Neurology Reviews

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Chronic inflammatory demyelinating polyradiculoneuropathy, or CIDP, is a rare immune-mediated nerve disorder characterized by progressive weakness and sensory impairment in the arms and legs, the result of an autoimmune attack on myelin.

Though some clustering of cases may occur in families, and susceptibility genes have been found, it is not considered a genetic disease. It can strike patients of either sex at any age, though most cases will occur in or after midlife.

Because its symptoms can overlap with a broad range of neuropathies, CIDP is notoriously complex to diagnose, relying on nerve conduction studies and careful clinical assessment rather than any definitive blood biomarker. Complicating matters further, CIDP has several variants whose symptoms differ from classical presentations.

Many patients who do not have CIDP end up being treated for it, and many CIDP patients experience delays to diagnosis and treatment that can potentially result in greater nerve damage and worse outcomes.

The good news, CIDP experts say, is that the last few years have seen important advances in diagnosis and treatment – including comprehensive new clinical guidelines and the June 2024 approval by the Food and Drug Administration of a new treatment, efgartigimod alfa and hyaluronidase-qvfc (Vyvgart, argenx). This antibody fragment represents the first non-steroid, non-immunoglobulin option for CIDP.

Despite the difficulties of recruiting patients with a tough-to-confirm disease that affects between 2 and 9 of every 100,000 people, according to the GPS-CIDP Foundation clinical trials have been successfully carried out in CIDP, and new ones continue to recruit. The experimental therapies being explored are based on a wide range of proposed disease pathways.

courtesy University of Minnesota

“It’s a very exciting time,” said Jeffrey Allen, MD, a neurologist at the University of Minnesota, Minneapolis, one of three CIDP experts who spoke about this challenging but treatable syndrome, its diagnosis and management, and the research questions that they hope to see answered.
 

Refining Diagnosis

In classical or typical CIDP, which accounts for most cases, patients present with progressive weakness and numbness that affects the arms and legs symmetrically, with the weakness being both proximal and distal. The disease usually evolves over a period of months, which helps distinguish it from Gullain-Barré syndrome, whose onset is more sudden and progression is less than 4 weeks.

CIDP was first described in the 1970s, and since that time more than a dozen sets of diagnostic criteria have been published. Starting about a decade ago, Dr. Allen and neurologist Richard Lewis, MD, of Cedars-Sinai Medical Center in Los Angeles, California, helped launch an effort to improve them.

“Experts in the field who were seeing patients with CIDP recognized that a lot of referrals coming to them were of people who actually didn’t have it, or they had the disease and were treated for it but didn’t need to be on treatment, or their treatment was very unconventional,” Dr. Allen said. “We wanted to try to put some data behind that.” In 2015 Dr. Allen and Dr. Lewis published a paper that found that nearly half of patients referred with a diagnosis of CIDP failed to meet basic diagnostic requirements.

courtesy Cedars-Sinai Medical Center

Erroneous interpretation of nerve conduction studies “was a significant factor” contributing to the misdiagnoses, Dr. Lewis said. And another major problem was that patients’ response to standard treatment with intravenous immunoglobulins (current treatments have also come to include subcutaneous immunoglobulins) was not being measured objectively. Instead of evaluating patients using grip strength, walking tests, or other objective instruments, clinicians asked patients whether they felt better. “The problem is that IVIg makes people feel good,” Dr. Lewis said, “possibly by reducing normal inflammatory agents in the body.”

The 2015 paper caught the attention of neurologists and neuromuscular specialists worldwide, who reported similar problems with misdiagnosis. “And from there we did other work to try to dissect out what the more specific issues are,” Dr. Allen said. “The electrophysiology was a big one.”

courtesy University of Buffalo

Neurologist Nicholas Silvestri, MD, of the University at Buffalo in New York, one of the centers of excellence recognized by the CIDP-GBS Foundation, affirmed that nerve conduction studies, which essential to diagnosing CIDP, “are not as objective as we think they are. They’re very prone to user error and overinterpretation error. If they’re not performed appropriately, things can look like CIDP when they’re not. Very common forms of neuropathy, like diabetic neuropathy, can be misinterpreted as CIDP.”
 

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”

Management: A Delicate Dance

Since the 1990s, the standard of care for CIDP has been IVIg and steroids. Newer subcutaneous immunoglobulin products, which take less time to administer, may be more convenient for patients than traditional IVIg and mitigate some concerning side effects.

Efgartigimod alfa and hyaluronidase-qvfc now offers an entirely different option that, while too new for clinicians to have much experience with in CIDP, represents further convenience for patients, with dosing in one 90-second subcutaneous injection per week.

In general, the sooner people are diagnosed and on therapy, the better they are likely to do, with fewer risks of irreversible axonal loss and disability. Referring to CIDP centers of excellence can help speed a definitive diagnosis.

Some patients will see a complete or near-complete recovery, while others will not. “It’s important to be up front with patients about what the benefit of treatments are, what are the expectations of treatment, what we can potentially get back, and what’s unlikely to come back,” Dr. Allen said. “We know that irreversible deficits are not uncommon in folks with CIDP. Part of that is driven by how severe their disease is or how long they’ve had it.”

Good CIDP management, according to the 2021 guidelines, involves making periodic dose reductions or withdrawing therapies on a trial basis, because people can and do experience remission. “We don’t have any test that tells us if somebody needs treatment or not. So this is the best we can do right now,” Dr. Allen said.

This process can be anxiety provoking for patients. “In my practice, there are no surprises,” he said. “We don’t typically say, ‘we’re going to stop your treatment today.’ It’s a discussion with a lead up that’s usually many months long.”

Management of CIDP also requires discussions to elicit when and whether worsening is occurring, along with a clear sense, by both patient and clinician, of what constitutes worsening.

Serial nerve conduction studies are not very useful, Dr. Lewis said, but objective disability measures are and should be more broadly adopted. These include the Medical Research Council sumscore, a test of 12 muscles that can determine weakness; a hand grip test; and functional disability scales such as Inflammatory Rasch Overall Disability Scale and Inflammatory Neuropathy Cause and Treatment scale. All are quick to administer in the office, and some can be done by the patient at home, providing the clinician useful information between visits.

“We could do a better job with educating [clinicians] on the value of different outcome measures that can really quantify disease activity,” Dr. Allen said, and pointed to the GBS-CIDP Foundation centers of excellence, which exist in most regions of the United States, as an outstanding resource for anyone wanting to know more.

“The centers are really, really helpful when you’re trying to work through some of these issues,” he said.

Suggested Reading

Allen JA and Lewis RA. Neurology. 2015 Aug 11;85(6):498-504. doi: 10.1212/WNL.0000000000001833.

Allen J et al. Neurology. 2024;102(17_supplement_1). doi: 10.1212/WNL-.0000000000206324.

Van den Bergh PYK et al. J Peripher Nerv Syst. 2021 Sep;26(3):242-268. doi: 10.1111/jns.12455.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Urgency of treatment is something that many physicians may not fully appreciate when it comes to neuromyelitis optica (NMO), according to experts on this rare autoimmune demyelinating disorder. This may be partly due to its similar presentation to multiple sclerosis (MS), said Michael Levy, MD, PhD, associate professor, Harvard Medical School, research director, Division of Neuroimmunology & Neuroinfectious Disease, and director, Neuroimmunology Clinic and Research Laboratory, at Massachusetts General Hospital in Boston. But while the two conditions share many clinical characteristics, “immunologically, they are about as different as can be,” he warned.

The urgency of distinction is important because where MS is known to have a relatively gradual progression, NMO is now red-flagged to potentially cause rapid and irreversible damage. While the course of MS might be described as a slow burn, NMO should be treated like a wildfire.

“That message has gotten muddled, particularly because acute treatment in MS has never been shown to affect outcome,” said Jeffrey Bennett, MD, PhD, professor of neurology and ophthalmology at the University of Colorado School of Medicine, Aurora. In contrast, rapid diagnosis and treatment of NMO “means potentially preventing future devastating neurologic injury,” he said.

First described by Dr. Eugène Devic in 1894, and sometimes known as Devic’s disease, NMO is believed to have a prevalence that varies widely depending on ethnicity and gender. A recent report suggests a prevalence of approximately1/100,000 population among Whites with an annual incidence of less than 1/million in this population, while the prevalence is higher among East Asians (approximately 3.5/100,000), and may reach as high as 10/100,000 in Blacks.¹ It has a high female-to-male ratio (up to 9:1) with a mean age of onset of about 40 years, although pediatric cases are described.

It has long been recognized that NMO lacks the “neurocerebritis” of MS, with inflammation predominant in the optic and spinal nerves, but it was not until 2004 that researchers at the Mayo Clinic identified serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) that could reliably distinguish NMO from MS. In 2015, the international consensus diagnostic criteria for neuromyelitis optica² cited core clinical characteristics required for patients with AQP4-IgG-positive NMO spectrum disorder (NMOSD) “including clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations.” Rarely, NMO patients can be seronegative for AQP4-IgG, but are still considered to have NMOSD for which non-opticospinal clinical and MRI characteristics findings are described. MS patients testing negative for AQP4-IgG should also be tested for the related myelin oligodendrocyte glycoprotein antibody disease (MOGAD), which has a prevalence about four to five times greater than NMO, Dr. Bennett said.
 

Testing

Because both NMO and MOGAD can be identified by antibodies, they are less commonly misdiagnosed as MS compared to previously. But, prior to the identification of the AQP4-IgG antibody in 2004, the misdiagnosis rate of NMO was probably about 95% said Dr. Levy.

“Of course, before we had the antibody test or clinical criteria, we couldn’t confirm a diagnosis of NMO, so basically everyone had a diagnosis of MS, and after the antibody test became commercially available in 2005/2006, we could confirm the diagnosis, with our study in 2012 showing a much lower misdiagnosis rate of 30%.”³ More recently, the misdiagnosis rates are even lower, he added. A recent study out of Argentina found a rate of only 12%.⁴

The specificity and sensitivity of cell binding assay serum AQP4-IgG testing is roughly 99% and 90%, respectively, better than ELIZA testing (which has a sensitivity in the 60-65% range), said Dr. Bennett. “That’s why we highly emphasize to physicians, that if you have a suspicion for NMOSD you go to a cell binding assay, and make sure that where you’re sending the serum, the lab can do that procedure.” Still, because of the risk of false positives, he urges restraint in testing for the disorder in the absence of a high suspicion for it. “If you test a lot of people indiscriminately for a rare disorder, you get a lot of false positives because the actual true positives are a very small fraction of that group. So, even with a specificity of around 99% that means 1% of the people you test are falsely positive. And if you’re testing a group of people indiscriminately, then your true positives are less than 1% by far, so then most of the people that you pick up are not truly with disease.”

Acute Treatment

While misdiagnosis of NMO as MS is less common than previously, it is still a concern, not only because of the irreversible risks associated with delayed acute treatment, but also the risks of inappropriate preventive MS therapy, which could be harmful to patients with NMO.

Acute flare-ups of NMO and MOGAD are currently all treated with the same decades-old mainstays for acute MS — intravenous steroids and plasma exchange — but the approach is more aggressive. Retrospective studies have shown that, for NMO, plasma exchange has shown an increased likelihood of improvement versus steroids alone, said Dr. Bennett, but since time is of the essence, treatment should begin before a definitive diagnosis is confirmed.

“What’s limiting our patients is, number one, recognizing NMOSD when the attack is happening in your face. You’ve got to know, hey, this is NMOSD or I’m suspicious of NMOSD and hence, I need to treat it urgently because the outcome has a high probability of not being good. You’ve got to realize that this is NMOSD before the test comes back, because by the time it comes back positive in several days, you’re probably missing the optimal window to treat. The point is to know that the presentation in front of you, the MRI pictures in front of you, the laboratory tests that you might have done in terms of spinal fluid analysis, all highly suggest NMOSD. And so hence, I’m going to take the chance that I might be wrong, but I’m going to treat as if it is and wait for the test to come back.”

Realistically, the risks associated with this approach are minor compared with the potential benefit, Dr. Bennett said. “For plasma exchange, there’s the placement of the central line, and the complications that could happen from that. Plasma exchange can lead to metabolic ionic changes in the blood, fluid shifts that might have to be watched in the hospital setting.”

While waiting for diagnostic results, one clue that may emerge from acute treatment is recovery time. “The recovery from MOGAD attacks is really distinct,” said Dr. Levy. “They get better a lot faster. So, if they’re blind in the hospital, and 3 months later they can see again with treatment, that’s MOGAD.” On the other hand, comorbidities such as lupus strongly favor NMO, he added. And another underrecognized, unique symptom of NMO is that about 10% of people may present with protracted episodes of nausea, vomiting, or hiccups, added Dr. Bennett. “What’s important is not that the neurologist recognize this per se in the emergency department, because they’re not going to be called for that patient — the GI doctors will be called for that patient. But when you’re seeing a patient who may have another presentation: a spinal cord attack, a vision attack with optic neuritis, and you ask them simply ‘have you ever had an episode of protracted nausea, vomiting, or hiccups?’ — I can’t tell you how many times I can have someone say ‘that’s weird I was just in the ED 3 months ago for that.’ And then, I know exactly what’s going on.”
 

Prevention of Relapse

Treatment of NMO presents some particular challenges for clinicians because the old treatment, rituximab, an anti-CD20 monoclonal antibody which has been used since 2005, has been so affordable and successful. “It’s hard to get people off,” said Dr. Levy. “It’s still the most commonly used drug for NMO in the US, even though it’s not approved. It’s cheap enough, and so people get started on that as a treatment, and then they just continue it, even as an outpatient.”

But since 2019, four new FDA-approved therapies have entered the scene with even better efficacy: the anti-CD-19 targeted medication inebilizumab (Uplizna, Viela Bio, approved in 2020), which requires two 90-minute infusions per year; the interleukin-6 (IL-6) receptor inhibitor satralizumab (Enspryng, Roche, approved in 2020), which is administered subcutaneously once monthly; and the anti-complement C5 inhibitors eculizumab (Soliris, Alexion Pharmaceuticals, approved in 2019), and ravulizumab (Ultomiris, Alexion Pharmaceuticals, approved in 2024), which require infusions every 2 weeks or every 2 months, respectively.

Both experts point to compelling clinical evidence to prescribe the Food and Drug Administration–approved drugs for newly diagnosed NMO, and to switch existing patients from rituximab to the new drugs. “The data is pretty clear that there’s about a 35% failure rate with rituximab, as opposed to less than 5% with the new drugs,” explained Dr. Levy. But ironically, where insurance companies used to balk at covering rituximab because it was not FDA approved for NMO, they are now balking at the FDA-approved options because of the cost. “Even in an academic center, where we get a discount on the drugs, the biosimilar generic of rituximab costs about $890 per dose,” he said. “So overall, it’s less than $4,000 a year for rituximab. Compare that with the most expensive FDA-approved option, which is eculizumab. That’s $715,000 per year. And then the other three drugs are below that, but none are less than about $290,000 a year.”

Patients are also hesitant to switch from rituximab if they’ve been well-controlled on it. “There’s a process to it, and I always talk my patients through it, but I would say less than half make the switch,” said Dr. Levy. “Most people want to stay. It’s a whole different schedule, and mixing two drugs. Are you going to overlap and overly immune suppress? Is the insurance going to approve it? It becomes more complicated.”

“Insurance companies are sometimes inappropriately pushing physicians, asking for patients to fail rituximab before they’ll approve an FDA-approved drug, which is like playing doctor when they’re not a licensed physician,” added Dr. Bennett. “And I think that is absolutely inappropriate, especially in light of the fact that before there were approved drugs, insurance companies used to deny rituximab because it was ‘experimental’ and ‘too expensive’ — and now it’s a cheaper alternative.”

Requiring failure on rituximab is also unethical, given the potential for irreversible damage, Dr. Levy pointed out. “With NMO we don’t tolerate a failure. That’s also how the trials of the new drugs were done. It was considered unethical to have an outcome of annualized relapse rate, like we used to in MS, where we say, OK if you have two attacks a year, then the drug has failed. With NMO, one failure, one breakthrough, and that drug is worthless. We switch.”
 

A Wealth of Treatment Choices

Patients opting for an FDA-approved treatment now have a “wildly effective” array of new drugs, said Dr. Levy, but choosing can be difficult when each has its own set of advantages and disadvantages. “I have equal numbers of patients on all the drugs, and I show all the data to my patients: efficacy, safety, logistics, cost, and then I ask ‘What are your priorities? Which of these things that I say really rings with you? Is it the infusion schedule? Is it the efficacy? Is it the safety concern? Is it the cost? What are you most concerned about?’ And then we start to have the conversation that way. It’s a shared decision-making process.”

There is definitely an art to finding the best fit for each patient, agreed Dr. Bennett, “both with the urgency of controlling the disease, the particular patient in front of you, their ability to adhere to certain therapies, their ability to have access to infusions, or to self-inject, or to get transported to an infusion center or have access to home infusion.”

Patient empowerment in the decision is very important, added Dr. Levy. “When people make the decision on their own, they’re much more likely to be compliant, rather than me telling them they have to do this. And that’s why I think we haven’t had a single relapse on the new drugs. There have been switches because of intolerance, and cost, and all those issues, but not because of a breakthrough attack.”
 

Future

Looking ahead in the field, Dr. Bennett sees the biggest potential for improvement is in the management of acute attacks, which he describes as “a major treatment gap.” Although plasma exchange is immediately effective in limiting the amount of circulating pathogenic AQP4-IgG “there are other approaches that could be even more beneficial,” he said. “A promising strategy is to use drugs that act immediately on arms of the immune response that are directly injuring brain tissue. These include serum complement and cells such as neutrophils and natural killer cells that release destructive enzymes and inflammatory mediators,” he explained. “Complement inhibitors, such as the C5 inhibitors eculizumab and ravulizumab, currently approved for NMOSD relapse prevention, act immediately to inhibit complement-mediated tissue injury. Similarly, high doses of antihistamines could be used to rapidly stop the release of the destructive enzyme elastase from neutrophils and natural killer cells, while elastase inhibitors could be given to minimize cell injury. Direct clinical studies are needed to find both the optimal treatment window and regimen.”

References

1. Hor JY et al. Epidemiology of Neuromyelitis Optica Spectrum Disorder and Its Prevalence and Incidence Worldwide. Front Neurol. 2020 Jun 26:11:501. doi: 10.3389/fneur.2020.00501.

2. Wingerchuk DM et al. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders. Neurology. 2015 Jul 14;85(2):177-89. doi: 10.1212/WNL.0000000000001729.

3. Mealy MA et al. Epidemiology of Neuromyelitis Optica in the United States: A Multicenter Analysis. Arch Neurol. 2012 Sep;69(9):1176-80. doi: 10.1001/archneurol.2012.314.

4. Contentti EC et al. Frequency of NMOSD Misdiagnosis in a Cohort From Latin America: Impact and Evaluation of Different Contributors. Mult Scler. 2023 Feb;29(2):277-286. doi: 10.1177/13524585221136259.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.

Duchenne muscular dystrophy (DMD) is a severe progressive inherited disease characterized by muscle wasting and ultimately culminating in death. Although rare (DMD affects between 1 in 3600 to 1 in 5000 births)¹ it’s “the most common form of muscular dystrophy in childhood. It’s a common enough neuromuscular disorder that pediatricians and family practice physicians are likely to see at least a couple of patients with DMD over the course of their career,” John Brandsema, MD, Neuromuscular Section Head, Division of Neurology, Children’s Hospital of Philadelphia in Pennsylvania, said in an interview. Healthcare providers should therefore be familiar with the disorder so as to provide timely diagnosis and early intervention as well as practical and emotional support to the patient and family/caregivers as they traverse the challenging and often heartbreaking journey with this condition.

Pathophysiology and Disease Trajectory

DMD is caused by pathogenic variants in the X-linked DMD gene, leading to reduction in dystrophin, a protein that serves as a cytoskeletal integrator, stabilizing the plasma membrane of striated muscle cells. Dystrophin is critical for muscle membrane stability.² In particular, mutations in the gene that encodes for dystrophin lead to dysfunction in Dp427m, which is the muscle isoform of dystrophin.^3,4

DMD is one of several types of muscular dystrophies. All are progressive disorders. Over time, healthy muscle fibers disappear and are replaced by fibrotic tissue and fat, making the muscles “less able to generate force for everyday activity.”² Ultimately, the skeletal muscle dysfunction affects not only the patient’s day-to-day mobility but other systems as well. Most patients with DMD eventually die of cardiac and/or respiratory failure between the ages of 20 and 40 years, with a median life expectancy of 22 years — although children born after 1990 have a somewhat higher median life expectancy (28 years), because of the improving standard of care.^3,5

Typically, DMD first presents with developmental delays and weakness in skeletal leg muscles. As the disease goes through stages of progression, it starts involving upper extremities and other systems. (Table 1)

Genetic Causes of DMD

The DMD gene, located on the X chromosome, encodes for the production of dystrophin. Variants of this gene result in the lack of dystrophin protein, leading in turn to muscle fiber degeneration and the progressive symptoms of DMD. Because of the gene’s location on the X chromosome, males (who don’t have a second copy of the X chromosome) cannot compensate for the mutated gene, which is why the disease affects male children. Females with this mutation are carriers and typically do not develop the same severity of symptoms, although they might have milder muscle cramps, weakness, and cardiac issues.³

A female carrier with DMD (or any other X-linked disorder) has a 25% chance to have a carrier daughter, a 25% change of having a noncarrier daughter, a 25% chance of having an affected son, and a 25% chance of having a nonaffected son. A male with the disorder will pass the mutated gene on to his daughters who then become carriers. He cannot pass the disorder on to his sons because males inherit only the Y chromosome from their fathers.³
 

Diagnosing DMD

“It can take as long as 1-3 years for a child to be diagnosed with DMD,” Dr. Brandsema said. “Parents typically have concerns and know that something is ‘off’ about their child and they’re sent to various specialists, but it usually takes time for an accurate diagnosis to be made.” The mean age at diagnosis of DMD is between ages 4 and 5 years.⁶

Early identification of infants at risk for developing DMD can help move the needle toward earlier diagnosis. Newborn screening for DMD has been researched and piloted in several programs.⁶ In 2023, DMD was nominated for inclusion in the Recommended Universal Screening Panel (RUSP) for universal newborn screening. But in May 2024, the advisory committee on Heritable Disorders in Newborns and Children decided to postpone the vote to include DMD in the RUSP, requesting additional information to ensure an evidence-based decision.

In the absence of universal newborn screening for DMD, alternative approaches have been proposed to reduce the delay in clinical diagnosis and specialist referral, including increasing awareness among healthcare providers (eg, pediatricians, pediatric neurologists, and primary care physicians).⁶

The National Task Force for Early Identification of Childhood Neuromuscular Disorders delineates the steps necessary to identify pediatric muscle weakness and signs of neuromuscular disease. Primary care providers are encouraged to engage in regular developmental surveillance. A surveillance aid lays out the timetable for recommended visits, typical developmental milestones, and components of surveillance. Clinical evaluation includes a detailed patient history, family history, and physical examination.

If a neuromuscular condition is suspected, laboratory work should include creatinine phosphokinase (CK).⁶ Elevated serum CK points to leakage of CK through the muscle membrane, suggesting muscle damage. If CK is elevated, genetic testing should be performed; and, if negative, it should be followed by genetic sequencing that tests for small-scale mutations in the DMD gene. If that test is negative, a muscle biopsy should be performed to test for deep intronic mutations in the DMD gene.⁴

The diagnostic process and immediate steps after a confirmed DMD diagnosis is found in Figure 1.

Targeting Inflammation in DMD

Traditionally, corticosteroids have been the only available medical treatment for DMD and they remain a cornerstone of DMD management. A meta-analysis found “moderate evidence” that corticosteroid therapy improves muscle strength and function in the short term (12 months), and strength up to 2 years.¹⁰

The two most common corticosteroids for DMD are prednisone and deflazacort. Deflazacort (Emflaza, PTC Therapeutics) was approved in 2017 to treat patients ages 5 years and older with DMD, subsequently expanded to 2 years and older. Deflazacort has been found to be more effective than prednisone in improving functional outcomes, delaying the onset of cardiomyopathy, and improving overall survival, with fewer adverse effects.¹¹

In 2023, vamorolone (Agamree, Catalyst Pharmaceuticals) was approved by the Food and Drug Administration (FDA) to treat DMD patients (ages 2 years and older). Vamorolone is a dissociative steroidal anti-inflammatory that reduces bone morbidities and is regarded as a safer alternative than prednisone. A clinical trial comparing two doses of vamorolone with prednisone for 24 weeks found that vamorolone 6 mg/kg per day met the primary endpoint (time to stand velocity) and four sequential secondary motor function endpoints, with less bone morbidity, compared to prednisone.¹² A more recent trial found improvements in motor outcomes at 48 weeks with a dose of 6 mg/kg per day of vamorolone. Bone morbidities of prednisone were reversed when the patient transitioned to vamorolone.¹³

“Steroid treatment has been proven to help, usually taken daily, although other schedules have been tried,” Dr. Brandsema said. However, all steroids are fraught with adverse effects and are suboptimal in the long term in reducing the disease burden.

The anti-inflammatory agent givinostat (Duvyzat, ITF Therapeutics), an oral histone deacetylase (HDAC) inhibitor, was approved in March 2024 for the treatment of DMD in patients 6 years of age and older. It is the first nonsteroidal drug to treat patients with all genetic variants of the disease, and it has a unique mechanism of action. Deficits in dystrophin can lead to increased HDAC activity in DMD, reducing the expression of genes involved in muscle regeneration. Givinostat therefore can help to counteract the pathogenic events downstream of dystrophin deficiency by inhibiting HDAC.¹⁴

Approval for givinostat was based on the phase 3 EPIDYS trial, which randomized 179 boys with DMD to receive either givinostat or placebo. Although results of a functional task worsened in both groups over the 12-month study period, the decline was significantly smaller with givinostat versus placebo. The most common adverse events were diarrhea and vomiting.14 Dr. Brandsema noted that monitoring of triglycerides and platelet count is required, as hypertriglyceridemia and thrombocytopenia can occur. This treatment was studied in tandem with corticosteroids as a combination approach to muscle stabilization.
 

New Pharmacotherapeutic Options: Exon-Skipping Agents

Today’s treatments have expanded beyond corticosteroids, with newer therapeutic options that include targeted exon-skipping therapies and, more recently, gene therapies. “These new treatment paradigms have changed the face of DMD treatment,” Dr. Brandsema said.

courtesy Children's Hospital of Philadelphia

Gene Transfer Therapies

Gene transfer therapies, a new class of agents, utilize a nonpathogenic viral vector (adeno-associated virus) to transfer specific genes to patients with DMD. Gene therapy involves overexpressing the micro-dystrophin gene to restore functional dystrophin expression.¹⁶

Multiple clinical trials of gene therapy are currently in progress. In 2023, delandistrogene moxeparvovec-rokl (Elevidys, Serepta) was granted accelerated FDA approval for ambulatory individuals with DMD between the ages of 4 and 5 years of age and a confirmed mutation in the DMD gene. It received expanded approval in June 2024 to include ambulatory and nonambulatory individuals aged 4 years and older with DMD and a confirmed mutation in the DMD gene (with the exception of exon 8 or 9 mutations).

The approval was based on preliminary data from two double-blind, placebo-controlled studies and two open-label studies, which enrolled a total of 218 male patients (including those who received placebo) with a confirmed disease-causing mutation in the DMD gene. 

Delandistrogene moxeparvovec-rokl is delivered as a one-time infusion and has been associated with side effects and “a lot of potential issues,” Dr. Brandsema said. “We’ve seen cardiac effects, immune system effects, increased muscle inflammation and hepatic complications, and some people who became quite unwell were hospitalized for a long time.”

Fortunately, he added, “these seem to be rare but they do happen. Once the medication has been delivered, it’s permanently in the body, so you’re managing the side effects potentially on a long-term basis.”

It is critical to discuss the risks and benefits of this treatment with the family and caregivers and with the patient as well, if he old enough and able to participate in the decision-making progress. “We don’t want to give unrealistic expectations and we want people to be aware of the potential downside of this treatment,” he said. “This is a very complex discussion because the trajectory of the disease is so devastating and this treatment does hold out hope that other therapies don’t necessarily have.”
 

Nonpharmacologic Interventions

Physical therapy is a mainstay in DMD treatment, addressing protection of fragile muscles, preservation of strength, and prevention of muscle contractures.¹⁶ Given the respiratory impairments that occur with DMD progression, respiratory monitoring and therapy are essential; however, the number and type of evaluations and interventions vary with the stage of the disease, intensifying as the disease progresses.¹⁶ Similarly, cardiac monitoring should begin early, with patients screened for cardiac complications, and should intensify through the stages of disease progression.¹⁶

Bone health is compromised in patients with DMD, both as a result of corticosteroid treatment and as part of the disease itself. Fractures may be asymptomatic and may go unnoticed. Thus, bone health surveillance and maintenance are critical components of DMD management.¹⁶

Patients with DMD often experience gastrointestinal issues. They may experience weight gain because of lack of mobility and corticosteroid use in early stages, or weight loss as a result of diet or fluid imbalance, low bone density, or dysphagia in later stages. Patients should be closely followed by a nutritionist, a gastroenterologist as needed, and a physical therapist.¹⁶

Psychosocial support “should be developed and implemented across the lifespan in a manner that promotes thinking about the future and sets expectations that individuals will actively participate in their care and daily activities.”⁹ This includes psychological care, neuropsychological evaluations, and educational support.
 

Assisting Patients and Families Through the DMD Journey

DMD care is best delivered in a multidisciplinary setting, where physicians of relevant specialties, physical and occupational therapists, nutritionists, social workers, and genetic counselors collaborate. At Children’s Hospital of Philadelphia, DMD care is delivered through this collaborative model.

Unfortunately, Dr. Brandsema said, many patients don’t have this type of multidisciplinary resource available. “One specialist, such as a pulmonologist or neurologist, might have to be the sole source of care.” Or parents may have to ferry their child to multiple specialists in disparate locations, placing extra stress on an already-stressed family system.

“It’s helpful to connect the family with a comprehensive care center, if possible,” Dr. Brandsema advised. If that’s not available, then he suggests recommending educational opportunities and resources through national organizations such as the Muscular Dystrophy Association; Parent Project MD; NORD; Friends, Family and Duchenne; and Cure Duchenne. Families and caregivers, along with affected individuals, can get education and support from people who understand the day-to-day reality of living with this disease.

One of the major challenges that families face is navigating the high cost of treating DMD, especially the new medications, Dr. Brandsema said. “The authorization process can be intensive and long, and the family may need to take an active role, together with the provider team, in advocating for the patient to get access.”

courtesy Children's Hospital of Philadelphia

Managing DMD Across the Lifespan

Another dimension of DMD care is providing resources and help to young people with DMD as they transition into adulthood. “In the past, we had limited treatment and mortality typically took place in the early 20s, so there weren’t a lot of patients who were adults. But as medication options have expanded and management of cardiac and respiratory failure has improved, we see a more significant proportion of adults who require adult-appropriate clinics — or, at the very least, specialists who are conversant in care or can provide care across the lifespan,” Dr. Brandsema said.

The DMD Care Considerations Working Group provides recommendations regarding care across the lifespan,⁹ as does the Adult North Star Network, of Muscular Dystrophy UK.^17,18

Dr. Brandsema emphasized that, despite their disability, many adults with DMD “still engage with the community, and live life to its fullest.” It is to be hoped that, with ongoing research, earlier diagnosis, and improved treatment options, the future will look bright for people with DMD.

Dr. Brandsema has served as a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Dyne, Edgewise, Fibrogen, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Takeda, and WaVe. He is on the medical advisory council member for Cure SMA and is a site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Biohaven, Catabasis, CSL Behring, Cytokinetics, Dyne, Fibrogen, Genentech, Ionis, Lilly, ML Bio, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, Summit, and WaVe. Ms. Kaschak has nothing to disclose.
 

References

1. Venugopal V and Pavlakis S. Duchenne Muscular Dystrophy. 2023 Jul 10. In: StatPearls [Internet]. Treasure Island, Florida: StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK482346/.

2. Gao QQ and McNally EM. Compr Physiol. 2015 Jul 1;5(3):1223-39. doi: 10.1002/cphy.c140048.

3. Duan D et al. Nat Rev Dis Primers. 2021 Feb 18;7(1):13. doi: 10.1038/s41572-021-00248-3.

4. Aartsma-Rus A et al. J Pediatr. 2019 Jan:204:305-313.e14. doi: 10.1016/j.jpeds.2018.10.043.

5. Broomfield J et al. Neurology. 2021 Dec 7;97(23):e2304-e2314. doi: 10.1212/WNL.0000000000012910.

6. Mercuri E et al. Front Pediatr. 2023 Nov 10:11:1276144. doi: 10.1212/WNL.0000000000012910.

7. Birnkrant DJ et al. Lancet Neurol. 2018 Mar;17(3):251-267. doi: 10.1016/S1474-4422(18)30024-3.

8. Birnkrant DJ et al. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5.

9. Birnkrant DJ et al. Lancet Neurol. 2018 May;17(5):445-455. doi: 10.1016/S1474-4422(18)30026-7.

10. Matthews E et al. Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.

11. Bylo M et al. Ann Pharmacother. 2020 Aug;54(8):788-794. doi: 10.1177/1060028019900500.

12. Guglieri M et al. JAMA Neurol. 2022 Oct 1;79(10):1005-1014. doi: 10.1001/jamaneurol.2022.2480.

13. Dang UJ et al. Neurology. 2024 Mar 12;102(5):e208112. doi: 10.1212/WNL.0000000000208112.

14. Mercuri E et al. Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.

15. Gushchina LV et al. Mol Ther Nucleic Acids. 2022 Nov 9:30:479-492. doi: 10.1016/j.omtn.2022.10.025.

16. Patterson G et al. Eur J Pharmacol. 2023 May 15:947:175675. doi: 10.1016/j.ejphar.2023.175675.

17. Quinlivan R et al. J Neuromuscul Dis. 2021;8(6):899-926. doi: 10.3233/JND-200609.

18. Narayan S et al. J Neuromuscul Dis. 2022;9(3):365-381. doi: 10.3233/JND-210707.

Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.

In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.

“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.

Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.

“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”¹

It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.

That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.

courtesy McGovern Medical School

“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.

“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
 

Repeating Nucleotides

Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.

The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.²

The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.³

The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.

“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.⁴
 

Managing Symptoms

There is no cure for Huntington’s disease. The current management approach is to treat the symptoms of the disease, although several promising strategies for moderating its severity are in development, say neurologists.

There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).

courtesy University of Alabama at Birmingham

“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.

Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.

“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.

Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.

Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.

In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.

As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
 

Disease-Modifying Therapies

As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.

courtesy Johns Hopkins University

“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.

The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.

“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
 

Gene Therapy

Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.

The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).

AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.

“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
 

Oral Splicing Modifier

PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.

The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.⁵

In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.

“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
 

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.

One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.⁶ The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.

Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.

Somatic Expansion

Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.

“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.

“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
 

Does HTT Lowering Mediate Progression?

“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.

One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.⁷ The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).

“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.

“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.

References

1. Huntington G. On Chorea. Reprinted in The Journal of Neuropsychiatry and Clinical Neurosciences. 2003;15(1):109-112. doi: 10.1176/jnp.15.1.109.

2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.

3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.

4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.

5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.

6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.

7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.

Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.

In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.

“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.

Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.

“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”¹

It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.

That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.

courtesy McGovern Medical School

“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.

“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
 

Repeating Nucleotides

Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.

The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.²

The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.³

The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.

“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.⁴
 

Managing Symptoms

There is no cure for Huntington’s disease. The current management approach is to treat the symptoms of the disease, although several promising strategies for moderating its severity are in development, say neurologists.

There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).

courtesy University of Alabama at Birmingham

“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.

Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.

“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.

Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.

Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.

In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.

As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
 

Disease-Modifying Therapies

As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.

courtesy Johns Hopkins University

“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.

The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.

“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
 

Gene Therapy

Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.

The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).

AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.

“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
 

Oral Splicing Modifier

PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.

The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.⁵

In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.

“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
 

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.

One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.⁶ The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.

Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.

Somatic Expansion

Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.

“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.

“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
 

Does HTT Lowering Mediate Progression?

“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.

One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.⁷ The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).

“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.

“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.

References

1. Huntington G. On Chorea. Reprinted in The Journal of Neuropsychiatry and Clinical Neurosciences. 2003;15(1):109-112. doi: 10.1176/jnp.15.1.109.

2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.

3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.

4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.

5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.

6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.

7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.

Much progress has been made in managing the symptoms of Huntington’s disease, but the real excitement lies in the development of disease-modifying drugs and genetic therapy.

In April 1872, The Medical and Surgical Reporter of Philadelphia published a roughly 3,000-word paper, titled “On Chorea,” by George Huntington, a 22-year-old family practice physician recently graduated from Columbia University, New York City.

“Chorea is essentially a disease of the nervous system. The name ‘chorea’ is given to the disease on account of the dancing propensities of those who are affected by it, and it is a very appropriate designation,” he wrote in the introduction.

Toward the end of the paper Dr. Huntington described a “hereditary chorea” that he had observed while on professional rounds with his father, also a physician, in towns on the eastern end of Long Island in New York.

“It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror, and not at all alluded to except through dire necessity, when it is mentioned as ‘that disorder,’ ” he wrote, noting later that “I have never known a recovery or even an amelioration of symptoms in this form of chorea; when once it begins it clings to the bitter end.”¹

It wasn’t until 1993 that a team of investigators identified the gene responsible for the neurodegenerative disorder we now know as Huntington’s disease.

That discovery sparked hope for better treatments and a cure, but progress over the last 31 years has been incremental. Nonetheless, recent intensive research into novel approaches for treating Huntington’s disease have considerably brightened prospects for patients and caregivers, experts say.

courtesy McGovern Medical School

“This is a devastating neurodegenerative disease and in talking to families that I have had the privilege and honor of following, I hear from them that ‘in 1993 when the gene was identified and my family member — parent, grandparent, aunt, uncle — had Huntington’s, we thought that there would be a curative or disease-modifying therapy in no time,’ ” said Erin Furr Stimming, MD, FAAN, FANA professor of neurology and Memorial Hermann Endowed Chair at the McGovern Medical School at University of Texas Health Science Center in Houston.

“Here we are in 2024. I think our families are still so incredibly resilient and courageous, and they are willing and able to participate in clinical trials. Families in the Huntington’s disease community at large are really ready to have trials that do, in fact, demonstrate some evidence of slowing of disease progression. It’s an exciting time,” she said in an interview.
 

Repeating Nucleotides

Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin gene (HTT), which encodes for the huntingtin protein (HTT). The multiple repeats result in expanded expression of mutant HTT. The mutated protein disrupts normal cellular processes, alters intracellular calcium homeostasis, and interferes with gene transcription, leading to progressive degeneration of neurons, and to a hallmark Huntington’s disease triad consisting of movement disorders, cognitive decline, and mood/behavioral issues.

The number of repeats determines the severity of disease and the age of onset. In nonaffected persons the gene contains about 20 CAG repeats, but as genetics research dating from the 1990s has shown, a single HTT allele containing more than 40 CAG repeats will inevitably result in disease, whereas carriers with fewer than 36 repeats on both alleles will remain unaffected.²

The prevalence of the mutation in Western populations is estimated to be from 4 to 10 per 100,000.³

The disease usually manifests first in adults aged 30-50 years but may also occur in children or adolescents and young adults. Early symptoms often include a decline in executive function that may be noticeable to the patient’s family and friends, mood changes, and chorea.

“Because of the uncontrolled movements (chorea), a person with Huntington’s disease may lose a lot of weight without intending to, and may have trouble walking, balancing, and moving around safely. They will eventually lose the ability to work, drive, and manage tasks at home, and may qualify for disability benefits. Over time, the individual will develop difficulty with speaking and swallowing, and their movements will become slow and stiff. People with advanced Huntington’s disease need full-time care to help with their day-to-day activities, and they ultimately succumb to pneumonia, heart failure, or other complications,” according to the Huntington’s Disease Society of America.⁴
 

Managing Symptoms

There is no cure for Huntington’s disease. The current management approach is to treat the symptoms of the disease, although several promising strategies for moderating its severity are in development, say neurologists.

There are currently three medications approved for the treatment of chorea, all in the class of agents known as vesicular monoamine transporter 2 inhibitors. These agents are tetrabenazine (Xenazine, Lundbeck), deutetrabenazine (Austedo XR, Teva), and valbenazine (Ingrezza, Neurocrine Biosciences).

courtesy University of Alabama at Birmingham

“These drugs can treat the chorea, but they also can help with some of the other motor features. For example, if a patient has chorea in the legs and you treat it, then maybe they’re walking will get better, or if they have chorea in the mouth and you treat the chorea, then maybe their speech and swallowing may improve,” Victor Sung, MD, professor of neurology and director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham, said in an interview.

Mood and behavioral symptoms associated with Huntington’s disease – depression, anxiety, irritability, impulsivity, etc – can be managed with off-label use of antidepressants, mood stabilizers, and antipsychotic agents.

“When it comes to the cognitive symptoms, that’s a big gap where we don’t have anything that’s [Food and Drug Administration] approved for Huntington’s disease,” Dr. Sung said.

Agents used to treat Alzheimer’s disease, such as cholinesterase inhibitors and the glutamate receptor antagonist memantine, have been studied extensively for preservation of cognition in Huntington’s disease, but have not shown significant benefit.

Dr. Sung said that one promising approach to the problem of cognitive protection in Huntington’s disease is the investigational agent dalzanemdor (SAGE-718), an N-methyl-D-aspartic (NMDA) acid receptor positive allosteric modulator. The drug is in development for cognitive disorders associated with NMDA receptor dysfunction, including Huntington’s disease and Alzheimer’s disease.

In the phase 2 SURVEYOR trial, which was not powered to show efficacy of dalzanemdor over placebo, patients with Huntington’s disease reportedly tolerated the drug well, with treatment-related adverse events primarily mild or moderate in severity.

As of this writing dalzanemdor is being evaluated for efficacy, compared with placebo, in the phase 2 DIMENSION trial. The primary endpoint of this trial is a change from baseline in composite score of the Huntington’s Disease Cognitive Assessment Battery.
 

Disease-Modifying Therapies

As previously noted, although there is no cure for Huntington’s disease, neurology investigators are developing new strategies for delaying, stalling, or even preventing disease progression.

courtesy Johns Hopkins University

“There are so many different approaches, it’s hard to know where to start,” Christopher A. Ross, MD, director of the Huntington’s Disease Center at Johns Hopkins University in Baltimore, Maryland, said in an interview.

The most actively investigated approach may be huntingtin-lowering therapies, based on the supposition that mutant huntingtin protein (mHTT) is the primary toxin in Huntington’s disease.

“What you need to do is in some way lower it, and there are a number of different ways to do that: antinsense olignoclueotides, small interfering RNA, CRISPR Cas, or other gene-editing techniques, as well as gene therapy with an adenoviral vector” he said.
 

Gene Therapy

Dr. Ross cited as promising a phase 1/2 clinical trial of an investigational gene therapy, AMT-130 (uniQure), which consists of an adeno-associated virus vector and a gene encoding a microRNA that is designed to recognize, bind, and nonselectively lower both mHTT and wild-type HTT.

The compound is injected directly into the corpus striatum. It was demonstrated to decrease signs of Huntington’s disease in animal models, and interim data on 29 patients with Huntington’s disease followed for up to 24 months showed a statically significant, dose-dependent slowing of Huntington’s disease progression and lowering of neurofilament light protein, a marker for neuronal degeneration in Huntington’s disease, in cerebrospinal fluid (CSF).

AMT-130 targets exon 1 of the HTT gene, which appears to be an important target, Dr. Ross commented.

“The huntingtin protein is really big. The polyglutamine expansion, which is what causes the toxicity, is right at the N-terminus of exon 1, and there is increasingly good evidence that you can have an exon 1 misspliced protein product which causes the toxicity, so it may be especially important to lower Huntington by targeting exon 1,” he said.
 

Oral Splicing Modifier

PTC Therapeutics, based in New Jersey, is developing PTC518, an oral small molecule drug that can cross the blood-brain barrier and is reported to target mutant huntingtin protein.

The drug is a splicing modifier that promotes insertion of a premature stop codon to HTT mRNA, thereby degrading and lowering the HTT levels.⁵

In June 2024, the company reported that, in the phase 2a PIVOT-HD study of PTC518 in patients with Huntington’s disease, 12 months of treatment was associated with a dose-dependent lowering of mHTT in blood and CSF in an interim cohort.

“In addition, favorable trends were demonstrated on several relevant Huntington’s disease clinical assessments including Total Motor Score and Composite Unified Huntington’s Disease Rating Scale. Furthermore, following 12 months of treatment, PTC518 continues to be safe and well tolerated,” the company stated in a press release.
 

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are short strands of DNA or RNA that bind to RNA sequences in faulty genes to modify production of target proteins.

One such drug, tominersen, developed jointly by Ionis and Roche, initially showed promise in a phase 1/2 trial for lowering mHTT in CSF without serious adverse events. But in a phase 3 trial, the intrathecally delivered agent was halted after an independent data monitoring committee recommended halting the trial, which Roche ended in 2021. The company reported in a letter to The New England Journal of Medicine that people in the high-dosage treatment group did measurably worse – although it remains unclear whether this was caused by excess protein lowering or an off-target effect.⁶ The tominersen program was the first to demonstrate that it was possible to lower HTT with an intervention, and the companies reported that they are continuing the agent’s development program.

Wave Life Sciences is developing an ASO, labeled WVE-003, designed to target a single-nucleotide polymorphism associated with the mHTT mRNA transcript within HTT. The company says that targeting the single-nucleotide polymorphism should allow lowering of expression of the mHTT will preserving wild-type HTT. This approach has the potential for therapies to prevent disease progression during the prodromal period, the company states.

Somatic Expansion

Dr. Furr Stimming and Dr. Ross both noted that there is considerable research interest into recently identified genetic modifiers that are believed to influence somatic instability, which in turn leads to somatic expansion.

“That seems to happen selectively in the neurons that are affected in Huntington’s disease. So a big puzzle for all of the neurodegenerative diseases is why are certain regions of the brain affected and other regions not? And it looks like, for the repeat expansion, this idea of somatic expansion seems to be increasingly central,” Dr. Ross said.

“The really exciting idea here is that, if somatic expansion is critical to the disease process and you could slow it down or stop it, you could go very early and potentially not just slow the progression of the disease once it starts, but conceivably even delay or possibly prevent the onset of Huntington’s disease,” he said.
 

Does HTT Lowering Mediate Progression?

“The next question is what does this mean clinically? Does lowering mutant huntingtin protein levels, and wild type for that matter, actually slow disease progression, which can be challenging to measure in a disease that is relatively slowly progressive?,” Dr. Furr Stimming said.

One important tool to help answer this question, she noted, is the Huntington’s Disease Integrated Staging System (HDISS), first described in 2022.⁷ The consensus-based system incorporates biological, clinical, and functional assessments, and characterizes patients from birth by stages, from stage 0 (persons who carry the mutation but have no detectable pathology), to stage 1 (measurable indicators of underlying pathophysiology), stage 2 (a detectable clinical phenotype), and finally to stage 3 (decline in function).

“The goal of the HDISS, which is designed for clinical research purposes, is to try to enroll individuals into clinical trials earlier rather than later, trying to get pharmaceutical companies and others to take advantage of the period prior to significant neurodegeneration occurring. Like Alzheimer’s disease and Parkinson’s disease, by the time we make a clinical diagnose significant neurodegeneration has occurred, so we really want to take advantage of the prodromal period to intervene with these potential disease-modifying therapies,” Dr. Furr Stimming said.

“At the end of the day, I suspect that we will not have just one effective disease-modifying therapy. I suspect that it will be a multifacted approach. We envision that we would hit the huntingtin protein from a few different angles. I envision that we would not only modify in some form or fashion production of the mutant huntingtin protein, but also try to influence the genetic modifiers that we think are important in somatic instability and expansion, which likely contributes to the rate of progression and symptom severity,” Dr. Furr Stimming said.

References

1. Huntington G. On Chorea. Reprinted in The Journal of Neuropsychiatry and Clinical Neurosciences. 2003;15(1):109-112. doi: 10.1176/jnp.15.1.109.

2. Kaemmerer WF and Grondin RC. Degener Neurol Neuromuscul Dis. 2019 Mar 8;9:3-17. doi: 10.2147/DNND.S163808.

3. Jimenez-Sanchez M et al. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240.

4. Huntington’s Disease Society of America. Overview of Huntington’s Disease. https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/.

5. Beers B et al. J Neurol Neurosurg Psychiatry. 2022;93:A96. https://jnnp.bmj.com/content/93/Suppl_1/A96.1.

6. McColgan P et al. N Engl J Med. 2023 Dec 7;389(23):2203-2205. doi: 10.1056/NEJMc2300400.

7. Tabrizi SJ et al. Lancet Neurol. 2022 Jul;21(7):632-644. doi: 10.1016/S1474-4422(22)00120-X.

Newborn screening programs are public health services aimed at ensuring that the close to 4 million infants born each year in the United States are screened for certain serious disorders at birth. These disorders, albeit rare, are detected in roughly 12,500 newborn babies every year.

Newborn screening isn’t new, although it has expanded and transformed over the decades. The first newborn screening test was developed in the 1960s to detect phenylketonuria (PKU).¹ Since then, the number of conditions screened for has increased, with programs in every US state and territory. “Newborn screening is well established now, not experimental or newfangled,” Wendy Chung, MD, PhD, professor of pediatrics, Harvard Medical School, Boston, Massachusetts, told Neurology Reviews.

Challenges in Expanding the Current Newborn Screening

One of the major drawbacks in the current system is that “we don’t screen for enough diseases,” according to Zhanzhi Hu, PhD, of the Department of Systems Biology and the Department of Biomedical Information, Columbia University, New York City. “There are over 10,000 rare genetic diseases, but we’re currently screening for fewer than 100,” he told Neurology Reviews. Although in the United States, there are about 700-800 drugs approved for genetic diseases, “we can’t identify patients with these diseases early enough for the ideal window when treatments are most effective.”

Moreover, it’s a “lengthy process” to add new diseases to RUSP. “New conditions are added at the pace of less than one per year, on average — even for the hundreds of diseases for which there are treatments,” he said. “If we keep going at the current pace, we won’t be able to screen for those diseases for another few hundred years.”

Screening and Drug Development Working in Tandem

Sequencing technologies have advanced and become more sophisticated as well as less costly, so interest in expanding newborn screening through newborn genome sequencing has increased. In fact, many states currently have incorporated genetic testing into newborn screening for conditions without biochemical markers. Additionally, newborn genomic sequencing is also used for further testing in infants with abnormal biochemical screening results.⁶

Genomic sequencing “identifies nucleotide changes that are the underlying etiology of monogenic disorders.”⁶ Its use could potentially enable identification of over 500 genetic disorders for which an newborn screening assay is not currently available, said Dr. Hu.

“Molecular DNA analysis has been integrated into newborn testing either as a first- or second-tier test for several conditions, including cystic fibrosis, severe combined immunodeficiency, and spinal muscular atrophy (SMA),” Dr. Hu said.

Dr. Hu pointed to SMA to illustrate the power and potential of newborn screening working hand-in-hand with the development of new treatments. SMA is a neurodegenerative disorder caused by mutations in SMN1, which encodes survival motor neuron protein (SMN).⁷ Deficiencies in SMN results in loss of motor neurons with muscle weakness and, often, early death.⁷A pilot study, on which Dr. Chung was the senior author, used both biochemical and genetic testing of close to 4000 newborns and found an SMA carrier frequency of 1.5%. One newborn was identified who had a homozygous SMN1 gene deletion and two copies of SMN2, strongly suggesting the presence of a severe type 1 SMA phenotype.⁸

At age 15 days, the baby was treated with nusinersen, an injection administered into the fluid surrounding the spinal cord, and the first FDA-approved genetic treatment for SMA. At the time of study publication, the baby was 12 months old, “meeting all developmental milestones and free of any respiratory issues,” the authors report.

“Screening for SMA — which was added to the RUSP in 2018 — has dramatically transformed what used to be the most common genetic cause of death in children under the age of 2,” Dr. Chung said. “Now, a once-and-done IV infusion of genetic therapy right after screening has transformed everything, taking what used to be a lethal condition and allowing children to grow up healthy.”
 

Advocating for Inclusion of Diseases With No Current Treatment

At present, any condition included in the RUSP is required to have a treatment, which can be dietary, surgical/procedural, or an FDA-approved drug-based agent. Unfortunately, a wide range of neurodevelopmental diseases still have no known treatments. But lack of availability of treatment shouldn’t invalidate a disease from being included in the RUSP, because even if there is no specific treatment for the condition itself, early intervention can still be initiated to prevent some of the manifestations of the condition, said Dr. Hu.

“For example, most patients with these diseases will sooner or later undergo seizures,” Dr. Hu remarked. “We know that repeated seizures can cause brain damage. If we can diagnose the disease before the seizures start to take place, we can put preventive seizure control interventions in place, even if there is no direct ‘treatment’ for the condition itself.”

Early identification can lead to early intervention, which can have other benefits, Dr. Hu noted. “If we train the brain at a young age, when the brain is most receptive, even though a disease may be progressive and will worsen, those abilities acquired earlier will last longer and remain in place longer. When these skills are acquired later, they’re forgotten sooner. This isn’t a ‘cure,’ but it will help with functional improvement.”

Moreover, parents are “interested in knowing that their child has a condition, even if no treatment is currently available for that disorder, according to our research,” Dr. Chung said. “We found that the parents we interviewed endorsed the nonmedical utility of having access to information, even in the absence of a ‘cure,’ so they could prepare for medical issues that might arise down the road and make informed choices.”⁹

Nina Gold, MD, director of Prenatal Medical Genetics and associate director for Research for Massachusetts General Brigham Personalized Medicine, Boston, obtained similar findings in her own research, which is currently under review for publication. “We conducted focus groups and one-on-one interviews with parents from diverse racial and socioeconomic backgrounds. At least one parent said they didn’t want to compare their child to other children if their child might have a different developmental trajectory. They stressed that the information would be helpful, even if there was no immediate clinical utility.”

Next Steps Following Screening

Rebecca Sponberg, NP, of the Children’s Hospital of Orange County, UC Irvine School of Medicine, California, is part of a broader multidisciplinary team that interfaces with parents whose newborns have screened positive for a genetic disorder. The team also includes a biochemical geneticist, a pediatric neurologist, a pediatric endocrinologist, a genetic counselor, and a social worker.

Different states and locations have different procedures for receiving test results, said Dr. Chung. In some, pediatricians are the ones who receive the results, and they are tasked with the responsibility of making sure the children can start getting appropriate care. In particular, these pediatricians are associated with centers of excellence that specialize in working with families around these conditions. Other facilities have multidisciplinary teams.

Educating and Involving Families

Part of the role of clinicians is to provide education regarding newborn screening to families, according to Ms. Sponberg. “In my role, I have to call parents to tell them their child screened positive for a genetic condition and that we need to proceed with confirmatory testing,” she said. “We let them know if there’s a high concern that this might be a true positive for the condition, and we offer them information so they know what to expect.”

Unfortunately, Ms. Sponberg said, in the absence of education, some families are skeptical. “When I call families directly, some think it’s a scam and it can be hard to earn their trust. We need to do a better job educating families, especially our pregnant individuals, that testing will occur and if anything is abnormal, they will receive a call.”

References

1. Levy HL. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int J Neonatal Screen. 2021 Jan 19;7(1):5. doi: 10.3390/ijns7010005.

2. Chace DH et al. Clinical Chemistry and Dried Blood Spots: Increasing Laboratory Utilization by Improved Understanding of Quantitative Challenges. Bioanalysis. 2014;6(21):2791-2794. doi: 10.4155/bio.14.237.

3. Gold NB et al. Perspectives of Rare Disease Experts on Newborn Genome Sequencing. JAMA Netw Open. 2023 May 1;6(5):e2312231. doi: 10.1001/jamanetworkopen.2023.12231.

4. Weismiller DG. Expanded Newborn Screening: Information and Resources for the Family Physician. Am Fam Physician. 2017 Jun 1;95(11):703-709. https://www.aafp.org/pubs/afp/issues/2017/0601/p703.html.

5. Neul JL et al. Trofinetide for the Treatment of Rett Syndrome: A Randomized Phase 3 Study. Nat Med. 2023 Jun;29(6):1468-1475. doi: 10.1038/s41591-023-02398-1.

6. Chen T et al. Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening. JAMA Netw Open. 2023 Sep 5;6(9):e2331162. doi: 10.1001/jamanetworkopen.2023.31162.

7. Mercuri E et al. Spinal Muscular Atrophy. Nat Rev Dis Primers. 2022 Aug 4;8(1):52. doi: 10.1038/s41572-022-00380-8.

8. Kraszewski JN et al. Pilot Study of Population-Based Newborn Screening for Spinal Muscular Atrophy in New York State. Genet Med. 2018 Jun;20(6):608-613. doi: 10.1038/gim.2017.152.

9. Timmins GT et al. Diverse Parental Perspectives of the Social and Educational Needs for Expanding Newborn Screening Through Genomic Sequencing. Public Health Genomics. 2022 Sep 15:1-8. doi: 10.1159/000526382.

10. Turk BR et al. X-linked Adrenoleukodystrophy: Pathology, Pathophysiology, Diagnostic Testing, Newborn Screening and Therapies. Int J Dev Neurosci. 2020 Feb;80(1):52-72. doi: 10.1002/jdn.10003.

Newborn screening programs are public health services aimed at ensuring that the close to 4 million infants born each year in the United States are screened for certain serious disorders at birth. These disorders, albeit rare, are detected in roughly 12,500 newborn babies every year.

Newborn screening isn’t new, although it has expanded and transformed over the decades. The first newborn screening test was developed in the 1960s to detect phenylketonuria (PKU).¹ Since then, the number of conditions screened for has increased, with programs in every US state and territory. “Newborn screening is well established now, not experimental or newfangled,” Wendy Chung, MD, PhD, professor of pediatrics, Harvard Medical School, Boston, Massachusetts, told Neurology Reviews.

Challenges in Expanding the Current Newborn Screening

One of the major drawbacks in the current system is that “we don’t screen for enough diseases,” according to Zhanzhi Hu, PhD, of the Department of Systems Biology and the Department of Biomedical Information, Columbia University, New York City. “There are over 10,000 rare genetic diseases, but we’re currently screening for fewer than 100,” he told Neurology Reviews. Although in the United States, there are about 700-800 drugs approved for genetic diseases, “we can’t identify patients with these diseases early enough for the ideal window when treatments are most effective.”

Moreover, it’s a “lengthy process” to add new diseases to RUSP. “New conditions are added at the pace of less than one per year, on average — even for the hundreds of diseases for which there are treatments,” he said. “If we keep going at the current pace, we won’t be able to screen for those diseases for another few hundred years.”

Screening and Drug Development Working in Tandem

Sequencing technologies have advanced and become more sophisticated as well as less costly, so interest in expanding newborn screening through newborn genome sequencing has increased. In fact, many states currently have incorporated genetic testing into newborn screening for conditions without biochemical markers. Additionally, newborn genomic sequencing is also used for further testing in infants with abnormal biochemical screening results.⁶

Genomic sequencing “identifies nucleotide changes that are the underlying etiology of monogenic disorders.”⁶ Its use could potentially enable identification of over 500 genetic disorders for which an newborn screening assay is not currently available, said Dr. Hu.

“Molecular DNA analysis has been integrated into newborn testing either as a first- or second-tier test for several conditions, including cystic fibrosis, severe combined immunodeficiency, and spinal muscular atrophy (SMA),” Dr. Hu said.

Dr. Hu pointed to SMA to illustrate the power and potential of newborn screening working hand-in-hand with the development of new treatments. SMA is a neurodegenerative disorder caused by mutations in SMN1, which encodes survival motor neuron protein (SMN).⁷ Deficiencies in SMN results in loss of motor neurons with muscle weakness and, often, early death.⁷A pilot study, on which Dr. Chung was the senior author, used both biochemical and genetic testing of close to 4000 newborns and found an SMA carrier frequency of 1.5%. One newborn was identified who had a homozygous SMN1 gene deletion and two copies of SMN2, strongly suggesting the presence of a severe type 1 SMA phenotype.⁸

At age 15 days, the baby was treated with nusinersen, an injection administered into the fluid surrounding the spinal cord, and the first FDA-approved genetic treatment for SMA. At the time of study publication, the baby was 12 months old, “meeting all developmental milestones and free of any respiratory issues,” the authors report.

“Screening for SMA — which was added to the RUSP in 2018 — has dramatically transformed what used to be the most common genetic cause of death in children under the age of 2,” Dr. Chung said. “Now, a once-and-done IV infusion of genetic therapy right after screening has transformed everything, taking what used to be a lethal condition and allowing children to grow up healthy.”
 

Advocating for Inclusion of Diseases With No Current Treatment

At present, any condition included in the RUSP is required to have a treatment, which can be dietary, surgical/procedural, or an FDA-approved drug-based agent. Unfortunately, a wide range of neurodevelopmental diseases still have no known treatments. But lack of availability of treatment shouldn’t invalidate a disease from being included in the RUSP, because even if there is no specific treatment for the condition itself, early intervention can still be initiated to prevent some of the manifestations of the condition, said Dr. Hu.

“For example, most patients with these diseases will sooner or later undergo seizures,” Dr. Hu remarked. “We know that repeated seizures can cause brain damage. If we can diagnose the disease before the seizures start to take place, we can put preventive seizure control interventions in place, even if there is no direct ‘treatment’ for the condition itself.”

Early identification can lead to early intervention, which can have other benefits, Dr. Hu noted. “If we train the brain at a young age, when the brain is most receptive, even though a disease may be progressive and will worsen, those abilities acquired earlier will last longer and remain in place longer. When these skills are acquired later, they’re forgotten sooner. This isn’t a ‘cure,’ but it will help with functional improvement.”

Moreover, parents are “interested in knowing that their child has a condition, even if no treatment is currently available for that disorder, according to our research,” Dr. Chung said. “We found that the parents we interviewed endorsed the nonmedical utility of having access to information, even in the absence of a ‘cure,’ so they could prepare for medical issues that might arise down the road and make informed choices.”⁹

Nina Gold, MD, director of Prenatal Medical Genetics and associate director for Research for Massachusetts General Brigham Personalized Medicine, Boston, obtained similar findings in her own research, which is currently under review for publication. “We conducted focus groups and one-on-one interviews with parents from diverse racial and socioeconomic backgrounds. At least one parent said they didn’t want to compare their child to other children if their child might have a different developmental trajectory. They stressed that the information would be helpful, even if there was no immediate clinical utility.”

Next Steps Following Screening

Rebecca Sponberg, NP, of the Children’s Hospital of Orange County, UC Irvine School of Medicine, California, is part of a broader multidisciplinary team that interfaces with parents whose newborns have screened positive for a genetic disorder. The team also includes a biochemical geneticist, a pediatric neurologist, a pediatric endocrinologist, a genetic counselor, and a social worker.

Different states and locations have different procedures for receiving test results, said Dr. Chung. In some, pediatricians are the ones who receive the results, and they are tasked with the responsibility of making sure the children can start getting appropriate care. In particular, these pediatricians are associated with centers of excellence that specialize in working with families around these conditions. Other facilities have multidisciplinary teams.

Educating and Involving Families

Part of the role of clinicians is to provide education regarding newborn screening to families, according to Ms. Sponberg. “In my role, I have to call parents to tell them their child screened positive for a genetic condition and that we need to proceed with confirmatory testing,” she said. “We let them know if there’s a high concern that this might be a true positive for the condition, and we offer them information so they know what to expect.”

Unfortunately, Ms. Sponberg said, in the absence of education, some families are skeptical. “When I call families directly, some think it’s a scam and it can be hard to earn their trust. We need to do a better job educating families, especially our pregnant individuals, that testing will occur and if anything is abnormal, they will receive a call.”

References

1. Levy HL. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int J Neonatal Screen. 2021 Jan 19;7(1):5. doi: 10.3390/ijns7010005.

2. Chace DH et al. Clinical Chemistry and Dried Blood Spots: Increasing Laboratory Utilization by Improved Understanding of Quantitative Challenges. Bioanalysis. 2014;6(21):2791-2794. doi: 10.4155/bio.14.237.

3. Gold NB et al. Perspectives of Rare Disease Experts on Newborn Genome Sequencing. JAMA Netw Open. 2023 May 1;6(5):e2312231. doi: 10.1001/jamanetworkopen.2023.12231.

4. Weismiller DG. Expanded Newborn Screening: Information and Resources for the Family Physician. Am Fam Physician. 2017 Jun 1;95(11):703-709. https://www.aafp.org/pubs/afp/issues/2017/0601/p703.html.

5. Neul JL et al. Trofinetide for the Treatment of Rett Syndrome: A Randomized Phase 3 Study. Nat Med. 2023 Jun;29(6):1468-1475. doi: 10.1038/s41591-023-02398-1.

6. Chen T et al. Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening. JAMA Netw Open. 2023 Sep 5;6(9):e2331162. doi: 10.1001/jamanetworkopen.2023.31162.

7. Mercuri E et al. Spinal Muscular Atrophy. Nat Rev Dis Primers. 2022 Aug 4;8(1):52. doi: 10.1038/s41572-022-00380-8.

8. Kraszewski JN et al. Pilot Study of Population-Based Newborn Screening for Spinal Muscular Atrophy in New York State. Genet Med. 2018 Jun;20(6):608-613. doi: 10.1038/gim.2017.152.

9. Timmins GT et al. Diverse Parental Perspectives of the Social and Educational Needs for Expanding Newborn Screening Through Genomic Sequencing. Public Health Genomics. 2022 Sep 15:1-8. doi: 10.1159/000526382.

10. Turk BR et al. X-linked Adrenoleukodystrophy: Pathology, Pathophysiology, Diagnostic Testing, Newborn Screening and Therapies. Int J Dev Neurosci. 2020 Feb;80(1):52-72. doi: 10.1002/jdn.10003.

Newborn screening programs are public health services aimed at ensuring that the close to 4 million infants born each year in the United States are screened for certain serious disorders at birth. These disorders, albeit rare, are detected in roughly 12,500 newborn babies every year.

Newborn screening isn’t new, although it has expanded and transformed over the decades. The first newborn screening test was developed in the 1960s to detect phenylketonuria (PKU).¹ Since then, the number of conditions screened for has increased, with programs in every US state and territory. “Newborn screening is well established now, not experimental or newfangled,” Wendy Chung, MD, PhD, professor of pediatrics, Harvard Medical School, Boston, Massachusetts, told Neurology Reviews.

Challenges in Expanding the Current Newborn Screening

One of the major drawbacks in the current system is that “we don’t screen for enough diseases,” according to Zhanzhi Hu, PhD, of the Department of Systems Biology and the Department of Biomedical Information, Columbia University, New York City. “There are over 10,000 rare genetic diseases, but we’re currently screening for fewer than 100,” he told Neurology Reviews. Although in the United States, there are about 700-800 drugs approved for genetic diseases, “we can’t identify patients with these diseases early enough for the ideal window when treatments are most effective.”

Moreover, it’s a “lengthy process” to add new diseases to RUSP. “New conditions are added at the pace of less than one per year, on average — even for the hundreds of diseases for which there are treatments,” he said. “If we keep going at the current pace, we won’t be able to screen for those diseases for another few hundred years.”

Screening and Drug Development Working in Tandem

Sequencing technologies have advanced and become more sophisticated as well as less costly, so interest in expanding newborn screening through newborn genome sequencing has increased. In fact, many states currently have incorporated genetic testing into newborn screening for conditions without biochemical markers. Additionally, newborn genomic sequencing is also used for further testing in infants with abnormal biochemical screening results.⁶

Genomic sequencing “identifies nucleotide changes that are the underlying etiology of monogenic disorders.”⁶ Its use could potentially enable identification of over 500 genetic disorders for which an newborn screening assay is not currently available, said Dr. Hu.

“Molecular DNA analysis has been integrated into newborn testing either as a first- or second-tier test for several conditions, including cystic fibrosis, severe combined immunodeficiency, and spinal muscular atrophy (SMA),” Dr. Hu said.

Dr. Hu pointed to SMA to illustrate the power and potential of newborn screening working hand-in-hand with the development of new treatments. SMA is a neurodegenerative disorder caused by mutations in SMN1, which encodes survival motor neuron protein (SMN).⁷ Deficiencies in SMN results in loss of motor neurons with muscle weakness and, often, early death.⁷A pilot study, on which Dr. Chung was the senior author, used both biochemical and genetic testing of close to 4000 newborns and found an SMA carrier frequency of 1.5%. One newborn was identified who had a homozygous SMN1 gene deletion and two copies of SMN2, strongly suggesting the presence of a severe type 1 SMA phenotype.⁸

At age 15 days, the baby was treated with nusinersen, an injection administered into the fluid surrounding the spinal cord, and the first FDA-approved genetic treatment for SMA. At the time of study publication, the baby was 12 months old, “meeting all developmental milestones and free of any respiratory issues,” the authors report.

“Screening for SMA — which was added to the RUSP in 2018 — has dramatically transformed what used to be the most common genetic cause of death in children under the age of 2,” Dr. Chung said. “Now, a once-and-done IV infusion of genetic therapy right after screening has transformed everything, taking what used to be a lethal condition and allowing children to grow up healthy.”
 

Advocating for Inclusion of Diseases With No Current Treatment

At present, any condition included in the RUSP is required to have a treatment, which can be dietary, surgical/procedural, or an FDA-approved drug-based agent. Unfortunately, a wide range of neurodevelopmental diseases still have no known treatments. But lack of availability of treatment shouldn’t invalidate a disease from being included in the RUSP, because even if there is no specific treatment for the condition itself, early intervention can still be initiated to prevent some of the manifestations of the condition, said Dr. Hu.

“For example, most patients with these diseases will sooner or later undergo seizures,” Dr. Hu remarked. “We know that repeated seizures can cause brain damage. If we can diagnose the disease before the seizures start to take place, we can put preventive seizure control interventions in place, even if there is no direct ‘treatment’ for the condition itself.”

Early identification can lead to early intervention, which can have other benefits, Dr. Hu noted. “If we train the brain at a young age, when the brain is most receptive, even though a disease may be progressive and will worsen, those abilities acquired earlier will last longer and remain in place longer. When these skills are acquired later, they’re forgotten sooner. This isn’t a ‘cure,’ but it will help with functional improvement.”

Moreover, parents are “interested in knowing that their child has a condition, even if no treatment is currently available for that disorder, according to our research,” Dr. Chung said. “We found that the parents we interviewed endorsed the nonmedical utility of having access to information, even in the absence of a ‘cure,’ so they could prepare for medical issues that might arise down the road and make informed choices.”⁹

Nina Gold, MD, director of Prenatal Medical Genetics and associate director for Research for Massachusetts General Brigham Personalized Medicine, Boston, obtained similar findings in her own research, which is currently under review for publication. “We conducted focus groups and one-on-one interviews with parents from diverse racial and socioeconomic backgrounds. At least one parent said they didn’t want to compare their child to other children if their child might have a different developmental trajectory. They stressed that the information would be helpful, even if there was no immediate clinical utility.”

Next Steps Following Screening

Rebecca Sponberg, NP, of the Children’s Hospital of Orange County, UC Irvine School of Medicine, California, is part of a broader multidisciplinary team that interfaces with parents whose newborns have screened positive for a genetic disorder. The team also includes a biochemical geneticist, a pediatric neurologist, a pediatric endocrinologist, a genetic counselor, and a social worker.

Different states and locations have different procedures for receiving test results, said Dr. Chung. In some, pediatricians are the ones who receive the results, and they are tasked with the responsibility of making sure the children can start getting appropriate care. In particular, these pediatricians are associated with centers of excellence that specialize in working with families around these conditions. Other facilities have multidisciplinary teams.

Educating and Involving Families

Part of the role of clinicians is to provide education regarding newborn screening to families, according to Ms. Sponberg. “In my role, I have to call parents to tell them their child screened positive for a genetic condition and that we need to proceed with confirmatory testing,” she said. “We let them know if there’s a high concern that this might be a true positive for the condition, and we offer them information so they know what to expect.”

Unfortunately, Ms. Sponberg said, in the absence of education, some families are skeptical. “When I call families directly, some think it’s a scam and it can be hard to earn their trust. We need to do a better job educating families, especially our pregnant individuals, that testing will occur and if anything is abnormal, they will receive a call.”

References

1. Levy HL. Robert Guthrie and the Trials and Tribulations of Newborn Screening. Int J Neonatal Screen. 2021 Jan 19;7(1):5. doi: 10.3390/ijns7010005.

2. Chace DH et al. Clinical Chemistry and Dried Blood Spots: Increasing Laboratory Utilization by Improved Understanding of Quantitative Challenges. Bioanalysis. 2014;6(21):2791-2794. doi: 10.4155/bio.14.237.

3. Gold NB et al. Perspectives of Rare Disease Experts on Newborn Genome Sequencing. JAMA Netw Open. 2023 May 1;6(5):e2312231. doi: 10.1001/jamanetworkopen.2023.12231.

4. Weismiller DG. Expanded Newborn Screening: Information and Resources for the Family Physician. Am Fam Physician. 2017 Jun 1;95(11):703-709. https://www.aafp.org/pubs/afp/issues/2017/0601/p703.html.

5. Neul JL et al. Trofinetide for the Treatment of Rett Syndrome: A Randomized Phase 3 Study. Nat Med. 2023 Jun;29(6):1468-1475. doi: 10.1038/s41591-023-02398-1.

6. Chen T et al. Genomic Sequencing as a First-Tier Screening Test and Outcomes of Newborn Screening. JAMA Netw Open. 2023 Sep 5;6(9):e2331162. doi: 10.1001/jamanetworkopen.2023.31162.

7. Mercuri E et al. Spinal Muscular Atrophy. Nat Rev Dis Primers. 2022 Aug 4;8(1):52. doi: 10.1038/s41572-022-00380-8.

8. Kraszewski JN et al. Pilot Study of Population-Based Newborn Screening for Spinal Muscular Atrophy in New York State. Genet Med. 2018 Jun;20(6):608-613. doi: 10.1038/gim.2017.152.

9. Timmins GT et al. Diverse Parental Perspectives of the Social and Educational Needs for Expanding Newborn Screening Through Genomic Sequencing. Public Health Genomics. 2022 Sep 15:1-8. doi: 10.1159/000526382.

10. Turk BR et al. X-linked Adrenoleukodystrophy: Pathology, Pathophysiology, Diagnostic Testing, Newborn Screening and Therapies. Int J Dev Neurosci. 2020 Feb;80(1):52-72. doi: 10.1002/jdn.10003.

“Here’s my records.”

I hear that a lot, usually in the context of a patient handing me a flash drive or (less commonly) trying to plug it into my computer. (I have the USB ports turned toward me to keep that from happening.)

Uh, no.

I love flash drives. They definitely make data transfer easy, compared with the CDs, ZIPs, JAZZ, floppies, paper, and punch cards of past years (I should also, as a childhood TRS-80 user, include cassette tapes).

At this point an encrypted flash drive is pretty much the entire briefcase I carry back and forth to work each day.

But there is no patient I trust enough to plug in one they handed me.

I’m sure most, if not all, are well meaning. But look at how many large corporations have been damaged by someone slipping in a flash drive with a malicious program somewhere in their network. Once in, it’s almost impossible to get out, and can spread quickly.

Even if the patient is benign, I have no idea who formatted the gadget, or put the records on. It could be a relative, or friend, with other motives. It could even be a random flash drive and they don’t even know what else is on it.

My desktop is my chart system. I have to protect the data of all my patients, so I exercise caution about what emails I open and what I plug into it. Even the person offering me the flash drive wants the info guarded.

So I don’t, as a rule, plug in anything a patient hands me. All it takes is one malicious file to compromise it all. Yeah, I pay for software to watch for that sort of thing, but you still can’t be too careful.

This is where paper still shines. It’s readable and it’s transportable (at least for small things like an MRI report and lab results). I can scan it into a PDF without risking any damage to my computer. And it definitely shouldn’t be plugged into a USB drive unless you’re trying to start a fire.

Of course, paper isn’t secure, either. If you have it piled up everywhere it’s pretty easy for an unsupervised person to walk off with it. That actually happened to a doctor I shared space with 20 years ago, albeit unintentionally. A patient had brought in a bunch of his records in a folder and set them down on the counter. When he left he grabbed another patient’s chart by mistake and didn’t realize it until the next day. Fortunately he returned them promptly, and there were no issues. But it had the potential to be worse.

Today my charts on roughly 20,000 patients can all fit on a gadget the size of my thumb instead of a multi-room shelving system and storage closet. That’s pretty cool, actually. But it also opens other vulnerabilities.

It ticks some patients off that I won’t plug in their flash drives, but I don’t care. Most of them understand when I explain it, because it’s to protect them, too.

The odds are that they don’t mean any harm, but I can’t take that chance.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

“Here’s my records.”

I hear that a lot, usually in the context of a patient handing me a flash drive or (less commonly) trying to plug it into my computer. (I have the USB ports turned toward me to keep that from happening.)

Uh, no.

I love flash drives. They definitely make data transfer easy, compared with the CDs, ZIPs, JAZZ, floppies, paper, and punch cards of past years (I should also, as a childhood TRS-80 user, include cassette tapes).

At this point an encrypted flash drive is pretty much the entire briefcase I carry back and forth to work each day.

But there is no patient I trust enough to plug in one they handed me.

I’m sure most, if not all, are well meaning. But look at how many large corporations have been damaged by someone slipping in a flash drive with a malicious program somewhere in their network. Once in, it’s almost impossible to get out, and can spread quickly.

Even if the patient is benign, I have no idea who formatted the gadget, or put the records on. It could be a relative, or friend, with other motives. It could even be a random flash drive and they don’t even know what else is on it.

My desktop is my chart system. I have to protect the data of all my patients, so I exercise caution about what emails I open and what I plug into it. Even the person offering me the flash drive wants the info guarded.

So I don’t, as a rule, plug in anything a patient hands me. All it takes is one malicious file to compromise it all. Yeah, I pay for software to watch for that sort of thing, but you still can’t be too careful.

This is where paper still shines. It’s readable and it’s transportable (at least for small things like an MRI report and lab results). I can scan it into a PDF without risking any damage to my computer. And it definitely shouldn’t be plugged into a USB drive unless you’re trying to start a fire.

Of course, paper isn’t secure, either. If you have it piled up everywhere it’s pretty easy for an unsupervised person to walk off with it. That actually happened to a doctor I shared space with 20 years ago, albeit unintentionally. A patient had brought in a bunch of his records in a folder and set them down on the counter. When he left he grabbed another patient’s chart by mistake and didn’t realize it until the next day. Fortunately he returned them promptly, and there were no issues. But it had the potential to be worse.

Today my charts on roughly 20,000 patients can all fit on a gadget the size of my thumb instead of a multi-room shelving system and storage closet. That’s pretty cool, actually. But it also opens other vulnerabilities.

It ticks some patients off that I won’t plug in their flash drives, but I don’t care. Most of them understand when I explain it, because it’s to protect them, too.

The odds are that they don’t mean any harm, but I can’t take that chance.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

“Here’s my records.”

I hear that a lot, usually in the context of a patient handing me a flash drive or (less commonly) trying to plug it into my computer. (I have the USB ports turned toward me to keep that from happening.)

Uh, no.

I love flash drives. They definitely make data transfer easy, compared with the CDs, ZIPs, JAZZ, floppies, paper, and punch cards of past years (I should also, as a childhood TRS-80 user, include cassette tapes).

At this point an encrypted flash drive is pretty much the entire briefcase I carry back and forth to work each day.

But there is no patient I trust enough to plug in one they handed me.

I’m sure most, if not all, are well meaning. But look at how many large corporations have been damaged by someone slipping in a flash drive with a malicious program somewhere in their network. Once in, it’s almost impossible to get out, and can spread quickly.

Even if the patient is benign, I have no idea who formatted the gadget, or put the records on. It could be a relative, or friend, with other motives. It could even be a random flash drive and they don’t even know what else is on it.

My desktop is my chart system. I have to protect the data of all my patients, so I exercise caution about what emails I open and what I plug into it. Even the person offering me the flash drive wants the info guarded.

So I don’t, as a rule, plug in anything a patient hands me. All it takes is one malicious file to compromise it all. Yeah, I pay for software to watch for that sort of thing, but you still can’t be too careful.

This is where paper still shines. It’s readable and it’s transportable (at least for small things like an MRI report and lab results). I can scan it into a PDF without risking any damage to my computer. And it definitely shouldn’t be plugged into a USB drive unless you’re trying to start a fire.

Of course, paper isn’t secure, either. If you have it piled up everywhere it’s pretty easy for an unsupervised person to walk off with it. That actually happened to a doctor I shared space with 20 years ago, albeit unintentionally. A patient had brought in a bunch of his records in a folder and set them down on the counter. When he left he grabbed another patient’s chart by mistake and didn’t realize it until the next day. Fortunately he returned them promptly, and there were no issues. But it had the potential to be worse.

Today my charts on roughly 20,000 patients can all fit on a gadget the size of my thumb instead of a multi-room shelving system and storage closet. That’s pretty cool, actually. But it also opens other vulnerabilities.

It ticks some patients off that I won’t plug in their flash drives, but I don’t care. Most of them understand when I explain it, because it’s to protect them, too.

The odds are that they don’t mean any harm, but I can’t take that chance.

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Residency programs across the country may have a few more slots for incoming residents due to a recent bump in Medicare funding.

Case in point: The University of Alabama at Birmingham (UAB). The state has one of the top stroke rates in the country, and yet UAB has the only hospital in the state training future doctors to help stroke patients recover. “Our hospital cares for Alabama’s sickest patients, many who need rehabilitation services,” said Craig Hoesley, MD, senior associate dean for medical education, who oversees graduate medical education (GME) or residency programs.

After decades of stagnant support, a recent bump in Medicare funding will allow UAB to add two more physical medicine and rehabilitation residents to the four residencies already receiving such funding.

Medicare also awarded UAB more funding last year to add an addiction medicine fellowship, one of two such training programs in the state for the specialty that helps treat patients fighting addiction.

UAB is among healthcare systems and hospitals nationwide benefiting from a recent hike in Medicare funding for residency programs after some 25 years at the same level of federal support. Medicare is the largest funder of training positions. Otherwise, hospitals finance training through means such as state support.

The latest round of funding, which went into effect in July, adds 200 positions to the doctor pipeline, creating more openings for residents seeking positions after medical school.

In the next few months, the Centers for Medicare & Medicaid Services (CMS) will notify teaching hospitals whether they’ll receive the next round of Medicare funding for more residency positions. At that time, CMS will have awarded nearly half of the 1200 residency training slots Congress approved in the past few years. In 2020 — for the first time since 1996 — Congress approved adding 1000 residency slots at teaching hospitals nationwide. CMS awards the money for 200 slots each year for 5 years.

More than half of the initial round of funding focused on training primary care specialists, with other slots designated for mental health specialists. Last year, Congress also approved a separate allocation of 200 more Medicare-funded residency positions, with at least half designated for psychiatry and related subspecialty residencies to help meet the growing need for more mental health specialists. On August 1, CMS announced it would distribute the funds next year, effective in 2026.

The additional Medicare funding attempts to address the shortage of healthcare providers and ensure future access to care, including in rural and underserved communities. The Association of American Medical Colleges (AAMC) estimates the nation will face a shortage of up to 86,000 physicians by 2036, including primary care doctors and specialists.

In addition, more than 100 million Americans, nearly a third of the nation, don’t have access to primary care due to the physician shortages in their communities, according to the National Association of Community Health Centers.

Major medical organizations, medical schools, and hospital groups have been pushing for years for increased Medicare funding to train new doctors to keep up with the demand for healthcare services and offset the physician shortage. As a cost-saving measure, Medicare set its cap in 1996 for how much it will reimburse each hospital offering GME training. However, according to the medical groups that continue to advocate to Congress for more funding, the funding hasn’t kept pace with the growing healthcare needs or rising medical school enrollment.
 

Adding Residency Spots

In April, Dr. Hoesley of UAB spoke at a Congressional briefing among health systems and hospitals that benefited from the additional funding. He told Congressional leaders how the increased number of GME positions affects UAB Medicine and its ability to care for rural areas.

“We have entire counties in Alabama that don’t have physicians. One way to address the physician shortage is to grow the GME programs. The funding we received will help us grow these programs and care for residents in our state.”

Still, the Medicare funding is only a drop in the bucket, Dr. Hoesley said. “We rely on Medicare funding alongside other funding partners to train residents and expand our care across the state.” He said many UAB residency programs are over their Medicare funding cap and would like to grow, but they can’t without more funding.

Mount Sinai Health System in New York City also will be able to expand its residency program after receiving Medicare support in the latest round of funding. The health system will use the federal funds to train an additional vascular surgeon. Mount Sinai currently receives CMS funding to train three residents in the specialty.

Over a 5-year program, that means CMS funding will help train 20 residents in the specialty that treats blood vessel blockages and diseases of the veins and arteries generally associated with aging.

“The funding is amazing,” said Peter L. Faries, MD, a surgery professor and system chief of vascular surgery at the Icahn School of Medicine at Mount Sinai, New York City, who directs the residency program.

“We don’t have the capacity to provide an individual training program without the funding. It’s not economically feasible.”

The need for more vascular surgeons increases as the population continues to age, he said. Mount Sinai treats patients throughout New York, including underserved areas in Harlem, the Bronx, Washington Heights, Brooklyn, and Queens. “These individuals might not receive an appropriate level of vascular care if we don’t have clinicians to treat them.”

Of the recent funding, Dr. Faries said it’s taken the residency program 15 years of advocacy to increase by two slots. “It’s a long process to get funding.” Vascular training programs can remain very selective with Medicare funding, typically receiving two applicants for every position,” said Dr. Faries.
 

Pushing for More Funds

Nearly 98,000 students enrolled in medical school this year, according to the National Resident Matching Program. A total of 44,853 applicants vied for the 38,494 first-year residency positions and 3009 second-year slots, leaving 3350 medical school graduates without a match.

“There are not enough spots to meet the growing demand,” said Jesse M. Ehrenfeld, MD, MPH, immediate past president of the American Medical Association. “Graduate medical education funding has not kept up.”

Despite the increase in medical school graduates over the past two decades, Medicare-supported training opportunities remained frozen at the 1996 level. A limited number of training positions meant residency programs couldn’t expand the physician pipeline to offset an aging workforce, contributing to the shortage. “The way to solve this is to expand GME,” Dr. Ehrenfeld said. “We continue to advocate to remove the cap.”

Dr. Ehrenfeld also told this news organization that he doesn’t mind that Congress recently designated GME funding to certain specialties, such as psychiatry, because he believes the need is great for residency spots across the board. “The good news is people recognize it’s challenging to get much through Congress.” He’s optimistic, though, about recent legislative efforts to increase funding.

AAMC, representing about a third of the nation’s 1100 teaching hospitals and health systems, feels the same. Congress “acknowledges and continues to recognize that the shortage is not getting better, and one way to address it is to increase Medicare-supported GME positions,” said Leonard Marquez, senior director of government relations and legislative advocacy.

Still, he said that the Medicare funding bump is only making a small dent in the need. AAMC estimates the average cost to train residents is $23 billion annually, and Medicare only funds 20% of that, or $5 billion. “Our members are at the point where they say: We already can’t add new training positions,” Mr. Marquez said. He added that without increasing residency slots, patient care will suffer. “We have to do anything possible we can to increase access to care.”

Mr. Marquez also believes Medicare funding should increase residency positions across the specialty spectrum, not just for psychiatry and primary care. He said that the targeted funding may prevent some teaching hospitals from applying for residency positions if they need other types of specialists based on their community’s needs.

Among the current proposals before Congress, the Resident Physician Shortage Reduction Act of 2023 would add 14,000 Medicare-supported residency slots over 7 years. Mr. Marquez said it may be more realistic to expect fewer new slots. A decision on potential legislation is expected at the end of the year. He said that if the medical groups aren’t pleased with the decision, they’ll advocate again in 2025.
 

A version of this article first appeared on Medscape.com.

Residency programs across the country may have a few more slots for incoming residents due to a recent bump in Medicare funding.

Case in point: The University of Alabama at Birmingham (UAB). The state has one of the top stroke rates in the country, and yet UAB has the only hospital in the state training future doctors to help stroke patients recover. “Our hospital cares for Alabama’s sickest patients, many who need rehabilitation services,” said Craig Hoesley, MD, senior associate dean for medical education, who oversees graduate medical education (GME) or residency programs.

After decades of stagnant support, a recent bump in Medicare funding will allow UAB to add two more physical medicine and rehabilitation residents to the four residencies already receiving such funding.

Medicare also awarded UAB more funding last year to add an addiction medicine fellowship, one of two such training programs in the state for the specialty that helps treat patients fighting addiction.

UAB is among healthcare systems and hospitals nationwide benefiting from a recent hike in Medicare funding for residency programs after some 25 years at the same level of federal support. Medicare is the largest funder of training positions. Otherwise, hospitals finance training through means such as state support.

The latest round of funding, which went into effect in July, adds 200 positions to the doctor pipeline, creating more openings for residents seeking positions after medical school.

In the next few months, the Centers for Medicare & Medicaid Services (CMS) will notify teaching hospitals whether they’ll receive the next round of Medicare funding for more residency positions. At that time, CMS will have awarded nearly half of the 1200 residency training slots Congress approved in the past few years. In 2020 — for the first time since 1996 — Congress approved adding 1000 residency slots at teaching hospitals nationwide. CMS awards the money for 200 slots each year for 5 years.

More than half of the initial round of funding focused on training primary care specialists, with other slots designated for mental health specialists. Last year, Congress also approved a separate allocation of 200 more Medicare-funded residency positions, with at least half designated for psychiatry and related subspecialty residencies to help meet the growing need for more mental health specialists. On August 1, CMS announced it would distribute the funds next year, effective in 2026.

The additional Medicare funding attempts to address the shortage of healthcare providers and ensure future access to care, including in rural and underserved communities. The Association of American Medical Colleges (AAMC) estimates the nation will face a shortage of up to 86,000 physicians by 2036, including primary care doctors and specialists.

In addition, more than 100 million Americans, nearly a third of the nation, don’t have access to primary care due to the physician shortages in their communities, according to the National Association of Community Health Centers.

Major medical organizations, medical schools, and hospital groups have been pushing for years for increased Medicare funding to train new doctors to keep up with the demand for healthcare services and offset the physician shortage. As a cost-saving measure, Medicare set its cap in 1996 for how much it will reimburse each hospital offering GME training. However, according to the medical groups that continue to advocate to Congress for more funding, the funding hasn’t kept pace with the growing healthcare needs or rising medical school enrollment.
 

Adding Residency Spots

In April, Dr. Hoesley of UAB spoke at a Congressional briefing among health systems and hospitals that benefited from the additional funding. He told Congressional leaders how the increased number of GME positions affects UAB Medicine and its ability to care for rural areas.

“We have entire counties in Alabama that don’t have physicians. One way to address the physician shortage is to grow the GME programs. The funding we received will help us grow these programs and care for residents in our state.”

Still, the Medicare funding is only a drop in the bucket, Dr. Hoesley said. “We rely on Medicare funding alongside other funding partners to train residents and expand our care across the state.” He said many UAB residency programs are over their Medicare funding cap and would like to grow, but they can’t without more funding.

Mount Sinai Health System in New York City also will be able to expand its residency program after receiving Medicare support in the latest round of funding. The health system will use the federal funds to train an additional vascular surgeon. Mount Sinai currently receives CMS funding to train three residents in the specialty.

Over a 5-year program, that means CMS funding will help train 20 residents in the specialty that treats blood vessel blockages and diseases of the veins and arteries generally associated with aging.

“The funding is amazing,” said Peter L. Faries, MD, a surgery professor and system chief of vascular surgery at the Icahn School of Medicine at Mount Sinai, New York City, who directs the residency program.

“We don’t have the capacity to provide an individual training program without the funding. It’s not economically feasible.”

The need for more vascular surgeons increases as the population continues to age, he said. Mount Sinai treats patients throughout New York, including underserved areas in Harlem, the Bronx, Washington Heights, Brooklyn, and Queens. “These individuals might not receive an appropriate level of vascular care if we don’t have clinicians to treat them.”

Of the recent funding, Dr. Faries said it’s taken the residency program 15 years of advocacy to increase by two slots. “It’s a long process to get funding.” Vascular training programs can remain very selective with Medicare funding, typically receiving two applicants for every position,” said Dr. Faries.
 

Pushing for More Funds

Nearly 98,000 students enrolled in medical school this year, according to the National Resident Matching Program. A total of 44,853 applicants vied for the 38,494 first-year residency positions and 3009 second-year slots, leaving 3350 medical school graduates without a match.

“There are not enough spots to meet the growing demand,” said Jesse M. Ehrenfeld, MD, MPH, immediate past president of the American Medical Association. “Graduate medical education funding has not kept up.”

Despite the increase in medical school graduates over the past two decades, Medicare-supported training opportunities remained frozen at the 1996 level. A limited number of training positions meant residency programs couldn’t expand the physician pipeline to offset an aging workforce, contributing to the shortage. “The way to solve this is to expand GME,” Dr. Ehrenfeld said. “We continue to advocate to remove the cap.”

Dr. Ehrenfeld also told this news organization that he doesn’t mind that Congress recently designated GME funding to certain specialties, such as psychiatry, because he believes the need is great for residency spots across the board. “The good news is people recognize it’s challenging to get much through Congress.” He’s optimistic, though, about recent legislative efforts to increase funding.

AAMC, representing about a third of the nation’s 1100 teaching hospitals and health systems, feels the same. Congress “acknowledges and continues to recognize that the shortage is not getting better, and one way to address it is to increase Medicare-supported GME positions,” said Leonard Marquez, senior director of government relations and legislative advocacy.

Still, he said that the Medicare funding bump is only making a small dent in the need. AAMC estimates the average cost to train residents is $23 billion annually, and Medicare only funds 20% of that, or $5 billion. “Our members are at the point where they say: We already can’t add new training positions,” Mr. Marquez said. He added that without increasing residency slots, patient care will suffer. “We have to do anything possible we can to increase access to care.”

Mr. Marquez also believes Medicare funding should increase residency positions across the specialty spectrum, not just for psychiatry and primary care. He said that the targeted funding may prevent some teaching hospitals from applying for residency positions if they need other types of specialists based on their community’s needs.

Among the current proposals before Congress, the Resident Physician Shortage Reduction Act of 2023 would add 14,000 Medicare-supported residency slots over 7 years. Mr. Marquez said it may be more realistic to expect fewer new slots. A decision on potential legislation is expected at the end of the year. He said that if the medical groups aren’t pleased with the decision, they’ll advocate again in 2025.
 

A version of this article first appeared on Medscape.com.

Residency programs across the country may have a few more slots for incoming residents due to a recent bump in Medicare funding.

Case in point: The University of Alabama at Birmingham (UAB). The state has one of the top stroke rates in the country, and yet UAB has the only hospital in the state training future doctors to help stroke patients recover. “Our hospital cares for Alabama’s sickest patients, many who need rehabilitation services,” said Craig Hoesley, MD, senior associate dean for medical education, who oversees graduate medical education (GME) or residency programs.

After decades of stagnant support, a recent bump in Medicare funding will allow UAB to add two more physical medicine and rehabilitation residents to the four residencies already receiving such funding.

Medicare also awarded UAB more funding last year to add an addiction medicine fellowship, one of two such training programs in the state for the specialty that helps treat patients fighting addiction.

UAB is among healthcare systems and hospitals nationwide benefiting from a recent hike in Medicare funding for residency programs after some 25 years at the same level of federal support. Medicare is the largest funder of training positions. Otherwise, hospitals finance training through means such as state support.

The latest round of funding, which went into effect in July, adds 200 positions to the doctor pipeline, creating more openings for residents seeking positions after medical school.

In the next few months, the Centers for Medicare & Medicaid Services (CMS) will notify teaching hospitals whether they’ll receive the next round of Medicare funding for more residency positions. At that time, CMS will have awarded nearly half of the 1200 residency training slots Congress approved in the past few years. In 2020 — for the first time since 1996 — Congress approved adding 1000 residency slots at teaching hospitals nationwide. CMS awards the money for 200 slots each year for 5 years.

More than half of the initial round of funding focused on training primary care specialists, with other slots designated for mental health specialists. Last year, Congress also approved a separate allocation of 200 more Medicare-funded residency positions, with at least half designated for psychiatry and related subspecialty residencies to help meet the growing need for more mental health specialists. On August 1, CMS announced it would distribute the funds next year, effective in 2026.

The additional Medicare funding attempts to address the shortage of healthcare providers and ensure future access to care, including in rural and underserved communities. The Association of American Medical Colleges (AAMC) estimates the nation will face a shortage of up to 86,000 physicians by 2036, including primary care doctors and specialists.

In addition, more than 100 million Americans, nearly a third of the nation, don’t have access to primary care due to the physician shortages in their communities, according to the National Association of Community Health Centers.

Major medical organizations, medical schools, and hospital groups have been pushing for years for increased Medicare funding to train new doctors to keep up with the demand for healthcare services and offset the physician shortage. As a cost-saving measure, Medicare set its cap in 1996 for how much it will reimburse each hospital offering GME training. However, according to the medical groups that continue to advocate to Congress for more funding, the funding hasn’t kept pace with the growing healthcare needs or rising medical school enrollment.
 

Adding Residency Spots

In April, Dr. Hoesley of UAB spoke at a Congressional briefing among health systems and hospitals that benefited from the additional funding. He told Congressional leaders how the increased number of GME positions affects UAB Medicine and its ability to care for rural areas.

“We have entire counties in Alabama that don’t have physicians. One way to address the physician shortage is to grow the GME programs. The funding we received will help us grow these programs and care for residents in our state.”

Still, the Medicare funding is only a drop in the bucket, Dr. Hoesley said. “We rely on Medicare funding alongside other funding partners to train residents and expand our care across the state.” He said many UAB residency programs are over their Medicare funding cap and would like to grow, but they can’t without more funding.

Mount Sinai Health System in New York City also will be able to expand its residency program after receiving Medicare support in the latest round of funding. The health system will use the federal funds to train an additional vascular surgeon. Mount Sinai currently receives CMS funding to train three residents in the specialty.

Over a 5-year program, that means CMS funding will help train 20 residents in the specialty that treats blood vessel blockages and diseases of the veins and arteries generally associated with aging.

“The funding is amazing,” said Peter L. Faries, MD, a surgery professor and system chief of vascular surgery at the Icahn School of Medicine at Mount Sinai, New York City, who directs the residency program.

“We don’t have the capacity to provide an individual training program without the funding. It’s not economically feasible.”

The need for more vascular surgeons increases as the population continues to age, he said. Mount Sinai treats patients throughout New York, including underserved areas in Harlem, the Bronx, Washington Heights, Brooklyn, and Queens. “These individuals might not receive an appropriate level of vascular care if we don’t have clinicians to treat them.”

Of the recent funding, Dr. Faries said it’s taken the residency program 15 years of advocacy to increase by two slots. “It’s a long process to get funding.” Vascular training programs can remain very selective with Medicare funding, typically receiving two applicants for every position,” said Dr. Faries.
 

Pushing for More Funds

Nearly 98,000 students enrolled in medical school this year, according to the National Resident Matching Program. A total of 44,853 applicants vied for the 38,494 first-year residency positions and 3009 second-year slots, leaving 3350 medical school graduates without a match.

“There are not enough spots to meet the growing demand,” said Jesse M. Ehrenfeld, MD, MPH, immediate past president of the American Medical Association. “Graduate medical education funding has not kept up.”

Despite the increase in medical school graduates over the past two decades, Medicare-supported training opportunities remained frozen at the 1996 level. A limited number of training positions meant residency programs couldn’t expand the physician pipeline to offset an aging workforce, contributing to the shortage. “The way to solve this is to expand GME,” Dr. Ehrenfeld said. “We continue to advocate to remove the cap.”

Dr. Ehrenfeld also told this news organization that he doesn’t mind that Congress recently designated GME funding to certain specialties, such as psychiatry, because he believes the need is great for residency spots across the board. “The good news is people recognize it’s challenging to get much through Congress.” He’s optimistic, though, about recent legislative efforts to increase funding.

AAMC, representing about a third of the nation’s 1100 teaching hospitals and health systems, feels the same. Congress “acknowledges and continues to recognize that the shortage is not getting better, and one way to address it is to increase Medicare-supported GME positions,” said Leonard Marquez, senior director of government relations and legislative advocacy.

Still, he said that the Medicare funding bump is only making a small dent in the need. AAMC estimates the average cost to train residents is $23 billion annually, and Medicare only funds 20% of that, or $5 billion. “Our members are at the point where they say: We already can’t add new training positions,” Mr. Marquez said. He added that without increasing residency slots, patient care will suffer. “We have to do anything possible we can to increase access to care.”

Mr. Marquez also believes Medicare funding should increase residency positions across the specialty spectrum, not just for psychiatry and primary care. He said that the targeted funding may prevent some teaching hospitals from applying for residency positions if they need other types of specialists based on their community’s needs.

Among the current proposals before Congress, the Resident Physician Shortage Reduction Act of 2023 would add 14,000 Medicare-supported residency slots over 7 years. Mr. Marquez said it may be more realistic to expect fewer new slots. A decision on potential legislation is expected at the end of the year. He said that if the medical groups aren’t pleased with the decision, they’ll advocate again in 2025.
 

A version of this article first appeared on Medscape.com.

The turf war between two types of anesthesia providers is escalating: The American Society of Anesthesiologists (ASA) has filed a trademark complaint against the recently renamed American Association of Nurse Anesthesiology (AANA), alleging its use of the word “anesthesiology” is “deceptively misdescriptive.”

At issue: Who can be called an anesthesiologist?

In its complaint, filed in June 2024 with the US Trademark Trial and Appeal Board, the 54,000-member physician society seeks to deny the nurse group the registration of its trademark. If ASA wins, it could sue AANA in federal court.

AANA denied the physicians’ allegations in its recent response to the complaint.

The dispute between the two associations comes at a time when physicians are facing challenges from providers such as nurse practitioners and physician assistants who seek new titles and more autonomy in medical decision-making.
 

A Controversial Name Change

In 2021, the 61,000-member AANA changed its name from the American Association of Nurse Anesthetists, saying the change “clarifies” the role of its members.

The ASA declared it was “gravely concerned” by the name change, which “confuses patients and creates discord in the care setting, ultimately risking patient safety.

“ ’Anesthesiologist’ has always been used to differentiate physicians trained in the science and study of anesthesiology from nonphysicians, including nurse anesthetists,” the physicians’ group said in a news release.

Chicago Intellectual Property Attorney Laura M. Schaefer, who represents AANA, told this news organization that certified registered nurse anesthetists (CRNAs) — “also known as nurse anesthesiologists or nurse anesthetists — have a 150-year track record of administering safe, effective anesthesia to patients in need of care. Not only are CRNAs highly trained and capable, they also use the exact same techniques to provide anesthesia as other anesthesiology professionals.”

Ms. Schaefer declined to comment further, and ASA declined to comment at all, citing pending litigation.

The scope of practice of nurse anesthetists has long been disputed. In mid-September, California health officials clarified what nurse anesthetists can do on the job after complaints about lack of oversight, The Modesto Bee reported.

According to nursing education site NurseJournal.org, CRNAs and anesthesiologists “perform many of the same duties,” although CRNAs are in more demand. Also, the site says some states require CRNAs to be supervised by anesthesiologists.

“It is possible that scope of practice debates are increasing in prominence due to the increase in demand for healthcare services, coupled with workforce shortages in certain areas,” Alice Chen, PhD, MBA, vice dean for research at the USC Sol Price School of Public Policy in Los Angeles, told this news organization. “For example, during COVID, the federal government temporarily expanded scope of practice to help address healthcare needs.”

She added her group’s research has shown that despite the large stakes perceived by both sides of the debate, changes in practice behavior were actually quite small in states that allowed CRNAs to practice without supervision.

“In fact, we found only modest reduction in anesthesiologist billing for supervision, and we did not find an increase in the supply of anesthesia care,” she noted.

Trademark law specialists told this news organization that they couldn’t predict which way the board will rule. However, they noted potential weaknesses of the ASA’s case.

Rebecca Tushnet, JD, a professor at Harvard Law School, Cambridge, Massachusetts, explained that a trademark “can’t misrepresent those goods or services in a way that deceives consumers.” However, if insurers, doctors, and hospitals are considered the “consumers” — and not patients — “then confusion is probably less likely because they will have relevant expertise to distinguish among groups.”

Christine Farley, JD, LLM, JSD, professor at American University Washington College of Law, said attacking the AANA’s trademark as deceptive may be one of the ASA’s strongest arguments. The suggestion, she said, is that “nurse anesthesiologist” is an oxymoron, like “jumbo shrimp.”

On the other hand, she said it’s not clear that people will miss the word “nurse” in AANA’s name and say, “ ’Well, obviously these people are doctors.’ So that that’s an uphill battle.”

What happens now? The Trademark Trial and Appeal Board will decide whether AANA’s trademark application should be granted or denied, said Kayla Jimenez, JD, a San Diego trademark attorney and adjunct law professor at the University of San Diego. The entire process can take 2-3 years, she said.

The board “cannot award attorneys’ fees or force a party to stop using a trademark,” she said. “You would have to go file a lawsuit in federal court if that is your endgame.” Also, she said, the board’s ultimate decision can be appealed in federal court.

Eric Goldman, JD, MBA, associate dean for research and professor at Santa Clara University School of Law, Santa Clara, California, doesn’t expect the trademark case will spell the end of this dispute.

“ASA is signaling that it will challenge AANA’s use of the term in multiple battlegrounds,” he said. “I see this as a move by ASA to contest AANA in every potentially relevant venue, even if neither side can score a knockout blow in the Trademark Trial and Appeal Board.”

Dr. Chen, Ms. Farley, Ms. Jimenez, and Mr. Goldman had no disclosures. 
 

A version of this article appeared on Medscape.com.

The turf war between two types of anesthesia providers is escalating: The American Society of Anesthesiologists (ASA) has filed a trademark complaint against the recently renamed American Association of Nurse Anesthesiology (AANA), alleging its use of the word “anesthesiology” is “deceptively misdescriptive.”

At issue: Who can be called an anesthesiologist?

In its complaint, filed in June 2024 with the US Trademark Trial and Appeal Board, the 54,000-member physician society seeks to deny the nurse group the registration of its trademark. If ASA wins, it could sue AANA in federal court.

AANA denied the physicians’ allegations in its recent response to the complaint.

The dispute between the two associations comes at a time when physicians are facing challenges from providers such as nurse practitioners and physician assistants who seek new titles and more autonomy in medical decision-making.
 

A Controversial Name Change

In 2021, the 61,000-member AANA changed its name from the American Association of Nurse Anesthetists, saying the change “clarifies” the role of its members.

The ASA declared it was “gravely concerned” by the name change, which “confuses patients and creates discord in the care setting, ultimately risking patient safety.

“ ’Anesthesiologist’ has always been used to differentiate physicians trained in the science and study of anesthesiology from nonphysicians, including nurse anesthetists,” the physicians’ group said in a news release.

Chicago Intellectual Property Attorney Laura M. Schaefer, who represents AANA, told this news organization that certified registered nurse anesthetists (CRNAs) — “also known as nurse anesthesiologists or nurse anesthetists — have a 150-year track record of administering safe, effective anesthesia to patients in need of care. Not only are CRNAs highly trained and capable, they also use the exact same techniques to provide anesthesia as other anesthesiology professionals.”

Ms. Schaefer declined to comment further, and ASA declined to comment at all, citing pending litigation.

The scope of practice of nurse anesthetists has long been disputed. In mid-September, California health officials clarified what nurse anesthetists can do on the job after complaints about lack of oversight, The Modesto Bee reported.

According to nursing education site NurseJournal.org, CRNAs and anesthesiologists “perform many of the same duties,” although CRNAs are in more demand. Also, the site says some states require CRNAs to be supervised by anesthesiologists.

“It is possible that scope of practice debates are increasing in prominence due to the increase in demand for healthcare services, coupled with workforce shortages in certain areas,” Alice Chen, PhD, MBA, vice dean for research at the USC Sol Price School of Public Policy in Los Angeles, told this news organization. “For example, during COVID, the federal government temporarily expanded scope of practice to help address healthcare needs.”

She added her group’s research has shown that despite the large stakes perceived by both sides of the debate, changes in practice behavior were actually quite small in states that allowed CRNAs to practice without supervision.

“In fact, we found only modest reduction in anesthesiologist billing for supervision, and we did not find an increase in the supply of anesthesia care,” she noted.

Trademark law specialists told this news organization that they couldn’t predict which way the board will rule. However, they noted potential weaknesses of the ASA’s case.

Rebecca Tushnet, JD, a professor at Harvard Law School, Cambridge, Massachusetts, explained that a trademark “can’t misrepresent those goods or services in a way that deceives consumers.” However, if insurers, doctors, and hospitals are considered the “consumers” — and not patients — “then confusion is probably less likely because they will have relevant expertise to distinguish among groups.”

Christine Farley, JD, LLM, JSD, professor at American University Washington College of Law, said attacking the AANA’s trademark as deceptive may be one of the ASA’s strongest arguments. The suggestion, she said, is that “nurse anesthesiologist” is an oxymoron, like “jumbo shrimp.”

On the other hand, she said it’s not clear that people will miss the word “nurse” in AANA’s name and say, “ ’Well, obviously these people are doctors.’ So that that’s an uphill battle.”

What happens now? The Trademark Trial and Appeal Board will decide whether AANA’s trademark application should be granted or denied, said Kayla Jimenez, JD, a San Diego trademark attorney and adjunct law professor at the University of San Diego. The entire process can take 2-3 years, she said.

The board “cannot award attorneys’ fees or force a party to stop using a trademark,” she said. “You would have to go file a lawsuit in federal court if that is your endgame.” Also, she said, the board’s ultimate decision can be appealed in federal court.

Eric Goldman, JD, MBA, associate dean for research and professor at Santa Clara University School of Law, Santa Clara, California, doesn’t expect the trademark case will spell the end of this dispute.

“ASA is signaling that it will challenge AANA’s use of the term in multiple battlegrounds,” he said. “I see this as a move by ASA to contest AANA in every potentially relevant venue, even if neither side can score a knockout blow in the Trademark Trial and Appeal Board.”

Dr. Chen, Ms. Farley, Ms. Jimenez, and Mr. Goldman had no disclosures. 
 

A version of this article appeared on Medscape.com.

The turf war between two types of anesthesia providers is escalating: The American Society of Anesthesiologists (ASA) has filed a trademark complaint against the recently renamed American Association of Nurse Anesthesiology (AANA), alleging its use of the word “anesthesiology” is “deceptively misdescriptive.”

At issue: Who can be called an anesthesiologist?

In its complaint, filed in June 2024 with the US Trademark Trial and Appeal Board, the 54,000-member physician society seeks to deny the nurse group the registration of its trademark. If ASA wins, it could sue AANA in federal court.

AANA denied the physicians’ allegations in its recent response to the complaint.

The dispute between the two associations comes at a time when physicians are facing challenges from providers such as nurse practitioners and physician assistants who seek new titles and more autonomy in medical decision-making.
 

A Controversial Name Change

In 2021, the 61,000-member AANA changed its name from the American Association of Nurse Anesthetists, saying the change “clarifies” the role of its members.

The ASA declared it was “gravely concerned” by the name change, which “confuses patients and creates discord in the care setting, ultimately risking patient safety.

“ ’Anesthesiologist’ has always been used to differentiate physicians trained in the science and study of anesthesiology from nonphysicians, including nurse anesthetists,” the physicians’ group said in a news release.

Chicago Intellectual Property Attorney Laura M. Schaefer, who represents AANA, told this news organization that certified registered nurse anesthetists (CRNAs) — “also known as nurse anesthesiologists or nurse anesthetists — have a 150-year track record of administering safe, effective anesthesia to patients in need of care. Not only are CRNAs highly trained and capable, they also use the exact same techniques to provide anesthesia as other anesthesiology professionals.”

Ms. Schaefer declined to comment further, and ASA declined to comment at all, citing pending litigation.

The scope of practice of nurse anesthetists has long been disputed. In mid-September, California health officials clarified what nurse anesthetists can do on the job after complaints about lack of oversight, The Modesto Bee reported.

According to nursing education site NurseJournal.org, CRNAs and anesthesiologists “perform many of the same duties,” although CRNAs are in more demand. Also, the site says some states require CRNAs to be supervised by anesthesiologists.

“It is possible that scope of practice debates are increasing in prominence due to the increase in demand for healthcare services, coupled with workforce shortages in certain areas,” Alice Chen, PhD, MBA, vice dean for research at the USC Sol Price School of Public Policy in Los Angeles, told this news organization. “For example, during COVID, the federal government temporarily expanded scope of practice to help address healthcare needs.”

She added her group’s research has shown that despite the large stakes perceived by both sides of the debate, changes in practice behavior were actually quite small in states that allowed CRNAs to practice without supervision.

“In fact, we found only modest reduction in anesthesiologist billing for supervision, and we did not find an increase in the supply of anesthesia care,” she noted.

Trademark law specialists told this news organization that they couldn’t predict which way the board will rule. However, they noted potential weaknesses of the ASA’s case.

Rebecca Tushnet, JD, a professor at Harvard Law School, Cambridge, Massachusetts, explained that a trademark “can’t misrepresent those goods or services in a way that deceives consumers.” However, if insurers, doctors, and hospitals are considered the “consumers” — and not patients — “then confusion is probably less likely because they will have relevant expertise to distinguish among groups.”

Christine Farley, JD, LLM, JSD, professor at American University Washington College of Law, said attacking the AANA’s trademark as deceptive may be one of the ASA’s strongest arguments. The suggestion, she said, is that “nurse anesthesiologist” is an oxymoron, like “jumbo shrimp.”

On the other hand, she said it’s not clear that people will miss the word “nurse” in AANA’s name and say, “ ’Well, obviously these people are doctors.’ So that that’s an uphill battle.”

What happens now? The Trademark Trial and Appeal Board will decide whether AANA’s trademark application should be granted or denied, said Kayla Jimenez, JD, a San Diego trademark attorney and adjunct law professor at the University of San Diego. The entire process can take 2-3 years, she said.

The board “cannot award attorneys’ fees or force a party to stop using a trademark,” she said. “You would have to go file a lawsuit in federal court if that is your endgame.” Also, she said, the board’s ultimate decision can be appealed in federal court.

Eric Goldman, JD, MBA, associate dean for research and professor at Santa Clara University School of Law, Santa Clara, California, doesn’t expect the trademark case will spell the end of this dispute.

“ASA is signaling that it will challenge AANA’s use of the term in multiple battlegrounds,” he said. “I see this as a move by ASA to contest AANA in every potentially relevant venue, even if neither side can score a knockout blow in the Trademark Trial and Appeal Board.”

Dr. Chen, Ms. Farley, Ms. Jimenez, and Mr. Goldman had no disclosures. 
 

A version of this article appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Medicare Advantage plans had lower adjusted total resource use than traditional Medicare for patients with cancer undergoing chemotherapy, with no difference in 18-month survival between the two groups.

METHODOLOGY:

• Private Medicare Advantage plans enroll more than half of the Medicare population, but it is unknown if or how the cost restrictions they impose affect chemotherapy, which accounts for a large portion of cancer care costs.
• Researchers conducted a cohort study using national Medicare data from January 2015 to December 2019 to look at Medicare Advantage enrollment and treatment patterns for patients with cancer receiving chemotherapy.
• The study included 96,501 Medicare Advantage enrollees and 206,274 traditional Medicare beneficiaries who initiated chemotherapy between January 2016 and December 2019 (mean age, ~73 years; ~56% women; Hispanic individuals, 15% and 8%; Black individuals, 15% and 8%; and White individuals, 75% and 86%, respectively).
• Resource use and care quality were measured during a 6-month period following chemotherapy initiation, and survival days were measured 18 months after beginning chemotherapy.
• Resource use measures included hospital inpatient services, outpatient care, prescription drugs, hospice services, and chemotherapy services. Quality measures included chemotherapy-related emergency visits and hospital admissions, as well as avoidable emergency visits and preventable hospitalizations.

TAKEAWAY:

• Medicare Advantage plans had lower resource use than traditional Medicare per enrollee with cancer undergoing chemotherapy ($8718 lower; 95% CI, $8343-$9094).
• The lower resource use was largely caused by fewer chemotherapy visits and less expensive chemotherapy per visit in Medicare Advantage plans ($5032 lower; 95% CI, $4772-$5293).
• Medicare Advantage enrollees had 2.5 percentage points fewer chemotherapy-related emergency department visits and 0.7 percentage points fewer chemotherapy-related hospitalizations than traditional Medicare beneficiaries.
• There was no clinically meaningful difference in survival between Medicare Advantage and traditional Medicare beneficiaries during the 18 months following chemotherapy initiation.

IN PRACTICE:

“Our new finding is that MA [Medicare Advantage] plans had lower resource use than TM [traditional Medicare] among enrollees with cancer undergoing chemotherapy — a serious condition managed by specialists and requiring expensive treatments. This suggests that MA’s cost advantages over TM are not limited to conditions for which low-cost primary care management can avoid costly services,” the authors wrote.

SOURCE:

The study was led by Yamini Kalidindi, PhD, McDermott+ Consulting, Washington, DC. It was published online on September 20, 2024, in JAMA Network Open (doi: 10.1001/jamanetworkopen.2024.34707), with a commentary.

LIMITATIONS:

The study’s findings may be affected by unobserved patient characteristics despite the use of inverse-probability weighting. The exclusion of Medicare Advantage enrollees in contracts with incomplete encounter data limits the generalizability of the results. The study does not apply to beneficiaries without Part D drug coverage. Quality measures were limited to those available from claims and encounter data, lacking information on patients’ cancer stage. The 18-month measure of survival might not adequately capture survival differences associated with early-stage cancers. The study did not measure whether patient care followed recommended guidelines.

DISCLOSURES:

Various authors reported grants from the National Institute on Aging, the National Institutes of Health, The Commonwealth Fund, Arnold Ventures, the National Cancer Institute, the Department of Defense, and the National Institute of Health Care Management. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Despite the “remarkable progress” in cancer research and care, cancer remains “an ongoing public health challenge,” which requires significant attention and funding, according to the Cancer Progress Report 2024 from the American Association for Cancer Research (AACR).

The AACR’s 216-page report — an annual endeavor now in its 14th year — focused on the “tremendous” strides made in cancer care, prevention, and early detection and highlighted areas where more research and attention are warranted. 

One key area is funding. For the first time since 2016, federal funding for the National Institutes of Health (NIH) and National Cancer Institute (NCI) decreased in the past year. The cuts followed nearly a decade of funding increases that saw the NIH budget expand by nearly $15 billion, and that allowed for a “rapid pace and broad scope” of advances in cancer, AACR’s chief executive officer Margaret Foti, MD, PhD, said during a press briefing.

These recent cuts “threaten to curtail the medical progress seen in recent years and stymie future advancements,” said Dr. Foti, who called on Congress to commit to funding cancer research at significant and consistent levels to “maintain the momentum of progress against cancer.”
 

Inside the Report: Big Progress

Overall, advances in prevention, early detection, and treatment have helped catch more cancers earlier and save lives. 

According to the AACR report, the age-adjusted overall cancer death rate in the United States fell by 33% between 1991 and 2021, meaning about 4.1 million cancer deaths were averted. The overall cancer death rate for children and adolescents has declined by 24% in the past 2 decades. The 5-year relative survival rate for children diagnosed with cancer in the US has improved from 58% for those diagnosed in the mid-1970s to 85% for those diagnosed between 2013 and 2019.

The past fiscal year has seen many new approvals for cancer drugs, diagnostics, and screening tests. From July 1, 2023, to June 30, 2024, the Food and Drug Administration (FDA) approved 15 new anticancer therapeutics, as well as 15 new indications for previously approved agents, one new imaging agent, several artificial intelligence (AI) tools to improve early cancer detection and diagnosis, and two minimally invasive tests for assessing inherited cancer risk or early cancer detection, according to the report.

“Cancer diagnostics are becoming more sophisticated,” AACR president Patricia M. LoRusso, DO, PhD, said during the briefing. “New technologies, such as spatial transcriptomics, are helping us study tumors at a cellular level, and helping to unveil things that we did not initially even begin to understand or think of. AI-based approaches are beginning to transform cancer detection, diagnosis, clinical decision-making, and treatment response monitoring.” 

The report also highlights the significant progress in many childhood and adolescent/young adult cancers, Dr. LoRusso noted. These include FDA approvals for two new molecularly targeted therapeutics: tovorafenib for children with certain types of brain tumor and repotrectinib for children with a wide array of cancer types that have a specific genetic alteration known as NTRK gene fusion. It also includes an expanded approval for eflornithine to reduce the risk for relapse in children with high-risk neuroblastoma.

“Decades — decades — of basic research discoveries, have led to these clinical breakthroughs,” she stressed. “These gains against cancer are because of the rapid progress in our ability to decode the cancer genome, which has opened new and innovative avenues for drug development.”
 

The Gaps

Even with progress in cancer prevention, early detection, and treatment, cancer remains a significant issue.

“In 2024, it is estimated that more than 2 million new cases of cancer will be diagnosed in the United States. More than 611,000 people will die from the disease,” according to the report.

The 2024 report shows that incidence rates for some cancers are increasing in the United States, including vaccine-preventable cancers such as human papillomavirus (HPV)–associated oral cancers and, in young adults, cervical cancers. A recent analysis also found that overall cervical cancer incidence among women aged 30-34 years increased by 2.5% a year between 2012 and 2019.

Furthermore, despite clear evidence demonstrating that the HPV vaccine reduces cervical cancer incidence, uptake has remained poor, with only 38.6% of US children and adolescents aged 9-17 years receiving at least one dose of the vaccine in 2022.

Early-onset cancers are also increasing. Rates of breast, colorectal, and other cancers are on the rise in adults younger than 50 years, the report noted.

The report also pointed to data that 40% of all cancer cases in the United States can be attributed to preventable factors, such as smoking, excess body weight, and alcohol. However, our understanding of these risk factors has improved. Excessive levels of alcohol consumption have, for instance, been shown to increase the risk for six different types of cancer: certain types of head and neck cancer, esophageal squamous cell carcinoma, and breast, colorectal, liver, and stomach cancers.

Financial toxicity remains prevalent as well.

The report explains that financial hardship following a cancer diagnosis is widespread, and the effects can last for years. In fact, more than 40% of patients can spend their entire life savings within the first 2 years of cancer treatment. Among adult survivors of childhood cancers, 20.7% had trouble paying their medical bills, 29.9% said they had been sent to debt collection for unpaid bills, 14.1% had forgone medical care, and 26.8% could not afford nutritious meals.

For young cancer survivors, the lifetime costs associated with a diagnosis of cancer are substantial, reaching an average of $259,324 per person.

On a global level, it is estimated that from 2020 to 2050, the cumulative economic burden of cancer will be $25.2 trillion.
 

The Path Forward

Despite these challenges, Dr. LoRusso said, “it is unquestionable that we are in a time of unparalleled opportunities in cancer research.

“I am excited about what the future holds for cancer research, and especially for patient care,” she said. 

However, funding commitments are needed to avoid impeding this momentum and losing a “talented and creative young workforce” that has brought new ideas and new technologies to the table.

Continued robust funding will help “to markedly improve cancer care, increase cancer survivorship, spur economic growth, and maintain the United States’ position as the global leader in science and medical research,” she added.

The AACR report specifically calls on Congress to:

• Appropriate at least $51.3 billion in fiscal year 2025 for the base budget of the NIH and at least $7.934 billion for the NCI.
• Provide $3.6 billion in dedicated funding for Cancer Moonshot activities through fiscal year 2026 in addition to other funding, consistent with the President’s fiscal year 2025 budget.
• Appropriate at least $472.4 million in fiscal year 2025 for the CDC’s Division of Cancer Prevention to support comprehensive cancer control, central cancer registries, and screening and awareness programs for specific cancers.
• Allocate $55 million in funding for the Oncology Center of Excellence at FDA in fiscal year 2025 to provide regulators with the staff and tools necessary to conduct expedited review of cancer-related medical products.

By working together with Congress and other stakeholders, “we will be able to accelerate the pace of progress and make major strides toward the lifesaving goal of preventing and curing all cancers at the earliest possible time,” Dr. Foti said. “I believe if we do that ... one day we will win this war on cancer.”

A version of this article first appeared on Medscape.com.

Despite the “remarkable progress” in cancer research and care, cancer remains “an ongoing public health challenge,” which requires significant attention and funding, according to the Cancer Progress Report 2024 from the American Association for Cancer Research (AACR).

The AACR’s 216-page report — an annual endeavor now in its 14th year — focused on the “tremendous” strides made in cancer care, prevention, and early detection and highlighted areas where more research and attention are warranted. 

One key area is funding. For the first time since 2016, federal funding for the National Institutes of Health (NIH) and National Cancer Institute (NCI) decreased in the past year. The cuts followed nearly a decade of funding increases that saw the NIH budget expand by nearly $15 billion, and that allowed for a “rapid pace and broad scope” of advances in cancer, AACR’s chief executive officer Margaret Foti, MD, PhD, said during a press briefing.

These recent cuts “threaten to curtail the medical progress seen in recent years and stymie future advancements,” said Dr. Foti, who called on Congress to commit to funding cancer research at significant and consistent levels to “maintain the momentum of progress against cancer.”
 

Inside the Report: Big Progress

Overall, advances in prevention, early detection, and treatment have helped catch more cancers earlier and save lives. 

According to the AACR report, the age-adjusted overall cancer death rate in the United States fell by 33% between 1991 and 2021, meaning about 4.1 million cancer deaths were averted. The overall cancer death rate for children and adolescents has declined by 24% in the past 2 decades. The 5-year relative survival rate for children diagnosed with cancer in the US has improved from 58% for those diagnosed in the mid-1970s to 85% for those diagnosed between 2013 and 2019.

The past fiscal year has seen many new approvals for cancer drugs, diagnostics, and screening tests. From July 1, 2023, to June 30, 2024, the Food and Drug Administration (FDA) approved 15 new anticancer therapeutics, as well as 15 new indications for previously approved agents, one new imaging agent, several artificial intelligence (AI) tools to improve early cancer detection and diagnosis, and two minimally invasive tests for assessing inherited cancer risk or early cancer detection, according to the report.

“Cancer diagnostics are becoming more sophisticated,” AACR president Patricia M. LoRusso, DO, PhD, said during the briefing. “New technologies, such as spatial transcriptomics, are helping us study tumors at a cellular level, and helping to unveil things that we did not initially even begin to understand or think of. AI-based approaches are beginning to transform cancer detection, diagnosis, clinical decision-making, and treatment response monitoring.” 

The report also highlights the significant progress in many childhood and adolescent/young adult cancers, Dr. LoRusso noted. These include FDA approvals for two new molecularly targeted therapeutics: tovorafenib for children with certain types of brain tumor and repotrectinib for children with a wide array of cancer types that have a specific genetic alteration known as NTRK gene fusion. It also includes an expanded approval for eflornithine to reduce the risk for relapse in children with high-risk neuroblastoma.

“Decades — decades — of basic research discoveries, have led to these clinical breakthroughs,” she stressed. “These gains against cancer are because of the rapid progress in our ability to decode the cancer genome, which has opened new and innovative avenues for drug development.”
 

The Gaps

Even with progress in cancer prevention, early detection, and treatment, cancer remains a significant issue.

“In 2024, it is estimated that more than 2 million new cases of cancer will be diagnosed in the United States. More than 611,000 people will die from the disease,” according to the report.

The 2024 report shows that incidence rates for some cancers are increasing in the United States, including vaccine-preventable cancers such as human papillomavirus (HPV)–associated oral cancers and, in young adults, cervical cancers. A recent analysis also found that overall cervical cancer incidence among women aged 30-34 years increased by 2.5% a year between 2012 and 2019.

Furthermore, despite clear evidence demonstrating that the HPV vaccine reduces cervical cancer incidence, uptake has remained poor, with only 38.6% of US children and adolescents aged 9-17 years receiving at least one dose of the vaccine in 2022.

Early-onset cancers are also increasing. Rates of breast, colorectal, and other cancers are on the rise in adults younger than 50 years, the report noted.

The report also pointed to data that 40% of all cancer cases in the United States can be attributed to preventable factors, such as smoking, excess body weight, and alcohol. However, our understanding of these risk factors has improved. Excessive levels of alcohol consumption have, for instance, been shown to increase the risk for six different types of cancer: certain types of head and neck cancer, esophageal squamous cell carcinoma, and breast, colorectal, liver, and stomach cancers.

Financial toxicity remains prevalent as well.

The report explains that financial hardship following a cancer diagnosis is widespread, and the effects can last for years. In fact, more than 40% of patients can spend their entire life savings within the first 2 years of cancer treatment. Among adult survivors of childhood cancers, 20.7% had trouble paying their medical bills, 29.9% said they had been sent to debt collection for unpaid bills, 14.1% had forgone medical care, and 26.8% could not afford nutritious meals.

For young cancer survivors, the lifetime costs associated with a diagnosis of cancer are substantial, reaching an average of $259,324 per person.

On a global level, it is estimated that from 2020 to 2050, the cumulative economic burden of cancer will be $25.2 trillion.
 

The Path Forward

Despite these challenges, Dr. LoRusso said, “it is unquestionable that we are in a time of unparalleled opportunities in cancer research.

“I am excited about what the future holds for cancer research, and especially for patient care,” she said. 

However, funding commitments are needed to avoid impeding this momentum and losing a “talented and creative young workforce” that has brought new ideas and new technologies to the table.

Continued robust funding will help “to markedly improve cancer care, increase cancer survivorship, spur economic growth, and maintain the United States’ position as the global leader in science and medical research,” she added.

The AACR report specifically calls on Congress to:

• Appropriate at least $51.3 billion in fiscal year 2025 for the base budget of the NIH and at least $7.934 billion for the NCI.
• Provide $3.6 billion in dedicated funding for Cancer Moonshot activities through fiscal year 2026 in addition to other funding, consistent with the President’s fiscal year 2025 budget.
• Appropriate at least $472.4 million in fiscal year 2025 for the CDC’s Division of Cancer Prevention to support comprehensive cancer control, central cancer registries, and screening and awareness programs for specific cancers.
• Allocate $55 million in funding for the Oncology Center of Excellence at FDA in fiscal year 2025 to provide regulators with the staff and tools necessary to conduct expedited review of cancer-related medical products.

By working together with Congress and other stakeholders, “we will be able to accelerate the pace of progress and make major strides toward the lifesaving goal of preventing and curing all cancers at the earliest possible time,” Dr. Foti said. “I believe if we do that ... one day we will win this war on cancer.”

A version of this article first appeared on Medscape.com.

Despite the “remarkable progress” in cancer research and care, cancer remains “an ongoing public health challenge,” which requires significant attention and funding, according to the Cancer Progress Report 2024 from the American Association for Cancer Research (AACR).

The AACR’s 216-page report — an annual endeavor now in its 14th year — focused on the “tremendous” strides made in cancer care, prevention, and early detection and highlighted areas where more research and attention are warranted. 

One key area is funding. For the first time since 2016, federal funding for the National Institutes of Health (NIH) and National Cancer Institute (NCI) decreased in the past year. The cuts followed nearly a decade of funding increases that saw the NIH budget expand by nearly $15 billion, and that allowed for a “rapid pace and broad scope” of advances in cancer, AACR’s chief executive officer Margaret Foti, MD, PhD, said during a press briefing.

These recent cuts “threaten to curtail the medical progress seen in recent years and stymie future advancements,” said Dr. Foti, who called on Congress to commit to funding cancer research at significant and consistent levels to “maintain the momentum of progress against cancer.”
 

Inside the Report: Big Progress

Overall, advances in prevention, early detection, and treatment have helped catch more cancers earlier and save lives. 

According to the AACR report, the age-adjusted overall cancer death rate in the United States fell by 33% between 1991 and 2021, meaning about 4.1 million cancer deaths were averted. The overall cancer death rate for children and adolescents has declined by 24% in the past 2 decades. The 5-year relative survival rate for children diagnosed with cancer in the US has improved from 58% for those diagnosed in the mid-1970s to 85% for those diagnosed between 2013 and 2019.

The past fiscal year has seen many new approvals for cancer drugs, diagnostics, and screening tests. From July 1, 2023, to June 30, 2024, the Food and Drug Administration (FDA) approved 15 new anticancer therapeutics, as well as 15 new indications for previously approved agents, one new imaging agent, several artificial intelligence (AI) tools to improve early cancer detection and diagnosis, and two minimally invasive tests for assessing inherited cancer risk or early cancer detection, according to the report.

“Cancer diagnostics are becoming more sophisticated,” AACR president Patricia M. LoRusso, DO, PhD, said during the briefing. “New technologies, such as spatial transcriptomics, are helping us study tumors at a cellular level, and helping to unveil things that we did not initially even begin to understand or think of. AI-based approaches are beginning to transform cancer detection, diagnosis, clinical decision-making, and treatment response monitoring.” 

The report also highlights the significant progress in many childhood and adolescent/young adult cancers, Dr. LoRusso noted. These include FDA approvals for two new molecularly targeted therapeutics: tovorafenib for children with certain types of brain tumor and repotrectinib for children with a wide array of cancer types that have a specific genetic alteration known as NTRK gene fusion. It also includes an expanded approval for eflornithine to reduce the risk for relapse in children with high-risk neuroblastoma.

“Decades — decades — of basic research discoveries, have led to these clinical breakthroughs,” she stressed. “These gains against cancer are because of the rapid progress in our ability to decode the cancer genome, which has opened new and innovative avenues for drug development.”
 

The Gaps

Even with progress in cancer prevention, early detection, and treatment, cancer remains a significant issue.

“In 2024, it is estimated that more than 2 million new cases of cancer will be diagnosed in the United States. More than 611,000 people will die from the disease,” according to the report.

The 2024 report shows that incidence rates for some cancers are increasing in the United States, including vaccine-preventable cancers such as human papillomavirus (HPV)–associated oral cancers and, in young adults, cervical cancers. A recent analysis also found that overall cervical cancer incidence among women aged 30-34 years increased by 2.5% a year between 2012 and 2019.

Furthermore, despite clear evidence demonstrating that the HPV vaccine reduces cervical cancer incidence, uptake has remained poor, with only 38.6% of US children and adolescents aged 9-17 years receiving at least one dose of the vaccine in 2022.

Early-onset cancers are also increasing. Rates of breast, colorectal, and other cancers are on the rise in adults younger than 50 years, the report noted.

The report also pointed to data that 40% of all cancer cases in the United States can be attributed to preventable factors, such as smoking, excess body weight, and alcohol. However, our understanding of these risk factors has improved. Excessive levels of alcohol consumption have, for instance, been shown to increase the risk for six different types of cancer: certain types of head and neck cancer, esophageal squamous cell carcinoma, and breast, colorectal, liver, and stomach cancers.

Financial toxicity remains prevalent as well.

The report explains that financial hardship following a cancer diagnosis is widespread, and the effects can last for years. In fact, more than 40% of patients can spend their entire life savings within the first 2 years of cancer treatment. Among adult survivors of childhood cancers, 20.7% had trouble paying their medical bills, 29.9% said they had been sent to debt collection for unpaid bills, 14.1% had forgone medical care, and 26.8% could not afford nutritious meals.

For young cancer survivors, the lifetime costs associated with a diagnosis of cancer are substantial, reaching an average of $259,324 per person.

On a global level, it is estimated that from 2020 to 2050, the cumulative economic burden of cancer will be $25.2 trillion.
 

The Path Forward

Despite these challenges, Dr. LoRusso said, “it is unquestionable that we are in a time of unparalleled opportunities in cancer research.

“I am excited about what the future holds for cancer research, and especially for patient care,” she said. 

However, funding commitments are needed to avoid impeding this momentum and losing a “talented and creative young workforce” that has brought new ideas and new technologies to the table.

Continued robust funding will help “to markedly improve cancer care, increase cancer survivorship, spur economic growth, and maintain the United States’ position as the global leader in science and medical research,” she added.

The AACR report specifically calls on Congress to:

• Appropriate at least $51.3 billion in fiscal year 2025 for the base budget of the NIH and at least $7.934 billion for the NCI.
• Provide $3.6 billion in dedicated funding for Cancer Moonshot activities through fiscal year 2026 in addition to other funding, consistent with the President’s fiscal year 2025 budget.
• Appropriate at least $472.4 million in fiscal year 2025 for the CDC’s Division of Cancer Prevention to support comprehensive cancer control, central cancer registries, and screening and awareness programs for specific cancers.
• Allocate $55 million in funding for the Oncology Center of Excellence at FDA in fiscal year 2025 to provide regulators with the staff and tools necessary to conduct expedited review of cancer-related medical products.

By working together with Congress and other stakeholders, “we will be able to accelerate the pace of progress and make major strides toward the lifesaving goal of preventing and curing all cancers at the earliest possible time,” Dr. Foti said. “I believe if we do that ... one day we will win this war on cancer.”

A version of this article first appeared on Medscape.com.