Early Respiratory Decline in Amyotrophic Lateral Sclerosis

By Pantelis P. Pavlakis, MD, PhD

Assistant Attending Neurologist, Hospital for Special Surgery, and Assistant Professor of Neurology, Weill Cornell Medical College

SYNOPSIS: Hypercapnia, a manifestation of early respiratory dysfunction, can be challenging to detect in amyotrophic lateral sclerosis (ALS) patients. Pulmonary function tests are helpful, but their specificity in detecting hypercapnia is low and their use is limited in patients with bulbar weakness. Specific symptoms, such as dyspnea at rest, dyspnea while talking, and use of medications for sleep, can be more reliable in detecting hypercapnia among ALS patients.

SOURCE: Michels S, Widmann P, Rapp D, et al. Predictive parameters of early respiratory decline in amyotrophic lateral sclerosis. Eur J Neurol 2022;29:3170-3176.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive upper and lower motor neuron loss and progressive weakness, including respiratory muscle weakness. Respiratory failure is a leading cause of morbidity and mortality among patients with ALS. Clinical features of early respiratory dysfunction include fatigue, daytime somnolence, cognitive symptoms, observed dyspnea, or accessory respiratory muscle.

Diagnostic tests that can detect respiratory dysfunction include pulmonary function tests (PFTs), such as forced vital capacity (FVC), slow vital capacity (SVC), peak cough flow (PCF), and peak inspiratory and expiratory flow. Arterial blood gas (ABG) testing and capnometry are other tests of respiratory function. However, these are not without limitations. PFT results can fluctuate; cognitive dysfunction, inability to form a tight lip seal because of facial weakness, or spasticity leading to impaired motor coordination can limit their use in ALS patients. Nocturnal hypercapnia, an earlier sign of respiratory dysfunction, cannot be detected by PFTs or ABG. Therefore, early detection of hypercapnia among patients with ALS can be challenging and relies upon the evaluation of symptoms. In this study, the authors evaluated different symptoms and tests (PFTs, ABG, and capnometry) as predictors of early hypercapnia among patients with ALS.

This study included consecutive inpatients with ALS (definite, probable, and possible, according to El Escorial criteria) admitted between September 2017 and August 2019. Use of mechanical or noninvasive ventilation (NIV), or severe cognitive dysfunction were exclusion criteria. Patients underwent nocturnal capnometry, followed by ABG, PFTs, and PCF the following morning. Hypercapnia was defined as arterial pCO₂ of ≥ 45 mmHg, mean pCO₂ of ≥ 47 mmHg, or maximum pCO₂ of ≥ 50 mmHg in nocturnal capnometry. Demographic information and disease-related clinical measures were recorded; patients also answered a 17-question yes/no questionnaire regarding respiratory symptoms.

A total of 109 patients (56 female and 53 male) with a mean age of 62.4 years were enrolled. Thirty-two patients (28.6%) had bulbar onset. Forty patients (36.7%) were hypercapnic. Among patients who underwent both capnometry and arterial blood testing, capnometry detected hypercapnia in 96% of patients as opposed to 38% detected by ABG. Hypercapnia tended to be more frequent in bulbar, compared to spinal, onset patients, although the difference was not statistically significant.

Compared to spinal onset patients, bulbar onset patients had statistically significantly higher median and arterial pCO₂ values and significantly lower FVC, forced expiratory volume (FEV1), and PCF. Among different PFTs, PCF was the most sensitive (87%) but the least specific (20%) measure in detecting hypercapnia. FEV1 had the highest specificity (65%; 95% confidence interval [CI], 45% to 84%) and had a sensitivity of 65% (95% CI, 45% to 80%) as well. Among evaluated symptoms, “dyspnea at rest” had the highest specificity of 95% (95% CI, 88% to 100%) and “dyspnea while talking” had a specificity of 75% (95% CI, 9% to 8%).

Patients with hypercapnia were nine times more likely to have dyspnea at rest (odds ratio, 9.0; 95% CI, 1.3 to 88.0). Feeling “tired at daytime” had the highest sensitivity 58% (95% CI, 40% to 76%) but lowest specificity 45% (95% CI, 32% to 58%). A logistic regression model showed that the likelihood of hypercapnia being present was 82% if all three questions (“dyspnea at rest,” “use of sleeping drugs,” and “dyspnea while talking”) were answered as “yes” as opposed to 26% if all three questions were answered as “no.”

COMMENTARY

Early detection of respiratory dysfunction in ALS is of great importance, since earlier initiation of treatment, such as NIV, can mitigate symptoms and prolong survival. The findings of this study suggest that hypercapnia, a manifestation of early respiratory dysfunction, can be challenging to detect; PFTs (PCF, FEV1, FVC) have high sensitivity but low specificity and their use is limited in subsets of ALS patients. Overnight capnometry is highly sensitive, more so than ABG, in detecting nocturnal hypercapnia but is not always practical in the everyday clinical setting. On the other hand, the presence of symptoms such as dyspnea at rest, dyspnea while talking, or use of medications for sleep, either alone or in combination, have a higher predictive value. The lack of association of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score with the presence of hypercapnia is of interest, likely reflecting the composition of the ALSFRS-R scale, as well as the fact that the onset of respiratory dysfunction in the course of the disease can vary among different patients.

This is an important study identifying predictors of hypercapnia in ALS, which easily can be ascertained while obtaining a history. This is particularly helpful in patients with bulbar weakness, in which PFTs are less reliable. However, this study included exclusively inpatients, which may not fully represent the clinical spectrum of ALS. In addition, the presence of respiratory comorbidities was not evaluated. Since ALS is a clinically heterogenous disease, individual patients’ clinical features should be considered in clinical decisions. Patients with coexisting cognitive dysfunction or predominantly upper motor neuron disease are subpopulations in which assessing respiratory function is challenging and may involve other mechanisms leading to respiratory dysfunction.