by John W. Day, M.D., Ph.D., and Stanley H. Appel, M.D. on Mon, 2010-11-01 15:15
|Editor’s note: The following commentary was written in response to an Aug. 18 paper in the Journal of Neuropathology and Experimental Neurology, and subsequent news stories suggesting that head trauma can cause a condition resembling ALS, and that perhaps Lou Gehrig didn’t have ALS after all. The authors of this editorial, both experienced neurologists affiliated with MDA, say there is insufficient evidence to support the claim that head injuries cause ALS or an ALS-like condition, although such injuries can cause “chronic traumatic encephalopathy” (CTE), a form of brain injury that can involve memory loss, confusion and depression months to years after the injuries. John Day, a neurologist and neurophysiologist, is a professor in the Department of Neurology and the Institute of Human Genetics at the University of Minnesota. He directs the MDA Clinic at Fairview-University Medical Center in Minneapolis and is an MDA research grantee. Neurologist Stanley Appel directs the MDA/ALS Center at Methodist Neurological Institute in Houston, where he is also an MDA research grantee. He heads MDA’s Medical Advisory Committee and is a member of MDA’s Board of Directors.
Published interviews with the authors of a recent scientific article (“TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy”1) raised concerns in the ALS community by suggesting that “brain trauma can mimic Lou Gehrig’s disease”2 and “Maybe Lou Gehrig Didn’t Die of Lou Gehrig’s Disease.”3 Neither statement is supported by the report or by available published scientific data.
The authors of the scientific report had previously described “chronic traumatic encephalopathy” (CTE) and tau protein aggregates in brains of boxers and football players who progressively lost cognitive function years after suffering repeated head trauma. This finding attracted media attention, in part because the National Football League had been in denial about whether trauma during a player’s career could result in progressive dementia years later. Therefore, the media focus was not surprising regarding the new autopsy findings in brains of 12 patients with CTE, three of whom were also diagnosed with ALS.
The paper demonstrated the signature pathological changes of CTE in all 12 specimens. In the three subjects who had a history of both head trauma and ALS, the investigators also identified motor neuron loss and abnormal inclusions of two proteins within surviving motor neurons: TDP43, which has previously been seen in most ALS autopsies, so was not unexpected; and tau protein, which has previously been seen in cerebral neurons of dementia patients, including those with CTE, but is uncommon in motor neurons except in frontotemporal dementia, a disorder that causes both progressive motor neuron loss and dementia. The authors interpreted their findings as showing “that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.”
However, the scope and design of their study prevents any conclusion about a cause-and-effect relationship between CTE and ALS. All subjects were specifically selected because of their head trauma history, so the fact that three of the 12 subjects had additionally been diagnosed with ALS cannot clarify whether head trauma can be responsible for motor neuron loss. A more likely conclusion is that the brains they investigated with CTE had CTE, while those with motor neuron loss had ALS, and thus the three patients with autopsy finding of both CTE and ALS truly had both diseases — CTE and ALS. In fact, one of the ALS patients was reported to have a “sibling with probable ALS” suggesting a familial form of the disease and further complicating interpretation of their findings.
ALS results in the progressive and relatively selective loss of the motor neurons required for voluntary movement and is diagnosed clinically — a neuromuscular specialist identifies specific clinical criteria by performing necessary tests, including a neurological examination and EMG (electromyogram), to make the diagnosis. Although these well-established criteria allow ALS to be diagnosed by experienced clinicians, the actual cause of the disease cannot be determined in most patients. Specific genetic changes explain a minority of cases, but in most patients the disease is presumed to result from combined effects of yet-undefined genetic and environmental risk factors — possibly including head trauma. Autopsy findings in ALS show motor neuron loss, but do not currently allow subcategorization into different types of the disease — ALS is diagnosed by well-defined clinical criteria and not by identifying any specific inclusions in nerves cells at autopsy.
An additional complexity of the recent article arose when one of the authors suggested in an interview that the “new” condition in the three ALS patients could be named “chronic traumatic encephalomyopathy,” or CTEM; inclusion of the term “myopathy” implies that the muscle itself is also diseased even though no clinical or pathological change in muscle was reported.
The reported three cases are too few, and too narrowly selected, to prove that head trauma, or chronic traumatic encephalopathy, can lead to ALS. Clearly both CTE and ALS occur separately in most patients; even if some individuals might be genetically prone to develop both CTE and ALS, there is no evidence that either of these conditions actually causes the other.
For decades, the plight of professional athletes with ALS has led investigators to try to find links between ALS and trauma, especially sports injuries. Lorene Nelson, a renowned neuroepidemiologist at Stanford University, recently commented that there was no strong epidemiologic evidence that physical trauma is a risk factor for the development of ALS. In a study of ALS in western Washington state, she and her colleagues did not find an association of ALS with previous head injuries or fractures.4 They did find slightly more fractures in ALS patients than in controls during the few years preceding ALS diagnosis, which was interpreted as showing that subclinical weakness increases risk of falls and fractures early in ALS. This conclusion was recently substantiated when British scientists analyzed years of medical data5 and found that head injury (or limb injury) was most likely a “consequence of undiagnosed ALS” resulting in an increased tendency to fall — in other words, the evidence indicated that ALS increased the risk of falls and injury, but not that trauma caused ALS.
In answer to the concerns of many in the ALS community, it is clear that Lou Gehrig was appropriately diagnosed with ALS by the clinical criteria discussed above. The cause of his disease is as unclear today as it was in his time. He had multiple sports injuries, but at no time demonstrated the dementia or cognitive dysfunction characteristic of CTE. Whether head trauma contributes to any patient’s ALS is conjectural, and attributing the development of ALS to head trauma in Lou Gehrig is purely speculative.
Furthermore, suggesting that Lou Gehrig did not have ALS is clearly ungrounded speculation and fails to recognize his place in history and in the ALS community. Further studies on the role of TDP43 and tau as potential therapeutic targets are warranted, as are studies of the role of trauma as a risk factor for ALS, but there is no purpose or value in questioning the diagnosis of former or current ALS patients diagnosed by established criteria and confronting the challenges of this devastating disease.
1 McKee, A.C., B.E. Gavett, R.A. Stern, C.J. Nowinski, et al. “TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy,” Journal of Neuropathology & Experimental Neurology 69 (2010): 918–929.
2 Schwarz, Alan. “Study Says Brain Trauma Can Mimic ALS,” The New York Times, August 18, 2010.
3 Park, Alice. “Maybe Lou Gehrig Didn’t Die of Lou Gehrig’s Disease,” Time, August 17, 2010.
4 Cruz, D.C., L.M. Nelson, V. McGuire, W.T. Longstreth Jr. “Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: A population-based case-control study,” Neuroepidemiology 18 (1999): 101-10.
5 Turner, M.R., J. Abisgold, D.G.R. Yeates, K. Talbot, M.J. Goldacre. “Head and other physical trauma requiring hospitalization is not a significant risk factor in the development of ALS,” Journal of Neurological Sciences 288 (2010): 45–48.