Behold! Phineas Gage revealed!

The Los Angeles Times reports that a daguerreotype depicting Phineas Gage has been discovered. In the next issue of the Journal of the History of the Neurosciences, an article establishing the identity of the man holding an iron rod (see photo to right) is that of Mr. Gage. This is the only known photograph of perhaps the most legendary neurology patient in history. To illustrate the executive function orchestrated by the prefrontal lobes, medical students throughout the country are told the story of the railroad construction foreman Phineas Gage, who, in 1848, suffered an accident on the job which resulted in a 13-pound iron rod shooting through the front of his brain. Gage survived the accident, and lived 11 years more. But he was never the same, exhibiting "frontal release" signs characterized by disinhibition and impulsivity.

The photograph was discovered by Jack and Beverly Wilgus, a couple from Massachusetts who owned the photograph for 30 years, thinking it depicted a whaler holding a harpoon. When they posted the picture online, an anonymous tipster suggested it might be Gage. The LA Times article continues the story: "Intrigued, the Wilguses compared their image to that of a life mask at Harvard Medical School's Warren Anatomical Museum and found it could be superimposed perfectly, with scars lining up correctly. Apparent writing on the metal rod in the image matches writing on Gage's iron rod, which is also in the Warren Museum."



The four-second video above is a computer simulation of the path taken by the tamping iron through Mr. Gage's skull. (Source: Ratiu P, Talos IF. The Tale of Phineas Gage: Digitally Remastered. New England Journal of Medicine. Vol 351:e21. Number 23. December 2, 2004.)

Neuropathologist investigating a murder case is featured in People Magazine

Neuropathologists continue to show up in the national news media! After reporting recently about Dr. John E. Donahue's appearance in The New York Post discussing the disposition of Michael Jackson's brain, I was informed that Dr. Peter Cummings (pictured), neuropathologist for the Massachusetts Medical Examiner's office, was featured in a People Magazine article in connection to a murder case in Maine. Entitled "A Cold Case Comes To Life", the article discusses Cummings' role in the re-investigation of the beating death of 16-year-old Joyce McLain in East Millinocket, Maine in August of 1980. Cummings was an 8-year-old boy living in the area at the time of the murder, and resolved back then that he would solve the case. Nearly thirty years later, Cummings was instrumental in getting Joyce McLain's body re-exhumed for further DNA testing which may help to solve the crime. Cummings is working on the case with renowned forensic experts Michael Baden, MD and Henry Lee, PhD.

Univ of Wisconsin tells 53 patients they are at risk for CJD

The Wisconsin State Journal reports today that the University of Wisconsin Hospital informed 53 patients that they face an “extremely low” risk of having contracting Creutzfeldt-Jakob disease (CJD) from surgical instruments used on a woman who died of CJD on Tuesday. The woman had been operated upon on June 11 to remove a benign brain tumor which was thought to be causing her problems with walking, vision, and memory. In retrospect, these symptoms seem to have been related to CJD. Although the instruments went through normal sterilization procedures between cases, destruction of the prion agent responsible for CJD requires more stringent cleaning procedures. “This is not mad cow disease,” said Dr. Nasia Safdar (pictured), a specialist in infectious diseases who oversees infection control at the hospital. “(People) need not be concerned about that relationship.” Despite her statement, Dr. Safdar admits that conclusive results ruling out "mad cow disease" (variant CJD) have not yet been received from the National Prion Disease Pathology Surveillance Center. To be frank, regardless of what Dr. Safdar says is being done to sterilize the surgical instruments, if I personally were undergoing surgery at the University of Wisconsin I would request that the instruments used on the CJD patient not be used in my procedure.

Best Post of May '09: D.T. Max writes the back story on prion disease

The next in our series of "Best Posts of the Month" is from May 7, 2009.

Most of us accept the party line that there are three basic forms of Creutzfeldt-Jakob disease (CJD): acquired, inherited, and sporadic. The general neurology and neuropathology textbooks do not acknowledge that the very existence of sporadic CJD is controversial. But D.T. Max (picture from nytimes.com), in his book The Family That Couldn't Sleep: A Medical Mystery (2006), does not skirt this controversy. Some patient advocacy groups claim that CJD cases now classified as sporadic are in fact infectious. "A surprising number of mainstream scientists also doubt the existence of sporadic CJD -- among them protein experts, epidemiologists, and neurologists," Max writes. "Their objection is that sporadic CJD is an unnecessary idea. If a disease is known to spread by infection, why assume that some people also get it by chance? Why not find the infectious source in their cases as well? They see theoretical gaps in the idea of sporadic CJD theory too. For one thing, it is strange, if sporadic CJD comes about as a result of the body's declining ability as it ages to manufacture proteins correctly, that the chance of getting sporadic CJD goes down at around seventy years of age." Among the sporadic CJD doubters is none other than D. Carleton Gajdusek, who in 1976 shared a Nobel prize for his work in tracking the cause of kuru (a disease later classified among the prion disorders) as resulting from the practice of funerary cannibalism among the Fore tribes in New Guinea. Of course, in 1976, the word prion had not yet been invented. It took Stanley B. Prusiner, who himself won the Nobel in 1997 for his discovery of prions as a new biologic principle of infection, to come up with that catchy term. But Gajdusek (who died this past December) never took to the term "prion", preferring to call the infectious proteins "nucleating amyloids" -- in large part because of his rabid animosity toward Prusiner. Gajdusek addresses Prusiner in this spicy journal entry made at the time of the announcement of Prusiner's award:

"I never heard a word of original thought from you nor read such ideas in anything you authored for which I did not recognize immediately its source, which you always went out of your way to obscure. You a heretic? You a martyr? You a defender of unacceptable ideas? Bullshit! You shrewdly jumped onto a bandwagon of creative ideas and experimental work and shrewdly got on to the winning cart, proclaiming outrageously in press and media it was yours! I respect you less and less as your despicable game succeeds and you bask in your coveted fame."

There is no doubt that the prejudice, jealousy, and ambition played a large role in both the development and elucidation of the prion diseases. D. T. Max has written a wonderful book about the fascinating history of this strange class of diseases -- including CJD, kuru, fatal familial insomnia, bovine spongiform encephalopathy, and scrapie. As the mysteries surrounding the prion diseases are further unraveled, the secrets behind the more common neurodegenerative diseases (which feature their own kinds of aberrant, aggregating proteins) may also begin to be revealed.

Neuropathologist talks about Jacko's brain in New York Post

Dr. John E. Donahue (pictured), neuropathologist at Brown University, is interviewed in a recent New York Post article regarding Michael Jackson's brain. Autopsy results on the brain have yet to be released. With all the press coverage about it, one wonders whether Jacko's brain will take on the same "treasured artefact" status held by Einstein's brain.

Michael Jackson's brain removed

According to a recent Associated Press report, singer Michael Jackson's brain was removed from his skull and is being held for further investigation. Brains at autopsy are often fixed in formalin for about two weeks to firm them up before cutting. According to the article, Los Angeles Assistant Chief Coroner Ed Winter said Jackson’s brain, or at least part of it, was still being held by investigators and would be returned to the family for interment once neuropathology tests were completed. Since Jackson died at UCLA medical center, I wonder if our friend and UCLA neuropathology chief Dr. Harry Vinters (pictured below) is performing the dissection in consultation with the coroner's office. Given the reported circumstances of Jackson's death, I would speculate that the autopsy findings not much more than some non-specific agonal cerebral edema.

Another quick quiz question

All of the following are CAG-repeat disorders EXCEPT:

A. Huntington disease
B. Myotonic dystrophy
C. Olivopontocerebellar atrophy (spinocerebellar ataxia type 2)
D. Kennedy disease (X-linked spinal and bulbar muscular atrophy)
E. Machado-Joseph disease (spinocerebelllar ataxia type 3)
F. Dentatorubral-pallidoluysian atrophy

The answer appears as a comment.

Quick Quiz Question

What's your diagnosis? (Answer is posted in the comment section.)

MGMT status of glioblastomas: Is PCR or IHC better?

Back in February '08 I wrote a post arguing that MGMT testing on glioblastomas is still not ready for clinical use outside of clinical trials. Since not all of our oncologist colleagues are Neuropathology Blog disciples, I continue to occasionally get a request from a clinician for MGMT testing on glioblastoma specimens. MGMT stands for O(6)-methylguanine DNA methyltransferase. Why are they asking for this test? Alkylating agents, like temazolamide, are more effective when MGMT is not active in a tumor because MGMT normally acts to remove the toxic methylguanine adducts provided by temozolamide. So MGMT silencing, usually due to gene promoter hypermethylation, predicts better response to temazolamide.

What's the best method for assessing MGMT activity in a tumor? According to a review article in the July 2009 issue of Archives of Pathology and Laboratory Medicine by Drs. Peter Pytel (pictured) and Rimas Lukas (Vol133:1062-1077) "immunohistochemical staining for MGMT does not offer a reliable way to stratify glioblastomas, and polymerase chain reaction-based assays are therefore necessary." Pytel and Lukas, of the University of Chicago Medical Center, provide the following two references for this position:

-- Yip S, Iafrate AJ, Louis DN. Molecular diagnostic testing in malignant gliomas: a practical update on predictive markers. J Neuropathol Exp Neurol. 2008;67:1-15.
-- Preusser M, Janzer RC, Felsberg J, et al. Anti-O6-methylguanine methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as a clinical biomarker. Brain Pathol. 2008;18(4):520-532.

On the other hand, some would argue that immunohistochemistry picks up more cases of MGMT than does PCR. Since its still really an experimental test, the issue ultimately may come down to what insurance will pay for. Immunohistochemistry is cheaper, so the patient may have an easier time getting his or her insurance to pay for it. My position is this: I will continue to discourage clinicians from getting the test until it becomes standard practice. If they insist on getting it, I would recommend immunohistochemistry for cost reasons and send it out to the Duke University laboratory of Dr. Roger McLendon to have it done. If, however, PCR is specifically demanded, I will send it to LabCorp, a commercial reference laboratory, which offers the MGMT PCR assay on paraffin-embedded tissue.