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CME / ABIM MOC

A Case of Mistaken Identity: Diagnostic Dilemmas in CIDP, MMN, and GBS

  • Authors: Jonathan S. Katz, MD; Jeffrey Allen, MD; Karissa L Gable, MD
  • CME / ABIM MOC Released: 7/26/2022
  • Valid for credit through: 7/26/2023
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This activity is intended for neurologists, primary care physicians, and orthopedists/orthopedic surgeons.

The goal of this activity is that learners will be better able to improve the ability of clinicians to diagnose neuromuscular conditions when the presentation falls beyond the textbook definition.

Upon completion of this activity, participants will:

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    • Diagnostic criteria for specific polyneuropathies
  • Have greater competence related to
    • Accurately diagnosing specific polyneuropathies


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Faculty

  • Jonathan S. Katz, MD

    Director Forbes Norris Center
    California Pacific Medical Center
    San Francisco, California

    Disclosures

    Jonathan S. Katz, MD, has the following relevant financial relationships:
    Consultant or advisor for: Alexion Pharmaceuticals; Amylyx; argenx SE; Biogen; Calico; Denali Therapeutics; Grifols; Lifesciences; Mitsubishi Tanabe Pharma; PTC Therapeutics; Takeda Pharmaceutical Company
    Speaker or member of speakers bureau for:  argenx SE
    Research funding from:  argenx SE; Biogen; BrainStorm; Genentech; Ra Pharmaceuticals

  • Jeffrey Allen, MD

    Associate Professor
    Department of Neurology
    University of Minnesota Medical School
    Minneapolis, Minnesota

    Disclosures

    Jeffrey Allen, MD, has the following relevant financial relationships:
    Consultant or advisor for: Akcea Therapeutics; argenx SE; Alexion Pharmaceuticals; Annexon Biosciences; CSL Behring; Grifols; Johnson & Johnson; Pfizer; Takeda Pharmaceutical Company
    Speaker or member of speakers bureau for: argenx SE; CSL Behring

  • Karissa L Gable, MD

    Associate Professor of Neurology
    Duke University School of Medicine
    Durham, NC

    Disclosures

    Karissa L Gable, MD, has no relevant financial relationships.

Editor

  • Lisette Arnaud-Hevi, PhD

    Medical Education Director, Medscape, LLC 

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    Lisette Arnaud-Hevi, PhD, has no relevant financial relationships. 

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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC

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    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC

A Case of Mistaken Identity: Diagnostic Dilemmas in CIDP, MMN, and GBS

Authors: Jonathan S. Katz, MD; Jeffrey Allen, MD; Karissa L Gable, MDFaculty and Disclosures

CME / ABIM MOC Released: 7/26/2022

Valid for credit through: 7/26/2023

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Activity Transcript

Jonathan Katz, MD: Hello, I'm Jonathan Katz, director of the Forbes Norris Center at California Pacific Medical Center in San Francisco, California. Welcome to this program, which is titled A Case of Mistaken Identity, Diagnostic Dilemmas in CIDP, MMN, and GBS. Joining me today are Dr Karissa Gable, who is associate professor of Neurology at Duke University School of Medicine in Durham, North Carolina, and Dr Jeffrey Allen, who is associate professor of Neurology at the University of Minnesota Medical School in Minneapolis, Minnesota. And welcome to everybody who has joined us.

Today, we're going to be talking about immune-mediated neuropathies. These in general are caused by immune responses against autoantigens in the peripheral nervous system. And they encompass a broad range of disorders differentiated by time course, which nerve fibers are affected in various disease associations. Some of these you're aware of inflammatory demyelinating polyradiculoneuropathies, and these include the acute version called the Guillain-Barre syndrome or GBS and the chronic version called CIDP or chronic inflammatory demyelinating polyneuropathy. We'll also touch base on other types of demyelinating neuropathies that can present acute or chronically, notably Miller Fisher syndrome and multifocal motor neuropathy. And we'll touch base on the broad differential diagnosis of disorders. These conditions can be confused for or mistaken for. In general, peripheral nerve diagnoses are based on clinical manifestations, electro diagnostic studies and other supportive evidence, including sometimes the detection of autoantibodies and also spinal fluid testing. Misdiagnosis can lead to a delay to identify the correct treatment, and that can result in unnecessary damage to the peripheral nervous system. Of course, over-diagnosis can also lead to unnecessary treatments. Thus, making the right diagnosis is crucial.

Let's go on to our first case. So, case one is a 54-year-old man who presented after just 6 hours of an unusual tightness in his back began upon awakening that morning. He also noticed that he was having difficulty walking. Ten days earlier, he had had a febrile illness, which was marked by fever, chills, and diarrhea, and 2 days after that, he noticed blistering in his mouth and then over the next day or 2, a rash on his hands and feet. When he presented the same day that he developed tightness in his back and the difficulty with gait, his exam actually didn't show any weakness, but the neurologist who saw him noted that he was areflexic and had decreased pinprick sensation in his feet. Proprioception was actually reported as normal. He still had these reddish residual spots over his hand and feet, although the sores in his mouth had healed. He had an MRI of the lumbar spine in the emergency room. It showed moderate-to-severe spinal stenosis. Do you, guys, if I stop here, have any thoughts that you want to discuss so far?

Jeffrey Allen, MD: Yeah. Well, it's an interesting case and the things that sort of strike me, and this is a story that we hear all the time is the person goes into the emergency room, they report back pain, they give them some pain medications and they go away and then they come back, and they can't walk. And so, really, the thing that jumps out to me is what are the red flags that maybe this is something more than just back pain and this is something that the neurologist picked up. And so, for this case, recognizing that there was an infection about 2 weeks before is a really important red flag, that maybe this is something more and then the generalized areflexia jumps out at me as well. If you see that combination, that really should sort of set the radar off that maybe this is something more about. Up to 90% of patients will have some sort of pain in their back, so it's a common thing to not to be missed.

Dr Katz: Good. From a sort of practical standpoint, Jeff hinted at this, but he's in the ER and the doctors do perform a spinal tap and his protein level comes back 150 mg/dL, and he is 20 white blood cells. Does the 20 white blood cells off your thinking in any way?

Karissa Gable, MD: Well, I think you're allowed to go kind up to 50. So, anything above 50, I definitely would alter my thinking for something other than kind of Guillain-Barre syndrome, so it's allowable that amount of white cells. There's no red cell count, so you'd have to know what that was to potentially know how relevant that number was for the white blood cells. And then, he does have spinal stenosis and that can contribute to increased protein levels in the spinal fluid, but when it gets to be above a 100 mg/dL, I start to think that there's something more going on than just stenosis contributing to that protein level.

Dr Katz: All right, good. We're in agreement, his IVIG was started that evening for the first time under the presumption that he had Guillain-Barre syndrome, as you guys alluded to the prior infection was thought to be hand, foot, and mouth disease from coxsackievirus. On the third day, after he's in the hospital, it starts becoming clear. His legs are getting very weak. He's starting to develop clear sensory changes. By a few more days after that, he's starting to develop cranial nerve involvement. And by a few days after that, he's starting to develop some clear autonomic changes, tachycardia, and bradycardia. Again, he had begun his IVIG on the date of admission, and as we noted, his weakness just began to worsen. And by the fifth day, as we just said, he had already completed his IVIG. At this point, his legs are paralyzed, he's become weak in his right arm, and by the sixth day, he's become weak in his left arm. And then, he is transferred to the ICU for shortness of breath with new swallowing difficulties and facial weakness, and he was intubated on about day 7 in the hospital. And then, over the coming days after that, he began to develop ophthalmoparesis and began to only be able to communicate with limited updates. So, my question to you at this point is you finish the course of IVIG and you're watching over the subsequent 4 or 5 days, the patient is still progressing. We're going to back up now because I've already sort of jumped forward, but here's the nerve conduction studies. The patient was in fact admitted on a Friday and the nerve conduction studies came the following Monday, at which time, the patient was, if you recall, getting weak in his legs, he didn’t really start getting weak in his arms yet, at this point. He was developing more and more sensory symptoms. Karissa, did these studies ring any bells? Confirm your thinking. Would they've changed anything?

Dr Gable: I think it just confirms the thinking there and you've got absent F-waves, you've got conduction block at non-compressible sites. I think that reduced conduction of velocity is prolonged due to saliencies in the motors. I think, although the sensories aren't completely absent, that's just depends on the timing of the study and the variant sometimes of what you're dealing with the Guillain-Barre syndrome.

Dr Katz: Yeah. I think everybody's in agreement. We have a very typical case of Guillain-Barre, but one that's fairly aggressive. Dr Allen, would you like to talk a little bit about other forms of Guillain-Barre syndrome and other variants?

Dr Allen: Sure. We know that GBS is now a syndrome. It's not a single disease, but it's a syndrome, and under that umbrella, there are a couple different variants, and you can group the variants based on the pathophysiology or based on the region of the body that's affected. One way we group them is by pathophysiology. In the United States and much of Europe, the most common variant is AIDP, which is the acute inflammatory demyelinating polyneuropathy form that we see here. There's other axonal forms and the 2 other axonal forms are AMAN, which is an acute motor axonal form, and AMSAN which is acute motor and sensory axonal variant. Now those tend to follow Campylobacter infections more common in parts of the world that have a lot more Campylobacter, but we certainly see them here as well. Is it important to know if something's axonal or demyelinating? Probably. Those axonal forms tend to have a worse prognosis, 6 months and beyond than the demyelinating forms. For obvious reasons, axonal are harder to regrow than demyelinating. There's also other variants including the Miller Fisher variant, which is associated with GQ1b antibodies, the classic triad of Miller Fisher is ataxia, ophthalmoplegia, and areflexia. Is that one important to recognize? Probably as well, in part, because that prognosis is much more favorable where most of those patients improve spontaneously and have little-to-no disability at 6 months. And there's an extension of Miller Fisher with Bickerstaff encephalitis. You can group them by pathophysiology, for sure.

Dr Katz: This next case is a patient who was referred to us with diagnosis of ALS, which we were asked for a second opinion on. This is a 46-year-old man with a 9-month history of progressive right-hand weakness, and I put progressive somewhat in quotes in this case, because I think sometimes in cases like this when you really listen to the history, the hand weakness isn't quite progressive as much as it sort of came on over the first few months and has been relatively static. He had a cervical MRI, which showed mild degenerative changes in his neck, but nothing that would help us make a diagnosis, and his exam showed isolated weakness really to just the ulnar nerve territory of his affected hand. And I say the ulnar territory because thumb abductor seemed to have normal strength. His finger extensors seemed to have normal strength and the remaining exam in his other limbs also seemed to be normal. His sensory exam was normal. The reflex were thought by us to be normal, but it had thought to be possibly slightly increased in the affected right hand by the doctor who referred the case to us. He had had GM1 antibodies ordered, which were normal. And the outside EMG showed a few fibrillation potentials, not just in the muscle that we thought was affected clinically, which is ulnar muscles in his hand, but there was also some consideration that there was positive sharp waves and fibrillations in his median innervated muscles in his hand. And there was a report of 1 plus fibrillation potentials in his thoracic paraspinal muscles. Dr Gable, do you want to make any comments on this history?

Dr Gable: Yeah, it's kind of a common thing when you go back and ask someone about the history like that sometimes it seemingly progressive, but really was more of a static sort of process after the initial development of the symptoms. And so, while the fibrillation potentials that are seen at thoracic paraspinals raised some concern for some kind of denervation process that's kind of more global. I think that I'd want to ask him more about his symptoms. Does he have any pulmonary symptoms or anything else that could indicate that there's something else going on. But it's still given the fact that it's sort of isolated and I guess there's no mention of pain, so it's unlikely to be vasculitic, I think, I would be concerned for those reasons that this might be not an ALS process, but more of an MMN and the timing of nine months could fit that MMN as well.

Dr Katz: So, here's his nerve conduction studies. In this case, there were a few findings outside of what we were seeing clinically. Let's just start with his right median study.

Dr Gable: Well, it looks like there's some conduction block there between non-compressible site and a reduced conduction velocity, so that seems to be demyelinating process there.

Dr Katz: What do you think about the fact that he's not showing any clinical manifestations in these nerves as far as we could detect?

Dr Gable: It's a little bit unusual, but it's not out of the realm of possibility that he might have some kind of subtly detectable things on exam that he's just not noticing because he's focused more on the really symptomatic side.

Dr Katz: Yeah. For what it's worth, I couldn’t even notice either when I examined them. Really, everything was sort of limited to that left ulnar territory, but even with that 50% drop in amplitude and dispersion, we really couldn't detect much weakness in that territory. We did have a high index of suspicion that this was multifocal motor neuropathy. I think the idea that it was ALS, we sort of excluded it pretty quickly because of the minimal amount of weakness and we didn't think there was other motor neuron signs, there's no fasciculations. We actually repeated his EMG and didn't quite agree that there was denervation of his thoracic paraspinal muscles. We thought those were normal. There was some clinical involvement of his motor units in some muscles we didn't think were weak, but that was very minimal. And I think we're pretty convinced that this case has multifocal motor neuropathy. Dr Gable, would you like to talk a little bit about the clinical criteria for multifocal motor neuropathy?

Dr Gable: Sure. As listed here, going over the core criteria that really has to be present in order to make that diagnosis, and then some other criteria that's supportive, and then exclusion criteria. So, to start with the core criteria, you really need the slow or stepwise progressive focal asymmetric limb weakness with so acute onset. It can involve greater than 2 nerves, at least for a month of symptoms. And there's really not much in the way of sensory symptoms or signs, and sometimes you might have patients complain about a little minimal of something, but if you're going to see normal sensory responses of the nerve conduction studies and you're going to have really... It's not a predominantly sensory symptoms that someone's complaining about, it's going to be the weakness. And the supportive criteria that can help you guide you to making the right diagnosis. It really mainly is affecting the upper limbs often with a wrist drop or something along those lines. You can see reduced reflexes in the affected limbs. Sometimes you get some muscle cramping and fasciculations, and that's why it's considered a mimic with ALS or other motor neuron disease, but that's not as common, but it can be seen. And then, really, it's that response to the immunomodulatory therapy that improves the disability of the muscle strength that really helps confirm and kind of reassure you that you have the right diagnosis. Exclusion criteria, if you have any upper motor neuron signs, bulbar involvement, sensory impairment, that's marked with a few symmetric weaknesses during the initial weeks, then you should be thinking about other processes

Dr Katz: So, this case technically wouldn't have met the criteria for multifocal motor neuropathy, and I'm always a little hesitant with the word "must" in any criteria, because there's always exceptions to the rule. In this case, probably has enough electrodiagnostic abnormality to put that clinical criteria aside and move forward with a trial therapy. Dr Gable, how is conduction block identified electrophysiologically with that introduction?

Dr Gable: Yeah. This is a nice flag, characterizing what is conduction block and what does that mean, and so, you refer to some of these CMAP, which is the motor response to the electrical activation of the entire nerve. And then, when you see conduction block. You have proximal amplitude in area of the CMAP is reduced compared with the distal amplitude in area of the CMAP. You can have no abnormal temporal dispersion, or as noted here, there's some temporal dispersion in which you see sort of stretching out of the wave form and that reflects the different fibers that make up that CMAP and some fire faster than others, and so, you're going to see... As you have that demyelinating effect, you're going to see sort of the excessive difference between those motor axons within that nerve and that's going to show up in this way when you're not looking at the nerve conduction studies.

Dr Katz: And I think with that, we can move on to case 3, which our point here is to look at the concept of over diagnosis of CIDP, and what's the broader differential and where might we get mixed up? This was a very interesting case. The 64-year-old man with a 3-year history of progressive weakness that had been diagnosed and treated as CIDP for the whole time, and he'd actually, even before his 3-year history of weakness, he'd had some subtle paresthesias in his legs for even a few years before that, but he mostly ignored the symptoms and didn't seek medical attention.

When he finally did seek medical attention, it was nearly a year after the onset of his weakness and probably 5 or 6 years after the onset of that subtle sensory loss. And he was found to have fairly marked generalized weakness in proximal and distal muscles in his upper and lower extremities. He was initially treated with high dose prednisone, which he says in retrospect had helped slightly and actually worsened when the dose was tapered. I think it helped him in something like the first couple of months after therapy started. But when prednisone clearly wasn't enough to resolve his symptoms, he was started on treatment with IVIG. And that was just months before we finally saw him, and his report was that the IVIG didn't help at all. By the time he saw our group, he was in a wheelchair, and he had this extra feature, which is, he just looks sick, so... I guess my first question for Dr Allen is, the CIDP patients generally look sick. You get the impression when you look at them. It's something might be wrong or is it just a neuropathy?

Dr Allen: Generally, not. It's certainly that one of those red flag symptoms that maybe there's something else happening, maybe there's something more systemic occurring. Whenever I see people with looks sick often, that means a lot of weight loss preceding their diagnosis or other medical problems. It's something not to be dismissed.

Dr Katz: His initial exam, when we saw him, showed this pattern of proximal and distal weakness in the upper and lower extremities, which most of the muscles were in the range of grade 4 to 4-, he had distal sensory loss and he was completely areflexic. In reviewing his records, we could see that when he had first presented, his spinal fluid protein was 130 mg/dL with no white or red blood cells in the spinal fluid. He'd also had a serum protein electrophoresis and an immunofixation electrophoresis that were both normal. We repeated his nerve conduction studies and compared them to studies he had had a few years earlier. The studies from a few years earlier showed small amplitudes in the tibial and peroneal nerve territories with abnormal temporal dispersion, velocities across the legs in the 20s and prolonged dispersed F-waves. And at that time, his arms were reported out as normal, except the ulnar F-wave on one side had a prolonged latency. Now, as we repeat the studies a few years later, we actually found fairly similar results, but by this point, the amplitudes in his arms had become reduced, but there wasn't a lot of conduction slowing for dispersion in his arms. Any thoughts about this? Can you see how he would've been diagnosed the CIDP? Do you have any other questions?

Dr Allen: Yeah. You can see how that mistake would be made. You've got somebody with several years of slowly progressive proximal and distal weakness with distal sensory losses and areflexia. So that sort of fits a lot of those definitions with CIDP. You've got a high protein, which is certainly not diagnostic of CIDP but falls within that supportive category, and you've got nerve conductions, which are clearly abnormal. It shows slowing, which is in one of the ranges that we would consider to demyelinating and abnormal dispersion. It's easy to make that conclusion that this is an acquired inflammatory demyelinating neuropathy and CIDP and treat as such. However, there are a couple of red flags that make you wonder about that. One is the lack of response to treatment, or at least a robust, meaningful response to treatment. And 2 first-line treatments were tried with prednisone and IVIG. So, to me, that's a huge red flag that maybe it's not CIDP. And number 2 is the looking sick and that's typically not something we see in CIDP as we mentioned. And then, just the degree of progressive, relentlessly progressive accumulation of disability. So, with those 3 things, it broadens the differential to a couple of things. One is certain genetically determined neuropathy and TTR amyloid might be the most important one. And number 2, AL amyloid is something to certainly think about and somebody with this picture. And the number 3 is POEMS. Even with the normal immunofixation, I don't think you can take POEMS off the table.

Dr Katz: Also, over the last year before we saw him, he had begun to develop diabetes and his TSH had become abnormal. So, stopping there, and I'll open this up to both of you, does this give you any clues or make you think twice about the diagnosis of CIDP?

Dr Gable: Yeah, of course, because all those things are included in sort of the minor criteria for the diagnosis of POEMS, so he is kind of starting to check off a lot of those boxes. I think the somewhat misleading thing or why he remains sort of maybe misdiagnosed for a little while is because the immunofixation still was normal. And one of the major criteria for diagnosis would be that you have a monoclonal protein. Although I've seen cases where that sort of smolders along, and so, you'll check it once and it'll be normal, you'll check it again, it'll be abnormal, and it'll be like a hint of a monoclonal protein. So, it's there, it's just maybe not being checked repeatedly. I mean, just checked once and then kind of left to that state.

Dr Katz: Yeah. At this point, the gentleman goes home, and we start to dig through his chart a little bit. And what we found is that an MRI scan, which had been ordered 5 years earlier, was reported to have an expansile lesion in the L3 vertebral body, that had been new compared to a film of 2 years before that. So, this is happening right around the time that his clinical symptoms are starting, and that lesion in the L3 vertebral body have been followed up with an HDP bone scan that was read as a mild facet joint inflammatory response, so they didn't really follow up on what had been seen on that MRI scan. Any thoughts on that finding? Any thoughts on bone scan and agents suspected of having bone syndrome?

Dr Allen: Yeah, it's an important part of the workup. If that's on the table, then I'll commonly obtain some sort of imaging with CAT scan or skeletal surveys to look for bone lesions, and for a case like this where there's a fairly high index of suspicion, it's an important thing to do.

Dr Katz: Yeah. So, on further testing too, he was anemic. We repeated his immunofixation, which was still normal and actually repeated. Or actually ordered a vascular endothelial growth factor test, which was also normal. We actually reviewed a skeletal survey, which now showed multiple osteosclerotic lesions. And we did have a high index of suspicion still that he had POEMS syndrome with all of these bone lesions, and we did a biopsy eventually of the original lesion that had showed up in his vertebral body, which showed a restricted monoclonal plasma cell, suggestive of a plasmacytoma. This case, our summary was that the patient presented as CIDP and at that beginning stage, really the only clue was that had that lesion on his vertebral body on an MRI scan, but that had been sort of disqualified and we went ahead and referred him to oncology, and subsequently, he is, in fact, being treated for POEMS syndrome. Dr Allen, any comments on a peripheral nerve workup in general with this case makes you think about?

Dr Allen: Yeah. Just some of the things that we suggest talked briefly about earlier, just general neuropathy workups for cases that are usually much different than this. But looking for endocrinopathies and vitamin deficiencies and other things that really come up based on what your level of suspicion is, you can often... Although the list of things that can cause neuropathy is to numerous accounts, you can often do a fairly targeted workup based on the clinical features and background that you know. And for this case in particular, again, that big red flag is the... Or one of them is the lack of response to treatment. We often think about patients that get treatments, like IVIG or steroids, and they do better, and that proves that their diagnosis is what we think it is, but we rarely think about it the other way, where if a treatment fails that argues that maybe the diagnosis isn't correct. And if you think about our true and effective therapies of steroids and IVIG 90% or more patients will respond to those, really, if you don't respond to it, it's really... Probably not that the treatment doesn't work, it's that the diagnosis is wrong. It's always something to keep in mind.

Dr Katz: So, let's talk a little bit now about CIDP clinical criteria in general. So, Jeff, do you mind sharing with us some clinical features and how the new criteria is sort of break things up into CIDP variants?

Dr Allen: Sure. So just like we know GBS is now a syndrome with variants, CIDP is also a syndrome with variants. And we think about CIDP, as having typical presentation, which is all based on the clinical features where those patients have relatively symmetric proximal and distal numbness and weakness that evolves over 2 months or more, and reflexes are diffusely reduced or absent, so that's sort of the typical presentation. And then, we know that there are variants of CIDP, which are still under that CIDP umbrella, but differ in which of those modalities, numbness or weakness are really predominant, or which part of the body is affected. So, the named variants of CIDP now are a distal variant where patients get numb and weak, but it's all distally usually in the lowers and sometimes the upper limbs. There's a multifocal variant, which also goes by the name of the Sumner syndrome or MADSAM, it's all the same thing, where patients get numb and weak, but it follows median nerve distributions or sometimes plexus distributions. There's a motor variant where patients get weak, but not numb, but the pattern of weakness is both proximal and distal and relatively symmetric. And then, there's a sensory variant, where patients get numb, but not weak. But again, it's not just distal, it's proximal and distal without motor involvement.

Dr Katz: And then, what about the nerve conduction studies for CIDP? Can you briefly go through? You have a case. Let's say for the sake of discussion, he's got a typical clinical presentation for CIDP. What do the criteria say about this? And you use the criteria the same way for every single form of CIDP?

Dr Allen: Yeah. So, it's a clinical diagnosis, but number 2, on the importance of things to look at for that diagnosis of the nerve conduction. Without going through all of these specifics, there are predefined abnormalities that we like to see on the nerve conduction study that increase our suspicion that this is really a demyelinating problem. For typical CIDP, that's usually a pretty easy thing to see the variants that can be a little more difficult. And there are new diagnostic criteria, the EAN/PNS diagnostic criteria for CDP that were published last year, and they sort of break down the electrodiagnostic criteria by each variant to give some really helpful guidance on what you might look for, not just in a typical case, but also with the variants. And so, it's a good reference to rely upon.

Dr Katz: And what about just getting back to where we were, if we break these variants down, the new criteria sort of want us to think about with each phenotype, what the broader differential diagnosis is and how that broader differential diagnosis might bring up different red flags. What sort of things do we want to think about?

Dr Allen: Yeah, one of the difficult things, and one of the reasons that CIDP has misdiagnosed so often is, of course, there is no single diagnostic test that may help us to reach that conclusion, to subsequently misdiagnose is quite common. Maybe, 50% to 80% of cases are misdiagnosed. And part of the difficulty also is that the differential for typical CIDP is not going to be the same as the differential for distal CIDP or motor or sensory CIDP, so the new diagnostic criteria have recognized that and have given some more helpful guidance on what you might think about depending on what variant that you're looking at. If you have typical CIDP, most of the time, this one is not the one that's misdiagnosed, but there are some things that you might want to think about. For example, if you had somebody that thought had typical CIDP, but had a marked tremor or ataxia, you might want to think about one of the autoimmune neuropathies, which are now split off from CIDP in part because their pathology is different, and their treatment response is different.

Dr Katz: Karissa do you want to go through the different clinical presentations one more time and talk to us about what the red flags are, the labs that would make you think otherwise about these clinical presentations?

Dr Gable: Sure. Yeah. We're looking at the typical case when you see a monoclonal gammopathy that can evolve to multiple myeloma or it could be AL amyloid or POEMS, so you always want to keep that in the back of your mind for those patients who have that. I just always get hematology/oncology involved because I feel like there's some things that they look for sometimes that maybe is on their radar raises their suspicion. And then, elevated CK raises a flag to it really shouldn't be elevated there, so you want to kind of keep in mind if you see that. And similarly, the distal variant that you might see, that could be potentially some of the diabetic neuropathies have gone unchecked for years can have significant distal weakness that can mimic CIDP case. And then again, if you have monoclonal gammopathy can be the same sort of things that you want to consider keeping in the back of your mind. The sensory variant, again, those can be typical background general underlying neuropathic kind of causes, like low vitamin B12 or history of chemotherapy or elevated or prediabetic levels or even elevated A1C and the diabetic levels, and then having normal motor and sensory conductions. And then, with the multifocal cases, you have to keep in mind that it could be potentially a vasculitic neuropathy. And in those cases, ... In those rare cases, we might do a nerve biopsy, particularly if there's a lot of pain associated, which is not very the most typical part of CIDP in the patients that I've seen, and so, I would keep that in mind and check rheumatologic labs and look for that. So, it's very different focus of treatment. And then, again, with the people who actually do have GM1 antibodies and you're considering MMN, and that guides a different kind of treatment decision.

Dr Katz: Thank you. Just sort of sum this up and I'll help you. You have a patient at the bedside clinically and you think they might have CIDP, spinal tap. How do you think about a spinal tap in a case of typical CIDP? Where do you draw the cutoff? Does it matter if the patient has diabetes? And then, I'll throw out another question, think a patient probably doesn't have CIDP, you do a spinal tap, the protein comes back borderline, like... How do you think about the spinal fluid protein in those cases?

Dr Gable: Yeah. As these are outlined, none of these supportive sorts of tests are diagnostic alone for CIDP. It always comes back to the history and physical and what the patient's presenting with, so these are really, I consider, supportive kind of things in gray zones. So, if someone has a very typical case of CIDP and their clinical history fits that, exam fits that, the electrodiagnostic testing fits that, and I don't typically do a spinal tap because in that case, it's pretty straightforward in my mind, unless something shows up later, like they have some kind of lack of response to treatment or something like that. In cases where it's not as clear, then I would pursue getting spinal fluid. As noted here and as outlined in papers that have been published about things that can influence protein levels, diabetes or spinal stenosis can cause some borderline increases of protein in the spinal fluid, so you have to keep that in mind when you are looking at this data, and that's how misdiagnosis and overdiagnosis happens when people are hopefully reliant on just the protein to make a diagnosis

And then, the test of treatment, as mentioned, is very important and using objective outcome measures as noted here with the INCAT and i-RODS and grip strength, when you have those outcome measures and you follow those over time along with the clinical exam, it can really help you guide treatment and help you understand the process, since there's not just one test to indicate whether or not this patient has this disease.

Dr Katz: Finally, in conclusion, hopefully, we've come across the spectrum of these diseases broadened and we're beginning to diagnose these conditions, not only the CIDP but by their subtypes. The common feature of all these diseases is speculated to be autoimmunity to proteins localized on components of the peripheral nerves. But obviously we don't know these in every single case, and a lot of what we're doing is relying on our clinical human with the supportive tests that we talked about. Making the right diagnosis in daily clinical practice can really be complicated. Nobody's going to pretend that this isn't the hard area with a lot of nuances and understanding the diseases and diagnosis. I think the recent criteria have been a big improvement in the way that we think about these diseases, and they're definitely worth a look. And I suspect with time, we'll probably develop better outcome markers, and better diagnostic markers that'll aid in our diagnosis. I want to thank Dr Gable and Dr Allen for this discussion. And I hope all of you enjoyed it. Thank you for participating in this activity. And please continue to answer the questions that follow and complete the evaluation. Thank you very much and have a great day.

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