Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS
Introduction
Despite published clinical observations and research spanning a 150 year period, the underlying pathological cascade leading to amyotrophic lateral sclerosis (ALS) remains uncertain [1]. ALS is a relentlessly progressive neurodegenerative disorder predominantly involving upper and lower motor neurons, with a median survival from symptom onset of 2–4 years, although characteristically with marked prognostic heterogeneity.
The identification of mutations in the superoxide dismutase-1 (SOD1), TAR DNA binding protein (TDP-43) and ‘fused in sarcoma’ (FUS) genes in a small proportion of the approximately 10% of cases with a family history have been important in advancing our understanding of the cellular pathology of ALS [2]. However, ALS is overwhelmingly a sporadic disorder and is likely to result from a complex mixture of polygenic and environmental risk factors operating in the context of an ageing nervous system [3]. The incidence of ALS (1–2/100,000/year) is consistent across populations, shows an increase as the population ages and there is an approximately 3:2 male:female ratio, which remains unexplained [4]. Epidemiological studies have failed to reveal a consistent environmental risk factor for the development of ALS. The concept of one or more external triggers in an individual ‘at risk’ by virtue of an as yet unidentified adverse polygenic profile, remains a plausible model for ALS causation, but the potential complexity and diversity of the influences which might lead to a final common disease pathway remains a challenge.
Head injury, and physical trauma in general, have been reported as risk factors for other neurodegenerative disorders such as Alzheimer's [5], [6] and Parkinson's diseases [7], [8], and largely discounted in other complex neurological disorders such as multiple sclerosis [9], [10], [11]. Loss of integrity of the blood–brain barrier resulting in exposure of the central nervous system to ‘external’ antigenic material is a common theme. The identification of a very high incidence of ALS among Italian professional footballers [12], and American football players [13], has led to speculation over whether head injury through contact with the football is a relevant explanation. There is conflicting evidence of a more general association between physical fitness and the later development of ALS [14], [15], [16], and it is plausible that a genetic profile which promotes physical prowess in youth may be deleterious to the ageing motor system [17], rather than exercise per se being detrimental to those at risk for another reason.
The Oxford Record Linkage Study (ORLS) includes brief statistical abstracts of records of all hospital admissions, including day cases, in UK National Health Service (NHS) hospitals in a defined part of southern England and of all deaths in its area. It is a potentially powerful resource for the assessment of disease associations and herein was used to study the relationship between recorded head, upper and lower limb trauma both before and after a diagnosis of ALS.
Section snippets
Population and data
We studied all available data from the Oxford Record Linkage Study (ORLS), which spans a period from January 1963 to March 1999. The hospital data were collected routinely in the NHS as the Oxford Regional Health Authority's hospital discharge statistics. The death data derive from death certificates. Data collection covered part of one health district from 1963 (population 350,000), two districts from 1966 (population 850,000), six districts from 1975 (population 1.9 million) and all eight
Results
There were 106,593 people in the head injury cohort, 97,950 in the cohort with upper limb injuries, 112,179 in the cohort with lower limb injuries, 281 in the ALS cohort, and 511,831 in the reference cohort. Table 1 shows the occurrence of head injury and ALS for different time intervals compared to the reference cohort. Overall, the adjusted rate ratio for ALS after head injury, compared with a control group, was 1.5 (95% confidence interval 1.1–2.1). An increase in the relative risk was
Discussion
This study highlights the immediate pre- and post-diagnostic period in ALS as a time of significantly higher risk for physical injury, but supports the evidence from other studies that the injury itself does not have a pathogenetic role. The fact that the immediate risk of ALS after injury fell back to that in the control group more than one year after injury appears incompatible with the hypothesis that injury initiates long-term pathological processes.
At least two thirds of ALS patients
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Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis
2017, NeuroToxicologyCitation Excerpt :This association supports the view that trauma may be a causal factor, because old trauma is unlikely to occur as a consequence of ALS. Therefore, although two recent studies argued that the traumas were the consequence instead of the cause of ALS (Beghi et al., 2010; Turner et al., 2010), previous trauma should still be considered a potential risk factor for ALS (Pupillo et al., 2012). If previous trauma is a risk factor for ALS, then some risk factors associated with ALS – professional sports, lower BMI, lower educations, and strenuous work – may have been confounded by previous trauma.
The epidemiology of amyotrophic lateral sclerosis
2016, Handbook of Clinical NeurologyCitation Excerpt :No significant effects were noted in cases compared to controls for vigorous activity such as marathon or triathlon participation or in occupational activity. History of traumatic brain injury has been hypothesized as a potential risk factor for ALS due to increased incidence of ALS among professional athletes (Qureshi et al., 2006; Schmidt et al., 2010; Turner et al., 2010; Sundman et al., 2014). However, results have been inconsistent, with some studies reporting a relationship and others failing to do so, and trauma discounted as a probable risk factor according to a 2003 evidence-based medicine analysis (Armon, 2003b; Lehman et al., 2012).
Head trauma in sport and neurodegenerative disease: An issue whose time has come?
2015, Neurobiology of AgingCitation Excerpt :A pilot investigation of a large case-control study under way in UK and Italy based on 61 ALS cases and 112 control subjects found no excess risk associated with trauma (Beghi et al., 2010). A large study undertaken using the Oxford Record-Linkage Study including about 100,000 cases of head, upper limb, and lower limb trauma each and 281 cases of ALS found a significant association between head injury and ALS (OR, 1.5; 95% CI, 1.1–2.1), but this increased risk was found only within 1 year after injury; the authors concluded that this finding is likely because of early signs of the diseases provoking the accident (Turner et al., 2010). Another small case-control study in Italy found a different pattern for clinical forms: head injury occurring at age 30–40 years was significantly associated with the bulbar form (OR, 17.4; 95% CI, 1.70–178.5), whereas head injury occurring before age 30 years was associated with the spinal form (OR, 7.13; 95% CI, 1.34–37.94) (Binazzi et al., 2009).
Neurodegenerative disease risk among former international rugby union players
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