Best Post of November '09" Finally, a simple cartoon depicting the anatomic location of the transentorhinal cortex

The next in our series of "Best Posts of the Month" is from November 17, 2009:

In our teaching and in our autopsy reports, we neuropathologists often make reference to the transentorhinal cortex as it is -- in the Braak and Braak staging system -- the region where the earliest Alzheimer pathology appears. I have found it difficult to find a clear illustration of the anatomic location of the transentorhinal cortex in texts or on the internet. However, I came across a nice cartoon of the divisions of the parahippocampal gyrus, including the transentorhinal cortex, in an online presentation by Prof. Jillian Kril of the Pathology Department at the University of Sydney, NSW. Prof. Kril kindly emailed me a copy of the illustration, which is depicted above with the addition of a label for the presubiculum.  Feel free to use this cartoon for teaching purposes with the following credit: Adapted from Harding AJ, Halliday GM, Kril JJ. Variation in hippocampal neuron number with age and brain volume. Cerebral Cortex (December, 1998) 8:710-718.

Interferon-gamma in the Pig PIN

Remember that outbreak of progressive inflammatory neuropathy (PIN) among pig abattoir workers back in 2007? If not, here's my blog post from January '08 summarizing the event. The good Dr. Mark Cohen (pictured at left) forwarded me a recently published article following up on the outbreak. Investigators found no infectious etiology; but they did find higher levels of interferon-gamma among PIN patients. Since elevated levels of interferon-gamma has been associated with both acute and chronic inflammatory demyelinating polyradiculoneuropathy, this finding supports an autoimmune mechanism for PIN.

A 'Rara Avis' has flown under my microscope

I was recently sent a specimen from the cerebellum of a 27-year-old female patient who, during a routine funduscopic exam at her optometrist, was found to have papilledema and retinal hemorrhages. She was completely asymptomatic -- which of course suggests that we are dealing with a slowly progressive process. A head MRI was obtained:

An image-guided craniotomy ensued, yielding a cerebellar specimen. Photomicrographs of that specimen, at progressively higher magnification, follow:

The top picture exhibits normal cerebellar cytoarchitecture on the right giving way, on the left, to an internal granule cell layer that has transformed into larger gangliocytic neurons. The bottom picture demonstrates the cytologic appearance of these transformed ganglion cells.

This is an example of dysplastic cerebellar gangliocytoma, otherwise known as Lhermitte-Duclos disease (LDD). Dr. Peter Burger and colleagues, in their Surgical Pathology of the Nervous System and Its Coverings (4th edition, page 274), make this comment about LDD: "In the parlance of bird-watching, an endeavor with many similarities to surgical pathology, Lhermitte-Duclos disease is an entity not likely to be found on the 'life-list' of most pathologists." Well, this rara avis is now on my life-list!

When I came upon this tumor, I immediately thought of Dr. Ty Abel (pictured to the left), neuropathologist at Vanderbilt, who in 2005 authored an immunohistochemical study of 31 cases of Lhermitte Duclos disease. I emailed him this question: "What is the current thinking on LDD? Is it a hamartoma or a neoplasm or something in between?"

Ty's response: "Something in between may be the best answer. We suggested in our paper that it was a 'hypertrophic phenomenon superimposed upon a developmental malformation'. Our observations, as well as those in Suzie Baker's mouse model of this, suggest that aberrant signaling in the pathway disrupts granule cell migration as well as leading to their hypertrophy. Histologically, there is little proliferation, so the increase in tumor size over time may be due to cellular hypertrophy or to the abnormal myelinization of the molecular layer or both.Still, they do grow and sometimes come back after resection, making them tumor-like. Does your patient have evidence of Cowden's?"

No, my patient does not have other clinical evidence of Cowden syndrome. But Ty put me in touch with a leading authority on Cowden syndrome at the Cleveland Clinic, Dr. Charis Eng (pictured to the right) who emailed me this comment: "What we found in our initial series is that adult-onset LDD is almost always associated with germline PTEN mutations, i.e., has Cowden syndrome."

Whether or not this patient gets germline PTEN testing, she should be closely surveilled for breast, thyroid, and endometrial cancer, as there is a high incidence of these tumors in patients with Cowden syndrome.

And now a recut slide of this rare bird gets filed away in my teaching set, only to be let out of its cage again by the eager inquiry of a resident.

What is the relative prevalence of CNS metastases versus primary tumors?: Simple question, complex answer

During the pre-exam pathology review session at my medical school, one of the students asked about the relative incidence of metastases to the CNS versus primary CNS neoplasms. I answered that metastases are ten times more common than primary tumors. After the presentation, a colleague in the audience pointed out to me that the current issue of Robbins and Cotran (p. 1330) says: "about half to three quarters are primary tumors, and the rest are metastatic." I said, "No way!" and produced another textbook (the current edition of "Greenfield's Neuropathology"), which states the following on page 2116: "Metastatic tumors to the brain are approximately 10 times more common than primary intracranial neoplasms."

As we investigated the issue further, it became clear that the two textbooks were starting with a completely different denominator in arriving at their proportions. In Robbins and Cotran, the authors were looking at incidence rates of metastases in patients presenting with brain tumors. In Greenfield's Neuropathology, the authors appear to be extrapolating from autopsy series which included patients who never had a pre-mortem brain biopsy because metastasis was presumed. You might say that none of this matters too much. And, in a way, you would be right to say that. The bottom line is that a significant proportion of brain tumors are metastatic lesions. But, this discussion does matter in that it is a nice example of how statistical estimates of the prevalence of disease can vary widely depending on what denominator the author chooses to use. It is incumbent upon the author to be crystal clear about the denominator; but, unfortunately, that is not always the case – in which case it is incumbent upon the reader to beware.

An unusual case of CADASIL? Or something else?

I recently did a brain autopsy on a 70-year-old woman who died from an intraparenchymal brain hemorrhage after a seven-year history of progressive dementia. The gross photograph (provided by Chad Jeffers, Memorial Medical Center, Springfield, IL)  follows:

I know what you're thinking: an amyloid angiopathic bleed, or perhaps a hypertensive bleed, in a patient with Alzheimer disease. That's what I was thinking until I saw in the chart that abnormal white matter changes on MRI prompted the neurologist to order Notch3 genetic testing on the patient, which surprisingly came back positive for a mutation. The patient therefore carried a clinical diagnosis of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), despite the fact that she had no clear family history indicative of this disease and despite the advanced age of symptom onset. At autopsy, there was no evidence of amyloid angiopathy on Congo red stain. She did appear to have the PAS-positive vessel wall deposits that would be consistent with a diagnosis of CADASIL (see photomicrographs below).  Plus, it is hard to refute a positive genetic test. The Notch3 test has excellent specificity, from what I hear. Although one does not typically think of intracranial hemorrhage in the context of CADASIL, a series out of Korea (Choi JC et al. Neurology 67(11), 12 December 2006, pp 2042-2044) found that 25% of their symptomatic patients with CADASIL had intracranial hemorrhage (ICH). If anyone has any other ideas about what might be the diagnosis in this case, I would love to hear from you.