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Distinguishing CIDP

Todd Levine, MD, Neurology, reviews the important characteristics of typical and atypical CIDP and how to differentiate them from other neuropathies.

Transcript

Distinguishing CIDP

Todd Levine, MD, Neurology, reviews the important characteristics of typical and atypical CIDP and how to differentiate them from other neuropathies.

Hi. I'm Dr. Todd Levine. And I'm going to talk today about distinguishing typical and atypical CIDPs from other types of demyelinating neuropathies.

When we talk about CIDP, the key thing here is that this is one of the few treatable neuropathies that we diagnose in neuromuscular disorders. We diagnose CIDP based on very characteristic patterns of weakness and sensory loss, which involves proximal and distal muscles as well as decreased reflexes.

When we see that pattern, the 2 diagnostic criteria are going to be between GBS (or Guillain-Barré) and CIDP. The distinction is really the time. If it's less than 8 weeks, we call it Guillain-Barré, if it's more than 8 weeks we call it CIDP. So that seems pretty straightforward. But what do we if there's progressive weakness that is asymmetric? Or what if it's only in the arms? Or what if it's only distal?

Well, it doesn't mean that it's not a chronic inflammatory demyelinating neuropathy. It simply means that we need to consider the atypical forms of demyelinating neuropathies. And also important to recognize is that these atypical forms of demyelinating neuropathies may be responsive to therapy.

So, here's a nice table that outlines for you the different types of demyelinating neuropathies you may encounter in your clinical practice. The first, as I said, is CIDP. This has the very characteristic symmetric proximal and distal weakness as well as sensory involvement and decreased reflexes. These symptoms will have been present for more than 8 weeks to make a diagnosis of CIDP.

When we think about Guillain-Barré, we typically think about symptoms that progress over days. So we have a variant of CIDP that we call acute, where the symptoms are still symmetric, distal, and proximal, but the symptoms have not been going on for 8 weeks. They may come to our attention quicker because the patient has more weakness, but otherwise they look just like CIDP.

The next is a form of demyelinating neuropathies, which is really only distal, and we call that DADS, or distal acquired demyelinating symmetric neuropathy. In this example we're going to talk about DADS that does not have antibodies against myelin-associated glycoprotein, as this is one of the true variants of CIDP. These patients will have symmetric muscle weakness but will only be found distally: almost always in the legs, more than in the hands. They still have sensory involvement and they still have decreased reflexes, but the reflexes may only be found in the distribution of their weakness. So if they have weakness only in their ankles, their arm reflexes will be normal. And this is very different than the typical CIDP patient who will have diffuse areflexia.

The next category we call MADSAM, or Lewis-Sumner syndrome. MADSAM stands for multifocal acquired demyelinating sensory and motor neuropathy. So again, in contrast to CIDP, which has symmetric proximal and distal weakness, MADSAM patients have asymmetric motor and sensory involvement. And almost always, MADSAM is present in the hands more so than in the legs. They may also have decreased reflexes but only in the distribution of the weakness.

Now, all of these contrast with multifocal motor neuropathy, which is not truly a form of CIDP. Multifocal motor neuropathy is asymmetric, distal weakness, again almost always in the hands first, but then distally may involve the legs. But the key distinguishing feature here is that MMN has no sensory involvement. So if you see someone that has weakness in their arms and sensory loss in their arms, then that may be MADSAM, which is a form of CIDP. If you see someone that has pure motor weakness, that would not be considered a form of CIDP.

And probably the single most important take-home message from this table is that if you look at all forms of CIDP that I've shown you here, both typical, acute, DADS, or MADSAM, they all have sensory involvement. Multifocal motor neuropathy has no sensory involvement.

Now, when we look at the nerve conduction studies, these all vary a little bit in terms of what happens to the motor amplitudes, whether there's conduction block, and what happens to the sensory amplitudes. The key thing to keep in mind again is that multifocal motor neuropathy will have normal sensory amplitudes. Conduction block can be found in most of these disorders, but less so in DADS. And the other ones can all have involvement of conduction velocity, F-wave latencies, or distal latencies.

So, going back to our pattern recognition approach then, if you see a patient that has asymmetric distal weakness without sensory loss, this brings up a number of possible diagnostic considerations. But the key feature here when you see that patient is what's happening to their reflexes. If their reflexes are increased and we see upper motor neuron findings, then almost always that's going to turn out to be ALS. On the other hand, if they do not have upper motor neuron findings, then that may be a lower motor neuron form called primary muscular atrophy or it may be multifocal motor neuropathy, which might be treatable. So it's an important distinction to keep in mind for these patients.

When we talk about patients that have DADS, the distal acquired demyelinating symmetric neuropathy without MAG, which is a variant of CIDP, these symptoms progress relatively slowly: 6 months, 1 year, 2 years. And their changes may not necessarily be truly length dependent. They can have conduction block and they can have decreased reflexes. But like other forms of CIDP, DADS without MAG is responsive to first-line therapies.

Now, when it comes to distinguishing typical CIDP, and DADS without MAG from MAG neuropathy, the key thing to keep in mind is that patients with MAG neuropathy have a very characteristic clinical appearance. They have predominant distal sensory loss and usually a very profound sensory ataxia. So their balance is very poor and they don't have a lot of pain typically. Many of these patients will have a tremor in their hands, even if their weakness is predominantly in their legs. And most of these patients will have an IgM monoclonal protein and over half of them will have antibodies against MAG.

MADSAM or Lewis-Sumner syndrome, again is both motor and sensory. It's multifocal and it's a variant of CIDP that predominantly affects the arms, much more so than it affects the legs. It can pick off individual nerves, hence the name multifocal, and it's often stepwise, so they'll lose a radial nerve and then 6 months later they'll lose an ulnar nerve. When they lose that nerve it's going to be both motor and sensory involvement of that nerve. These patients will usually have conduction block in the distribution of the nerve that's affected. And the spinal fluid will be markedly elevated like in patients with CIDP and the majority of patients with MADSAM. And this is another distinguishing feature from patients with multifocal motor neuropathy, who less than 10% of the time will have elevations in their spinal fluid.

MADSAM, like typical forms of CIDP, respond to first-line treatments for CIDP. Because MADSAM and multifocal motor neuropathy both involve the hands, it's important to draw that distinction, as MADSAM is a variant of CIDP but multifocal motor neuropathy is not. Multifocal motor neuropathy is a purely motor syndrome and the main differential is really ALS. Multifocal motor neuropathy and MADSAM both share the fact that their symptoms begin in the hands and can both be stepwise.

We use labs to help diagnose multifocal motor neuropathy. Nerve conduction studies can show focal conduction block. But as I said previously, the spinal fluid is usually normal in MMN, but elevated in MADSAM. And about half of the patients with multifocal motor neuropathy will have IgM antibodies against GM1.

So what are the criteria to diagnose both the typical and the atypical forms of CIDP? Well the typical CIDP is progressive, symmetric, and proximal distal weakness, with sensory involvement, decreased reflexes, and symptoms that progress for more than 8 weeks. We can use lab evaluation, spinal fluid, and nerve biopsies to help diagnose typical CIDP.

Features that might suggest atypical CIDP are symptoms that are predominantly distal, symptoms that are asymmetric or focal, or symptoms that are pure motor and sensory. And then other factors to keep in mind are exclusionary criteria for CIDP. So, first and foremost, the typical distinction that becomes an issue is deciding between hereditary demyelinating neuropathies and an acquired demyelinating neuropathy like CIDP. And here you might look at family history, you might examine family members, or even do genetic testing. If there is an IgM paraprotein present, then there would also be exclusionary for a diagnosis of CIDP.

There are other diseases that can cause demyelination in addition to the inherited neuropathies and the inflammatory demyelinating neuropathies, and those will be discussed in future talks. So, keep these features in mind when you're trying to decide between typical and atypical CIDP, as well as when you're trying to decide when a patient's diagnosis might fall outside of the realm of CIDP.

Thank you for joining me for this lecture, and I hope it's helped elucidate the various forms of CIDP, both typical and atypical that you may see in your patients.

Transcript

Distinguishing CIDP

Todd Levine, MD, Neurology, reviews the important characteristics of typical and atypical CIDP and how to differentiate them from other neuropathies.

Hi. I'm Dr. Todd Levine. And I'm going to talk today about distinguishing typical and atypical CIDPs from other types of demyelinating neuropathies.

When we talk about CIDP, the key thing here is that this is one of the few treatable neuropathies that we diagnose in neuromuscular disorders. We diagnose CIDP based on very characteristic patterns of weakness and sensory loss, which involves proximal and distal muscles as well as decreased reflexes.

When we see that pattern, the 2 diagnostic criteria are going to be between GBS (or Guillain-Barré) and CIDP. The distinction is really the time. If it's less than 8 weeks, we call it Guillain-Barré, if it's more than 8 weeks we call it CIDP. So that seems pretty straightforward. But what do we if there's progressive weakness that is asymmetric? Or what if it's only in the arms? Or what if it's only distal?

Well, it doesn't mean that it's not a chronic inflammatory demyelinating neuropathy. It simply means that we need to consider the atypical forms of demyelinating neuropathies. And also important to recognize is that these atypical forms of demyelinating neuropathies may be responsive to therapy.

So, here's a nice table that outlines for you the different types of demyelinating neuropathies you may encounter in your clinical practice. The first, as I said, is CIDP. This has the very characteristic symmetric proximal and distal weakness as well as sensory involvement and decreased reflexes. These symptoms will have been present for more than 8 weeks to make a diagnosis of CIDP.

When we think about Guillain-Barré, we typically think about symptoms that progress over days. So we have a variant of CIDP that we call acute, where the symptoms are still symmetric, distal, and proximal, but the symptoms have not been going on for 8 weeks. They may come to our attention quicker because the patient has more weakness, but otherwise they look just like CIDP.

The next is a form of demyelinating neuropathies, which is really only distal, and we call that DADS, or distal acquired demyelinating symmetric neuropathy. In this example we're going to talk about DADS that does not have antibodies against myelin-associated glycoprotein, as this is one of the true variants of CIDP. These patients will have symmetric muscle weakness but will only be found distally: almost always in the legs, more than in the hands. They still have sensory involvement and they still have decreased reflexes, but the reflexes may only be found in the distribution of their weakness. So if they have weakness only in their ankles, their arm reflexes will be normal. And this is very different than the typical CIDP patient who will have diffuse areflexia.

The next category we call MADSAM, or Lewis-Sumner syndrome. MADSAM stands for multifocal acquired demyelinating sensory and motor neuropathy. So again, in contrast to CIDP, which has symmetric proximal and distal weakness, MADSAM patients have asymmetric motor and sensory involvement. And almost always, MADSAM is present in the hands more so than in the legs. They may also have decreased reflexes but only in the distribution of the weakness.

Now, all of these contrast with multifocal motor neuropathy, which is not truly a form of CIDP. Multifocal motor neuropathy is asymmetric, distal weakness, again almost always in the hands first, but then distally may involve the legs. But the key distinguishing feature here is that MMN has no sensory involvement. So if you see someone that has weakness in their arms and sensory loss in their arms, then that may be MADSAM, which is a form of CIDP. If you see someone that has pure motor weakness, that would not be considered a form of CIDP.

And probably the single most important take-home message from this table is that if you look at all forms of CIDP that I've shown you here, both typical, acute, DADS, or MADSAM, they all have sensory involvement. Multifocal motor neuropathy has no sensory involvement.

Now, when we look at the nerve conduction studies, these all vary a little bit in terms of what happens to the motor amplitudes, whether there's conduction block, and what happens to the sensory amplitudes. The key thing to keep in mind again is that multifocal motor neuropathy will have normal sensory amplitudes. Conduction block can be found in most of these disorders, but less so in DADS. And the other ones can all have involvement of conduction velocity, F-wave latencies, or distal latencies.

So, going back to our pattern recognition approach then, if you see a patient that has asymmetric distal weakness without sensory loss, this brings up a number of possible diagnostic considerations. But the key feature here when you see that patient is what's happening to their reflexes. If their reflexes are increased and we see upper motor neuron findings, then almost always that's going to turn out to be ALS. On the other hand, if they do not have upper motor neuron findings, then that may be a lower motor neuron form called primary muscular atrophy or it may be multifocal motor neuropathy, which might be treatable. So it's an important distinction to keep in mind for these patients.

When we talk about patients that have DADS, the distal acquired demyelinating symmetric neuropathy without MAG, which is a variant of CIDP, these symptoms progress relatively slowly: 6 months, 1 year, 2 years. And their changes may not necessarily be truly length dependent. They can have conduction block and they can have decreased reflexes. But like other forms of CIDP, DADS without MAG is responsive to first-line therapies.

Now, when it comes to distinguishing typical CIDP, and DADS without MAG from MAG neuropathy, the key thing to keep in mind is that patients with MAG neuropathy have a very characteristic clinical appearance. They have predominant distal sensory loss and usually a very profound sensory ataxia. So their balance is very poor and they don't have a lot of pain typically. Many of these patients will have a tremor in their hands, even if their weakness is predominantly in their legs. And most of these patients will have an IgM monoclonal protein and over half of them will have antibodies against MAG.

MADSAM or Lewis-Sumner syndrome, again is both motor and sensory. It's multifocal and it's a variant of CIDP that predominantly affects the arms, much more so than it affects the legs. It can pick off individual nerves, hence the name multifocal, and it's often stepwise, so they'll lose a radial nerve and then 6 months later they'll lose an ulnar nerve. When they lose that nerve it's going to be both motor and sensory involvement of that nerve. These patients will usually have conduction block in the distribution of the nerve that's affected. And the spinal fluid will be markedly elevated like in patients with CIDP and the majority of patients with MADSAM. And this is another distinguishing feature from patients with multifocal motor neuropathy, who less than 10% of the time will have elevations in their spinal fluid.

MADSAM, like typical forms of CIDP, respond to first-line treatments for CIDP. Because MADSAM and multifocal motor neuropathy both involve the hands, it's important to draw that distinction, as MADSAM is a variant of CIDP but multifocal motor neuropathy is not. Multifocal motor neuropathy is a purely motor syndrome and the main differential is really ALS. Multifocal motor neuropathy and MADSAM both share the fact that their symptoms begin in the hands and can both be stepwise.

We use labs to help diagnose multifocal motor neuropathy. Nerve conduction studies can show focal conduction block. But as I said previously, the spinal fluid is usually normal in MMN, but elevated in MADSAM. And about half of the patients with multifocal motor neuropathy will have IgM antibodies against GM1.

So what are the criteria to diagnose both the typical and the atypical forms of CIDP? Well the typical CIDP is progressive, symmetric, and proximal distal weakness, with sensory involvement, decreased reflexes, and symptoms that progress for more than 8 weeks. We can use lab evaluation, spinal fluid, and nerve biopsies to help diagnose typical CIDP.

Features that might suggest atypical CIDP are symptoms that are predominantly distal, symptoms that are asymmetric or focal, or symptoms that are pure motor and sensory. And then other factors to keep in mind are exclusionary criteria for CIDP. So, first and foremost, the typical distinction that becomes an issue is deciding between hereditary demyelinating neuropathies and an acquired demyelinating neuropathy like CIDP. And here you might look at family history, you might examine family members, or even do genetic testing. If there is an IgM paraprotein present, then there would also be exclusionary for a diagnosis of CIDP.

There are other diseases that can cause demyelination in addition to the inherited neuropathies and the inflammatory demyelinating neuropathies, and those will be discussed in future talks. So, keep these features in mind when you're trying to decide between typical and atypical CIDP, as well as when you're trying to decide when a patient's diagnosis might fall outside of the realm of CIDP.

Thank you for joining me for this lecture, and I hope it's helped elucidate the various forms of CIDP, both typical and atypical that you may see in your patients.


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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.

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

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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.

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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).

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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.

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