Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis
Abstract
Background: Prior studies have suggested that head injury might be a potential risk factor of amyotrophic lateral sclerosis (ALS). However, the association has not been well established. We aimed to provide a synopsis of the current understanding of head injury’s role in ALS. Methods: We performed a systematic search in PubMed for observational studies that quantitatively investigated the association between head injury and ALS risk published before April 10, 2020. We used a random-effects model to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Fourteen eligible articles including 10,703 cases and 2,159,324 controls were selected in current meta-analysis. We found that head injury was associated with an increased risk of ALS (OR = 1.38, 95% CI: 1.20–1.60) and the association was slightly stronger concerning severe head injury and ALS risk (OR = 1.69, 95% CI: 1.27–2.23). Considering the number of head injuries (N) and ALS risk, the association was weak (OR = 1.23, 95% CI: 1.10–1.37, N = 1; OR = 1.29, 95% CI: 0.89–1.86, N ≥ 2). In addition, a strong association with ALS risk was found in individuals who suffered head injury <1 year (OR = 4.05, 95% CI: 2.79–5.89), and when the time lag was set at 1–5, 5–10, and >10 years, the pooled OR was 1.13, 1.35, and 1.10, respectively. Conclusion: This meta-analysis indicates that head injury, especially severe head injury, could increase ALS risk. Although a strong association is found between head injury <1 year and ALS risk in the current study, this result suggests a possibility of reverse causation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The threefold risk for head injuries occurring less than a year before diagnosis potentially indicates reverse causation.
“The risk was three times as high for injuries occurring less than a year before diagnosis, indicating potentially reverse causation, considering that ALS is a disease with at least 1 year of diagnostic delay.”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
A recent meta-analysis found a positive association between a history of head trauma and risk for ALS.
“A recent meta-analysis by Liu et al. [51] found a positive association between a history of head trauma and risk for ALS.”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
The risk of ALS was three times as high for head injuries occurring less than a year before diagnosis.
“The risk was three times as high for injuries occurring less than a year before diagnosis, indicating potentially reverse causation, considering that ALS is a disease with at least 1 year of diagnostic delay.”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
Both severe and less severe head trauma were associated with an increased risk for ALS.
“Both severe and less severe head trauma were associated with an increased risk for ALS.”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
TDP-43 depositions have been found in animal models following head trauma and in cases of chronic traumatic encephalopathy.
“Additional indications for a role of head trauma in neurodegeneration include the TDP-43 depositions found in animal models following head trauma and in cases of chronic traumatic encephalopathy [51, 52].”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
Head injury has been suggested as a risk factor for several neurodegenerative diseases because head trauma may disrupt the permeability of the blood-brain barrier.
“Head injury has been suggested as a risk factor for several neurodegenerative diseases as head trauma may for instance disrupt the permeability of the blood–brain barrier [51].”
From Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study (2024) · cites this paper as [51]
Cites
Quantifying heterogeneity in a meta‐analysis
Higgins, J. P. T., & Thompson, S. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1186 · Cited by 36,763 · see citing works
Stroup, D. F. (2000) · JAMA · doi:10.1001/jama.283.15.2008 · Cited by 20,623 · see citing works
Stang, A. (2010) · European Journal of Epidemiology · doi:10.1007/s10654-010-9491-z · Cited by 17,396 · see citing works
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280 · see citing works
Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury
McKee, A. C., Cantu, R. C., Nowinski, C. J., Hedley-Whyte, E. T., Gavett, B. E., Budson, A. E., Santini, V. E., Lee, H.-S., Kubilus, C. A., & Stern, R. A. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181a9d503 · Cited by 2,295 · see citing works
The spectrum of disease in chronic traumatic encephalopathy
McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., Lee, H.-S., Hall, G., Wojtowicz, S. M., Baugh, C. M., et al. (2013) · Brain · doi:10.1093/brain/aws307 · Cited by 2,098 · see citing works
The impact of traumatic brain injuries: A global perspective
Hyder, A. A., Wunderlich, C. A., Puvanachandra, P., Gururaj, G., & Kobusingye, O. C. (2007) · Neurorehabilitation · doi:10.3233/nre-2007-22502 · Cited by 1,816 · see citing works
Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury
Shlosberg, D., Benifla, M., Kaufer, D., & Friedman, A. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.74 · Cited by 897 · see citing works
TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy
McKee, A. C., Gavett, B. E., Stern, R. A., Nowinski, C. J., Cantu, R. C., Kowall, N. W., Perl, D. P., Hedley-Whyte, E. T., Price, B., Sullivan, C., et al. (2010) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181ee7d85 · Cited by 659 · see citing works
Neurodegenerative causes of death among retired National Football League players
Lehman, E. J., Hein, M. J., Baron, S. L., & Gersic, C. M. (2012) · Neurology · doi:10.1212/wnl.0b013e31826daf50 · Cited by 638 · see citing works
Global neurotrauma research challenges and opportunities
Rubiano, A., Carney, N., Chesnut, R., & Puyana, J. (2015) · Nature · doi:10.1038/nature16035 · Cited by 479 · see citing works
Risk factors for amyotrophic lateral sclerosis
Fang, F., Ingre, C., Roos, P. M., Kamel, F., & Piehl, F. (2015) · Clinical Epidemiology · doi:10.2147/clep.s37505 · Cited by 470 · see citing works
Perry, D. C., Sturm, V. E., Peterson, M. J., Pieper, C. F., Bullock, T., Boeve, B. F., Miller, B. L., Guskiewicz, K. M., Berger, M. S., Kramer, J. H., et al. (2016) · Journal of Neurosurgery · doi:10.3171/2015.2.jns14503 · Cited by 440 · see citing works
Xu, L., Liu, T., Liu, L., Yao, X., Chen, L., Fan, D., Zhan, S., & Wang, S. (2019) · Journal of Neurology · doi:10.1007/s00415-019-09652-y · Cited by 330 · see citing works
Head injury and risk of Parkinson disease: A systematic review and meta‐analysis
Jafari, S., Etminan, M., Aminzadeh, F., & Samii, A. (2013) · Movement Disorders · doi:10.1002/mds.25458 · Cited by 282 · see citing works
Head Injury and Amyotrophic Lateral Sclerosis
Chen, H., Richard, M., Sandler, D. P., Umbach, D. M., & Kamel, F. (2007) · American Journal of Epidemiology · doi:10.1093/aje/kwm153 · Cited by 279 · see citing works
Li, Y., Li, Y., Li, X., Zhang, S., Zhao, J., Zhu, X., & Tian, G. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169650 · Cited by 243 · see citing works
Self-citationA CASE-CONTROL STUDY OF AMYOTROPHIC LATERAL SCLEROSIS1
Deapen, D., & Henderson, B. E. (1986) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a114308 · Cited by 184 · see citing works
Brain injury and neurologic sequelae
Williams, D. B., Annegers, J. F., Kokmen, E., O’Brien, P. C., & Kurland, L. T. (1991) · Neurology · doi:10.1212/wnl.41.10.1554 · Cited by 149 · see citing works
Belli, S., & Vanacore, N. (2005) · European Journal of Epidemiology · doi:10.1007/s10654-004-6879-7 · Cited by 140 · see citing works
Epidemiology of amyotrophic lateral sclerosis
Kurtzke, J. F., & Beebe, G. W. (1980) · Neurology · doi:10.1212/wnl.30.5.453 · Cited by 136 · see citing works
Vanitallie, T. (2019) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2019.07.007 · Cited by 132 · see citing works
Association of ALS with head injury, cigarette smoking and APOE genotypes
Schmidt, S., Kwee, L. C., Allen, K. D., & Oddone, E. Z. (2010) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2010.01.011 · Cited by 117 · see citing works
Case-Control Studies of Motor Neuron Disease
Kondo, K. (1981) · Archives of Neurology · doi:10.1001/archneur.1981.00510040046007 · Cited by 112 · see citing works
Qureshi, M., Hayden, D., Urbinelli, L., Ferrante, K. L., Newhall, K., Myers, D. E., Hilgenberg, S. L., Smart, R. J., Brown, R. H., & Cudkowicz, M. (2006) · Amyotrophic Lateral Sclerosis · doi:10.1080/14660820600640596 · Cited by 108 · see citing works
Prior medical conditions and the risk of amyotrophic lateral sclerosis
Seelen, M., van Doormaal, P. T. C., Visser, A. E., Huisman, M. H. B., Roozekrans, M., de Jong, S. W., van der Kooi, A. J., de Visser, M., Voermans, N. C., Veldink, J. H., et al. (2014) · Journal of Neurology · doi:10.1007/s00415-014-7445-1 · Cited by 100 · see citing works
Traumatic injury induces stress granule formation and enhances motor dysfunctions in ALS/FTD models
Anderson, E. N., Gochenaur, L., Singh, A., Grant, R., Patel, K., Watkins, S., Wu, J. Y., & Pandey, U. B. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy047 · Cited by 96 · see citing works
Johnson, V. E., Stewart, W., Trojanowski, J. Q., & Smith, D. H. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0909-9 · Cited by 87 · see citing works
Raj, R., Kaprio, J. A., Korja, M., Mikkonen, E. D., Jousilahti, P., & Siironen, J. O. (2017) · PLoS Medicine · doi:10.1371/journal.pmed.1002316 · Cited by 78 · see citing works
Trauma and amyotrophic lateral sclerosis: A report of 78 patients
Gallagher, J. P., & Sanders, M. (1987) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1987.tb07909.x · Cited by 62 · see citing works
Filippini, T., Fiore, M., Tesauro, M., Malagoli, C., Consonni, M., Violi, F., Arcolin, E., Iacuzio, L., Conti, G. O., Cristaldi, A., et al. (2020) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph17030857 · Cited by 58 · see citing works
Turner, M. R., Abisgold, J., Yeates, D., Talbot, K., & Goldacre, M. J. (2009) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2009.10.010 · Cited by 55 · see citing works
The sinister side of Italian soccer
Beretta, S., Carrı̀, M. T., Beghi, E., et al. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00579-9 · Cited by 52 · see citing works
Lian, L., Liu, M., Cui, L., Guan, Y., Liu, T., Cui, B., Zhang, K., Tai, H., & Shen, D. (2019) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2019.05.036 · Cited by 52 · see citing works
Reversible induction of TDP-43 granules in cortical neurons after traumatic injury
Wiesner, D., Tar, L., Linkus, B., Chandrasekar, A., Heuvel, F. O., Dupuis, L., Tsao, W., Wong, P. C., Ludolph, A. C., & Roselli, F. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.09.011 · Cited by 47 · see citing works
Binazzi, A., Belli, S., Uccelli, R., Desiato, M. T., Talamanca, I. F., Antonini, G., Corsi, F. M., Scoppetta, C., Inghilleri, M., Pontieri, F. E., et al. (2009) · Amyotrophic Lateral Sclerosis · doi:10.3109/17482960802382313 · Cited by 46 · see citing works
Severe head injury and amyotrophic lateral sclerosis
Peters, T. L., Fang, F., Weibull, C. E., Sandler, D. P., Kamel, F., & Ye, W. (2013) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.3109/21678421.2012.754043 · Cited by 45 · see citing works
Chronic Traumatic Encephalopathy Within an Amyotrophic Lateral Sclerosis Brain Bank Cohort
Walt, G. S., Burris, H. M., Brady, C. B., Spencer, K. R., Alvarez, V. E., Huber, B. R., Guilderson, L., Abdul Rauf, N., Collins, D., Singh, T., et al. (2018) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nly092 · Cited by 45 · see citing works
Lunny, C., Fraser, S. N., & Knopp‐Sihota, J. (2013) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2013.08.011 · Cited by 43 · see citing works
Seals, R. M., Hansen, J., Gredal, O., & Weisskopf, M. G. (2016) · American Journal of Epidemiology · doi:10.1093/aje/kwv169 · Cited by 42 · see citing works
Pupillo, E., Poloni, M., Bianchi, E., Giussani, G., Logroscino, G., Zoccolella, S., Chiò, A., Calvo, A., Corbo, M., Lunetta, C., et al. (2017) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2017.1386687 · Cited by 37 · see citing works
Watanabe, Y., & Watanabe, T. (2017) · European Journal of Epidemiology · doi:10.1007/s10654-017-0327-y · Cited by 27 · see citing works
Evaluation and Management of Amyotrophic Lateral Sclerosis
Valadi, N. (2015) · Primary Care Clinics in Office Practice · doi:10.1016/j.pop.2015.01.009 · Cited by 26 · see citing works
Impact of traumatic brain injury on amyotrophic lateral sclerosis: from bedside to bench
Franz, C. K., Joshi, D., Daley, E. L., Grant, R. A., Dalamagkas, K., Leung, A., Finan, J. D., & Kiskinis, E. (2019) · Journal of Neurophysiology · doi:10.1152/jn.00572.2018 · Cited by 26 · see citing works
Amyotrophic Lateral Sclerosis Among Veterans Deployed in Support of Post-9/11 U.S. Conflicts
Sagiraju, H. K. R., Živković, S., VanCott, A. C., Patwa, H. S., Gimeno, D., Amuan, M. E., & Pugh, M. J. (2019) · Military Medicine · doi:10.1093/milmed/usz350 · Cited by 25 · see citing works
Tsai, C., Hu, C., & Lee, C. T. (2018) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2018.1522354 · Cited by 24 · see citing works
TRAUMA AS A CAUSE OF AMYOTROPHIC LATERAL SCLEROSIS
Woods, A. H. (1911) · JAMA · doi:10.1001/jama.1911.02560250012006 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy
Coleman, M. P. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01297-6 · Cited by 33 · see citing works
“Finally, axons are known to be highly vulnerable to proposed environmental risk factors for sporadic ALS, such as traumatic brain injury [53].”
BackgroundChourpiliadis, C., Seitz, C., Lovik, A., Joyce, E. E., Pan, L., Hu, Y., Kläppe, U., Samuelsson, K., Press, R., Ingre, C., et al. (2024) · Journal of Neurology · doi:10.1007/s00415-024-12496-w · Cited by 10 · see citing works
Martinez-Nunez, A. E., Guo, J., Dorsey, E. R., Ruffing, K. W., Wymer, J., & Okun, M. S. (2026) · BMJ Neurology Open · doi:10.1136/bmjno-2026-001574 · Cited by 1 · see citing works
“…through prospective studies with objective measures of exposure, they highlight the potential importance of environmental factors in ALS progression and suggest that exposure history should be potentially considered in clinical prognostication, treat-ment planning and enrolment in clinical trials.”
- Authors
- Liu, G., Ou, S., Cui, H., Li, X., Yin, Z., Gu, D., & Wang, Z.
- Affiliations
- Army Medical University (CN)
- Venue
- Neuroepidemiology
- Publisher
- S. Karger AG
- Published
- 2021
- Volume
- 55
- Issue
- 1
- Pages
- 11-19
- ISSN
- 0251-5350 (ISSN-L)
- 1423-0208
- OpenAlex
- W3129726204
- Semantic Scholar
- 0d82b886f9fbab2d58667631f7d7d6dbd93761c2
- Cited by
- 41
- References
- 47
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 8 · 2022: 6 · 2021: 3
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroepidemiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Keywords
- traumatic brain injury, amyotrophic lateral sclerosis, ALS risk, severe traumatic brain injury, time delay, reverse causality, risk factors
- MeSH terms
- Amyotrophic Lateral Sclerosis, Craniocerebral Trauma, Humans, Risk Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
