How to diagnose and manage polyneuropathy

Clinicians may find diagnosing polyneuropathy challenging due to the vague and insidious onset of symptoms. Identifying signs consistent with polyneuropathy and determining which investigations to conduct and when to be concerned can be daunting.

Polyneuropathy involves simultaneous dysfunction of multiple peripheral nerves, with the most common form being distal symmetric polyneuropathy. Symptoms primarily occur distally, mainly at the bottom of the feet, and progress proximally. Sensory symptoms are more frequent than motor symptoms and signs. Patients with distal symmetric polyneuropathy may experience neuropathic pain, impairments in walking, and distal motor function, significantly impacting their quality of life.

Dr. Ario Mirian, a fifth-year neurology resident at the University of Western Ontario's Schulich School of Medicine and Dentistry, is the lead author of a review article in CMAJ entitled "Diagnosis and management of patients with polyneuropathy". In this episode, Dr. Mirian presents a practical approach to diagnosing and managing polyneuropathy while highlighting 'red flags' that should prompt clinicians to investigate potentially serious underlying causes, such as malignancy or vasculitis.

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Transcript

Dr. Mojola Omole:
Hi, I'm Mojola Omole.

Dr. Blair Bigham:
I'm Blair Bigham. This is a CMAJ podcast.

Dr. Mojola Omole:
Today, we are talking about polyneuropathy. I'm the first to have to admit that I had to Google what exactly polyneuropathy was because I was like, "What is this word? I know neuropathy, I know what poly is, but I've never seen them put together."

 After I Googled, and then when I read the article, it was really interesting because this is a very common complaint that even I have noticed that patients do talk about in terms of their symptomology. This paper really tried to help family physicians and clinicians have an algorithm when a patient comes in with distal symmetrical polyneuropathy. It talks about diagnosis, things to rule out such as red flags, and then what are some of the treatment options and just some caution around what expectations around treatment is, and then also, when to refer on to a neurologist, especially when there's no red flags.

 What was really important that I liked in the article is that it talked about some of the, not necessarily controversial, but there's no consensus around some of the studies that could be done for diagnosis. I thought that was really helpful. Blair, you didn't want to talk about this episode. Tell me why.

Dr. Blair Bigham:
I have vivid nightmares preparing for my Royal College exam of trying to memorize the polyneuropathy chapter of Rosen's Emergency Medicine.

Dr. Mojola Omole:
Oh, wow.

Dr. Blair Bigham:
It's pretty complicated. There's so many boxes. There's this algorithm which goes, and I think there's six different types, and they all have these weird acronyms that are similar. There's peripheral and symmetrical and asymmetrical. It just gets a little bit overwhelming. I feel like in the emergency department, I don't even know how to order the testing. I don't think I can get nerve conduction studies. I don't think I can get EMGs. It takes three months for a neurologist to see a patient I refer. I just feel like this is a very frustrating box for a lot of clinicians. The differential's kind of complicated. The workup is difficult to access. The specialists are also, in many places, difficult to access. I did not want to do this topic as an episode. Our podcast producer, Neil, thankfully said, "Well, wait a minute. Isn't that a great reason to do it?" I went, "Well, I don't know. I still don't want to do it." I was very hesitant. But I had been convinced that we will talk to an expert on this topic and see if we can make it make sense for people who encounter this in the office, or in the emergency department, or in the internal medicine clinic.

Dr. Mojola Omole:
Blair, I am going to be your Polyneuropathy Sherpa. I'm going to take you through this journey.

Dr. Blair Bigham:
All right. The person who is going to make polyneuropathy less overwhelming for us, I hope, is Dr. Ario Mirian. Dr. Mirian is a fifth year neurology resident at the University of Western Ontario's Schulich School of Medicine and Dentistry, and is on his way to Boston this summer for a neuromuscular fellowship. He's a lead author on the review article in CMAJ entitled “Diagnosis and management of patients with polyneuropathy”. Ario, thanks for joining us. Just a heads up, we have a big ask of you today. Help us understand polyneuropathy.

Dr. Ario Mirian:
Thank you guys for having me.

Dr. Blair Bigham:
Earlier, Ario, I was talking about how polyneuropathy is my nightmare exam question. I have all this stress that I remember from my fifth year of residency getting ready for my Royal College exam. There's tables, the tables are some of the ugliest tables in the textbook. Polyneuropathy, for people who don't see it every day, can feel a little overwhelming. Tell us why is that the case? What makes this so challenging?

Dr. Ario Mirian:
Well, I think first of all, when patients typically present with polyneuropathy, sometimes their symptoms can be vague. They can have pins and needles, paresthesias, weakness. It can start very insidiously, but is ultimately, for most patients, progressive. Sometimes the clinical symptoms aren't easily elicitable. I think the next biggest challenge is identifying what signs on the exam are consistent with polyneuropathy, and then the next step is what to do with that. What investigations to send off, what are tests that are high yield for patient presenting with polyneuropathy, and also, when to be worried. A lot of these symptoms overlap. There may not be clear understanding of when the more urgent management is necessary. I think all those things combined make it a pretty challenging clinical scenario, especially on first encounter for these patients.

Dr. Blair Bigham:
What motivated you to write this practice summary for people? What were you seeing in clinic that made you say, "Ah, man, we got to do this?"

Dr. Ario Mirian:
Well, I think as a neurology resident going through the approach to polyneuropathy is very daunting. There's so many etiologies. There's so much different algorithms and work-up that you can do, that it's hard to make sense of what's the practical approach. I think that was a motivating factor. Another personal story is that my wife is a family practitioner. She has many colleagues, of course, that practice family medicine. We were having dinner, and they were ranting to me about how confusing it is, how they don't know what to order, when should they be worried. It all lended to a potentially good review article that I could touch on those things.

Dr. Mojola Omole:
Ario, I have to admit that I had to Google what polyneuropathy is. My understanding is from Wikipedia. Can you explain... Just give the surgeon's primer to what a polyneuropathy is.

Dr. Ario Mirian:
Yeah. Polyneuropathy really refers to simultaneous involvement of multiple peripheral nerves. That's really at the core of what a polyneuropathy is, but there are different types of polyneuropathy, which I think confuse the matter. The one that we focused on in the review article is the most common. That's referred to as distal symmetric polyneuropathy. For those phenotypes or presentations, that's when symptoms and signs occur most distally, so at the bottom of the feet. They progress approximately and they're usually sensory predominant. The sensory symptoms are way more than motor symptoms and signs.

Dr. Mojola Omole:
What is the impact of polyneuropathy in patients?

Dr. Ario Mirian:
It could be quite significant. Because it's such a broad condition with different causes, I'll start with the most common for distal symmetric polyneuropathy. Many of us have encountered patients with diabetes, and that's the most common cause of a distal symmetric polyneuropathy. It could have a pretty significant impact on quality of life, mainly with neuropathic pain, but if it progresses enough, there can be impairments in walking and distal motor function in those patients. Then you have a whole subset of other patients that have more uncommon causes of polyneuropathy, whether that's vasculitis or a malignancy. That comes with a whole other host of debilitating symptoms.

Dr. Blair Bigham:
Let's start with the common stuff like the distal symmetrical polyneuropathies. What are some of the main takeaways that people need to be reassured that they're not missing something more serious? Are there red flags that would guide you away from one of those more, I'll use the term benign, maybe that's not the right word, diagnoses?

Dr. Ario Mirian:
Initially, patients really should have a symmetric, slowly progressive sensory predominant symptoms. That could be pins and needles, loss of sensation, burning pain starting in the toes, and that gradually moves up approximately. We say it's length dependent because it starts in the longest nerves first, which are in our legs, and then by the time it gets to the knees, we expect that the fingertips become involved in terms of symptoms because the nerve lengths are equivalent roughly at that point.

 Following that, or roughly around that stage, you expect some weakness in the toe and then in the ankle. It's a symmetric, really slowly progressive process that begins in the legs, moves proximally, and then by the time it hits close to the knees, it starts to affect the hands. That kind of captures most, or the phenotype of distal symmetric polyneuropathy, which helps recognize times that are inconsistent with that or may point to red flags for etiologies that need more urgent assessment.

 Any process that is very asymmetric would be inconsistent with a distal symmetric polyneuropathy.

Dr. Mojola Omole:
That would be a red flag.

Dr. Ario Mirian:
That would be a red flag. Symptoms and signs that are occurring quickly, so things are occurring very quickly, is less than eight weeks. That's generally a good timeline to suggest that this is not slowly progressive. This is in fact a subacute process. That hints to inflammatory causes or other more uncommon causes of a neuropathy. And those associated with pain. A patient may present with a wrist drop and then subsequently a foot drop. It's an asymmetric process that is happening acutely in terms of nerve involvement. That would be another major red flag.

 The last point that we made in the article was systemic signs that accompany the neuropathy. That can be a bit tricky, but ultimately, any constitutional symptoms that are new with polyneuropathy should be a red flag as well.

Dr. Blair Bigham:
I have two questions. The first is, what studies can confirm your diagnosis of a more benign process, like a symmetrical polyneuropathy that's flow onset and distal? When would you bother to order them? Is there any yield in doing that, say in someone who has well-known poorly controlled diabetes?

Dr. Ario Mirian:
Yeah, I guess I'll start with what tests to order for a patient presenting with distal symmetric polyneuropathy without red flags. There's consensus in the literature in terms of what exactly to test, but high yield tests for any patient would include CBC, liver function, in particular, vitamin B12 levels and serum protein electrophoresis. The last two are considered high yield and treatable in terms of potential causes for the polyneuropathy.

Dr. Blair Bigham:
I don't think I've ever ordered serum plasmapheresis. What are you looking for on that?

Dr. Ario Mirian:
What you'd most commonly would anticipate to see is you could see IgG or IgA elevation. That's really common with an axonal polyneuropathy. Again, a distal symmetric polyneuropathy that has axonal impairment that you find on studies. It's just a very common association. However, there are circumstances where patients may have an underlying hematologic malignancy that has a neuropathy as a consequence, and so it becomes an etiology you don't want to miss when evaluating patients with distal symmetric polyneuropathy because it can behave and look very similar to someone that has, for instance, either B12 as a cause, or another diabetic polyneuropathy.

Dr. Blair Bigham:
When are you doing additional tests on an urgent basis for a nerve conduction study, or an EMG, or something like that?

Dr. Ario Mirian:
Those red flags that I mentioned would warrant urgent nerve conduction studies in EMG. Asymmetry, rapid progression, systemic signs, painful neuropathy, and the other situation would be a traumatic cause, but I would say if someone presents with a distal symmetric polyneuropathy and you're following them and it's progressive and you're seeing motor impairments, that would be an easy indication to have them have studies. It's not only would you want diagnostic confirmation, but you would want the studies to see if they could identify any pattern that may suggest a treatable cause outside of the ones that we discuss as first-line.

Dr. Blair Bigham:
A lot of the time when we talk about this, it's hard for me to find tangible. Can you tell me a story about a great catch that you had where you found a disease quickly that affected management for someone? Or maybe you can describe a case where something was a delayed diagnosis and it was picked up finally and you were able to really help someone improve?

Dr. Ario Mirian:
Yeah, I think some of the more common situations in a neuromuscular clinic may be that having neuropathic symptoms that suggested a polyneuropathy both in the hands and feet. It seemed length dependent. There's some signs on exam that were consistent with that diagnosis, but it was through evaluating what medications they were on, and in this case, herbal supplements, one of which included a lot of vitamin B6, and they were toxic on that, and that was likely the culprit of their polyneuropathy, was a good example of just having an approach to the potential causes and just keeping an eye on medications or other reversible etiologies for this condition.

Dr. Mojola Omole:
What are other common drugs, and even supplements, that would be a risk factor for developing polyneuropathy?

Dr. Ario Mirian:
In terms of supplements, vitamin B6 toxicity or over supplementation is going to be a common culprit. That can result in different types of polyneuropathies, but polyneuropathy overall. Outside of chemotherapy, things like metronidazole, phenytoin, linezolid, even nitrofurantoin  can do it. There's a whole relatively long list, and if you look it up, it's overwhelmingly long, but in the article we listed at least some of the more commonly used medications that could result in a polyneuropathy. Just one thing that's noteworthy as well is that alcohol is a very common cause of polyneuropathy. That's another important thing to screen for because that could yield, at least an etiology that is not reversible in most circumstances, but at least you could stop the worsening.

Dr. Blair Bigham:
If you have a distal polyneuropathy and you're pretty confident that you've got this sort of symmetrical presentation, you're ready to call it, at what point would you start therapies for that? What's available to help people suffering from that?

Dr. Ario Mirian:
In terms of therapies overall, part of the first line testing is to identify something that you could at least treat. For the most part, patients may have slow improvements. In the case of vitamin B12 deficiency, those are things that can often help with the symptoms and then help with perhaps slow improvement. For polyneuropathy as a whole, directed treatment at the nerves and not at the underlying etiology, there's really nothing specifically. We have mainly symptomatic therapy.

Dr. Blair Bigham: 
What are some of the options for people who are suffering from pain, say from diabetic neuropathy? I see a lot of people on gabapentin. I see a lot of people on Lyrica. There's a big debate in the emergency department about whether or not emergency doctors should be using these types of medications for this sort of chronic nerve pain. What's your take on that?

Dr. Ario Mirian:
Overall, first line therapy could be divided into gabapentinoids, like you mentioned, SNRIs, sodium channel blockers like valproic acid or lamotrigine. For the most part, those are equivalent. The guideline indicates that these are equivalent options and that to align a patient's expectation for what is the anticipated benefit, they've highlighted a reduction in pain of roughly 30%. Roughly 40 or 50% of patients may get to that type of pain reduction.

Dr. Blair Bigham:
I assume that there's a bit of communication there with patients so that you set their expectations. Is there some additional hope there if, let's say, between the two of you, you were able to get better control of your diabetes? Can these symptoms get better with controlling the underlying condition, or is it like you're just going to have to live with this and maybe some people will have some improvement?

Dr. Ario Mirian:
It does become a matter of reducing the pain as much as possible. Some of these medications, as you know, come with side effect profile that isn't easy to tolerate. You want to get them on a regimen that works for them that maximizes quality of life, but for a majority of patients, they're not going to have complete remission of their neuropathic symptoms. Saying that upfront and giving that as an expectation, I think is helpful while you think of other potential contributors to their pain perceptions, mood and OSA and stuff like that.

Dr. Mojola Omole:
We're going to take a short break and then we'll be right back with Dr. Ario Mirian.

 Can we just kind of recap? Someone comes into the family physician's office and is complaining of distal polyneuropathy in their feet. You've ruled out all of the causes from medications, supplements. There's no red flags. It's not a quick progression under eight weeks. I feel like I'm in a test from this.

Dr. Blair Bigham:
This is an oral board, Mojola.

Dr. Mojola Omole:
There's no red flags. There's no constitutional symptoms. It is symmetrical on both sides. Did I miss anything in the red flag?

Dr. Ario Mirian:
No, I think that's pretty good. Non-painful.

Dr. Blair Bigham:
You get to keep your scalpel.

Dr. Mojola Omole:
No one could ever take... You got to pry it from dead hands. Then you order a CBC and then something funky called a serum electrophoresis.

Dr. Ario Mirian:
Yep. Yep.

Dr. Mojola Omole:
Not necessarily that we have to order an EMG?

Dr. Ario Mirian: 
It's not completely agreed upon whether to order studies for every patient, but it would be reasonable to have them completed for diagnostic confirmation. Yeah.

Dr. Mojola Omole:
Okay. So I decide to put one in. The next step is we get our results back and it's da da, polyneuropathy that is symmetrical and is distal. We talk to them that there's only going to be a 30% improvement with medication. Medication options are calcium channel blockers, as you said. That's literally all I remember. Oh, and then the gabapentinoids, and that's it.

Dr. Ario Mirian: 
Yeah, you have four categories for first line options. It would be the gabapentinoids, like gabapentin and pregabalin, tricyclic antidepressants, like amytriptyline and...

Dr. Mojola Omole:
Love those. I give them to patients for abdominal pain.

Dr. Ario Mirian:
Then SNRIs, and then I said voltage gated sodium blockers, which is valproic acid, lamotrigine. Those are less commonly used. Most people are going to use gabapentin, pregabalin, amitriptyline for these patients.

Dr. Mojola Omole:
I, as a great family doctor, do this. Outside of the red flags, when should I refer it to you?

Dr. Ario Mirian:
Yeah, that's a good question. Part of that would be whether, either on the referring physician's end or the patient's end, how much they would value diagnostic confirmation of the clinical diagnosis? Knowing that nerve conduction studies are not perfect test, they're not perfectly sensitive, so there are patients that can have mild symptoms in a normal nerve conduction study. It doesn't completely rule out that diagnosis. One would be if diagnostic confirmation is the objective. The second thing would be if the symptoms are progressive enough that they're resulting in disability despite, let's say, no red flags, and it's still gradually progressive. I think that's a very reasonable time to then refer to anyone practicing neuromuscular medicine to have those studies done in that circumstance. Not necessarily all patients, but we'd argue that a good subset of patients would be reasonable to have studies for.

Dr. Blair Bigham:
Ario, I think we're going to cut it off there. Thank you so much for joining us, that was super helpful. I am slightly less panicked now about having to be able to...

Dr. Mojola Omole:
I think I did a good recap. I think I could pass some sort of board exam.

Dr. Ario Mirian:
Yeah. Hopefully I answered the questions with...

Dr. Mojola Omole:
You did. I learned.

Dr. Ario Mirian:
... some sort of clarity around the topic. I know there's a lot of grays in it, so I think that makes it a bit challenging.

Dr. Mojola Omole:
Well, I think what I learned is... What I've learned so far in neurology is that you guys don't really go for cure, you just go for better. And better for you... Because we did our migraine, it was the same thing. They're like, people just have only a few headaches that week. I'm like, what?

Dr. Ario Mirian: Yeah.

Dr. Mojola Omole: That's hell.

Dr. Ario Mirian:
Yeah, I would say vast... Yeah, you're right. Vast majority of neurological conditions like complete remission is very hard to find. It's mainly about symptomatic control or slowing progression, stuff like that.

Dr. Blair Bigham:
And prevention, I guess, at the end of the day. If once you have your peripheral neuropathy because you never had good access to insulin therapy, you never had good access to all those things that keep diabetes at bay, it really is sort of a sad permanent development.

Dr. Ario Mirian:
Yeah. No, totally.

Dr. Blair Bigham:
It's so interesting. Ario, thank you so much.

Dr. Mojola Omole:
Thank you so much for joining us.

Dr. Ario Mirian:
Oh, thanks for having me. Yeah.

Dr. Blair Bigham:
Dr. Ario Mirian is a fifth year neurology resident at Western University.

Dr. Mojola Omole:
Blair, we just finished talking to Ario. How are you feeling now about the topic, and also as me being your Sherpa?

Dr. Blair Bigham:
I'm a little embarrassed because you just totally rocked the oral board question, and I still don't know that I could. I guess, in some ways, this has been a helpful exercise for me. Distal symmetrical polyneuropathy, that is its own entity. That is something that a lot of people suffer from. We see those people, whether you're a surgeon, an emergency doctor, a family doctor, a rheumatologist, a neurologist, you're seeing those patients because that is a chronic disease that isn't getting any better. I think that the framework around that, thinking about B6 toxicity and chemotherapy, and really impressing upon how important diabetes glycemic control is, these types of things are a nice foundation for me to build on. I'm still though a little bit nervous about those people with red flags, with asymmetric presentations.

Dr. Mojola Omole:
Sorry, why? If it is a red flag, refer them.

Dr. Blair Bigham:
Well, yeah. If it's a red flag, you just call a neurologist, but it's not easy just to get neurology access. I work in a really large hospital. We don't have neurology after 4:00 PM. We can't even call them. Referrals can take many weeks or months to be seen. I just feel like there's still this void where primary care practitioners, family doctors, emergency doctors, are left trying to scramble to do a bit of a workup so that by the time they get to the neurologist, they can hopefully arrive at a diagnosis and hopefully start some therapy.

Dr. Mojola Omole:
I guess to me, that's a systems issue. If there's no access to an urgent neurology consult after hours, even if it's for the next day, that there's a clinic, a rapid assessment clinic that they could be seen at the next day.

 I feel better. I kind of know what it is now.

Dr. Blair Bigham:
Well, now we know more about-

Dr. Mojola Omole:
I  really think it matters.

Dr. Blair Bigham:
... distal symmetrical polyneuropathy, but there's just so many polyneuropathies.

Dr. Mojola Omole:
Well, you know what? We start one poly at a time. It's like a polyamorous relationship. Just one person at a time.

Dr. Blair Bigham:
Thanks Polyneuropathy Sherpa.

Dr. Mojola Omole:
You're welcome.

Dr. Blair Bigham:
Thanks for joining us. That's it for this week on the CMAJ Podcast. Please remember to and share our podcast wherever it is you download your audio. It goes a long way to helping us engage people and get the message out. I'm Blair Bigham.

Dr. Mojola Omole:
I'm Mojola Omole. Until next time, be well.