Article

Not everyone with AD treated with dupilumab gets clear or almost clear in clinical trials. The study by Cork and colleagues looked to see whether those patients who did not get to clear or almost clear were still having clinically meaningful improvement. To test this, the investigators looked at patients who still had mild or worse disease and then at the proportion of those patients at week 16 who achieved a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms, and quality of life: ≥50% improvement in Eczema Area and Severity Index or ≥4-point reduction in worst scratch/itch numerical rating scale, or ≥6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients, both clinically and statistically significantly more, receiving dupilumab vs placebo achieved the composite endpoint (77.7% vs 24.6%; P < .0001). 

The "success rate" reported in clinical trials underestimates how often patients can be successfully treated with dupilumab. I don't need a complicated composite outcome to know this. I just use the standardized 2-point Patient Global Assessment measure. I ask patients, "How are you doing?" If they say "Great," that's success. If they say, "Not so good," that's failure. I think about 80% of patients with AD treated with dupilumab have success based on this standard.

Hand dermatitis can be quite resistant to treatment. Even making a diagnosis can be challenging, as psoriasis and dermatitis of the hands looks so similar to me (and when I used to send biopsies and ask the pathologist whether it's dermatitis or psoriasis, invariably the dermatopathologist responded "yes"). The study by Kamphuis and colleagues examined the efficacy of abrocitinib in just over 100 patients with hand eczema who were enrolled in the BioDay registry. Such registries are very helpful for assessing real-world results. The drug seemed reasonably successful, with only about 30% discontinuing treatment. About two thirds of the discontinuations were due to inefficacy and about one third to an adverse event.

I think there's real value in prescribing the treatments patients want. Studies like the one by Ameen and colleagues, using a discrete-choice methodology, allows one to determine patients' average preferences. In this study, the discrete-choice approach found that patients prefer safety over other attributes. Some years ago, my colleagues and I queried patients to get a sense of their quantitative preferences for different treatments. Our study also found that patients preferred safety over other attributes. However, when we asked them to choose among different treatment options, they didn't choose the safest one. I think they believe that they prefer safety, but I'm not sure they really do. In any case, the average preference of the entire population of people with AD isn't really all that important when we've got just one patient sitting in front of us. It's that particular patient's preference that should drive the treatment plan.

Not everyone with AD treated with dupilumab gets clear or almost clear in clinical trials. The study by Cork and colleagues looked to see whether those patients who did not get to clear or almost clear were still having clinically meaningful improvement. To test this, the investigators looked at patients who still had mild or worse disease and then at the proportion of those patients at week 16 who achieved a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms, and quality of life: ≥50% improvement in Eczema Area and Severity Index or ≥4-point reduction in worst scratch/itch numerical rating scale, or ≥6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients, both clinically and statistically significantly more, receiving dupilumab vs placebo achieved the composite endpoint (77.7% vs 24.6%; P < .0001). 

The "success rate" reported in clinical trials underestimates how often patients can be successfully treated with dupilumab. I don't need a complicated composite outcome to know this. I just use the standardized 2-point Patient Global Assessment measure. I ask patients, "How are you doing?" If they say "Great," that's success. If they say, "Not so good," that's failure. I think about 80% of patients with AD treated with dupilumab have success based on this standard.

Hand dermatitis can be quite resistant to treatment. Even making a diagnosis can be challenging, as psoriasis and dermatitis of the hands looks so similar to me (and when I used to send biopsies and ask the pathologist whether it's dermatitis or psoriasis, invariably the dermatopathologist responded "yes"). The study by Kamphuis and colleagues examined the efficacy of abrocitinib in just over 100 patients with hand eczema who were enrolled in the BioDay registry. Such registries are very helpful for assessing real-world results. The drug seemed reasonably successful, with only about 30% discontinuing treatment. About two thirds of the discontinuations were due to inefficacy and about one third to an adverse event.

I think there's real value in prescribing the treatments patients want. Studies like the one by Ameen and colleagues, using a discrete-choice methodology, allows one to determine patients' average preferences. In this study, the discrete-choice approach found that patients prefer safety over other attributes. Some years ago, my colleagues and I queried patients to get a sense of their quantitative preferences for different treatments. Our study also found that patients preferred safety over other attributes. However, when we asked them to choose among different treatment options, they didn't choose the safest one. I think they believe that they prefer safety, but I'm not sure they really do. In any case, the average preference of the entire population of people with AD isn't really all that important when we've got just one patient sitting in front of us. It's that particular patient's preference that should drive the treatment plan.

Not everyone with AD treated with dupilumab gets clear or almost clear in clinical trials. The study by Cork and colleagues looked to see whether those patients who did not get to clear or almost clear were still having clinically meaningful improvement. To test this, the investigators looked at patients who still had mild or worse disease and then at the proportion of those patients at week 16 who achieved a composite endpoint encompassing clinically meaningful changes in AD signs, symptoms, and quality of life: ≥50% improvement in Eczema Area and Severity Index or ≥4-point reduction in worst scratch/itch numerical rating scale, or ≥6-point reduction in Children's Dermatology Life Quality Index/Infants' Dermatitis Quality of Life Index. Significantly more patients, both clinically and statistically significantly more, receiving dupilumab vs placebo achieved the composite endpoint (77.7% vs 24.6%; P < .0001). 

The "success rate" reported in clinical trials underestimates how often patients can be successfully treated with dupilumab. I don't need a complicated composite outcome to know this. I just use the standardized 2-point Patient Global Assessment measure. I ask patients, "How are you doing?" If they say "Great," that's success. If they say, "Not so good," that's failure. I think about 80% of patients with AD treated with dupilumab have success based on this standard.

Hand dermatitis can be quite resistant to treatment. Even making a diagnosis can be challenging, as psoriasis and dermatitis of the hands looks so similar to me (and when I used to send biopsies and ask the pathologist whether it's dermatitis or psoriasis, invariably the dermatopathologist responded "yes"). The study by Kamphuis and colleagues examined the efficacy of abrocitinib in just over 100 patients with hand eczema who were enrolled in the BioDay registry. Such registries are very helpful for assessing real-world results. The drug seemed reasonably successful, with only about 30% discontinuing treatment. About two thirds of the discontinuations were due to inefficacy and about one third to an adverse event.

I think there's real value in prescribing the treatments patients want. Studies like the one by Ameen and colleagues, using a discrete-choice methodology, allows one to determine patients' average preferences. In this study, the discrete-choice approach found that patients prefer safety over other attributes. Some years ago, my colleagues and I queried patients to get a sense of their quantitative preferences for different treatments. Our study also found that patients preferred safety over other attributes. However, when we asked them to choose among different treatment options, they didn't choose the safest one. I think they believe that they prefer safety, but I'm not sure they really do. In any case, the average preference of the entire population of people with AD isn't really all that important when we've got just one patient sitting in front of us. It's that particular patient's preference that should drive the treatment plan.

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Nicholas J. Silvestri, MD: Hi there. My name is Dr Nick Silvestri, and I'm at the University of Buffalo. Today, I'd like to answer a few questions that I commonly receive from colleagues about the treatment of myasthenia gravis. As you know, over the past several years, we've had many new treatments approved to treat myasthenia gravis. One of the common questions that I get is, how do these new treatments fit into my treatment paradigm? 

First and foremost, I'd like to say that we've been very successful at treating myasthenia gravis for many years. The mainstay of therapy has typically been acetylcholinesterase inhibitors, corticosteroids, and nonsteroidal immunosuppressants. These medicines by and large have helped control the disease in many, but maybe not all, patients. 

The good news about these treatments is they're very efficacious, and as I said, they are able to treat most patients with myasthenia gravis. But the bad news on these medications is that they can have some serious short- and long-term consequences. So as I think about the treatment paradigm right now in 2024 and treating patients with myasthenia gravis, I typically start with prednisone or corticosteroids and transition patients onto an oral immunosuppressant. 

But because it takes about a year for those oral immunosuppressants to become effective, I'm typically using steroids as a bridge. The goal, really, is to have patients on an oral immunosuppressant alone at the 1-year mark or thereabouts so that we don't have patients on steroids. 

When it comes to the new therapies, one of the things that I'm doing is I'm using them, if a patient does not respond to an oral immunosuppressant or in situations where patients have medical comorbidities that make me not want to use steroids or use steroids at high doses. 

Specifically, FcRn antagonists are often used as next-line therapy after an oral immunosuppressant fails or if I don't feel comfortable using prednisone at the outset and possibly bringing the patient to the oral immunosuppressant. The rationale behind this is that these medications are effective. They've been shown to be effective in clinical trials. They work fairly quickly, usually within 2-4 weeks. They're convenient for patients. And they have a pretty good safety profile. 

The major side effects with the FcRn antagonists tend to be an increased risk for infection, which is true for most medications used to treat myasthenia gravis. One is associated with headache. And they can be associated with joint pains and infusion issues as well. But by and large, they are well tolerated. So again, if a patient is not responding to an oral immunosuppressant or it has toxicity or side effects, or I'm leery of using prednisone, I'll typically use an FcRn antagonist. 

The other main class of medications is complement inhibitors. There are three complement inhibitors approved to use in the United States. Complement inhibitors are also very effective medications. I've used them with success in a number of patients, and I think that the paradigm is shifting. 

I've used complement inhibitors, as with the FcRn antagonists, in patients who aren't responding to the first line of therapy or if they have toxicity. I've also used complement inhibitors in instances where patients have not responded very robustly to FcRn antagonists, which thankfully is the minority of patients, but it's worth noting. 

I view the treatment paradigm for 2024 as oral immunosuppressant first, then FcRn antagonist next, and then complement inhibitor next. But to be truthful, we don't have head-to-head comparisons right now. What works for one patient may not work for another. In myasthenia gravis, it would be great to have biomarkers that allow us to predict who would respond to what form of therapy better. 

In other words, it would be great to be able to send off a test to know whether a patient would respond to an oral immunosuppressant better than perhaps to one of the newer therapies, or whether a patient would respond to an FcRn antagonist better than a complement inhibitor or vice versa. That's really one of the gold standards or holy grails in the treatment of myasthenia gravis. 

Another thing that comes up in relation to the first question has to do with, what patient characteristics do I keep in mind when selecting therapies? There's a couple of things. I think that first and foremost, many of our patients with myasthenia gravis are women of childbearing age. So we want to be mindful that many pregnancies are not planned, and be careful when we're choosing therapies that might have a role or might be deleterious to fetuses. 

This is particularly true with oral immunosuppressants, many of which are contraindicated in pregnancy. But medical comorbidities in general are helpful to understand. Again, using the corticosteroid example, in patients with high blood pressure, diabetes, or osteoporosis, I'm very leery about corticosteroids and may use one of the newer therapies earlier on. 

Another aspect is patient preference. We have oral therapies, we have intravenous therapies, we now have subcutaneous therapies. Route of administration is very important to consider as well, not only for patient comfort — some patients may prefer intravenous routes of administration vs subcutaneous — but also for patient convenience. 

Many of our patients with myasthenia gravis have very busy lives, with full-time jobs and other responsibilities, such as parenting or taking care of parents that are maybe older in age. So I think that tolerability and convenience are very important to getting patients the therapies they need and allowing patients the flexibility and convenience to be able to live their lives as well. 

I hope this was helpful to you. I look forward to speaking with you again at some point in the very near future. Stay well. 

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

Andrew Solomon, MD, from the University of Vermont in Burlington, highlights key findings presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024.

Dr Solomon begins by discussing a study on the potential benefits of antipyretics to manage overheating associated with exercise, a common symptom among MS patients. Results showed that MS patients who took aspirin or acetaminophen had less increase in body temperature after a maximal exercise test than those who took placebo.

He next reports on a study that examined whether a combination of two imaging biomarkers specific for MS, namely the central vein sign and the paramagnetic rim lesion, could improve diagnostic specificity. This study found that the presence of at least one of the signs contributed to improved diagnosis.

Dr Solomon then discusses a post hoc analysis of the ULTIMATE I and II trials which reconsidered how to confirm relapses of MS. The study found that follow-up MRI could distinguish relapse from pseudoexacerbations.

Finally, he reports on a study that examined the feasibility and tolerability of low-field brain MRI in MS. The equipment is smaller, portable, and more cost-effective than standard MRI and has high acceptability from patients. Although the precision of these devices needs further testing, Dr Solomon suggests that portable MRI could make MS diagnosis and monitoring available to broader populations.

--

Andrew J. Solomon, MD, Professor, Neurological Sciences, Larner College of Medicine, University of Vermont; Division Chief, Multiple Sclerosis, University Health Center, Burlington, Vermont

Andrew J. Solomon, MD, has disclosed the following relevant financial relationships: Received research grant from: Bristol Myers Squibb

Over the past two decades, the therapeutic landscape for psoriatic arthritis (PsA) has been transformed by the introduction of more than a dozen targeted therapies.

For most patients with active PsA, a tumor necrosis factor (TNF) inhibitor is recommended as the first-line biologic therapy. But some patients do not achieve an adequate response to TNF inhibitors or are intolerant to these therapies.

Choosing the right treatment after failure of the first biologic requires that clinicians consider several factors. Dr Atul Deodhar, of Oregon Health & Science University, discusses guidelines from the American College of Rheumatology/National Psoriasis Foundation and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) for appropriate treatment strategies.

He also discusses factors critical to the optimal choice of the next therapy, such as the domains of disease activity, patient comorbidities, and whether the biologic's failure was primary or secondary.

Aside from choosing a new biologic, Dr Deodhar notes that there are other options to intensify the effect of the initial biologic. He says the clinician and patient may consider increasing the dose and frequency of the initial biologic medication or moving to a combination therapy by adding another drug, such as methotrexate.

--

Atul A. Deodhar, MD, Professor of Medicine, Division of Arthritis and Rheumatic Diseases, School of Medicine, Oregon Health & Science University; Medical Director, Rheumatology Clinics, OHSU Hospital, Portland, Oregon

Atul A. Deodhar, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant, for: Bristol Myers Squibb; Eli Lilly; Janssen; MoonLake; Novartis; Pfizer; UCB

Serve(d) as a speaker for: Eli Lilly; Novartis; Pfizer; UCB

Received research grant from: AbbVie; Bristol Myers Squibb; Celgene; Janssen; MoonLake; Novartis; Pfizer; UCB

Received income in an amount equal to or greater than $250 from: Bristol Myers Squibb; Eli Lilly; Janssen; Novartis; Pfizer; Samsung Bioepis; UCB

Over the past two decades, the therapeutic landscape for psoriatic arthritis (PsA) has been transformed by the introduction of more than a dozen targeted therapies.

For most patients with active PsA, a tumor necrosis factor (TNF) inhibitor is recommended as the first-line biologic therapy. But some patients do not achieve an adequate response to TNF inhibitors or are intolerant to these therapies.

Choosing the right treatment after failure of the first biologic requires that clinicians consider several factors. Dr Atul Deodhar, of Oregon Health & Science University, discusses guidelines from the American College of Rheumatology/National Psoriasis Foundation and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) for appropriate treatment strategies.

He also discusses factors critical to the optimal choice of the next therapy, such as the domains of disease activity, patient comorbidities, and whether the biologic's failure was primary or secondary.

Aside from choosing a new biologic, Dr Deodhar notes that there are other options to intensify the effect of the initial biologic. He says the clinician and patient may consider increasing the dose and frequency of the initial biologic medication or moving to a combination therapy by adding another drug, such as methotrexate.

--

Atul A. Deodhar, MD, Professor of Medicine, Division of Arthritis and Rheumatic Diseases, School of Medicine, Oregon Health & Science University; Medical Director, Rheumatology Clinics, OHSU Hospital, Portland, Oregon

Atul A. Deodhar, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant, for: Bristol Myers Squibb; Eli Lilly; Janssen; MoonLake; Novartis; Pfizer; UCB

Serve(d) as a speaker for: Eli Lilly; Novartis; Pfizer; UCB

Received research grant from: AbbVie; Bristol Myers Squibb; Celgene; Janssen; MoonLake; Novartis; Pfizer; UCB

Received income in an amount equal to or greater than $250 from: Bristol Myers Squibb; Eli Lilly; Janssen; Novartis; Pfizer; Samsung Bioepis; UCB

Over the past two decades, the therapeutic landscape for psoriatic arthritis (PsA) has been transformed by the introduction of more than a dozen targeted therapies.

For most patients with active PsA, a tumor necrosis factor (TNF) inhibitor is recommended as the first-line biologic therapy. But some patients do not achieve an adequate response to TNF inhibitors or are intolerant to these therapies.

Choosing the right treatment after failure of the first biologic requires that clinicians consider several factors. Dr Atul Deodhar, of Oregon Health & Science University, discusses guidelines from the American College of Rheumatology/National Psoriasis Foundation and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) for appropriate treatment strategies.

He also discusses factors critical to the optimal choice of the next therapy, such as the domains of disease activity, patient comorbidities, and whether the biologic's failure was primary or secondary.

Aside from choosing a new biologic, Dr Deodhar notes that there are other options to intensify the effect of the initial biologic. He says the clinician and patient may consider increasing the dose and frequency of the initial biologic medication or moving to a combination therapy by adding another drug, such as methotrexate.

--

Atul A. Deodhar, MD, Professor of Medicine, Division of Arthritis and Rheumatic Diseases, School of Medicine, Oregon Health & Science University; Medical Director, Rheumatology Clinics, OHSU Hospital, Portland, Oregon

Atul A. Deodhar, MD, has disclosed the following relevant financial relationships:

Serve(d) as a consultant, for: Bristol Myers Squibb; Eli Lilly; Janssen; MoonLake; Novartis; Pfizer; UCB

Serve(d) as a speaker for: Eli Lilly; Novartis; Pfizer; UCB

Received research grant from: AbbVie; Bristol Myers Squibb; Celgene; Janssen; MoonLake; Novartis; Pfizer; UCB

Received income in an amount equal to or greater than $250 from: Bristol Myers Squibb; Eli Lilly; Janssen; Novartis; Pfizer; Samsung Bioepis; UCB

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

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Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

Primary biliary cholangitis is a rare progressive autoimmune liver disease that specifically targets biliary epithelial cells. In this article, Dr. Kowdley describes prognostic markers of disease, current and investigational medical therapies, liver transplant, and focusing on maximizing favorable long-term outcomes.

Click Here to Read More

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

To the Editor:

A 73-year-old man was admitted to the hospital with progressive abdominal and hip pain of several weeks’ duration that was accompanied by unilateral swelling of the left leg. He had a medical history of hypertension, hyperlipidemia, and prediabetes. Computed tomography (CT) showed extensive intra-abdominal, retroperitoneal, and pelvic lymphadenopathy in addition to poorly defined hepatic lesions.

A CT-guided core biopsy of a left inguinal lymph node showed Burkitt lymphoma. Fluorescence in situ hybridization was positive for oncogene c-MYC rearrangement on chromosome 8q24 and negative for B-cell lymphoma 2 (BCL2) and B-cell lymphoma 6 (BCL6) gene rearrangements. Flow cytometry demonstrated an aberrant population of κ light chain-restricted CD5⁻CD10⁺ B lymphocytes.

The patient’s overall disease burden was consistent with stage IV Burkitt lymphoma. R-miniCHOP chemotherapy—rituximab plus a reduced dose of cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone—was initiated. Approximately 2 weeks after chemotherapy was initiated, the patient developed a firm erythematous eruption on the left hip (Figure 1A). His regimen was then switched to R-EPOCH—rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin—at the time of discharge, and he was referred to dermatology due to an initial concern of an adverse reaction to R-EPOCH chemotherapy. The patient denied any pain, pruritus, or irritation. Physical examination showed multifocal, subcutaneous, indurated, erythematous and violaceous nodules without epidermal changes. Some nodules on the lateral aspect of the hip coalesced to form firm plaques.

A punch biopsy specimen showed markedly atypical lymphocytes with enlarged nuclei and scant cytoplasm present throughout the dermis (Figures 2A and 2B). Numerous apoptotic cells and cellular debris were seen. Immunohistochemical staining demonstrated that the lymphocytic infiltrate comprised CD79a⁺ B cells that were positive for Bcl-6 and CD10 and negative for Bcl-2 (Figures 2C and 2D). There also was diminished focal expression of CD20. Ki-67 protein staining was intensely positive and demonstrated a very high proliferative index.

Taken together, these findings were consistent with a diagnosis of cutaneous metastasis of Burkitt lymphoma. The patient’s cutaneous lesions improved after continued aggressive chemotherapy. At follow-up 2 weeks after biopsy, he was receiving his second round of R-EPOCH chemotherapy with appreciable regression of skin lesions (Figure 1B). However, he then developed right-side double vision, ptosis, and right-side facial paresthesia. Although magnetic resonance imaging of the brain and lumbar puncture did not show evidence of central nervous system involvement, the chemotherapy regimen was switched to dose-adjusted CVAD-R—hypercyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone plus rituximab—for empiric treatment of central nervous system disease. Although treatment was complicated by sepsis with extended-spectrum β-lactamase-producing Enterobacter cloacae, Burkitt lymphoma was found to be in remission after 3 cycles of CVAD-R and 5 months of chemotherapy.

Burkitt lymphoma is a B-cell non-Hodgkin malignancy caused by translocation of chromosome 8 and chromosome 14, leading to overexpression of c-MYC and subsequent hyperproliferation of B lymphocytes.^1,2 The disease is divided into 3 major categories: sporadic, endemic, and immunodeficiency related.³ The endemic variant is the most prevalent subtype in Africa and is associated with Plasmodium falciparum malaria; the sporadic variant is the most common subtype in the rest of the world.⁴

Burkitt lymphoma is highly aggressive and is characterized by unusually high rates of mitosis and apoptosis that result in abundant cellular debris and a distinctive starry-sky pattern on histopathology.^5,6 Extranodal metastasis is common,⁷ but cutaneous involvement is exceedingly rare, with only a few cases having been reported.^8-14 Cutaneous metastasis of Burkitt lymphoma often is associated with a high overall disease burden and poor prognosis.^8,11

Immunodeficiency-related Burkitt lymphoma is particularly aggressive. Notably, 3 of 7 (42.9%) reported cases of cutaneous Burkitt lymphoma occurred in HIV-positive patients.^11,13 In one case, cutaneous involvement was the first sign of relapsed disease that had been in remission.¹²

Although c-MYC rearrangement is required to make a diagnosis of Burkitt lymphoma, the disease also is present in a minority of cases of diffuse large B-cell lymphoma (DLBCL)(6%).¹⁵ Although DLBCL typically can be differentiated from Burkitt lymphoma by the large nuclear size and characteristic vesicular nuclei of B cells, few cases of DLBCL with c-MYC rearrangement histologically mimic Burkitt lymphoma. However, key features such as immunohistochemical staining for Bcl-2 and CD10 can be used to distinguish these 2 entities.¹⁶ Bcl-2 negativity and CD10 positivity, as seen in our patient, is considered more characteristic of Burkitt lymphoma. This staining pattern in combination with a high Ki-67 fraction (>95%) and the presence of monomorphic medium-sized cells is more consistent with a diagnosis of Burkitt lymphoma than of DLBCL.¹⁷

Earlier case reports have documented that cutaneous lesions of Burkitt lymphoma can occur in a variety of ways. Hematogenous spread is the likely route of metastasis for lesions distant to the primary site or those that have widespread distribution.¹⁸ Alternatively, other reports have suggested that cutaneous metastases can occur from local invasion and subcutaneous extension of malignant cells after a surgical procedure.^10,19 For example, cutaneous Burkitt lymphoma has been reported in the setting of celioscopy, occurring directly at the surgical site.¹⁹ In our patient, we believe that the route of metastatic spread likely was through subcutaneous invasion secondary to CT-guided core biopsy, which was supported by the observation that the onset of cutaneous manifestations was temporally related to the procedure and that the lesions occurred on the skin directly overlying the biopsy site.

In conclusion, we describe an exceedingly rare presentation of cutaneous Burkitt lymphoma in which a surgical procedure likely served as an inciting event that triggered seeding of malignant cells to the skin. Cutaneous spread of Burkitt lymphoma is infrequently reported; all such reports that provide long-term follow-up data have described it in association with high disease burden and often a lethal outcome.^8,11,12 Our patient had complete resolution of cutaneous lesions with chemotherapy. It is unclear if the presence of cutaneous lesions can serve as a prognostic indicator and requires further investigation. However, our case provides preliminary evidence to suggest that cutaneous metastases do not always represent aggressive disease and that cutaneous lesions may respond well to chemotherapy.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

The Diagnosis: Acquired Cutaneous Lymphangiectasia

Histopathology showed a cluster of widely ectatic, thin-walled lymphatic spaces immediately subjacent to the epidermis and flanked by an epidermal collarette (Figure, A). The vessels did not extend any further than the papillary dermis and were not accompanied by any notable inflammation (Figure, B). A single layer of bland endothelial cells lined each lymphatic space (Figure, C). A diagnosis of acquired cutaneous lymphangiectasia secondary to surgical and radiation treatment of breast cancer was made. Clinical monitoring was recommended, but no treatment was required unless symptoms arose. At 2-year follow-up, she continued to do well.

Acquired cutaneous lymphangiectasia is characterized by benign dilations of surface lymphatic vessels, likely resulting from disruption of the lymphatic system.¹ This finding most commonly occurs on the external genitalia following combined surgical and radiation treatment of malignancy, though in a minority of cases it is seen with surgical or radiation treatment alone.² Acquired cutaneous lymphangiectasia secondary to radical mastectomy for breast cancer was first reported in 1956 in a patient with persistent ipsilateral lymphadenopathy.³ The presentation in a patient with Cowden syndrome is rare. Cowden syndrome (also called PTEN hamartoma tumor syndrome) is a rare autosomal-dominant disorder caused by mutations in the tumor suppressor phosphatase and tensin homolog gene, PTEN. It is characterized by multiple hamartomas and substantially increased risk for breast, endometrial, and thyroid malignancy.⁴ In addition to breast cancer, our patient had a history of papillary thyroid carcinoma, cerebellar dysplastic gangliocytoma, and multiple cutaneous fibromas and angiolipomas.

A diagnosis of syringomas—benign tumors that arise from the intraepidermal aspect of eccrine sweat ducts— could be considered in the differential diagnosis. Cases of eruptive syringoma on the breast have been reported, but the biopsy would show a circumscribed proliferation of tadpole-shaped tubules comprised of secretory cells in a sclerotic stroma.5 Hidrocystomas are benign sweat gland cysts that present on the face, especially around the eyes, but rarely have been reported on the trunk, particularly the axillae.6 Although they clinically manifest as translucent papules, histopathology shows fluid-filled cysts lined by a layer of secretory columnar epithelium.7 Metastatic breast carcinoma was considered, given the patient’s history of breast cancer. Cutaneous metastases often are found on the chest wall but also can occur at distant sites. Histopathology can reveal various patterns, including islands of tumor cells with glandular formation or single files of cells infiltrating through dermal collagen.

Angiosarcoma also must be considered in the setting of any vasoformative proliferation arising on previously irradiated skin. Angiosarcomas can sometimes be well differentiated with paradoxically bland cytomorphology but characteristically have anastomosing vessels and infiltrative architecture, which were not identified in our patient. Other diagnostic features of angiosarcoma include endothelial nuclear atypia, multilayering, and mitoses. Radiation-associated angiosarcomas amplify MYC, a transcription factor that affects multiple aspects of the cell cycle and is an oncogene implicated in several different types of malignancy.⁸MYC immunohistochemistry testing should be performed whenever a vasoformative proliferation on irradiated skin is partially sampled or shows any features concerning for angiosarcoma. Lastly, the term postradiation atypical vascular lesion has been introduced to describe discrete papular proliferations that show close histopathologic overlap with lymphangioma/lymphatic malformations. In contrast, atypical vascular lesions show wedge-shaped intradermal growth that can cause diagnostic confusion with well-differentiated angiosarcoma. Unlike angiosarcomas, they do not express MYC. Postradiation atypical vascular lesions sometimes have an associated inflammatory infiltrate.⁹ Considerable histomorphologic overlap among lymphangiomas, atypical vascular lesions, and well-differentiated angiosarcomas exists; thus, lesions should be removed in their perceived totality whenever possible to help permit diagnostic distinction. In our patient, the abrupt discontinuation of vessels at the interface of the papillary and reticular dermis was reassuring of benignancy.

Our patient’s diagnosis of acquired cutaneous lymphangiectasia was a benign adverse effect of prior breast cancer treatments. This case demonstrates a rare dermatologic sequela that may arise in patients who receive surgical or radiation treatment of breast cancer. Given the heightened risk for angiosarcoma after radiation therapy as well as the increased risk for malignancy in patients with Cowden syndrome, biopsy can be an important diagnostic step in the management of these patients.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Migraines are episodic or chronic headaches, typically occurring on one side of the head, that have distinct characteristics and definitions from the International Classification of Headache Disorders, 3rd edition (ICHD 3). Migraine can occur at any age and is thought to affect about 5% of children before puberty, increases in prevalence after puberty, and reaches about 30% prevalence at age 25-30 years. Patients with migraine with aura have recurrent, fully reversible symptoms that can include diplopia, motor or sensory disturbances, and/or trouble with language that generally precede headache development. In some cases, aura may develop and resolve without headache. Migraine with aura can present at any age from early childhood onward and is present in about 30% of children and adolescents with migraine. In general, migraine with aura is more prevalent in female than in male individuals, especially adolescents. 

Migraine with brainstem aura, as is the case here, is a specific subtype of migraine with aura, in which the aura specifically reflects an origin within the brainstem. Brainstem symptoms include diplopia, vertigo, difficulty controlling speech muscles, tinnitus, hearing loss, loss of coordination, and possibly impaired consciousness. For the diagnosis of migraine with brainstem aura, patients must not have motor or retinal symptoms. Aura development often is preceded by premonitory symptoms, such as fatigue, hunger or food cravings, and mood elevations.

Migraine without aura, in contrast, is characterized by recurrent moderate to severe pulsating headache lasting from a few hours to up to 3 days. Migraine without aura often causes nausea and sensitivity to light and/or sound.

Chronic migraine is defined as headache (with or without aura) occurring 15 or more days per month for at least the past 3 months. This patient's history does not fit the definition of chronic migraine.

Tension-type headaches generally are bilateral, with durations ranging from minutes to days. They tend to be mild to moderate in intensity and symptoms are not worsened by physical activity. In addition to their bilateral nature, these headaches differ from migraine in lacking associated visual, cortical, or other symptoms. 

Any diagnosis of migraine requires assessment over time, using diagnostic criteria established by the International Headache Society in ICHD 3. It is not necessary to perform neuroimaging studies or CT in patients with migraine symptoms and an otherwise normal neurologic exam.

When a diagnosis of migraine with brainstem aura is established, pediatric or adolescent patients and their families should first be counseled on nonpharmacologic interventions. These interventions, which have demonstrated benefits in reducing headache frequency, include lifestyle modifications, regular sleep and meal schedules, adequate fluid intake, cognitive-behavioral therapy, stress management techniques, massage, and biofeedback techniques. Recommended for acute treatment of migraine are nonsteroidal anti-inflammatory drugs, acetaminophen, and triptans. There is limited evidence in pediatric or adolescent patients with use of preventive medications, such as topiramate, amitriptyline, or onabotulinumtoxinA. In clinical trials, patients receiving placebo saw improvements, and active treatments were only marginally, if at all, more effective. Current guidelines recommend a frank discussion with parents about the limitations of preventive therapies before making decisions to use them. 

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.