CIDP Learning Zone
Transcript: Interview with Eduardo Nobile-Orazio
Eduardo Nobile-Orazio, MD, PhD
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It is very important to make the diagnosis as soon as possible, because if you delay the diagnosis, the patient might get worse, and the more they get worse, the problem will be that there will be accumulated disability, and not always we can solve this disability, we can improve. So the earlier we do the diagnosis, that is the most important thing, and so that is a very critical issue in this patient. You know, the diagnosis, we should think about this diagnosis and do all the tests we desire.
Not so many tests, just the ones which are necessary for the diagnosis, because as soon as you can make this diagnosis, you can. And if you don't make it, we see that we see patients that maybe have a delayed diagnosis even by years, and at that condition there is an accumulation of damage, axonal damage, and the recovery might not be complete. And also the responsive therapy might not be as good as if you, you know, like when you do early in the course of the disease. The diagnosis of CIDP, we have always to think when we have a neuropathy that progress over weeks and months. So it's different from Guillain-Barré, where you have a disease that progress and the patient gets to the maximum worsening within say a few days or one week, and there is a cutoff time for the diagnosis of one month. But sometimes we have patient that they come, and then you find out that the disease that they come to visit has been present, say, for weeks, has been progressive for a few months. So when you have, you know, I mean, I'm talking about initial diagnosis, so we always have to think about this diagnosis whenever you have a patient who has a progressive disease which is progressing over weeks or months. So that is the first thing.
So there are not so many disease which is an asymmetric disease, where a patient has a sensory impairment, paresthesia, loss of sensation, and they have weakness, and also if they have weakness, which is not just distant, so affecting the hand and foot, but also that they have a proximal weakness of the thigh. So they have difficulty in climbing the stairs, of course difficulty running, or difficulty in raising their arm. It's difficult, different from many neuropathy, which are mostly distal. This is a disease that affects muscle sensation proximally and distally, so that is something, we have to think about this. The average age of patients, you know, even there are 40, 50, but there are patients who have announced it in their twenties, in their thirties. So those are things that we have to consider. I think that the most important thing is to listen to the patients, and to making the right question, asking them. Sometimes you have patients who say, you know, "I came to the emergency room because I'm not able to walk in the fast." But did you start already? "You know, well, actually, I have to say that starting already, four months ago I started to have some weakness, but I didn't pay attention, so I didn't look." So that is the first thing that you have. Second, you know, not many patient has pain, but they have a numbness, a loss of sensation, weakness, difficulty in walking, sometimes difficulty in running. So it's is a super acuteness of the disease that make it, because most other neuropathy where you deal with, you know, diabetic neuropathy or other neuropathy.
Maybe in diabetic neuropathy, you have more pain than in CIDP, or rather they are more painful and they are more chronic. So there is not a special tip. I see the patient and make the diagnosis. You have to listen to the story, talk to the patient, and visiting the patient. And when you visiting the patient and you find that he have loss of reflex, that he has weakness, that he's also weak in his arm, and not adjusting the forearm, that is something that should raise your attention on this. And there is also something which may be more difficult. You know, patient who has just pure motor neuropathy, pure motor CIDP, these are even more difficult, because they have just motor. But also in this case, you expect that this patient has a more widespread distribution. This patient do not have cramp. Sometimes there is differential diagnosis with motor-neurone disease, but that is a different presentation, and the reflex usually in motor neurone disease is at risk. In this patient, they are reduced. The mandatory, test and the one which is most useful and you make a diagnosis in 90% or 80% of the case, is nerve conduction studies.
That is the test. If I have a suspicion of a patient who has this, the first things I do is ask for nerve conduction studies. I ask to do nerve conduction studies in the four limbs, or at least in two limbs, in one limb, one upper limb and one lower limb, and do sensory and motor, and do to have all the tests that say nerve conduction velocity, CMAP amplitude, temporal dispersion, all these parts of which are necessary. Relay to myography and say muscle examination is not that important, but nerve conduction studies are critical, and of course even if the guideline, the main point in the guideline are the clinical presentation and nerve conduction status. So if you have these two points with a disease that is progressing at least over two months with weakness and sensory impairment, which may be sometimes just sensory, sometimes just motor, but they're very minority, you know, the vary, and they are typical presentation of 10 to 15%, they are mostly sensory motor. Then the second point is nerve conduction studies. If you have diagnostics, nerve conduction studies, you find conduction block, reduce velocity, increase latency, or delay the F-wave latency, then you can make a diagnosis. We did a study where we show in the Italian database that despite the fact that 70% of, I mean, out of 450 when we look at the data, 350 did the lumbar puncture examination, and in about just 50 of them, they were helpful in supporting the diagnosis. In all the other patients, the diagnosis could be just made with clinical examination. History of the patient, clinical examination, and conduction studies. The main long term complication is the fact that the patient does not respond. There are a few percent, which is less than 10% of the patient, who do not respond, who do not improve, maybe who do not improve. Within all the therapy we have, we have about 85% of treated patients that improve with therapy.
So there is this 15% of the patient of course where they do not respond. So the first point, if the patient sometimes responds to treatment, it can be also helpful in confirming the diagnosis. In other ones, like anti-MAG neuropathy, but that is a very slow progressive. It's difficult to ascertain in this patient. But you know, in this patient we do not. So if you have a patient who do not respond to therapy, the first thing you have to think, well, I made a wrong diagnosis. So that is a point. Even though I would to say the most frequently used therapy are intravenous immunoglobulin steroids, and it's also known that if the patient does not respond to other, 50% of the patient who do not respond to one of the two will not the respond to the other therapy. But still, whenever you have a patient who does not respond to you, start to say, maybe I'm wrong, maybe I just want to see a patient, that this patient has CIDP, but B, he doesn't have it, so start to think again and reconsider the diagnosis. Over the long term, about complication. Well, the complication, say for steroids, you know, if the long use of steroids, so that's why. But the point is that steroids are easy to use.
You know, you give the pills, you don't have to see the patient, but they have some long-term side effects. Diabetes, agitation, Hypertrichosis, ulcers, but it's not all the country you can afford to use this, you know, to use immunoglobulin because they are expensive. So even in Italy, there are some place where the administration of the hospital prefer that you start with steroids, and if they don't work, we go with immunoglobulin. Immunoglobulin are much faster in their use. You know, you usually see an improvement within one or two months. If you don't respond to two months of therapy in immunoglobulin, it's very unlikely that the patient will respond. And also in this, you have to reconsider the diagnosis, but of course you know the lack of response doesn't exclude the diagnosis. The complication of IVIG are kind of very infrequent. In patients where the, at the beginning when we were using a lot and there was this willingness to reduce the administration of immunoglobulin, sometimes we were giving immunoglobulin faster than usual. And so there were some case of thrombosis, a few cases were reported with brain ischemia, I mean brain infarct, or patients who were at risk for arteriosclerosis or myocardial infarction, but these are very rare condition. Most of the patient, let's say 95% of the patient do not have complication because, and the other thing is if you have kidney disease or renal insufficiency, you should not give this therapy. So in the decision of the initial therapy, one of the things you have to consider, if the patient has any side adverse having contraindication to the use of IVIG. If you have thrombosis, something like that, any thrombophilic condition, you know, immunoglobulin might contraindicate. If you have renal insufficiency, immunoglobulin can be contraindicate. If you have diabetes, steroids are contraindicate. If you have liver pathology, immuno steroids might not be the first choice. So there is a number, if you have gastric ulcer of course, you know, because steroids are not indicated. If you have manic depressive, steroids are not indicated. So it is also important to always consider the patient as a whole, and not just the symptom of the disease and forget about the other disease. When it's talking about the patient, first you have to think about the diagnosis.
Then you think about the test you might do. And then you also have to think and ask about all the other concomitant pathology the patient might have, because that this will lead you in the decision of the therapy. I would say what we usually prefer to do if we have a young patient, or a patient with a recent onset, personally we prefer to start with immunoglobulin, because they are better tolerate and we can treat the patient on day service, but of course that cannot be a general rule, because as I mentioned before, immunoglobulin is much more expensive than steroids. Of course in Italy, the cost of one year of steroids will not reach 1000 euro. If you talk about immunoglobulin, we are talking about 40 to 50,000, at least 40 to 50,000 euros. So that is something you have to consider. And also if it depends, in Italy we have a social system. You know, the hospital, the social system pay. In other country, it might not be that condition. So if you do not have an insurance, you have to consider this point. But from a clinical point of view we prefer to use immunoglobulin. Of course immunoglobulin, at the beginning, the patient has to come to the clinic, and if you use steroids, with steroids, it takes longer to work. So if the patient has a recent disease, you know, they might have to wait three to four months before improving. With immunoglobulin, the improvement is faster, and so also you stop the progression of the disease from the beginning, but it's more expensive. When we discuss with the patient we do not decide what to give. We might have an idea, but it is our policy to discuss about the pros and cons. So for instance, I say, okay, you can take steroids, so you take pills, or you take intravenous, but usually you take pills so you don't have to come to the hospital, but if you take steroids, you have to take also gastro protector because of ulcer, because of insomnia, or other things, and check for other things. Or you might just come once a week, or twice a month, you know, to take immunoglobulin, and you do that, and then you go home and you do your normal life.
Then we have therapy we can change, you know, instead of giving intravenous, we can go to subcutaneous immunoglobulin, which you can be easily doing at home. But we usually, of course, you know, if we can afford both therapy, if the patient is in a place where they cannot afford, because immunoglobulin and now you have to do, immunoglobulin I don't have the money to pay for that. So it depends on who pays for the treatment. But more in general, I think it is crucial to explain the patient why you prefer to give a therapy that's better than the other, and then you share the decision within. It's not that you say, "You have to do this and that." No, that is not the policy, and even in the guideline, there is no written that one of the missing point in the European Academy and PNS guideline is it doesn't tell you how to start treatment. They say, well, you can choose one of the first treatments, which is IVIG steroids, and plasma change. Actually, we do not suggest plasma change as a starting therapy. It's inconvenient, the patient has to come every time to the hospital today. It is more invasive. And so that is something we just consider in patient who has not respond to IVIG and steroids. But between the two, you know, we have these two main points. Who pays for it, who covers the cost, and what is, you know, I would say that in Italy, most of the patients prefer to go to a intravenous immunoglobulin. It's very rare to have a patient who says, oh no, okay, I prefer to take the pills home, and not to take days off to come to the hospital. So there are things that you have to discuss with the patient. I think that if the patient, initially, we just do the therapy, and if the patient is more disabled, or already has some impairment, difficulty walking, we support and suggest to do some physiotherapy. And actually, when they're admitted, if we have to admit to the hospital, we do some physiotherapy for the patient for a certain period of time, and we recommend this. We do not suggest too many other activity for the patient. I think that physiotherapy is the only one they need when they are in a phase where they're disabled. Of course, you know, if the patient is severely impaired, then we have to look for other things. But basically, that is the point. We are pretty happy with the current treatment and we are not fully happy with the current treatment because as I mentioned to you before, another patient, but if we look at the Italian registry, we have that, excluding the patient that are so mild that you don't think it's necessary, to a patient with just sensory symptoms, and they're not sick, moderately affected, or they're mildly effected, you know, IVG or steroids, 85% or 90% of patients I treat respond well to them.
So I think we have it pretty good, but, you know, we have some problems. We have some patients who might become resistant to IVIG, so you have to increase. Patient might be bothered by the fact of coming to a hospital on a monthly basis, or you know, you might suggest them to take a subcutaneous immunoglobulin, so they should do that at home. Steroids, it's difficult to have patients taking steroids for a longer period of time, because of the side effect. There was people who was allergic to IVIG, and then we found that it was not IVIG, but the excipient that you have in IVIG. So that is something. So of course you have to monitor the patient at the beginning. That is a good thing. The good thing to do is to initially treat the patient at home. Steroids are widely used, so you should know what are the side effects. So if you take steroids, you know that the patient might not not sleep at night, might become hyperactive, or manic, or get ulcer, or if they have diabetes, that they might have a complication of diabetes. So these are all things you have to consider. But these are mainly related. It is not like a Guillain-Barre syndrome that you might be worried that you start to treat the patient, and the patient stop to breath because of the diseases still going on. We do not have these things in CIDP. You have the time to watch a patient and know the side effect of the therapy, and be ready to face them if they come out. The more main goal, or the new therapy, should be addressed to patient who fail to respond to conventional therapy, say IVIG, steroids, any case on a successful plasma change. But there are, I mean, according from the study they performed, they published, or that came out of congress, this new therapy seems to be promising. The only therapy who basically affected the immune system, and immunoglobulin, you know, they take under control the therapy, but they do not, you have to take this therapy until the patient going on remission. But they will need again to take the therapy, Steroids, you know we cannot use for a long period of time, but they are effective on the immune system. The sinus, the sort of immunosuppressive, they block the immune system. Plasma change just removes the antibodies. And other new therapies that are made are not curing the disease. They are blocking possibly the mechanism of complement.
They're facilitating the internal catabolic destruction of the immunoglobulin. But this does not prevent that the immune system is still active, still producing antibodies, they producing complement. So the patient is not cured. All these effective therapy are just treating the patient. The patient is treated because we block the mechanism of the patient. So I think, ideally, I think we should have an immunosuppressive therapy. We did a study where rituximab, unfortunately the results were not that exciting, but at least to have a therapy that blocks the immuno pathogenic mechanism at the basis, not, you know, the terminal step of this immuno pathogen, but block the immune system.
Most autoimmune disease just want to block the autoimmunity that causes the disease. So that is the most important needed, to find an immune suppressive therapy who blocks the immune system, so the patient with this therapy, they know that the disease is blocked. I know that there is another study they are doing, they're trying to do in United States, with the same molecule, which is another immunosuppressive. And I am, and most, you know, we are doing another studies in early onset CIDP, just to see whether this therapy might be effective early in disease, because it might be also important, because we saw in other disease, like myasthenia gravis, that if you treat the patient very early in the disease, you can stop the disease with rituximab. But if you do late on, you know, the immune system becomes sort of, you know, is more resistant to this therapy. So that is another part. I think that is where we should go.
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