Head Trauma May Lead to ALS-Like Disorder

Repetitive head trauma resulting from collision sports such as football and boxing may be associated with a motor neuron disease that is similar to, yet distinct from, amyotrophic lateral sclerosis (ALS), researchers reported in the September issue of the Journal of Neuropathology and Experimental Neurology. The findings may represent the first pathologic evidence of a connection between motor neuron disease and head trauma, but they may also call into question past diagnoses of ALS, particularly in the case of athletes who play contact sports and military veterans, who are diagnosed with ALS at a higher rate than the general population.

Ann C. McKee, MD, and colleagues observed the brains and spinal cords of 12 deceased athletes who had chronic traumatic encephalopathy (CTE), 10 of whom had widespread TDP-43 proteinopathy affecting multiple areas of the brain. Three of the former athletes with CTE also had TDP-43 and abnormal tau protein in their spinal cords and had developed a progressive motor neuron disease several years before death.

Two of the athletes were former football players and had been clinically diagnosed with ALS, and the third, an ex-boxer and military veteran, had been diagnosed with atypical ALS with dementia. The three athletes with motor neuron disease had a distinctive pattern of TDP-43 pathology in the brain and spinal cord that has not been described in sporadic ALS. In addition, tau pathology was found in their brain and spinal cord tissue, whereas tau pathology is not a feature of sporadic ALS, noted Dr. McKee.

“We found a unique pathologic disease in three professional athletes who suffered long-standing repetitive brain trauma,” Dr. McKee, Associate Professor of Neurology and Pathology and Codirector of the Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, toldNeurology Reviews. “The disease—chronic traumatic encephalomyelopathy (CTEM)—is characterized by the build-up of two abnormal proteins—tau and TDP-43—in the brain and spinal cord and is associated with symptoms that mimic ALS.”

Motor neuron disease is similar to dementia, in that its etiology is heterogeneous, according to Dr. McKee, who is also Director of Neuropathology for the New England Veterans Health Care System. “Although the most common cause of motor neuron disease is sporadic ALS, our findings indicate that other disorders may have a similar clinical presentation and should be considered in the differential diagnosis,” she commented. “Understanding how traumatic injury may trigger a motor neuron disease offers the hope of better insight into pathogenetic mechanisms underlying this neurodegenerative process. Analyzing the nervous system response to repetitive mild trauma may provide critical discoveries in understanding motor neuron disease in general.”

Concussions in Sports

The 12 former athletes in the study ranged in age from 42 to 85 and included seven former football players, four retired professional boxers, and one hockey player. Prior research by Dr. McKee and colleagues found that repetitive head injury may be associated with CTE in a dozen former National Football League (NFL) players. The findings helped push the NFL to adopt new rules regarding when players could return to the game after being diagnosed with a concussion. When asked if the NFL and other sports organizations should take stronger precautions in light of the new findings, Dr. McKee replied, “Absolutely and immediately.”

Diagnosing Lou Gehrig

The findings have also led some to reconsider whether Lou Gehrig was accurately diagnosed with ALS—subsequently referred to as Lou Gehrig’s disease—in 1939. Gehrig reportedly had multiple concussions, including one in 1934 in which he was knocked unconscious after being hit on the head by a pitched baseball while not wearing a helmet. Gehrig died in 1941 and was cremated.

“We will never know whether Lou Gehrig had sporadic ALS or CTEM,” Dr. McKee commented. “It may be interesting for some to speculate about, as he certainly suffered considerable repetitive head injury while playing baseball and perhaps, football, but we will never know. However, the speculation that he might have had CTEM may be useful as it highlights how long-held assumptions can be wrong.”

Dr. McKee also pointed out that her findings are preliminary. “We have studied only three cases, and certainly, we need to study many more individuals with repetitive head injury and motor neuron disease to fully understand the relationship,” she said.

—Colby Stong

Suggested Reading
McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69(9):918-929.

The Mayo Clinic Got It Right—Lou Gehrig Had ALS

Stephen Scelsa, MD, Director of the Neuromuscular Division and ALS Center, Beth Israel Medical Center Associate Professor of Clinical Neurology, Albert Einstein College of Medicine New York City.

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.

12. Yang W, Sopper MM, Leystra-Lantz C, Strong MJ. Microtubule-associated tau protein positive neuronal and glial inclusions in ALS.Neurology. 2003;61(12):1766-1773.

13. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 2008;115(1):133-145.

14. Hewitt C, Kirby J, Highley JR, et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2010;67(4):455-461.
15. Takehisa Y, Ujike H, Ishizu H, et al. Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions. Arch Neurol. 2001;58(5):736-740.

Repetitive head trauma resulting from collision sports such as football and boxing may be associated with a motor neuron disease that is similar to, yet distinct from, amyotrophic lateral sclerosis (ALS), researchers reported in the September issue of the Journal of Neuropathology and Experimental Neurology. The findings may represent the first pathologic evidence of a connection between motor neuron disease and head trauma, but they may also call into question past diagnoses of ALS, particularly in the case of athletes who play contact sports and military veterans, who are diagnosed with ALS at a higher rate than the general population.

Ann C. McKee, MD, and colleagues observed the brains and spinal cords of 12 deceased athletes who had chronic traumatic encephalopathy (CTE), 10 of whom had widespread TDP-43 proteinopathy affecting multiple areas of the brain. Three of the former athletes with CTE also had TDP-43 and abnormal tau protein in their spinal cords and had developed a progressive motor neuron disease several years before death.

Two of the athletes were former football players and had been clinically diagnosed with ALS, and the third, an ex-boxer and military veteran, had been diagnosed with atypical ALS with dementia. The three athletes with motor neuron disease had a distinctive pattern of TDP-43 pathology in the brain and spinal cord that has not been described in sporadic ALS. In addition, tau pathology was found in their brain and spinal cord tissue, whereas tau pathology is not a feature of sporadic ALS, noted Dr. McKee.

“We found a unique pathologic disease in three professional athletes who suffered long-standing repetitive brain trauma,” Dr. McKee, Associate Professor of Neurology and Pathology and Codirector of the Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, toldNeurology Reviews. “The disease—chronic traumatic encephalomyelopathy (CTEM)—is characterized by the build-up of two abnormal proteins—tau and TDP-43—in the brain and spinal cord and is associated with symptoms that mimic ALS.”

Motor neuron disease is similar to dementia, in that its etiology is heterogeneous, according to Dr. McKee, who is also Director of Neuropathology for the New England Veterans Health Care System. “Although the most common cause of motor neuron disease is sporadic ALS, our findings indicate that other disorders may have a similar clinical presentation and should be considered in the differential diagnosis,” she commented. “Understanding how traumatic injury may trigger a motor neuron disease offers the hope of better insight into pathogenetic mechanisms underlying this neurodegenerative process. Analyzing the nervous system response to repetitive mild trauma may provide critical discoveries in understanding motor neuron disease in general.”

Concussions in Sports

The 12 former athletes in the study ranged in age from 42 to 85 and included seven former football players, four retired professional boxers, and one hockey player. Prior research by Dr. McKee and colleagues found that repetitive head injury may be associated with CTE in a dozen former National Football League (NFL) players. The findings helped push the NFL to adopt new rules regarding when players could return to the game after being diagnosed with a concussion. When asked if the NFL and other sports organizations should take stronger precautions in light of the new findings, Dr. McKee replied, “Absolutely and immediately.”

Diagnosing Lou Gehrig

The findings have also led some to reconsider whether Lou Gehrig was accurately diagnosed with ALS—subsequently referred to as Lou Gehrig’s disease—in 1939. Gehrig reportedly had multiple concussions, including one in 1934 in which he was knocked unconscious after being hit on the head by a pitched baseball while not wearing a helmet. Gehrig died in 1941 and was cremated.

“We will never know whether Lou Gehrig had sporadic ALS or CTEM,” Dr. McKee commented. “It may be interesting for some to speculate about, as he certainly suffered considerable repetitive head injury while playing baseball and perhaps, football, but we will never know. However, the speculation that he might have had CTEM may be useful as it highlights how long-held assumptions can be wrong.”

Dr. McKee also pointed out that her findings are preliminary. “We have studied only three cases, and certainly, we need to study many more individuals with repetitive head injury and motor neuron disease to fully understand the relationship,” she said.

—Colby Stong

Suggested Reading
McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69(9):918-929.

The Mayo Clinic Got It Right—Lou Gehrig Had ALS

Stephen Scelsa, MD, Director of the Neuromuscular Division and ALS Center, Beth Israel Medical Center Associate Professor of Clinical Neurology, Albert Einstein College of Medicine New York City.

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.

12. Yang W, Sopper MM, Leystra-Lantz C, Strong MJ. Microtubule-associated tau protein positive neuronal and glial inclusions in ALS.Neurology. 2003;61(12):1766-1773.

13. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 2008;115(1):133-145.

14. Hewitt C, Kirby J, Highley JR, et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2010;67(4):455-461.
15. Takehisa Y, Ujike H, Ishizu H, et al. Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions. Arch Neurol. 2001;58(5):736-740.

Repetitive head trauma resulting from collision sports such as football and boxing may be associated with a motor neuron disease that is similar to, yet distinct from, amyotrophic lateral sclerosis (ALS), researchers reported in the September issue of the Journal of Neuropathology and Experimental Neurology. The findings may represent the first pathologic evidence of a connection between motor neuron disease and head trauma, but they may also call into question past diagnoses of ALS, particularly in the case of athletes who play contact sports and military veterans, who are diagnosed with ALS at a higher rate than the general population.

Ann C. McKee, MD, and colleagues observed the brains and spinal cords of 12 deceased athletes who had chronic traumatic encephalopathy (CTE), 10 of whom had widespread TDP-43 proteinopathy affecting multiple areas of the brain. Three of the former athletes with CTE also had TDP-43 and abnormal tau protein in their spinal cords and had developed a progressive motor neuron disease several years before death.

Two of the athletes were former football players and had been clinically diagnosed with ALS, and the third, an ex-boxer and military veteran, had been diagnosed with atypical ALS with dementia. The three athletes with motor neuron disease had a distinctive pattern of TDP-43 pathology in the brain and spinal cord that has not been described in sporadic ALS. In addition, tau pathology was found in their brain and spinal cord tissue, whereas tau pathology is not a feature of sporadic ALS, noted Dr. McKee.

“We found a unique pathologic disease in three professional athletes who suffered long-standing repetitive brain trauma,” Dr. McKee, Associate Professor of Neurology and Pathology and Codirector of the Center for the Study of Traumatic Encephalopathy, Boston University School of Medicine, toldNeurology Reviews. “The disease—chronic traumatic encephalomyelopathy (CTEM)—is characterized by the build-up of two abnormal proteins—tau and TDP-43—in the brain and spinal cord and is associated with symptoms that mimic ALS.”

Motor neuron disease is similar to dementia, in that its etiology is heterogeneous, according to Dr. McKee, who is also Director of Neuropathology for the New England Veterans Health Care System. “Although the most common cause of motor neuron disease is sporadic ALS, our findings indicate that other disorders may have a similar clinical presentation and should be considered in the differential diagnosis,” she commented. “Understanding how traumatic injury may trigger a motor neuron disease offers the hope of better insight into pathogenetic mechanisms underlying this neurodegenerative process. Analyzing the nervous system response to repetitive mild trauma may provide critical discoveries in understanding motor neuron disease in general.”

Concussions in Sports

The 12 former athletes in the study ranged in age from 42 to 85 and included seven former football players, four retired professional boxers, and one hockey player. Prior research by Dr. McKee and colleagues found that repetitive head injury may be associated with CTE in a dozen former National Football League (NFL) players. The findings helped push the NFL to adopt new rules regarding when players could return to the game after being diagnosed with a concussion. When asked if the NFL and other sports organizations should take stronger precautions in light of the new findings, Dr. McKee replied, “Absolutely and immediately.”

Diagnosing Lou Gehrig

The findings have also led some to reconsider whether Lou Gehrig was accurately diagnosed with ALS—subsequently referred to as Lou Gehrig’s disease—in 1939. Gehrig reportedly had multiple concussions, including one in 1934 in which he was knocked unconscious after being hit on the head by a pitched baseball while not wearing a helmet. Gehrig died in 1941 and was cremated.

“We will never know whether Lou Gehrig had sporadic ALS or CTEM,” Dr. McKee commented. “It may be interesting for some to speculate about, as he certainly suffered considerable repetitive head injury while playing baseball and perhaps, football, but we will never know. However, the speculation that he might have had CTEM may be useful as it highlights how long-held assumptions can be wrong.”

Dr. McKee also pointed out that her findings are preliminary. “We have studied only three cases, and certainly, we need to study many more individuals with repetitive head injury and motor neuron disease to fully understand the relationship,” she said.

—Colby Stong

Suggested Reading
McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69(9):918-929.

The Mayo Clinic Got It Right—Lou Gehrig Had ALS

Stephen Scelsa, MD, Director of the Neuromuscular Division and ALS Center, Beth Israel Medical Center Associate Professor of Clinical Neurology, Albert Einstein College of Medicine New York City.

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.

12. Yang W, Sopper MM, Leystra-Lantz C, Strong MJ. Microtubule-associated tau protein positive neuronal and glial inclusions in ALS.Neurology. 2003;61(12):1766-1773.

13. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol. 2008;115(1):133-145.

14. Hewitt C, Kirby J, Highley JR, et al. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2010;67(4):455-461.
15. Takehisa Y, Ujike H, Ishizu H, et al. Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions. Arch Neurol. 2001;58(5):736-740.