Another Neuropathologist Heads West

Dr. Alexander Judkins (pictured), currently a neuropathologist at the Children's Hospital of Philiadelphia, is moving to sunny California to become chair of  pathology at Children's Hospital of Los Angeles. Judkins joins another neuropathologist transplanting to the Golden State: Dr. Arie Perry leaves Washington University in St. Louis next month to take a job at UCSF.

Infamous Frontal Lobotomist was once President of the American Association of Neuropathologists

You may be surprised to learn that the infamous Walter J. Freeman,
MD (1895-1972), America's most prolific frontal lobotomist, was once president of the American Association of Neuropathologists. The AANP website lists Dr. Freeman (pictured) as having been president of the organization in 1946.

If you want to learn more about Dr. Freeman, get hold of a PBS documentary called The Lobotomist, which explores the background of the procedure popularization during the 1940’s through the ‘60’s. The neurologist Walter J. Freeman of Washington, DC was primarily responsible for the widespread performance of this surgery in the United States by developing the 10-minute, outpatient “ice pick lobotomy”. An ice pick-like instrument was inserted beneath the eyelid and over the eyeball of a patient who was rendered temporarily unconscious by electroshock. (The photo below from 1960 depicts the procedure performed on 12-year-old Howard Dully whose stepmother complained of the child's chronic misbehavior). When the instrument hit the thin orbital plate of the frontal bone, a few taps with a mallet would allow entrance into the intracranial cavity. The ice pick was then advanced upward, after which it was swept back and forth like a windshield wiper blade. The instrument was then extracted and the procedure was repeated on the opposite side. Approximately 30,000 of these procedures were performed before the medical establishment decided that it was ill-advised.

These procedures were designed to sever the connections of the brain with the prefrontal cortex. The goal was to leave patients with a degree of abulia, but with no focal deficits.

ATPase versus Immunohistochemistry for fiber typing in muscle biopsies: which is better?

When I receive a complex muscle biopsy case, I send my specimens to the excellent muscle specialists at the University of Iowa Department of Pathology. I recently got a consultation report back from Dr. Leslie Bruch (pictured) at that institution. In her report, she noted that immunoperoxidase staining for slow and fast myosin heavy chains were performed to assess fiber type distribution. For that purpose, I use ATPase at pH 9.4 and 4.6. I asked Dr. Bruch whether there were any advantages to the immunohistochemistry approach versus ATPase. Here's her response: "The reasons we changed to immunohistochemistry for fiber typing here was that it is more consistently reliable than our ATPase stains, as well as less expensive in terms of tech time and reagents, etc. One limitation is that you cannot subtype the type II fibers as you can with using ATPase at 3 different pHs. We have been happy with it since the change."

If anyone has any further thoughts on the relative advantages of the two methodologies, please comment.

Ellsworth C. "Buster" Alvord, Jr., MD (1923-2010)

Ellsworth C. “Buster” Alvord, Jr. died on January 19, 2010 at the age of 86. His career as a neuropathologist, scientist, and teacher spanned more than 6 decades.  He began his early research career investigating immune-mediated injury to the CNS and wrote seminal works on inflammatory models of demyelinating disease (experimental allergic encephalomyelitis, EAE).  Dr. Alvord was president of the American Association of Neuropathologists in 1965. 

Born in 1923, Alvord received an M.D. from Cornell University in 1946 and did postgraduate training in pathology and neuropathology. Buster moved to the University of Washington in Seattle in 1960, where he trained untold numbers of neurology, neurosurgery, and pathology residents. He also ran the diagnostic service and publishing 93 additional manuscripts that touched on virtually all facets of neurologic disease and neuropathology.  In Buster’s own words at his “retirement” party in 2002, “EAE was probably the high point” of a scientific career that included eight publications in Science and three in Nature.  In his later years, he focused on mathematical modeling of glioma growth.  At the time of his death, he had four manuscripts under preparation including one that described suffering a stroke from his own experience. 

Buster was an enthusiastic teacher with a keen wit and wry smile.  He was warm and encouraged critical thought, but did not ever allow his students to get away with sloppy thought or speech.  For decades, he would take residents and fellows on 6 AM road trips to Pacific Northwest hospitals to perform brain cuttings free of charge and to teach outlying pathologists the gospel of neuropathology.  He was so enthusiastic about teaching that he made arrangements for the donation of his own brain for teaching purposes with the instructions that it should be used for the benefit of all. 

Buster had a love of fleece jackets, white socks, outlandish ties, and fresh oysters.  Outside of neuropathology, he and his family were generous patrons of the arts in Seattle.  He was a thoughtful scientist, keen researcher, outstanding diagnostic neuropathologist, generous benefactor and giving teacher.  We are all diminished by his passing, but were enriched by his life.

The above memorial was contributed by Drs. Joshua A. Sonnen and Thomas Montine, neuropathologists at the University of Washington in Seattle.

John J. Kepes, MD (1928-2010)

"His death epitomizes the dwindling generation of classic neuropathologists." That's what the Mayo Clinic's Bernd Scheithauer, MD  had to say in a recent obituary for John Janos Kepes in the journal Brain Pathology. Dr. Kepes was born on March 31, 1928. He was the son of a Budapest otorhinolaryngologist and a mother who died when young John was only four years old. Dr. Kepes grew up to attend medical school in Budapest. He later escaped from Hungary with his young family as Russian forces invaded the country. Dr. Kepes ultimately made his way to the United States, where he did a neuropathology fellowship at the Mayo Clinic. He then settled in Kansas City, Missouri, where he devoted the next 48 years of his life to the University of Kansas Pathology Department. Scheithauer writes: "Key career contributions had included a 1982 monograph entitled 'Meningiomas: Biology, Pathology and Differential Diagnosis,' his 1991 co-discovery with Dr. Lucien Rubinstein of 'Pleomorphic Xanthoastrocytoma,' as well as his detailed 1993 description of 'Tumefactive Demyelination.' "

I myself had the honor of looking at slides with Dr. Kepes once in 2005. I'll always remember his insightful observations on the cytology of a case of papillary ependymoma.

In an obituary in the Journal of Neuropathology and Experimental Neurology, Dr. Lucy Rorke-Adams remembers that, "John was the ultimate in erudition, and no diagnostic problem was too difficult for him to unravel." The JNEN article continues to quote Dr. Rorke-Adams: "Dr. Kepes grew up in Hungary, 'a land he loved but which rejected him and his family at a stage in their lives when they were ready to contribute gifts of healing to their countrymen. The Kepeses' desperate escape from horrors brought them to our country, where John ripened into one of the most learned and distinguished neuropathologists of our generation.' "

After the loss of his beloved wife, Magda, in 2006, Dr. Kepes moved to an assisted living residence in the Kansas City area. It was there, according to his obituary in the Kansas City Star, in the early hours of February 2, 2010, that Dr. Kepes passed away peacefully, with his daughter by his side.

The skull's shape takes its cues from the brain's topography

I recently received the brain specimen pictured above from an outside institution in a form I had never seen before: with the skull cap still attached! If you look closely, you can see how the subtle undulations of the skull's inner surface coincide with the gyral pattern of the brain's outer surface. As the skull ossifies during development, it seems to adjust to the pattern present on the brain surface. That patterning persists for the rest of one's life. Cool.

New Neuropathologist Job Opening at the University of Michigan

It has been said that Neuropathology Blog has the most complete neuropathology job listing on the web. That has a lot to do with the ever-helpful Sherry Miller, wife of University of Missouri neuropathologist Doug Miller. This morning, Sherry sent me this newly listed job opening:

ANN ARBOR, MICHIGAN (USA). The Department of Pathology at the University of Michigan Health System is seeking an academic neuropathologist with subspecialty expertise in interpretation of nerve and muscle biopsies. Interested candidates should submit curriculum vitae, and the names and addresses of five individuals who can provide letters of recommendation to:
 
Jeffrey L. Myers, M.D.
A. James French Professor and Director,
Division of Anatomic Pathology
1500 E. Medical Center Drive, 2G332 UH
Ann Arbor, MI 48109-5054

Telephone: (734) 936-1888
Email: myerjeff@umich.edu



Thanks, Sherry!

Best Post of November '09" Finally, a simple cartoon depicting the anatomic location of the transentorhinal cortex

The next in our series of "Best Posts of the Month" is from November 17, 2009:

In our teaching and in our autopsy reports, we neuropathologists often make reference to the transentorhinal cortex as it is -- in the Braak and Braak staging system -- the region where the earliest Alzheimer pathology appears. I have found it difficult to find a clear illustration of the anatomic location of the transentorhinal cortex in texts or on the internet. However, I came across a nice cartoon of the divisions of the parahippocampal gyrus, including the transentorhinal cortex, in an online presentation by Prof. Jillian Kril of the Pathology Department at the University of Sydney, NSW. Prof. Kril kindly emailed me a copy of the illustration, which is depicted above with the addition of a label for the presubiculum.  Feel free to use this cartoon for teaching purposes with the following credit: Adapted from Harding AJ, Halliday GM, Kril JJ. Variation in hippocampal neuron number with age and brain volume. Cerebral Cortex (December, 1998) 8:710-718.

Interferon-gamma in the Pig PIN

Remember that outbreak of progressive inflammatory neuropathy (PIN) among pig abattoir workers back in 2007? If not, here's my blog post from January '08 summarizing the event. The good Dr. Mark Cohen (pictured at left) forwarded me a recently published article following up on the outbreak. Investigators found no infectious etiology; but they did find higher levels of interferon-gamma among PIN patients. Since elevated levels of interferon-gamma has been associated with both acute and chronic inflammatory demyelinating polyradiculoneuropathy, this finding supports an autoimmune mechanism for PIN.

A 'Rara Avis' has flown under my microscope

I was recently sent a specimen from the cerebellum of a 27-year-old female patient who, during a routine funduscopic exam at her optometrist, was found to have papilledema and retinal hemorrhages. She was completely asymptomatic -- which of course suggests that we are dealing with a slowly progressive process. A head MRI was obtained:

An image-guided craniotomy ensued, yielding a cerebellar specimen. Photomicrographs of that specimen, at progressively higher magnification, follow:

The top picture exhibits normal cerebellar cytoarchitecture on the right giving way, on the left, to an internal granule cell layer that has transformed into larger gangliocytic neurons. The bottom picture demonstrates the cytologic appearance of these transformed ganglion cells.

This is an example of dysplastic cerebellar gangliocytoma, otherwise known as Lhermitte-Duclos disease (LDD). Dr. Peter Burger and colleagues, in their Surgical Pathology of the Nervous System and Its Coverings (4th edition, page 274), make this comment about LDD: "In the parlance of bird-watching, an endeavor with many similarities to surgical pathology, Lhermitte-Duclos disease is an entity not likely to be found on the 'life-list' of most pathologists." Well, this rara avis is now on my life-list!

When I came upon this tumor, I immediately thought of Dr. Ty Abel (pictured to the left), neuropathologist at Vanderbilt, who in 2005 authored an immunohistochemical study of 31 cases of Lhermitte Duclos disease. I emailed him this question: "What is the current thinking on LDD? Is it a hamartoma or a neoplasm or something in between?"

Ty's response: "Something in between may be the best answer. We suggested in our paper that it was a 'hypertrophic phenomenon superimposed upon a developmental malformation'. Our observations, as well as those in Suzie Baker's mouse model of this, suggest that aberrant signaling in the pathway disrupts granule cell migration as well as leading to their hypertrophy. Histologically, there is little proliferation, so the increase in tumor size over time may be due to cellular hypertrophy or to the abnormal myelinization of the molecular layer or both.Still, they do grow and sometimes come back after resection, making them tumor-like. Does your patient have evidence of Cowden's?"

No, my patient does not have other clinical evidence of Cowden syndrome. But Ty put me in touch with a leading authority on Cowden syndrome at the Cleveland Clinic, Dr. Charis Eng (pictured to the right) who emailed me this comment: "What we found in our initial series is that adult-onset LDD is almost always associated with germline PTEN mutations, i.e., has Cowden syndrome."

Whether or not this patient gets germline PTEN testing, she should be closely surveilled for breast, thyroid, and endometrial cancer, as there is a high incidence of these tumors in patients with Cowden syndrome.

And now a recut slide of this rare bird gets filed away in my teaching set, only to be let out of its cage again by the eager inquiry of a resident.

What is the relative prevalence of CNS metastases versus primary tumors?: Simple question, complex answer

During the pre-exam pathology review session at my medical school, one of the students asked about the relative incidence of metastases to the CNS versus primary CNS neoplasms. I answered that metastases are ten times more common than primary tumors. After the presentation, a colleague in the audience pointed out to me that the current issue of Robbins and Cotran (p. 1330) says: "about half to three quarters are primary tumors, and the rest are metastatic." I said, "No way!" and produced another textbook (the current edition of "Greenfield's Neuropathology"), which states the following on page 2116: "Metastatic tumors to the brain are approximately 10 times more common than primary intracranial neoplasms."

As we investigated the issue further, it became clear that the two textbooks were starting with a completely different denominator in arriving at their proportions. In Robbins and Cotran, the authors were looking at incidence rates of metastases in patients presenting with brain tumors. In Greenfield's Neuropathology, the authors appear to be extrapolating from autopsy series which included patients who never had a pre-mortem brain biopsy because metastasis was presumed. You might say that none of this matters too much. And, in a way, you would be right to say that. The bottom line is that a significant proportion of brain tumors are metastatic lesions. But, this discussion does matter in that it is a nice example of how statistical estimates of the prevalence of disease can vary widely depending on what denominator the author chooses to use. It is incumbent upon the author to be crystal clear about the denominator; but, unfortunately, that is not always the case – in which case it is incumbent upon the reader to beware.