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.

Care management in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disease characterized by progressive weakness of voluntary muscles of movement as well as those for swallowing, speech and respiration. In the absence of curative treatment, care can improve quality of life, prolong survival, and support ALS patients and their families, and also help them to anticipate and prepare for the end of life. Multidisciplinary management in tertiary centers is recommended in close collaboration with general practitioners, home carers and a dedicated health network. Patients' follow-up deals mainly with motor impairment and physical disability, adaptation, nutrition and respiratory function. Involvement of palliative care as part of the multidisciplinary team management offers patients the possibility of discussing their end of life issues. This review summarizes the different aspects of ALS care, from delivering the diagnosis to the end of life, and the organization of its management.

[Electrodiagnostic criteria for early diagnosis of bulbar-onset ALS: a comparison of El Escorial, revised El Escorial and Awaji algorithm]. / Apport de l'électromyogramme dans le diagnostic précoce des SLA à début bulbaire: comparaison des critères d'El Escorial, d'El Escorial modifiés et d'Awaji.

INTRODUCTION: Diagnosis of bulbar ALS is difficult at the early stage of the disease. According to guidelines, early diagnosis is better in view to optimize the management of affected patients. To improve the sensitivity without losing specificity of the prior criteria, the Board of Awaji has proposed modified electrodiagnostic criteria for ALS. The aim of this study was to evaluate the contribution of needle electromyography in early diagnosis of bulbar ALS by comparing the El Escorial criteria (EEC), Revised El Escorial Criteria (R-EEC) and Awaji algorithm (AA). METHODS: In a retrospective study, we analysed clinical and electrophysiological data of 46 patients followed in our center for a bulbar-onset ALS seen for the first time between January 2007 and February 2011. All these patients had bulbar-onset ALS probable or certain at the last follow-up. All data were collected during the first clinical examination and the first electrophysiological study. RESULTS: Mean age of the population was 69 (37-90years, sex ratio: 0.91). Using the EEC, 9 patients were diagnosed as definite or probable ALS at the first consultation. Applying the R-EEC, 13 patients were diagnosed as definite or probable ALS and using the AA, 23 patients were diagnosed as definite or probable ALS. The sensitivity of the EEC was 19.5%, the R-EEC was 28.2% and for AA was 49.98%. CONCLUSION: AA are more sensitive in early diagnosis of bulbar ALS compared to R-EEC with the contribution of ENMG and when fasciculations are considered as evidence of spontaneous activity. Such an approach can contribute to accelerate an optimal management of the disease. AA are a breakthrough in the diagnosis of ALS especially in the bulbar-onset forms.

[Subjectivity, decision and neurodegenerative diseases: reflexions on the role of the clinical psychologist in medical decision making]. / Subjectivité, décision et maladies neurodégénératives: réflexions sur la place du psychologue clinicien dans le processus décisionnel.

Should a patient be forced to accept a treatment, especially when suffering from a neurodegenerative disease? We argue that physicians, nurses and care givers should instead accept his or her choice in accordance with the principle that every patient is an autonomous person able to make a choice, even in case of declined cognition. Beside the legal obligation, we suggest a theoretical approach and focus on the practical impacts of the patient's decision. Our objective is to promote the value of ethical doubt and attentive listening to individual opinions, so as to improve the quality of the medical staff's work and reduce patients' distress when affected by fatal diseases.

[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.

[Epidemiology of amyotrophic lateral sclerosis]. / Epidémiologie de la SLA.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. Loss of pyramidal and anterior horn motor neurons leads to progressive limb weakness, disability, dysarthria, dysphagia and respiratory insufficiency with a progressive fatal course. The incidence of ALS ranges between 1.5 to 2.5 for 100,000 per year. Although there are familial cases of ALS, about 90% are sporadic and of unknown etiology. Several exogenous risk factors have been documented. However, no convincing evidence has demonstrated in a reproducible manner an association between an environmental or lifestyle risk factor and ALS. Disease duration varies considerably, ranging from a few months to 10-15 years with a mean survival of about 36 months. Prognostic factors such as age, site of disease onset, nutritional, functional and respiratory status at the diagnosis or delay between beginning of the disease and diagnosis have been reported but they appear to be insufficient to explain prognostic variability. These last 15 years, development of supportive care for ALS patients and management in ALS centers may have contributed to improve survival. Finally, ALS centres, and particularly French ALS centres, have developed databases to improve our knowledge of ALS, phenotypic characterization, more accurate phenotype-genotype correlations and thus contribute to new therapeutics developments.

[Mills' syndrome: a rare clinical entity]. / Syndrome de Mills: une entité clinique rare.

INTRODUCTION: Mills' syndrome is a rare motor neuron disease, initially described by Mills in 1900 as a progressive ascending or descending hemiplegia without significant sensory involvement. This syndrome is of uncertain nosological status, and is supposedly due to unilateral primary degeneration of corticospinal pathway. Some authors have suggested that it could represent a variant of primary lateral sclerosis. METHODS: We retrospectively studied the clinical and paraclinical data from eight patients with suspected Mills' syndrome hospitalized for diagnosis. RESULTS: For all patients, the clinical course was slowly progressive, with motor deficiency, unilateral pyramidal signs (or bilateral with asymmetry), without bulbar signs, fasciculations or sensory deficit. Final diagnosis was Mills' syndrome (n=3), primary lateral sclerosis (n=1), myelitis of unknown origin (n=2), progressive primary multiple sclerosis (n=1), and antiphospholipid syndrome (n=1). The main arguments for final diagnosis were brought by electrophysiology and brain and spinal MRI. CONCLUSION: Mills' syndrome is a rare clinical diagnosis, requiring exhaustive investigations.

[Psychological reactions to the announcement of a severe disease diagnosis: the amyotrophic lateral sclerosis example]. / Réactions psychologiques à l'annonce d'un diagnostic de maladie grave: spécificités de la SLA.

To face the traumatic shock after the announcement of a severe and fatal disease, patients build psychological defences that physician must identify and respect as long as they don't endanger the patient's psychological fate and his medical care. ALS patient's do not have any curative perspective thus they will try "to escape" using different strategies the traumatic reality, that they cannot integrate and control. The physician has to prove his understanding and empathy facing these psychological reactions that could become of pathological appearance. The physician has to progressively bring the patient to consult the clinical psychologist; however he has not to forget that he is equally responsible about the way the patient go though his disease.

[What physical therapy techniques can be used to improve airway freedom in amyotrophic lateral sclerosis?]. / Quelles sont les modalités de thérapie physique symptomatique incluant les techniques de désencombrement bronchique?

In individuals with ALS rehabilitation is mainly designed to prevent fatigue and contracture, to improve independence and activities for as long as possible, to optimize ability to live with the handicap, and finally to maximize quality of life. The functional impairment must be defined and physical therapy techniques have to be adapted to each patient and reevaluated frequently during the course of the disease. Various types of massage and exercise, monitored by a physical therapist are effective. Strengthening or endurance exercises are controversial as exercise may injure muscle fibres and motor neurons. Isometric exercise, short of fatigue, of unaffected muscles is recommended. Range of motion exercise is critically important for preventing contraction. Assistive and adaptative equipments are essential for maintaining the patient's activities of daily living and home equipment preserves independence. Several orthoses for hand, arm, foot or cervical weakness are available. A wheelchair is an important adaptative device when walking becomes too fatiguing or impossible. Choice for special options and features may require attention. Pulmonary complications are prevented with adapted techniques for bronchic obstruction. Based on the degree of weakness of limb and axial muscles six stages of functional impairment can be defined ranging from fully ambulatory in stage I to bedridden and totally dependent in stage VI. This staging provides a framework for physical therapy evaluation and guidance for appropriate rehabilitation in ALS patients.

[Treatment of progressive multiple sclerosis with monthly pulsed cyclophosphamide-methylprednisolone: predictive factors of treatment response]. / Association cyclophosphamide-méthylprednisolone en traitement de fond des scléroses en plaques de type progressif: facteurs prédictifs d'une réponse clinique.

INTRODUCTION: Cyclophospamide is used in the treatment of progressive multiple sclerosis. We were looking for predictive indicators of treatment response. MATERIAL AND METHODS: Forty-seven patients with secondary progressive multiple sclerosis and seven others with primary progressive received monthly infusions of cyclophosphamide (750mg/m2) and methylprednisolone (500mg). During the year before cyclophosphamide the EDSS had worsened one point in all patients with or without surimposed relapses. Evaluation was based on EDSS change at 6, 12, 24 months and 5 years. RESULTS: Among secondary progressive patients, 91 per 100 (43/47) were stable or improved at 12 months, 65 per 100 (26/40) at 24 months and 22 per 100 (5/23) at 5 years. Annual relapse rate decreased from 0.81 before treatment to 0.48 during treatment and 0.12 after treatment (p<0.001). At 24 months, efficacy was correlated to a progressive phase lasting less than 5 years (p<0.01) and to a rapid increase of EDSS of at least 2 points the year before treatment (p<0.05). There were no influences of age, EDSS and surimposed relapses at the beginning of treatment, and other immunoactive drugs administrated before cyclophosphamide. There was no significant difference in quality of response to treatment between patients with primary progressive and secondary progressive multiple sclerosis. CONCLUSION: Cyclophosphamide appears to be more efficient in early stage of progressive multiple sclerosis independently of age, relapses or neurological disability scale.

[Report of four women with Duchenne or Becker muscular dystrophy]. / A propos de quatre cas féminins de dystrophie musculaire de Duchenne et Becker.

INTRODUCTION: Duchenne and Becker muscular dystrophy are X-linked and affect mainly males. The authors report four female cases. EXEGESIS: Four patients presented muscular deficiency predominant to lower limbs and chronic disease. Female distrophinopathy is understandable by three mechanisms: Turner's syndrome, translocation X-chromosome with an autosome and skewed X-chromosome inactivation. CONCLUSION: Diagnosis of female Duchenne and Becker muscular dystrophy is really difficult if there is not male case in family.