2nd Edition of "Biopsy Diagnosis of Peripheral Neuropathy" to be released August 31, 2014

The second edition of Biopsy Diagnosis of Peripheral Neuropathy by Drs. Juan M. Bilbao and Robert E. Schmidt is set to come out on August 31, 2014. The is from the book's description from amazon.com:
"This book presents a simple, logical method for constructing a differential diagnosis based on pathology and clinical presentation. It also provides advice on the selection of ancillary molecular, immunohistochemical and genetic techniques to establish a definitive diagnosis. Clear, authoritative guidance is offered on diagnosis of the full range of neuropathies with the aid of a wealth of high-quality color photomicrographs and electron micrographs. The pathologist will benefit greatly from the identification of a variety of artifacts and normal structures occasionally encountered in nerve biopsies that need to be distinguished from specific pathologic alterations"

The first edition, also co-authored by Bilbao, was released back in 1995. Given the advent of new diagnoses and techniques of analysis and the impact of molecular genetics, there is without doubt a dire need for this book, which is authored by well-established authorities in the field.

Thanks to the inimitable Dr. Mark Cohen for alerting me to the imminent release of this text.

Horbinski Group develops online tool to estimate likelihood of IDH1/2 mutation in a glioma

Craig Horbinski, MD, PhD.

The illustrious Craig Horbinski, MD, PhD wrote in to share a link to an online tool which his team developed which helps triage brain tumor cases that might benefit from additional molecular testing.   Here's what the University of Kentucky neuropathologist had to say about this new website: "We have developed an online-based tool to provide a statistical estimate of the likelihood of an IDH1/2 mutation in a glioma, based

on a few easily-obtained parameters. Several variables like patient age, WHO grade, etc. are well-known to correlate with mutations, but no formula has yet been developed that synthesizes those variables into one unified probability score. An added feature is that it generates separate scores if no testing has been done at all, and if R132H IDH1 immunostain was done but is negative. Hopefully this will help pathologists and investigators better triage cases that would benefit from additional testing, both in clinical and in research endeavors."

Thanks, Craig!

Rocky Report from Columbia, MO

Dispatch from University of Missouri Neuropathologist Douglas C. Miller, MD, PhD:
"I saw this rock today while out walking for exercise. To me it looks like half an axially cut midbrain. No PD here!"

Higgins Leads Athena's Quest for More Specific Epilepsy Diagnoses

Joseph J. Higgins, MD

Last month I had an opportunity to sit down with Joseph J. Higgins, MD at the American Academy of Neurology Annual Meeting in Philadelphia. Dr. Higgins is Athena Diagnostics' recently named medical director for neurology.
Among the topics we discussed is Athena's new advances in helping clinicians diagnose autoimmune epilepsy disorders. A growing body of evidence points to an autoimmune etiology for a proportion of drug-resistant epilepsy cases. Dr. Higgins, with the horsepower of Athena's parent company Quest Diagnostics behind him, is leading the way in making auto-antibody testing available to patients with intractable epilepsy. While patients with pathogenic auto-antibodies often experience heightened adverse effects and typically respond poorly to conventional treatment, they can respond very well to immunomodulatory therapy. Autoantibodies to surface proteins that influence neuronal excitability have been found in the serum and cerebral spinal fluid of well over 10% of patients with epilepsy—whether the epilepsy was newly-diagnosed or established. In many cases, once identified, autoimmune epilepsy can be slowed, halted, or even reversed with adjunctive immunotherapy. Testing to establish an accurate diagnosis is an important part of selecting an optimal treatment plan. In a recent study (see reference below), 81% of adult patients diagnosed with autoimmune epilepsy experienced significant improvement in seizure status when immunotherapy was used in combination with anti-epileptic medications; 67% achieved complete seizure freedom.

Among the clinical syndromes that can be investigated using CSF auto-antibody assays are Morvan's Syndrome (by testing for VGKC complex, predominantly CASPR2) and NMDA Receptor Antibody Encephalitis (by testing for NMDA receptor, NR1 subunit). Dr. Higgins is at the forefront of personalized epilepsy treatment. Athena's advances in this field will ultimately improve patient outcomes while reducing medical costs. 


Reference: Quek AM, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582-93.

Joseph J. Higgins, M.D.

Joseph J. Higgins, M.D.

Primary progressive aphasia (non-fluent/agrammatic variant) in a patient with Pick disease

I recently performed an autopsy on a 67-year-old man had a seven-year history of progressive difficulty with halting speech. His wife described him as seeming to be “groping for words”. Three years after initial presentation, he demonstrated profound difficulty both initiating and finishing sentences. His verbal communication was marked by jumbled grammatical errors in which he put words in the wrong order and tense. For example, when asked by his neurologist to recount his activities over the day, he responded: “Go I… the grocery store… to.” He had no difficulty with naming objects or understanding their use. He had only mild amnestic deficits and no visuospatial difficulties. During the last months of his life, he began to become more rigid in his personality and more socially withdrawn. 
 
The clinical diagnosis in this patient is primary progressive aphasia, non-fluent/agrammatic variant. The pathologic diagnosis is frontotemporal lobar degeneration with 3R tau inclusions (FTLD-tau), commonly known as Pick disease.  The clinical presentation of FTLD can be divided into two types: the behavioral variant (bvFTLD) and primary progressive aphasia (PPA). Neurologists subclassify PPA into three subtypes: semantic variant (sv-PPA), non-fluent/agrammatic variant (na-PPA), and logopenic/phonologic variant (lv-PPA). While sv-PPA and na-PPA generally correspond to FTLD pathology, lv-PPA typically corresponds to Alzheimer disease (AD) pathology (and is accordingly referred to as the “language variant” of AD).  The syndrome of na-PPA is characterized by predominant language dysfunction in which there is a disordering of words in sentences, an inability to repeat complex words (e.g., saying “castaphory” when asked to repeat back the word “catastrophe”), inability to construct complex sentences, and other deficits in grammar and phonology.  In contrast, a diagnosis of sv-PPA is given to patients who exhibit a general deficit in their ability to understand word and object meaning. Patients with sv-PPA also show difficulty in naming objects and understanding what they are used for. A diagnosis of bvFTLD is ruled out as this patient only showed behavioral changes only late in the disease course

Pick disease was demonstrated pathologically by the presence of 3R tau positive Pick bodies (see photomicrograph) in the frontal and temporal lobes as well as the dentate fascia of the hippocampus, cornu Ammonis of the hippocampus, presubiculum, cingulate gyrus, insula, and inferior parietal lobe.

3R tau positive Pick body in the inferior temporal gyrus

For the practicing neuropathologist, FTLD’s are not yet classified on a molecular basis (although some day they surely will be),  but rather according to the particular protein aggregation which is detected using immunohistochemistry. The five possible FTLD subtypes, based on specific associated protein aggregations, are represented in the following table: 

FTLD type	Associated Protein Aggregation
FTLD-tau	Tau (can be further subclassified into 3-repeat [3R], 4-repeat [4R], or 3R+4R tau)
FTLD-TDP	Transactive response DNA-binding protein of 43 kDa (TDP-43)
FTLD-FUS	Fused in sarcoma (FUS)
FTLD-UPS	Ubiquitin (with UPS standing for ubiquitin-proteasome system)
FTLD-ni	No immunoreactivity

In 80% of cases of sv-PPA, the underlying histopathology is that of FTLD-TDP; while in the majority of na-PPA cases, the pathologic substrate is FTLD-tau.  Although not denoting a specific clinical syndrome, the term “Pick disease” has come to denote FTLD-tau, particularly referring to aggregation of the tau isoform in which there are three repeats (3R) of the phosphate-binding domain.

References:

Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol. 2012;124(3):353-372.

Zdenek R, Matej R. Current Concepts in the Classification and Diagnosis of Frontotemporal Lobar Degenerations: A Practical Approach. Arch Pathol Lab Med. 2014;138:132-138.

Anosognosia

Anosognosia -  Real or feigned ignorance of the presence of disease, especially of paralysis.

Dr. Sandra Camelo-Piragua's upcoming atlas will fill a needed niche in the neuropathology literature

I recently received an email from the illustrious neuropathologis at the University of Michigan, Sandra Camelo-Piragua, MD: "I just wanted to let you know about a book I have been working on, in conjunction with two neuropathy colleagues from England, Drs. Kathreena Kurian and Tim Moss. The book is coming out in September of this year.  Atlas of Gross Neuropathology: A Practical Approach has a large collection of gross images covering a wide range of adult and pediatric CNS-related diseases. The aim of this book is to give a visual reference and guide for a variety of gross neuropathologic entities during post-mortem examination. It is geared towards pathologist, neurologists, radiologist, neurosurgeons and related specialties that need to study and examine gross details of neuropathologic entities. We hope this text book becomes a reference book for many."

I'm very much looking forward to purchasing this book when it comes out this fall!

Dr. Sandra Camelo-Piragua

Dr. Kathreena Kurian

Dr. Tim Moss