Nusinersen treatment in adults with severe spinal muscular atrophy: A real-life retrospective observational cohort study.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease due to homozygous loss-of-function of the survival motor neuron gene SMN1 with absence of the functional SMN protein. Nusinersen, a costly intrathecally administered drug approved in 2017 in Europe, induces alternative splicing of the SMN2 gene, which then produces functional SMN protein, whose amount generally increases with the number of SMN2 gene copies. METHODS: We retrospectively collected data from consecutive wheelchair-bound adults with SMA managed at a single center in 2018-2020. The following were collected at each injection, on days 1, 14, 28, 63, 183, and 303: 32-item Motor Function Measurement (MFM) total score and D2 and D3 subscores; the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores; and lung function tests. The patients were divided into two groups based on whether their MFM total score was

Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies.

BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.

Increased incidence of Campylobacter jejuni-associated Guillain-Barré syndromes in the Greater Paris area.

The role of Campylobacter jejuni as the triggering agent of Guillain-Barré syndrome (GBS) has not been reassessed since the end of the 1990s in France. We report that the number of C. jejuni-related GBS cases increased continuously between 1996 and 2007 in the Paris region (mean annual increment: 7%, P = 0·007).

Be careful about abdominal discomfort in adult patients with muscular dystrophy.

Muscular dystrophies are genetic muscular disease with disability. Heart failure is a classical complication mainly in Duchenne muscular dystrophy (DMD). We report 2 cases of severe acute heart failure revealed by abdominal discomfort in a patient with DMD and in a patient with gamma-sarcoglycanopathy.

Strength of shock-loaded single-crystal tantalum [100] determined using in situ broadband x-ray Laue diffraction.

The strength of shock-loaded single crystal tantalum [100] has been experimentally determined using in situ broadband x-ray Laue diffraction to measure the strain state of the compressed crystal, and elastic constants calculated from first principles. The inferred strength reaches 35 GPa at a shock pressure of 181 GPa and is in excellent agreement with a multiscale strength model [N. R. Barton et al., J. Appl. Phys. 109, 073501 (2011)], which employs a hierarchy of simulation methods over a range of length scales to calculate strength from first principles.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

[Heart involvement in sarcoglycanopathies]. / Cœur et sarcoglycanopathies.

Sarcoglycanopathies (SG) are autosomic recessive muscular dystrophies, secondary to mutations of the sarcoglycan complex. Clinical pictures include muscle weakness affecting mainly the proximal limb girdle musculature. We review heart involvement in this group of disease.

Development of a GIS method to localize critical source areas of diffuse nitrate pollution.

The present study aimed at developing a universal method for the localization of critical source areas (CSAs) of diffuse nitrate (NO3-) pollution in rural catchments with low data availability. Based on existing methods, land use, soil, slope, riparian buffer strips and distance to surface waters were identified as the most relevant indicator parameters for diffuse agricultural NO3- pollution. The five parameters were averaged in a GIS-overlay to localize areas with low, medium and high risk of NO3- pollution. A first application of the GIS approach to the Ic catchment in France, showed that identified CSAs were in good agreement with results from river monitoring and numerical modelling. Additionally, the GIS approach showed low sensitivity to single parameters, which makes it robust to varying data availability. As a result, the tested GIS-approach provides a promising, easy-to-use CSA identification concept, applicable for a wide range of rural catchments.

Tongue weakness is associated with respiratory failure in patients with severe Guillain-Barré syndrome.

OBJECTIVE: Swallowing impairment may worsen respiratory weakness and conduct to respiratory complications such as aspiration pneumonia in Guillain-Barré syndrome (GBS). We prospectively evaluate how tongue weakness could be associated to bulbar dysfunction and respiratory weakness in severe GBS patients. MEASUREMENTS AND MAIN RESULTS: Tongue strength, dysphagia and respiratory parameters were measured in 16 GBS patients at intensive care unit (ICU) admission and discharge and in seven controls. Tongue strength was decreased in the GBS patients compared with the controls. At admission, patients with dysphagia and those requiring mechanical ventilation (MV) had greater tongue weakness. All the patients with initial tongue strength <150 g required MV during ICU stay. Tongue strength correlated significantly with respiratory parameters. CONCLUSION: This study confirms the strong association between bulbar and respiratory dysfunction in GBS admitted to ICU. Tongue weakness may be present in GBS, especially during the phase of increasing paralysis, and resolves during the recovery phase. Tongue strength and indices of global and respiratory strength vary in parallel throughout the course of GBS. Further studies are needed to assess if, when used in combination with other respiratory tests, tongue strength measurement could contribute to identify patients at high risk for respiratory complications.

Measuring inspiratory muscle strength in neuromuscular disease: one test or two?

Inspiratory muscle strength monitoring is crucial in patients with neuromuscular disorders. The sniff nasal inspiratory pressure (SNIP) and maximal inspiratory pressure (P(I,max)) are usually measured. The present study investigated whether the test yielding the best value at baseline continued to yield the best value during follow-up. The present study included 25 patients with Duchenne muscular dystrophy (DMD) and 61 with myotonic muscular dystrophy (MMD). SNIP and P(I,max) were measured at baseline and then annually. At baseline, SNIP was lower than P(I,max) in 20 (80%) DMD patients and 32 (52%) MMD patients. During follow-up in DMD patients, changes in the best method always occurred from SNIP to P(I,max). In MMD patients, when SNIP was better than P(I,max) at baseline, SNIP was usually (88%) better during follow-up, whereas a better P(I,max) than SNIP at baseline was frequently (50%) followed by a shift to SNIP. Maximal inspiratory pressure may be sufficient for monitoring inspiratory muscle function in Duchenne muscular dystrophy adults. In myotonic muscular dystrophy, the marked variability in the test yielding the best value at baseline indicates a need for performance of both tests at baseline. However, when sniff nasal inspiratory pressure measurement yields the best value at baseline, using sniff nasal inspiratory pressure alone during follow-up may be appropriate.

Complete atrioventricular block in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. It is characterized by progressive muscle wasting and weakness of variable distribution and severity. Heart is involved leading to heart failure. Conduction abnormalities are unusual. We report a case of complete atrio-ventricular block in a DMD patient.

Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders.

BACKGROUND: Chronic alveolar hypoventilation is a common complication of many neuromuscular and chest wall disorders. Long-term nocturnal mechanical ventilation is increasingly used to treat it. OBJECTIVES: To examine the efficacy of nocturnal mechanical ventilation in relieving hypoventilation related symptoms and in prolonging survival in people with neuromuscular or chest wall disorders. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to June 2006), and EMBASE (from January 1980 to June 2006) for randomised trials and contacted authors of trials and other experts in the field. SELECTION CRITERIA: We searched for quasi-randomised or randomised controlled trials of participants with neuromuscular or chest wall disorder-related stable chronic hypoventilation of all ages and all degrees of severity, receiving any type and any mode of nocturnal mechanical ventilation. The primary outcome measure was short-term and long-term reversal of hypoventilation related clinical symptoms and secondary outcomes were unplanned hospital admission, one year mortality, short-term and long-term reversal of daytime hypercapnia, improvement of lung function and sleep breathing disorders. DATA COLLECTION AND ANALYSIS: We identified eight randomised trials. MAIN RESULTS: The eight eligible trials included a total of 144 participants. The relative risk of 'no improvement of hypoventilation related clinical symptoms' in the short-term following nocturnal mechanical ventilation was available in only one trial with 10 participants and was not significant, 0.09 (95% confidence interval (CI) 0.01 to 1.31). The relative risk of 'no reversal of daytime hypercapnia' in the short-term following nocturnal ventilation was significant and favoured treatment, 0.37 (95% CI 0.20 to 0.65). The weighted mean difference of nocturnal mean oxygen saturation was 5.45% (95% CI 1.47 to 9.44) more improvement in participants treated with nocturnal mechanical ventilation. For most of the outcome measures there was no significant long-term difference between nocturnal mechanical ventilation and no ventilation. However, the estimated risk of death based on three studies was reduced following nocturnal ventilation, 0.62 (95% CI 0.42 to 0.91). There was considerable and significant heterogeneity between the trials possibly related to differences between the study populations. Most of the secondary outcomes were not assessed in the eligible trials. Data from two crossover trials suggested no evidence for a difference in reversal of daytime hypercapnia and sleep study parameters between volume-cycled and pressure-cycled ventilation. No data could be summarised for the comparisons between invasive and non-invasive mechanical ventilation or between intermittent positive pressure and negative pressure ventilation. AUTHORS' CONCLUSIONS: Current evidence about the therapeutic benefit of mechanical ventilation is weak, but consistent, suggesting alleviation of the symptoms of chronic hypoventilation in the short-term. In three small studies survival was prolonged mainly in participants with motor neuron diseases. With the exception of motor neuron disease, further larger randomised trials are needed to confirm long-term beneficial effects of nocturnal mechanical ventilation on quality of life, morbidity and mortality, to assess its cost-benefit ratio in neuromuscular and chest wall diseases and to compare the different types and modes of ventilation.

[Campylobacter jejuni and cytomegalovirus (CMV) infections in patients with the Guillain-Barre syndrome]. / Infections à Campylobacter jejuni et à cytomégalovirus (CMV) associées au syndrome de Guillain-Barré (SGB).

Guillain-Barre syndrome (GBS) is a rare disease triggered by postinfectious mechanisms. The disease concerns all ages, and is widely distributed around the world. The principal risks are respiratory failure, especially during the initial phase of the disease, and persisting deficit at long term. Among the infectious known agents, Campylobacter jejuni and CMV represent more than 40% of GBS causes. The clinical presentation, and the long-term prognosis of GBS related to these two etiologies are different. The physiopathological mechanisms of the nervous attack are probably also different. There is no proof, at this time, that anti-infectious treatment can improve the prognosis. The treatment is based on the early use of immunomodulatory treatments like intravenous immunoglobulins or plasma exchanges.

[Long term domiciliary mechanical ventilation in patients with neuromuscular disease (indications, establishment and follow up)]. / Ventilation mécanique a domicile et au long cours des patients neuromusculaires (indication, mise en place et surveillance).

UNLABELLED: Neuromuscular diseases represent a heterogeneous group of pathologies which common feature is the development of a restrictive ventilatory failure. BACKGROUND: Respiratory insufficiency of neuromuscular origin manifests itself by functional symptoms that must be carefully searched for in the history, such as headaches, sleep disorders, or dyspnoea of effort, sometimes very mild, or in severe cases associated with orthopnoea. Follow up should be multi-disciplinary. On the respiratory level regular measurement of blood gases, vital capacity, maximum inspiratory and expiratory pressures as well as sleep studies, will detect the criteria for mechanical ventilation (hypercarbia > 45 mm Hg, nocturnal desaturation < 88%, vital capacity < 60%, PImax < 60 cm H2O). STATE OF THE ART: The establishment of mechanical ventilation is a major decision for patients with neuromuscular disease because of the important physical, psychological, social and sometimes financial consequences. The patients and their family must be instructed precisely in order to obtain the best possible observation and compliance. The establishment requires a stay in hospital of several days to optimise the choice of ventilator, its settings, and connections. The link with the organisation managing the domiciliary ventilation is fundamental in ensuring follow up after discharge from hospital. Techniques of cough assistance must be taught to each neuromuscular patient requiring mechanical ventilation. CONCLUSION: Ventilation of neuromuscular patients requires careful evaluation of the indications and rigorous follow up by a multidisciplinary team with wide experience of this type of disease.

[Respiratory and intensive care aspects of muscular dystrophies]. / Aspects respiratoires et réanimatoires des dystrophies musculaires.

Among the various myopathies, Duchenne muscular dystrophy represents the myopathy with the most stereotypical respiratory evolution. This progressive respiratory failure is going to develop in a parallel way of motor deficit, conducting patients to mechanical ventilation at the end of their second decade. In the absence of curative therapeutics, respiratory cares like home ventilation and prevention of respiratory complications, in a systematic and organized way, allowed to decrease the morbidity and the mortality of these patients. It is not exceptional to meet patients with life expectancy of which overtakes about forty. Besides axial stabilization, cough assistance techniques and swallowing disorders management need to be associated to mechanical ventilation. Invasive techniques of ventilation as tracheostomy keep their place in this pathology even if alternative techniques allowing full day non-invasive ventilation were generalized these last years.

Monocyte chemoattractant protein 1 and chemokine receptor CCR2 productions in Guillain-Barré syndrome and experimental autoimmune neuritis.

Infiltration of activated lymphocytes and monocytes is a key phenomenon in the pathogenesis of Guillain-Barré syndrome (GBS) and experimental autoimmune neuritis (EAN). To investigate the role of chemokines, we determined the blood and nerve tissue expression of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, and its receptor CCR2 in GBS and EAN. MCP-1 circulating levels (ng/ml) in GBS were increased at the time of progression, peaked at the time of plateau and normalized with recovery. MCP-1 circulating levels were the highest in the most disabled patients. The number of circulating CCR2 positive cells was lower in patients with GBS than in healthy subjects (p<0.004). In GBS, MCP-1 expression was observed in epineurial and endoneurial vessels, on infiltrating cells, Schwann cells and in the endoneurial extracellular matrix. Some CCR2 positive cells were observed in nerve biopsies of GBS patients. In EAN, a slight positivity for MCP-1 was observed in the sciatic nerve. There was no circulating CCR2 positive cells. However, at the time of plateau, a conspicuous infiltration of CCR2 positive cells was observed in the sciatic nerve that was no longer observed at the time of recovery. These results suggest that MCP-1 and CCR2 may participate to the recruitment of circulating mononuclear cells in nerve tissue in EAN and GBS.

A comparison of recording modalities of P300 event-related potentials (ERP) for brain-computer interface (BCI) paradigm.

AIMS OF THE STUDY: A brain-computer interface aims at restoring communication and control in severely disabled people by identification and classification of EEG features such as event-related potentials (ERPs). The aim of this study is to compare different modalities of EEG recording for extraction of ERPs. The first comparison evaluates the performance of six disc electrodes with that of the EMOTIV headset, while the second evaluates three different electrode types (disc, needle, and large squared electrode). MATERIAL AND METHODS: Ten healthy volunteers gave informed consent and were randomized to try the traditional EEG system (six disc electrodes with gel and skin preparation) or the EMOTIV Headset first. Together with the six disc electrodes, a needle and a square electrode of larger surface were simultaneously recording near lead Cz. Each modality was evaluated over three sessions of auditory P300 separated by one hour. RESULTS: No statically significant effect was found for the electrode type, nor was the interaction between electrode type and session number. There was no statistically significant difference of performance between the EMOTIV and the six traditional EEG disc electrodes, although there was a trend showing worse performance of the EMOTIV headset. However, the modality-session interaction was highly significant (P<0.001) showing that, while the performance of the six disc electrodes stay constant over sessions, the performance of the EMOTIV headset drops dramatically between 2 and 3h of use. Finally, the evaluation of comfort by participants revealed an increasing discomfort with the EMOTIV headset starting with the second hour of use. CONCLUSION: Our study does not recommend the use of one modality over another based on performance but suggests the choice should be made on more practical considerations such as the expected length of use, the availability of skilled labor for system setup and above all, the patient comfort.