INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a multifaceted neurodegenerative disorder marked
by the deterioration of upper and lower motor neurons. It generally begins in adulthood,
approximately at 55 to 75 years of age. It follows a progressive course, with a median
survival of ∼ 3 years after symptom onset, though life expectancy can range from months
to more than 10 years. Respiratory failure predominantly accounts for mortality. The
disorder exhibits clinical and genetic heterogeneity, resulting in a broad range of
pathogenic mechanisms across the spectrum of the disease.[1]
To date, the disease remains incurable, with a poor prognosis. Weight loss and malnutrition
emerge as significant clinical features during disease progression, resulting from
reduced food intake or energy deficit due to dysphagia and/or hypermetabolism.[2] Evidence suggests that weight loss at the time of ALS diagnosis is a significant
prognostic factor. Therefore, preventing or minimizing weight loss after diagnosis
could extend the patient's lifespan.[3] The present study aimed to explore how demographic and clinical characteristics
relate to survival in ALS patients, emphasizing the role of weight loss percentage
at the time of diagnosis.
METHODS
Study design and population
The current is a retrospective study that used the database of the ALS Multidisciplinary
Care Center at Hospital Universitário Onofre Lopes (HUOL), in the city of Natal, state
of Rio Grande do Norte (RN), Brazil, covering the period from January 2008 to March
2022. Additional data and cohort characteristics have been published previously.[4] The study was approved by the Ethics in Research Committee of HUOL (CEP HUOL/UFRN
3540209).
Data collection
Patients with ALS were referred to the center by neurologists or general practitioners.
This center, an outpatient clinic within the Brazilian health network, is the only
ALS treatment facility in RN. These patients were diagnosed following the revised
El Escorial criteria.[5] Subsequently, each patient underwent regular follow-up appointments every 3 to 4
months, which included those with the nutrition team. The initial nutritional assessment
was conducted at the time of diagnosis.
Data on sex, age at disease onset, disease progression rate according to the revised
ALS functional rating scale (ALSFRS-R),[6] survival, usual weight, and current weight were extracted from the computerized
database of the ALS Multidisciplinary Care Center. This database contains prospectively-collected
clinical data from all ALS patients followed at the center.
Disease onset was recorded as the moment when the patient or family first noticed
signs/symptoms of muscle weakness. Survival was defined as the time, in months, from
the disease onset to death or tracheostomy, whichever occurred first, or until the
censoring date (March 31, 2023). Progression rate was calculated as: (48 - ALSFRS-R
score at the time of diagnosis)/duration from onset to diagnosis in months. The results
were categorized into slow (< 0.5), intermediate (0.5–1.0), and fast (> 1.0) progression
rates.[7] The percentage of weight loss was used to assess the weight change of the patients
at the time of diagnosis (early weight loss). This variable was calculated as: (usual
weight - current weight)/usual weight × 100. Subsequently, the patients were categorized
into subgroups of percentage of weight loss ≥ 10% and < 10%.
Cases originating from locations outside of RN, those lacking usual or current weight
recordings, those with incomplete documentation on disease onset or submission to
gastrostomy, as well as patients with irregular follow-up were excluded from the analysis.
Statistical analysis
Associations involving the categorical variables were determined by the Chi-squared
(χ2) test. Quantitative averages were compared using the Mann–Whitney U test. Survival
was calculated from symptom onset to death/tracheostomy or censoring date; it was
analyzed using the Kaplan-Meier method and compared with the log-rank test. Multivariable
analysis for survival was performed with the Cox proportional hazards model. Statistical
analysis was performed using the IBM SPSS Statistics for Windows (IBM Corp.) software,
version 28.0. A significance level of 5% was adopted for all analyses.
RESULTS
Demographics, clinical characteristics, and weight loss
A total of 132 patients were included in the study; however, some variables (progression
rate and submission to gastrostomy) had missing data. Associations of demographic
and clinical characteristics of the participants with the percentage of weight loss
at the time of diagnosis are presented in [Table 1]. The mean age of the participants at symptom onset was of 56.9 ± 12.1 years, with
a higher proportion of male patients, accounting for 59.8% of the cases. Most participants
presented the spine as the site of onset (62.1%), had been submitted to gastrostomy
(55%) and non-invasive ventilation (72.7%), and presented intermediate or fast disease
progression rates (76.8%). The median time from the onset of symptoms to gastrostomy
placement was of 24 (interquartile range [IQR]: 17–38) months. The minority of them
were tracheostomized (34.8%) and presented weight loss ≥ 10% (40.9%) at the time of
diagnosis.
Table 1
Association of participants' demographic and clinical characteristics with the percentage
of weight loss at the time of diagnosis
|
Characteristics
|
Total
(n = 132)
|
Percentage of weight loss
|
p-valuea
|
|
< 10%
(n = 78)
|
≥ 10%
(n = 54)
|
|
Sex: n (%)
|
Male
|
79 (59.8)
|
50 (64.1)
|
29 (53.7)
|
0.231
|
|
Female
|
53 (40.2)
|
28 (35.9)
|
25 (46.3)
|
|
Total
|
132 (100)
|
78 (100)
|
54 (100)
|
|
Age at disease onset: n (%)
|
< 60 years
|
77 (58.3)
|
51 (65.4)
|
26 (48.1)
|
0.048
|
|
≥ 60 years
|
55 (41.7)
|
27 (34.6)
|
28 (51.9)
|
|
Total
|
132 (100)
|
78 (100)
|
54 (100)
|
|
Site of onset of amyotrophic lateral sclerosis: n (%)
|
Bulbar
|
50 (37.9)
|
21 (26.9)
|
29 (53.7)
|
0.002
|
|
Spinal
|
82 (62.1)
|
57 (73.1)
|
25 (46.3)
|
|
Total
|
132 (100)
|
78 (100)
|
54 (100)
|
|
Submission to gastrostomy: n (%)
|
No
|
58 (45)
|
35 (45.5)
|
23 (44.2)
|
0.891
|
|
Yes
|
71 (55)
|
42 (54.5)
|
29 (55.8)
|
|
Totalb
|
129 (100)
|
77 (100)
|
52 (100)
|
|
Submission to non-invasive ventilation: n (%)
|
No
|
36 (27.3)
|
22 (28.2)
|
14 (25.9)
|
0.773
|
|
Yes
|
96 (72.7)
|
56 (71.8)
|
40 (74.1)
|
|
Total
|
132 (100)
|
78 (100)
|
54 (100)
|
|
Tracheostomy: n (%)
|
No
|
86 (65.2)
|
50 (64.1)
|
36 (66.7)
|
0.761
|
|
Yes
|
46 (34.8)
|
28 (35.9)
|
18 (33.3)
|
|
Total
|
132 (100)
|
78 (100)
|
54 (100)
|
|
Disease progression rate: n (%)
|
Slow
|
30 (23.3)
|
23 (30.3)
|
7 (13.2)
|
0.013
|
|
Intermediate
|
49 (38)
|
29 (38.2)
|
20 (37.7)
|
|
Fast
|
50 (38.8)
|
24 (31.6)
|
26 (49.1)
|
|
Totalb
|
129 (100)
|
76 (100)
|
53 (100)
|
Notes: aChi-squared; test; values in bold indicate statistical significance (p < 0.05). bFewer than 132 participants due to missing data.
No significant association was found between the percentage of weight loss and sex,
submission to gastrostomy, submission to non-invasive ventilation, and tracheostomy.
However, those with weight loss ≥ 10% at the time of diagnosis were older (≥ 60 years)
(p = 0.048) and presented bulbar onset (p = 0.002) and faster disease progression rate (p = 0.013) ([Table 1]).
Survival and prognostic factors
Associations of demographic and clinical characteristics of the participants with
the outcome are presented in [Table 2]. No significant association was found between the outcome and sex or site of ALS
onset. However, a significantly higher proportion of participants who experienced
the outcomes of death or tracheostomy (indicating shorter survival) were older at
the disease onset (≥ 60 years) (p = 0.012), had experienced weight loss ≥ 10% at the time of diagnosis (p = 0.016), presented faster disease progression rate (p < 0.01), and had been submitted to either gastrostomy (p < 0.01) or non-invasive ventilation (p = 0.010) ([Table 2]).
Table 2
Association of participants' demographic and clinical characteristics with the outcome
of interest
|
Variables
|
Outcome of interest: death or tracheostomy
|
Total
|
p-valuea
|
|
Yes
|
No
|
|
Sex: n (%)
|
Male
|
56 (70.9)
|
23 (29.1)
|
79 (100.0)
|
0.735
|
|
Female
|
39 (73.6)
|
14 (26.4)
|
53 (100.0)
|
|
Age at disease onset: n (%)
|
< 60 years
|
49 (63.6)
|
28 (36.4)
|
77 (100.0)
|
0.012
|
|
≥ 60 years
|
46 (83.6)
|
9 (16.4)
|
55 (100.0)
|
|
Site of onset of amyotrophic lateral sclerosis: n (%)
|
Bulbar
|
39 (78.0)
|
11 (22.0)
|
50 (100.0)
|
0.228
|
|
Spinal
|
56 (68.3)
|
26 (31.7)
|
82 (100.0)
|
|
Weight loss at diagnosis: n (%)
|
< 10%
|
50 (64.1)
|
28 (35.9)
|
78 (100.0)
|
0.016
|
|
≥ 10%
|
45 (83.3)
|
9 (16.7)
|
54 (100.0)
|
|
Disease progression rate: n (%)
|
Slow
|
13 (43.3)
|
17 (56.7)
|
30 (100.0)
|
< 0.01
|
|
Intermediate
|
35 (71.4)
|
14 (28.6)
|
49 (100.0)
|
|
Fast
|
44 (88.0)
|
6 (12.0)
|
50 (100.0)
|
|
Submission to gastrostomy: n (%)
|
Yes
|
63 (88.7)
|
8 (11.3)
|
71 (100.0)
|
< 0.01
|
|
No
|
29 (50.0)
|
29 (50.0)
|
58 (100.0)
|
|
Submission to non-invasive ventilation: n (%)
|
Yes
|
75 (78.1)
|
21 (21.9)
|
96 (100.0)
|
0.010
|
|
No
|
20 (55.6)
|
16 (44.4)
|
36 (100.0)
|
Notes: aChi-squared; test; values in bold indicate statistical significance (p < 0.05).
The survival analysis evaluated 132 cases of patients with ALS with a mean follow-up
of 41.5 ± 28.4 months and a median of 32 (IQR: 22.0–57.8) months. Of the total of
132 patients, 72% presented the outcome of interest (death or tracheostomy). The participants
presented an overall survival of 90.9% at 12 months, of 65.7% at 24 months, and of
44.1% at 36 months of follow-up. The median survival time was of 34 (95%CI: 30.9–37.1)
months ([Figure 1A]).
Figure 1 Kaplan-Meier cumulative survival (A), and survival curves by sex (B), age (C), site of onset (D), weight loss (E), disease progression rate (F), use of gastrostomy (G), and use of non-invasive ventilation (H) of patients with amyotrophic lateral sclerosis.
Survival was shorter for individuals with age ≥ 60 years ([Figure 1C]), weight loss ≥ 10% ([Figure 1E]), intermediate and fast disease progression rates ([Figure 1F]), and those submitted to gastrostomy ([Figure 1G]). No significant difference in survival was observed regarding sex, site of onset,
and submission to non-invasive ventilation ([Figures 1B], [1D], and [1H]).
In the multivariable analysis, we observed that patients aged ≥ 60 years were 1.66
times more likely to reach the outcome of interest (95%CI: 1.07–2.58). Subjects with
early weight loss ≥ 10% were 2.06 times more likely to achieve the outcome of interest
(95%CI: 1.32–3.21). Patients with intermediate and fast progression rates were 4.17
(95%CI: 2.04–8.55) and 5.83 times (95%CI: 2.93–11.60) more likely to reach the outcome
of interest respectively. Finally, individuals submitted to gastrostomy were 1.98
times more likely to present the outcome of interest (95%CI: 1.25–3.15) ([Table 3]).
Table 3
Characteristics of the patients associated with the outcome of interest (death or
tracheostomy) identified by multivariate analysis
|
Characteristics
|
HRG
a
|
95%CI
|
p
b
|
HRA
a
|
95%CI
|
p
b
|
|
Age at disease onset ≥ 60 years
|
1.52
|
1.01–2.28
|
0.045
|
1.66
|
1.07–2.58
|
0.024
|
|
Weight loss at diagnosis ≥ 10%
|
2.42
|
1.59–3.69
|
< 0.001
|
2.06
|
1.32–3.21
|
0.001
|
|
Intermediate disease progression rate
|
3.86
|
1.93–7.71
|
< 0.001
|
4.17
|
2.04–8.55
|
< 0.001
|
|
Fast disease progression rate
|
6.31
|
3.23–12.33
|
< 0.001
|
5.83
|
2.93–11.60
|
< 0.001
|
|
Submission to gastrostomy
|
2.24
|
1.42–3.53
|
< 0.001
|
1.98
|
1.25–3.15
|
0.004
|
Abbreviations: HRG, gross hazard ratio; HRA, adjusted hazard ratio.
Notes: aHRG and HRA: hazard Ratios calculated using the Cox regression model. bSignificance by the Wald Chi-square test; values in bold indicate statistical significance
(p < 0.05).
DISCUSSION
The present study investigated the associations involving demographic and clinical
characteristics and survival in ALS patients, focusing on the percentage of weight
loss at the time of diagnosis. We found that older age, bulbar onset, and faster disease
progression were associated with weight loss ≥ 10% at diagnosis. Additionally, age
at disease onset, weight loss at diagnosis, faster disease progression, and submission
to gastrostomy or non-invasive ventilation were associated with the outcome of interest
(death or tracheostomy). Out of 132 patients, 72.% experienced the outcome of interest,
and the median survival time was of 34 months (2.8 years). Survival was shorter for
individuals aged ≥ 60 years, those with weight loss ≥ 10%, intermediate to fast disease
progression, and those submitted to gastrostomy. Among these factors, disease progression
rate and weight loss at diagnosis were the strongest predictors of shorter survival.
Our results on the negative impact of weight loss ≥ 10% at the time of diagnosis,
associated with factors such as older age, bulbar onset, and faster disease progression,
are supported by other studies.[8]
[9] This association may be attributed to age-related vulnerability,[10] loss of appetite,[11] high prevalence of dysphagia, reduced food intake,[12]
[13] and hypermetabolism or energy deficits,[14] particularly in ALS patients with bulbar onset. These factors collectively worsen
nutritional status and prognosis.
It is well established that the nutritional status of ALS patients significantly impacts
their prognosis, underscoring the importance of nutritional care as a core component
of multidisciplinary treatment.[15] For the anthropometric nutritional assessment of ALS patients, guidelines recommend
simple measurements such as of the body mass index (BMI) and weight loss percentage
to monitor nutritional status regularly.[16]
[17] Since BMI does not capture body composition or quantify weight loss,[9]
[18] the percentage of weight loss is more predictive of prognosis. Studies[3]
[9]
[19] indicate that weight loss ≥ 10% at onset or during disease progression is a significant
prognostic factor for survival in ALS patients.
The current study demonstrated survival probabilities of 90.9% at 12 months, 65.7%
at 24 months, and 44.1% at 36 months, with a median survival from onset of 34 months.
Millul et al.[20] reported survival rates of 78% at 12 months, 56% at 24 months, and 32% at 48 months,
as well as a median survival from onset of 39.2 months. Pupillo et al.[21] observed a 1-year survival of 76.2% and a median survival of 26 months. Other studies[22]
[23] have reported variations in median survival rates among ALS patients. These differences
may be attributed to variations in study design, patient demographics, access to care,
availability of multidisciplinary treatments, and advancements in palliative care.
In the present study, survival was shorter for individuals aged ≥ 60 years, those
with ≥ 10% of weight loss, and those with intermediate or fast disease progression.
These findings are corroborated by those of other studies.[9]
[18]
[24]
[25]
In the current study, we found an association between submission to gastrostomy and
shorter survival. Research on this topic has yielded mixed results. Some studies[9]
[26]
[27] have linked gastrostomy to prolonged survival in ALS patients, while a recent Cochrane
review[28] of 23 non-randomized studies noted a lack of well-designed randomized trials to
investigate this issue. This review[28] highlighted the limited availability of high-quality evidence supporting tube feeding
in ALS, despite endorsements from international experts and guidelines. This inconsistency
may result from several factors, including the timing of the placement of the percutaneous
endoscopic gastrostomy (PEG) tube, respiratory function status, severity of dysphagia,
age, nutritional status, and the adequacy of energy and nutrient intake.
A retrospective study[29] aimed to investigate a comprehensive flow of 188 ALS patients before and after PEG
tube placement. The authors[29] highlight the critical timing for PEG tube insertion in ALS patients. They calculated
a recommended time point for gastrostomy (T-rec), which was defined as the earlier
time point between a weight loss of more than 10% and advanced dysphagia indicated
by the ALSFRS-R swallowing subscore ≤ 2. Their analysis revealed a T-rec of 22 months
after symptom onset; however, there was an 8-month delay between the T-rec and the
actual PEG placement, which was associated with a rapid decline in the ALSFRS-R score.[29] Another study[30] did not find a survival benefit from gastrostomy, likely due to the procedure being
performed too late. Delays in PEG tube placement are often linked to disease progression
and worsening symptoms, including dysphagia, bronchial aspiration, weight loss, and
nutritional decline. These factors profoundly affect the prognosis and should be carefully
evaluated alongside the timing of PEG placement. Another factor that may affect the
progression of the disease is the cognitive status, which should be evaluated and
considered when making decisions regarding the timing of invasive interventions.
Additionally, discussions about gastrostomy and ventilation options can be emotionally
challenging for ALS patients, requiring sensitive and empathetic communication. Decisions
on gastrostomy involve patient and family preferences, support systems, socioeconomic
factors, and healthcare access. The healthcare team should explain the risks and benefits
clearly, prioritizing patient autonomy and informed decision-making.[31] A multidisciplinary approach with regular symptom monitoring should guide discussions
on the optimal timing for PEG insertion, as the timing of the procedure can significantly
impact postprocedure survival and overall patient outcomes.
Respiratory function is a critical factor influencing the risk of ventilatory complications
during PEG placement, potentially affecting patient prognosis. However, individual
cases can be effectively managed by an experienced multidisciplinary team. Even ALS
patients with severe ventilatory impairment can safely undergo PEG placement with
nasal non-invasive ventilation (NIV) support.[26]
[32] A risk stratification tool combined with procedural adaptations for PEG placement
has been proposed to enhance safety for higher-risk ALS patients.[33] Respiratory function can independently influence the survival time of ALS patients,
especially in those with delayed PEG placement.
The progression of dysphagia closely mirrors the advancement of ALS, and it is associated
with reduced food intake, dehydration, and compromised nutritional status. In the
study by López-Gómez et al.,[34] dysphagia was observed in 78% of the patients, with 38.8% receiving a PEG. Their
findings suggest that early PEG placement not only reduces hospital admissions related
to dysphagia complications but also offers significant benefits for patients who might
otherwise delay the procedure. Despite the variety of tools and assessments available
to evaluate dysphagia, there is still a need to identify the most effective method
to guide decisions on PEG insertion in ALS patients, based on the extent of swallowing
deterioration.[35] These considerations prompt us to reflect that the long-term benefits of PEG may
be compromised by severe dysphagia, malnutrition, and the advanced stages of ALS.
Studies have shown that age, bulbar onset, and poor nutritional status are linked
to decreased survival in ALS patients. Age-related vulnerability not only accelerates
disease progression[10] but may also increase the risk of complications during or after PEG placement.[36] Improved nutritional status and minimal weight loss prior to PEG placement have
been associated with better survival outcomes. In a prospective cohort study, the
median survival following gastrostomy was of 12 months for ALS patients who experienced
10% or less of weight loss since diagnosis, while those who lost more than 10% of
their body weight presented a median survival of 7.7 months.[37] This highlights that the patient's nutritional status at the time of PEG placement
plays a significant role in determining survival outcomes following the procedure.
Discussing PEG insertion before significant weight loss or severe dysphagia develops
is crucial, and minimizing the delay between recommendation and insertion should be
a priority. Efforts should focus on reducing delays, and compromised respiratory function
should not prevent patients from undergoing the procedure.[29]
The adequacy of energy and nutrient intake is the final, yet equally important, factor
influencing survival time after PEG placement in ALS. The adequacy of energy and nutrient
consumption following gastrostomy has a significant impact on the patient's nutritional
status and, consequently, survival. Theoretically, the immediate benefits of PEG are
adequate food intake and weight stabilization;[26] however, in practice, many factors can influence this adequacy, such as vomiting,
regurgitation, constipation, diarrhea and gastric stasis, abdominal distention, and
feeding tube obstruction.[38] Achieving adequate energy and nutrient intake through homemade feeding in home enteral
nutrition can be challenging. While homemade enteral feeding has certain advantages,
it often provides lower caloric density, insufficient levels of nutrients, and it
is related to a higher number of complications compared with the industrialized formulas.[39] However, industrialized formulas, despite being nutritionally superior, are costly,
particularly in resource-limited settings or developing countries.[39] Moreover, even when using industrialized formulas, failing to meet patients' nutritional
requirements can result in energy and nutrient deficits, ultimately leading to weight
loss and malnutrition.
While timely PEG placement is essential to address dysphagia and nutritional deficits
in ALS, the procedure alone does not guarantee adequate energy and nutrient intake.
During a 12-month follow-up,[40] a high-calorie diet in ALS patients with gastrostomy showed potential for improving
nutritional status and extending survival. Effective nutritional support depends on
an individualized dietary plan and its proper implementation following gastrostomy.
Furthermore, the progression of ALS, which varies greatly among individuals, also
significantly impacts prognosis. Therefore, survival outcomes cannot be attributed
solely to the performance or timing of gastrostomy without considering the critical
factors previously discussed.
Most participants in the present study, who are assisted at our center, are covered
by Brazil's federal public health system and come from lower socioeconomic backgrounds.
This is associated with limited access to food and nutritional supplements. Most patients'
families are required to go to court to obtain industrialized enteral formulas for
their dietary plan after PEG placement. Given these challenges, we believe many participants
in the current study were unable to meet their energy and nutrient requirements after
PEG placement, which may have influenced their survival time after the procedure,
alongside other potential factors.
An important aspect to consider is the use of the El Escorial criteria for patient
inclusion in the present study. If we had used the more recent Gold Coast criteria,
with improved diagnostic sensitivity and predictive value, we might have enabled the
inclusion of a broader spectrum of ALS cases, particularly those with bulbar-predominant
presentations. Given that bulbar-onset ALS is associated with a more aggressive course
and higher mortality, its increased representation under the Gold Coast criteria could
influence survival estimates and the observed impact of weight loss. We chose to use
the El Escorial criteria because the Gold Coast criteria, while designed to enhance
early diagnosis in clinical settings, may carry a higher risk of overdiagnosis, potentially
including cases of ALS-mimic syndromes. Moreover, the El Escorial criteria remain
the standard in clinical research, ensuring greater diagnostic specificity within
study cohorts. Future studies incorporating the Gold Coast criteria may offer further
insights into the relationship involving weight loss, disease progression, and survival,
while also assessing the potential impact of broader diagnostic inclusion.
In conclusion, the current study highlights the significant impact of weight loss
and disease progression on survival in ALS patients, emphasizing the importance of
early nutritional and clinical interventions. The findings underscore the critical
need for comprehensive, multidisciplinary care strategies to address key prognostic
factors and improve patient outcomes. However, the study has several limitations,
including its retrospective design, incomplete data on progression rate and submission
to gastrostomy, and reliance on data from a single reference center in Brazil. Additionally,
information on the adequacy of energy and nutrient intake was not collected. Despite
these limitations, epidemiological studies examining the relationship involving demographic
and clinical characteristics and survival in ALS patients in Brazil remain scarce.
The present study provides valuable insights into patient outcomes, particularly the
role of weight loss percentage at diagnosis and its influence on survival following
PEG placement. Future multicenter cohort studies with larger sample sizes are needed
to deepen our understanding of these critical issues. Our findings reinforce the importance
of timely, targeted interventions and multidisciplinary care to improve the prognosis
and quality of life for ALS patients.
