"Adams and Victor" is a must-have for neuropathologists too

I am not a neurologist; but as a neuropathologist, I work with them often. I find myself reaching for "Adams and Victor" as frequently as I do my pathology textbooks! As mentioned in a recent post about Dr. Ray Adams, the ninth edition of this text just came out. I have access to this book for free electronically through my medical library, but its so much easier to have a hard copy within reach. (I am not a technophobe; I just think that sometimes a tangible book is more efficient.) One more thing: the price for this book ($127 on Amazon) is ridiculously low given the incredible amount of information that is packed into the nearly 1600 pages.

Genentech is looking for a neuropathologist

Courtney Grafe of Genentech recently informed me of a neuropathology position at the South San Francisco-based company. It looks as though they want someone who can straddle the worlds of research and clinical neuropathology. It looks like a great job for the right person. Details from the Genentech website follow. Contact Courtney at grafe.courtney@gene.com for more details.

RESPONSIBILITIES:The neuropathologist is appointed within the Department of Pathology, which is embedded within the Research Organization. The neuropathologist works with scientists in the Neuroscience Department, and in the Research and Development Organization to ensure that strategies for the treatment and cure of neurological diseases are based on accurate analyses of pathogenetic mechanisms. Pathologists participate both as collaborators and leaders in the discovery, characterization, and preclinical development of novel products in Neuroscience. This can include participation on teams devoted to the development of predictive and prognostic markers. At Genentech, pathologists have access to cutting edge equipment and techniques, including laser capture microdissection, confocal microscopy, advanced imaging morphometry and tissue microarrays that complement histology, immunohistochemistry, immunofluorescence, and in situ hybridization analyses. For applicants with the qualifications to lead a research program, the position comes with staff for technical support and access to in-house core facilities for histology, clinical pathology, microscopy, antibody generation, and transgenic and gene knockout models. The department has strong ties with academic and clinical groups both in the US and abroad. Publication in peer-reviewed journals is expected.

REQUIREMENTS:
The position requires an earned MD or DVM, completion of post-graduate residency training in diagnostic pathology, appropriate Board Certification in Anatomic Pathology, subspecialty training in neuropathology, Board Certification in Neuropathology, and a track record of creative and independent scientific productivity in a neuroscience-relevant discipline. An earned PhD in a related field will be highly desirable but not required. We seek candidates who can interpret traditional diagnostic categories in the context of a detailed and current understanding of molecular and cellular biology of the central and peripheral nervous systems. Candidates must have demonstrated their ability to handle several projects at any given time, to work successfully in teams and to communicate clearly both verbally and in writing to a variety of audiences.

William "The Refrigerator" Perry hospitalized in serious condition due to complications of Guillan-Barré syndrome

According to an associated press report, the gargantuan defensive tackle William "The Refrigerator" Perry (pictured below), who helped lead the Chicago Bears to a 1985 Super Bowl victory, has been hospitalized after complications related to Guillan-Barré syndrome (GBS).


Perry remains in serious condition at Aiken Regional Medical Center, located in his boyhood home of Aiken, South Carolina. Perry's nephew, Purnell Perry, said Tuesday that his uncle was admitted more than a week ago but was expected to recover. According to thebrainmatters.org, a website of the American Academy of Neurology Foundation, GBS "can be a devastating disorder because of its sudden and unexpected onset. Most people reach the stage of greatest weakness within the first 2 weeks after symptoms appear, and by the third week of the illness 90 percent of all patients are at their weakest. The recovery period may be as little as a few weeks or as long as a few years. About 30 percent of those with Guillain-Barré still have a residual weakness after 3 years. About 3 percent may suffer a relapse of muscle weakness and tingling sensations many years after the initial attack."

According to Perry's agent, Adam Plotkin of NOPAC Talent Agency, Perry's GBS had developed into a chronic form known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Depicted below is an electron photomicrograph of a transerve section of peripheral nerve involved with CIDP. Note the the thinly myelinated axons at the 3, 5, and 10 o'clock positions. Surrounding these axons are "onion-bulb" formations wherein multiple Schwann cells are concentrically arranged around inadequately myelinated axons.

Thanks to Mark B. Weiss of Earthwise Productions for alerting me to Perry's condition.

A quick question on brain regions affected by hypoglycemia

Here's a question from Neuropathology Review, 2nd edition, by Dr. Richard Prayson (Humana Press, 2008):

Hypoglycemic neuronal necrosis preferentially affects all of the following areas except:
A. Cortex - layers II and III
B. CA1 region of hippocampus
C. Dentate
D. Caudate
E. Purkinje cells

The answer appears as a comment to this post.

Beta-2 Transferrin: The Tau of Trauma

Jeannie Williams, a laboratory technician at Memorial Hospital in Springfield, IL, posed a question about beta-2 transferrin testing on cerebrospinal fluid (CSF). Because beta-2 transferrin is a normal constituent of CSF, but not of plasma or mucosal secretions, it is useful in determining whether a patient's nose or ear is leaking CSF versus some other fluid. This is important in determining whether an occult skull fracture or defect has opened a potential route of infection into the central nervous system. In addition to the CSF, beta-2 transferrin is present in the occular humors and the inner ear fluid, which could be an alternative source of this protein in trauma cases where the central nervous system is not actually breached.  In the hospital laboratory, beta-2 transferrin can be detected electrophoretically by immunofixation. Thanks for the question, Jeannie!

Sources:
Tietz Clinical Guide to Laboratory Tests, 4th Edition, Alan H.B. Wu (editor), Saunders Elsevier 2006, p. 1063-5.
Molecular Biology of the Cell, 4th Edition, Bruce Alberts, et al. (editors), Garland Science 2002, p. 935.

"What should exist?"

"What should exist?" Those are the words that guide the philanthropy of Microsoft Co-Founder Paul Allen's Institute for Brain Science. One thing that Mr. Allen believes should exist is a genetic map of the murine brain, and he put up the $100 million to get that done. The searchable digital atlas of gene expression presents a comprehensive online platform for exploration of the brain at the cellular and molecular level. It is available on-line, for free, to anyone who wants to know which of the 21,000 genes in the mouse genome is activated in a particular area of the mouse brain. Pictured is a sample photomicrograph demonstrating the expression of a type of GABA receptor via in situ hybridization in one sagittal brain slice. In recognition of this and his other initiatives on behalf of brain science, Mr. Allen is being awarded the 2009 Public Leadership in Neurology Award by the American Academy of Neurology.

What is the role of "utrophin" immunofluorescent staining in muscle biopsy evaluation?

We received a muscle biopsy recently from a 5-year-old girl who was likely a dystrophin mutation carrier. Her muscle biopsy displayed a patchwork pattern of dystrophin positive and dystrophin negative muscle fibers. Utrophin was upregulated in fibers deficient for dystrophin.

So, what is utrophin? It is the autosomal homologue of dystrophin. To quote the Dubowitz muscle biopsy text: "[S]arcolemmal labelling of utrophin peaks at about 20 weeks of gestation. After about 26 weeks of gestation and in mature muscle utrophin is no longer seen on the sarcolemma and it is confined to blood vessels and neuromuscular junctions.... In the absence of dystrophin, or reduced dystrophin, as in Duchenne and Becker muscular dystrophy, and in inflammatory myopathies, sarcolemmal utrophin is prominent." So it appears that utrophin is upregulated to take the place of dystrophin when the latter is not sufficiently present or is abnormal. It serves as a confirmatory positive assay when one sees reduced dystrophin in a biopsy. The fact that it disappears during gestation suggests the possibility that it might be a phylogenetically more ancient protein than is dystrophin. In any case, utrophin may play a therapeutic role since muscular dystrophy patients have an intact utrophin gene that could theoretically be upregulated to take the place of dystrophin. At least one animal model suggests this possibility.

Reference:
Dubowitz V and Sewry CA. Muscle Biopsy: A Practical Approach (3rd Edition). Saunders Elsevier (2007) p 207-8.

LGMD2I: alpha-dystroglycan without the sugar-coating

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).

Best Post of February '09: Why does the herpes virus love the temporal lobes?

Next up in the "Best of the Month" series is February 2009's pick. From Feb. 26:


After my recent lecture on infections of the CNS, Southern Illinois University medical student Mike Sinha came up to the podium to ask why the herpes virus had a predilection for attacking the temporal lobes. I passed Mike's question on to Dr. Tom Smith, the neuropathologist who provided the photographs (see above) of herpes encephalitis for Robbins and Cotran Pathologic Basis of Disease (7^th edition). Dr. Smith wrote that the question is not completely resolved, but he directed me to a 2002 review article which addressed the issue (Journal of Neurology Neurosurgery and Psychiatry 2002;73:237-238). I quote from that article:

"Regarding the site specificity of herpes simplex encephalitis (HSE), the pathway of viral spread is probably more important than cell-type viral susceptibility. The unique anatomical localisation has been thought to result from entry of the virus via the olfactory pathway with spread along the base of the brain to the temporal lobes, a view that is supported by the immunocytochemical evidence of HSV antigens in the olfactory tract and cortex, as well as temporal lobes, hippocampus, amygdaloid nucleus, insula, and cingulate gyrus in patients dying from HSE. Another suggestion is that HSE may result from viral spread from the trigeminal ganglia to the temporal and frontal cortex, a view that is consistent with this known site of HSV latency."

Thanks to Mike Sinha for a provocative question and to Tom Smith for researching the response.

On this day in 1984: Marvin Gay killed (indirectly) by a brain tumor

Twenty-five years ago today, one day before his 45th birthday, legendary singer and songwriter Marvin Gaye was fatally shot by his father when the younger Gaye attempted to intervene during an argument between his parents purportedly over misplaced business documents. Marvin Sr. used a gun that Marvin Jr. had given his father only four months earlier. Marvin Sr. was sentenced to six years probation after pleading guilty to manslaughter. Charges of first-degree murder were dropped after doctors discovered Marvin Sr. had a brain tumor which may have impaired the elder Gaye's judgement. Thanks to Dr. Doug Shevlin of Springfield, IL for alerting me to this connection between Marvin Gaye's death and neuro-oncologic disease.