[Proposals from a French expert panel for respiratory care in ALS patients]. / Propositions formulées par un groupe d'experts français concernant la prise en charge respiratoire chez les patients atteints de sclérose latérale amyotrophique.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres. METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel. RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients. CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.

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.

Proposals from a French expert panel for respiratory care in ALS patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres. METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel. RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients. CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.

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.

Segmental somatosensory-evoked potentials as a diagnostic tool in chronic inflammatory demyelinating polyneuropathies, and other sensory neuropathies.

PURPOSE OF THE STUDY: Somatosensory-evoked potentials with segmental recordings were performed with the aim of distinguishing chronic inflammatory demyelinating polyneuropathy from other sensory neuropathies. PATIENTS AND METHODS: Four groups of 20 subjects each corresponded to patients with (1) possible sensory chronic inflammatory demyelinating polyneuropathy, (2) patients with sensory polyneuropathy of unknown origin, (3) patients with amyotrophic lateral sclerosis and (4) normal subjects. The patients selected for this study had preserved sensory potentials on electroneuromyogram and all waves were recordable in evoked potentials. Somatosensory-evoked potentials evaluations were carried out by stimulation of the posterior tibial nerve at the ankle, recording peripheral nerve potential in the popliteal fossa, radicular potential and spinal potential at the L4-L5 and T12 levels, and cortical at C'z, with determination of distal conduction time, proximal and radicular conduction time and central conduction time. RESULTS: In the group of chronic inflammatory demyelinating polyneuropathy, 80% of patients had abnormal conduction in the N8-N22 segment and 95% had abnormal N18-N22 conduction time. In the group of neuropathies, distal conduction was abnormal in most cases, whereas 60% of patients had no proximal abnormality. None of the patients in the group of amyotrophic lateral sclerosis had an abnormal N18-N22 conduction time. CONCLUSION: Somatosensory-evoked potentials with segmental recording can be used to distinguish between atypical sensory chronic inflammatory demyelinating polyneuropathy and other sensory neuropathies, at the early stage of the disease. Graphical representation of segmental conduction times provides a rapid and accurate visualization of the profile of each patient.

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.

Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.

OBJECTIVE: We report the cases of 2 patients with late-onset spinal muscular atrophy (SMA) type III, who were hemizygous for SMN1 deletion and carriers of novel SMN1 intragenic missense mutations, and we investigate the genotype-phenotype relationship. METHODS: Patients were tested for SMN1 deletions with standard methodology. Sequencing of all exons, exon-intron junctions, and flanking sequences of SMN1 by nested PCR was used to detect intragenic point mutations. SMN1 and SMN2 quantification was undertaken to investigate the genotype-phenotype relationship. RESULTS: Two novel point mutations were identified in exon 3 of SMN1 (p.Tyr130Cys and p.Tyr130His) in the highly conserved Tudor domain of the Smn protein. CONCLUSIONS: The genetic basis of SMA in the rare cases of compound heterozygous carriers of SMN1 deletions is complex. Small intragenic SMN1 mutations often lead to severe SMA phenotypes, especially if the point mutations lie in exon 3 that codes for the highly conserved Tudor domain of the Smn protein. Although both our patients were carriers of intragenic SMN1 mutations in the coding region of the Tudor domain, they presented with a mild SMA phenotype despite a low SMN2 copy number. We discuss the possible determinant role of these novel missense mutations in the phenotypic outcome and compensatory mechanisms that may account for the genotype-phenotype discrepancy.

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

BACKGROUND: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. METHODS: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. RESULTS: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. CONCLUSIONS: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease.

BACKGROUND: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). METHODS: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. RESULTS: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. CONCLUSIONS: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden.

BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

[Breaking bad news during the course of amyotrophic lateral sclerosis: how and when]. / Contenu et modalités de l'annonce de l'évolution et des étapes de la maladie.

Operatory procedures can help to break bad news in ALS but the main goal of this unpleasant task stands in the quality of the relationship between the physician and his patient which must be preserved throughout the course of the disease. Plasticity is obviously the best way to characterize the appropriate kind of care in such a variable disease. The caregivers and the psychological factors must also be taken into account. As it is the case for therapeutic research, breaking bad news in ALS requieres a specific know-how which should be ideally performed by specialized teams within the framework of dedicated ALS centers.

A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length.

Our study aims to provide a comprehensive view of the endocrine features in Kennedy's disease (KD). Twenty-two men with KD underwent detailed endocrine investigations. Clinical signs of partial androgen resistance were present in more than 80% of the patients, with gynecomastia being the most prominent. Gynecomastia was postpubertal but appeared before muscular weakness in most cases. Thirteen patients had alteration of testicular exocrine function. Hormonal profile of partial androgen resistance was present in 86% of the patients, with an elevated testosterone level in 68%. Androgen insensitivity seems to appear later in life in KD, similar to the development of neurological signs. Although we confirm the previously reported correlation between the CAG repeat length and the early onset of the neurological disease, we describe a significant correlation between repeat length and the age of onset of gynecomastia as well as biological indexes of androgen insensitivity. This is supported by numerous in vitro data correlating variations in the CAG tract with androgen receptor activity; the longer the CAG repeats, the weaker the receptor transactivation. Ours is the first study to show such a clear and prominent pattern of androgen insensitivity in KD. In clinical practice, KD patients are often misdiagnosed as having amyotrophic lateral sclerosis. Careful examination of the endocrine component could avoid such a deleterious misdiagnosis.

[Tolerance of riluzole in a phase IIIb clinical trial]. / Tolérance du riluzole dans un essai ouvert (phase IIIb).

Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.

[Nocturnal oxymetry in patients with amyotrophic lateral sclerosis: role in predicting survival]. / Oxymétrie nocturne chez les patients atteints de sclérose latérale amyotrophique: analyse de son rôle prédictif sur la survie.

Death is the most important end point along the course of amyotrophic lateral sclerosis (ALS). It is commonly attributed to a respiratory failure in relation with a restrictive respiratory disorder. However, in clinical practice, it is frequent to observe that death has not direct relation with the values of the respiratory function, at least measured with vital capacity. It is also frequent that relatives report sudden death during nocturnal sleep. All these features raised the question of the possible relation between death and nocturnal oxymetry in ALS patients. In a prospective study, we studied 69 ALS patients. We recorded demographic data, clinical parameters as manual muscle testing and functional scales, various parameters of oxymetry measured by pulse oxymetry recorded during night, slow vital capacity and survival time. There is a strong correlation between survival time measured by Kaplan Meier curves and log rank and the mean nocturnal saturation. We determined 93 mmHg as a threshold value. Below this threshold, mean survival time was 7.5+/-1.6 months and above it was equal to 18.5+/-1.5; relative risk was 3.31. These data confirm the importance of nocturnal oxymetry on survival in ALS patients both in clinical practice and in view of therapeutic trials.

APOE: a potential marker of disease progression in ALS.

Although documented in AD, the role of APOE remains unclear in ALS. APOE phenotype and plasma levels were measured in 403 patients with ALS and were correlated with clinical parameters and survival time. No correlations were observed between the APOE phenotype and these variables. In contrast, APOE plasma levels were correlated with both rate of deterioration and survival time and appeared to be an important risk factor for decreased survival time with a relative risk of 0.647 (95% CI: 0.465 to 0.901; p = 0.01).

Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature.

The question of whether primary lateral sclerosis (PLS) is a nosological entity distinct from amyotrophic lateral sclerosis (ALS) has been the subject of controversy since it was first described in the nineteenth century. PLS has been defined as a rare, non-hereditary disease characterized by progressive spinobulbar spasticity, related to the selective loss of precentral pyramidal neurones, with secondary pyramidal tract degeneration and preservation of anterior horn motor neurones. In the recent clinical literature, the frontier between ALS and neurodegenerative disease remains poorly defined. We studied 20 patients with a diagnosis of PLS. We carried out a variety of tests in order to determine the presence of a more diffuse neurodegenerative process. We also performed a longitudinal electrophysiological evaluation. Our clinical, electrophysiological and pathological investigations provide evidence that the disease has a heterogeneous clinical presentation and that degeneration is not restricted to the central motor system.