Respiratory Function In Amyotrophic Lateral Sclerosis Research Articles

Regulation of the Innate Immune System as a Therapeutic Approach to Supporting Respiratory Function in ALS

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

Respiratory measurements and airway clearance device prescription over one year in amyotrophic lateral sclerosis

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of cough adjuncts which aim to increase cough strength are unknown. The primary aim of this study was to quantify declines in respiratory function in ALS using PCF, Sniff Nasal Inspiratory Pressure (SNIP) and Slow Vital Capacity (SVC). Secondary aims were to measure respiratory morbidity, audit the characteristics of those prescribed cough adjuncts, and compare outcomes between treated and untreated cohorts. Methods: A prospective, longitudinal, observational, cohort study evaluated respiratory measures, morbidity, and physical function in ALS patients at three monthly intervals, over one year. Patient and disease characteristics of those prescribed cough adjuncts were profiled at the time of device prescription. Results: one hundred and eight participants with mean age 62.1 ± 11.5 years participated. PCF declined rapidly at a rate of 124.8L/min/year (p < 0.001). SNIP, SVC (%predicted), and ALSFRS-R also declined significantly at rates of 18.72cmH2O, 17.49%, and 9.62 units per year respectively (p < 0.001). Thirty-two (29.6%) patients reported 56 incidences of chest infection and 21 died. Patients prescribed a cough adjunct (44.4%) had significantly lower average PCF, SNIP, SVC percent predicted, and ALSFRS-R (p < 0.001). Conclusions: This study identified a rapid rate of decline in PCF, a similar decline in SNIP, and slower declines in SVC and ALSFRS-R. Cough adjunct prescription was triggered by declining respiratory measures and recommended PCF thresholds, but also by respiratory symptoms. Chest infections were common in patients regardless of cough adjunct prescription and should be closely monitored.

Prognostic value of phrenic nerve conduction study in amyotrophic lateral sclerosis: Systematic review and meta-analysis

ObjectivesTo assess the prognostic value of phrenic nerve conduction (PNC) in amyotrophic lateral sclerosis (ALS). MethodsWe conducted a systematic review to identify studies reporting on PNC, and mortality and/or forced vital capacity (FVC) in patients with ALS. We searched Medline, EMBASE, and Web of Science. Two independent authors selected studies and extracted data. Risk of bias was assessed using the QUIPS tool. Hazard-ratios and correlation coefficients were pooled using a random effects generic inverse-variance model. Evidence quality was evaluated with GRADE. ResultsIn the pooled analysis, patients with CMAP-amplitude equal or below 0.4 mV are 2.021 more likely to die over the studied period (95%CI 1.161–3.522; I2 = 55.9%; 338 participants). CMAP-amplitude showed a moderate positive correlation with FVC (r = 0.400, 95%CI = 0.226–0.550; I2 = 69.77%; 381 participants). However, there was a weak negative correlation between CMAP-latency and FVC (r = −0.235; 95%CI = −0.447 to −0.024; I2 = 15.92%; 112 participants). ConclusionsThere is moderate-quality evidence that CMAP-amplitude of the PNC is correlated with FVC. Results favour a predictive value for mortality, but the risk of bias is high. SignificancePNC is a simple test that should be considered to assess respiratory function in ALS, especially in patients with bulbar involvement or cognitive impairment.

Phrenic nerve stimulation is more sensitive than ultrasound measurement of diaphragm thickness in assessing early ALS progression

To compare the assessment of respiratory decline with conventional tests, measurement of diaphragm compound muscle action potential (CMAP) to phrenic nerve stimulation and diaphragm thickness to ultrasound (US) investigation in amyotrophic lateral sclerosis (ALS) patients followed for a short period of time. We evaluated in 40 consecutive ALS patients, the clinical functional scale (ALSFRS-R), forced vital capacity (FVC), maximal voluntary ventilation (MVV), maximal inspiratory (MIP) and expiratory (MEP) pressures, sniff nasal inspiratory pressure (SNIP), Diaphragm-CMAP (latency and amplitude) and diaphragm US (maximal and minimal diaphragm thickness during full inspiration and expiration, respectively). Patients were evaluated at study entry and 4 months later. Clinical functional assessment (ALSFRS-R), MEP, SNIP, and Diaphragm-CMAP amplitude declined significantly. Conversely, FVC, MVV, MIP, and diaphragm thickness showed a non-significant decline. We found significant correlations between all variables measured at both evaluation times. In this study, we included patients who might be potentially eligible for a clinical trial and re-evaluated them within 4 months. In this short time, diaphragm thickness as assessed by US is not sensitive to detect changes. However, Diaphragm-CMAP amplitude was confirmed to be a sensitive non-volitional method to measure respiratory function in ALS.

Association of paraspinal and diaphragm denervation in ALS

Paraspinal EMG needle examination is commonly performed in amyotrophic lateral sclerosis (ALS) for diagnosis. Because lower motor neurons for axial muscles and diaphragm are located medially in the anterior horn, we tested if involvement of axial muscles is associated with diaphragm weakness in ALS. Forty-four ALS patients were included with ALSFRS greater than 20/40. We used needle EMG to search for signs of denervation in biceps, tibialis anterior, C6 and T5 paraspinal muscles, and intercostal and diaphragm muscles. We also evaluated phrenic nerve motor responses and forced vital capacity (FVC). We tested specificity, sensitivity, and discriminative strength (ROC analysis). Fibs-sw in C6 and T5 paraspinal muscles, as well as fibs-sw in diaphragm and intercostal muscles showed high specificity and positive predictive value for FVC<80%. Discriminative strength was good for all the above tests, as well as for phrenic nerve amplitude and ALSFRS regarding FVC<80%. Axial muscles denervation is related to diaphragm denervation and therefore to poor respiratory function in ALS. We suggest that medially located lower motor neurons are affected concurrently in ALS.

Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review)

To systematically review evidence bearing on the management of patients with amyotrophic lateral sclerosis (ALS). The authors analyzed studies from 1998 to 2007 to update the 1999 practice parameter. Topics covered in this section include slowing disease progression, nutrition, and respiratory management for patients with ALS. The authors identified 8 Class I studies, 5 Class II studies, and 43 Class III studies in ALS. Important treatments are available for patients with ALS that are underutilized. Noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole are particularly important and have the best evidence. More studies are needed to examine the best tests of respiratory function in ALS, as well as the optimal time for starting PEG, the impact of PEG on quality of life and survival, and the effect of vitamins and supplements on ALS. Riluzole should be offered to slow disease progression (Level A). PEG should be considered to stabilize weight and to prolong survival in patients with ALS (Level B). NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B) and to slow the decline of forced vital capacity (Level B). NIV may be considered to improve quality of life (Level C) [corrected].Early initiation of NIV may increase compliance (Level C), and insufflation/exsufflation may be considered to help clear secretions (Level C).