Metabolic and Toxic Myelopathies with Dr. Kathryn Holroyd

Too much, or not enough? A wide range of nutritional deficiencies and toxic exposures may cause spinal cord dysfunction. To make matters even more confusing, the clinical presentations for these disorders may overlap.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Kathryn Holroyd, MD, an author of the article “Metabolic and Toxic Myelopathies,” in the Continuum February 2024 Spinal Cord Disorders issue.

Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.

Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut.

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Read the article: Metabolic and Toxic Myelopathies

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Transcript

 Full transcript available on Libsyn

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you’re not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Kathryn Holroyd on toxic metabolic myelopathies, which is part of the February Continuum issue on spinal cord disorders. Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut. Katie, thank you so much for being with us on the podcast, and thank you so much for your excellent article. It was filled with a lot of really great tips.

Dr Holroyd: Thank you - happy to be here.

Dr. Monteith: I want to start off with knowing, how did you gain expertise in spinal cord diseases?

Dr Holroyd: Yeah, I have a fairly diverse clinical background. My primary work now is as a neurohospitalist. But after residency training, I did two one-year fellowships: one in neuroimmunology and one in neuroinfectious diseases. I think, with those things together – you know, a lot of these, especially acute-onset myelopathies, tend to present inpatient for diagnosis – so, we see a lot of those in my hospital practice. Then, I think, specifically for toxic metabolic myelopathies - to identify these, you often have to know what it's not. So, my experience with some of the other autoimmune and infectious disorders really comes into play. Then finally, I kind of focused on global health work, which is why I primarily do neurohospitalist work - to allow for travel. I spent the past year working at a neuro HIV research site in Thailand, and I've done some work (mainly with education) in Zambia. But I've seen that, kind of, all how people's environments and local areas can really affect what disorders are more common, and I think it's really important to take that into account with especially this topic, as well.

Dr Monteith: Well, your work in global health could be a whole other area, a whole other podcast that I would really want to record with you. But let's start with, what did you seek to accomplish when writing your article?

Dr Holroyd: I think, when I was writing the article along with Dr. Berkowitz, the co-author, we really wanted to focus on things that would be clinically relevant, not just for neurologists, but for clinicians all over who may not have access to a subspecialist neurologist. We tried to focus less on metabolic pathways or disturbances and focus more on clinical pearls. I tried to think, “When I see these patients, what are the questions that I have that are not easily answerable from Google or UpToDate or a textbook? And how can we really use primary evidence to answer some of those questions? For example, what percent of patients with B₁₂ deficiency actually have an abnormal MRI? Those are the things we were asking ourselves and, hopefully, that we were able to answer through the article. We focused on three main categories of toxic metabolic myelopathies, as you can see from the work.

Dr Monteith: So, specifically, you've been writing about nutritional deficiencies, environmental and dietary toxins, drug abuse, medical illnesses, and oncological treatments. When you wrote your article and, comparing it to even, like, five or ten years ago, what has changed?

Dr Holroyd: It's a great question because, I think, even when I started writing the article, it's easy to feel like not much has changed in these particular disorders. But if you go deeper, I think that's not the case. The main ways in which things have changed, I think, on the nutritional front, is there’s been an increase in weight loss and weight-loss surgery, which is one of the main contributors to all nutritional deficiencies. The second main category is - in some of these toxic myelopathies - is the increasing rates of drug use, particularly heroin, which we talk about in detail in the article. Additionally, along those lines, with climate change - we often don't think about the way that climate change can really affect disorders that are related to nutrition or the way that certain foods are prepared, especially with increasing rates of drought, and that really relates to konzo. Finally, there's been great advances in the treatment of all sorts of cancers, particularly with immunologic therapy. The one immunologic complication we talk about is with immune checkpoint inhibitors, and I think there's been a huge increase in clinicians seeing these as complications of checkpoint inhibition. So, those are the three main ways that I think these have evolved in the past decade.

Dr Monteith: Great. You spoke about your interest in clinical pearls - can you describe some essential points that you wanted readers to take away with when diagnosing and managing patients that are presenting with myelopathies thought to be due to toxic or metabolic etiologies?

Dr Holroyd: Yeah, and a lot of these are so different it's hard to find overarching themes, but I think there are a few that come through in the article. The first is that a lot - not all, but a lot - of these are reversible. Diagnosing them early is important and can really make a difference in patient outcomes. The second is a real clinical principle of all neurology that I learned from Dr Berkowitz, my co-author - is that neurology really is time course and localization. Amongst these, I think it's important to look at the time course, whether it's acute or subacute, and the location in the cord, whether it's a subacute combined degeneration or a more dorsal-column-only-predominant myelopathy - that can help you narrow the differential. A couple other small things is that, overall, these toxic myelopathies tend to be more thoracic cord-predominant and affect the legs more than the arms. In the majority of cases, the MRI will actually be normal, which is a big difference from a lot of the other autoimmune or infectious myelopathies. I think those are some main takeaways. And finally, you really have to be careful when you're interpreting the lab tests and make sure that the clinical picture fits with the lab tests that you're measuring - for example, the vitamin or other cause - and make sure that you really are correlating the diagnosis with that test. Then, I think the cause of the deficiency will affect your treatment choice; whether you're dosing supplements orally or IV, and what dose you choose - those are the major things to take into account.

Dr Monteith: I really like what you say because, I think, as neurologists, we are always thinking about localization, localization, localization, but that time course also matters for a number of diseases.

Dr Holroyd: And to that point, I think the clinical diagnosis is particularly important in resource-limited settings, where advanced diagnostics, such as MRI or lumbar puncture, may not be available. For example, konzo - the WHO has very clear clinical criteria of how to define this disorder, given that in most of the regions where cassava root is primarily eaten, there are not these diagnostics. I think we can apply that globally or even in our own practice in areas of the US or other places - to really rely on your clinical judgment and the time course and the localization of the biolopathy[IG1] .

Dr Monteith: Yeah. What was that like when you were practicing in Zambia?

Dr Holroyd: I worked primarily with Dr Deanna Saylor, who is there funding and working with neurology residents, and we would see a wide variety of clinical cases but have very little real-time information. So, I really admire the residents who train and work in Zambia and have to make clinical decisions with very little information. In those settings, the history – so, asking people about recent ingestions, any drugs, diet at home, any exposures that might cause increased risk of these conditions - is very important. And sometimes you have to rely on empiric treatments, such as vitamin B₁₂, in cases where you may not be able to send for those tests - especially more specific tests, such as methylmalonic acid or homocysteine.

Dr Monteith: With your hospitalist experience, can you think of some cases, or like, one case that stands out that made you lose sleep at night, that you cracked the puzzle? Just so that we have this on our radar.

Dr Holroyd: Yeah, I think that there's some more unusual causes of toxic myelopathies. We saw a young woman who came in with a very acute, very severe myelopathy after studying for a test. She had a dorsal column-predominant hyperintensity, but all of her other diagnostics - lumbar puncture, everything else - was completely normal. We weren't really thinking of nutritional deficiencies because it was such an acute onset in such a young woman; we are really thinking this must be autoimmune or something else. And it actually came out that she had been ingesting whippets – so, inhaled nitric oxide, which came out a bit later in the history. And we checked for a B₁₂, which was very low, and it turned out to be a nitric oxide-induced vitamin B₁₂ myelopathy, which can be seen but is relatively rare and really stuck out in my mind. Thankfully, she made a full recovery with the supplementation of vitamin B₁₂ and cessation of drug use.

Dr Monteith: Wow, that is an impressive story. I'm glad that was on your mind and you figured it out.

Dr Holroyd: Thanks. Yeah - team effort.

Dr Monteith: What should we take away about nutritional deficiencies?

Dr Holroyd: Nutritional myelopathies – I think there are kind of the four main ones that we speak about in the article - vitamin B₁₂, folate, vitamin E and copper - and I think these really have more similarities than differences. They all present clinically very similarly, with the subacute combined degeneration of the cord (the dorsal columns and the corticospinal tracts) - that's going to give you, basically, spasticity and upper motor neuron signs, as well as sensory symptoms (loss of vibration and proprioception). Weakness can be a part of it, but that's usually a bit later in the course. Secondly, they all have similar diagnostics. As I mentioned, the MRI is going to be normal in over 50% of cases of all of these, but when it's abnormal, generally they'll be a T2/FLAIR hyperintensity in the dorsal column, and that will be the most common finding. Often, we don't have a lot of lumbar puncture data from these conditions, but generally, when lumbar puncture is performed, it will be relatively normal or noninflammatory. So, those are some of the similarities. Some of the differences are the risk factors. Vitamin B₁₂ - the risks are going to be mainly bariatric surgery, a vegan diet, or autoimmune pernicious anemia. Folate deficiency from nutritional causes is very rare, so that's usually going to come from someone with an increased folate requirement (sickle cell anemia or certain hematologic malignancies). Vitamin E often comes from malabsorption, as seen in cystic fibrosis, or abetalipoproteinemia, or hepatobiliary disorders. And then finally, copper generally comes from gastric surgeries or from excessive zinc intake, the classic example of being denture cream. I think one way to differentiate these is by looking at the person's risk factors. Finally, I think I tried to categorize them in my head in a few different ways with clues that might give you a specific clue. So, if someone comes in with a subacute myelopathy and they also have a macrocytic anemia, that would push you more towards vitamin B₁₂ or folate. However, if they're presenting with a myeloneuropathy (so, that's upper motor neuron signs) but also a peripheral neuropathy on exam, you might think more vitamin B₁₂ or copper. Then finally, if someone comes in with a myelopathy as well as ataxia, you might think more likely vitamin E deficiency. Those are some ways to categorize these that may otherwise appear very similar. But I think, at the end of the day, and someone with a subacute myelopathy and a nutritional risk factor, you'll end up sending all four of these blood tests to evaluate for appropriate treatment.

Dr Monteith: Well, let's move on to climate change. It's not often that we see climate change in a neurology article, but yet it's a thing that affects patients. Can you talk about konzo? I wasn't familiar with the term before reading your article, so thank you.

Dr Holroyd: Yeah, it's one of these that we debated - should we include this in the article (because it is relatively rare). But I think it is important to keep a global perspective. Konzo and lathyrism are the two nutritional toxic myelopathies that we talk about, but I'll just focus on konzo for brevity. This occurs in populations that rely on the cassava root for nutrition and generally occurs in times of drought, and that's because drought increases the cyanide content in the cassava root. After higher rates of ingestion, especially in people with protein malnutrition (so, a lot of children and young women), you can actually get a toxic myelopathy from cyanide. And the mechanism is not totally understood, but it tends to be quite acute onset, primarily with spasticity, impaired gait, and weakness. It will self-stabilize, but there really is no way to improve symptoms after it's occurred. It is relatively permanent. There really isn't a lot of data on MRI findings or CSF findings, but the few case reports that have been published, they tend to be normal. I think what's important is that there are very easy public health interventions to prevent these toxicities – so, by simply increasing the wetting time of the cassava root (so, soaking it for longer), you can reduce the cyanide content and really effectively prevent this condition. So, I think the big picture takeaway that can be connected to a lot of other neurologic disorders globally is that we need to be aware of how climate change will affect our environment - and dietary changes, environmental exposures - and focus on early public health interventions to prevent these. So, how can we help prevent these rather than treat them once they happen.

Dr Monteith: Are we seeing more of it, or is it just better diagnosed?

Dr Holroyd: There's not great public health data on the rates throughout areas. It (so far) has only been reported in the African continent. There have been increases and decreases in numbers based on, I think, both the climate (so, times of drought or worse, malnutrition), but also, I think the reporting - I think it fluctuates not only with the weather but also with the amount of ability to publish on cases. So, I don't think we have a good grasp on whether, globally, their rates of konzo or lathyrism are increasing or not.

Dr Monteith: Then, heroin - we have to talk about heroin, right? It's just simply remarkable that close to a million individuals in the US over the age of twelve use heroin in 2020. So, now you just have to talk to us about heroin myelopathy because it's something that we could see.

Dr Holroyd: Absolutely. It's not something that I think most clinicians are familiar with as the complication of heroin use. But I'm sure that heroin touches all of our lives as clinicians in any field. There are two types of myelopathy related to heroin. There can be a slower, subacute myelopathy with chronic use. But what's more common, actually, is in people who have a long history of heroin use and then abstain for days to weeks and then use heroin again. This causes a very acute-onset longitudinal myelopathy that often has MRI abnormalities as well and can affect both the cervical and the thoracic cord and be quite severe, affecting all modalities (sensation as well as weakness). The mechanism really is not well understood for this and, therefore, the treatments really aren't well understood, either. Some case reports have trialed IV corticosteroids, but really, there's an unclear benefit for this. Most people will regain some recovery of function, but often it's not full recovery, and some may have no recovery. I think the follow-up question to this is, as we see the composition of drugs change – so, now there's a predominance of fentanyl, actually, whereas most of these case reports were from more traditional heroin. I was actually looking into it - this isn't covered in the article - but there has been one case report in 2019 about fentanyl use in someone who primarily used heroin, was abstinent for eight days but continued to use fentanyl patch, and developed an acute-onset, severe cervical myelopathy quite similar to this traditional heroin myelopathy. So, it seems like fentanyl will probably still have the same risks, but it's slightly less well understood at this point.

Dr Monteith: And important also for chronic pain – just, like, poorly managed chronic pain that we might see, as you do during a hospital consultation.

Dr Holroyd: Absolutely, yes - especially because this was from a fentanyl patch itself.

Dr Monteith: Great. So, why don't you wrap up the most important clinical takeaways from your article?

Dr Holroyd: I think one takeaway that we haven't really focused on is that, actually, most of the primary literature on a lot of these topics, especially the nutritional topics, are twenty to thirty years old, and I think updated case series would really inform clinical practice. When it came down to it, actually - folate deficiency - we really only found four to five case reports in all the literature, which I really think is disproportionate to how much we learned about it in medical school and residency. I think, really, a better understanding of (in this era) what the prevalence of these disorders are, how they're presenting, and effective treatments, is really needed. I think that a lot of the exciting work will also occur in the field of oncology, with new treatments, with immune checkpoint inhibitors, and better understanding of how we can mitigate the risks of neurologic complications while still allowing patients the benefit of their cancer treatment. So, I think diagnosing toxic metabolic myelopathies early is very important. And in someone with a subacute, or even acute myelopathy without a clear cause, you should really delve into nutritional, drug use, demographics (kind of, where they're from) - all of these things that we often don't take time to do on history but might be more important in these cases because a lot of them are treatable - it's really important to get to those risk factors early on. I think that's what I would like clinicians to take away from our article.

Dr Monteith: Well, I think the article is fully packed with a lot of clinical tips - important tips - but a lot of public health relevance in a really special way that it was written. Any exciting breakthroughs that you're excited about or use of technologies to advance this area?

Dr Holroyd: Right now, there really aren't a lot of novel technologies in these areas, or diagnostics. I think, in the future, with some of the more cancer-related radiotherapies or intrathecal chemotherapies, the neuro-oncologists and oncologists will really be at the forefront of minimizing these toxicities. Again, I really think that's where a lot of the more advanced diagnostics will come into play. For the others, I think it's really about early diagnosis and public health awareness, especially as it relates to heroin myelopathy in the US.

Dr Monteith: Well, excellent, and thank you for being a part of that public health awareness. Thank you for being on the podcast.

Dr Holroyd: Thank you. Thank you so much for having me.

Dr Monteith: Thank you, Dr Holroyd for joining me on Continuum Audio. Again, today we've been interviewing Dr Kathryn Holroyd, whose article on toxic metabolic myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues, and thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.