Respiratory Function Changes as Early Signs of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a debilitating neurological disorder involving the degeneration of motor neurons. Paralysis is progressive, and the average time to death from symptom onset is 3–5 years. Definitive diagnosis of ALS is based on criteria described by the El Escorial World Federation of Neurology and involves the clinical history, physical examination, and electrodiagnostic, neuroimaging, and laboratory studies [1, 2]. The disease is labeled as “possible,” “probable,” or “definite” ALS, and this assessment requires a longitudinal follow-up of the patient. To date, there is a lack of a marker or a single diagnostic test that can confirm the diagnosis of ALS. Respiratory muscle weakness has been described as the first manifestation of the disease in only 1–3% of patients. While most ALS patients early in their disease course may not have dyspnea at rest, it may become apparent with physical activity or is highlighted by diagnostic procedures, suggesting that the onset of respiratory muscle involvement may occur early during the onset of the disease [3]. However, pulmonary assessment has never been considered useful in the early diagnosis of ALS, and studies of pulmonary function in this patient category are lacking. This study aimed to assess the pulmonary function in subjects with unspecific symptoms in whom the diagnosis of ALS was only possible in the 2 years following the initial visit and to evaluate if any pulmonary function data in patients with unspecific findings of motor neuron disease might prompt a tighter follow-up for ALS.

The subjects gave their written informed consent, and the study protocol (“PRESLA”) was approved by the Local Ethics Committee “Campania Sud” (No. 215/COV, June 9, 2022). All the subjects were recruited between 2013 and 2017 at the Pulmonary Division of “M. Scarlato” Hospital in Scafati, Italy, and grouped into three categories according to standard ALS criteria [2]: established ALS (n = 29); 415 patients who had been referred to the Pulmonary Function (PF) Laboratory over 5 years, being asymptomatic at rest but reporting fatigue during physical activities, together with shortness of breath or inability to take deep breaths; in none of these patients, an ALS diagnosis was possible, at the time of the PFTs, based on the currently available diagnostic tools and guidelines [2] due to lack of specific ALS symptoms and/or signs. Of these 415 subjects, 35 were diagnosed with ALS within the following 2 years from the initial PF assessment, and we will refer to this group as “pre-ALS.” We compared this group with 28 control patients, attending the PF laboratory for a routine checkup or preoperative evaluations for minor and elective surgeries, and with 29 patients with established ALS diagnosis at the time of the initial assessment. Exclusion criteria were ever smokers with more than 5 pack/years of smoking history and the presence of asthma, chronic bronchitis, emphysema, or other cardiac, renal, and/or metabolic comorbidities.

All patients belonging to ALS and pre-ALS groups had, at the time of the PFTs, a complete neurological evaluation, including standard laboratory tests, electromyography, multimodal evoked potentials, and magnetic resonance imaging of the brain and cervical spinal cord, to confirm the diagnosis of ALS. All patients had spontaneous breathing and active mobility at the time of enrollment. None of the patients with established ALS were on invasive ventilation at any time during the study. The ALS patients were all diagnosed according to Gold Coast criteria, which are the current gold standards for the diagnosis of ALS [2]. These criteria require (1) progressive upper and lower motor neuron symptoms and signs in one limb or body segment, or (2) progressive lower motor neuron symptoms and signs in at least two body segments, and (3) absence of electrophysiologic, neuroimaging, and pathologic evidence of other disease processes that might explain the signs of lower and/or upper motor neuron degeneration. All the patients with established ALS had involvement of both the cranial and spinal districts and both the first and the second motoneuron. The average duration of the disease in those with established ALS was 14 months from the initial diagnosis. The patients with established ALS underwent a neurological assessment according to the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) [4]. They presented mainly grammar and verbal fluency troubles, apathy, loss of empathy, and changes in eating behaviors. In the pre-PFT group, since, at the time of the PFT, there was no clinical suspicion of ALS, only pulmonary function, physical capacity, and effort tolerance were assessed. The PFTs were performed according to the ATS/ERS Statement on Respiratory Muscle Testing [5], and included lung volumes and residual volume [6], respiratory muscle strength (maximal inspiratory pressure [MIP], and maximal expiratory pressure [MEP]), forced and slow vital capacity measured in the supine position, to detect any early sign of diaphragmatic weakness. Arterial gases (P_O2 and P_CO2) and pH were corrected by body temperature and determined in a sitting position, at rest. The inspiratory depression of airway pressure, which is achieved after 100 ms of occlusion of the airways (P_0.1) and represents an indirect measurement of the activity of the respiratory drive [7], was also measured.

Pre-ALS patients were significantly younger than ALS patients, and their body weight was significantly heavier than controls (Table 1). In patients with established ALS, the age of onset was 65 ± 10 years. As expected, patients with established ALS had a restrictive profile, with both forced vital capacity and forced expiratory volume at 1 s significantly lower than patients with pre-ALS and controls. However, PaO₂ was lower in patients with established ALS versus controls, even in the absence of hypoxemia. MIP and MEP were significantly lower in patients with established ALS and pre-ALS versus controls and in patients with established ALS versus pre-ALS. The respiratory drive (P_0.1) was significantly higher in both patients with established ALS and pre-ALS compared to controls. Last, the ratio between respiratory drive and inspiratory muscle strength (P_0.1/MIP) (Fig. 1) was significantly similar between ALS and pre-ALS but in both groups significantly greater than in controls.

This is the first study in the literature that assessed pulmonary function, including P_0.1, MIP, and P_0.1/MIP ratio, in subjects with unspecific neurological symptoms/signs in whom an ALS diagnosis was not possible at the time the pulmonary function tests were performed, and it was achieved only 2 years after the initial assessment.

In previous studies [3, 8, 9], only patients with established ALS diagnosis had been included. In our study, the patients that we defined as “pre-ALS” did not receive a diagnosis of ALS until 2 years after the initial clinical and pulmonary evaluation, as they lacked specific ALS symptoms and signs that could be detected by neurological evaluation, including standard laboratory tests, pulmonary function, electromyography, multimodal evoked potentials, and magnetic resonance imaging of the brain and cervical spinal cord, to confirm the diagnosis of ALS. Our study seeks to leverage the use of P_0.1, MIP, and P_0.1/MIP ratio in the presence of nuanced symptoms suggestive of ALS but with the clinical diagnostic criteria unmet. In these cases, we show that P_0.1, MIP, and P_0.1/MIP ratio can be a helpful tool to look at and make the diagnosis earlier than waiting for limbs to get weak or the classical respiratory function tests to be compromised.

The respiratory impairment in advanced ALS, caused by generalized muscle weakness, is well established and can lead to hypoventilation with hypoxic and hypercapnic respiratory failure [9]. Thus, an early evaluation of respiratory function in patients with suspected ALS is mandatory. The very initial stages of the disease, when neurological and electrophysiological changes are still subclinical and assessment of respiratory symptoms is unremarkable, are hard to diagnose, and studies targeting this population of patients are lacking. Previous evidence shows that patients with early-stage ALS, in the absence of respiratory symptoms, tend to hypoventilate during sleep [10]. However, the decrease in lung volumes often becomes evident only late in the progression of ALS, and it normally does not occur in the preclinical phases of the disease.

Our study examines for the first time not only the spirometry parameters in sitting and supine (more sensitive to diaphragmatic weakness) positions but also the respiratory drive and muscle strength in patients with unspecific ALS-like symptoms and still negative neurological tests. Our main finding is that the respiratory drive (P_0.1), the MIP, and their ratio (MIP/P_0.1) are sensitive enough to discriminate patients with preclinical ALS from the controls way ahead of time.

We show that, early in the onset of ALS, subtle weakening of the muscles is sufficient to induce increases in the P_0.1, reflecting the increased metabolic demand coming from the central and peripheral chemosensors and muscular mechanoreceptors, as it occurs in osteoporosis [11]. Even after normalizing P_0.1 for the inspiratory muscle strength, we still found it to be higher in patients with pre-ALS versus controls, confirming that this parameter has high sensitivity, specificity, and positive predicted value to detect ALS in preclinical stages.

One limitation of the study is that we did not obtain genetic data from the subjects. However, this is not required by the current guidelines [2] for ALS diagnosis. Additionally, our sample size is relatively small, although we initially screened 415 patients in our clinic. Nonetheless, the fact that we still found significant differences between patients’ groups despite the low sample size is reassuring, as it provides an impetus for studying a larger cohort which can lead to changing practice guidelines. In patients with unspecific symptoms, where ALS diagnosis cannot be achieved with the currently available diagnostic tools, abnormally high P_0.1 and low MIP measurements might prompt a tighter follow-up for ALS. Also, from a therapeutic standpoint, identifying preclinical ALS is crucial as the earlier the treatment is started, the bigger the impact it can have on the disease progression.

In conclusion, changes in P_0.1, MIP, and MIP/P_0.1 ratio might be associated with preclinical ALS when the spirometry and neurodiagnostic tests are still inconclusive. MIP and P_0.1 are noninvasive measures that can be easily assessed in an ambulatory setting. Future studies on larger cohorts are needed to validate the use of these parameters in the preclinical stages of ALS as well as in other neuromuscular diseases.

The study protocol (“PRESLA”) was approved by the Local Ethics Committee “Campania Sud” (No. 215/COV, June 9, 2022). The subjects gave their written informed consent.

Francesca Polverino has received unrestricted funds from Boehringer Ingelheim and Baylor College of Medicine and is the section editor for the European Respiratory Journal.

Francesca Polverino is funded by NHLBI HL149744 and unrestricted funds from Baylor College of Medicine.

M.P., C.S., and F.P. designed the study; S.S., A.C., M.F., M.A., C.S., and M.P. conducted the clinical work and the analyses; and M.P., S.S., A.C., M.F., M.A., E.S., C.S., J.P.O., and F.P. interpreted the data and wrote and manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.