Best Post of October 2011: Treatable Neurologic Disorders Misdiagnosed as Creutzfeldt-Jakob Disease

The next in our "Best of the Month" series is from October 17, 2011:

A case of primary CNS angiitis thought to be sCJD

Dr. Mark Cohen and a team of workers at Case Medical Center in Cleveland, Ohio have published an important article in the Annals of Neurology entitled Treatable Neurological Disorders Misdiagnosed as Creutzfeldt-Jakob Disease (Ann Neurol 2011;70:437–444). Why is this article important? Well, because mistaking a survivable, treatable disorder for a fatal, non-treatable disorder is not optimal. Cohen's team reviewed the pathologic diagnoses of 1,106 patients who were referred for potential prion disease to the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University from 2006 to 2009. About one-third of the cases did not have prion disease, with Alzheimer disease and vascular disease being the most common conditions accounting for dementia. Further, about one-quarter of the non-prion cases had treatable diseases, including immune-mediated disorders, neoplastic disorders such as lymphoma, as well as infectious and metabolic disorders. The immune-mediated disorders included primary angiitis of the CNS, acute disseminated encephalomyelitis, limbic encephalitis, neurosarcoidosis, paraneoplastic cerebellar degeneration, and one case of Wegener granulomatosis. Of note, more than half of patients with a treatable dementia had a positive CSF 14-3-3 protein test, highlighting the danger of relying too heavily on this test in making a diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). It turns out that the most specific test for distinguishing CJD from other diseases was magnetic resonance imaging. Drs. David Perry and Michael Geschwind, in a review of this study in the September 2011 issue of Nature Reviews Neurology, (Perry, D. C. & Geschwind, M. D. Nat. Rev. Neurol. 2011:7, 479–480) write: "The fact that many of the non-prion diagnoses in the present study were potentially treatable RPDs [rapidly progressive dementias] should prompt thorough diagnostic testing in patients who are suspected of having sCJD, in order to rule out mimics. The use of CSF testing, contrast-enhanced MRI, and autoimmune antibody screening is supported by this study."

Troy Aikman says he wouldn't be inclined to encourage a 10-year-old son to play football

"If I had a 10-year-old boy, I don't know that I'd be real inclined to encourage him to go play football in light of what we are learning from head injury [research]."  - Troy Aikman

Here's the two-minute interview.

Thanks to pathologist Doug Shevlin, MD (pictured below on left, with a man named "Cue') for sending me this link.

"Esterase Lamp" by Derek A. Mathis, MD

"ATPase 4.6 tile" by Derek A. Mathis, MD

Derek Mathis Week Begins Today

This week I'll be featuring the art photography of Derek A. Mathis, MD, a second-year neuropathology fellow at UT Southwestern Medical Center. Perhaps because he has an undergraduate degree in art, Mathis tends to look at the objects and phenomena around him from a different perspective. Throw a little neuropathology training into the mix, and you end up with a truly unique take on things. For example, here are some pictures Mathis took of cracks in a frozen pond. He calls them "Frozen pond astrocyte #1" and "Frozen pond astrocyte #2:

Stay tuned for more Mathis masterpieces later this week....

Best Post of September 2011: The Five Hottest Topics in Neuropathology Today

The next in our "Best of the Month" series is from September 13, 2011:

By consensus, I present to you the five hottest topics in neuropathology today:

1. Chronic Traumatic Encephalopathy - There is an emerging recognition of CTE among those who have played contact sports. The elucidation of CTE will continue to have major public health policy implications.

2. Molecular Subtyping of Brain Tumors - For example, determination of the presence of O(6)-methylguanine DNA methyltransferase (MGMT) activity as a prognosticator of response to alkylating chemotherapy in gliomas is becoming increasingly important to our clinical neuro-oncology colleagues. Other molecular tests that are gaining popularity include IDH1 and EGFR. Molecular profile panels will become the standard of practice in the coming decades.

3. Brain Tumor Stem Cells - Questions about their existence and potential as targets for therapy have energized neuro-oncologic research.

4. Role of Microvascular Disease in Expression and Pathogenesis of Alzheimer Disease - The concept that Alzheimer disease may have a vascular pathogenesis may radically change the way the disease is prevented and treated.

5. Molecular Developments in Frontotemporal Lobar Degeneration -  As UCSF neurologist Bruce Miller, MD said: "Classification of FTLD is moving from a syndromic approach toward one based upon neuropathology and genetics." In particular, the description of the TDP-43 proteinopathies has had a major impact on our understanding of a previously unrecognized form of dementing disease.

There you have it. Thank you to everyone who contributed to this list. I think that it will help raise our collective eyes to the horizon.

Spinocerebellar ataxia type 6 autopsy photographs

On the left is the brain of an 82-year-old patient with a diagnosis of spincocerebellar ataxia, type 6 (SCA6). On the right is the brain of a 96-year-old "control" patient with Alzheimer disease:

Note comparative diminution of the cerebellum in the SCA6 patient.  Here's a closer look at the cerebellum:

SCA6 is one several autosomal dominant cerebellar ataxias. SCA6 results from a CAG trinucleotide repeat expansion in the CACNA1A gene on chromosome 19p.

Lodging info for the AANP meeting in Chicago

The Palmer House Lobby in Chicago.... Pretty sweet!!!

I'm currently booking lodging now for the The Palmer House in Chicago for the 2012 annual meeting of the American Association of Neuropathologists. For those of you who are planning on bunking up with a buddy, note that the AANP nightly group rate of $219 is only good for a single king-size bed room. If you want two double beds, you're gonna have to pay the standard rate of $259 per night. I love the Chicago location; but I am still pushing for someday having our conference in Little Rock, Arkansas, which in 2008 won our poll for preferred places to hold the meeting!

New SAD Treatment – Shining Light Into The Brain Through The Ears

I'm not sure whether or not this is legit, but this story outlines an interesting theory.

Thanks to the ever-awake Doug Shevlin, MD for alerting me to this article.

An 82-year-old Parkinson's patient who had undergone a right-sided pallidotomy procedure twelve years prior to death

Photomicrographs of the pallidotomy site:

Contralateral globus pallidus appearing to exhibit neuronal loss:

Eberhart questions glial-to-endothelial transdifferentiation in real-world glioblastomas

I'd like to share with you this email, which I received from the illustrious Dr. Charles Eberhart this morning:
 

Hi Brian,

I was curious what other neuropathologists thought about the issue of brain tumor cells transdifferentiating into endothelium and making up significant proportions of the growing vasculature. As you may know, last year two high profile papers stated that half or more of vascular endothelial cells in brain tumors derived from genetically altered neoplastic cells. This seemed inconsistent with our clinical experience, and four of us recently published a report expressing our views. I would be curious to know what other practicing surgical neuropathologists thought, and your blog might be one forum in which to have that conversation. This is one area where I believe that practicing pathologists have something to teach basic scientists.

Regards,

Charles Eberhart, MD PhD

Professor of Pathology, Ophthalmology and Oncology Director of Neuropathology Chief of Ophthalmic Pathology Johns Hopkins University School of Medicine

Please post your comments. If for some reason you are unable to access the article through the link provided above, here is the reference and abstract:

Rodriguez FJ, Orr BA, Ligon KL, Eberhart CG. Neoplastic Cells are a rare component in human glioblastoma microvasculature. Oncotarget 2012;3:98-106.

Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. Although rare CD34 positive neoplastic cells unassociated with vessels were identified (<1%), this analysis did not identify EGFR amplified cells within vascular linings, and further supports our observations that incorporation of glioblastoma cells into the tumor vessels is at best extremely rare, and therefore of questionable clinical or therapeutic significance.