Is it just me....

... or does everyone see extramedullary hematopoesis in the majority of their chronic subdural hematoma specimens? Here's yet another example that landed on my desk today:

Something you don't see every day....

A binucleated cerebellar Purkinje cell:

Marathon brain cutting session at UCSD streamed live today

The Brain Observatory at the University of California San Diego is today beginning a 30-hour brain cutting session with a live online stream of the procedure wherein the brain of H.M., an amnestic patient, is being thinly sliced from front to back into whole-mount frozen histologic sections. Each brain slice will be approximately 70 microns thick, about the thickness of a human hair. An average-sized brain produces 2,600 to 3,000 such slices. The UCSD Brain Observatory, headed by Dr. Jacopo Annese, is dedicated to the study of the architecture of the human brain using multiple complementary imaging modalities, including autopsy. Thanks to Thomasina Bailey for alerting me to this extraordinary brain cutting event!

Best Post of March '09: What's the deal with subcortical U-fibers?

The next in our series of "Best Posts of the Month" is for March, 2009. I chose this one as the best of the month partly because of the interesting comments it elicited from Dr. Doug Miller. Here's the post from March 19th:



FrontalCortex.com features lots of neuropathology, including podcasts from one of our favorite neuropathologists, Dr. Mark Cohen. In a podcast on demyelinating diseases, Dr. Cohen clarifies questions I've long harbored about the so-called subcortical U-fibers. The photomicrograph above (from the textbook Neuropathology by Ellison and Love) shows a blue myelin stain of an adrenoleukodystrophy case where the subcortical U-fibers are spared. The following is a transcription of Dr. Cohen's insightful comments on this topic. I should first clarify that when Dr. Cohen talks about the subcortical U-fibers being the "slowest myelinating fibers within the nervous system", he is not talking about conduction velocity, but rather about how long they take during one's lifetime to get completely myelinated. OK, here's Cohen:

"As you read through either your textbooks or the literature on leukodystrophies, you'll inevitably comes across a statement which describes either preservation, or lack of preservation, of the subcortical U-fibers. The subcortical U-fibers are, as the name implies, myelinated fibers just at the junction of the gray matter and the white matter which travel in a tangential, rather than radial, fashion connecting areas of cortex to other areas of cortex. What's special about these U-fibers, and why they are either spared or not in leukodystrophies, is that they comprise the slowest myelinating fibers within the nervous system. These U-fibers begin myelination early in gestation and often aren't completely myelinated until the third or fourth decade of life. Therefore, leukodystrophies in which the pathology is dependent on myelin turnover will demonstrate relative sparing of these fibers as the turnover is extremely slow; while in leukodystrophies which depend on toxic damage to the oligodendroglial cell, subcortical U-fibers are as vulnerable as other myelinated fibers within the nervous system."

What's the deal with the subcortical U-fibers?

FrontalCortex.com features lots of neuropathology, including podcasts from one of our favorite neuropathologists, Dr. Mark Cohen. In a podcast on demyelinating diseases, Dr. Cohen clarifies questions I've long harbored about the so-called subcortical U-fibers. The photomicrograph above (from the textbook Neuropathology by Ellison and Love) shows a blue myelin stain of an adrenoleukodystrophy case where the subcortical U-fibers are spared. The following is a transcription of Dr. Cohen's insightful comments on this topic. I should first clarify that when Dr. Cohen talks about the subcortical U-fibers being the "slowest myelinating fibers within the nervous system", he is not talking about conduction velocity, but rather about how long they take during one's lifetime to get completely myelinated. OK, here's Cohen:

"As you read through either your textbooks or the literature on leukodystrophies, you'll inevitably comes across a statement which describes either preservation, or lack of preservation, of the subcortical U-fibers. The subcortical U-fibers are, as the name implies, myelinated fibers just at the junction of the gray matter and the white matter which travel in a tangential, rather than radial, fashion connecting areas of cortex to other areas of cortex. What's special about these U-fibers, and why they are either spared or not in leukodystrophies, is that they comprise the slowest myelinating fibers within the nervous system. These U-fibers begin myelination early in gestation and often aren't completely myelinated until the third or fourth decade of life. Therefore, leukodystrophies in which the pathology is dependent on myelin turnover will demonstrate relative sparing of these fibers as the turnover is extremely slow; while in leukodystrophies which depend on toxic damage to the oligodendroglial cell, subcortical U-fibers are as vulnerable as other myelinated fibers within the nervous system."

Thank you, Dr. Cohen!

Best Post of November '08: Whither the Illusory Cowdry B Inclusion of Polio

And now for another installment of the "Best of the Month" series. In this post from November 13, 2008, I wrote about the alleged existence of polio-related Cowdry B inclusions. No one has yet been able to produce a photomicrograph of such an inclusion, despite having increased the reward from $10 all the way up to $12. Anyway, here's the post:

-->

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!

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.

Whither the Illusory Cowdry B Inclusion of Polio?

-->

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.”

-->

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!

"... 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!

Loss of von Economo neurons may be associated with frontotemporal dementia

On Wednesday, 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.

Another interthalamic adhesion picture

This is a high-power picture of the interthalamic adhesion of an 81-year-old man with a clinical diagnosis of Dementia with Lewy Bodies. Again, see the collection of neuron cell bodies along with glial cells. I should remind you that not everyone has an interthalamic adhesion (about 20% are lacking this grey matter), and women are more likely to have this structure than do men. Nobody knows why this is, or what the function of the structure is. I supporse there are two possibilites, either it is of no practical importance, or there is an alternative way in which those lacking an interthalamic adhesion can process the information otherwise reserved for this structure.

Erratum regarding the interthalamic adhesion

I must revise a post from May 19, 2008 in which I quoted Dr. George R. Leichnetz, neuroanatomist at Virginia Commonwealth University and author of Digital Neuroanatomy: An Interactive CD Atlas with Text (Wiley-Liss, 2006). At that time, Dr. Leichnetz emailed me the following: “The 'interthalamic adhesion' or 'massa intermedia' is (as its name implies) an adherence of the ependymal lining of the midline third ventricle. Importantly, it is not a commissure, ie. there are no inter-thalamic fibers exchanged between the two thalami."

At that time, I said that I would confirm this view under the microscope by taking some sections of the interthalamic adhesion at autopsy. Well, it turns out that there are plenty of neuron cell bodies and nerve tracts within the massa intermedia. Above is pictured the massa intermedia from an 85-year-old lady with Alzheimer disease. Notice the bipolar neurons, particularly convincing is the neuron with the prominent nucleolus. Since this slide was stained with luxol fast blue, which stains myelin blue, you can see that there are indeed nerve tracts running through the massa intermedia. As I did further research on the internet, I found a consensus that the massa intermedia is indeed grey matter, and not simply an adherence of ependymal lining as was stated by Dr. Leichnetz. Sorry about any confusion I may have caused regarding this matter.

Why do most of us have an interthalamic adhesion?

Neil asks a very good question. What is the difference between those with, and those without, an interthalamic adhesion. I found a 1991 article in Science by Ann Gibbons entitled “The brain as ‘sexual organ’” (Science 30 August 1991: 957-959) which states that the “massa intermedia tends to be absent altogether in men more frequently than it is in women. While the function of the massa intermedia isn't known, some early NIH studies have found a correlation between the presence of it and I.Q. scores (with different patterns in men and women). Says [Sandra J.] Witelson, [a McMaster University behavioral neuroscientist]: ‘Obviously, intelligence isn't situated in the massa intermedia, but it could be correlated with other anatomical features that are relevant to some aspects of intelligence.’”

However, I posed Neil’s question to Dr. George R. Leichnetz, neuroanatomist at Virginia Commonwealth University and author of Digital Neuroanatomy: An Interactive CD Atlas with Text (Wiley-Liss, 2006). Here is Dr Leichnetz’s emailed response to my query:
“The "interthalamic adhesion" or "massa intermedia" is (as its name implies) an adherence of the ependymal lining of the midline third ventricle. Importantly, it is not a commissure, ie. there are no inter-thalamic fibers exchanged between the two thalami. In subhuman primates and other mammals there is a true midline commissure through which fibers are exchanged. But in man the functions of the two cerebral hemispheres are specialized and separate, hence, their principal source of afferents, the thalamus, are separate. It would be functionally disadvantagious if there were a commissure at the level of the thalamus. So, the absence of this adhesion has no negative functional consequence as far as I know.”

The next time I do a brain autopsy, I’ll take a microscopic section of the interthalamic adhesion and post a photomicrograph to prove Dr. Leichnetz’ point. Given Dr. Leichnetz’ comments, it would be highly unlikely that the presence of an interthalamic adhesion would have anything directly to do with intelligence -- or anything else, for that matter!

Grumose degeneration in the cerebellar dentate nucleus

It’s hard to find a picture of grumose degeneration in a textbook or online. I did, however, find one in an article by Yamanouchi et al. entitled “An Autopsy case of ornithine transcarbamylase deficiency” [Brain & Development 24 (2002) 91-94]. Grumose degeneration appears as eosinophilic granular material around dentate neurons. Neuropathologists usually think of grumose degeneration of the cerebellar dentate as an autopsy finding in progressive supranuclear palsy (PSP). But the authors of this article describe the same finding in a case of ornithine transcarbamylase deficiency, the most common heritable urea cycle disorder. They point out that although grumose degeneration was first described in a patient with PSP, it has also been reported in certain other neurodegenerative disorders, such as dentatorubropallidoluysian atrophy, Ramsay-Hunt syndrome, and juvenile Alzheimer disease with myoclonus. Ultrastructural studies have revealed that this eosinophilic material corresponds to degenerate Purkinje cell axon terminals. By the way, the word ‘grumose’, which can also be spelled ‘grumous’, means granular and refers to something that resembles grume, which is (according to Webster’s online dictionary) a thick, viscid fluid or clot-like material.

Frontal lobe metastases cause Phinaes Gage syndrome

I got this email from my esteemed colleague and friend, Dr. Gerald Colvin:

"Hi Brian,
Here is an addition to your blog from your esteemed colleague and friend. This patient has metastatic non-small cell lung carcinoma and presented to us with mental status changes. He was found to have bilateral frontal lobe tumors causing significant edema. What is interesting about this case was that he has personality changes reminded me of those of Phineas P. Gage was reported to have. Gage's remains I believe are housed in Boston. I did see something on display in a London museum when I was there a million years ago
Ger-"

Most of us know 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. His physician, Dr. Harlow, describes Phineas some time after the accident as “fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires.” (Reference: Phineas Gage: A Gruesome But True Story About Brain Science by John Fleischman, HMCo Children’s Books, 2004).

The arachnoid is a recent discovery

According to the Fuller/Goodman book, the meningeal arachnoid is a relatively recent discovery. Although the dura mater and leptomeninges were described as long ago as 200 BC by Galen, the discovery of an arachnoid portion of the leptomeninges was not made until AD 1664 by Dutch anatomist Fredrik Ruysch.

More on the JNEN article

I was never clear on exactly which cells contained the glial cell inclusions (GCIs) in Multiple System Atrophy. This article clears that issue up. I quote: "GCIs are faintly eosinophilic, sickle-shaped, oval or conical inclusions that displace the nucleus eccentrically. Their localization to microglia has been established by double staining techniques." There you have it!