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Misdiagnosis of CIDP

Ken Gorson, MD, Neurology, gives an overview of misdiagnosis of CIDP, including diagnostic data and causes of misdiagnosis.

Transcript

Misdiagnosis of CIDP

Ken Gorson, MD, Neurology, gives an overview of misdiagnosis of CIDP, including diagnostic data and causes of misdiagnosis.

Hello. My name is Ken Gorson and I'm professor of neurology of Tufts University School of Medicine, and I'd like to give a brief presentation on the misdiagnosis of CIDP. In our neuromuscular community, certainly in the United States and perhaps even internationally, we have an enormous problem of misdiagnosis, overdiagnosis, of CIDP, and overtreatment of patients who are called CIDP and in fact don't have the disease.

I, along with several colleagues, wrote an editorial several years ago for a plea for a rigorous approach to establish the diagnosis and treatment of CIDP, to use consistent criteria so that when we make the diagnosis we're fairly confident about its accuracy, which can then guide proper therapy. Our own personal experience and that of many colleagues around the country has been that many people are misdiagnosed with CIDP when they're referred for second opinion. And many have accordingly been treated with prednisone, or plasma exchange, or years of IVIG infusions without any meaningful clinical benefit.

This anecdotal experience has now been demonstrated more quantitatively by a paper from Jeff Allen and Richard Lewis, termed "the CIDP diagnostic pitfalls and treatment benefit." And in that paper, Jeff Allen had reviewed 59 patients who were sent to him with a diagnosis of CIDP for a second opinion, and he found almost 50% of them were misdiagnosed.

He then de-identified the data and sent the data to Rich Lewis, who then reviewed the cases independently, and they concurred on which ones made criteria for CIDP and which ones didn't.

What was interesting was that over two-thirds of the patients who didn't have CIDP found subjectively that they had some sort of improvement, but there was no associated corollary in terms of objective clinical findings.

So these were some of the diagnoses that were called CIDP, and idiopathic axonal neuropathy was the most common such that the patient probably had a distal sensory motor pattern, a length-dependent neuropathy, and had no clear demyelinating features on EMG studies.

A substantial number of patients also had a hereditary neuropathy, and that certainly is understandable given the confusing nature of demyelination in nerve conduction studies for some of those patients.

And that substantial number of patients had diabetic neuropathy that were called CIDP. And you can see the other associated abnormalities there, that patients had chronic fatigue syndrome in some cases with normal neurological examinations. Other patients had a small fiber neuropathy with no evidence of weakness or areflexia, and even some patients had a primary muscle disease such as inclusion body myositis.

When looking further into the information, Jeff was able to distinguish the CIDP from the non-CIDP cases in trying to determine where were some of the pitfalls in making the diagnosis. And so what you can see is the bulk of the patients with CIDP fulfill nerve conduction criteria for the disease, whereas that was true for only 16% of patients who didn't have the disease.

The spinal fluid abnormalities were slightly more of a problem, knowing that about a third of patients called CIDP did have some CSF protein level elevation. And what you can see here is from a subjective perspective, the bulk of patients who had CIDP, as well as the majority who did not, still felt the treatment was beneficial. And this, I think, speaks to a placebo response or significant psychological component to the treatment.

So what were some of the issues in terms of establishing why these cases were misdiagnosed? Well, clinically, it turns out that most of the cases did not have typical CIDP. They were considered variance. They didn't have the classical pattern proximal distance weakness. They did not meet clinical criteria for EFNS/PNS criteria, and, in fact, some of the patients had a history of residual Guillain-Barré Syndrome with stable symptoms but were somehow felt to progress in a manner that represented CIDP and were treated, but of course did not improve.

There were a number of issues with electrodiagnostic studies. Frequently, the nerve conduction studies were misinterpreted with conduction philosophy slowing, called demyelinating, but it didn't really meet demyelinating criteria where the amplitudes were so reduced one could not be certain about an element of demyelination.

Often conduction slowing in sites of common entrapment such as the perineal nerve at the fibular head, or the ulner nerve at the groove, or median nerve at carpal tunnel were called demyelinating abnormalities and, of course, those abnormalities need to be excluded from establishing electrodiagnostic criteria for CIDP.

And then there were demyelinating abnormalities that were probably genuine seen in diabetics but those diabetic patients did not have the clinical phenotype of CIDP, but were thus labeled CIDP because of the demyelinating abnormalities. But we know that diabetics frequently have demyelinating changes on their nerve conduction studies.

In terms of the laboratory pitfall, there was an emphasis of ... an overemphasis of mild CSF protein elevation, and increasingly we can see this in diabetics and people with thyroid disease and a number of other conditions that have no relationship to CIDP. Thank you for your attention and I hope this information is helpful to you in managing your patients.

Transcript

Misdiagnosis of CIDP

Ken Gorson, MD, Neurology, gives an overview of misdiagnosis of CIDP, including diagnostic data and causes of misdiagnosis.

Hello. My name is Ken Gorson and I'm professor of neurology of Tufts University School of Medicine, and I'd like to give a brief presentation on the misdiagnosis of CIDP. In our neuromuscular community, certainly in the United States and perhaps even internationally, we have an enormous problem of misdiagnosis, overdiagnosis, of CIDP, and overtreatment of patients who are called CIDP and in fact don't have the disease.

I, along with several colleagues, wrote an editorial several years ago for a plea for a rigorous approach to establish the diagnosis and treatment of CIDP, to use consistent criteria so that when we make the diagnosis we're fairly confident about its accuracy, which can then guide proper therapy. Our own personal experience and that of many colleagues around the country has been that many people are misdiagnosed with CIDP when they're referred for second opinion. And many have accordingly been treated with prednisone, or plasma exchange, or years of IVIG infusions without any meaningful clinical benefit.

This anecdotal experience has now been demonstrated more quantitatively by a paper from Jeff Allen and Richard Lewis, termed "the CIDP diagnostic pitfalls and treatment benefit." And in that paper, Jeff Allen had reviewed 59 patients who were sent to him with a diagnosis of CIDP for a second opinion, and he found almost 50% of them were misdiagnosed.

He then de-identified the data and sent the data to Rich Lewis, who then reviewed the cases independently, and they concurred on which ones made criteria for CIDP and which ones didn't.

What was interesting was that over two-thirds of the patients who didn't have CIDP found subjectively that they had some sort of improvement, but there was no associated corollary in terms of objective clinical findings.

So these were some of the diagnoses that were called CIDP, and idiopathic axonal neuropathy was the most common such that the patient probably had a distal sensory motor pattern, a length-dependent neuropathy, and had no clear demyelinating features on EMG studies.

A substantial number of patients also had a hereditary neuropathy, and that certainly is understandable given the confusing nature of demyelination in nerve conduction studies for some of those patients.

And that substantial number of patients had diabetic neuropathy that were called CIDP. And you can see the other associated abnormalities there, that patients had chronic fatigue syndrome in some cases with normal neurological examinations. Other patients had a small fiber neuropathy with no evidence of weakness or areflexia, and even some patients had a primary muscle disease such as inclusion body myositis.

When looking further into the information, Jeff was able to distinguish the CIDP from the non-CIDP cases in trying to determine where were some of the pitfalls in making the diagnosis. And so what you can see is the bulk of the patients with CIDP fulfill nerve conduction criteria for the disease, whereas that was true for only 16% of patients who didn't have the disease.

The spinal fluid abnormalities were slightly more of a problem, knowing that about a third of patients called CIDP did have some CSF protein level elevation. And what you can see here is from a subjective perspective, the bulk of patients who had CIDP, as well as the majority who did not, still felt the treatment was beneficial. And this, I think, speaks to a placebo response or significant psychological component to the treatment.

So what were some of the issues in terms of establishing why these cases were misdiagnosed? Well, clinically, it turns out that most of the cases did not have typical CIDP. They were considered variance. They didn't have the classical pattern proximal distance weakness. They did not meet clinical criteria for EFNS/PNS criteria, and, in fact, some of the patients had a history of residual Guillain-Barré Syndrome with stable symptoms but were somehow felt to progress in a manner that represented CIDP and were treated, but of course did not improve.

There were a number of issues with electrodiagnostic studies. Frequently, the nerve conduction studies were misinterpreted with conduction philosophy slowing, called demyelinating, but it didn't really meet demyelinating criteria where the amplitudes were so reduced one could not be certain about an element of demyelination.

Often conduction slowing in sites of common entrapment such as the perineal nerve at the fibular head, or the ulner nerve at the groove, or median nerve at carpal tunnel were called demyelinating abnormalities and, of course, those abnormalities need to be excluded from establishing electrodiagnostic criteria for CIDP.

And then there were demyelinating abnormalities that were probably genuine seen in diabetics but those diabetic patients did not have the clinical phenotype of CIDP, but were thus labeled CIDP because of the demyelinating abnormalities. But we know that diabetics frequently have demyelinating changes on their nerve conduction studies.

In terms of the laboratory pitfall, there was an emphasis of ... an overemphasis of mild CSF protein elevation, and increasingly we can see this in diabetics and people with thyroid disease and a number of other conditions that have no relationship to CIDP. Thank you for your attention and I hope this information is helpful to you in managing 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.

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.

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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.

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

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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.

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