Comorbidity in amyotrophic lateral sclerosis: structure and prognostic aspects

Full Text

Introduction

Amyotrophic lateral sclerosis (ALS) is a chronic degenerative disease of the nervous system that predominantly affects motor neurons and manifests as progressive muscle weakness, bulbar syndrome, and respiratory failure. Key pathogenetic mechanisms of ALS include oxidative stress, glutamate excitotoxicity, impaired proteostasis with aggregation of pathological proteins (TDP-43), and mitochondrial dysfunction. In a subset of patients, a monogenic form of the disease is identified due to mutations in genes such as SOD1, C9orf72, TARDBP, FUS and others. Life expectancy in ALS is 2–5 years. Current treatment is largely palliative [1].

Comorbid conditions are common in patients with ALS and may negatively impact the disease course [2]. Their prevalence may vary considerably across populations, highlighting the need to study this issue in different ethnogeographic groups. The relationship between various types of comorbidity and ALS is of substantial interest. Such data could improve our understanding of disease pathogenesis and inform new approaches to pathogenetic and palliative therapy.

The study aim is to analyze the structure of comorbid conditions in ALS and their impact on disease course and prognosis.

Materials and methods

We conducted a retrospective analysis of electronic medical records of patients with ALS (G12.2 according to ICD-10) residing in the Republic of Bashkortostan, who were diagnosed according to the El Escorial criteria [3] between 2013 and 2024. At the screening stage, records of patients with a questionable diagnosis not meeting the diagnostic criteria were excluded.

We analyzed clinical and medical history data obtained during neurological examination, demographic characteristics, age at diagnosis and at symptom onset, social status at diagnosis (employed, unemployed, retired, disabled), disease onset type (spinal, bulbar), and phenotypic variant (classic form, ALS with frontotemporal dementia, primary lateral sclerosis). Survival was calculated from symptom onset and from diagnosis to death, as well as the disease progression rate using the formula [4, 5]:

(48 — ALSFRS-R score at diagnosis) / disease duration in months up to the first assessment.

A progression rate of < 0.5 was defined as slow, 0.5 to 1.0 as moderate, and ≥ 1.0 as rapid [4].

We recorded chronic comorbidities present at the time of ALS diagnosis, regularly used medications, as well as external exposures and surgeries occurring within 10 years prior to disease onset. To assess the cumulative burden of chronic comorbidities potentially affecting survival, the Charlson Comorbidity Index (CCI) was calculated, which includes 19 pathological conditions with weights from 1 to 6; one point was added for every 10 years of age over 40 [6].

Statistical analysis was performed using IBM SPSS Statistics v. 27 (IBM). Normality of distribution was assessed using the Kolmogorov–Smirnov test. As the data were non-normally distributed, non-parametric methods were used. Data are presented as median and interquartile range (IQR). Correlations were assessed using Spearman's rank correlation coefficient. Binary data were compared using the chi-square test; Fisher's exact test was applied when the expected frequency in 20% or more of cells was less than 5. Ordinal and continuous data were compared using the Mann–Whitney U test; comparisons across more than two groups were performed using the Kruskal–Wallis test. Given the exploratory nature of the study, no correction for multiple comparisons was applied.

To assess the independent effect of comorbidities on survival in ALS patients, a multivariate Cox proportional hazards regression model was used. The dependent variable was time from diagnosis to death (in months). As all patients included in the study reached the endpoint (death), there were no censored observations.

The model included the CCI, as well as factors previously shown to significantly affect survival in ALS patients (sex, disease onset type, progression rate, and forced vital capacity) [7]. Male sex was used as the reference category. Age was excluded from the independent variables due to collinearity with the CCI.

The independent effect of comorbidities on ALS progression rate was assessed using linear regression analysis. The dependent variable was the ALS progression rate. Independent variables were selected using the same approach as in the Cox regression model. A p-value < 0.05 was considered statistically significant.

Results

A total of 541 electronic medical records were reviewed. Analysis of the available clinical and laboratory-instrumental data confirmed a diagnosis of ALS or primary lateral sclerosis in 336 patients. Among these, classic ALS with simultaneous involvement of upper and lower motor neurons was present in 312 (92.8%) patients; the remainder had either ALS with frontotemporal dementia or primary lateral sclerosis. All 336 patients were included in the study. Of these, 217 patients had definite ALS according to the El Escorial criteria, and 99 had probable ALS. All patients met the Gold Coast criteria [8]. The patient selection process is illustrated in Figure 1. Baseline characteristics of the study participants are summarized in Table 1. None of the 336 patients received disease-modifying therapy for ALS.

 

Figure 1. Patient selection flowchart.

 

Table 1. Main characteristics of included patients with ALS

Parameter	Variable (n = 336)
Age, years (Ме [Q1; Q3])	60.00 [53.00; 67.00]
Sex, n (%):
male	169 (50.3%)
female	167 (49.7%)
Phenotypic variants, n (%):
classic form	312 (92.8%)
ALS with frontotemporal dementia	15 (4.5%)
primary lateral sclerosis	9 (2.7%)
Classic ALS onset type (n = 312), n (%):
spinal	207 (66.3%)
bulbar	105 (33.7%)
Age at symptom onset, years (Ме [Q1; Q3])	59.00 [52.00; 65.00]
Age at symptom onset by group, n (%):
< 45 years	25 (7.4%)
45–70 years	263 (78.3%)
> 70 years	48 (14.3%)
Time to diagnosis, months (Ме [Q1; Q3])	12.00 [8.00; 19.00]
Disease duration from symptom onset, months (Ме [Q1; Q3])	29.00 [20.00; 41.00]
Disease duration from diagnosis, months (Ме [Q1; Q3])	14.0 [9.00; 24.00]
Progression rate (Ме [Q1; Q3])	1.12 [0.56; 2.00]
Progression rate category, n (%):
slow (< 0.5)	74 (22.0%)
moderate (0.5–1.0)	85 (25.3%)
rapid (> 1.0)	177 (52.7%)
Forced vital capacity, L (Ме [Q1; Q3])	2.38 [1.78; 3.39]
Gastrostomy, n (%):
performed	20 (5.95%)
not performed	316 (94.05%)
Non-invasive ventilation, n (%):
performed	5 (1.48%)
not performed	331 (98.52%)

 

Post-hoc power analysis was performed using GPower v. 3.1. It showed that with n = 336 and α = 0.05, the study had 80% power to detect a small effect (Cohen's d = 0.31) in the overall cohort, but in subgroups with n < 30, only large effects (d ≥ 0.8) could be detected. A priori power calculation was not performed due to the exploratory nature of the study and the lack of prior data on effect size.

Chronic comorbid conditions were documented in 222 (66.1%) patients with ALS. The most frequent comorbidities were cardiovascular diseases, present in 195 patients (58%). The structure of comorbid conditions in ALS patients is presented in Table 2. Diseases occurring in isolated cases were grouped under "Other diseases".

 

Table 2. Structure of comorbid conditions in patients with ALS (n = 336)

Disorders	Number of cases
	n	%
Hypertension	138	41.1
Coronary artery disease without atrial fibrillation	24	7.1
Coronary artery disease with atrial fibrillation	5	1.5
History of myocardial infarction	13	3.9
History of stroke	15	4.5
Type 2 diabetes mellitus	17	5.1
Thyroid disorders	23	6.8
Malignancies	8	2.4
Gastrointestinal disorders	38	11.3
Pelvic organ disorders (benign prostatic hyperplasia, uterine fibroids, polyps)	15	4.5
Respiratory diseases	26	7.7
Musculoskeletal disorders	14	4.2
Other diseases	43	12.8

 

Other neurodegenerative diseases prior to ALS were documented in 9 cases (2.7%). These included Parkinson's disease, and isolated cases of Alzheimer's disease and progressive supranuclear palsy [9, 10]. COVID-19 within one year prior to ALS onset was confirmed in 12 patients (3.6%).

Regular medication use before the diagnosis of ALS was reported in 179 patients (53.3%). One-quarter of the patients (n = 87) were taking cardiovascular drugs (antihypertensives, antianginal agents, antiarrhythmics). The main medication groups regularly used by ALS patients are shown in Figure 2.

 

Figure 2. Main medication groups regularly used by ALS patients before disease onset.

 

Data on smoking and stressful life events prior to ALS onset were available for 300 patients. Significant negative life events (e.g., death or serious illness of a close relative, divorce, etc.) within 6 months before symptom onset were reported by 84 patients (25%). A history of cigarette smoking was reported by 114 patients (34%). The structure of external exposures, including injuries, is presented in Table 3.

 

Table 3. Structure of external exposures, including injuries, recorded in ALS patients (n = 336) within 10 years prior to diagnosis

External exposures	Number of cases
	n	%
Head injuries	17	5.1
Trunk injuries	10	3.0
Spinal injuries	9	2.7
Limb injuries	27	8.0
Other injuries	2	0.6
Current smoking at diagnosis (n = 300)	45	13.5
History of smoking (n = 300)	69	20.5
Stress within 6 months before symptom onset (n = 300)	84	25.0

 

A history of surgical interventions was reported in 133 patients (39.6%), of which 107 (31.8%) were performed under general anesthesia and 47 (14%) under local anesthesia. Within 12 months prior to ALS symptom onset, 36 patients (10.7%) had undergone surgery, while 87 patients (25.9%) had surgery more than 12 months before. The structure of surgical interventions is presented in Table 4.

 

Table 4. Structure of surgical interventions in ALS patients (n = 336)

Procedures	Number of cases
	n	%
Orthopedic surgeries	15	4.5
Abdominal surgeries	44	13.1
Brain surgeries	3	0.9
Cardiac surgeries	16	4.8
Vascular surgeries of the limbs	7	2.1
Tumor resections	6	1.8
Pelvic surgeries	25	7.4
Inguinal hernia repair	11	3.3
Skin lesion removal (basal cell carcinoma, nevus)	9	2.7
Spine surgeries	9	2.7
Kidney surgeries (nephrectomy, renal cyst, urolithiasis)	6	1.8
Thyroid surgeries	2	0.6
ENT surgeries	11	3.3
Ocular surgeries	9	2.7
Other procedures (mediastinal lipoma, scalenotomy, median nerve neurolysis, lung lobectomy, reduction mammoplasty, neck phlegmon)	8	2.4

 

Comparative analysis showed that patients with ALS onset after age 70 had a higher prevalence of coronary artery disease (p = 0.012) and were more likely to use antihypertensive, antianginal, and antiarrhythmic drugs (p = 0.022) compared to patients with onset between 45 and 70 years. Patients in the older age group underwent surgery more frequently than middle-aged patients, particularly for kidney disease (p < 0.001), pelvic organ disorders (p = 0.005), and eye conditions (p = 0.015). Patients with ALS onset after age 70 were also more likely to have undergone surgery within 1 year before symptom onset (p = 0.050) and to have had procedures under local anesthesia (p = 0.030) compared to the 45–70-year age group.

Thyroid disorders were more common in patients with bulbar onset than in those with spinal onset: 11 (10.5%) vs. 9 (4.5%); p = 0.044. Patients with spinal onset underwent surgery more frequently overall (28 (13.9%) vs. 5 (4.8%); p = 0.014), and specifically spine surgery (8 (4.0%) vs. 0 (0%); p = 0.038) within 1 year before symptom onset.

Analysis of the impact of comorbidities and surgical interventions on prognosis showed that they may negatively affect survival in ALS patients. Patients with hypertension had a median survival from symptom onset of 27.00 [18.00; 37.75] months, compared to 31.50 [21.00; 48.25] months in those without hypertension (p = 0.015). Survival was twice as short in patients who had undergone kidney surgery (15 [11.00; 21.00] vs. 30 [20.00; 41.50] months; p = 0.009), and their ALS progression rate was twice as high (2.67 [1.82; 3.04] vs. 1.29 [0.71; 2.19]; p = 0.025).

The mean CCI in ALS patients was 3.00 [2.00; 3.00]. Patients with onset after age 70 had a higher CCI (4.00 [4.00; 4.75]) than those with onset between 45 and 70 years (3.00 [2.00; 3.00]); p < 0.001. Patients with rapid disease progression had a higher CCI than those with slow or moderate progression: 3.00 [2.00; 4.00], 2.00 [2.00; 3.00], and 3.00 [2.00; 3.00], respectively; p = 0.007. Correlation analysis revealed a weak negative correlation between the CCI and survival from symptom onset (r = –0.233; p < 0.001), as well as from diagnosis (r = –0.252; p < 0.001), and a positive correlation with disease progression rate (r = 0.201; p = 0.002).

To clarify the effect of comorbidity on survival after diagnosis, multivariate Cox regression analysis was performed (Table 5). The covariates included the CCI, as well as parameters previously shown to affect survival in ALS patients: sex, progression rate, ALS onset type (bulbar/spinal), and forced vital capacity at the initial visit [11].

 

Table 5. Multivariate Cox regression analysis results

Parameter	Beta coefficient (B)	Standard error	Significance	Exp(B)	95% confidence interval for Exp(B)
Sex	–0.342	0.238	0.150	0.711	0.446–1.132
Charlson Comorbidity Index	0.106	0.098	0.277	1.112	0.918–1.347
Forced vital capacity	–0.471	0.116	< 0.001	0.624	0.497–0.783
Classic ALS onset type	0.024	0.113	0.835	1.024	0.820–1.278
Progression rate	0.209	0.048	< 0.001	1.233	1.122–1.354

 

Table 6. Linear regression analysis results

Parameter	Unstandardized coefficients		Standardized coefficients Beta	t	95% confidence interval for B
	B	standard error
Constant	2.200	1.037		0.035	0.152–4.249
Sex	–0.834	0.369	–0.192	0.025	–1.564–(–0.104)
Forced vital capacity	–0.068	0.207	–0.030	0.742	–0.477–0.341
Charlson Comorbidity Index	0.356	0.163	0.183	2.176	0.031–0.033
Classic ALS onset type	–0.069	0.179	–0.031	0.699	–0.424–0.285

 

Independent factors negatively affecting survival from diagnosis were lower forced vital capacity and higher disease progression rate.

To identify independent predictors of disease progression rate, linear regression analysis was performed. It showed that male sex and a higher CCI were independent predictors of faster ALS progression. The regression model explained 9% of the variance in the dependent variable (R² = 0.09).

Discussion

Analysis of data from 336 patients with ALS revealed a substantial prevalence of comorbidity in this patient group, documented in 66% of cases. Comorbid conditions and a history of surgery were associated with shorter survival.

Cardiovascular diseases predominated in the comorbidity structure (58%), with hypertension being the most frequent (41%). Coronary artery disease was significantly more common in patients with later ALS onset. A previous meta-analysis showed that the prevalence of cardiovascular comorbidity in ALS varies widely across populations (from 4% to 56%) [12]. In the present study, the frequency of hypertension was at its highest, which may be related to the high proportion of elderly patients in the sample. However, the prevalence of hypertension among ALS patients did not exceed that in the general Russian population, which is approximately 44% [13]. Some authors have reported that hypertension negatively affects survival in ALS patients. This may occur through autonomic dysfunction, which is frequently observed in ALS [14] and may increase the risk of cardiovascular decompensation. Cardiovascular diseases may also exacerbate respiratory impairment, which develops at advanced disease stages [12].

Thyroid disorders were relatively common in ALS (6.8%), approximately four times higher than in the general population [15]. They were more frequent in patients with the bulbar form of the disease. It is plausible that altered thyroid status may negatively affect energy metabolism and the severity of oxidative stress in corticobulbar motor neurons [16]. However, given the small number of observations (23 patients) and the results of previous studies [17], the association between ALS and thyroid disorders remains unclear and requires cautious interpretation.

Approximately one-quarter of patients reported a stressful life event within 6 months prior to ALS onset. The diverse pathological effects of stress suggest a possible link with ALS development; however, the study design does not permit conclusions about causal relationships.

Among surgical interventions, kidney surgery was associated with shorter survival in ALS¹. The frequency of kidney surgery did not exceed the general population average (2–5%) [18]. Kidney damage may have several negative effects, including the development of a systemic inflammatory response with immunosuppression, reduced erythropoietin production, impaired vitamin D metabolism, increased sympathetic nervous system activity, and others [19].

Patients with spinal-onset ALS had significantly more surgical interventions overall, and spine surgeries in particular, within 10 years before symptom onset compared to those with bulbar onset. The higher frequency of spine surgeries in patients with spinal onset is likely related to misdiagnosis of ALS at an early stage. However, surgical trauma in general may be associated with the development of spinal-onset ALS. It is hypothesized that this association is mediated by a systemic inflammatory response and other factors that may damage peripheral motor neuron axons, triggering their degeneration in the context of genetic predisposition [19, 20].

Comorbidity may negatively affect the course of ALS [2]. In this cohort, the CCI, which reflects the burden of chronic conditions potentially affecting mortality, was significantly correlated with both the ALS progression rate and survival in correlation analysis. However, multivariate Cox regression analysis showed that the CCI was not an independent predictor of survival in ALS patients. The effects of comorbidity are likely mediated indirectly, through worsening of respiratory function and acceleration of disease progression. The CCI, along with male sex, was an independent predictor of disease progression rate. However, the model explained only 9% of the variance in progression rate, underscoring the substantial contribution of other factors, including genetic ones, to disease progression.

Limitations of this study include its retrospective design, the regional nature of the cohort, and the lack of genetic data. The small number of patients with certain comorbidities or surgical procedures limits the reliability of conclusions regarding their association with survival. Interpretation of the observed association between stress and ALS onset requires caution, as the assessment was retrospective and subject to recall bias. The inclusion of patients with primary lateral sclerosis in the cohort may have increased sample heterogeneity.

Conclusion

Patients with ALS present a wide range of comorbid conditions. Cardiovascular diseases, particularly hypertension, account for the largest proportion; however, their prevalence does not exceed population averages. An association was also found between surgical interventions and spinal-onset ALS. Based on the obtained data, it can be hypothesized that comorbidity may be associated with shorter survival in ALS patients through a negative impact on respiratory function and acceleration of disease progression.

Future studies should clarify the mechanisms underlying the negative effects of comorbidity on ALS course. This would advance our understanding of disease pathogenesis and may identify new therapeutic targets. From a practical standpoint, managing somatic comorbidity is important in the context of palliative care. The effects of comorbidity on ALS course in patients with different genetic backgrounds warrant further investigation.

¹ National Cancer Institute. SEER Cancer Stat Facts: Kidney and Renal Pelvis Cancer. Bethesda; 2025. URL: https://seer.cancer.gov/statfacts/html/kidrp.html (data of access: 18.03.2025).

About the authors

Ekaterina V. Pervushina

Bashkir State Medical University

Email: mansur.kutlubaev@yahoo.com
ORCID iD: 0000-0002-9352-5783

Cand. Sci. (Med.), Assoc. Prof., Department of Neurology

Russian Federation, Ufa

Mansur A. Kutlubaev

Bashkir State Medical University

Author for correspondence.
Email: mansur.kutlubaev@yahoo.com
ORCID iD: 0000-0003-1001-2024

Dr. Sci. (Med.), Head, Department of Neurology

Russian Federation, Ufa

References

Supplementary files