ABSTRACT
Objective
Conflicting findings have been reported on the association between military service and the risk of motor neuron disease (MND) whereas the clinical characteristics of MND patients with previous military service have rarely been described.
Methods
We conducted a nationwide nested case–control study, including 1452 incident cases of MND diagnosed during 2015–2023 according to the Swedish MND Quality Registry and 7276 age‐ and sex‐matched controls identified from the Swedish Total Population Register. Conditional logistic regression was used to assess the risk of MND in relation to previous military service. We also described the clinical characteristics of MND patients with military service.
Results
Ten MND patients (0.7%) and 62 controls (0.9%) had previous military service. No association was found between military service and future risk of MND (OR = 0.71; 95% CI: 0.36–1.40). Compared with other patients, MND patients with previous military service appeared to have a lower age at diagnosis, a higher prevalence of non‐bulbar onset, as well as a longer survival.
Conclusions
Military service was not associated with the risk of MND. MND patients with military service appeared to demonstrate a different phenotype compared to other MND patients.
Keywords: military service, MND, nested case–control study, Sweden
1. Introduction
Motor neuron disease (MND) is a relatively rare neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to a decline in various motor functions [1]. MND is comprised of amyotrophic lateral sclerosis (ALS), accounting for approximately 90% of cases, primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and other MNDs [2]. Although genetic predisposition, advanced age, and sex are established risk factors for MND, various environmental risk factors have also been proposed [3]. Exposure to a hazardous working environment and occupations involving toxic chemicals have, for instance, been proposed in the development of ALS due to their neurotoxic effects, impairing the structural integrity and functionality of the nervous system [4, 5, 6].
Particular attention has been given to the link between military service and ALS, potentially through exposure to heavy metals like lead, pesticides, and burning chemicals [7]. A previous meta‐analysis reported an increased risk of ALS among individuals with military service experience [8]. This result, however, was later contradicted by null findings from population‐based studies conducted in the USA, Denmark, and Sweden [3, 9, 10]. The conflicting results might be due to different factors like small sample size and potentially biased control selection in some studies. Further, few studies have examined whether military service would influence the clinical characteristics of ALS, at the time of diagnosis or thereafter. To this end, we used the Swedish population and health registers, including the Swedish Motor Neuron Disease (MND) Quality Registry, and conducted a nationwide nested case–control study to investigate the association of previous military service with the risk of MND and to describe the phenotype of MND patients with such occupational exposure.
2. Methods
2.1. Study Population
The Swedish MND Quality Registry includes information on patients diagnosed with different forms of MND in Sweden from 2015 onward [11]. This study included 1452 patients with a newly diagnosed MND, including definite, probable, or possible ALS, PLS, PSMA, and unspecified MND, between January 2015 and August 2023 identified from this registry. Using the method of incidence density sampling [12], we randomly selected from the Swedish Total Population Register five population controls per MND case, who were free of MND until the index date (i.e., the date of diagnosis of the MND case) and individually matched to the MND case by age and sex. The MND Quality Registry includes about 80% of all MND patients in Sweden; we therefore linked the controls to the Swedish Patient Register [13], which includes information on inpatient care since 1964 and hospital‐based outpatient care since 2001 in Sweden, to identify potential MND cases among the controls using the Swedish personal identity number. A hospital visit concerning MND was identified using different ICD codes (ICD‐7 code: 355.0; ICD‐8 code: 348.0; ICD‐9 code: 335.2; ICD‐10 code: G12.2) and four controls were excluded from the analysis due to such avisit.
2.2. Ascertainment of Military Service
To collect information on occupational history, we linked the cases and controls to the Swedish Population and Housing Census (FoB) and the Swedish Longitudinal Integrated Database for Health Insurance and Labour Market Studies (LISA) which have collected information on socioeconomic status among Swedish residents since the 1960s. Military service was identified using an occupational code, an educational code, and a military branch code (please find details in the Materials S1).
2.3. Statistical Analysis
We first described the characteristics of the cases and their individually matched controls. A conditional logistic regression model was then used to assess the risk of MND in relation to military service, after adjustment for educational attainment at index date as a potential confounder, according to LISA. Given the individually matched design and incidence density sampling, age, sex, and calendar time were inherently adjusted for in the analysis. Finally, we described the clinical characteristics at the time of diagnosis and thereafter for all MND patients with previous military service in contrast to all MND patients. To address the potential influence of age and sex, we also selected a sample of age‐matched (±1 year) male MND patients who had no military service as a comparison.
3. Results
We included 1452 incident MND patients (1032 ALS, 44 PLS, 66 PSMA, 310 unspecified MND) and 7276 controls in the analysis. Cases and controls had a median age of approximately 67 years at the index date, and 44.5% of the cases were women (Table 1). Ten MND patients (0.7%) and 62 controls (0.9%) had previous military service. No significant association was found between military service and a future risk of MND (OR = 0.71; 95% CI: 0.36–1.40).
TABLE 1.
Baseline characteristics of MND patients and their individually matched population controls.
| Characteristics | Cases, N = 1452 | Controls, N = 7276 |
|---|---|---|
| Age, years | 67.3 (11.6) | 67.3 (11.6) |
| Sex, N (%) | ||
| Male | 807 (55.6) | 4041 (55.5) |
| Female | 645 (44.4) | 3235 (44.5) |
| BMI at diagnosis, kg/m2, mean (SD) | 24.2 (4.3) | |
| Education attainment, N (%) | ||
| < 9 years | 151 (10.4) | 973 (13.4) |
| 9–10 years | 147 (10.1) | 789 (10.8) |
| Upper‐secondary | 601 (41.4) | 3159 (43.4) |
| Post‐secondary < 2 years | 82 (5.6) | 356 (4.9) |
| Post‐secondary ≥ 2 years | 437 (30.1) | 1845 (25.4) |
| Postgraduate | 26 (1.8) | 80 (1.1) |
| Unkown | 8 (0.6) | 74 (1.0) |
| MND subtypes, N (%) | ||
| ALS | 1032 (71.1) | |
| PLS | 44 (3.0) | |
| PSMA | 66 (4.6) | |
| UMND | 310 (21.3) | |
| Bulbar onset, N (%) | 275 (18.9) | |
| Familial disease, N (%). | ||
| Yes | 59 (4.1) | |
| No | 495 (34.1) | |
| Unkown | 898 (61.9) | |
| ALSFRS‐R at diagnosis, mean (SD) | 36.6 (8.2) | |
| Progression rate at diagnosis, median (P25‐P75) | 0.7 (0.3–1.4) | |
| Diagnostic delay, months, median (P25‐P75) | 12.2 (7.3–20.4) | |
| Riluzole, N (%) | 1033 (71.1) | |
| Invasive ventilation, N (%) | ||
| Yes | 20 (1.4) | |
| No | 480 (33.0) | |
| Unkown | 952 (65.6) | |
| PEG, N (%) | ||
| Yes | 284 (19.6) | |
| No | 135 (9.3) | |
| Unkown | 1033 (71.1) | |
| History of military service | ||
| Yes | 10 (0.7) | 62 (0.9) |
| No | 1442 (99.3) | 7214 (99.1) |
| Military subtypes, N (%) | ||
| Military officer | 1 (10.0) | 5 (8.1) |
| Air defense | 1 (10.0) | 4 (6.4) |
| Army defense | 0 (0.0) | 5 (8.1) |
| Navy defense | 0 (0.0) | 3 (4.8) |
| Joint defense | 4 (40.0) | 10 (16.1) |
| Unclassified defense | 4 (40.0) | 35 (56.5) |
Abbreviations: ALS, Amyotrophic Lateral Sclerosis; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale—revised; BMI, body mass index; MND, motor neuron disease; PEG, percutaneous endoscopic gastrostomy; PLS, primary lateral sclerosis; PSMA, progressive spinal muscular atrophy; UD, unclassfied defense; UMND, unspecified motor neuron disease.
Table 2 presents the characteristics of the 10 MND patients with military experience, among whom the mean age at diagnosis was 63 years and all were men. All patients had a non‐bulbar onset with symptoms starting in the hands, arms, legs, or feet, and half of these patients received riluzole. Due to missing information, we only observed one patient (10%) with percutaneous endoscopic gastrostomy, and no patient had invasive ventilation. By the end of follow‐up (August 5, 2023), 60% of the patients had died, with a median survival time of 22.8 months. In comparison, among all the 1452 MND patients, 81.1% experienced non‐bulbar onset, 74.0% died by the end of follow‐up with a median survival of 15.9 months, 71.1% used riluzole, 19.6% underwent gastrostomy, and 1.4% received invasive ventilation. The sample of age‐matched male MND patients without military service (N = 363) also demonstrated a higher prevalence of bulbar onset (14.3%), a higher frequency of riluzole (74.7%) and gastrostomy (17.9%) use, a higher risk of death by the end of follow‐up (74.7%), and a shorter survival among the deceased patients (median = 16.0 months).
TABLE 2.
Clinical characteristics of the ten MND patients with a history of military service.
| Characteristics | Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | Case 6 | Case 7 | Case 8 | Case 9 | Case 10 |
|---|---|---|---|---|---|---|---|---|---|---|
| BMI at diagnosis, kg/m2 | 33.2 | 24.0 | 21.5 | 24.5 | 22.8 | 19.9 | 24.8 | 24.0 | 22.2 | 22.1 |
| Educational attainment | Upper‐secondary | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Post‐secondary ≥ 2 years | Upper‐secondary |
| MND subtypes | ALS | UMND | ALS | ALS | ALS | UMND | ALS | UMD | ALS | ALS |
| Bulbar onset | No | No | No | No | No | No | No | No | No | No |
| Familial disease | No | No | Yes | |||||||
| Year of diagnosis | 2021 | 2019 | 2022 | 2017 | 2020 | 2020 | 2016 | 2016 | 2018 | 2020 |
| ALSFRS‐R at diagnosis | 34 | 39 | 33 | 35 | ||||||
| Progression rate at diagnosis | 1.03 | 0.47 | 1.19 | 0.16 | 7.27 | |||||
| Survival status by the end of follow up | Dead | Dead | Alive | Dead | Alive | Dead | Dead | Alive | Alive | Dead |
| Survival time, months | 11.3 | 20.3 | 8.7 | 25.4 | 42.4 | 17.4 | 46.7 | 82.7 | 62.0 | 2.2 |
| Riluzole | No | Yes | No | Yes | Yes | No | Yes | No | No | Yes |
| Invasive ventilation | No | No | ||||||||
| PEG | No | Yes |
Abbreviations: ALS, Amyotrophic Lateral Sclerosis; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale—revised; BMI, body mass index; MND, motor neuron disease; PEG, percutaneous endoscopic gastrostomy; PLS, primary lateral sclerosis; PSMA, progressive spinal muscular atrophy; UD, unclassfied defense; UMND, unspecified motor neuron disease.
4. Discussion
Based on data from Swedish population and health registers, including the Swedish MND Quality Registry, the findings of the present population‐based case–control study align with those of previous studies conducted in the USA, Sweden, and Denmark demonstrating a lack of association between military service and a future risk of MND (USA: OR = 1.09; 95% CI: 0.67–1.78; Sweden, OR = 0.77; 95% CI: 0.52–1.14; Denmark, OR = 1.15; 95% CI: 0.92–1.43) [3, 9, 10]. However, these results differ from two other studies in the USA and Denmark, which suggested an increased risk of ALS among armed force personnel (USA, RR = 1.92; 95% CI: 1.29–2.84; Denmark, OR = 1.3; 95% CI: 1.1–1.6), particularly air force personnel (USA, RR = 2.68; 95% CI: 1.24–5.78; Denmark, OR = 1.5; 95% CI: 1.0–2.3) [14, 15]. Given the small number of MND patients with military experience, we did not examine specific military branches in this study.
Different reasons might underlie the contrasting findings between these studies. First, some of the military personnel included in the studies from the USA and Denmark [3, 9] might have directly or indirectly participated in combat missions or training when deployed (e.g., Gulf War, World War II, the Korean War, the Vietnam War, or post‐9/11 conflicts) and might have been exposed to neurotoxic agents and bodily injuries [7, 10, 16, 17]. In contrast, Swedish military personnel have rarely been deployed abroad for any modern conflict, indicating a lower level of relevant exposure. There might also be a cohort effect. In our study, the recruitment period of MND cases spanned from 2015 to 2023 whereas the study period was from 1982 to 2009 in the Danish study [9] and from 1990 to 2000 in the US study [3]. Differences in the level of exposure to neurotoxic agents over time (pre‐2000, 2000–2010, and 2010‐present) due to other factors, such as new protective measures and updated military training programs, could also contribute to the different results. Finally, a substantial sex difference exists in the study populations of these studies. In our study, less than 50% of the MND patients were women, compared to about 25% in the Danish study [9] and 12% in the US study [3]. Regardless, the small number of MND patients with military experience in the present study might have contributed to an inflated chance of a false negative finding.
The study is among the first to describe the clinical characteristics of MND patients with a previous military experience both at the time of diagnosis and thereafter. Identifying the clinical characteristics of MND in relation to military experience might assist in risk stratification and disease phenotyping. Although the number of patients with previous military exposure is small in the present study, these patients appeared to differ from all MND patients in Sweden, by demonstrating a lower age at diagnosis, a higher prevalence of non‐bulbar onset, and a longer survival. Given the large degree of missing information on treatment, the difference noted in the use of invasive ventilation and gastrostomy should be interpreted with caution. Regardless, if these differences are observed in studies of independent samples, it suggests that MND patients with a history of military service might constitute a phenotypically distinct subgroup. The lack of data on specific exposures related to military service, such as trauma, exposure to metals and chemicals, physical activity, deployment, etc. is a limitation of the study. Finally, generalizability of the present findings to other military populations remains unknown.
In conclusion, military service in Sweden was not associated with the risk of MND. Further, compared to other MND patients, MND patients with military service demonstrated a lower age at diagnosis, a higher prevalence of non‐bulbar onset, and a longer survival.
Author Contributions
Tian Xiao: drafting/revision of the manuscript for content, including medical writing for content; study concept or design, analysis or interpretation of data. Charilaos Chourpiliadis: revision of the manuscript for content and major role in the acquisition of data. Anette Linnersjö: revision of the manuscript for content and interpretation of data. Caroline Ingre: revision of the manuscript for content. Rayomand Press: revision of the manuscript for content. Kristin Samuelsson: revision of the manuscript for content. Jenny Selander: revision of the manuscript for content and interpretation of data. Fang Fang: revision of the manuscript for content, major role in the acquisition of data, study concept or design, and interpretation of data.
Disclosure
The authors have nothing to report.
Ethics Statement
This study was approved by the Swedish Ethical Review Authority (DNR: 2022–02314‐01). Given the register‐based nature of this study, informed consent was waived by this approval. Information related to the disclosure of any recognizable participants was removed, ensuring compliance with publication standards and ethical requirements.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Data S1.
Xiao T., Chourpiliadis C., Linnersjö A., et al., “Military Service and Motor Neuron Disease—Evidence From the Swedish Motor Neuron Disease Quality Registry,” European Journal of Neurology 32, no. 8 (2025): e70311, 10.1111/ene.70311.
Funding: This work was supported by the US Center for Disease Control and Prevention, R01TS000348, the Swedish Research Council, 2023‐02428.
Data Availability Statement
Data are not publicly available due to Swedish and European regulations. Please contact the corresponding author for more information.
References
- 1. Feldman E. L., Goutman S. A., Petri S., et al., “Amyotrophic Lateral Sclerosis,” Lancet 400 (2022): 1363–1380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Imrell S., Fang F., Ingre C., and Sennfält S., “Increased Incidence of Motor Neuron Disease in Sweden: A Population‐Based Study During 2002–2021,” Journal of Neurology 271 (2024): 2730–2735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Andrew A. S., Caller T. A., Tandan R., et al., “Environmental and Occupational Exposures and Amyotrophic Lateral Sclerosis (ALS) in New England,” Neurodegenerative Diseases 17 (2017): 110–116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Marin B., Fontana A., Arcuti S., et al., “Age‐Specific ALS Incidence: A Dose‐Response Meta‐Analysis,” European Journal of Epidemiology 33 (2018): 621–634. [DOI] [PubMed] [Google Scholar]
- 5. Goldstein G. W., “Lead Poisoning and Brain Cell Function,” Environmental Health Perspectives 89 (1990): 91–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Sainio M. A., “Neurotoxicity of Solvents,” Handbook of Clinical Neurology 131 (2015): 93–110. [DOI] [PubMed] [Google Scholar]
- 7. McKay K. A., Smith K. A., Smertinaite L., Fang F., Ingre C., and Taube F., “Military Service and Related Risk Factors for Amyotrophic Lateral Sclerosis,” Acta Neurologica Scandinavica 143 (2021): 39–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Tai H., Cui L., Shen D., Li D., Cui B., and Fang J., “Military Service and the Risk of Amyotrophic Lateral Sclerosis: A Meta‐Analysis,” Journal of Clinical Neuroscience 45 (2017): 337–342. [DOI] [PubMed] [Google Scholar]
- 9. Dickerson A. S., Hansen J., Kioumourtzoglou M.‐A., Specht A. J., Gredal O., and Weisskopf M. G., “Study of Occupation and Amyotrophic Lateral Sclerosis in a Danish Cohort,” Occupational and Environmental Medicine 75 (2018): 630–638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Peters T. L., Kamel F., Lundholm C., et al., “Occupational Exposures and the Risk of Amyotrophic Lateral Sclerosis,” Occupational and Environmental Medicine 74 (2017): 87–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Longinetti E., Regodón Wallin A., Samuelsson K., et al., “The Swedish Motor Neuron Disease Quality Registry,” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 19 (2018): 528–537. [DOI] [PubMed] [Google Scholar]
- 12. Richardson D. B., “An Incidence Density Sampling Program for Nested Case‐Control Analyses,” Occupational and Environmental Medicine 61 (2004): e59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Ludvigsson J. F., Andersson E., Ekbom A., et al., “External Review and Validation of the Swedish National Inpatient Register,” BMC Public Health 11 (2011): 450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Seals R. M., Kioumourtzoglou M.‐A., Gredal O., Hansen J., and Weisskopf M. G., “ALS and the Military: A Population‐Based Study in the Danish Registries,” Epidemiology (Cambridge, Mass.) 27 (2016): 188–193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Horner R. D., Kamins K. G., Feussner J. R., et al., “Occurrence of Amyotrophic Lateral Sclerosis Among Gulf War Veterans,” Neurology 61 (2003): 742–749. [DOI] [PubMed] [Google Scholar]
- 16. Chen H., Richard M., Sandler D. P., Umbach D. M., and Kamel F., “Head Injury and Amyotrophic Lateral Sclerosis,” American Journal of Epidemiology 166 (2007): 810–816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Beard J. D. and Kamel F., “Military Service, Deployments, and Exposures in Relation to Amyotrophic Lateral Sclerosis Etiology and Survival,” Epidemiologic Reviews 37 (2015): 55–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
Data are not publicly available due to Swedish and European regulations. Please contact the corresponding author for more information.