Article

Head Trauma May Lead to ALS-Like Disorder


 

There is a growing body of literature suggesting that repeated head trauma may be associated with amyotrophic lateral sclerosis (ALS). When Horner et al showed an approximate twofold increased risk of ALS after the 1991 Gulf War among military personnel who were on active duty and Haley reported an increased risk of ALS in Gulf War veterans younger than 45, the reason for the association was unclear.1,2 Exposure to organophosphates, vaccines, emotional stress, sleep deprivation, cigarette smoking, trauma, and statistical biases were raised as possible explanations.

When a study of Italian soccer players suggested a 6.5-times higher incidence of ALS in soccer players compared with the regional population, it pointed to the possibility that heading the ball with resulting head and neck trauma increased the risk of ALS.3 This study was later supported by a case-control study that showed an increased risk of ALS in subjects with multiple head injuries.4 Most ALS specialists have seen rare patients who develop ALS after a concussive injury, but until recently, it was unknown if this was simply a chance occurrence.

A recent article in the New York Times suggested that Lou Gehrig may not have had ALS, since he sustained multiple concussive injuries playing baseball, and a new pathologic study found evidence of chronic traumatic encephalopathy in three patients who were clinically diagnosed with ALS.5 ALS is diagnosed by clinical criteria (see El Escorial World Federation of Neurology criteria) and is supported by the presence of generalized active and chronic denervation changes on needle EMG.

Classic pathologic criteria of ALS are degeneration of motor neurons and corticospinal tracts with astrocytic gliosis and intraneuronal inclusions.6 In recent years, more refined immunohistochemistry has further characterized the molecular composition of various inclusions in familial ALS, sporadic ALS, and frontotemporal dementia (FTD) with ALS. The pathologic hallmark common to all forms is the presence of TDP (Tar DNA binding protein)-43–positive inclusions.7,8 ALS cases with or without FTD generally show ubiquinated inclusions but little or no intraneuronal tau inclusions.7,9,10 However, astrocytic and neuronal tau inclusions occur in the frontal cortex of ALS patients with and without cognitive impairment and in some families with FTD-ALS.11,12 Tau-positive tangles are present in the spinal cord of patients with parkinsonism-dementia complex and ALS of Guam.13 In addition, in some sporadic and familial cases of ALS, other inclusions, such as FUS/TLS protein and Lewy body-like hyaline inclusions, occur.14,15

So while the recent paper that suggests chronic traumatic encephalopathy, a progressive tauopathy, may be associated with an ALS-like illness (in addition to parkinsonism and dementia), the predominant pathologic finding in the few patients studied was the presence of TDP-43 positive inclusions (typical of ALS), and tau inclusions do rarely occur in ALS.5,11-13 It is not clear why head trauma would result in prominent TDP-43 proteinopathy and tau neurofibrillary changes in the spinal cord (rather than the cortex alone).

In conclusion, although there is increasing clinical and pathologic evidence that head trauma may trigger ALS (presumably in genetically susceptible individuals), once clinical signs of ALS develop, motor neuron degeneration will ensue, likely with neuropathologic evidence of ALS at autopsy.

However, further studies are needed to determine if intraneuronal inclusions in post-traumatic cases truly differ from other sporadic ALS cases. Lou Gehrig had ALS. We will never know if he had a few more tau inclusions than typically seen in sporadic ALS.

References

1. Horner RD, Kamins KG, Feussner JR, et al. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003;61(6):742-749.

2. Haley RW. Excess incidence of ALS in young Gulf War veterans. Neurology. 2003;61(6):750-756.

3. Chio A, Benzi G, Dossena M, et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005;128(Pt 3):472-476.

4. Chen H, Richard M, Sandler DP, et al. Head injury and amyotrophic lateral sclerosis. Am J Epidemiol. 2007;166(7):810-816.

5. McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Aug 11; [Epub ahead of print].

6. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344(22):1688-1700.

7. Geser F, Martinez-Lage M, Robinson J, et al. Clinical and pathologic continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009;66(2):180-189.

8. Dickson DW. Neuropathology of non-Alzheimer degenerative disorders. Int J Clin Exp Pathol. 2009;3(1):1-23.

9. Cairns NJ, Bigio EH, MacKenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114(1):5-22.

10. Hirano A. Neuropathology of ALS: an overview. Neurology. 1996;47(Suppl 2):S63-S66.

11. Wilhelmsen KC, Forman MS, Rosen HJ, et al. 17q-linked frontotemporal dementia-amyotrophic lateral sclerosis without tau mutations with tau and alpha-synuclein inclusions. Arch Neurol. 2004;61(3):398-406.

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