College of American Pathologists spotlights blogging pathologists

Neuropathology Blog is mentioned in an article in the June '09 issue of CAP Today, a monthly publication of the College of American Pathologists. The article -- entitled Tapping into an audience: Growing numbers of pathologists engaging in the business of blogging -- focuses on several pathologist/bloggers, including Dr. Bruce Friedman (pictured) and his Lab Soft News blog. Blogging, Friedman says, in no way replaces academic journals or textbooks, but rather fills a different communication niche. "I believe my blog affords me a greater opportunity to disseminate new ideas than my academic writing," he says. Friedman, professor emeritus at the University of Michigan, also likes blogging because it prompts him to review "a wide swath of news covering lab information technology, the clinical lab industry, and health care in general, which I then blog about. Blogging has allowed me to climb out of this very focused academic silo." The final paragraph of the article quotes me as saying that once pathogists embrace the Web 2.0 movement, which includes blogging, "they'll see the benefit of it in terms of creating a global community of pathologists who can learn from each other."

"Modern Surgical Neuropathology" by Doug C. Miller to be published next month

I just pre-ordered Modern Surgical Neuropathology by Douglas C. Miller, MD, PhD from Cambridge University Press, which provides this description: "Brain and spinal cord tumors are the predominant focus, but a full spectrum of infectious, inflammatory, and congenital disorders are also covered in detail, in both pediatric and adult populations, with a full range of diagnostic modalities. The book is illustrated with more than 1,200 full-color photomicrographs and accompanied by a CD-ROM of all images in a downloadable format." For those of us who teach, those downloadable digital images are a big selling point.

If you can keep a secret, I'll share with you a promotional code which will reduce the price of the book from $235 down to $188. When ordering here, from the Cambridge University Press, use the promotional code "MSN09" and you get the bargain-basement discount. Keep this between you and me, will ya?

By the way, Cambridge University Press is this year celebrating its 425th anniversary! The publishing house has been in continuous operation since 1584. That's young compared to the University of Cambridge itself, which this year is celebrating its 800th anniversary.

An extramedullary, parasagittal tumor in a 55-year-old male

This intracranial, parasagittal, well-circumscribed, contrast-enhancing mass in a 55-year-old male was thought radiologically to be a meningioma. Cursory inspection at low-power reveals some architectural whirling of cells (above), suggestive of meningioma. However, inspection of other areas (below) show many cells heavily burdened with neuromelanin. This finding of course raises the spectre of metastatic or primary melanoma. But since there are no malignant histomorphologic features, and the immunohistochemical MIB-1 proliferation index is less than 1%, the diagnosis is melanocytoma -- a benign proliferation of native leptomeningeal melanocytes. The meningeal melanocytoma is akin to the blue nevus of the skin.

Ependymoblastoma: Dear, Damned, Distracting Diagnosis, Farewell!

In an article entitled "Ependymoblastoma: Dear, Damned, Distracting Diagnosis, Farewell!" published online in Brain Pathology, authors Alexander R. Judkins (UPenn) and David W. Ellison (St. Jude's, Memphis) adapt a line from Alexander Pope's poem A Farewell to London (1715) for their title. Judkins and Ellison conclude the following: "We believe that ependymoblastoma as a diagnosis is neither precise nor specific and that it is time once and for all to retire this diagnosis from the lexicon of neuropathology." For now, the World Health Organization tumor classification sytem continues to recognize ependymoblastoma as a distinct nosologic entity. These neoplasms are often large, supratentorial, and usually connect to the ventricles. Although there is no definitive feature of ependymoblastoma, the ependymoblastomatous rosette is a histologic characteristic that has been used in making the diagnosis. A photomicrograph of such a rosette from the Judkins & Ellison article is shown. In this picture, epithelial membrane antigen (EMA) immunohistochemistry highlights the limiting lumenal membrane of rossette. (Note: Although published online in December '08, I got word today via email from Dr. Ellison that this article will likely appear in print in the next issue of Brain Pathology.)

American Association of Neuropathologists wraps up its annual meeting in San Antonio

The American Association of Neuropathologists (AANP) finished up their annual meeting this past Sunday in San Antonio, Texas. Dr. John Donahue snapped the photo above at the reception dinner. Dr. Donahue had this to say: "The most fascinating thing I heard [at the meeting] was that A-beta, particularly 1-42, is a superb antimicrobial agent and may be the reason it's formed endogenously." Another attendee, Dr. Robert Struble, tells me that the meeting was better than it had been in recent years, with several interesting presentations. He suggests that the success of the meeting may be a sign of a reinvigorated organization.

A Primer on Myasthenia Gravis

General
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by immune-mediated loss of acetylcholine receptors and exhibiting characteristic clinical signs as well as drug responses. The disease prevalence is about 3 per 100,000, with a female predominance in cases arising before the age of 40. In some cases, MG represents a paraneoplastic syndrome, typically bronchogenic carcinoma, although Lambert-Eaton Syndrome is the myasthenic syndrome most commonly associated with malignancy.


Pathophysiology
MG is associated with a decrease in the number of neuromuscular junction acetylcholine receptors (AChRs) as well as the presence of circulating antibodies to the AChR. Light microscopic examination of muscle biopsies from affected patients is usually unremarkable, although fiber type 2 atrophy may be seen in cases where there is secondary muscle disuse. Ultrastructurally, the post-synaptic membrane is simplified, with loss of AChRs. Electron microscopy can also reveal immune complexes and the membrane attack complex (C5-Cq) along the postsynaptic membrane. Autoantibodies block acetylcholine binding of receptors, and increases degradation of receptors. Complement fixation on AChRs also causes direct injury to the post-synaptic membrane.

Clinical Presentation and Course
Classically, physical examination of MG patients demonstrates decreased muscle strength with repeated use. As the extraocular muscles are often the first to be affected, ptosis and diplopia are frequently the presenting signs. But, in some cases, fluctuating generalized weakness is the patient's initial complaint. Sensory and autonomic findings are usually unremarkable. Thymic hyperplasia is present in 65% of patients with MG, and thymoma is found in 15%. With improved methods of ventilatory support in recent decades, five-year survival now exceeds 95%.

Diagnostic tests
Electrophysiologic testing reveals a decrement in motor response with repeated stimulation, while nerve conduction studies are normal. Patients show improvement in strength in response to anticholinesterase agents. Although most MG patients exhibit elevated serum anti-AChR antibodies, there is not always a good correlation between antibody levels and extent of neurologic deficit.

Treatment
Even though the link between thymic abnormalities and the presence of anti-AChR antibodies is unclear, most patients improve clinically after thymectomy. Other effective treatments include anticholinesterase drugs, prednisone, and plasmapheresis.

Reference
Kumar V et al, eds., Robbins and Cotran Pathologic Basis of Disease, 7th edition. (2005). p1344.

American Association of Neuropathologists annual meeting begins today

The annual meeting of the American Association of Neuropathologists gets underway today in San Antonio, Texas. The conference goes through Sunday. I cannot be there this year; but I hope to make the 2010 meeting in Philadelphia.

Fetal stem cells pass safety test for use in combatting Batten disease

Thanks to Dr. Doug Shevlin for alerting me to a report about this study which clears the way for further investigation of the use of fetal stem cells in the treatment of Batten disease. As yet, no specific treatment is known that can halt or reverse the symptoms of Batten disease.

Study sheds light on Huntington disease with implications for other neurodegenerative disorders

A common theme among neurodegenerative diseases is that there is a some kind of "nucleating protein" which aggregates within specific areas of the brain. There is debate as to whether the aggregates cause disease, or are simply an attempt by brain cells to sequester bad proteins. If the former is true, then therapy should be aimed at disaggregating the bad protein. If the latter is true, then therapy should be focused on helping the brain to inactivate the free-floating bad proteins. A recent advance in the understanding of Huntington disease (HD) suggests that the free-floating form of the protein may be the culprit, lending support to the idea that other neurodegenerative diseases like Alzheimer's and Parkinson's may also be caused by soluble proteins rather than the aggregates that we neuropathologists focus on under the microscope.

Scientists have known for some time that HD is associated with a trinucleotide repeat mutation in the protein huntingtin on chromosome 4. But, since huntingtin is present throughout the brain, why does neurodegeneration in HD take place predominantly in the striatum (caudate and putamen)? Solomon H. Snyder and his team at Johns Hopkins University, in the June 5th issue of the journal Science, show that cytotoxicity in HD takes place because of the interaction of mutant huntingtin with a second protein, known as Rhes. It turns out that Rhes is a striatal specific protein, thus explaining the anatomic specificity of neurodegeneration in HD. Snyder and colleagues go on to show that cells in culture tend to sequester mutant huntingtin into an aggregate. But in the presence of Rhes, mutatant huntingtin cannot aggregate, suggesting that the soluble form of the bad protein is what causes damage.

An Associated Press article about the discovery posted on Forbes.com quotes Walter J. Koroshetz of NIH's National Institute of Neurological Disorders and Stroke as follows regarding the implications of this new study: "The answers in one disease may have implications for another... There's been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem."

The most famous Huntington patient was the iconic folk singer Woody Guthrie. And it was my colleague Doug W. Shevlin, who writes a pretty widely read music blog which today features a Woody Guthrie song, who alerted me to this break-through study. In a stroke of synchronicity, it so happens that my good friend Mark B. Weiss (pictured) is representing a performer at next month's Woody Guthrie Folk Festival in Okemah, Oklahoma.

New Neurology Radio Show on XM and streamable over the 'net

The American Academy of Neurology (AAN) and ReachMD have launched a new radio program called NeuroFrontiers that is geared toward helping health care professionals get the latest updates in neurology. The show can be heard daily on XM Satellite Radio Channel 160 and is hosted by AAN member Anthony Alessi, MD (pictured).

NeuroFrontiers covers a 15-minute topic and features interviews with AAN members on a variety of neurology issues. Notable news, editorial and clinical discussion, and other hot topics pertaining to neurology and the Academy (such as AAN practice parameters and position statements wherever applicable) are also covered.

All shows are available as a live stream or a downloadable podcast. Listen now!

ReachMD is an innovative communications, information, and education company that provides medical news and information to health care practitioners. Its aim is to help increasingly time-constrained medical providers stay abreast of new research, treatment protocols, and continuing education requirements.

Best Post of April '09 - LGMD2I: alpha-dystroglycan without the sugar coating

The next in our series of "Best Posts of the Month" is from April 8, 2009.

A muscle biopsy from 16-year-old girl with exercise intolerance and no family history of muscular dystrophy was received by my institution several months ago. Laboratory studies showed that the girl had elevated creatinine kinase and liver enzyme levels. In consultation with Dr. Steven A. Moore at the University of Iowa, it was determined that the girl likely has a mutation causing abnormal glycosylation of alpha-dystroglycan. Alpha-dystroglycan helps to anchor the extracellular matrix to the intracellular actin filaments in muscle fibers. Hypoglycosylated alpha-dystroglycan is unable to properly bind to the extracellular matrix (see illustration). The vaguely indecent name of Fukutin-Related Protein (FKRP) is given to the gene most frequently mutated in non-congenital dystroglycanopathy; and the disease associated with this mutation is known as Limb Girdle Muscular Dystrophy 2I (LGMD2I). (Fukutin, which has sequence homology to FKRP, is named for its association with the eponymic Fukuyama Congenital Muscular Dystrophy).

Two commercial monoclonal antibodies to alpha-dystroglycan are available (Millipore's IIH6 and VIA4-1), each of which recognize glycosylated epitopes. In our patient, immunofluoresence showed reduced signal for both of these epitopes. There appears to be a correlation between degree of hypoglycosylation and clinical severity.

LGMD2I, one of the more common forms of limb-girdle muscular dystrophy among people of Northern European descent, has a wide clinical spectrum. Patients can present in childhood, adolescence, or adulthood. Some patients lose ambulation in their teens, while others remain ambulant well into adulthood. Dilated cardiomyopathy is common, and respiratory failure is a complication that also can be seen in this disease.

Given the cardiopulmonary risk associated with LGMD2I, our patient was referred to cardiology and to pulmonology for baseline assessments. She will also be referred to a muscular dystrophy clinic for possible physical rehabilitation. It is unclear whether she will get genetic testing to definitively determine whether or not FKRP is mutated.

Sources:
Dubowitz V and Sewry CA. Muscle Biopsy: A Practical Approach (3rd Edition). Saunders Elsevier (2007) p 341-347.
Illustration from Ross ME. Full Circle to Cobbled Brain. Nature 418, 376-377 (25 July 2002).