What is amyloid?

The following is adapted from Phenomena, the Phenopath newsletter, Winter 2018 (21:1):

Rudolph Virchow, introduced the term “amyloid” to refer to extracellular deposits in human tissues that exhibited a positive blue-violet staining reaction to iodine and dilute acid. Based on this reaction, Virchow mistakenly identified these aggregates as composed of starch (amylum is Latin for starch).  Subsequent microscopic studies have shown that amyloid deposits exhibit an affinity for Congo red dyes, which also yield a property known as “dichroic birefringence” in which crossed polarizing filters produce apple-green birefringence. In the 20th century, X-ray diffraction analysis revealed amyloid to be composed of fibrils ordered in a beta pleated sheet conformation. Using the criteria of “congophilia,” dichroic birefringence, and fibrillar morphology, more than 30 biochemically distinct forms of amyloid have been identified, many associated with unique clinical syndromes. Examples of protein that can form an amyloid configuration include: immunoglobulin light chain, amyloid A, beta-amyloid, transthyretin, apolipoprotein A-I, lysozyme, and fibrinogen A α-chain. Identification of the amyloid protein can have important diagnostic, prognostic, and therapeutic implications.

Sural nerve in a case of amyloid neuropathy: congophilic amyloid circled

Best Post of September 2014: New ISN book on Peripherap Nerve Disorders coming soon

The next in our "Best of the Month Series is from September 26, 2014. The update on this post is that the book is NOW AVAILABLE!  The cost is a reasonable £119.11 (€148.80). (Don't ask me what that means in greenbacks!)

New ISN book – Peripheral Nerve Disorders – coming soon

A new book covering peripheral nerve diseases (part of the International Society of Neuropathology series)  is about to be released . The book editors are Jean-Michel Vallet and Joachim Weiss and includes chapters from a range of other international experts who have produced a clinically orientated guide to the pathology of peripheral nerve disorders. The book includes the latest molecular and pathological findings to provide the most up-to-date understanding of the pathogenesis of these disorders.

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.

Epidermal nerve fiber density assessment: probably not worth doing in-house

About a month ago, I addressed the issue of skin biopsies for patients with peripheral neuropathy to assess for nerve fiber density. Since that post, I have heard that this test is not something to be taken lightly. Dr. Tom Smith (pictured) of the University of Massachusetts had this to say about the test: "Basically, to assess fiber density correctly in these skin biopsies, you need a considerable investment in technology (e.g. a confocal microscope, morphometric software program, etc) and technician training -- do you really have time to sit and count fibers?" Dr. Smith went on to say that in his opinion, there is a rather high initial investment for a relatively small volume of cases. Since a few university labs and Therapath already offer this service, its probably wise for most institutions of small or medium size to outsource this particular test. Finally, might these skin biopsies ultimately turn out to be a fad? Do these biopsies really provide useful information beyond what one could gain from clinical and electrophysiologic exam? Given these concerns, I'll likely recommend Therapath to any clinician looking for an epidermal nerve fiber density assessment.

Is anyone assessing epidermal nerve fiber density in skin biopsies?

I recently received an advertising pamphlet from Therapath, a New York company offering to evaluate skin punch biopsy specimens in patients with suspected small fiber neuropathy. The pamphlet trumpets Therapath's proficiency, including "board certified neuropathologists meticulously reviewing cases". Although I have heard of this test, no clients of my practice have yet requested such a test. According to Therapath, the result is "reported as the average number of nerve fibers that cross the basement membrane at the dermal epidermal border, over a length of 1 mm. Making the correct diagnosis explains the symptoms, guides the evaluation for the underlying cause, and helps decide treatment". See the photomicrograph from Therapath's website of normal skin with small fibers (arrow) traversing the basement membrane (arrowhead) and coursing through the epidermis. Accompanying the pamphlet is a letter from "neuropathologist and laboratory director" William Harrington, MD in which he states that the American Academy of Neurology has added a practice guideline to include skin biopsy in the scope of practice when evaluating for polyneuropathies. He goes on to say that "skin biopsy for the determination of epidermal nerve fiber density is the most sensitive test for small fiber neuropathy". Therapath provides the clinician with a kit for biopsy collection and shipping to their facility at no extra charge. Eight to 12 days later, Therapath provides a full-color, quantitative laboratory report with images. If anyone has had experience with evaluating such biopsies, please comment on this post and provide us with your insights regarding the utility and technical requirements of this test. I'm not sure whether I would have to use a service such as Therapath's, or perform the service in-house. Thanks!

When you've exhausted your differential diagnoses for a nerve mass, Dr. Kleinschmidt-DeMasters is here to help

In the same issue of Archives of Pathology and Laboratory Medicine that was referenced in the previous post, a team including Bette K. Kleinschmidt-DeMasters, MD (pictured) authored an interesting article entitled Rare Nerve Lesions of Non-Nerve Sheath Origin: a 17-year Retrospective Series. DeMasters, neuropathology chief at the University of Colorado in Denver, and her team did a computer search of all peripheral nerve masses at her institution from 1991 through mid-2008. After coming up with 458 cases, they threw out all the schwannomas, neurofibromas, and other nerve sheath tumors, ending up with a mere 37 cases to review. I was surprised by the number of spinal nerve root hemangioblastomas they came up with (7). Also notable were the four cases of brachial plexus "desmoid-type fibromatosis", which are not nerve masses per se, but are often at first mistaken for neurofibromas. The AFIP Tumor Atlas (Tumors of the Soft Tissues, third series) defines extra-abdominal desmoid fibromatosis as "an infiltrating fibroproliferative process that develops in the soft tissues deep to the subcutaneous tissue and is composed of fibrocytes, fibroblasts, and myofibroblasts set within a collagenous to myxoid stroma that possesses uniformly bland nuclear features" (page 71). Other unusual diagnoses are featured in this article include sclerosing meningioma invading nerve (WHO knows how to grade that one?), extrarenal rhabdoid tumor, and primary Ewing sarcoma of the brachial plexus. This article, along with a similar one published a few years ago by Kim et al. (see reference below), are good to keep in mind to help with your differential diagnosis the next time you are faced with a specimen called a "schwannoma" by the radiologist but bearing no histological resemblance to any of the typical nerve sheath tumors.

Reference: Kim DH, Murovic JA, Tiel RL, Moes G, Kline DG. A series of 146 peripheral non-neural sheath nerve tumors: 30-year experience at Louisiana State University Health Science Center. J Neurosurg. 2005;102:256-266.

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.

What are Remak cells?

Remak cells, named after Polish-born Robert Remak (1815-1865)(pictured), are Schwann cells which do not myelinate, but rather surround unmyelinated peripheral nerve fibers. According to Greenfield's Neuropathology (8th Edition), "unmyelinated axons are always of small diamter and pass through the nerve trunk in groups of 8-15 within a common chain of Schwann cells".

PIG PIN

A few weeks ago, I reported on a cluster of atypical inflammatory neuropathy cases among workers at pig processing plants in the midwest.

My colleague, the esteemed Dr. David Stahl, emailed me a link which describes a break in the case.

CNN reports that authorities have figured out how to contain the disease, which they have dubbed Progressive Inflamatory Neuropathy (PIN). They think its an autoimmune phenomenon related to exposure to aerosolized pig brain tissue. Here's the report from CNN:

http://www.cnn.com/2008/HEALTH/conditions/02/28/medical.mystery/index.html

Dr. Sanjay Gupta, CNN's chief medical correspondent, will report on the issue tonight on Anderson Cooper 360 at 9PM central time.

Urgent Bulletin to Neurologists about patients working with the heads of pigs!

The CDC has sent out an urgent notice to be on the lookout for patients who work in pig processing plants complaining of pain, numbness, and tingling in the extremities. In the fall of 2007, clinicians at the Mayo Clinic in Rochester, Minnesota notified the Minnesota Department of Health of an unusual cluster of 12 patients with inflammatory neuropathy among workers at a pork processing plant in Minnesota. An initial investigation has revealed that they all have worked in the same area of the plant where the heads of the pig are processed. Additional patients have been identified in Indiana, among workers in a similar plant. At this point an etiologic agent has not been identified.
The CDC bulletin reads: “neurologists who have diagnosed patients with peripheral neuropathy, myelopathy, or a mixed clinical presentation of peripheral / central (and, more specifically, myelopathic) involvement in persons with exposure to pig butchering or processing during the past year are asked to report this information to their state health department, and contact the CDC at 770-488-7100.”