ALS is the most common motor neuron disease. Its causes are largely unknown although likely involve environmental components. In this case-control study, head injury was associated with an elevated risk of ALS, particularly for recent repeated head injuries. Based on small numbers, the odd of having ALS was 11 times higher for individuals with more than one head injury in the 10 years prior to diagnosis. Consistent with the recent reports on ALS patients among Italian soccer players, ALS cases with a previous head injury were more likely to have an early and bulbar onset. The meta-analysis further supports a link between head injury and ALS. These findings are consistent with the hypothesis that head injury increases ALS risk. An alternative explanation is that the preclinical symptoms of ALS might have predisposed patients to a higher risk of physical injuries. Although the authors could not exclude this possibility, its plausibility is weakened by the lack of associations between ALS and overall injury or injuries at other parts of the body which were assessed along with head injury in the same structured question, and also by the fact that a slightly stronger association was found when injuries within 3 years of the reference date were excluded from the analysis. By the same token, a significant recall bias is not a likely explanation for our results as previous antecedent reports implicated more frequently injuries involving shoulders and arms(12
), which might have been more publicized among patients.
Recent data showed that ALS mortality among Italian professional soccer players was about 12-fold higher than expected,(4
) while mortality from other causes was generally lower or comparable to that of the general population. This finding was subsequently confirmed by an incidence study among 7,325 Italian professional soccer players who played between 1970 and 2001.(5
) The incidence was 6.5 times higher than expected, and cases were clinically characterized by early onset and bulbar involvement at diagnosis. Although both analyses were based on small numbers, the consistency of the results and the relative large effect estimates suggest that the association is probably not spurious. Several hypotheses have been proposed to explain this association, including vigorous physical activity, use of performance enhancing drugs, excessive pesticide exposures, and head trauma.(5
) The head trauma explanation was particularly interesting because three of the five patients in the incidence study(5
) had a bulbar onset that could be linked to the soccer specific head trauma and also because some prior data support a link between head trauma and ALS.
An association between physical trauma and ALS has been suggested by many case reports(12
) and was evaluated in several case-control studies.(3
) In some studies, the nature of physical trauma was not clearly specified, and in others the definitions varied across studies, from fractures, mechanical injuries, and electric shock, to surgery. Not surprisingly, the results from these studies are inconsistent. The studies were further limited by small study sizes, inadequate exposure assessments, use of convenience controls, and lack of adjustment for potential confounders, and therefore suffered from low statistical power, confounding, and a variety of potential biases.(3
) Two recent population-based case-control studies both failed to show an association between overall trauma and risk of ALS.(15
) However, neither study provided specific information on injury site or the number of injuries. Of these previous studies, a few included head injury in the analyses (). All but one were case-control in design and suffered from many of the same limitations as mentioned above. Further, in these studies, rarely were any specific details on head injury presented. The only prospective study included 821 patients with documented head injury but only one ALS patient was identified during the follow-up.(17
) Although these studies all suffered from a variety of limitations, the meta-analysis provides preliminary evidence for a positive association between head injury and risk of ALS.
Consistently, the detailed analyses from our study support this link and further suggest that recent repeated injuries may be more etiologically relevant. Recent findings from both clinical observations of asymptomatic SOD1 mutant carriers(18
) and experimental studies of SOD1 mutant mice(19
) suggest that the preclinical motor neuron loss in ALS, like its post-diagnosis clinical course, may also be dramatic and aggressive, indicating the importance of recent acute exposures or accumulative exposures over exposures in the distant past. Our observation of a stronger association with recent repeated head injuries is consistent with this notion.
The mechanisms by which head injury may be implicated in ALS are not known. However, several biological explanations have been proposed for a possible role of brain injury in other common neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease or dementia.(20
) These diseases share some clinical, pathological, and epidemiological characteristics with ALS and, on rare occasions, occur together.(22
) Proposed mechanisms include trauma related neuro-inflammation and microglial activation, disruption of the blood-brain barrier, mitochondrial dysfunction and excessive oxidative and nitric radicals, and the accumulation of tau protein.(20
) While the relevance of these explanations to our observation is unknown, they should be evaluated in future studies of ALS.
This case-control study was among one of the well-conducted epidemiological studies on ALS (23
). Compared with previous investigations on head injury and ALS, the current study was better designed with a clearly defined study population. Further, the authors collected much more detailed information on head injury and, for the first time, were able to show a clear relationship between recent repeated head injury and a higher risk of ALS. Finally, multivariate analyses were conducted to adjust for several potential confounders.
The major limitation of this study is that cases and controls were interviewed by different methods and therefore potential bias from this source is of concern. Although the authors could not exclude this possibility, the lack of associations with injuries at other body sites, such as arms or shoulders, argues against a substantial bias from this source. As with many of the previous studies, the statistical analyses were limited by small sample sizes. Therefore, the authors can not exclude chance as a potential explanation for the findings. Finally, the exposure assessment in current study was not independently validated and the meaning of severe injury is, to some extent, open to individual interpretations. Further the definition of head injury requiring medical attention may, to some extend, limit the generalizability of our findings. Therefore, future investigations should be larger and should collect more details about each episode of head injury among various populations.
In summary, in line with the recent observations of higher ALS risk among Italian soccer players, this study reported that recent repeated head injury was related to a higher risk of ALS in an American population. Therefore, a possible role of head injury in ALS etiology should be further evaluated in both human and experimental studies.