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Projeto de investigação
Comprehensive Evaluation of Circulating MicroRNA as Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis
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Phrenic nerve study as outcome in clinical trials for amyotrophic lateral sclerosis
Publication . Pinto, Susana; Carvalho, Mamede
Introduction: Respiratory tests are fundamental for monitoring respiratory function in ALS, and essential in clinical trials. Slow vital capacity (SVC) was canceled in some countries to prevent COVID-19 transmission. We aimed to test phrenic nerve motor responses as an option to SVC in clinical trials. Methodology: Patients followed-up in our unit were selected respecting inclusion criteria used elsewhere: possible/probable/definite disease; onset-age 18-80years; disease duration from disease duration ≤24months; body mass index (BMI)>20kg/m2; respiratory subscore of the revised ALS functional rating scale (ALSFRS-R)≥11; upright SVC ≥ 70%. We added normal phrenic responses (meanPhrenAmpl, ≥0.4mV). All patients were on riluzole. SVC and meanPhrenAmpl were recorded at study entry (T0) and 24 weeks later (T1). Decays were determined. Sample size was calculated for a treatment effect of 30% on the decay rate. Results: We included 317 ALS patients (191 males, 225 spinal-onset), mean onset-age 59.9 ± 10.7 (31-80)years, mean onset BMI 25.48 ± 3.2 (20.1-35)kg/m2, mean disease duration 10.5 ± 5.6 (1-24)months, mean ALSFRS-R 41.54 ± 4.3 (22-47) and respiratory subscore 11.83 ± 0.38 (11-12). MeanPhrenAmpl and SVC were weakly but significantly correlated at T0 and T1. At T1, MeanPhrenAmpl decayed 16.94 ± 16.45% and SVC 13.5 ± 16.86%. For the proposed drug effect, 174 and 272 patients would be needed to recruit using respectively meanPhrenAmpl and SVC decline as the primary outcome measurement (accepting no dropouts). Discussion: Contrary to SVC, meanPhrenAmpl is non-volitional and not associated with aerosolization risk. Lower recruitment number (98 patients less) would be needed, translating shorter inclusion period, trial length and costs, and probable lower missed data rate. MeanPhrenAmp is an alternative test in ALS clinical trials.
Compensatory metabolic and central respiratory drive mechanisms in ALS
Publication . Pinto, Susana; Swash, Michael; Carvalho, Mamede
Introduction: Airway pressure in the first 100 ms of an occluded inspiration (P0.1) evaluates respiratory center activity. Its increase compensates for respiratory muscle weakness in amyotrophic lateral sclerosis (ALS). We aimed to evaluate if an exhaustion over disease progression emerges. Methods: Consecutive ALS patients with P0.1 at baseline (T0) above 90th percentile for the whole population were included. There were two patient categories within this population: G1 patients had respiratory function tests (RFT) at T0 and 6 months later (T1); G2 patients were immediately adapted to noninvasive ventilation at T0. Functional ALS rating scale (ALSFRS) and its subscores, RFT including maximal inspiratory pressure (MIP), P0.1 percentage (%P0.1), P0.1/MIP, blood gas analyses, phrenic nerve motor amplitude and nocturnal pulsed oximetry (NPO) were compared at T0 between groups (Mann-Whitney U test) and longitudinal progression in G1 was assessed (Wilcoxon test). p < 0.05 was taken as significant. Results: Forty-nine patients were studied: 13 men, mean disease duration 17.1 ± 19.5 months, 21 with spinal-onset; 27 bulbar-onset; one with respiratory presentation. In G1, there was a progressive deterioration in all variables but P0.1/MIP did not significantly change (p = 0.394). PCO2 (p = 0.045) and bicarbonate ion (HCO3-p = 0.054) increased. In G2, the ALSFRS (p = 0.049) scores were lower, PCO2 (p = 0.057) and HCO3- (p = 0.016) higher, and reduced arterial oxygen saturation (SpO2<90%) at NPO (p = 0.007). Discussion: Patients with high central respiratory drive responses did not develop a short-term "exhaustion phenomenon". Both metabolic and central respiratory mechanisms interact to compensate for respiratory muscle weakness. The role of spasticity and the respiratory-metabolic-renal buffering system deserves further studies.
Percutaneous gastrostomy in amyotrophic lateral sclerosis: a review
Publication . Castanheira, André; Swash, Michael; Carvalho, Mamede
Amyotrophic lateral sclerosis (ALS) causes dysphagia and consequent poor nutrition. Sometimes enteral feeding is offered. Percutaneous endoscopic gastrostomy (PEG) is currently the technique of choice for enteral nutrition of these patients. This systematic review addresses the role of PEG and other enteral feeding techniques in maintaining ALS patients' survival and quality of life and in identifying prognostic factors for survival, in order to optimize their usefulness. We also evaluated the mortality of enteral feeding in the first 30 days after each procedure and its complications. Studies were retrieved from Pubmed, Google Scholar, and Cochrane databases, using the relevant keywords, and by hand search. The inclusion criteria were prospective and retrospective designs of studies of people with clinically diagnosed ALS in whom gastrostomy or nasogastric enteral feeding were used in management, published in English. Studies with sample sizes <40, or which focused on a specific gastrostomy technique utilizing less than 30 subjects were excluded in order to avoid small sample bias. We conclude that PEG is safe and probably prolongs survival in non-malnourished ALS patients. However, older age at onset, marked loss of weight or reduced body mass index from symptomatic onset, and marked respiratory dysfunction negatively influence the outcome after PEG insertion. The currently available evidence does not meaningfully address the impact of PEG on quality of life in ALS. The literature about other enteral feeding techniques is insufficient for reliable conclusions. The optimum time for PEG insertion and preferences for specific gastrostomy techniques also require more investigation.
Mouth occlusion pressure at 100ms (P0.1) as a respiratory biomarker in amyotrophic lateral sclerosis
Publication . Pinto, Susana; Swash, Michael; Carvalho, Mamede
Airway pressure in the first 100ms of an occluded inspiration (P0.1) evaluates the respiratory center activity, increasing in the presence of respiratory muscle weakness. It is uncertain if its activity can compensate for respiratory muscles weakness in amyotrophic lateral sclerosis (ALS). Methods: Consecutive ALS patients with P0.1 evaluated at first visit were included. Depending on P0.1 percentile, patients were divided in three groups: G1 (<25th percentile); G2 (25th-74th percentiles); G3 (≥75th percentile); two subgroups were further considered: SG0 (<10th percentile); SG1 (>90th percentile). Body mass index (BMI), functional ALS rating scale and its subscores, respiratory function tests, including forced vital capacity, maximal inspiratory (MIP) and expiratory pressures, percentage of P0.1 (%P0.1), blood gas analyses, phrenic nerve motor amplitude (MeanPhrenAmpl) were compared. P0.1/MIP and %P0.1 predictors were explored by linear and multinomial logistic regression analyses. p < 0.05 was considered as significant. Results: From the 497 patients included, 124 were in G1 and G3 each, 249 in G2, 49 in SG0 and SG1 each. G1 included more men, with higher BMI (p < 0.001). G3 had older women, with predominant bulbar phenotype (p < 0.001). Lower respiratory function (p < 0.05) was present in both groups. SG0 (%P0.1 < 51.73%, P0.1/MIP = 1.48 ± 1.02) had more spinal-onset men (p < 0.001) with lower MeanPhrenAmpl (p < 0.004). SG1 (P0.1 > 147.12, P0.1/MIP = 7.92 ± 4.62) predominantly included older patients (p = 0.033), women (p = 0.012), with lower MeanPhrenAmpl (p = 0.039). Discussion: ALS patients with respiratory failure can show high or low P01 values, related to phenotype. Possible central drive reactivity and exhaustion, and the role of respiratory-metabolic-renal buffering system should be further addressed.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/MEC-NEU/31195/2017