Rowland, Lewis P. MD; Mitsumoto, Hiroshi MD; Hays, Arthur P. MD
Did Lou Gehrig have Lou Gehrig's disease? The question about Gehrig's diagnosis arises now because of a new paper by Ann C. McKee, MD, and colleagues published in a prominent neuropathology journal, ascribing motor neuron disease to chronic traumatic encephalopathy (CTE). It is also the subject of a story by Jamie Talan on page 1 of this issue.
Writing about the paper by Dr. McKee and colleagues in the Aug. 18 New York Times, the reporter Alan Schwarz commented: “Although the paper does not discuss Gehrig specifically, its authors in interviews acknowledged the clear implication: Lou Gehrig might not have had Lou Gehrig's disease.”
What was the evidence for the contrary view?
Dr. McKee, et al, examined postmortem tissues from 12 patients with CTE, including two former football players and one former professional boxer; all three had both CTE and “MND [motor neuron disease]”. (The authors seemed to avoid the term, amyotrophic lateral sclerosis (ALS) deliberately; apparently they considered the condition to be related to ALS but not quite typical.)
In 10 of the 12 CTE patients and all three with MND, the investigators found deposits of TAR DNA-binding protein 43 (TDP-43) in the brain and spinal cord. The presence of TDP-43 is a reliable marker for the postmortem diagnosis of ALS; it is found in almost all cases.
In experimental studies, TDP-43 is thought to mark neurons for destruction. Mutations in the gene for TDP-43 can cause ALS in humans and in transgenic rodents.
The investigators concluded: “This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development or motor neuron disease.”
But the four neurologists interviewed for the Neurology Today story were unanimous in their assessment of the study: The fact that three of 12 patients with CTE also had ALS could have been a chance occurrence of the two conditions in a single person. That possibility persists even though autopsies showed deposits of both tau (a known feature and possible cause of CTE) and TDP-43 (a probable cause of ALS). The chances of finding this combination are undoubtedly small but not nil. It is not clear why so many patients showed deposits of TDP-43 or what role that may have had in the three patients with ALS.
Five neurologists are now unanimous; it is a remarkable concordance that is not likely to be attributed to chance.
There are also many reasons to question the suggestion picked up by the lay press that Lou Gehrig may not have had ALS. First, there is the question of diagnosis. In a living patient there is no specific test for the diagnosis of “sporadic” ALS, when no one else in the family is affected.
In those circumstances, even sophisticated modern technology can do no more than confirm the clinical diagnosis.
EMG, nerve conduction studies, and MRI are the most helpful tests in excluding look-alike disorders. CSF examination and muscle biopsy are not specific and are often bypassed. An absolutely certain diagnosis can be made only by postmortem examination. Nevertheless, an accurate diagnosis can be achieved reliably by a neurologist experienced in the disease.
In familial ALS, DNA tests may be useful in determining which mutations are affecting which relatives. However, concomitant genetic counseling is added to help patients understand the meaning of the results and the choices to be made in the future.
Today, ALS centers are scattered throughout the country but no such research and treatment centers existed in Gehrig's time. The diagnosis of Gehrig's neurological illness was made by an experienced clinician at the Mayo Clinic, where records are sealed and are not available for review. Moreover, there was no autopsy, which would have provided an unequivocal diagnosis one way or the other.
Also, published statistics recorded Gehrig's declining prowess as a player and photographs of his atrophic hand muscles leave no doubt the ALS diagnosis was correct. In a tour de force biography, Paul Gordon and Melisa Lewis used published photographs, information from the baseball Hall of Fame about uniforms of the day, and even analyzed Rawhide, a movie starring Gehrig as a cowboy. Assembling this information, they even ascertained the onset of Gehrig's symptoms as starting in May 1938.
Gehrig had another characteristic that some authorities consider a risk factor for ALS. He was, by all accounts, a very nice person — thoughtful, kind to others, devoted to his parents and to his wife, and modest despite his tremendous achievements on the baseball field. His famous “luckiest man in the world” speech when he retired was utterly modest. The reason he gave was that he could no longer do what his teammates expected him to do.
Gehrig was such a popular and iconic baseball player that his fatal disease has been the subject of several writers.
It may or may not be epidemiologically proven that repeated brain trauma increases the chances of developing ALS, but Lou Gehrig most certainly did have Lou Gehrig's disease.
Dr. Rowland, former editor-in-chief of Neurology Today, founded the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University in New York. Dr. Mitsumoto has been director of the Center since 1999. Dr. Hays has been neuropathologist for neuromuscular studies since 1977.