Uncover the expertise

Key opinion leaders discuss how to recognize, confirm, and treat CIDP

hub_kol_K101_confirm_differences_in_distal_neuropathies

Differences in Distal Neuropathies

Jon Katz, MD, Neurology, focuses on differentiating CIDP from DADS (no MAG) and other distal acquired demyelinating neuropathies.

Transcript

Differences in Distal Neuropathies

Jon Katz, MD, Neurology, focuses on differentiating CIDP from DADS (no MAG) and other distal acquired demyelinating neuropathies.

Today we're going to talk about differentiating between DADS no MAG, which is a essentially a variant of CIDP, and other distal acquired demyelinating neuropathies. I'm Jon Katz from San Francisco.

Now, I'm going to talk about the clinical findings of distal acquired demyelinating neuropathies. In particular, just how do these patients present? So, what you're talking about here is a large fiber sensory neuropathy. And these are the patients that come in and say, "Doc, I have numb feet." And what we're talking about here is they've sensory loss, it tends to be large fibers, so they are losing vibration, touch, joint position sense more than they're losing pin or temperature. And again, by length dependent, we mean it's got this distal proximal gradient. So, the feet get numb as the condition gets worse. The numbness rises up the legs. As it rises up the legs more, to, say, the knees, you might start getting numbness in your hands. So, hence that's the concept of length dependent.

Not surprisingly they tend to have a Romberg sign. If it's severe enough, they can develop some sensory ataxia. They lose the reflexes in the same sort of gradient as the sensory involvement. So, ankles first then they lose their knee reflexes and in the most severe cases they will be totally areflexic. And the motor signs are predominant in 15 to 20% of cases, or the advanced cases. And that's another way to say that this is basically a length-dependent neuropathy, because as that sensory involvement starts to advance, say once the numbness gets up to the calves or up to the knees, you start seeing weakness in the toes and ankles, because that's about the same length from the spinal cord as the sensory fibers. And, flipping it around, the cranial nerves aren't affected because they tend to be very short. And autonomic function is spared because this neuropathy tends to affect large fibers.

So, now I'm going to switch over and talk about a specific type of distal acquired demyelinating neuropathy with MAG antibodies. So, this is really a very specific phenotype and should be considered its own clinical entity. Who has this? Well, it's 85% of the cases are males. They tend to be older aged between 60 and 80 at the time of onset. This tends to be a very slowly progressive length-dependent neuropathy that evolves over many years. The symptoms are present, as I said before, for years before the initial evaluation, in most cases. These cases will tend to get to you a year, 2 years, sometimes 3 years or more after the disease starts. I'd just like the last slides mentioned again. Length dependent. It's a distal symmetrical sensory—more than motor—pattern. The motor features show up as the disease becomes more advanced. Patients complain of paresthesias, in many of the cases—the distal numbness, the imbalance, and the sensory ataxia. And in some of these cases, you start to see a tremor. And the tremor is present in about 15%.

Again, what do we see on the electrodiagnostic studies of these DADS cases with MAG antibodies? The main feature that you look for are these prolonged distal motor latencies, which are present in most nerves. The conduction velocities in the proximal segments tend to be a little bit more variable and tend not to be as severe as the distal segments. So, you will see these long distal latencies. And then the conduction slowing across the forearm or across the leg tends to be somewhere between minimal and moderate.

Conduction block is generally uncommon in these cases. So when you hear the term uniform slowing, we're just talking about slowing in the nerves without these features of conduction block and dispersion. And in another feature, which people sometimes overlook, is that axon loss is common in these diseases. So, it's not a pure demyelinating neuropathy. They tend to have reduced motor amplitudes, absent sensory potentials, and if you do an EMG you will see denervation in the distal muscles. This probably reflects the chronicity of the disorder as well as the pathophysiology of the disorder. It sometimes can make the assessment a little bit difficult, and it has important implications for treatment responses because if you have axonal loss it may be hard to get the function back no matter what you do. And we will talk about that a few slides ahead of here.

And in rare cases, the involvement can be so severe from an axonal point of view that you won't see any motor responses or sensory potentials. So, again this is limited to the very advanced cases and end-stage cases.

So now we'll talk about the laboratory features of distal acquired demyelinating neuropathy with MAG antibody. And once you've found the length-dependent pattern and you've seen the demyelination or the suspicion about the nerve conduction studies that we just talked about with the distal latencies, next thing you're going to think about is ordering a serum protein electrophoresis or an immunofixation electrophoresis. And what you are going to find in those cases—what you are going to look for—is an IgM paraprotein because the distal demyelinating neuropathies are IgM specific. That's the only paraprotein you are looking for. And once you find that, you are going to be thinking now about this DADS MAG case because you found the clinical phenotype, electrodiagnostic phenotype, and the IgM paraprotein, which is the key laboratory feature.

Now this IgM paraprotein is going to be associated with the kappa light chain most of the time. Rarely with a lambda light chain. Usually, these cases have relatively low amounts less than 1.5 grams of the IgM paraprotein. Some people refer to that as a monoclonal gammopathy of uncertain significance. Although here it has significance cause the IgM paraprotein is not an unknown. It's part of this neuropathy. But, you'll hear that term from time to time.

There's a tendency for some neurologists to search for a plasma cell dyscrasia in these cases, particularly if the amount of IgM paraprotein is greater than 1.5 grams. And if that's the case, you would be thinking about sending the case to a hem/onc person and the hem/onc person can look at their bone marrow or consider further workup.

Now, once you've found this IgM paraprotein, this is the place where we think about ordering an anti-MA antibody. So, that's an antibody against myelin-associated glycoprotein. Once you've put together the phenotype, the electrical tests, and the laboratory tests, about 50% of those patients are going to turn out to have MAG on their laboratory study.

So, more about the laboratory features and this is kind of the inverse of what we talked about in the last slide. The MAG antibody test doesn't need to be ordered in patients that have a length-dependent neuropathy and an IgG or an IgA monoclonal gammopathy and in those cases would truly be considered MGUS because we don't know what the significance is. We tend to use an ELISA system as a standard for this to measure the anti-MAG titer. Western blot tends to be more sensitive, and it may be positive in the cases where the ELISA system is negative. And titers less than 1 to 6400 may not be clinically relevant. The reliability of the laboratory should be established using the appropriate methodology, which is true for any tests, but sometimes these antibody tests can fool you if you are sending them to obscure labs.

So, what is the treatment for this DADS neuropathy? Well, we have to go back to the beginning again and break it up into 2 separate categories again. I want to establish this so everybody understands it, but distal acquired demyelinating neuropathies with no MAG are basically variants of CIDP. So, if you don't find the IgM paraprotein, if you don't find the MAG antibody, we start thinking about this as any CIDP, and we treat it the same way we treat other CIDPs. So, IVIG, prednisone, or other responses, and we think of it as being similar to any of the other variants.

Now what if you have the MAG neuropathy? What's the treatment there? Well, here we have some more controversy, and we always ask the question, "Is treatment really always necessary?" And part of the reason we ask that is that randomized controlled trials to date have not found evidence that's statistically significant with respect to a response to therapy.

Let's talk a little more about the treatment of anti-MAG neuropathy. At this time rituximab is the favorite treatment. But, the total number of published cases that were given rituximab is still less than a hundred cases. And seven of these cases have actually had paradoxal worsening after rituximab. There's been a couple of randomized trials, and let's talk about this one by Leger for a second called, "Placebo-Controlled Trial of Rituximab in IgM Anti-Myelin-Associated Glycoprotein." I think this paper gives us a pretty good feel for what the treatment response is in this disease.

I'll start off by saying that they were able to show that they were able to reduce the titers of MAG antibodies in the disease. So one would think that by reducing MAG antibodies you might see the patients get better, but when we look at the clinical responses in this study, we find that the patients didn't get better at all. There are actually very few statistically significant endpoints with respect to the clinical response to the neuropathy. They did measure many different endpoints and a couple of these things were statistically significant. But, by no means did the study give any sort of strong signal and a lot of neurologists that looked at this study concluded that the treatment is not particularly effective.

Here's where we are with treating anti-MAG neuropathy at this time. There's really no compelling data the treatment works. We only have anecdotal evidence, case reports that some patients respond, and within these randomized trials there were some individual patients that got better.

It's an indolent condition. So, when we flip around the idea of treatment, we're looking at a treatment that tends to affect older people. It's very indolent. It's very slow and it's hard to measure objective change. So, you could look at that 2 different ways. It's going to be very hard to do a study and show effectiveness in a disease that changes this slowly. And patients certainly aren't getting dramatically better. But, if you flip it around, it's an indolent condition. So, are you going to give it therapy over and over again over time in a disease that really doesn't change very much?

So, the next question we ask is, "Must all patients be treated with this condition?" And we think that the answer is no. Is there a subset of patients that should be treated, and how do we decide who should be treated? Well, neurologists think that if there's a lot of functional disability it's worth giving a trial of rituximab or some other treatment, and if the patients are progressing towards disability, it may be worth giving a trial. But, because there is no studies that are effective we are left with the question, "If you are going to treat them, of what treatment is it, rituximab or should it be something else?"

So, here's the summary for indications for anti-MAG neuropathy. First, I will talk again about antibody testing. We should check for anti-MAG antibodies when we have a chronic progressive large fiber sensory neuropathy. Again, that's length dependent. We find that an IgM monoclonal protein is present when we ordered serum protein electrophoresis or immunofixation electrophoresis, and our nerve conduction studies show these long distal latencies. Flipping it around, anti-MAG antibodies should not be ordered when we have an inherited neuropathy, a motor predominate pattern, a multifocal pattern, a prominent painful neuropathic pattern. When we see rapid progression. When we don't see an M spike when we order our testing and when we see a pure axonal pattern. In other words, we don't order anti-MAG antibodies when they have neuropathies that are different from DADS with an IgM paraprotein.

I thank you and I hope this information helps you with treating your patients.

Transcript

Differences in Distal Neuropathies

Jon Katz, MD, Neurology, focuses on differentiating CIDP from DADS (no MAG) and other distal acquired demyelinating neuropathies.

Today we're going to talk about differentiating between DADS no MAG, which is a essentially a variant of CIDP, and other distal acquired demyelinating neuropathies. I'm Jon Katz from San Francisco.

Now, I'm going to talk about the clinical findings of distal acquired demyelinating neuropathies. In particular, just how do these patients present? So, what you're talking about here is a large fiber sensory neuropathy. And these are the patients that come in and say, "Doc, I have numb feet." And what we're talking about here is they've sensory loss, it tends to be large fibers, so they are losing vibration, touch, joint position sense more than they're losing pin or temperature. And again, by length dependent, we mean it's got this distal proximal gradient. So, the feet get numb as the condition gets worse. The numbness rises up the legs. As it rises up the legs more, to, say, the knees, you might start getting numbness in your hands. So, hence that's the concept of length dependent.

Not surprisingly they tend to have a Romberg sign. If it's severe enough, they can develop some sensory ataxia. They lose the reflexes in the same sort of gradient as the sensory involvement. So, ankles first then they lose their knee reflexes and in the most severe cases they will be totally areflexic. And the motor signs are predominant in 15 to 20% of cases, or the advanced cases. And that's another way to say that this is basically a length-dependent neuropathy, because as that sensory involvement starts to advance, say once the numbness gets up to the calves or up to the knees, you start seeing weakness in the toes and ankles, because that's about the same length from the spinal cord as the sensory fibers. And, flipping it around, the cranial nerves aren't affected because they tend to be very short. And autonomic function is spared because this neuropathy tends to affect large fibers.

So, now I'm going to switch over and talk about a specific type of distal acquired demyelinating neuropathy with MAG antibodies. So, this is really a very specific phenotype and should be considered its own clinical entity. Who has this? Well, it's 85% of the cases are males. They tend to be older aged between 60 and 80 at the time of onset. This tends to be a very slowly progressive length-dependent neuropathy that evolves over many years. The symptoms are present, as I said before, for years before the initial evaluation, in most cases. These cases will tend to get to you a year, 2 years, sometimes 3 years or more after the disease starts. I'd just like the last slides mentioned again. Length dependent. It's a distal symmetrical sensory—more than motor—pattern. The motor features show up as the disease becomes more advanced. Patients complain of paresthesias, in many of the cases—the distal numbness, the imbalance, and the sensory ataxia. And in some of these cases, you start to see a tremor. And the tremor is present in about 15%.

Again, what do we see on the electrodiagnostic studies of these DADS cases with MAG antibodies? The main feature that you look for are these prolonged distal motor latencies, which are present in most nerves. The conduction velocities in the proximal segments tend to be a little bit more variable and tend not to be as severe as the distal segments. So, you will see these long distal latencies. And then the conduction slowing across the forearm or across the leg tends to be somewhere between minimal and moderate.

Conduction block is generally uncommon in these cases. So when you hear the term uniform slowing, we're just talking about slowing in the nerves without these features of conduction block and dispersion. And in another feature, which people sometimes overlook, is that axon loss is common in these diseases. So, it's not a pure demyelinating neuropathy. They tend to have reduced motor amplitudes, absent sensory potentials, and if you do an EMG you will see denervation in the distal muscles. This probably reflects the chronicity of the disorder as well as the pathophysiology of the disorder. It sometimes can make the assessment a little bit difficult, and it has important implications for treatment responses because if you have axonal loss it may be hard to get the function back no matter what you do. And we will talk about that a few slides ahead of here.

And in rare cases, the involvement can be so severe from an axonal point of view that you won't see any motor responses or sensory potentials. So, again this is limited to the very advanced cases and end-stage cases.

So now we'll talk about the laboratory features of distal acquired demyelinating neuropathy with MAG antibody. And once you've found the length-dependent pattern and you've seen the demyelination or the suspicion about the nerve conduction studies that we just talked about with the distal latencies, next thing you're going to think about is ordering a serum protein electrophoresis or an immunofixation electrophoresis. And what you are going to find in those cases—what you are going to look for—is an IgM paraprotein because the distal demyelinating neuropathies are IgM specific. That's the only paraprotein you are looking for. And once you find that, you are going to be thinking now about this DADS MAG case because you found the clinical phenotype, electrodiagnostic phenotype, and the IgM paraprotein, which is the key laboratory feature.

Now this IgM paraprotein is going to be associated with the kappa light chain most of the time. Rarely with a lambda light chain. Usually, these cases have relatively low amounts less than 1.5 grams of the IgM paraprotein. Some people refer to that as a monoclonal gammopathy of uncertain significance. Although here it has significance cause the IgM paraprotein is not an unknown. It's part of this neuropathy. But, you'll hear that term from time to time.

There's a tendency for some neurologists to search for a plasma cell dyscrasia in these cases, particularly if the amount of IgM paraprotein is greater than 1.5 grams. And if that's the case, you would be thinking about sending the case to a hem/onc person and the hem/onc person can look at their bone marrow or consider further workup.

Now, once you've found this IgM paraprotein, this is the place where we think about ordering an anti-MA antibody. So, that's an antibody against myelin-associated glycoprotein. Once you've put together the phenotype, the electrical tests, and the laboratory tests, about 50% of those patients are going to turn out to have MAG on their laboratory study.

So, more about the laboratory features and this is kind of the inverse of what we talked about in the last slide. The MAG antibody test doesn't need to be ordered in patients that have a length-dependent neuropathy and an IgG or an IgA monoclonal gammopathy and in those cases would truly be considered MGUS because we don't know what the significance is. We tend to use an ELISA system as a standard for this to measure the anti-MAG titer. Western blot tends to be more sensitive, and it may be positive in the cases where the ELISA system is negative. And titers less than 1 to 6400 may not be clinically relevant. The reliability of the laboratory should be established using the appropriate methodology, which is true for any tests, but sometimes these antibody tests can fool you if you are sending them to obscure labs.

So, what is the treatment for this DADS neuropathy? Well, we have to go back to the beginning again and break it up into 2 separate categories again. I want to establish this so everybody understands it, but distal acquired demyelinating neuropathies with no MAG are basically variants of CIDP. So, if you don't find the IgM paraprotein, if you don't find the MAG antibody, we start thinking about this as any CIDP, and we treat it the same way we treat other CIDPs. So, IVIG, prednisone, or other responses, and we think of it as being similar to any of the other variants.

Now what if you have the MAG neuropathy? What's the treatment there? Well, here we have some more controversy, and we always ask the question, "Is treatment really always necessary?" And part of the reason we ask that is that randomized controlled trials to date have not found evidence that's statistically significant with respect to a response to therapy.

Let's talk a little more about the treatment of anti-MAG neuropathy. At this time rituximab is the favorite treatment. But, the total number of published cases that were given rituximab is still less than a hundred cases. And seven of these cases have actually had paradoxal worsening after rituximab. There's been a couple of randomized trials, and let's talk about this one by Leger for a second called, "Placebo-Controlled Trial of Rituximab in IgM Anti-Myelin-Associated Glycoprotein." I think this paper gives us a pretty good feel for what the treatment response is in this disease.

I'll start off by saying that they were able to show that they were able to reduce the titers of MAG antibodies in the disease. So one would think that by reducing MAG antibodies you might see the patients get better, but when we look at the clinical responses in this study, we find that the patients didn't get better at all. There are actually very few statistically significant endpoints with respect to the clinical response to the neuropathy. They did measure many different endpoints and a couple of these things were statistically significant. But, by no means did the study give any sort of strong signal and a lot of neurologists that looked at this study concluded that the treatment is not particularly effective.

Here's where we are with treating anti-MAG neuropathy at this time. There's really no compelling data the treatment works. We only have anecdotal evidence, case reports that some patients respond, and within these randomized trials there were some individual patients that got better.

It's an indolent condition. So, when we flip around the idea of treatment, we're looking at a treatment that tends to affect older people. It's very indolent. It's very slow and it's hard to measure objective change. So, you could look at that 2 different ways. It's going to be very hard to do a study and show effectiveness in a disease that changes this slowly. And patients certainly aren't getting dramatically better. But, if you flip it around, it's an indolent condition. So, are you going to give it therapy over and over again over time in a disease that really doesn't change very much?

So, the next question we ask is, "Must all patients be treated with this condition?" And we think that the answer is no. Is there a subset of patients that should be treated, and how do we decide who should be treated? Well, neurologists think that if there's a lot of functional disability it's worth giving a trial of rituximab or some other treatment, and if the patients are progressing towards disability, it may be worth giving a trial. But, because there is no studies that are effective we are left with the question, "If you are going to treat them, of what treatment is it, rituximab or should it be something else?"

So, here's the summary for indications for anti-MAG neuropathy. First, I will talk again about antibody testing. We should check for anti-MAG antibodies when we have a chronic progressive large fiber sensory neuropathy. Again, that's length dependent. We find that an IgM monoclonal protein is present when we ordered serum protein electrophoresis or immunofixation electrophoresis, and our nerve conduction studies show these long distal latencies. Flipping it around, anti-MAG antibodies should not be ordered when we have an inherited neuropathy, a motor predominate pattern, a multifocal pattern, a prominent painful neuropathic pattern. When we see rapid progression. When we don't see an M spike when we order our testing and when we see a pure axonal pattern. In other words, we don't order anti-MAG antibodies when they have neuropathies that are different from DADS with an IgM paraprotein.

I thank you and I hope this information helps you with treating your patients.


Gamunex Connexions Support 1-888-MYGAMUNEX (1-888-694-2686)

GAMUNEX®-C (immune globulin injection [human], 10% caprylate/chromatography purified) is indicated for the treatment of primary humoral immunodeficiency disease (PIDD) in patients 2 years of age and older, idiopathic thrombocytopenic purpura (ITP) in adults and children, and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults.

Thrombosis may occur with immune globulin products, including GAMUNEX-C. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMUNEX-C at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IVIG) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of preexisting renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIG products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.

GAMUNEX-C is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. It is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Severe hypersensitivity reactions may occur with IVIG products, including GAMUNEX-C. In case of hypersensitivity, discontinue GAMUNEX-C infusion immediately and institute appropriate treatment.

Monitor renal function, including blood urea nitrogen (BUN), serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IVIG treatment, including GAMUNEX-C.

There have been reports of aseptic meningitis, hemolytic anemia, and noncardiogenic pulmonary edema (transfusion-related acute lung injury [TRALI]) in patients administered with IVIG, including GAMUNEX-C.

The high-dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern.

Because GAMUNEX-C is made from human blood, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Do not administer GAMUNEX-C subcutaneously in patients with ITP because of the risk of hematoma formation.

Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMUNEX-C and at appropriate intervals thereafter.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis.

If signs and/or symptoms of hemolysis are present after an infusion of GAMUNEX-C, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and patient's serum.

After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation.

In clinical studies, the most common adverse reactions with GAMUNEX-C were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia (in CIDP); cough, rhinitis, pharyngitis, headache, asthma, nausea, fever, diarrhea, and sinusitis with intravenous use (in PIDD) and local infusion-site reactions, fatigue, headache, upper respiratory tract infection, arthralgia, diarrhea, nausea, sinusitis, bronchitis, depression, allergic dermatitis, migraine, myalgia, viral infection, and pyrexia with subcutaneous use (in PIDD); and headache, ecchymosis, vomiting, fever, nausea, rash, abdominal pain, back pain, and dyspepsia (in ITP).

The most serious adverse reactions in clinical studies were pulmonary embolism (PE) in 1 subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in 1 subject (in PIDD), and myocarditis in 1 subject that occurred 50 days post-study drug infusion and was not considered drug related (in ITP).

Please see accompanying full Prescribing Information for GAMUNEX-C.

Terms to know

IG=immune globulin, CIDP=chronic inflammatory demyelinating polyneuropathy, PIDD=primary immunodeficiency disease, ITP=idiopathic thrombocytopenic purpura, Sub Q=subcutaneous, IV=intravenous, ICE=10% caprylate-chromatography purified immune globulin intravenous (IGIV-C) CIDP efficacy.

Are you sure you want to leave our site?

Please be advised that Grifols has no control over the content or presentation of the site you are about to view.

Please select "Continue" if you wish to be taken to this third-party website.