Clinical features of amyotrophic lateral sclerosis and their prognostic value.

In classic amyotrophic lateral sclerosis (ALS), the relative degree of impairment of cortical vs spinal motor neurons serving the different body regions is highly variable. This means that an accurate, systematic assessment of the patient's clinical presentation is essential for both the diagnosis and prognosis. The patient's phenotype, rate of disease progression, time of onset (if early) of respiratory failure and nutritional status all have prognostic value, and should be specified in the nosological classification of the disease.

Ethical considerations and palliative care in patients with amyotrophic lateral sclerosis: A review.

Amyotrophic lateral sclerosis (ALS) is not a curable disease, but it is treatable. By definition, much of the care provided to ALS patients is palliative, even though active life-sustaining strategies are available to prolong survival. Healthcare professionals must develop communication skills that help patients cope with the inexorable progression of the disease and the inevitability of death. Symptomatic treatments as well as respiratory insufficiency and nutritional life-sustaining therapies must be regularly evaluated as the disease progresses, without losing sight of the burden placed on the patient's non-professional caregivers. The decision-making process regarding tracheostomy with invasive ventilation (TIV) is of greater complexity. Providing full information is crucial. Several long interviews are necessary to explain, discuss and allow assimilation of the information. Also, physicians should be careful not to focus exclusively on the biomedical aspects of disease, as ALS patients generally welcome the opportunity to discuss end-of-life issues with their physicians. Psychological factors, education level and cognitive status (especially the level of executive dysfunction) have a major influence on their decisions. However, as many patients do not complete advance directives with regard to TIV, advance care planning may instead be suggested in anticipation of emergency interventions. This should be discussed by healthcare professionals and the patient, and based on the wishes of the patient and caregiver(s), and communicated to all healthcare professionals. Many healthcare professionals are involved in the management of an ALS patient: they include not only those at ALS centers who provide diagnosis, follow-up and treatment initiation (particularly for respiratory and nutritional care), but also the medical and social care networks involved in disability support and home care. Specialist palliative care teams can work in partnership with ALS centers early in the course of the disease, with the center coordinating information-sharing and collaborative discussions.

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.

The Borg dyspnoea score: a relevant clinical marker of inspiratory muscle weakness in amyotrophic lateral sclerosis.

The aim of the study was to determine whether the Borg dyspnoea scale could be a useful and simple marker to predict respiratory muscle weakness in amyotrophic lateral sclerosis (ALS). From April 1997 to 2001, respiratory function was perfomed in 72 patients together with the Borg score in both the upright (uBorg) and supine (sBorg) positions. Mean upright vital capacity (VC) was 81+/-24% predicted, sniff nasal inspiratory pressure (SNIP) was 55+/-26% pred, maximal inspiratory pressure (P(I,max)) was 57+/-26% pred and arterial carbon dioxide tension (P(a,CO(2))) was 41+/-6 mmHg. The mean Borg scores in the upright and supine positions were 1.7+/-1.5 and 2.2+/-2, respectively. A significant relationship between SNIP and uBorg (r = 0.4; p = 0.0007) and SNIP and sBorg (r = 0.58; p<0.0001) was observed. Upright VC, DeltaVC (measured as the supine fall in VC as a percentage of seated VC), P(I,max) and P(a,CO(2)) were significantly correlated with SNIP. A cut-off value of 3 on the sBorg scale provided the best sensitivity (80%) and specificity (78%) (area under the curve 0.8) to predict a SNIP < or =40 cmH(2)O, indicating severe inspiratory muscle weakness. Patients with a sBorg score > or =3 also exhibited significantly lower VC, P(I,max) and twitch mouth pressure during cervical magnetic stimulation, and slightly higher P(a,CO(2)) (43.7+/-7 versus 39.2+/-5 mmHg; p = 0.05). The Borg dyspnoea scale is a valuable noninvasive test for the prediction of inspiratory muscle weakness in ALS patients.

[Issues of France's "Leonetti Act": Involvement of amyotrophic lateral sclerosis patients in prior discussions concerning respiratory support and end-of-life care]. / Les enjeux de la loi Leonetti: participation des patients atteints de sclérose latérale amyotrophique à une discussion anticipée sur la réanimation respiratoire et les soins de fin de vie.

In accordance with the principle of personal autonomy, expert consensus statements on amyotrophic lateral sclerosis (ALS) recommend early engagement with terminal-phase patients on the type of symptomatic treatment to be administered in the event of respiratory failure, since decompensation progresses too rapidly to allow time for a discussion. The French Parliamentary Act on Patients' Rights and End-of-Life Care (dated 22 April 2005) grants individuals the right to refuse unreasonable treatment and obliges physicians to take account of any prior instructions given by a person before he/she became incapable of communicating. The provision of prior instructions is a very reassuring situation for the physician: the autonomous patient indicates his or her choice of end-of-life care. However, there are two pitfalls which must be avoided: (i) holding a discussion for the sole purpose of obtaining prior instructions and (ii) not acknowledging the patient's vulnerability. The present study dealt with 35 ALS patients for whom the question of either intensive care or palliative end-of-life care remained open. Even though the great majority of these individuals were keen to know their exact state of health, 48% refused to consider this circumstance and only 20% expressed prior instructions. These results prompted us to question the ethical dimension of the concept of autonomy beyond its founding formulation: can one envisage an incapacity to confront oneself with the existential question of possible death? In 80% of cases, the physician will have to take a care decision in the absence of any prior instructions from the patient. This amounts to more than respecting a person's autonomy and involves exercising medical responsibility.

[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.

Causes of death amongst French patients with amyotrophic lateral sclerosis: a prospective study.

BACKGROUND AND PURPOSE: To prospectively investigate causes of death and the circumstances surrounding death in 302 patients with amyotrophic lateral sclerosis (ALS). The functional status of patients immediately before death was also determined. METHODS: Information was obtained from neurologists at ALS centres, patients' files, and, when deaths occurred outside a medical facility, attending physicians. RESULTS: Most patients (63%) died in a medical facility. The most frequently reported cause of death was respiratory failure (77%), including terminal respiratory insufficiency (58%), pneumonia (14%), asphyxia due to a foreign body (3%) and pulmonary embolism (2%). Ten per cent of patients died from other causes: post-surgical or traumatic conditions (5%), cardiac causes (3.4%), suicide (1.3%) and sudden death of unknown origin (0.7%). The cause of death could not be determined in 13% of cases (6% inside a medical facility and 25% outside). At the time of death, only 55% of patients were receiving riluzole, 33% were undergoing non-invasive ventilation, 3% had a tracheotomy and 37% a gastrostomy. CONCLUSION: The information provided by this study helps to improve our understanding of the natural history of the disease and may help optimize the quality of care we can offer patients at the end of life.

MRI of the cervical spinal cord predicts respiratory dysfunction in ALS.

For patients with amyotrophic lateral sclerosis (ALS), the primary therapeutic goal is to minimize morbidity. Non-invasive ventilation improves survival. We aim to assess whether Magnetic Resonance Imaging (MRI) of the cervical spinal cord predicts the progression of respiratory disorders in ALS. Brain and spinal MRI was repeatedly performed in the SOD1G86R mouse model, in 40 patients and in healthy controls. Atrophy, iron overload, white matter diffusivity and neuronal loss were assessed. In Superoxide Dismutase-1 (SOD1) mice, iron accumulation appeared in the cervical spinal cord at symptom onset but disappeared with disease progression (after the onset of atrophy). In ALS patients, the volumes of the motor cortex and the medulla oblongata were already abnormally low at the time of diagnosis. Baseline diffusivity in the internal capsule was predictive of functional handicap. The decrease in cervical spinal cord volume from diagnosis to 3 months was predictive of the change in slow vital capacity at 12 months. MRI revealed marked abnormalities at the time of ALS diagnosis. Early atrophy of the cervical spinal cord may predict the progression of respiratory disorders, and so may be of value in patient care and as a primary endpoint in pilot neuroprotection studies.

FLAGdb/FST: a database of mapped flanking insertion sites (FSTs) of Arabidopsis thaliana T-DNA transformants.

A large collection of T-DNA insertion transformants of Arabidopsis thaliana has been generated at the Institute of Agronomic Research, Versailles, France. The molecular characterisation of the insertion sites is currently performed by sequencing genomic regions flanking the inserted T-DNA (FST). The almost complete sequence of the nuclear genome of A.thaliana provides the framework for organising FSTs in a genome oriented database, FLAGdb/FST (http://genoplante-info.infobiogen.fr). The main scope of FLAGdb/FST is to help biologists to find the FSTs that interrupt the genes in which they are interested. FSTs are anchored to the genome sequences of A.thaliana and positions of both predicted genes and FSTs are shown graphically on sequences. Requests to locate the genomic position of a query sequence are made using BLAST programs. The response delivered by FLAGdb/FST is a graphical representation of the putative FSTs and of predicted genes in a 20 kb region.

[Handicap and quality of life assessment in amyotrophic lateral sclerosis]. / Evaluation du handicap et de la qualité de vie dans la sclérose latérale amyotrophique.

Measures of handicap progression alone are insufficient for assessing what a patient experiences. Handicap results from the interaction between a person's disabilities and the social, familial and environmental factors which determine his or her living conditions. Other factors condition quality of life: of these, psychological and existential factors and an individual's ability to adapt play a fundamental role. Measuring handicap and quality of life must provide medical care providers with comprehensive knowledge of the way in which an individual experiences the disease, his or her handicap and the side effects and constraints of treatments within his or her own life context.

[Management and treatment of respiratory failure associated with amyotrophic lateral sclerosis]. / Surveillance et traitement des troubles respiratoires associés à la sclérose latérale amyotrophique.

INTRODUCTION: In amyotrophic lateral sclerosis (ALS), respiratory muscle involvement is highly predictive of survival and quality of life (QOL). There is compelling evidence that non invasive ventilation (NIV) prolongs survival by several months and improves QOL more than any other currently available treatment. Frequent testing of pulmonary function and regular evaluations are recommended since 1999 by the American Academy of Neurology in order to take appropriate treatment decisions. STATE OF ART: There are numerous tests available to evaluate respiratory status in ALS and it is important to know their sensitivity and specificity to recognize clinical risk situations. Some recent data suggest that sniff nasal pressure and maximal inspiratory pressure (MIP) can be performed reliably by most ALS patients and are more sensitive to decrements in inspiratory muscle strength than spirometry or arterial blood gasometry. PERSPECTIVES: Airway obstruction caused by ineffective coughing is the principal cause of intolerance to NIV. Several factors other than respiratory muscle strength may affect pulmonary function: postural changes, nutritional status, infectious disease, drugs. CONCLUSION: The neurologist has to coordinate multidisciplinary care, with attention to individual patient preferences, and with a frank and compassionate discussion between the patient, the family, the physicians and the caregivers.

[Cavernous angioma of the cervical spinal cord]. / Angiome caverneux de la moelle cervicale.

A 34-year old man gradually developed a paraparesis which spontaneously regressed within a few months. One year later, the patient suffered from acute torticollis immediately followed by flaccid tetraparesis with pyramidal signs, dissociated sensory deficit and acute retention of urine. Magnetic resonance imaging (MRI) showed, in the cervical cord, a vascular malformation that was not opacified at angiography. The lesion, a cavernous angioma, was surgically removed, leading to recovery. So far, thirty five cases of spinal cord angioma have been published, most of them since the advent of MRI which makes it possible to determine the exact incidence of this lesion, as well as its signs, symptoms and course.

[Klippel-Trenaunay syndrome and ischemic neurologic complications]. / Syndrome de Klippel-Trenaunay et complications neurologiques ischémiques.

In 1900 Klippel and Trenaunay defined a new entity characterized by cutaneous angioma associated with varices and hypertrophy of bone and soft tissues. The syndrome is present in the earliest years and becomes accentuated as the child grows. It typically affects one half of the body. We report two cases of Klippel-Trenaunay syndrome. The first patient presented with flaccid paraplegia. On T1-weighted MRI sequences a diffuse heterogeneous high-intensity signal was visible opposite the T8 and T9 vertebral bodies. Spinal cord angiography showed occlusion of the anterior spinal artery issued from Adamkiewicz's artery, suggesting thrombosis. Serum fibrinopeptide A level was very high and compatible with hypercoagulability. The second patient presented with left hemiplegia caused by a right superficial sylvian artery infarct, and carotid angiography showed an image of right internal carotid artery dissection. These two cases suggest that Klippel-Trenaunay syndrome includes a state of hypercoagulability facilitating the occurrence of arterial thrombotic accidents, and an abnormality of the arterial wall capable of determining spontaneous dissection. A study of arterial wall-dependent coagulation factors should establish a link between these two aetiological factors. All this argues in favor of a diffuse vascular pathology, which makes this syndrome close to phakomatoses.

Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations.

OBJECTIVE: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. METHODS: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. RESULTS: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). CONCLUSION: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.