A 48-year-old man with mental confusion

We had an interesting case here last week of a 48-year-old gentleman with a clinical diagnosis of exacerbation of "some kind of an autoimmune encephalitis". The clinicians were wondering about CNS vasculitis and multiple sclerosis but really didn't know what the cause of the patient's problem was. An MRI showed multifocal edema and infarcts. He had been receiving weekly steroids with some improvement, but was now getting more symptoms of encephalopathy (confusion, weakness, etc.). A brain biopsy was performed, which showed the small vessels stuffed with neoplastic B-cell lymphocytes. The diagnosis based on brain biopsy was intravascular (angiotrophic) large B-cell lymphoma, a rare lymphoma wherein the neoplastic cells lack the capacity for diapedesis, remaining captured within the vascular lumen (pictured) and causing secondary brain infarction.

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.

Breaking News: Neuropathologist Kevin Roth named UAB pathology chair

I just heard that Kevin Roth, MD, director of neuropathology at the University of Alabama, has been named chair of the UAB Department of Pathology. Congratulations, Dr. Roth!

Brain Factoid

"The average adult brain weight of a human is 1300-1400 g; an adult gorilla's brain weighs only 500 g."

- From Dan Brat's introductory chapter in Prayson's Neuropathology (2005). By the way, it is rumored that Prayson has agreed with the publisher (Elsevier) to come out with a second edition of this book, perhaps sometime in 2010.

Robert Novak to quit his job because brain tumor prognosis is "dire"

I just heard on National Public Radio that conservative columnist Robert Novak, about whom I wrote last week when it was announced that he had a brain tumor, will no longer be working for the Chicago Sun-Times. When you hear the word "dire" on a news story in connection to a brain tumor, you have to think that they're talking about a glioblastoma multiforme. That's probably the diagnosis for Senator Ted Kennedy's tumor as well.

Best Post of April '08: Neuropathologists meet in San Diego

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. This one, which features the illustrious Dr. Mark Cohen (pictured) is from Thursday, April 10, 2008:

The esteemed and illustrious Dr. John Donahue attended the recent American Association of Neuropathologists annual meeting in San Diego. He was kind enough to provide a summary of the famous Diagnostic Slide Session from that meeting as follows:

“It came time for the Diagnostic Slide Session, now being moderated by Anthony Yachnis. It can be summed up as follows: "Dr. Mark Cohen, ROCK STAR!!!" He had to get at least 7/10 cases absolutely correct. He was diagnosing things I had never even heard of. There was a case of "vanishing white matter disease," also called "childhood ataxia with central hypomyelination" and "ovarian leukodystrophy," due to a mutation in eukaryotic initiation factor 2B, and he nailed it! I have never even remotely heard of that disease. There was also a case of intractable epilepsy due to "filamin A" (on chromosome X) astrocytic inclusions that look superficially like Rosenthal fibers, and he nailed it! I never heard of that, either. It was one of the most impressive diagnostic exhibitions I have ever seen. I asked him how long he's been doing this; he said 15 years or so. The cases were so hard that I only felt comfortable going up to the mic once, and after I gave my differential diagnosis, the speaker said "What did you do with the unstained slide that I provided?" I said, "I didn't want to waste it, so I was waiting to see the right answer." That generated laughter and applause!”

Thanks for your contribution, Dr. Donahue. And congratulations are in order. It turns out that an image from Dr. Donahue’s article Apolipoprotein E, Amyloid-[beta], and Blood-Brain Barrier Permeability in Alzheimer Disease appears on the cover of the current issue of the Journal of Neuropathology and Experimental Neurology.

Next week, I’ll be posting from the annual meeting of the American Academy of Neurology in Chicago, IL. The meeting celebrates the 60th anniversary of the organization. The first annual meeting, featuring 38 presented papers, was held at the French Lick Springs Hotel in 1949. Two thousand abstracts have been accepted for this year’s meeting.

Tarenflurbil, a gamma-secretase modulator, does not seem to work in Alzheimer’s disease

Long-awaited results of a Phase III trial of tarenflurbil (Flurizan) have failed to achieve statistical significance on either of its two primary endpoints (cognition and activities of daily living). The company developing the drug, Myriad Genetics, is abandoning development of the compound for Alzheimer's disease.

Tarenflurbil had been shown in nonclinical studies to modulate gamma-secretase activity. The drug was in trials in people with mild Alzheimer's to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

This was the largest and longest placebo-controlled Alzheimer disease treatment trial ever completed. The results were reported today at the Alzheimer's Association International Conference on Alzheimer's Disease being held in Chicago. Read more about the results of the study here.

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).

Robert Novak has brain tumor

Conservative political columnist Robert Novak has a brain tumor, although the lesion has yet to be biopsied for diagnosis. According to an article in the on-line New York Times, "Last week, while driving in Washington, Mr. Novak struck a pedestrian, who was not seriously hurt, and said later that he had not been aware he had hit anyone. It is not clear whether the brain tumor contributed to that accident." Thanks to the illustrious Dr. Ranleigh Fleshman for alerting me to this piece of news. I'll let you know what the diagnosis is once it is made public.

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.