Activity Transcript

Colin Quinn, MD​: Hello, my name is Colin Quinn. I'm a neuromuscular neurologist here at the University of Pennsylvania. I appreciate the opportunity to speak with you all today.

We're going to spend about 25 minutes of actual talking, about a rare but important disease entity, multifocal motor neuropathy (MMN). Our goal today is to discuss the causes, symptoms, and diagnostic approach to MMN. MMN is pretty unusual, so it often goes unrecognized. And I think my sense of the audience is, that I would not expect most of you to go through the full diagnostic workup for MMN, but even if you recognize it, and can refer to a neuromuscular specialist, I think that's a huge step forward. If you are already a neuromuscular specialist, there are some helpful diagnostic tips here as well.

I am a clinician, and so, I'm inclined to think of everything in terms of patients I've seen or could see in clinic. So I think it's helpful to just start with a case. This is a 45-year-old man who has pure progressive weakness over the last 6 months. He's noticed weakness, particularly in his hands. He has difficulty extending his fingers and wrists. He describes cramps and fasciculations in his arm. He has absent reflexes in the arms, and normal in the legs. He has undergone a nerve conduction study, that shows asymmetric polyneuropathy with multiple areas of conduction block. Now there might be a lot on there that we're not sure about, and certainly, if we saw this person in clinic, and you weren't familiar with multifocal motor neuropathy, you might know something is wrong, but it's not necessarily clear what to do next. And part of the next half hour is to make sure that we get to that place.

So we first want to kind of define multifocal motor neuropathy, what is it? Well, it's a chronic immune mediated pure motor neuropathy. So the fact that it's immune mediated means we might be able to intervene upon it. So that's one of the important reasons to recognize it. It's progressive, which means that if you don't treat it, it will get worse over time. It's asymmetric generally, so that helps distinguish it from some other autoimmune neuropathies.

Nerve conduction studies have this somewhat unique feature called conduction block, in motor nerves only. Importantly, this can occur in entrapment sites outside of the setting of MMN. So carpal tunnel or ulnar neuropathy of the elbow. So these are conduction blocks that are occurring in unusual locations. We'll talk a little bit about the fact that this is an autoimmune disease, and what we do know about it, but we have a long way to go to understand them completely.

And it's a treatable disorder. We're not going to talk about treatment today, but it is a treatable disorder. And again, that's a very important reason to recognize it.

As I've mentioned, it's rare. So the estimated worldwide prevalence is less than 1 per 100,000 people. It's more common in men than women, and it's kind of a disease of young to middle-aged, so 80% of people are younger than 50 years old. Like anything, there are exceptions. So people can present younger and older, but we're commonly thinking of this diagnosis before 50 years of age.

So what are the common clinical features? Again, progressive asymmetric weakness. And this is a critical part, without sensory loss. Now sensory loss occurs for people in all sorts of scenarios. Someone might have diabetic neuropathy, but they also have MMN. So if someone has any sensory loss, I don't think that means you cross off MMN entirely. You have to kind of contextualize what is the proportion of weakness to sensory loss?

It tends to affect the arms more than the legs. About a third of people have leg weakness, it's usually distal. So if you see proximal leg weakness, that is unusual for men. Cramps and fasciculations are common, which often is part of the confusion, because a lot of people think that that's associated with amyotrophic lateral sclerosis (ALS), which it is, but can also be seen in MMN.

One distinguishing feature from ALS is that the deep tendon reflexes are reduced, or preserved in particularly unaffected areas. This contrasts with ALS, where hyperreflexia is very common.

So anytime you have a clinically based diagnosis, it's helpful to use core criteria. So there's the European Federation of Neurological Societies and peripheral nerve criteria, that were, I think, last updated in 2010, but are still actually quite helpful. These are the core criteria for diagnosis, clinical criteria. So they have clinical criteria and electrodiagnostic criteria. A slow step-wise, progressive focal asymmetrical limb weakness, involving more than 2 nerves for more than a month. So usually, this is a months to years progression process, not days to weeks. That should make us think of other things, which we'll talk about.

And no sensory signs or symptoms, though they leave a little wiggle for the fact that people can have some mild sensory disturbance, that typically isn't related to MMN. Although, in very severe MMN, some people have suggested that there might be minor sensory disturbance.

They also list supportive criteria, and many of these we've already touched on. So generally, MMN affects the upper limbs. If I see someone coming in, and they are a young man with progressive weakness of the hands, particularly the hand and wrist extensors, I'm definitely on the lookout for MMN.

Reflexes should be reduced or absent. Again, cramps and fasciculations are common. The muscles of the bulbar and respiratory regions are not affected, and that is a distinguishing feature from something like ALS.

And one thing that can be interesting is that, in longstanding disease, you can see atrophy, but one of the things that people notice early in MMN is that, you might have a muscle that's quite weak that isn't atrophied yet, because the axon is still connected to the muscle, it's just blocked from connecting to the muscle electrically.

And another supportive criteria is just, did they get better when you treated them? Because that's what we would generally expect with MMN.

They also include exclusion criteria. So if people have upper motor neuron signs, hyperreflexia, spasticity, increased tone, that is not expected in MMN. If there's bulbar involvement, so difficulty speaking or swallowing, or significant sensory impairment. And diffuse symmetric weakness that comes on rapidly usually makes us think of something like Guillain-Barré and not MMN.

So, what is conduction block? I think I've said it a couple times, and I think that this can be a term that neuromuscular people throw around a lot, but anyone who's not a neuromuscular neurologist might not know exactly what we're talking about. I think it's kind of helpful to think of the nerve like a wire. And the axon is like the metal in the wire. And then the wire is coated with myelin. If you are discussing conduction block, it refers the inability of an axon to send an electrical impulse through the axon to its target organ. This means that the axon is present, but something is not allowing the electrical signal to propagate.

This is different than, say, if you primarily injured and destroyed an axon, and nothing would, no electrical signal would travel down, because there's nothing to travel on. In the case of MMN, it appears that this block is occurring due to either direct problems at the node of Ranvier, which is basically, little gaps that occur between the myelin on peripheral nerves, that allow signal to jump from one node of Ranvier to the next, is what allows our nerves to conduct quickly.

Or injury near the node of Ranvier, injuring the myelin sheath. Most of this however, when we think about conduction block, we think about injury to myelin, where you've lost so much insulation on the nerve that it's conducting, conducting, conducting, and then it can no longer conduct to that area of high resistance. So conduction block, in a pathophysiologic sense, is failure to transmit an electrical impulse, the full length of the nerve.

But what does that, how do we determine conduction block? Because you can't see conduction block clinically. You see that someone is weak, right? But you can't actually see is this is an axonal process in which no electrical signal can be generated, vs a conduction block process, in which the signal is generated and traveling through the nerve, but can't pass through, due to an electrical block.

Well, fortunately we have nerve conduction studies, and this allows us to very clearly demonstrate what we see in multifocal motor neuropathy. This is an unusual study, because the way this is set up is that, you're recording both a motor response, over in the thumb region, and then a sensory response in the finger at the same time. And you're stimulating the nerve and recording both. And what you'll notice is that, at the most distal side of stimulation at A1, you get this R1 response. So you get this nice curve both in motor and sensory. And then you move the stimulator a little closer, and you see, you still get a response, both the R2 response and the motor and sensory.

But when you move what must be proximal to the area of block, suddenly the signal goes away. So the signal was there and then it's not there. You're not able to conduct. And this is what we call complete conduction block, in which there's no signal transmitted through the area of block. You can also have partial block, in which some signal gets through, and the response just gets smaller, which we're going to talk about in a second. But of note, you'll see this sensory response is completely fine. It's unaffected. So this is a pure motor conduction block that we can see electrophysiologically.

So it's a little in the weeds, I think, to talk about conduction block, and then really in the weeds to talk about temporal dispersion. But something we have to understand when we're talking about conduction block is that, the other thing that can reduce the height or amplitude of a response, is if this response gets spread out. And what I like to picture is, if you were trying to race an Olympic athlete, right? If you were only racing for 10 feet, an Olympic athlete might not beat you by very much. So in the top curve, on the right-hand side of the panel, there's a little bit of spread there, but not a lot. What you see as you run a longer distance, or as the nerve is traveling through the axon for a longer distance, that the widening of the response can become more dramatic. And this is particularly true in demyelinating diseases, in which some axons have lost more myelin than others. And so, some are traveling faster, some are traveling slower.

Well, importantly, that'll affect, if you stretch out the response, that'll affect the height of the response. So there's actually a kind of correction for this built into this. So these are the electrophysiologic criteria, as I mentioned earlier, they were clinical criteria. Well, the electrophysiologic criteria just account for the fact that to have definite MMN by electrophysiologic criteria, that curve, that amplitude response, has to be reduced by 50%, but that assumes, for definite disease, but that assumes that there's not less than 30% dispersion, which is an increase in the duration.

But as you have more temporal dispersion, you're less sure that there's actual conduction block there, and you actually need a more dramatic reduction in amplitude, even to get to probable conduction block. So I mean, I think that's quite a complicated issue. I don't think that most people who aren't doing nerve conduction studies should know about that. I think it's just important to understand that that is what they're talking about, when we talk about electrophysiologic criteria for MMN.

So as with anything, no one walks into clinic and says, "I have MMN." So it's very helpful to think about what else should be on your differential, when someone's presenting with painless progressive weakness? And I've included the things here that we most commonly think of. ALS is a very important disorder to consider. It causes progressive weakness, which can be in the limbs. Usually, people with ALS have hyperreflexia, and that would distinguish it from MMN.

Some people have only lower motor neuron disease. We call that progressive muscular atrophy (PMA), and that can be harder to distinguish from MMN, but we will check for GM1 antibodies, which, if they're high, suggests MMN over ALS. Although, a low titer can be seen in ALS. There are no conduction blocks seen on nerve conduction studies in ALS, so that should help us out. And if there's any bulbar or respiratory involvement, that would suggest that the answer is not MMN, but would be more concerning for ALS.

Another disorder that actually happens in young men, typically on the younger end, say teens to 20s, this progressive hand weakness sometimes often asymmetrically so, caused by monomelic amyotrophy, or Hirayama. So if a young person, say in their teens or 20s, comes in with this, we often get a magnetic resonance imaging (MRI) flexion, with the neck flexed, to look for the posterior longitudinal ligament kind of compressing the spine. Additionally, they would not have conduction block on nerve conduction studies.

So MMN is not the only autoimmune neuropathy. There are other things to consider such as Guillain-Barré, chronic inflammatory demyelinating polyneuropathy (CIDP), and vasculitis. I think, importantly, all 3 of those usually should have a sensory component to them. Sometimes there's more motor than sensory, and that can be when you're kind of vacillating between MMN and these. GBS, or Guillain-Barré syndrome, is acute onset and rapidly progressive. So that's someone who progresses over days to weeks. CIDP is chronic, but again, usually involves motor and sensory symptoms. Both of these are usually symmetric, as opposed to MMN, which is quite asymmetric.

There is a form of CIDP called multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), that can be asymmetric. And also, there's something called vasculitis. Vasculitis is an inflammatory disorder of the nerve. It can be part of a broader inflammatory disorder, or a primary nerve disorder. It's typically quite painful and MMN isn't. Again, all of these generally have sensory symptoms for the most part.

In the case of Guillain-Barré and CIDP, you usually do a spinal tap, and the protein level is quite high, while as the cell count is normal, that is what we call albumino cytological dissociation. And the men can have slight elevations in protein, but generally not as high as you'd see in Guillain-Barré or CIDP, which are often above 100.

It's much easier to test for genetic neuropathies than it used to be, so our threshold is lower. But usually, they have a longer time course. One of the genetic neuropathies that can kind of mimic MMN is something called hereditary neuropathy with liability pressure palsies. And they typically have a longer time course, like I said, and usually, it's occurring in areas of compression. Again, they usually have some sensory symptoms. Our threshold for genetic testing has gotten a lot lower, however, so it's common to do genetic testing.

GM1 antibodies. So you think this is an autoimmune disease, there must be an associated antibody. And there is, GM1 antibodies are the most commonly associated antibodies with MMN. GM1, the ganglia, is a ganglioside that's found in the central nervous system and in the peripheral nervous system. It's kind of located in the right spot, because it's concentrated in that node of Ranvier, and near the node of Ranvier. But it's still not entirely clear if MMN antibodies are pathogenic, or epiphenomenon. And they're not part of the diagnostic criteria, because it's an insensitive test, depending on which test you use, and which paper you look at. Let's just say about half of people with MMN have antibodies, which means half don't. And then, you can see kind of modest elevations in other diseases, such as ALS and CIDP.

So I'll be honest, and say we don't use a great deal of imaging here, but there are multiple papers that demonstrate that imaging studies may be helpful. MRI, in this case of the brachial plexus ultrasound, can show enlargement of nerves which might distinguish MMN from ALS, for example.

All right, so let's put it all together. We got to think about, we have a patient, they come in, we first think about the clinical criteria. Painless progressive weakness, upper extremity, usually a younger man, but not always. I do have women in my clinic who have MMN. We then are going to, in almost everyone or everyone, we're going to do nerve conduction studies, to look for conduction block. And we're going to do some blood testing, including the GM1 antibodies, although they're neither sensitive nor 100% specific. I often send muscle enzymes, just because in cases where people have painless progressive weakness, we're trying to exclude a myopathy. And so, if the creatine kinase is in the, above 1000, we start to think about whether or not that's a possibility.

Again, genetic testing has become much more common, due to the presence of sponsored testing, meaning we can often test people for free.

These are tests that we do less of the 3 tests. The first 3 tests are ones we do less frequently. So if you're concerned about CIDP, or certainly if someone's had a more rapid progression, and you're thinking about Guillain-Barré over again, days, weeks, you might perform a spinal tap, and a protein of 100, above 100, would suggest that CIDP was, or Guillain-Barré was more likely.

Again, imaging can be used. Nerve biopsy is pretty rarely used, not the test of choice. You can see some inflammation, but usually, we don't have to get there.

And then, one of my favorite things to do is, if you think it possibly is MMN, just treat them, and you see if there's an objective response to treatment.

Okay, so this is the study, the case that we initially looked at, that might have felt a little daunting 20 minutes ago. But my hope is, that by marching through all the things that we've discussed, we have a pretty good sense of what's going on with this gentleman. So, he's 45. 80% of patients are aged less than 50 at the onset of MMN. He has progressive weakness, particularly affecting the hands, and particularly affecting finger and wrist extension. He has conduction block, with no sensory block. So he has motor conduction block, and no block in the sensory nerves. That is a hallmark of MMN. And in this case, he actually has immunoglobulin M (IgM) antibodies, GM1 antibodies. Which while not always present, if it is present, particularly at a high titer, is very suggestive of MMN.

So that last patient, it seems pretty clear that they have MMN. We would probably treat them. We'd probably treat them with intravenous immunoglobulin (IVIG). We'll refer them to a neuromuscular specialist to reduce.

This next patient may look similar initially, but then, I think, we have to kind of consider other issues. So he's a 50-year-old gentleman, so similar age range. He has progressive weakness over 6 months, although his weakness is of the proximal legs, which is a little concerning. He has fasciculations in his arms and legs. Again, that can be seen in MMN, but can be seen in other diseases. And his reflexes are brisk, which that is concerning, because we don't expect to see brisk reflexes or increased reflexes in MMN.

His nerve conduction studies are normal. So there's no signs of conduction block or loss of myelin on his studies. And it's not listed here, but I'm guessing, that his needle study would show that there's been damage to the motor neurons going to his muscles. His cerebrospinal fluid (CSF) protein level was normal, although I can't say that based upon the story, I would necessarily have done a tap. If one was done, we would expect the protein level to be normal. So in this case, rather than MMN, we would say the diagnosis is ALS. And of course, the treatment course there is quite different.

So in conclusion, MMN is a progressive but treatable disease. So it's important to recognize you don't have to go through the full diagnostic arsenal yourself. You can refer to someone. But early diagnosis and treatment are essential to slow the progression. There are guidelines that are quite helpful to guide diagnosis and treatment. And as I said, neuromuscular experts are happy to see these patients, and try to help you if you feel that this is what might be going on.

Thank you very much for participating in this activity. To earn CME credit, there's a link here, or click on the earn credit icon.

All right. Well, I think that concludes this session. I very much appreciate everyone's time, and have a great day.

This transcript has not been copyedited.