Head and other physical trauma requiring hospitalisation is not a significant risk factor in the development of ALS

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Abstract

The pathogenesis of ALS is not fully understood but, as an overwhelmingly sporadic disorder, it is likely to result from a complex mixture of polygenic and environmental risk factors operating in the context of an ageing nervous system. Physical trauma, in particular head injury, has been variably associated with both Alzheimer's and Parkinson's disease, and largely discounted in relation to multiple sclerosis. Several case–control studies in ALS have reported an association with physical trauma or head injury, but such studies are greatly limited by recall bias. The Oxford Record Linkage Study (ORLS) includes brief statistical abstracts of records of all hospital admissions, including day cases, and all deaths for a defined region of UK National Health Service hospitals. We used ORLS spanning a 36 year period to study the relationship between recorded head, upper and lower limb trauma both before and after a diagnosis of ALS. 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); but this elevation of risk was only found within the first year after injury, and we speculate that this is most likely to be a consequence of incipient ALS causing a tendency to fall. We conclude that there is no association between antecedent injury requiring hospitalisation, and the later development of ALS. The high risk of head injury observed in the immediate post-diagnosis period may be amenable to primary prevention.

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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