-Poly-AMU template, which currently covers vertebral levels C1 to T6. New subjects can be registered to the template using a dedicated image processing pipeline. Validation was conducted on 16 additional subjects by comparing an automatic template-based segmentation and manual segmentation, yielding a median Dice coefficient of 0.89. The registration pipeline is rapid (~15 min), automatic after one C2/C3 landmark manual identification, and robust, thereby reducing subjective variability and bias associated with manual segmentation. The template can notably be used for measurements of spinal cord cross-sectional area, voxel-based morphometry, identification of anatomical features (e.g., vertebral levels, white and gray matter location) and unbiased extraction of multi-parametric data.

Revisiting the spectrum of lower motor neuron diseases with snake eyes appearance on magnetic resonance imaging.

BACKGROUND AND PURPOSE: The 'snake eyes' sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors. METHODS: A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling. RESULTS: Twenty-nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow-up. CONCLUSION: The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.

271st ENMC international workshop: Towards a unifying effort to fight Kennedy's disease. 20-22 October 2023, Hoofddorp, Netherlands.

The workshop held in the Netherlands from October 20-22, 2023, united 27 scientists from academia, healthcare, and industry representing 11 countries, alongside four patient and charity representatives. Focused on Kennedy's Disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), the workshop aimed to consolidate knowledge, align on clinical trial designs, and promote participative medicine for effective treatments. Discussions emphasized KD's molecular mechanisms, highlighting its status as a neuromuscular disorder with motor neuron degeneration. Strategies for therapeutic intervention, including AR activity modulation and targeting post-translational modifications, were proposed. The need for diagnostic, prognostic, and target engagement biomarkers was stressed. Challenges in patient stratification and clinical trial recruitment were acknowledged, with the International KD/SBMA Registry praised for its role. The workshop concluded with a patient-focused session, underscoring challenges in KD diagnosis and the vital support provided by patient associations.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

[Radiation-induced neuropathies: collateral damage of improved cancer prognosis]. / Neuropathies post-radiques: un dommage collatéral chez les patients cancéreux long-survivants.

INTRODUCTION: Because of the improvement of cancer prognosis, long-term damages of treatments become a medical and public health problem. Among the iatrogenic complications, neurological impairment is crucial to consider since motor disability and pain have a considerable impact on quality of life of long cancer survivors. However, radiation-induced neuropathies have not been the focus of great attention. The objective of this paper is to provide an updated review about the radiation-induced lesions of the peripheral nerve system. STATE OF THE ART: Radiation-induced neuropathies are characterized by their heterogeneity in both symptoms and disease course. Signs and symptoms depend on the affected structures of the peripheral nerve system (nerve roots, nerve plexus or nerve trunks). Early-onset complications are often transient and late complications are usually progressive and associated with a poor prognosis. The most frequent and well known is delayed radiation-induced brachial plexopathy, which may follow breast cancer irradiation. Radiation-induced lumbosacral radiculoplexopathy is characterized by pure or predominant lower motor neuron signs. They can be misdiagnosed, confused with amyotrophic lateral sclerosis (ALS) or with leptomeningeal metastases since nodular MRI enhancement of the nerve roots of the cauda equina and increased cerebrospinal fluid protein content can be observed. In the absence of specific markers of the link with radiotherapy, the diagnosis of post-radiation neuropathy may be difficult. Recently, a posteriori conformal radiotherapy with 3D dosimetric reconstitution has been developed to link a precise anatomical site to unexpected excess irradiation. PERSPECTIVES AND CONCLUSION: The importance of early diagnosis of radiation-induced neuropathies is underscored by the emergence of new disease-modifying treatments. Although the pathophysiology is not fully understood, it is already possible to target radiation-induced fibrosis but also associated factors such as ischemia, oxidative stress and inflammation. A phase III trial evaluating the association of pentoxifylline, tocopherol and clodronate (PENTOCLO, NCT01291433) in radiation-induced neuropathies is now recruiting.

Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI.

Characterizing demyelination/degeneration of spinal pathways in traumatic spinal cord injured (SCI) patients is crucial for assessing the prognosis of functional rehabilitation. Novel techniques based on diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetization transfer (MT) imaging provide sensitive and specific markers of white matter pathology. In this paper we combined for the first time high angular resolution diffusion-weighted imaging (HARDI), MT imaging and atrophy measurements to evaluate the cervical spinal cord of fourteen SCI patients and age-matched controls. We used high in-plane resolution to delineate dorsal and ventrolateral pathways. Significant differences were detected between patients and controls in the normal-appearing white matter for fractional anisotropy (FA, p<0.0001), axial diffusivity (p<0.05), radial diffusivity (p<0.05), generalized fractional anisotropy (GFA, p<0.0001), magnetization transfer ratio (MTR, p<0.0001) and cord area (p<0.05). No significant difference was detected in mean diffusivity (p=0.41), T1-weighted (p=0.76) and T2-weighted (p=0.09) signals. MRI metrics were remarkably well correlated with clinical disability (Pearson's correlations, FA: p<0.01, GFA: p<0.01, radial diffusivity: p=0.01, MTR: p=0.04 and atrophy: p<0.01). Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord predicted the sensory disability whereas measures of MTR in the ventro-lateral spinal cord predicted the motor disability (ASIA score). However, diffusion metrics were not specific to the sensorimotor scores. Due to the specificity of axial and radial diffusivity and MT measurements, results suggest the detection of demyelination and degeneration in SCI patients. Combining HARDI with MT imaging is a promising approach to gain specificity in characterizing spinal cord pathways in traumatic injury.

[Research in amyotrophic lateral sclerosis: what is new in 2009?]. / La recherche sur la SLA en 2009 : compte rendu du groupe bibliographique de la coordination des centres SLA.

This paper, written by French amyotrophic lateral sclerosis (ALS) center experts, presents an update of recent advances in fundamental, epidemiological and clinical research in ALS based on a review of the literature between September 2008 and November 2009. Among other pathophysiological mechanisms, the role of stress of the endoplasmic reticulum and the importance of energetic metabolic disturbances have been underscored. In the field of genetics, research has been advanced through the identification of mutations of the gene FUsed in Sarcoma/Translated in LipoSarcoma (FUS/TLS) in individuals with familial and sporadic ALS. This gene is involved in the regulation of transcription, splicing and RNA transport, and has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration. A report showed that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and frontotemporal lobar degeneration with ubiquitin aggregates (FTLD-U), providing a new animal model that may help to better understand the pathophysiology and test new therapeutics. Beside genetic studies, several epidemiologic studies have investigated the role of environmental factors. A recent study suggests that smoking is a risk factor for developing ALS and it is hypothesized that this could occur through lipid peroxidation via formaldehyde exposure. From a neuroprotective perspective, trials with IGF-1, sodium valproate, coenzyme Q or glatiramer acetate have failed to demonstrate any beneficial effect. A study published in 2008 argued that lithium may have a neuroprotective effect in ALS mice and also in patients. However, two preclinical studies failed to replicate the neuroprotective effect of lithium in ALS mice. Therapeutic trials have been performed or are currently ongoing in Europe and North America. Their results have not yet been published.

[Update on fundamental and clinical research in amyotrophic lateral sclerosis]. / Actualités dans la recherche fondamentale et clinique sur la sclérose latérale amyotrophique.

This paper from a group of French experts in amyotrophic lateral sclerosis (ALS) presents an update of recent advances in fundamental, epidemiological and clinical research in ALS. Recent development in the pathogenesis of ALS suggests that motor neuron degeneration is a multifactorial and noncell autonomous process. Research has been advanced through the identification of the TAR-DNA-binding protein (TDP-43) as a common neuropathological marker of ALS and frontotemporal lobar degeneration with ubiquitin-positive inclusions. Recently, mutations in the TDP-43 gene have been described in individuals with familial and sporadic ALS. Fundamental research in ALS is expected to lead to the disclosure of new diagnostic markers and therapeutic targets. A small trial has suggested that lithium carbonate may slow ALS progression but larger trials will be needed to confirm these results.

Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year. MATERIALS AND METHODS: Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year. RESULTS: Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls (P = .004) compared with spinal cord atrophy (P = .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline (R = 0.56 for gray matter and R = 0.55 for spinal cord; P < .01). Prediction at 1 year with clinical scores (R2 = 0.54) was improved when including a combination of gray matter and white matter cross-sectional areas (R2 = 0.74). CONCLUSIONS: Although improvements over spinal cord cross-sectional areas were modest, this study suggests the potential use of gray matter cross-sectional areas as an MR imaging structural biomarker to monitor the evolution of amyotrophic lateral sclerosis.

[Classical and atypical clinical features in amyotrophic lateral sclerosis]. / Quels sont les signes cliniques, classiques et inhabituels, devant faire évoquer une sclérose latérale amyotrophique?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving primarily motor neurons in the cerebral cortex, brainstem and spinal cord. In the absence of any biological marker, the diagnosis of ALS is based on clinical analysis, combined with the results of electromyography. Consensus diagnosis criteria (El Escorial criteria) have been developed to define workable and internationally acceptable guidelines for the diagnosis of ALS. A combination of lower and upper motor neuron signs with evidence of spread within a region or to other regions is required. The diagnosis of ALS has been categorized into various levels of certainty depending on the presence of upper motor neuron and lower motor neuron signs together in the same topographical anatomic region (brainstem and cervical, thoracic or lumbosacral spinal cord). Clinical types and patterns of ALS have been defined. The emerging concept of "ALS plus" is characterized by the presence of atypical clinical features, e.g. extrapyramidal signs or dementia, in association with the classical phenotype of ALS. This paper reviews the classical and atypical clinical features of ALS.