Autoimmune Axonal Neuropathies (Peripheral Nerve and Motor Neuron Disorders October 2023)

Educational Objectives

The goal of this program is to improve management of autoimmune axonal neuropathies. After hearing and assimilating this program, the clinician will be better able to:

1. Maintain a high index of suspicion for autoimmune axonal neuropathies in patients with red flag symptoms.
2. Choose appropriate diagnostic methods to detect underlying causes of neuropathy.

Summary

Autoimmune Axonal Neuropathies

Dr Berkowitz: This is Aaron Berkowitz with Continuum Audio. Today, I have the pleasure of interviewing Dr Kelly Gwathmey, the Guest Editor of the Peripheral Nerve and Motor Neuron Disorders issue of Continuum. We’ll be discussing the article, “Autoimmune Axonal Neuropathies” by Dr Jennifer Tracy from this issue. Dr Gwathmey is Associate Professor of Neurology and Division Chair of the Neuromuscular Medicine Division at Virginia Commonwealth University in Richmond, Virginia. Thank you so much for joining us today, Dr Gwathmey.

Dr Gwathmey: Thank you so much for having me, Dr Berkowitz.

Dr Berkowitz: So this article covers a number of relatively uncommon autoimmune peripheral nervous system disorders, including vasculitic neuropathy, neuropathy associated with rheumatologic disease, and paraneoplastic neuropathy. In some of these conditions, the neuropathy may actually be the presenting manifestation of the underlying systemic rheumatologic disease or cancer, so it’s extremely important for neurologists to be able to recognize these conditions and understand how to perform the appropriate evaluation for the underlying cause. Now, Dr Gwathmey, peripheral neuropathy is so common in clinical practice and we’re all familiar with the AAN guidelines that advise us to test for diabetes, B₁₂ deficiency, and paraprotein-associated neuropathies with SPEP and immunofixation for patients who have a distal symmetric sensory neuropathy. Often though, all these tests tend to come back normal in many cases. So what are the clinical scenarios in which you recommend considering an autoimmune etiology of the patient’s neuropathy and expanding beyond this basic workup? In other words, what are the red flags for a clinical presentation of neuropathy that lead you to consider less common causes?

Dr Gwathmey: I think this is an excellent question, and a topic that I like to discuss with my trainees on a daily basis. So, whenever someone doesn’t fit the mold, if you will — if they don’t present with your typical distal symmetric sensory polyneuropathy symptoms and exam, you need to be thinking about these autoimmune conditions. And so, the patients that have autoimmune-associated peripheral neuropathies often will have an acute or subacute onset of their symptoms. Often, it’s very painful. Often, their symptoms are asymmetric or nonlength-dependent and rapidly progressive. So, anytime you see a patient that has that constellation of symptoms, you really want to expand your laboratory testing to include laboratory studies for some of these vasculitic neuropathies, rheumatological diseases, and also the paraneoplastic syndromes.

Dr Berkowitz: Well, that’s incredibly helpful. So, just to make sure I have the main points here, red flags for peripheral neuropathy that should lead us to consider an autoimmune etiology are a rapid pace of progression (rapidly progressive acute or subacute neuropathy), nonlength-dependent distribution of symptoms and signs, or asymmetric distribution of symptoms and signs, or severe pain as part of the presentation. Are those — have I summarized properly — the key points they’ve given us for when to think about an autoimmune cause of neuropathy?

Dr Gwathmey: Yes, that’s an excellent summary of them.

Dr Berkowitz: Okay, so let’s focus now specifically on vasculitic neuropathy. What’s the clinical presentation of vasculitic neuropathy and how is the diagnosis made?

Dr Gwathmey: So, the vasculitic neuropathies, as we were just discussing, tend to be acute or subacute in nature. And I like to think about it as, the patient is essentially infarcting their individual peripheral nerves. And so, as you might imagine, that’s quite painful. And you’re going to affect both the sensory and the motor nerve fibers, right? So you have inflammation in the blood vessels that are feeding these individual peripheral nerves. And so, as an example, patients might develop a very painful right foot drop, followed by a painful left wrist drop. So it tends to present with nonlength-dependent, asymmetrical features because you’re picking off these individual peripheral nerves. And so, this multifocal nature — you have heard of it and you see it in the literature — is considered the mononeuritis multiplex pattern, right? So, the inflammation of multiple mononeuropathies. And so, these may, over time, progress to develop overlapping features. So, if you take out enough individual peripheral nerves and they overlap, it can start to look more length-dependent occasionally, like a length-dependent polyneuropathy. But if you ask and take a good history from the patient, then they often will tell you, in the beginning there were the features of multiple mononeuropathies. And then if you look very carefully on electrodiagnostic studies, a lot of times you can glean some of the asymmetries that you would expect to see in someone who has multiple mononeuropathies kind of underneath it all. And then in addition, a lot of our patients, especially those with the systemic vasculitides, will have constitutional symptoms too. So you always want to ask your patients, a complete review of systems, right? And so we ask them about fevers and weight loss and muscle aches and joint pain, and that can be a clue in these patients that there’s something more systemic going on. And so, also, you want to ask about other organ involvement. So. you’ll ask if they’re having any difficulties with shortness of breath, or kidney involvement, rashes — things like that — that might clue you in that this is a systemic problem.

Dr Berkowitz: So, based on these clinical features of mononeuritis multiplex, painful multifocal mononeuropathies — or a sort of painful confluent neuropathy that has evolved from multiple mononeuropathies — you’re considering a vasculitic neuropathy. What diagnostic evaluation should be pursued to try to determine the underlying cause?

Dr Gwathmey: So, when a patient is evaluated in our clinic and we’re concerned about vasculitic neuropathy as a potential etiology for their presentation, we will quickly (moments later) obtain electrodiagnostic testing. So, your nerve conduction studies and your EMG will be helpful, as I already alluded to, as they will hopefully show you evidence of multiple mononeuropathies. And sometimes, actually, when we perform the nerve conduction studies in these patients, we are so fortunate as to capture pseudoconduction block right after a nerve has become affected by vasculitis. Sometimes you get what appears to be conduction block on routine motor nerve conduction studies, but really, it’s just at the site where there is the inflammation from the vasculitis. And then several days later, if you were to repeat the study, you get the secondary Wallerian degeneration and it looks more axonal. And so, it’s really this interesting feature that we see kind of in a hyperacute setting of completing these nerve conductions in someone with vasculitis. But, all that said, if you see the multiple mononeuropathies or the asymmetrical polyneuropathy picture, that would suggest that you are dealing with a vasculitic neuropathy. And then also, I should state, the electrodiagnostic studies can be quite helpful in terms of determining what nerve we ultimately go on to biopsy. So, once we’ve completed the EMG and we have a high clinical suspicion that this is a vasculitic neuropathy, we will proceed and check some laboratory studies on our patients. And now, we say, in vasculitic neuropathies, this is your time to check a bunch of labs. You know, not in your routine distal symmetric sensory polyneuropathy patients, but in these patients, they deserve to have a lot of laboratory studies drawn. So we recommend routine blood counts, a comprehensive metabolic panel, antinuclear antibodies, and other rheumatological labs such as SSA, SSB, rheumatoid factor, and so on. We will, of course, check our ANCAs. We will check an SPEP and immunofixation, hepatitis B, and hepatitis C labs. I like to check a sed rate as well as a CRP. And then, to circle back around, why do we check ANCAs? This is your time to check them, right? So, ANCAs are antineutrophil cytoplasmic antibodies that we see commonly in our systemic vasculitides. And so, recall that our c-ANCAs, that target the cytoplasmic antigens, are really directed towards proteinase 3, and our p-ANCAs, which target perinuclear antigens, are targeting myeloperoxidase. And so, when you get a positive ANCA back, it can clue you in as to which systemic vasculitis the patient might have. And so it makes your job a lot easier when that comes back positive. Now, beyond these laboratory studies, and recall in our patients who have nonsystemic vasculitic neuropathy, right, they might not have an underlying cause of their vasculitic neuropathy that is either a systemic vasculitis or a rheumatological condition or viral infection. You might not see anything abnormal on these laboratory studies. And so, a lot of times, we then proceed with nerve and muscle biopsy. I’d like to state that, in systemic vasculitis, if the patient has already had biopsy of another affected organ, you do not need to proceed with a nerve and muscle biopsy in straightforward clinical cases of vasculitic neuropathy. Sometimes, however, as you mentioned at the beginning of this interview, the vasculitic neuropathy could be the very first presentation of someone’s systemic vasculitis. And so, in those situations, we would proceed with a nerve and muscle biopsy. And then always, if we have a clinical suspicion of nonsystemic vasculitic neuropathy, will we proceed with nerve and muscle biopsy. So, we tend to choose a cutaneous sensory nerve for biopsy, and one that is affected on the nerve conduction studies. And then, a lot of times, we will ask for a muscle to be biopsied at the same time, preferably through the same incision, because it may increase the yield of identifying vasculitis by up to about 25%. And so, it’s important to realize, too, when we’re talking about biopsies and vasculitic neuropathy, that these are patchy processes. Unfortunately, sometimes the biopsy comes back and we don’t capture the vasculitis, so that’s something to keep in mind as well.

Dr Berkowitz: So, let’s say you are able to make the diagnosis of vasculitic neuropathy, either as an isolated vasculitic neuropathy, as you mentioned, based on nerve biopsy, or as a manifestation of an underlying systemic disease. How are these vasculitic neuropathies typically treated?

Dr Gwathmey: We do have some recent updates on this. So, in the ANCA-associated vasculitides — in 2021, the American College of Rheumatology Vasculitis Foundation did publish some guidelines and suggested that the best first-line treatments for induction in ANCA-associated vasculitis is glucocorticoids and rituximab. Now, this is a change. So, when I started looking at this literature about a decade ago, everything said, “start with glucocorticoids and cyclophosphamide.” So we’ve really pivoted in the ANCA-associated vasculitides to use rituximab first-line. And so, following induction treatment, we want to think about how we’re going to maintain the therapeutic response. So, in these patients, you can continue with rituximab, you may consider azathioprine, you may consider methotrexate. And so, for the non–ANCA-associated vasculitides, if there is a viral infection (such as hepatitis B or hepatitis C) thought to be triggering this, we will use antivirals as well, preferably often before we start systemic immunosuppression. And then, in the nonsystemic vasculitic neuropathies as well as the rheumatologic disease-associated vasculitic neuropathies, we’re still going to corticosteroids, as well as cyclophosphamide, if necessary. And then, as mentioned, with the ANCA-associated vasculitides, we like to pivot eventually to a steroid-sparing agent to hopefully decrease and take the patient off the glucocorticoids over time.

Dr Berkowitz: Well, thank you for that excellent and comprehensive review of vasculitic neuropathies in terms of clinical presentation, diagnosis, and treatment. Let’s turn now to the neuropathies associated with systemic rheumatologic diseases. So again, as we’ve been discussing, sometimes a neuropathy is the initial presentation of an underlying rheumatologic disease. So, what types of clinical presentation of neuropathy would lead you to consider particular underlying rheumatologic diseases?

Dr Gwathmey: So, similar to our discussion at the beginning of the interview, and similar to our discussion with the vasculitic neuropathies, it’s really the patients who don’t fit the mold. So, some of the rheumatological diseases are associated with nonlength-dependent, painful, asymmetrical, sensory-predominant presentation. So, I’d like to start off by just highlighting the sensory neuronopathies or dorsal root ganglionopathies that are characteristic, really, of Sjögren syndrome more than any other rheumatological disease. Because when a patient comes in presenting with a sensory neuronopathy, you really need to be thinking of one of two things: either Sjögren syndrome or paraneoplastic neuropathy. And so, these patients have an unusual presentation of rapidly progressive, asymmetric, nonlength-dependent sensory loss that affects the large-fiber sensory tracts primarily. And so they have early onset of sensory ataxia. And you will see evidence of pseudoathetosis often on exam, and so the patients will have unusual writhing movements of their fingers and their toes (especially when they close their eyes), due to the impaired proprioceptive feedback. They really don’t know where their fingers or toes or limbs are in space. And so, anytime you see that coming in through your office or the emergency department, I’d really encourage you to think about a possible underlying rheumatological condition, such as Sjögren’s, or a paraneoplastic syndrome. Now, in addition to that presentation, the rheumatologic diseases can be associated with a wide spectrum of different types of peripheral neuropathies. We will see associated small-fiber neuropathies, trigeminal neuropathies, cranial mononeuropathies, polyradiculopathies, autonomic neuropathies — you name it — it’s pretty much been reported with rheumatologic disease. Now, if we take a few moments and break it down by the common systemic rheumatological diseases — as I mentioned, Sjögren’s first — that truly can do anything. Now, it is more likely to affect the sensory nerve fibers, so either the sensory neuronopathy presentation which I already mentioned or a small-fiber sensory neuropathy that’s often nonlength-dependent or asymmetrical. But it also classically can affect just the trigeminal nerve in isolation or in combination with a polyneuropathy. If we turn to rheumatoid arthritis, this becomes a bit more “garden variety.” So, these patients can have associated length-dependent sensory or sensorimotor polyneuropathies, and they’re often subclinical. So sometimes you’ll find this out in the EMG lab. So, the patient might not be complaining of anything other than carpal tunnel syndrome, and they’re there with you in the EMG lab and you see evidence of a subclinical polyneuropathy, and it could be related to the rheumatoid arthritis. Now, we didn’t touch on it too much in the prior discussion, but rheumatoid arthritis can be a cause of a vasculitic neuropathy as well. We don’t see that as often these days, due to very good biological treatments. But rheumatoid vasculitis does still exist and can affect the peripheral nerves. And, a couple other points here: don’t forget that rheumatoid arthritis commonly presents with a median mononeuropathy at the wrist, such as we see in carpal tunnel syndrome, and don’t forget that the TNF-alpha inhibitors that we commonly use in rheumatoid arthritis can also trigger off an autoimmune demyelinating neuropathy, like CIDP. And if we turn to lupus — lupus also can present with a peripheral polyneuropathy that affects the sensory or sensory and motor nerves, and much less commonly can affect the cranial nerves. And CIDP and AIDP have been reported in lupus patients as well.

Dr Berkowitz: That’s excellent. So, these rheumatologic diseases are not uncommon, and it’s also not uncommon that patients with rheumatologic disease present to us in neurology with symptoms and signs of peripheral neuropathy. My practice is to still go ahead and send the hemoglobin A_1c, the vitamin B₁₂ level, the serum protein electrophoresis with immunofixation, in patients with rheumatologic conditions (or even any presumed cause of their neuropathy, such as recent exposure to chemotherapy) to make sure there’s not a separate common reversible cause. To my knowledge, there’s no evidence for that practice, but is that reasonable? And what’s your practice here?

Dr Gwathmey: I agree completely. The last thing we all want to do is miss something that is treatable or that we would manage in a different manner. And so, regardless of the patient’s background, comorbid conditions, I will always check the basic standard labs that you just listed in every patient presenting with a polyneuropathy.

Dr Berkowitz: So last here, let’s talk about paraneoplastic neuropathies. As is discussed in the article, paraneoplastic neurologic conditions often precede the diagnosis of the underlying cancer and may end up leading to the discovery of the cancer based on the neurologist identifying that the neuropathy has some of the red flags we’ve been discussing and discovering an autoantibody associated with paraneoplasia. So, what features here of a neuropathy should raise concern for a paraneoplastic etiology and lead to an evaluation both for the autoantibodies and a search for an underlying cancer?

Dr Gwathmey: Excellent question. And I will respond by saying you’ll notice a theme here that, also, paraneoplastic neuropathies tend to present acutely or subacutely, and often in an unusual pattern. So, I already described the sensory neuronopathy pattern when we were talking about Sjögren syndrome, and mentioned that this too can present as a paraneoplastic neuropathy. Now interestingly, in paraneoplastic syndromes, there’s often a lot of overlap. So you might see a sensory neuropathy but with some motor features, or perhaps overlapping with limbic encephalitis, or autonomic failure, and so it becomes a more complex presentation. And these patients tend to be quite ill — they present with this rapid progression; they often come in through the emergency department and are hospitalized. And so, anytime someone presents like this, you really want to think about paraneoplastic syndromes as an underlying etiology.

Dr Berkowitz: What are some of the most common autoantibodies associated with paraneoplastic neuropathy, and what are their most commonly associated cancers?

Dr Gwathmey: So, we’ll start off with the anti-Hu antibody, which also goes by “ANNA1” or the “type 1 antineuronal nuclear autoantibody.” And this is classically associated with small cell lung cancer and sensory neuronopathies. Also, we consider CRMP5, which goes by “anti-CV2,” as a common autoantibody in paraneoplastic neuropathies. This antibody can be associated with a painful polyradicular neuropathy. And then finally, the third common one that I think of is amphiphysin antibodies, which, in addition to lung cancer, can be associated with breast cancer.

Dr Berkowitz: So, in addition to treatment of the underlying cancer when it’s discovered, how should these neuropathies be treated?

Dr Gwathmey: So, these neuropathies can be extremely challenging to treat. And so, what you will often see is that patients, especially with the anti-Hu autoantibodies, will be treated with everything from IVIG to plasma exchange to corticosteroids and cyclophosphamide, and they often have a fairly poor treatment response. So we don’t have any great evidence-based medicine to support what the treatment algorithm should be in patients with paraneoplastic neuropathies, especially associated with anti-Hu antibodies. Now, when we think about CRMP5, there is a little bit of literature to support that corticosteroids may be helpful. And then with the amphyphysin antibodies, there has been use of cyclophosphamide, IVIG, and methylprednisolone, with some benefit.

Dr Berkotwitz: Well, thank you so much, Dr Gwathmey, for taking the time to speak with us today. I learned a lot from you, and I know our listeners will as well. And we’ll learn a lot from reading the article that covers a large variety of additional and rare autoimmune neuropathies that we did not have time to get to today. But I think, to summarize the main points that you’ve emphasized many times — and that I think are very helpful — which is, when to worry about a patient with a clinical presentation of peripheral neuropathy. And, to make sure I have all of your excellent teaching points here, one is the pace of the illness that the neuropathic symptoms are presenting, emerging, evolving — rapidly, acutely, or subacutely. Another would be nonlength-dependent distribution of symptoms and signs. Another would be asymmetry of neuropathy symptoms and signs. And then, in some of these, as you mentioned, severe pain associated with the neuropathy. Have I captured the red flags that you’ve presented to us that should guide us to perform further evaluation looking for autoimmune causes of neuropathy in our patients?

Dr Gwaathmey: You absolutely have. That was an excellent summary.

Dr Berkowitz: Fantastic. Well, thank you so much again for speaking with us today.

Dr Gwathmey: Thank you for having me.

The material presented in Continuum Audio has been made available by the AAN for educational purposes only and is not intended to represent the only method or procedure for the medical situations discussed but rather to present an approach, view, statement, or opinion of the speaker(s), which may be helpful to others who face similar situations. Opinions expressed by the speakers are not necessarily those of the AAN, its affiliates, or the publisher. The AAN, its affiliates, and the publisher disclaim any liability to any party for the accuracy, completeness, efficacy, or availability of the material contained in this program (including drug dosages) or for any damages arising out of the use or nonuse of any of the material contained in this program.

Readings

Tracy J. Autoimmune axonal neuropathies. Continuum (Minneap Minn) 2023;29(5, Peripheral Nerve and Motor Neuron Disorders).

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr Gwathmey has received personal compensation in the range of $5000 to $9999 for serving on a scientific advisory or data safety monitoring board for Alexion Pharmaceuticals, Inc, and in the range of $500 to $4999 for serving as a consultant for Alexion Pharmaceuticals, Inc, argenx, UCB S.A., and Xeris Biopharma and for serving on a speakers bureau for Alexion Pharmaceuticals, Inc.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Gwathmey reports no disclosure.

To view disclosures of planning committee members with relevant financial relationships, visit: legacy.audio-digest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

Acknowledgements

CME/CE INFO

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Lecture ID:

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