Doug Miller moves to Missouri

Dr. Douglas C. Miller, former neuropathologist at NYU, has recently moved to the University of Missouri at Columbia. Good luck in Mizzou, Doug!

Medial lemniscus

Brain cutting sessions with residents can get repetitive after a while unless you have new neuroanatomy information to share with them every so often. To that end, here's a nice description of the course of the medial lemniscus as it ascends through the brainstem written with a visual metaphor that will really stick in your mind. You can use this metaphor in describing the medial lemniscus during your next brain cutting session. The source is my favorite basic neuropathology book: "Practical Review of Neuropathology" by Fuller and Goodman. From page 113:

"The ascending proprioceptive and fine touch system has its relay nuclei, the nucleus gracilus for lower extremity and trunk, and the nucleus cuneatus for upper extremity, neck, and upper trunk...at the cervicomedullary junction. The second order neurons from these nuclei decussate to form the medial lemniscus that ascends through the brainstem to eventually innervate the ventral posterior lateral (VPL) nuclues of the thalamus. In the medulla, the medial lemniscus is arranged as a vertical (ventral to dorsal ) strip of fibers in the midline with the upper extremity fibers being most dorsal and the lower extremetiy fibers being most ventral; i.e., the sensory homunculus in the medulla is 'standing straight up'. The medial lemniscus rotates to the horizontal in the pons and by the time it reaches the midbrain has rotated further so that the fibers from the lower extremity are now more dorsal than those of the upper extremity. Imagine a reveler on Bourbon Street in New Orleans. Early in the evening, the individual is standing vertically against a lamppost enjoying the libations and this is analogous to the position of the medial lemniscus in the medulla. By mid-evening, the partygoer slides down the lamppost and lays on the street analogous to the increasingly horizonatal disposition of the medial lemniscus in the pons. Finally, the besotted reveler is pulled from the street by his ankles by the local constabulary analogous to the 'feet up' orientation of the medial lemniscus in the midbrain."

I should note that I had to correct a few typos in this as I transcribed it. For example, the authors write "Bourdon Street" instead of "Bourbon Street" in New Orleans. And they refer to the "nucleu gracilus" instead of the "nucleus gracilus". That being said, I still think that Fuller and Goodman provide a wonderful analogy that really helps in explaining the anatomy of the medial lemniscus!

Neuropathology Course on the Web

Dr. Dimitri P. Agamanolis of Akron Children's Hospital has a neuropathology website that essentially provides a primer on the basics of neuropathology. Check it out at:
http://www.neuropathologyweb.org/
I'll be away on vacation until after Christmas, so there will be no new posts until that time. Merry Christmas!

Upcoming American Academy of Neurology Annual Meetings

For those of you who like to plan ahead, the 2008 AAN annual meeting will be in Chicago. The 2009 AAN meeting will be in Seattle, Washington. The 2010 Annual Meeting will be in Toronto, Ontario, Canada. There's a link to the AAN website below.

Dr. Asao Hirano

For those wondering who the older gentleman is in the picture with me below, it is none other than the esteemed Dr. Asao Hirano, after whom the actin-associated intraneuronal inclusions known as Hirano bodies are named. He is currently on faculty at Albert Einstein College of Medicine in New York City.

Answer to Quiz Question

Joseph Merrick was originally thought to be suffering from neurofibromatosis type I, a genetic disorder also known as von Recklinghausen's disease. However, it was postulated in 1986 that Merrick actually suffered from Proteus syndrome (a condition which had been identified by Michael Cohen seven years earlier). Unlike neurofibromatosis, Proteus syndrome (named for the shape-shifting god Proteus) affects tissue other than nerves, and is a sporadic rather than familially transmitted disorder. In July 2003, Dr. Charis Eng announced that as a result of DNA tests on samples of Merrick's hair and bone, she had determined that Merrick certainly suffered Proteus syndrome, and may have had neurofibromatosis type I as well. (The above information is adapted from the wikipedia article. But I can vouch for its authenticity.)

The clinical manifestations of Proteus syndrome are, as the name implies, protean. They include:
- Partial gigantism of hands or feet
- Hemihypertrophy
- Subcutaneous lipomas
- Multiple nevi
- Areas of thickened skin and subcutaneous tissue
- Macrocephaly
- Skull anomalies
- Accelerated growth in long bones
- Mentation can be normal or retarded

Quiz Question

From which of the phakomatoses did Joseph Merrick (played by John Hurt in the movie 'Elephant Man') suffer? The answer will appear in tomorrow's posting.

Pediatric Neuro-Onc Meeting this summer

For those looking for a meeting to attend, the International Symposium on Pediatric Neuro-Oncology (ISPNO 2008) wil take place June 30 – July 2, 2008 in Chicago. The abstract submission deadline is January 15th. Here's the link for more info:
http://www.ispno.com/page/page/4477724.htm

14-3-3 protein

A clinician at my hospital ordered a CSF 14-3-3 protein on a lethargic elderly woman with a urinary tract infection. What a waste! The problem with clinicians ordering this test unnecessarily is that it obligates the lab technicians to decontaminate equipment to protect against the possibility of prion contamination. It's an inefficient use of resources for a test that is very non-specific. The patient in question had none of the characteristic clincal signs, nor did she have an EEG done to gathter evidence that she may have CJD. Ordering that test in this patient is just bad medicine.

Innervation of the pineal gland

The pineal gland is innervated by the nervi conarii. This name was derived from the fact that an antiquated term for the pineal gland is the "conarium", which literally means "cone". The nervi conarii are sympathetic fibers with cell bodies situated in the superior cervical ganglion.

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.

The Best Intro Neuropath Book

I've looked at several introductory neuropath books for use by residents rotating in neuropatholgy (these include neurologist only in my case, but some institutions have neurosurgeons and general pathology residents rotating with them as well). Well, these residents need a handy, simple reference text. I recommend Practcal Review of Neuropathology (by Greg Fuller and J. Clay Goodman). The one caveat is that the pictures are black and white, and not the best quality. That being said, I think the pictures are adequate to get the idea of what is being discussed. I have compared this book to the Prayson book, the Escourolle and Poirier book, and the most recent competitor by Haberland. Even though all these books have been published more recently, Fuller and Goodman is the best. I hope they come out with a second edition with color pictures. If so, they will CRUSH the competition.

Not all neuropathologists have their primary training in general pathology

J. Clay Goodman, M.D., Assistant Dean for Medical Education at Baylor, did a residency in neurology, not pathology, before getting fellowship training in neuropathology. Another prominenet neuropathologist, John E. Donahue, had a similar trajectory, having done a neurology residency at Tufts before doing a fellowship in neuropathology at Brown University in Rhode Island, where he is now an attending. Most of us, however, had general pathology training before becoming neuropathologists.

Abstract from journal Cell on stem cells

This is off topic, but there's big news today regarding the
creation of pluripotent cells from human skin fibroblasts.
Here's the abstract from the Yamanaka study in Cell:
"Successful reprogramming of differentiated human
somatic cells into a pluripotent state would
allow creation of patient- and disease-specific
stem cells. We previously reported generation
of induced pluripotent stem (iPS) cells, capable
of germline transmission, from mouse somatic
cells by transduction of four defined transcription
factors. Here, we demonstrate the
generation of iPS cells from adult human dermal
fibroblasts with the same four factors: Oct3/4,
Sox2, Klf4, and c-Myc. Human iPS cells were
similar to human embryonic stem (ES) cells in
morphology, proliferation, surface antigens,
gene expression, epigenetic status of pluripotent
cell-specific genes, and telomerase activity.
Furthermore, these cells could differentiate
into cell types of the three germ layers in vitro
and in teratomas. These findings demonstrate
that iPS cells can be generated from adult
human fibroblasts."

CNS Whipple disease

Somebody asked me the other day about CNS Whipple disease. I said that I thought it was an instestinal infection and didn't think it had a CNS manifestation. I thought wrong. Caused by Tropheryma whippelii, a gram positive intracellular actinomycete, Whipple disease of the CNS can cause various symptoms, including ophthalmoplegia.

Final posting on the JNEN review article

The bottom line here is that although PD, DLB, and MSA are all synucleinopathies, they differ from one another in terms of composition of the inclusions. And, even among different patient there are differences in protein compostion of each inclusion (i.e., not all brainstem Lewy bodies are created equal). These are very complex issues that are far from being understood.

Yet more on the JNEN review article

Regarding brainstem Lewy bodies, here's something interesting from the article: "The ultrastructural similarities among filaments in LBs [Lewy bodies], pale bodies, and perikaryal threads prompted the hypothesis that AS [alpha-synuclein] perikaryal threads are an early stage of filament assembly that may then progress to pale bodies and, finally, to classic LBs."

Poll results

I see that no one voted in the poll. I suppose no one actually reads this blog. But, then again, most bloggers blog for reasons other than being read by others. In any case, my choice of a site for the AANP meeting of the four options is Little Rock, AK. When would you otherwise have a chance to go there?

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!

JNEN article on synucleinopathies

In the introduction to the article cited yesterday, the authors describe two subtypes of multiple system atrophy (MSA-P and MSA-C). What about the type in which primary autonomic failure is the predominant presentation? Does the dysautonomic subtype (formerly known as Shy-Drager syndrome) have a specific MSA subtype designation? And, where would one find neuropathologic evidence of disease in that subtype? That information is missing from the introduction. Given that this is supposed to be a review article, I would think that that aspect of MSA would be addressed.

Protein aggregation in the synucleinopathies

The current issue of the Journal of Neuropathology and Experimental Neurology has a review article about alpha-synuclein aggregation mechanisms in the major synucleinopathies: Parkinson's disease, Dementia with Lewy Bodies, and Multiple System Atrophy. The article was written by Drs. Katrin Beyer and Aurelio Ariza from Barcelona, Spain. I'll have more to say about this article in future posts.

The problem with muscle biopsies in adults

By the time the adult patient comes to the point where they need a muscle biopsy, all other diagnostic maneuvers have been exhausted. Often, the biopsy is of little to no help and the clinician is left wondering what the diagnosis is. I often find muscle biopsies frustrating because I know that the patient had to undergo minor surgery to have the biopsy done, and then I cannot really do much with the biopsy to help the clinician. Part of it may be my own diagnostic limitations. But, I see the reports of other neuropathologists, and they are also often vague and non-specific as well. I suppose it is helpful when I can identify features consistent with polymyositis. But, when there is a clinical suspicion of polymyositis, what's the harm in a trial of steroids to see if the patient gets better? I realize that an unnecessary course of steroids is not worth the risk in some patients, but in many such a trial would be an acceptable route to go rather than subjecting the patient to biopsy.

Emerging drugs for the treatment of glioblastoma

Bevacizumab (Avastin) is an angiogenesis inhibitor that is being used in the treatment of glioblastoma multiforme (GBM). AQ4N (Banoxantrone) is a prodrug that becomes active in hypoxic regions (i.e., tumor) that is also being examined as a useful chemotherapeutic agent for GBM.

Muscle biopsy

Today I'm looking at a muscle biopsy from a 63-year-old female with muscle cramping and increased creatinine level. There appears to be a chronic inflammatory infiltrate surrounding scattered non-necrotic muscle fibers. This is most consistent with polymyositis. I suppose, given the prefix "poly", that by definition polymyositis is in more than one muscle. So, given that I have a single biopsy of a single muscle, I can only claim that these histologic findings are consistent with polymyositis.

Inflamed eyeball

Today I received a specimen labelled "left eye". It was the eyeball of a 57-year-old gentleman who had sustained trauma to that eye several months ago. The eye was blind and painful, so enucleation was performed. Grossly, there wasn't much to report other than opacity in about half of the cornea. Microscopically, I saw acute and chronic inflammation in the cornea, iris and ciliary body. There also appeared to be mild optic nerve atrophy. The changes were far too acute to allow time for the development of a cyclitic membrane.

The Cyclitic Membrane

In examining chronically inflamed eyeball specimens, the presence of a cyclitic membrane is not infrequently noted. A cyclitic membrane is connective tissue that extends across the eye from one aspect of the ciliary body to the other. In 1937, Dr. Harvey D. Lamb of St. Louis wrote an article entitled "The Genesis of the Cyclitic Membrane" in the Transcripts of the American Ophthalmologic Society. In it, he explains that "the essential factor in the formation of the cyclitic membrne is the conversion of the macrophage into a connective-tissue cell or fibroblast." He states that since the native fibroblasts of the ciliary body are fixed tissue cells, it "is not possible for them to proliferate through the unbroken pigmented and unpigmented ciliary epithelia". He made these claims on purely morphological grounds (hey, what do you want? it was 1937 after all). However, he does cite in vitro findings wherein cultures of macrophages underwent differentiation and yielded colonies of fibroblasts. In any case, the formation of a cyclitic membrane in chronically inflamed eyes is an interesting phenomenon and one which, when seen in enucleation specimens, I mention as part of my histologic description.

Jeff Joseph has three dogs

I was surprised to learn that Jeff Joseph, the author of "Diagnostic Neuropathology Smears", owns three dogs (Kakoe, Ares, and Jasper). These canines are among those, along with his wife and son, to whom he dedicates his book.

Frozen/Permanent discrepency article in Archives of Pathology

This article in the October '07 issue of Archives of Pathology and Laboratory Medicine, by Plesec and Prayson at the Cleveland Clinic, looks at 57 instances (out of a pool of 2156 cases) where a diagnostic discrepancy was found between frozen and later permanent sections. Of those 57, the authors were able to identify a few pitfalls that one should be aware of when attempting to make a diagnosis at frozen section.

As I read this article, I wondered about all the cases in which the pathologist wrote something so vague that a discrepancy was virtually impossible. An example of such a frozen section diagnosis might be "lesional tissue present, defer to permanents". This is sometimes a legitimate diagnosis and all the surgeon needs to know. I cannot believe that vague frozen section diagnoses like that are never rendered at the Cleveland Clinic. So, what happened to those cases in their study? Were those put in the nondescrepant category? If so, the study is only looking at cases where the neuropathologist tended to somewhat "adventuresome" in making a specific diagnosis at frozen section.

In any case, to quote the authors: "The discrepencies did not significantly impact patient management in any of the cases because postoperative management was predicated on the final diagnosis." That goes to show you how important our frozen section diagnoses are!!!

Important tips to be gleaned from this article include: 1. Perivascular hemosiderin deposition is more likely to be seen in schwannomas as opposed to meningiomas; 2. Consider CNS lymphoma when contemplating a frozen section diagnosis of small cell glioblastoma; 3. Consider sarcoma when contemplating a frozen section diagnosis of schwannoma.

Inauguration of the new blog about neuropathology

This is the first entry in a blog that will focus on the practice of neuropathology. The focus will be on issues raised in practice, and less on experimental neuropathology. I will comment on recent articles, discuss neuropathology trivia, gossip about other neuropathologists, and so on. I hope you enjoy it.