What's an 'atypical pituitary adenoma'?

We recently had a case at our institution of an atypical pituitary adenoma, confirmed by Bernd Scheithauer at the Mayo Clinic. What is implied by the designation of a pituitary adenoma as being “atypical”? Burger, Scheithauer, and Vogel -- in their textbook Surgical Pathology of the Nervous System and Its Coverings by (4^th Edition, 2002), page 469 – have the following to say on the matter: “In an effort to identify tumors likely to behave in an aggressive manner, a histologic category intermediate between ordinary or ‘typical’ adenomas and pituitary carcinoma has be established. The designation ‘atypical adenoma’ denotes tumors showing increased proliferative activity, that is, more than an occasional mitosis, an MIB-1 labeling index exceeding 3%, and p53 immunoreactivity. Because combinations of these findings are clearly associated with invasion and/or recurrence, the designation ‘atypical’ earmarks potentially more aggressive lesions. Its utility in identifying tumors capable of metastasis remains to be established in prospective studies.” In an associated photo caption, it is mentioned that nucleolar prominence is also a common feature of atypical pituitary adenoma.

This marks the last post for the month of December. Neuropathology Blog will be on hiatus until the new year. In the meantime, happy holidays!

Even Cowdry himself wasn't so sure of the significance of the Cowdry B inclusion

Here's a follow-up on my recent post on the presence of Cowdry B inclusions in poliomyelitis. Thanks to Dr. Doug Shevlin, who encouraged me to go back to the original paper by EV Cowdry to find out exactly what Cowdry meant when he described type B inclusions as being characteristic of polio. Here's a quotation from his original 1934 paper on the topic of viral inclusions: "[W]ith these type B inclusions the existence of a virus should not be taken for granted. They may be simply the expression of nuclear modifications occuring not only in some virus diseases but also in many condidtions for which viruses are probably not responsible." There you have it, even O'l Cowdry wasn't so sure about the correlation of these inclusions to polio. Perhaps it's finally time to eliminate from textbooks the "fact" that Cowdry B inclusions occur in polio. (With this additional information, I now feel comfortable increasing my reward to anyone who can email me a photomicrograph of a polio-associated Cowdry B inclusion from $10 up to $12. Good luck -- you'll need it!)

Best Post of August '08: Loss of von Economo neurons may be associated with frontotemporal dementia

And now for another in my occasional “Best of the Month” series, where I march through the past months choosing only the very best blog posts. Since publishing this post, I have been looking for von Economo neurons in my autopsy cases. I believe that I have come upon three in a row, as depicted in the following photomicrograph from the the right anterior cingulate gyrus of an Alzheimer patient. As you can see, von Economo neurons are huge spindle-shaped neurons. (Compare their size to nearby pyramidal neurons):

With that update, I now present my "Best of the Month" post for August '08:

On Wednesday [Aug 6 '08], I wrote about the fact that the brains of gorillas weigh only about 40% as much as human brains. There is, however, one way in which our brains are similar to simians: the presence of the von Economo neuron (VEN).

Constantin von Economo demonstrated in the 1920’s that these neurons are present only in the anterior cingulate and insular cortices (layer Vb). It was later determined that VENs are only present in hominids (humans and great apes), and that they are more numerous on the right side of the brain. Also referred to as spindle neurons because of their spindle-shaped cell bodies, VENs are larger than pyramidal neurons and tend to cluster parallel to small arterioles (pictured on right as compared to pyramidal neuron). More recently, it was found that VENs are also present in various species of whales and in elephants. The common theme here is that VENs are present in social animals with large brains. Since the VEN-populated areas of the brain are preferentially affected in frontotemporal dementia (FTD), it is thought that perhaps loss of these neurons may be related to the aberrant social functioning seen in FTD patients.

Senator Ted Kennedy's malignant brain tumor not keeping him from work on The Hill

I reported in May 2008 on the diagnosis of a malignant brain tumor in Massachusetts Senator Ted Kennedy (1969 picture from Life Magazine). The Voice of American (VOA) recently provided an update on Sen. Kennedy's status, based on a statement he release this past Monday. According to the VOA, the Senator has returned to Washington to work health care reform, laying the groundwork for early action by Congress on health reform after President-elect Barack Obama takes office in January.

It remarkable that Kennedy hasn't simply retired, given his grave diagnosis. His example is truly a profile in courage.

The VOA report goes on to say that "the Massachusetts senator, who was first elected in 1962, underwent surgery in June for a malignant brain tumor. He made a brief appearance in the Senate in July, and delivered a speech supporting Mr. Obama at the Democratic National Convention in August."

Neuropathology Blog featured on CAP Transformation Campaign Website

Some weeks ago, I wrote about the new campaign by the College of American Pathologists to transform the specialty of pathology. Well, Neuropathology Blog has just been recognized as one of the agents effecting that change. Read more here.

Whither the Illusory Cowdry B Inclusion of Polio?

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In a recent post about poliomyelitis, the illustrious Dr. John Donahue of Brown University (pictured) correctly pointed out that I did not mention the presence of Cowdry B inclusions in my histological description of the disease. Having never seen polio under the microscope, I went looking in textbooks and on the web for a photomicrograph of a polio-related Cowdry B inclusion. Failing in my search, I turned to the esteemed Dr. Tom Smith of the University of Massachusetts to see if he had such a picture. With his permission, I quote Dr. Smith’s email to me:

“I have the same problem you and everyone else seems to have -- I've never seen one myself and cannot find any photos of one either in my own file or anywhere in books or on the web. I remember reading a description a long time ago - I think it might have been from the old AFIP neuropath teaching slide set - that they were supposed to be small eosinophilic (?) nuclear inclusions that were sometimes seen in neurons in poliomyelitis. I don't remember actually seeing them in the slide in that teaching set. From the description, I had the impression they might have resembled Marinesco bodies or maybe even normal but prominent nucleoli... or perhaps those small inclusions seen in some neurodegenerative dementias. They don't seem to be as 'specific' as Cowdry A inclusions and perhaps they don't even exist? Frankly I think Cowdry B inclusions have reached the point where they should be relegated to the trashbin of neuropathology.” (Emphasis added.)

I recently photographed a Marinesco body (see picture, arrow points to the eosinophilic body) within the

nucleus (outlined) of a pigmented neuron in the substantia nigra.

Could the Cowdry B inclusion be an elaborate hoax perpetrated upon us by Dr. E.V. Cowdry when he first described Cowdry type A and type B inclusions in 1934? Dr. Smith’s response:

“Well, I doubt that it was a hoax but I think some of those folks were quite prone to seeing things that just the passage of time (and new information) has proved to be ‘not real’. Another case in point - how many Alzheimer type 1 astrocytes have you

seen?”

I then wrote back to the individual who got me started on this hunt for the illusory Cowdry B in the first place: John E Donahue, MD. Here’s what Dr. Donahue had to say about the issue:

“I think these descriptions are very old and go back to the day where everything was described visually, without knowing etiology. (Remember, there are eight structures of Scherer from the original 1938 article, only three of which are really relevant anymore, and maybe even the gliosarcoma being a tertiary structure may be going the way of the dinosaur since I've heard recently that the gliosarcoma arises from a single precursor cell)…”

Fuller and Goodman, in Practical Review of Neuropathology (Lippincott, 2001), define a Cowdry B purely on morphological grounds -- with no implication as to the cause (polio or otherwise) -- as being small, eosinophilic, intranuclear inclusions with no halo and causing no nuclear effacement. I quote page 20: “[T]he quotidian Marinesco bodies that are routinely observed in the neurons of the pigmented brainstem nuclei are sterling examples of the Cowdry type B beau ideal.”

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Perhaps the Marinesco body, rather than a “sterling example”, may in fact be the only example of a Cowdry B inclusion! Come to think of it, I think I’ll offer a $10 reward for anyone who can send me a photomicrograph of a polio-related Cowdry B inclusion. Email me the photo at brian.moore@ucdenver.edu

I hope you have better luck finding one than I did!

Surgical Science Museum in Chicago Features Surgicogenomics Exhibit

Karen Everingham -- formerly of the Illinois Association of Museums and now of the Historic Sites Division of the Illinois Historic Preservation Agency -- has provided me with yet another interesting link to a medical museum. The International Museum of Surgical Science, located in Chicago, is dedicated to the enhancing the understanding of the history, development, and advances of surgery and related subjects in health and medicine. Currently, there is a interesting new exhibit there titled Surgicogenomics: Genes and Stem Cells in Surgery, which addresses the use of stem cells in cutting-edge surgical procedures that have the potential to treat such conditions as Parkinson's disease and Duschenne Muscular Dystrophy. One of the scientific advisors of the exhibit is the respected pathologist Arno A. Roscher, MD of California (pictured). Thanks again to Karen Everingham for letting me know about this fascinating museum!

nNOS: The Canary in the Mine

Yesterday's post focused on the utility of neuronal nitric oxide synthase (nNOS) histochemisty in muscle biopsies. Dr. Steve Moore, who was also featured yesterday, kindly sent me a link to an article by a fellow University of Iowa faculty member, Dr. Kevin Campbell (pictured with his lab staff) and colleagues. Recently published in Nature, the article is titled: Sarcolemma-localized nNOS is required to maintain activity after mild exercise.

Campbell and colleagues address the phenomenon of exaggerated muscle fatigue after exercise, a finding present in many neuromuscular disorders. Using mouse models, the Campbell lab showed that sarcolemma-localized signalling by nNOS in skeletal muscle is required to maintain activity after mild exercise. To quote the abstract: "We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise.... Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling." It is interesting that there was no histomorphological pathology in the nNOS-null mice, suggesting that nNOS histochemical staining of patient biopsies might reveal an underlying disease process in otherwise non-specific biopsy findings. Or, as Steve Moore put it, nNOS can function as the "canary in the mine" for detecting myopathies.

Best Post of July, 2008: "What is nNOS? And why is nNOS histochemistry useful in muscle biopsies?"

From time to time, I feature an installment of my “Best Post Of The Month” series. The next month up for review is July '08, and I feel that this was the best item posted that month:

WHAT IS nNOS? AND WHY IS nNOS HISTOCHEMISTRY USEFUL IN MUSCLE BIOPSIES?

I recently sent a specimen out for histochemistry to see if the muscle had diminished dystrophin and/or dystrophin-associated proteins. One of the histochemical stains in the panel was neuronal nitric oxide synthase (nNOS). I honestly didn’t know what the deal was with that particular protein, so I thought I’d share with you what I found out.

In normal muscle, histochemistry for nNOS shows uniform sarcolemmal labeling. Internal sarcoplasmal labeling can also be present. Blood vessel walls are also positive. In Duchenne or Becker muscular dystrophy, nNOS is absent or reduced in the sarcolemma. Immature fibers will also lack nNOS histochemical staining.

An article by Ehmsen et al in the Journal of Cell Science states the following: “The production of nitric oxide (NO) by nNOS is important for increasing local blood flow to match the increased metabolic load of contracting muscles, such as during exercise… [P]atients with DMD [Duchenne muscular dystrophy] show abnormal blood vessel constriction presumably due to lack of nNOS at the sarcolemma… However, abolishing nNOS expression alone in mice does not cause overt dystrophy.”

So if it doesn’t cause overt dystrophy, what’s the point of doing this particular histochemical stain?

Dr. Steve Moore (pictured), muscle pathology guru at the University of Iowa, emailed me the following response when I queried him on the subject: “[nNOS] is quite sensitive to dystrophin mutations, meaning that it is virtually always absent in DMD and reduced to absent in BMD. In milder cases of BMD, nNOS sometimes can be the "canary in the mine" for detecting a dystrophinopathy. In the setting of a possible dystrophin mutation carrier, it provides one more marker for the muscle cells expressing either normal or mutant dystrophin. Dystrophin-negative fibers are also nNOS negative. This contrasts with the dystrophin-negative fibers being utrophin positive (utrophin is frequently expressed at the sarcolemma when dystrophin is missing or abnormal). Bottom line - using nNOS increases my confidence in the interpretation of the other immunostains in selected cases.”

References:

Dubowitz V and Sewry CA. Muscle Biopsy: A Practical Approach, 3^rd edition (2007) p 261 and 279.

Ehmsen J et al., The dystrophin-associated protein complex. Journal of Cell Science 115 (14) p. 2801-3.

Moore, Steven A. Univ. of Iowa, email communication (July 28, 2008).

The Mutter Museum in Philadelphia Provides a Unique Perspective on Neuroanatomy

Karen Everingham -- formerly of the Illinois Association of Museums and now of the Historic Sites Division of the Illinois Historic Preservation Agency -- told me about an unusual medical museum sponsored by the College of Physicians of Philadelphia called the Mutter Museum. Among the medical curios and artifacts housed at the Mutter is a unique set of sliced sections of the human head prepared for the museum in 1910. What's special about this series of sections is that it demonstrates the human brain in situ within the context of the entire head. The first section in the series (pictured) shows the face of the subject sectioned. The next time I'm in Philadephia, I will surely visit the Mutter. Thanks, Karen!

Happy First Birthday to Neuropathology Blog!

Today marks the first anniversary of Neuropathology Blog! There have been 128 posts in the last year, and over 200 comments by readers. Geographic tracking shows that people from as near as Springfield, IL and as far away as India and Japan have accessed this blog. Also, there have been more than 1,200 views of my profile during the past 12 months. I've enjoyed the experience, and hope that I've provided some education and entertainment along the way. I look forward to the next year of neuropathology blogging!

14-3-3 protein: What is it good for?

The neurology residents and I got into a discussion today about the utility of the 14-3-3 protein immunoassay on CSF fluid. I published a post on this assay many months ago in which I called it essentially useless. Now that I've done some more research on the topic, I've revised my opinion and feel that it is a decent confirmatory test -- but only in those cases in which there is a fairly high pre-test likelihood of prion disease based on observation of an evolving mental deterioration along with some type of involuntary movement or periodic EEG activity. In a prospective study of 110 patients done in The Netherlands (see reference below), it was found that the 14-3-3 assay was 97% sensitive and 87% specific. It must be emphasized that these results are based on a population of patients who have other clinical features that point to a prion disease. Of course, routine CSF tests should also be run on these patients because, as the authors state, "abnormalities of the routine examination of CSF almost exclude CJD as a diagnosis". They go on to say that "conditions associated with increased cell counts or total protein (e.g., meningitis and encephalitis) are known sources of false-positive 14-3-3 test-results. Therefore, it is reasonable to consider other diagnoses first if total protein or cell count is increased in patients with initially suspected CJD."
(Reference: Lemstra AW, et al. 14-3-3 testing in diagnosing Creutzfeldt-Jakob disease: A prospective study in 112 patients. Neurology 2000;55:514-516.)

3D imaging and virtual reality technology is the next wave in brain tumor diagnosis and treatment

A friend emailed me a link to the Iowa State Virtual Reality Applications Center, where they are doing interesting things with 3D rendering that will have implications for brain tumor operations. Here's what one researcher there, Eliot Winer (pictured), is up to:
"Dr. Winer's research team is currently working on a project that will allow physicians to view 3-D images of patients' complex internal systems. The images could be delivered over the internet or could be rendered in real-time while the patient undergoes surgery, thus providing more complete and timely information. Essentially, Dr. Winer believes that complex systems will eventually become data centric, a term he coined to describe a system that addresses multiple fidelities. In short, 'all the data has to come together so everyone can access the data simultaneously and collaborate more effectively.'"
I don't profess to know exactly what all this means, but it sounds like a an exciting frontier in cancer treatment. Let's hope pathologists, as they move to toward a transformation of their profession, are involved in the development and implementation of this new technology.

College of American Pathologists Set to Transform the Profession

The College of American Pathologists (CAP) announced a new initiative at the September national meeting in San Diego entitled: The CAP Campaign for the Transformation of the Specialty of Pathology. A cornerstone of the campaign is the CAP's new certificate program to be launched in June '09 through the CAP Institute . The certificate program is designed to allow pathologists to earn time-limited certificates in broad areas of expertise not currently offered as a subspecialty board certification (such as breast pathology) as well as in narrow skill sets (such as ultrasound-guided fine needle aspiration). Read more about all the efforts encompassed by the campaign here. Thanks to CAP House Delegate Doug Shevlin, MD (pictured on the right next to me on the left) who informed me about this exciting new initiative by the CAP.

Brain Food

A reader from Springfield, IL recently sent me this picture of a market that once stood on Chouteau Avenue in St. Louis.  "Brains & Eggs" was once a popular dish, particularly in the southeastern United States. 

Polio: Once ubiquitous, now a disease of poverty

Today is Global Blog Action Day ‘08, which this year focuses on the topic of poverty. One important place where poverty and neuropathology intersect is in the disease known as poliomyelitis (polio). This is a highly infectious viral disease, which mainly affects young children. The virus is transmitted through contaminated food and water, facilitated by crowding and poor sanitation. The virus multiplies in the intestine and then can invade the nervous system. In a small proportion of cases, the disease causes paralysis, which is often permanent. Although the spinal cord is usually involved, the distribution of paralysis depends upon the distribution of lesions within the CNS. The paralysis is usually asymmetric and involves the legs more often than the arms.

There is no cure for polio, it can only be prevented through immunization. The introduction in the 1950s of the Salk vaccine and in the early 1960s of the Sabin vaccine caused a sharp decline in the incidence of poliomyelitis. Polio vaccine, given multiple times, almost always protects a child for life.

Histopathologically, neuronophagia is prominent from a very early stage, as lymphocytes and microglia aggregate around dying neurons like vultures around a carcass. (The photomicrograph depicts neuronophagia of a neuron in the inferior olive of a patient with brainstem encephalitis caused by coxsackievirus.) Eventually, only clusters of microglia remain where the neuron once lay. In patients who die years after onset of the illness, autopsy examination of the spinal cord reveals anterior horn neuronal loss and corresponding discoloration of anterior nerve roots.

The World Health Organization (WHO), in collaboration with other agencies, has been working on a global immunization initiative since 1988. The Global Polio Eradication Initiative has been working to immunize children in impoverished regions of the world, where education and health care resources are scarce. The results of this initiative are encouraging: polio cases have decreased by over 99% since 1988 -- from an estimated 350, 000 cases then, to 1,997 reported cases in 2006. In 2008, only four countries in the world remain polio-endemic, down from more than 125 in 1988. The remaining endemic countries are Afghanistan, India, Nigeria and Pakistan.

References:

1. World Health Organization website: http://www.who.int/topics/poliomyelitis/en/

2. Greenfield’s Neuropathology (8^th edition), Love S, Louis DN, and Ellison DW (eds). Edward Arnold Publishers (2008). Chapter 17: Viral Infections. Love S and Wiley CA. pages 1285-1291.

3. Global Polio Eradication Initiative website: http://www.polioeradication.org/

The best meningioma lecture I've ever seen

Dr. Mark Cohen (pictured) of Case Western Reserve University just published a podcast presentation on frontalcortex.com that is by far the very best lecture on meningiomas and their mimics that I have ever seen. He incorporates the latest World Health Organization criteria on grading of meningiomas in a truly masterful presentation. Plus, Cohen has a great speaking voice. Pathologists, neurologists, neurosurgeons: go see this lecture!

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.

What's is meant by "luysian" in dentatorubral-pallidoluysian atrophy?

Dentatorubral-pallidoluysian atrophy is an autosomal dominant spinocerebellar ataxia which occurs most frequently among the Japanese. "Dentato" refers to the dentate nucleus of the cerebellum; and "rubral" alludes to the red nucleus. "Pallido" of course indicates the globus pallidus. But what does "luysian" refer to? I posed this question to the illustrious Dr. John Donahue (pictured), neuroanatomist extraordinaire, who reminded me that the subthalamic nucleus is also knows as the "Body of Luys" or "Corpus Luysii", named in honor of the noted French neurologist Jules Bernard Luys (1828–1897), who gave the first detailed description of this structure in the basal ganglia.

Neuropathology Blog initiates new feature

On more than one occasion, I have been discussing something with a colleague and remembered that I had blogged about that very same issue some months previously. Then, in order to find the post, I would have to try to remember when I posted on the subject if I wanted to find the entry in the archives. That was fine back when I had only twenty or thirty posts on this site. Now, I have more than one hundred posts; and finding old posts has become tedious. Not to worry. The people at blogger provide a feature called "labels" which allows me to attach search terms to each of my posts. I have renamed the feature "tags", as it sounds more appropriate to me. From now on, you will see along the right-hand column of the page a list of tags, with the number of posts tagged with a particular subject heading. I know this will make searching the archive much easier. It will take about a week for me to go through each post on the site and make tags for each, but it will eventually make searching this blog a whole lot easier.

If the brain were a hard disk

According to Prof. Jeff Lichtman (pictured) of Harvard's Center for Brain Science, the data storage capacity of the human brain is 1 million petabytes. A petabyte is equal to 1000 terabytes; and a terabyte is equal to 1000 gigabytes. In other words, the human brain has storage equivalent to 1000 billion gigabytes of information. So, why can't I remember where I put my car keys?

What are Remak cells?

Remak cells, named after Polish-born Robert Remak (1815-1865)(pictured), are Schwann cells which do not myelinate, but rather surround unmyelinated peripheral nerve fibers. According to Greenfield's Neuropathology (8th Edition), "unmyelinated axons are always of small diamter and pass through the nerve trunk in groups of 8-15 within a common chain of Schwann cells".

Central core disease

Central core disease is a congenital myopathy defined by the presence on muscle biopsy microscopy of numerous muscle fibers that lack oxidative activity, thus making "cores" on NADH-stained slides within muscle fibers. Reported to be one of the most frequent forms of congenital myopathy, this disease usually becomes apparent in infancy or childhood. Facial, neck, and proximal limb weakness with generalized hypotonia are the characteristic clinical features; but phenotypic severity is widely variable. The disease is linked to a ryanodine receptor gene mutation (RYR1, chromosome 19q13). The ryanodine receptor is depicted in the illustration. Malignant hyperthermia is highly associated with central core disease, independent of the degree of muscle weakness.

(Main source: Mark Cohen's chapter in Prayson's Neuropathology, A volume in the Foundations in Diagnostic Pathology series, first edition)

Estimated US brain cancer cases in 2008

The American Cancer Society recently put out a publication entitled Cancer Facts and Figures 2008 in which it is reported that there will be 21,810 new brain and other nervous system cancers in the United States in 2008. Compare that to the estimated number of new lung and bronchus cancers: 215,020.