Diagnostic criteria commonly used to ensure an accurate diagnosis of hereditary ATTR amyloidosis is dissected.
John L. Berk, MD: Dr Brannagan, let’s shift gears and talk about diagnostic testing and how you assess a patient who you think potentially may have peripheral neuropathy on the basis of hATTR [hereditary amyloidosis transthyretin]. Can you start us off with electromyography [EMG]?
Thomas H. Brannagan III, MD: Electromyography and nerve conductions are standard tests to confirm the presence of hATTR neuropathy as well as any other type of neuropathy. For hereditary TTR [transthyretin] amyloidosis, we’d be looking for signs of an axonal neuropathy. We also frequently assess for carpal tunnel for treatment reasons because carpal tunnel could be treated with wrist braces or surgery. We also would like to confirm the presence of a neuropathy to differentiate it from other symptoms. Not everybody with numbness has a peripheral neuropathy. You could have spinal problems, anxiety, multiple sclerosis, or many other problems. It’s also important to note that if somebody has an EMG or nerve conductions that do not show a polyneuropathy, it doesn’t mean that they don’t have a neuropathy. It just means that the large myelinated fibers that are measured in the muscles are normal. However, there could still be small fiber involvement; the pain and temperature fibers and the autonomic fibers.
John L. Berk, MD: That’s great. I appreciate you making that point. Dr Polydefkis, you run a lab that focuses on epidermal nerve fiber densities. Can you explain to us what the utility of that analysis is and how it complements electromyography?
Michael J. Polydefkis, MD: As Dr Brannagan said, nerve conduction focuses on a subset of fibers, large myelinated fibers. Skin biopsy looks at small unmyelinated fibers, so together the 2 tests are complementary. Skin biopsy detects a loss of epidermal or small unmyelinated fibers, and that’s a hallmark of small fiber neuropathy typically associated with distal pain, burning, dysesthesias. Then the tissue can also be used to detect amyloid and additionally to gain some insight into sudomotor function and sweat function by looking at sweat gland innervation.
John L. Berk, MD: Great. Dr Polydefkis says that you can see amyloid on skin punch biopsies. Is that your experience, Dr Brannagan?
Thomas H. Brannagan III, MD: Yes, we’ve seen amyloid periodically from skin biopsies. We’ve also seen people who have confirmed hereditary TTR amyloid that the skin biopsy has been negative for amyloid. Dr Polydefkis doesn’t claim that it has 100% specificity, but it has been a useful test to document tissue deposition of amyloid.
John L. Berk, MD: Dr. Polydefkis, I neglected to ask you what the sensitivity of the skin punch biopsies are for demonstrating small fiber neuropathy.
Michael J. Polydefkis, MD: For patients who are symptomatic with neuropathy, it’s on the order of 75%.
John L. Berk, MD: OK. Dr Dyck, first of all, do you use skin punch biopsies? I’ll have some questions about additional testing that you might have experience with.
P. James B. Dyck, MD: We run a peripheral nerve pathology lab in which we process both cold nerves. We’re looking at large and small fibers, as well as epidermal nerve fiber density. We do our own lab as well for a skin biopsy.
John L. Berk, MD: Can you give us a little information about the utility of heart rate deep breathing or perhaps SUDOSCAN assessments?
P. James B. Dyck, MD: At the Mayo Clinic, we are very spoiled in that we have more testing for small fibers than most places would have. We have autonomic reflex screens in which we can interrogate the autonomic nervous system and we can look at different components of that. We have thermoregulatory sweat tests, where we can paint patients from stem to stern, throw them in an oven and cook them, and see how they sweat; it gives us a good idea of what is happening to unmyelinated fibers. We have epidermal nerve fiber density testing that we can do. For that reason, we don’t actually use SUDOSCANs and things like that, because we have more sophisticated tests at interrogating small fiber function. The heart rate variability with deep breathing is part of the autonomic reflex screens. When we’re seeing patients, we’re doing the whole test and not just that. The problem we’ve had with that in the studies is that if patients have dysrhythmias, that part of the testing goes out the window. In fact, the inotersen trial used that as an end point. When Alnylam Pharmaceuticals Inc and patisiran came along, they just went to measuring orthostatic blood pressures so that they could look at all patients.
John L. Berk, MD: Dr Witteles, can you give us a little perspective on noninvasive diagnosis of TTR amyloid cardiomyopathy?
Ronald Witteles, MD: Sure. This has been 1 of the biggest factors that’s led to the explosion in diagnosis of TTR cardiomyopathy, which is because most patients can be diagnosed easily and noninvasively. It’s really a 2-step process. Step 1 is making sure that you don’t miss AL [light chain] amyloidosis. That’s done with blood and urine testing to rule out a monoclonal protein with the serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. Assuming there’s no evidence of a monoclonal protein, then you can move on to what sometimes is called bone scintigraphy or, in this country, technetium pyrophosphate, also known as PYP imaging which will typically show a characteristic pattern of uptake of the tracer in hearts infiltrated with TTR amyloid fibrils. In these days, that is how most patients are diagnosed, it’s an acceptable way of making a confirmative diagnosis and being able to start therapy. If there are any doubts or patients do have a monoclonal protein, then you need to go on to biopsy, and we can debate where the best spot is to biopsy in that case.
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Transcript Edited for Clarity