Ophthalmic pathology faces a shortfall

A front page feature in the September ’08 issue of CAP Today, from the College of American Pathologists, alerts us to the fact that ophthalmic pathology is in a decline more precipitous than the Dow Jones Average of late. Quoted in the article is Dr. Thaddeus Dryja, with whom I did an eye pathology rotation during my fellowship training. Dr. Dryja says: “Whenver you read about a shortage of any type of professional …. what’s really meant is that employers don’t want to pay what the work is worth. If you paid enough, you’d have enough nurses and high-tech engineers, for example. Eye pathology is no different. Primary care physicians are also on the list.” The article lists that among the conditions that can be missed by pathologists not specifically trained in ophthalmic pathology are: keratectasia, primary intraocular lymphoma, sebaceous carcinoma of the eye, and acanthamoeba infection causing keratitis. To address the problem, some institutions are turning to cyber solutions to expose residents to an adequate volume of material. Among the institutions providing web-based tools (some with a fee) are the University of Illinois at Chicago, Emory University, and Duke University. Duke hosts The EyePathologist, which is free and includes a database of more than 5,000 vision-related diseases and 4,000 images. There’s also a glossary of more than 6,000 ophthalmic terms. The site, authored by neuropathologist Gordon K. Klintworth, MD, PhD. (pictured above), has gained a lot of popularity, with more than 9,000 current registrants from 158 countries.

"... this is a bad cell because I sat next to somebody who told me it was a bad cell..."

After a clinician presents a case at a clinicopathologic conference, he or she will not infrequently turn to the pathologists and say: "and now for the answer". The truth is that surgical pathology is interpretive and subjective. I was reminded of this when I read a quotation from Richard Friedberg, MD, PhD (pictured), chair of pathology at Baystate Health in Massachusetts, in the latest issue of CAP Today from the College of American Pathologists. Dr. Friedberg was discussing the introduction of computer-assisted imaging analysis into his practice with the aim of improving inter-observer reproducibility in the interpretation of surgical immunohistochemical slides. Here's what Dr. Friedberg had to say on the topic: "We're getting away from the idea that this is a bad cell because I sat next to somebody who told me it was a bad cell -- that sort of guild mentality with anointed experts -- and moving toward more quantifiable, reproducible, validated, specific, and reliable approaches." Finally, anatomic pathology is taking its first, furtive steps into the 21st century!

CNS Whipple's disease factsheet

The topic of CNS Whipple’s disease came up in a recent email exchange, so I thought I’d share with you a fact sheet on the disease:

DESCRIPTION:

First described by George Whipple in 1907, Whipple disease is a multisystem disorder that usually includes the intestinal tract. The causative organism is a Gram-positive actinomycete called Tropheryma whippleii.

EPIDEMIOLOGY:

Interestingly, Whipple’s disease occurs about six times more commonly in men than in women. The disease tends to occur in late middle age.

CLINICAL PRESENTATION:

Most patients present with such symptoms as arthralgia, weight loss, steatorrhea, lymphadenopathy, and hyperpigmentation. Some patients develop neurological disease, usually in combination with systemic symptoms. The most common neurologic manifestations are dementia, ophthalmoplegia, hypothalamopituitary dysfunction, and myoclonus. Occulofacial-skeletal myorhythmia is particularly suggestive of Whipple’s disease. Only rarely is Whipple’s disease confined exclusively to the central nervous system.

PATHOLOGIC DIAGNOSIS:

Intestinal biopsy: The diagnosis is usually made by jejunal biopsy, which demonstrates the characteristic macrophages containing PAS-positive rod-shaped structures, termed sickle particle containing (SPC) cells. This microscopic finding may be present even in patients without clinically apparent intestinal involvement. PCR-based assays of intestinal tissue may allow the confirmation of suspected CNS Whipple’s disease, even when histology is not revealing. In patients with neurological manifestations, SPC cells may rarely be found in the CSF.

Brain biopsy: Exceptionally, brain biopsy is required to establish the diagnosis; however, PCR analysis of CSF or synovial fluid allows the diagnosis to be made in most instances. Microscopically, accumulation of macrophages is seen, often with a perivascular distribution, surrounded by a lymphocytic and plasma cell inflammatory reaction of variable intensity, and gliotic brain tissue containing hypertrophied astrocytes. Macrophages with lipid-filled cytoplasm containing sickle-shaped inclusions that are PAS-positive are seen [see figure]. The organisms, which are also Gram-positive and methenamine silver-positive, can also be seen free within the tissue.

DISEASE DISTRIBUTION WITHIN THE CNS

The pathology is usually characterized by small lesions disseminated throughout the entire CNS but especially abundant in the cortex. Larger intracerebral pseudo-tumors are uncommon. Leptomeningeal involvement is occasionally complicated by tiny infarcts scattered throughout the brain; and first presentation as a multiple stroke syndrome has been reported.

REFERENCE:

Greenfield’s Neuropathology (8^th edition), Love S, Louis DN, and Ellison DW (eds). Edward Arnold Publishers (2008). Chapter 18: Bacterial Infections, by Brown E. and Gray F. pages 1426-7.

Neuropathology Blog adds a new feature

I’ve added a new gadget which allows you to become part of the public fan base for this blog. Followers allows you to see who else is following this blog, see the blogs they’re writing, and read the other blogs they’re following. It’s a means of organically creating a network of people interested in neuropathology. Readers who become official followers of the blog can have their profile picture displayed in the followers list if they so wish. Finally, this feature allows you to see the blogs I follow by clicking on view my complete profile under my picture in the column on the right. Just click the “follow this blog” link on the right side of this page, and add yourself as a regular reader. Let’s see where this brings us!

Extramedullary hematopoesis is not an uncommon finding in chronic subdural hematomas

I received a case in consultation this week from a general pathologist who was concerned about clusters of unusual-looking cells within a chronic subdural hematoma (SDH), a specimen the surgeons call a "subdural membrane" (look at the picture above of a resected chronic subdural hematoma from Greenfield's textbook to see why surgeons use that term). I felt that the cluster of cells represented foci of extramedullary hematopoesis (EMH). Another general pathology colleague was doubtful that such a phenomenon was likely in an patient with no other hematological disorders. I countered that perhaps 25% of SDH cases in hematologically intact patients show EMH. This prompted an email to the illustrious Hopkins neuropathologist Peter Burger (pictured), who provided me with a reference to an 2007 article by Juan Rosai and colleagues. In their article, Rosai and friends cited a larger study by Muller et al. (reference 1) in which "a microscopic study of 130 chronic subdural hematomas... found nucleated red blood cells in 41 cases (32%). In a subsequent study, the same authors found erythroblasts in 33% of 38 cases, and this percentage increased to 57% after serial sections were taken." The Rosai article itself (reference 2) describes in detail two cases with the aim of documenting the fact that "such lesions can fool the 'general' surgical pathologists, including some who can hardly be regarded as 'junior'."

References:

1. Muller W, Zimmermann E, Firsching R. Erythropoiesis in chronic subdural hacmatomas. Acta Neurochir (Wien). 1988;93:137-139.

2. Kuhn E, Dorji T, Rodriguez J, Rosai J. Extramedullary Erythropoiesis in Chronic Subdural Hematoma Simulating Metastatic Small Round Cell Tumor. International Journal of Surgical Pathology 15:3 [July 2007] p.288-291.

Brain of Oldest Person in the World is Autopsied

Post-mortem examination of a 115-year-old Dutch woman, recorded as the oldest living human at the time of her death from gastric cancer in 2005, revealed almost no signs of Alzheimer disease, with no amyloid plaques and only a few neurofibrillary tangles (Braak tangle stage II). Pictured is the patient's hippocampus and parahippocampal gyrus. These structures, the first to atrophy in Alzheimer patients, look rather robust in this case. Additionally, she had almost no atherosclerotic changes in her cerebral vessels. These findings correspond to her cognitive function late in life: Henrikjje van Andel Schipperr performed better on neuropsychological assessments than the average 60- to 75-year-old adult! Why might Mrs. van Andel Schipperr have had such a healthy brain even at such an advanced age? Here are some speculative advantages that experts think might have been neuroprotective: she was a woman, she did not smoke, she drank an occasional glass of wine, and she did not eat much. But perhaps the most important factor is that longevity ran in her family (Mrs. van Andel Schipperr’s mother lived to be 100-years-old). Thanks to neurologist Tom Ala, MD of Southern Illinois University School of Medicine for alerting me to this article.

Best Post of June, 2008: Pathologists and lab techs beware!

The choice for the Best Post of June '08 was an easy one, since I had only one post that month! Here it is:

I’m glad to be back in the blogosphere and will mark my return by noting a report brought to my attention by Dr. Chad DeFrain. According to an article in the May 28, 2008 issue of JAMA (299:20, p 2375-6), formaldehyde exposure seems to be a risk factor for amyotrophic lateral sclerosis (ALS). The author reports on data presented at this year’s American Academy of Neurology meeting in Chicago. (I attended that meeting, but missed this presentation. I must have been sitting by the hotel pool!) In any case, the link between formaldehyde exposure and ALS is based on a large prospective cohort study by Dr. Marc Weisskopf and colleagues at the Harvard School of Public Health. Researchers found a more than 4-fold increase risk of ALS among those who reported formaldehyde exposure over a course of more than ten years. Physicians were among the at-risk occupations for formaldehyde exposure. I suppose pathologists would be particularly vulnerable. If you look on the container of 10%-buffered formalin solution you use to fix your specimens, you’ll see that it is composed of 4% formaldehyde. Other at-risk occupations include laboratory technicians, morticians, firefighters, beauticians, and others. Yikes!

Best Post of May 2008: LGMD2B versus Myoshi Myopathy

I read through the posts from May of 2008 for this entry in my "Best of the Month" series. I must give credit to Dr. Laura Rufibach for providing a great primer on LGMD2B and its cousin, Myoshi Myopathy:

I asked the good people at the Jain Foundation (https://www.jain-foundation.org/), an organization devoted to the treatment of Limb Girdle Muscular Dystrophy 2B/Miyoshi myopathy, to help me understand the difference between the two diseases. The Jain Foundation’s director of research, Laura Rufibach, PhD, gave the following informative response:

“Limb-girdle muscular dystrophy and Miyoshi Myopathy are general clinical designations that are given depending on the initial pattern of muscle weakness seen in patients. LGMD is characterized by proximal muscle weakness, while Miyoshi Myopathy is characterized by distal muscle weakness.

“There are 19 genetically defined forms of LGMD (6 dominant and 13 recessive). Clinically, many of the LGMDs are similar and the exact form can only be identified by protein screening or the identification of mutations. For LGMD2B, the “2” signifies the recessive nature of the disease and the “B” indicates that the LGMD is caused by a problem with the dysferlin protein.

“Miyoshi Myopathy is also a genetically heterogeneous form of muscular dystrophy with 3 different linked loci identified to date. At present, mutations in only one gene have been identified that are known to result in Miyoshi Myopathy. That gene, like LGMD2B, is dysferlin.

“Therefore, LGMD2B and Miyoshi Myopathy (caused by mutations in dysferlin) are allelic disorders. The initial clinical presentation (i.e. pattern of muscle weakness) of LGMD2B and Miyoshi Myopathy are very distinct. However as the disease progresses, the majority of patients begin to show a mixture of both distal and proximal weakness. Some patients even initially present with a mixture of both proximal and distal muscle weakness. There are even some reports of both an LGMD2B and Miyoshi Myopathy presentation occurring in siblings within the same family with the same genetic mutations.

“Therefore from my perspective as a geneticist, LGMD2B and Miyoshi Myopathy (resulting from mutations in dysferlin) are the same disease and the variations in clinical presentation are the result of other modifiers (genetic or environmental) that have yet to be identified. Given this fact both LGMD2B and Miyoshi Myopathy could be treated with the same genetic therapeutic approaches (i.e. gene therapy, exon skipping, etc). This is why we include both types of patients in our patient registry."

How many lobes does the human cerebrum have?

A. Two
B. Four
C. Five
D. Six
E. Seven

(The answer appears as a comment to this post.)

Featured Neuropathologist: Douglas C Miller MD,PhD

From time to time on Neuropathologyblog, we like to feature a prominent neuropathologist. My staff at the home office has been working overtime collecting data on one of our favorite neuropathologists: Dr. Doug Miller (picture courtesy of Doug’s wife, Sherry). As many of you know, Doug moved from New York City to God’s Country about a year ago. He’s happily working along with Dr. Doug Anthony at the University of Missouri School of Medicine. Except for a recent Achilles’s tendon tear, Doug has been getting along swimmingly at Mizzou. The injury has forced him to take elevators rather than the stairs to go up to frozen sections, but he gets there.

Doug’s big news is that he is close to finishing a surgical neuropathology textbook. Rather than deal with the uncertainties (and missed deadlines!) of editing a multi-authored text, Doug is writing the book entirely on his own. Doug gave me more details on the upcoming book in a recent email: “The book is divided into four parts: I Neoplasms, II Non-neoplastic Mass Lesions, III Biopsies for non-neoplastic diseases not presenting as a mass, and IV Epilepsy Pathology. Part I is further divided into brain and spinal cord sections, and then of course individual chapters cover the gamut of tumor types. While this is a text, not an atlas, it is also heavily illustrated, with hundreds of photographs organized into multi-part figures. All of this is in color except of course for a smattering of EM pictures and MRI or CT pictures, but the large majority of illustrations are photomicrographs in color, with H&E, special stains, and immunostains. As this represents a distillation of my work and teaching over the last 25 or so years I deviate here and there from dogma as espoused by the WHO and others, but I think this is going to be a good practical diagnostic textbook of use to neuropathologists in training and maybe occasionally in practice, to surgical pathologists at all levels, and perhaps also a useful reference for neurologists, neurosurgeons, oncologists, et alia. The publisher is Cambridge University Press, and the working title is “Modern Neuropathology” (their idea, not mine; I liked “Comprehensive Surgical Neuropathology”, but they are paying the bills…)” The book should be out in time for the American Association of Neuropathologists meeting next June in San Antonio, Texas. Neuropathologyblog will, of course, feature the book when it hits stores next spring.

Doug is known as someone who is willing to buck the trend and go his own way. In an era when single-authored texts are almost unheard of, Doug’s willingness to author an entire text by himself is a rather heroic act. He is indeed an inspiration.

One more thing: Doug is putting the finishing touches on his book and is looking for a picture of a pituitary adenoma with gangliocytic differentiation. If any readers have such a picture, I’m sure Doug would gratefully acknowledge the contributor. You can contact him at the University of Missouri Pathology and Anatomical Sciences Department. Best of luck, Doug!

Pinhole glasses: a simple concept that works

OK, this is a bit of a stretch for a neuropathology blog; but since ophthalmic pathology is generally within the purview (pun intended) of neuropathology, I thought I'd post on the topic. I was recently sent a pair of "pinhole glasses" to see if it would help to correct my myopia. The concept is quite simple: you look through a collection of tiny holes. The small holes refract the light enough so that you can actually see more clearly! This is not something you would wear while driving, since peripheral vision is restricted; but for safe indoor tasks, it works quite well! Here's a link to the site where the pinhole glasses are sold.