Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

OBJECTIVE: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation. METHODS: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level. RESULTS: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome. INTERPRETATION: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.

Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.

Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis.

Direct laryngoscopy should be procedure of choice in the airway management of patients with dental cellulitis.

CONTEXT: Airway management of patients with dental cellulitis can be difficult due to laryngeal deviation and oedema. Awake fibre-optic intubation has been recommended. OBJECTIVE: The aim of this study was to assess our routine procedure which is based mainly on direct laryngoscopy. DESIGN: This was a prospective observational study. SETTING: In a single centre between February 2008 and February 2009. PATIENTS: All patients suffering from dental cellulitis and requiring emergency surgery were included except pregnant women and patients under 18 years. INTERVENTION: Nasotracheal intubation by direct laryngoscopy under general anaesthesia was performed unless the supine position was not tolerated, or difficult mask ventilation or intubation was anticipated, when awake nasotracheal fibre-optic intubation was indicated. In the case of failure at the first attempt, orotracheal intubation by direct laryngoscopy was attempted. If failure persisted, tracheotomy was then performed. MAIN OUTCOME MEASURES: The principal endpoint was the incidence of difficult mask ventilation which was expected to be less than 5%. Secondary endpoints were the incidence of difficult tracheal intubation and tracheotomy. RESULTS: We included 127 consecutive patients (mouth opening 20±10 mm). One did not tolerate the supine position and was successfully intubated using the fiberscope. Among the 126 remaining, difficult mask ventilation did not occur [0%, 95% confidence interval (CI) 0-3%], 124 (98%) patients were intubated by direct laryngoscopy and two (2%) required tracheotomy. Retrognathia (odds ratio 8.2, 95% CI 1.3-50.1) and extension to oral floor (odds ratio 15.1, 95% CI 1.8-129.5) were significantly associated with the prediction of intubation failure at the first attempt. CONCLUSION: Most patients with dental cellulitis can be safely intubated through direct laryngoscopy even if mouth opening is limited.