https://orcid.org/0000-0002-7146-414X
Abstract
Objective
Motor Neuron Diseases (MND) have a large clinical spectrum, being the most common amyotrophic lateral sclerosis (ALS) but there is significant clinical heterogeneity. Our goal was to investigate this heterogeneity and any potential changes during a long period.
Methods
We performed a retrospective cohort study among a large Portuguese cohort of MND patients (n = 1550) and investigated changing patterns in clinical and demographic characteristics over the 27-year period of our database. With that aim, patients were divided into three 9-year groups according to the date of their first visit to our unit: P1, 1994–2002; P2, 2003–2011; P3, 2012–2020.
Results
The overall cohort’s clinical and demographic characteristics are consistent with clinical experience, but our findings point to gradual changes over time. Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, the proportin of patients using respiratory support with noninvasive ventilation (NIV), time to NIV, and survival. Across time, in the overall cohort, we found an increasing age at onset (p = 0.029), a decrease of two months in diagnostic delay (p < 0.001) and a higher relative frequency of progressive muscular atrophy patients. For ALS patients with spinal onset, from P1 to P2, there was a more widespread (54.8% vs 69.4%, p = 0.005) and earlier (36.9 vs 27.2 months, p = 0.05) use of NIV and a noteworthy 13-month increase in median survival (p = 0.041).
Conclusions
Our results probably reflect better comprehensive care, and they are relevant for future studies exploring the impact of new treatments on ALS patients.
Introduction
Motor neuron disease (MND) consists of a heterogeneous clinical spectrum of progressive upper and/or lower motor neurons (UMN/LMN) dysfunction. The most common type of MND is amyotrophic lateral sclerosis (ALS) (Citation1–3). In about two-thirds of ALS, patients present with spinal-onset (s-ALS), while approximately 20–25% of patients present with bulbar-onset (b-ALS) (Citation1,Citation2). Although scarcer, other presentations occur, namely axial/respiratory (ar-ALS) (Citation4,Citation5); cognitive onset (c-ALS) (Citation1,Citation2), and generalised (g-ALS) (Citation6). Progressive muscular atrophy (PMA), a clinically pure LMN syndrome, constitutes 5–10% of the MND cases (Citation2,Citation7). Due to its progressive nature and associated neuropathological and neurophysiological changes showing UMN abnormality, PMA is considered a phenotype of ALS (Citation8,Citation9). Other MNDs include the slowly progressive primary lateral sclerosis (PLS), characterized by pure UMN dysfunction for at least four years (Citation2,Citation10) and monomelic amyotrophy, a rare rather benign form of LMN dysfunction, in general of juvenile onset (Citation11,Citation12).
During the past 27 years we have been collecting data from patients diagnosed with MND attending our unit using a common clinical protocol, with a standardized questionnaire (including disease onset and its progression) and formal neurological findings. Here, we describe the clinical and demographic characteristics of this large cohort of patients. Taking advantage of the long-time interval under analysis, changes over time will also be addressed.
Material and methods
Patient data collection
This retrospective single-center study includes data from patients who were observed in the ALS clinic at our hospital (CHULN) in a consecutive period of 27 years. Our ALS clinic serves the Lisbon metropolitan area, whose population has increased from 2.2 million in 1995 to 2.8 million nowadays. However, depending on the patient’s preference, our ALS Clinic accepts patients from other parts of the country (10.3 million). Inclusion criteria were: first visit between 1994 and 2020, and a definite clinical diagnosis of MND using conventional criteria existent during this period (Citation7,Citation12). All patients were initially observed and categorized by the same neurologist (MdC). Patients without a confirmed diagnosis of MND during follow-up were excluded. Follow-up visits were routinely scheduled every 3-6 months. For the analysis of progressive functional decline, we set as inclusion criteria a minimum of two visits within one-year of follow-up.
Of 1569 patients with an initial diagnosis of MND supported by neurophysiological investigation, 19 were excluded during follow-up due to misdiagnosis. In what concerns s-ALS and b-ALS, this was defined as usually by the region of onset. The g-ALS classification was applied to patients with two or more regions affected simultaneously at onset, despite a careful questionnaire concerning the first affected region. The ar-ALS patients had respiratory and/or axial muscles affected first, including those with drop-neck presentation, while patients with initial cognitive changes before motor weakness in any region were classified as c-ALS. Patients who presented with pure LMN signs were included in the PMA group, including those with pure bulbar weakness since in all of those, except one, the disease progressed to other anatomical regions within six months.
In the analysis were included 1550 patients and the following variables: age at onset, gender, phenotype (as above), disease duration at study entry and diagnostic delay, baseline and follow-up functional status (described below), rate and time of noninvasive ventilation (NIV) and survival. Patients were followed-up until death, loss to follow-up, or census day (July 31, 2021). To explore differences over this period, subjects were divided into three groups as defined by three similar time periods, according to the date of their first visit to our unit: P1, 1994–2002; P2, 2003–2011; P3, 2012–2020. Except for NIV and functional scale in the first time period, missing data did not exceed 5% for any variable within the three groups (Table S1). ALS patients were diagnosed according to El Escorial criteria but including patients with PMA (Citation13). Demographic and clinical characteristics are recorded for the various MND subtypes in each time frame. Due to the short follow-up time for many patients included in P3, statistical comparisons for time to NIV and survival were only done between P1 and P2. To investigate possible changes in P3, and to control for an association between potential follow-up time and group period, one, two, three and four-year survival analyses was also performed.
Assessment of functional status
Since 1996 we have applied the ALS functional rating scale (ALSFRS) (Citation14), but we chose to use only data obtained with the revised version (ALSFRS-R) (Citation15). We calculated the rate of disease progression at baseline, using the standard formula: (48-ALSFRS-R at baseline)/disease duration (in months). Regarding the functional decline rate, we used the formula: (ALSFRS-R at baseline - ALSFRS-R at re-evaluation)/time (in months).
Survival
Total survival was analyzed from symptom onset until death or reaching the study datum event (July 31, 2021).
Statistical analysis
The Chi-square test was used to compare categorical variables and the Kruskal-Wallis test was applied for all non-categorical variables. All post hoc tests were adjusted by the Bonferroni correction. Time to NIV and survival estimation were made using the Kaplan Meier statistic. The log-rank test was used to compare time-to-events curves. The Cox proportional hazards model was used for univariate and multivariate analyses. The Hazard Ratio (HR) was calculated for each variable. P < 0.05 was considered statistically significant.
This study was approved by the local Ethics’ Committee (ref 162/21).
Results
Cohort description
The mean age at disease onset was 62.2 years [SD, 12.6]; 56.6% were men. The MND subgroup distribution is shown in . The results are summarized in and . Male to female ratio was increased in ALS (p = 0.005), PMA (p < 0.001) and monomelic (p = 0.001) disease. Male predominance was significant in s-ALS, ar-ALS, and PMA, while in b-ALS women were more frequently represented (all p < 0.001). The median age of onset varied between 61 and 70 years, with s-ALS being significantly younger than ar-ALS, b-ALS and PMA (all p < 0.001). Patients with ALS and PMA were significantly older than PLS (both p < 0.001) and monomelic patients (p = 0.001 and p < 0.001, respectively). The overall frequency of familial MND was 8.0%, with PLS having a significantly higher proportion of familial cases (17.6%) than ALS (8.8%, p = 0.032) or PMA (7.3%, p = 0.002).
Figure 1. MND subgroups’ distribution.
Table 1. Demographic and clinical characteristics of MND patients.
Table 2. Demographic and clinical characteristics of PMA and ALS patients according to the site of onset.
Diagnostic delay was approximately 4 times longer in c-ALS than in any other subgroup and was significantly shorter in b-ALS than in s-ALS (p < 0.001) and PMA (p = 0.004). At baseline, only s-ALS and PMA differed in terms of functional score (p = 0.008), but on progression rate, several differences were found: in c-ALS progression was slower than in other phenotypes before motor symptom onset; in PMA it was slower than in b-ALS (p < 0.001), ar-ALS (p = 0.002) and g-ALS (p = 0.002); and in s-ALS it was slower than in b-ALS (p < 0.001) and g-ALS (p = 0.028). On average, after one year of follow-up, ALS patients lost 11 points on the ALSFRS-R scale, with c-ALS having the greatest decline, corresponding to the onset of motor involvement. Monomelic patients differed markedly from the other groups, concerning minor functional disability, no respiratory impairment and a 100% survival rate over the 27-year period of the analysis. Diagnostic delay in monomelic patients was similar to PLS, but significantly longer than in ALS and PMA (both p < 0.001). PLS patients progressed slower than PMA subjects (p < 0.001).
The rate of NIV intervention was similar between ALS and PMA but was prescribed sooner in ALS patients (21.4 months of median difference, p < 0.001), and less frequently prescribed in PLS (vs ALS p < 0.001 and vs PMA p = 0.001). NIV was prescribed sooner and more frequently in ar-ALS patients than in other phenotypes, followed by patients with g-ALS and b-ALS. PMA had the best prognosis with survival times greater than s-ALS (p = 0.001), b-ALS (p < 0.001), ar-ALS (p < 0.001) and g-ALS (p < 0.001). s-ALS in turn had a significantly longer survival than b-ALS (p < 0.001), ar-ALS (p < 0.001) and g-ALS (p = 0.003), while no differences were detected between survival in b-ALS, ar-ALS, and g-ALS (). Within the PMA subgroup, compared with spinal onset, the thirteen patients with bulbar onset tended to be older and diagnosed earlier, functional impairment at baseline and the rate of NIV were similar, although survival was substantially shorter.
Figure 2. Kaplan–Meier survival curves stratified by phenotype.
Transitional pattern analysis
The total number of patients in each group defined according to the time of first visit was: P1 (1994–2002) n = 236; P2(2003–2011), n = 502; P3 (2012–2020) n = 812. reports demographic and clinical data comparing the three time periods for a cohort composed of the three most representative MND subgroups: s-ALS, b-ALS and PMA.
Table 3. Demographic and clinical characteristics of s-ALS, b-ALS and PMA patients according to group period.
The distribution of these three subgroups notably changed over time. Although the b-ALS proportion remained approximately stable, PMA patients increased from 5.9% in P1 to 17.4% in P3, while s-ALS decreased from 59.3% to 47.5% (P1 vs P3 p < 0.001). Across time we disclosed a higher median age in P3 (P1: 62.3; P2: 62.3; P3: 64.4, P1 vs P3 p = 0.031), but when stratified by phenotype there was no difference between the three periods (). There was no change in the proportion of familial cases (P1: 5.7%; P2: 8.4%; P3: 9.7%, p = 0.171). The same pattern was confirmed when stratification by phenotype was done.
Comparing to P1 and P2, the diagnostic delay was 2 months shorter in P3 (p = 0.001). This trend to earlier diagnosis over time was significant for the three main phenotypes (). Pairwise comparisons showed that in s-ALS this was due to differences between P1 and P3 (p = 0.018) while in b-ALS and PMA this finding was due to differences between P2 and P3 (p = 0.009 and p = 0.026 respectively).
Comparing the three time periods, functional impairment at entry and its progression over time was similar. Between P1 and P2, the percentage of NIV rate increased from 62.6% to 70.8%. Analyzing each subtype independently this change was significant for s-ALS (). Regarding the median time to NIV, we found that, on average, in P2 NIV was used 4 months earlier than in P1, but s-ALS was the only phenotype for which such time reduction was significant ().
Survival analysis comparing time periods showed increased median survival (months) from P1 (34.3 ± 2.3) to P2 (42.3 ± 1.8) (p = 0.036). However, when considering phenotypes, the longer survival was significant only for s-ALS (p = 0.041) (). In line with total survival analysis, survival data at four pre-specified time points (1-, 2-, 3- and 4-years) (Table S2) showed that b-ALS prognosis was significantly worse than s-ALS and PMA (in 2-, 3- and 4-years), and s-ALS was worse than PMA (in 3- and 4-years). Analyzing time periods, we found an overall pattern of longer survival in more recent periods, which was significant for s–ALS (p = 0.041). Using P1 as reference, both P2 and P3 showed significant increases, but no difference was found between P2 and P3. On univariate Cox regression high functional decay at baseline (p < 0.001, HR [95%CI] 1.03 [1.025–1.036]), older age at disease onset (p < 0.001, HR [95%CI] 2.344 [2.196–2.503], and shorter disease duration at diagnosis (p < 0.001, HR 0.965 [0.96–0.97]) were poor predictors for survival. These were included in the multivariable Cox regression model (). Baseline functional decay and diagnostic delay were independent predictors of survival for all phenotypes. Aging had a deleterious effect in s–ALS and PMA, but not in b–ALS. In s–ALS, after adjusting for demographic and clinical variables, the HR [95% CI] for death in 2003–2011 versus 1994–2002 was 0.57 [0.423–0.755].
Table 4. Multivariate Cox regression model- Independent survival predictors.
Discussion
MND classes
Demographic and clinical characteristics differ significantly depending on the MND phenotype and our results validate earlier studies (Citation2,Citation11). ALS was the most prevalent phenotype, present in 82% (Citation15,Citation16). Median ALS survival and age of onset are within the range of values reported in population-based studies in Southern Europe (Citation17). The PMA proportion was greater than usually described (Citation18). Male predominance was evident in ALS, PMA and monomelic ALS but, as in other studies (Citation15,Citation19,Citation20), this was not found in PLS. We also confirmed that ALS and PMA occurred later in life, contrary to PLS and monomelic patients (Citation11,Citation12). ALS progression has been described as a sigmoid-shaped curve in which, ALSFRS-R scores at first decline slowly, followed by a phase of uniform progression until the severity of disability re-attains a plateau (Citation21,Citation22). The increased rate of disease progression after one-year of follow-up in our ALS population suggests that most of our patients arrive at our center in the initial slowly progressing phase.
Onset region in ALS
Our results support that the onset region is a feature that predicts prognosis (Citation23–26). Even for the less frequent phenotypes ar-ALS, c-ALS and g-ALS relevant differences were found, emphasizing the importance of studying these populations separately. For example, ar-ALS patients were older and required NIV immediately. Survival in this group was significantly shorter than other ALS phenotypes (Citation26) in contradistinction to some other reports (Citation5,Citation15). In g-ALS, presentation occurred with a more severe functional status, the shortest diagnostic delay and accordingly, the worst prognosis. The few patients (1%) presenting with isolated cognitive changes (c-ALS) stand out with the highest diagnostic delay, lowest functional progression rate at entry and longest survival, since disease onset was defined by the cognitive symptoms. However, from weakness onset c-ALS does not differ from other phenotypes regarding disease progression and survival (Citation27). The most prevalent phenotype, s-ALS, mainly affects younger men. Aside from the special case of c-ALS, s-ALS was the phenotype with the longest diagnostic delay, slowest functional progression, and longest survival. On the other hand, b-ALS was commoner in older women, functional status was lower at baseline and after one-year of follow-up, associated with shorter survival (Citation28).
Transitional pattern analysis
Time pattern analysis revealed statistically significant differences in the distribution of clinical phenotypes, the average age of onset, diagnostic delay, time and NIV rate, and survival.
The observed differences in the distribution of b-ALS and s-ALS phenotypes, contrast with the higher relative frequency of b-ALS reported by Chen (Citation29) or the increase of s-ALS reported by Czaplinski (Citation30). The increasing prevalence of PMA in our cohort probably reflects a greater reliance on neurophysiology in supporting diagnosis and the impact of population aging. The absence of a decrease of b-ALS in the face of an increase in PMA, is probably due to population aging, with a relative decrease in s-ALS.
Our data agree with the results of other studies, which observed an increase in disease-onset age with time (Citation29–31). While improved diagnosis in the elderly is one possible explanation, aging of the population is another, as in the last 30 years the number over 65 has increased by 9.8%, making up 23.4% of the Portuguese population (Citation32).
Reducing diagnostic delay is a major concern in clinical practice but has not been meaningfully shortened in the last 20 years (Citation33). Chío (Citation31) reported a decrease of 0.4 months from 1995 to 2014 and at our center there was a 2-month reduction from 2003 to 2020.
The increasing number of patients receiving NIV(30,34,35) is probably associated with changing clinical guidelines. Since this intervention usually occurs later in the disease course, we did not compare proportions with the third period. Nonetheless, we observed an apparent contemporary stabilization suggesting that this treatment is available to most patients in our center, so this is not just a reflection of the relatively short follow-up period in this group.
The increasing age at onset, shorter delay in diagnosis and faster disease progression are commonly reported as significant independent predictors of shorter survival (Citation23,Citation34–36) and our data support these findings. However, the association between age and survival was not significant for the b-ALS phenotype, probably because the number of young patients in this group impairs the necessary statistical power. After adjusting for the previous variables, the striking increase in survival in s-ALS between P1 and P2 (13 months) was still significant. Faster diagnosis, increasing earlier NIV use and generalized riluzole treatment might play a key role in s-ALS survival. We did not observe such increased survival in b-ALS presumably because of the rapid disease progression and worse tolerance to NIV (Citation37). On the other hand, the apparent decrease in PMA survival was not confirmed after adjusting for confounding variables in the multivariate model.
In the literature, we found contradictory results in studies that evaluated whether survival in ALS had changed over time, but none of them did such analysis independently of phenotype or included PMA patients. To compare our data, we made a supplementary analysis for ALS globally (excluding PMA) (Table S3). We concluded that there was a 9-month longer survival from P1 to P2 that remained significant after adjusting for age, diagnostic delay, and baseline functional status (HR for death in P2 vs P1 of 0.67, p < 0.001). This increase is in line with some studies (Citation30,Citation34,Citation38), but contrasts with others in which no differences across time were found (Citation35,Citation39) or with those that reported a decrease in survival (Citation36,Citation40). Nevertheless, the periods under analysis, study designs, and criteria used for analysis differed between these studies. In pursuance of an accurate and reliable comparison, a meta-analysis should be performed in future studies. Since in Portugal riluzole has been freely available for ALS patients since 1997, and virtually all our patients tolerated this drug, this unlikely influenced the results.
Strengths and limitations
The major strengths of this study were its size and the data acquisition at entry done by the same physician for all patients, Furthermore, the stratified analysis by phenotypes addressed the high heterogeneity of MND and provided a comprehensive characterization of patients. Investigating a long-time span is also a strength.
The unequal sample size between time periods was one of our study’s limitations. The number of MND patients seen in our unit has increased in recent years, but we believe that the main reason is that data collection has been less comprehensive in the past, undermining the comparability of the first third of the 27-year study period. Another limitation was the impossibility of adding genetic information since this was not systematically collected in all periods. Hospital-based studies are described as biased in favor of slow-progression younger patients with the less-severe disease (Citation41) however given the characteristics of our health system, all patients with ALS/MND visit the clinic regularly throughout their illness. Moreover, our results are in line with population-based studies elsewhere in Southern Europe (Citation17). Due to distinct classifications, strategies of stratification and statistical methods used by other authors, comparisons were made only with those that more closely resemble our analysis.
Our results are positive suggesting a trend toward a shorter diagnostic delay, more widespread use of NIV and longer survival. These positive results are relevant for future studies exploring the impact of new treatments on the populations of ALS patients.
Supplemental Material
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The authors have no competing interests to declare that are relevant to the content of this article.
Data availability statement
The data that support the findings of this study are available from the corresponding author, [IA], upon reasonable request.
Additional information
Funding
References
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