MDedge Neurology

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

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

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

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

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

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

I got an interesting fax recently.

It started with how tough things have been for small practices during the pandemic (like I need reminding) and suggests it has solutions for my practice to stay afloat.

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

I got an interesting fax recently.

It started with how tough things have been for small practices during the pandemic (like I need reminding) and suggests it has solutions for my practice to stay afloat.

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

I got an interesting fax recently.

It started with how tough things have been for small practices during the pandemic (like I need reminding) and suggests it has solutions for my practice to stay afloat.

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

The Food and Drug Administration has approved the antisense oligonucleotide casimersen (Amondys 45, Sarepta Therapeutics) injection for the treatment of patients with Duchenne muscular dystrophy (DMD) plus a rare DMD mutation, the agency has announced. 

This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.

“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
 

Approved – with cautions

The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.

As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.  

The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.

The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.

Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.

Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.

Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.

Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.

However, it noted that definitive clinical benefits such as improved motor function were not “established.”

“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.

It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.

The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.

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

The Food and Drug Administration has approved the antisense oligonucleotide casimersen (Amondys 45, Sarepta Therapeutics) injection for the treatment of patients with Duchenne muscular dystrophy (DMD) plus a rare DMD mutation, the agency has announced. 

This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.

“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
 

Approved – with cautions

The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.

As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.  

The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.

The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.

Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.

Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.

Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.

Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.

However, it noted that definitive clinical benefits such as improved motor function were not “established.”

“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.

It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.

The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.

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

The Food and Drug Administration has approved the antisense oligonucleotide casimersen (Amondys 45, Sarepta Therapeutics) injection for the treatment of patients with Duchenne muscular dystrophy (DMD) plus a rare DMD mutation, the agency has announced. 

This particular mutation of the DMD gene “is amenable to exon 45 skipping,” the FDA noted in a press release. The agency added that this is its first approval of a targeted treatment for patients with the mutation.

“Developing drugs designed for patients with specific mutations is a critical part of personalized medicine,” Eric Bastings, MD, deputy director of the Office of Neuroscience at the FDA’s Center for Drug Evaluation and Research, said in a statement.

The approval was based on results from a 43-person randomized controlled trial. Patients who received casimersen had a greater increase in production of the muscle-fiber protein dystrophin compared with their counterparts who received placebo.
 

Approved – with cautions

The FDA noted that DMD prevalence worldwide is about 1 in 3,600 boys – although it can also affect girls in rare cases. Symptoms of the disorder are commonly first observed around age 3 years but worsen steadily over time. DMD gene mutations lead to a decrease in dystrophin.

As reported by Medscape Medical News in August, the FDA approved viltolarsen (Viltepso, NS Pharma) for the treatment of DMD in patients with a confirmed mutation amenable to exon 53 skipping, following approval of golodirsen injection (Vyondys 53, Sarepta Therapeutics) for the same indication in December 2019.  

The DMD gene mutation that is amenable to exon 45 skipping is present in about 8% of patients with DMD.

The trial that carried weight with the FDA included 43 male participants with DMD aged 7-20 years. All were confirmed to have the exon 45-skipping gene mutation and all were randomly assigned 2:1 to received IV casimersen 30 mg/kg or matching placebo.

Results showed that, between baseline and 48 weeks post treatment, the casimersen group showed a significantly higher increase in levels of dystrophin protein than in the placebo group.

Upper respiratory tract infections, fever, joint and throat pain, headache, and cough were the most common adverse events experienced by the active-treatment group.

Although the clinical studies assessing casimersen did not show any reports of kidney toxicity, the adverse event was observed in some nonclinical studies. Therefore, clinicians should monitor kidney function in any patient receiving this treatment, the FDA recommended.

Overall, “the FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit” in this patient population, the agency said in its press release.

However, it noted that definitive clinical benefits such as improved motor function were not “established.”

“In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of [other] available therapy,” the agency said.

It added that the manufacturer is currently conducting a multicenter study focused on the safety and efficacy of the drug in ambulatory patients with DMD.

The FDA approved casimersen using its Accelerated Approval pathway, granted Fast Track and Priority Review designations to its applications, and gave the treatment Orphan Drug designation.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease, but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.

“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” said senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney.

“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Dr. Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.

The study was published online Feb. 17 in Neurology.
 

Difficult diagnosis

“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Dr. Landin-Romero. He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.

“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.

Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.

FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Dr. Landin-Romero said.

WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Dr. Landin-Romero.
 

Higher disease severity

To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or Alzheimer’s disease (n = 65; mean age, 64.66 years).

Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared with 66 age-, sex-, and education-matched healthy control persons (mean age, 64.69 years).

Some participants in the FTD, Alzheimer’s disease, and healthy control groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and Alzheimer’s disease participants (n = 13 and 5, respectively).

The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.

The FTD and Alzheimer’s disease groups did not differ with regard to disease duration (3.55 years; standard deviation, 1.75, and 3.24 years; SD, 1.59, respectively). However, disease severity was significantly higher among those with FTD than among those with Alzheimer’s disease, as measured by the FTD Rating Scale Rasch score (–0.52; SD, 1.28, vs. 0.78; SD, 1.55; P < .001).

Compared with healthy controls, patients in the FTD and Alzheimer’s disease groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with Alzheimer’s disease showed “disproportionately larger deficits” in memory and visuospatial processing, compared with those with FTD, whereas those with FTD performed significantly worse than those with Alzheimer’s disease in the fluency subdomain.

A larger number of patients in the FTD group screened positive for genetic abnormalities than in the Alzheimer’s disease group; no participants in the healthy control group had genetic mutations.
 

Unexpected findings

Mean WMH volume was significantly higher in participants with FTD than in participants with Alzheimer’s disease and in healthy controls (mean, 0.76 mL, 0.40 mL, and 0.12 mL respectively). These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors stated. Among patients with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.

After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the Alzheimer’s disease group.

Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in Alzheimer’s disease. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.

“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and Alzheimer’s disease, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Dr. Landin-Romero.

The findings were not what he and his research colleagues expected. “We were expecting that the amounts of WMH would be similar in FTD and Alzheimer’s disease, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or Alzheimer’s disease who had more severe disease would have more WMH, but that finding only held true for people with FTD.

“In sum, our findings show that WMH are a core feature of FTD and Alzheimer’s disease that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Dr. Landin-Romero.
 

Major research contribution

Commenting on the study, Jordi Matias-Guiu, PhD, MD, of the department of neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.” Dr. Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.

“WMH are present in both Alzheimer’s disease and FTD and are relevant to cognitive deficits found in these disorders,” he added.

The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Dr. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimer’s Disease and the ARC Center of Excellence in Cognition and Its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Dr. Matias-Guiu reports no relevant financial relationships.

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

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

The prevalence of asymptomatic central sleep apnea after acute coronary syndrome is high and may be associated with the use of ticagrelor, a new study finds.
Prior studies have suggested that ticagrelor is associated with an increased likelihood of central sleep apnea. The drug’s label notes that two respiratory conditions – central sleep apnea and Cheyne-Stokes respiration – are adverse reactions that were identified after the drug’s approval in the United States in 2011. “Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure,” the label says. 
Among 80 patients receiving ticagrelor, 24 had central sleep apnea hypopnea syndrome (CSAHS), whereas of 41 patients not taking ticagrelor, 3 had this condition (30% vs. 7.3%, P = .004), in the new study published online Jan. 20, 2021, in Sleep Medicine. A multivariable analysis included in the paper found that age and ticagrelor administration were the only two factors associated with the occurrence of CSAHS.

Findings are ‘striking’

The different rates of central sleep apnea in the study are striking, but it is not clear that asymptomatic central sleep apnea in patients taking ticagrelor is a concern, Ofer Jacobowitz, MD, PhD, associate professor of otolaryngology at Hofstra University, Hempstead, N.Y, said in an interview.

Study author continues to prescribe ticagrelor

One of the study authors, Philippe Meurin, MD, said that he continues to prescribe ticagrelor every day and that the side effect is not necessarily important. 
It is possible that central sleep apnea may resolve, although further studies would need to examine central sleep apnea over time to establish the duration of the condition, he added. Nevertheless, awareness of the association could have implications for clinical practice, Dr. Meurin said.
Central sleep apnea is rare, and if doctors detect it during a sleep study, they may perform extensive tests to assess for possible neurologic diseases, for example, when the cause may be attributed to the medication, he said. In addition, if a patient who is taking ticagrelor has dyspnea, the presence of central sleep apnea may suggest that dyspnea could be related to the drug, although this possibility needs further study, he noted.

Study included patients with ACS history, but no heart failure

Dr. Meurin, of Centre de Réadaptation Cardiaque de La Brie, Les Grands Prés, Villeneuve-Saint-Denis, France, and colleagues included in their study patients between 1 week and 1 year after acute coronary syndrome who did not have heart failure or a history of sleep apnea.
After an overnight sleep study, they classified patients as normal, as having CSAHS (i.e., an apnea-hypopnea index of 15 or greater, mostly with central sleep apneas), or as having obstructive sleep apnea hypopnea syndrome (OSAHS; i.e., an apnea-hypopnea index of 15 or greater, mostly with obstructive sleep apneas).
The prospective study included 121 consecutive patients between January 2018 and March 2020. Patients had a mean age of 56.8, and 88% were men.

Switching to another P2Y12 inhibitor ‘does not seem appropriate’

“CSAHS could be promoted by the use of ticagrelor, a relatively new drug that modifies the apneic threshold,” the study authors wrote. “Regarding underlying mechanisms, the most probable explanation seems to be increased chemosensitivity to hypercapnia by a direct P2Y12 inhibitory effect on the central nervous system.”
Doctors should not overestimate the severity of the adverse reaction or consider it the same way they do OSASH, they added. 
Among patients with acute coronary syndrome in the PLATO study, ticagrelor, compared with clopidogrel, “significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke,” Dr. Meurin and colleagues said. “Because in this study more than 9,000 patients received ticagrelor for 12 months, CSAHS (even if it seems frequent in our study) did not seem to impair the good efficacy/tolerance balance of the drug. Therefore, in asymptomatic CSAHS patients, switching from ticagrelor to another P2Y12 inhibitor does not seem appropriate.”
A recent analysis of data from randomized, controlled trials with ticagrelor did not find excess cases of sleep apnea with the drug. But an asymptomatic adverse event such as central sleep apnea “cannot emerge from a post hoc analysis,” Dr. Meurin and colleagues said.
The analysis of randomized trial data was conducted by Marc S. Sabatine, MD, MPH, chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital, and coauthors. It was published in JACC: Cardiovascular Interventions in April 2020.
They “used the gold standard for medical evidence (randomized, placebo-controlled trials) and found 158 cases of sleep apnea reported, with absolutely no difference between ticagrelor and placebo,” Dr. Sabatine said in an interview. Their analysis examined clinically overt apnea, he noted.
“It is quite clear that when looking at large numbers in placebo-controlled trials, there is no excess,” Dr. Sabatine said. “Meurin et al. are examining a different outcome: the results of a lab test in what may be entirely asymptomatic patients.”
A randomized trial could confirm the association, he said.
“The association may be real, but also may be play of chance or confounded,” said Dr. Sabatine. “To convince the medical community, the next step would be for the investigators to do a randomized trial and test whether ticagrelor increases the risk of central sleep apnea.”
Dr. Meurin and the study coauthors had no disclosures. The analysis of randomized, controlled trial data by Dr. Sabatine and colleagues was funded by AstraZeneca, which distributes ticagrelor under the trade name Brilinta. Dr. Sabatine has been a consultant for AstraZeneca and received research grants through Brigham and Women’s Hospital from AstraZeneca. He has consulted for and received grants through the hospital from other companies as well. Dr. Jacobowitz had no relevant disclosures.
[email protected] 

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

Continuous intracranial electroencephalography (cEEG) may help pinpoint optimal timing of diagnostic studies and treatment for patients with focal epilepsy, new research suggests. Findings from a large longitudinal study show that seizure onset in patients with focal epilepsy follows circadian, multiday, and annual cycles.

“Although daily and multiday rhythms have previously been identified, the extent to which these nonrandom rhythms exist in a larger cohort has been unclear,” said study investigator Joline Marie Fan, MD, a clinical fellow at the University of California, San Francisco. “This means that a patient with epilepsy may have a unique combination of seizure rhythms that can inform the days and timing of his or her highest seizure risk,” she added.

The study was published online Feb. 8 in JAMA Neurology.
 

Distinct chronotypes

Clinicians and patients alike have long observed cyclical patterns in the onset of epileptic seizures. However, such patterns have rarely been measured in a quantitative way.

Previous studies have examined seizure cycles using inpatient seizure monitoring and patients’ seizure diaries, but the duration of these recordings and their accuracy have been limited. Within the past decade, the advent of cEEG has allowed researchers to observe the cyclical pattern of interictal epileptiform activity, but the numbers of patients involved in such studies have been limited.

To investigate seizure chronotypes in greater detail, the researchers examined retrospective data for 222 adults with medically refractory focal epilepsy who took part in clinical trials of the NeuroPace responsive neurostimulation (RNS) system.

After implantation in the brain, this system monitors the seizure focus or foci continuously and delivers stimulation to stop seizures. Participants also kept seizure diaries and classified their seizures as simple motor, simple other, complex partial, and generalized tonic-clonic.

Dr. Fan’s group examined three subpopulations of patients to investigate three durations of seizure cycles. They examined self-reported disabling seizures, electrographic seizures, and interictal epileptiform activity. Because patients did not record the time of their disabling seizures, the investigators examined them only in multidien and circannual cycles.

To examine circannual seizure cycles, the investigators included 194 patients who kept continuous seizure diaries for 2 or more years and who reported 24 or more days in which disabling seizures occurred.

To examine multidien seizure cycles, they included 186 participants who reported 24 or more days with disabling seizures over a period of 6 or more months during which the RNS system collected cEEG data. They included 85 patients who had 48 hours or more in which electrographic seizure counts were above zero during 6 or more months of cEEG data collection to examine circadian seizure cycles.

Phase-locking value (PLV) was used to determine the strength of a cycle (i.e., the degree of consistency with which seizures occur during certain phases of a cycle). A PLV of 0 represents a uniform distribution of events during various phases of a cycle; a PLV of 1 indicates that all events occur exactly at the same phase of a cycle.

The population’s median age was 35 years, and the sample included approximately equal numbers of men and women. Patients’ focal epilepsies included mesiotemporal (57.2%), frontal (14.0%), neocortical-temporal (9.9%), parietal (4.1%), occipital (1.4%), and multifocal (13.5%). The data included 1,118 patient-years of cEEG, 754,108 electrographic seizures, and 313,995 self-reported seizures.

The prevalence of statistically significant circannual seizure cycles in this population was 12%. The prevalence of multidien seizure cycles was 60%, and the prevalence of circadian seizure cycles was 89%. Multidien cycles (mean PLV, 0.34) and circadian cycles (mean PLV, 0.34) were stronger than were circannual cycles (mean PLV, 0.17).

Among patients with circannual seizure cycles, there was a weak to moderate tendency for seizures to occur during one of the four seasons. There was no overall trend toward seizure onset in one season among this group.

Among patients with multidien seizure cycles, investigators identified five patterns of interictal epileptiform activity fluctuations. One pattern had irregular periodicity, and the others reached peak periodicity at 7, 15, 20, and 30 days. For some patients, one or more periodicities occurred. For most patients, electrographic or self-reported seizures tended to occur on the rising phase of the interictal epileptiform activity cycle. Interictal epileptiform activity increased on days around seizures.

Results showed there were five main seizure peak times among patients with circadian seizure cycles: midnight, 3:00 a.m., 9:00 a.m., 2:00 p.m., and 6:00 p.m. These findings corroborate the observations of previous investigations, the researchers noted. Hourly interictal epileptiform activity peaked during the night, regardless of peak seizure time.

“Although the neurostimulation device offers us a unique opportunity to investigate electrographic seizure activity quantitatively, the generalizability of our study is limited to the patient cohort that we studied,” said Dr. Fan. “The study findings are limited to patients with neurostimulation devices used for intractable focal epilepsies.”

The results support patients’ impressions that their seizures occur in a cyclical pattern.

“Ultimately, these findings will be helpful for developing models to aid with seizure forecasting and prediction in order to help reduce the uncertainty of seizure timing for patients with epilepsy,” said Dr. Fan.

“Other implications include optimizing the timing for patients to be admitted into the hospital for seizure characterization based on their seizure chronotype, or possibly tailoring a medication regimen in accordance with a patient’s seizure cycles,” she added.
 

Need for more research

Commenting on the findings, Tobias Loddenkemper, MD, professor of neurology at Harvard Medical School, Boston, noted that the study is “one of the largest longitudinal seizure pattern analyses, based on the gold standard of intracranially recorded epileptic seizures.”

The research, he added, extends neurologists’ understanding of seizure patterns over time, expands knowledge about seizure chronotypes, and emphasizes a relationship between interictal epileptiform activity and seizures.

The strengths of the study include the recording of seizures with intracranial EEG, its large number of participants, and the long duration of recordings, Dr. Loddenkemper said.

However, he said, it is important to note that self-reports are not always reliable. The results may also reflect the influence of potential confounders of seizure patterns, such as seizure triggers, treatment, stimulation, or sleep-wake, circadian, or hormonal cycles, he added.

“In the short term, validation studies, as well as confirmatory studies with less invasive sensors, may be needed,” said Dr. Loddenkemper.

“This could potentially include a trial that confirms findings prospectively, utilizing results from video EEG monitoring admissions. In the long term, seizure detection and prediction, as well as interventional chronotherapeutic trials, may be enabled, predicting seizures in individual patients and treating at times of greatest seizure susceptibility.”

The study was supported by grants to some of the authors from the Wyss Center for Bio and Neuroengineering, the Ernest Gallo Foundation, the Swiss National Science Foundation, and the Velux Stiftung. Dr. Fan has disclosed no relevant financial relationships.

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson &amp; Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson &amp; Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

New findings suggest the Janssen/Johnson & Johnson COVID-19 vaccine can reduce the risk of an immunized person unknowingly passing along the virus to others.

Johnson &amp; Johnson

The single-dose vaccine reduces the risk of asymptomatic transmission by 74% at 71 days, compared with placebo, according to documents released today by the U.S. Food and Drug Administration.

“The decrease in asymptomatic transmission is very welcome news too in curbing the spread of the virus,” Phyllis Tien, MD, told this news organization.

“While the earlier press release reported that the vaccine was effective against preventing severe COVID-19 disease, as well as hospitalizations and death, this new data shows that the vaccine can also decrease transmission, which is very important on a public health level,” said Dr. Tien, professor of medicine in the division of infectious diseases at the University of California, San Francisco.

“It is extremely important in terms of getting to herd immunity,” Paul Goepfert, MD, director of the Alabama Vaccine Research Clinic and infectious disease specialist at the University of Alabama, Birmingham, said in an interview. “It means that this vaccine is likely preventing subsequent transmission after a single dose, which could have huge implications once we get the majority of folks vaccinated.”

The FDA cautioned that the numbers of participants included in the study are relatively small and need to be verified. However, the Johnson & Johnson vaccine might not be the only product offering this advantage. Early data suggest that the Pfizer/BioNTech vaccine also decreases transmission, providing further evidence that the protection offered by immunization goes beyond the individual.

The new analyses were provided by the FDA in advance of its review of the Janssen/Johnson & Johnson vaccine. The agency plans to fully address the Ad26.COV2.S vaccine at its Vaccines and Related Biological Products Advisory Committee Meeting on Friday, including evaluating its safety and efficacy.

The agency’s decision on whether or not to grant emergency use authorization (EUA) to the Johnson & Johnson vaccine could come as early as Friday evening or Saturday.

In addition to the newly released data, officials are likely to discuss phase 3 data, released Jan. 29, that reveal an 85% efficacy for the vaccine against severe COVID-19 illness globally, including data from South America, South Africa, and the United States. When the analysis was restricted to data from U.S. participants, the trial showed a 73% efficacy against moderate to severe COVID-19.

If and when the FDA grants an EUA, it remains unclear how much of the new vaccine will be immediately available. Initially, Johnson & Johnson predicted 18 million doses would be ready by the end of February, but others stated the figure will be closer to 2-4 million. The manufacturer’s contract with the U.S. government stipulates production of 100-million doses by the end of June.

Dr. Tien received support from Johnson & Johnson to conduct the J&J COVID-19 vaccine trial in the SF VA HealthCare System. Dr. Goepfert has disclosed no relevant financial relationships. 

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

Novel research from the Concussion Assessment, Research and Education (CARE) Consortium sheds new light on how to effectively reduce the incidence of concussion and head injury exposure in college football.

The study, led by neurotrauma experts Michael McCrea, PhD, and Brian Stemper, PhD, professors of neurosurgery at the Medical College of Wisconsin in Milwaukee, reports data from hundreds of college football players across five seasons and shows concussion incidence and head injury exposure are disproportionately higher in the preseason versus the regular season.

The research also reveals that such injuries occur more often during practices than games.

“We think that with the findings from this paper, there’s a role for everybody to play in reducing injury,” Dr. McCrea said. “We hope these data help inform broad-based policy about practice and preseason training policies in collegiate football. We also think there’s a role for athletic administrators, coaches, and even athletes themselves.”

The study was published online Feb. 1 in JAMA Neurology.
 

More injuries in preseason

Concussion is one of the most common injuries in football. Beyond these harms are growing concerns that repetitive HIE may increase the risk of long-term neurologic health problems including chronic traumatic encephalopathy (CTE).

The CARE Consortium, which has been conducting research with college athletes across 26 sports and military cadets since 2014, has been interested in multiple facets of concussion and brain trauma.

“We’ve enrolled more than 50,000 athletes and service academy cadets into the consortium over the last 6 years to research all involved aspects including the clinical core, the imaging core, the blood biomarker core, and the genetic core, and we have a head impact measurement core.”

To investigate the pattern of concussion incidence across the football season in college players, the investigators used impact measurement technology across six Division I NCAA football programs participating in the CARE Consortium from 2015 to 2019.

A total of 658 players – all male, mean age 19 years – were fitted with the Head Impact Telemetry System (HITS) sensor arrays in their helmets to measure head impact frequency, location, and magnitude during play.

“This particular study had built-in algorithms that weeded out impacts that were below 10G of linear magnitude, because those have been determined not likely to be real impacts,” Dr. McCrea said.

Across the five seasons studied, 528,684 head impacts recorded met the quality standards for analysis. Players sustained a median of 415 (interquartile range [IQR], 190-727) impacts per season.

Of those, 68 players sustained a diagnosed concussion. In total, 48.5% of concussions occurred during preseason training, despite preseason representing only 20.8% of the football season. Total head injury exposure in the preseason occurred at twice the proportion of the regular season (324.9 vs. 162.4 impacts per team per day; mean difference, 162.6 impacts; 95% confidence interval, 110.9-214.3; P < .001).

“Preseason training often has a much higher intensity to it, in terms of the total hours, the actual training, and the heavy emphasis on full-contact drills like tackling and blocking,” said Dr. McCrea. “Even the volume of players that are participating is greater.”

Results also showed that in each of the five seasons, head injury exposure per athlete was highest in August (preseason) (median, 146.0 impacts; IQR, 63.0-247.8) and lowest in November (median, 80.0 impacts; IQR, 35.0-148.0). In the studied period, 72% of concussions and 66.9% of head injury exposure occurred in practice. Even within the regular season, total head injury exposure in practices was 84.2% higher than in games.

“This incredible dataset we have on head impact measurement also gives us the opportunity to compare it with our other research looking at the correlation between a single head impact and changes in brain structure and function on MRI, on blood biomarkers, giving us the ability to look at the connection between mechanism of effect of injury and recovery from injury,” said Dr. McCrea.

These findings also provide an opportunity to modify approaches to preseason training and football practices to keep players safer, said Dr. McCrea, noting that about half of the variance in head injury exposure is at the level of the individual athlete.

“With this large body of athletes we’ve instrumented, we can look at, for instance, all of the running backs and understand the athlete and what his head injury exposure looks like compared to all other running backs. If we find out that an athlete has a rate of head injury exposure that’s 300% higher than most other players that play the same position, we can take that data directly to the athlete to work on their technique and approach to the game.

“Every researcher wishes that their basic science or their clinical research findings will have some impact on the health and well-being of the population they’re studying. By modifying practices and preseason training, football teams could greatly reduce the risk of injury and exposure for their players, while still maintaining the competitive nature of game play,” he added.  

Through a combination of policy and education, similar strategies could be implemented to help prevent concussion and HIE in high school and youth football too, said Dr. McCrea.

‘Shocking’ findings

In an accompanying editorial, Christopher J. Nowinski, PhD, of the Concussion Legacy Foundation, Boston, and Robert C. Cantu, MD, department of neurosurgery, Emerson Hospital, Concord, Massachusetts, said the findings could have significant policy implications and offer a valuable expansion of prior research.

“From 2005 to 2010, studies on college football revealed that about two-thirds of head impacts occurred in practice,” they noted. “We cited this data in 2010 when we proposed to the NFL Players Association that the most effective way to reduce the risks of negative neurological outcomes was to reduce hitting in practice. They agreed, and in 2011 collectively bargained for severe contact limits in practice, with 14 full-contact practices allowed during the 17-week season. Since that rule was implemented, only 18% of NFL concussions have occurred in practice.”

“Against this backdrop, the results of the study by McCrea et al. are shocking,” they added. “It reveals that college football players still experience 72% of their concussions and 67% of their total head injury exposure in practice.”

Even more shocking, noted Dr. Nowinski and Dr. Cantu, is that these numbers are almost certainly an underestimate of the dangers of practice.

“As a former college football player and a former team physician, respectively, we find this situation inexcusable. Concussions in games are inevitable, but concussions in practice are preventable,” they wrote.  

“Laudably,” they added “the investigators call on the NCAA and football conferences to explore policy and rule changes to reduce concussion incidence and HIE and to create robust educational offerings to encourage change from coaches and college administrators.”

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

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

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

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

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

More than 50% of health care workers infected with SARS-CoV-2 report that their sense of smell has not returned to normal an average of 5 months post infection, new research shows.

Nenad Cavoski/iStock/Getty Images Plus

The findings illustrate that olfactory problems are common not only during the acute COVID-19 phase but also “in the long run” and that these problems should be “taken into consideration” when following up these patients, study investigator Johannes Frasnelli, MD, professor, department of anatomy, Université du Québec à Trois-Rivières, said in an interview.

Loss of the sense of smell can affect quality of life because it affects eating and drinking, and may even be dangerous, said Dr. Frasnelli. “If your sense of smell is impaired, you may unknowingly eat spoiled food, or you may not smell smoke or gas in your home,” he said. In addition, Dr. Frasnelli noted that an impaired sense of smell is associated with higher rates of depression. The findings will be presented at the annual meeting of the American Academy of Neurology in April.

‘Striking’ finding

Research shows that about 60% of patients with COVID-19 lose their sense of smell to some degree during the acute phase of the disease. “But we wanted to go further and look at the longer-term effects of loss of smell and taste,” said Dr. Frasnelli.

The analysis included 813 health care workers in the province of Quebec. For all the patients, SARS-CoV-2 infection was confirmed through testing with a nasopharyngeal viral swab.

Participants completed a 64-item online questionnaire that asked about three senses: olfactory; gustatory, which includes tastes such as sweet, sour, bitter, salty, savory and umami; and trigeminal, which includes sensations such as spiciness of hot peppers and “coolness” of mint.

They were asked to rate these on a scale of 0 (no perception) to 10 (very strong perception) before the infection, during the infection, and currently. They were also asked about other symptoms, including fatigue.

Most respondents had been infected in the first wave of the virus in March and April of 2020 and responded to the questionnaire an average of 5 months later.

The vast majority of respondents (84.1%) were women, which Dr. Frasnelli said was not surprising because women predominate in the health care field.

The analysis showed that average smell ratings were 8.98 before infection, 2.85 during the acute phase, and 7.41 when respondents answered the questionnaire. The sense of taste was less affected and recovered faster than did the sense of smell. Results for taste were 9.20 before infection, 3.59 during the acute phase, and 8.05 after COVID-19.

Among 580 respondents who indicated a compromised sense of smell during the acute phase, the average smell rating when answering the questionnaire was 6.89, compared to 9.03 before the infection. More than half (51.2%) reported not regaining full olfactory function.

The fact that the sense of smell had not returned to normal for half the participants so long after being infected is “novel and quite striking,” said Dr. Frasnelli.

However, he noted, this doesn’t necessarily mean all those with a compromised sense of smell “have huge problems.” In some cases, he said, the problem “is more subtle.”
 

Not a CNS problem?

Respondents also completed a chemosensory dysfunction home test (CD-HT). They were asked to prepare common household food items, such as peanut butter, sugar, salt, and vinegar, in a particular way – for example, to add sugar or salt to water – and provide feedback on how they smell and taste.

For this CD-HT analysis, 18.4% of respondents reported having persistent loss of smell. This, Dr. Frasnelli said, adds to evidence from self-reported responses and suggests that in some cases, the problem is more than senses not returning to normal.

“From the questionnaires, roughly 50% said their sense of smell is still not back to normal, and when we look at the CD home test, we see that almost 20% of subjects indeed have pretty strong impairment of their sense of smell,” he said.

The results showed no sex differences, although Dr. Frasnelli noted that most of the sample were women. “It’s tricky to look at the data with regard to sex because it’s a bit skewed,” he said.

Male respondents were older than female participants, but there was no difference in impairment between age groups. Dr. Frasnelli said this was “quite interesting,” inasmuch as older people usually lose some sense of smell.

The researchers have not yet examined whether the results differ by type of health care worker.

They also have not examined in detail whether infection severity affects the risk for extended olfactory impairment. Although some research suggests that the problem with smell is more common in less severe cases, Dr. Frasnelli noted this could be because loss of smell is not a huge problem for patients battling grave health problems.

As for other symptoms, many respondents reported lingering fatigue; some reported debilitating fatigue, said Dr. Frasnelli. However, he cautioned that this is difficult to interpret, because the participants were health care workers, many of whom returned to work during the pandemic and perhaps had not fully rested.

He also noted that he and his colleagues have not “made the link” between impaired smell and the degree of fatigue.

The COVID-19 virus appears to attack supporting sustentacular cells in the olfactory epithelium, not nerve cells.

“Right now, it seems that the smell problem is not a central nervous system problem but a peripheral problem,” said Dr. Frasnelli. “But we don’t know for sure; it may be that the virus somehow gets into the brain and some symptoms are caused by the effects of the infection on the brain.”

The researchers will extend their research with another questionnaire to assess senses 10-12 months after COVID-19.

Limitations of the study include the subjective nature of the smell and taste ratings and the single time point at which data were collected.
 

Confirmatory findings

Commenting on the research in an interview, Thomas Hummel, MD, professor, smell and taste clinic, department of otorhinolaryngology, Technische Universität Dresden (Germany), said the new results regarding loss of smell after COVID-19 are “very congruent” with what he and his colleagues have observed.

Research shows that up to one in five of those infected with SARS-CoV-2 experience olfactory loss. “While the numbers may vary a bit from study to study or lab to lab, I think 5% to 20% of post–COVID-19 patients exhibit long-term olfactory loss,” Dr. Hummel said.

His group has observed that “many more are not back to normal,” which conforms with what Dr. Frasnelli’s study reveals, said Dr. Hummel.

Also commenting on the research, Kenneth L. Tyler, MD, professor of neurology, University of Colorado at Denver, Aurora, and a fellow of the American Academy of Neurology, said the study was relatively large and the results “interesting.”

Although it “provides more evidence there’s a subset of patients with symptoms even well past the acute phase” of COVID-19, the results are “mostly confirmatory” and include “nothing super surprising,” Dr. Tyler said in an interview.

However, the investigators did attempt to make the study “a little more quantitative” and “to confirm the self-reporting with their validated CD home test,” he said.

Dr. Tyler wondered how representative the sample was and whether the study drew more participants with impaired senses. “If I had a loss of smell or taste, maybe I would be more likely to respond to such a survey,” he said.

He also noted the difficulty of separating loss of smell from loss of taste.

“If you lose your sense of smell, things don’t taste right, so it can be confounding as to how to separate out those two,” he noted.
The study was supported by the Foundation of the Université du Québec à Trois-Rivières and the Province of Quebec. Dr. Frasnelli has received royalties from Styriabooks in Austria for a book on olfaction published in 2019 and has received honoraria for speaking engagements. Dr. Hummel and Dr. Tyler have disclosed no relevant financial relationships.

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

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

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

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

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

Exposure to Group A streptococcus (GAS) does not appear to worsen symptoms of Tourette syndrome and other chronic tic disorders (CTDs) in children and adolescents, new research suggests.

Investigators studied over 700 children and teenagers with CTDs, one-third of whom also had attention deficit hyperactivity disorder and one-third who had obsessive-compulsive disorder (OCD).

The youngsters were followed for an average of 16 months and evaluated at 4-month intervals to see if they were infected with GAS. Tic severity was monitored through telephone interviews, in-person visits, and parental reports.

A little less than half the children experienced worsening of tics during the study period, but the researchers found no association between these exacerbations and GAS exposure.

There was also no link between GAS and worsening OCD. However, researchers did find an association between GAS exposure and an increase in hyperactivity and impulsivity in patients with ADHD.

“This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD,” the authors note.

“Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended,” they conclude.

The study was published online in Neurology.
 

‘Intense debate’

The association between GAS and CTD stems from the description of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection (PANDAS) – a condition that is now incorporated in the pediatric acute neuropsychiatric syndromes (PANS), the authors note. Tics constitute an “accompanying feature” of this condition.

However, neither population-based nor longitudinal clinical studies “could definitely establish if tic exacerbations in CTD are associated with GAS infections,” they note.  

“The link between streptococcus and tics in children is still a matter of intense debate,” said study author Davide Martino, MD, PhD, director of the Movement Disorders Program at the University of Calgary (Alta.), in a press release.

“We wanted to look at that question, as well as a possible link between strep and behavioral symptoms like obsessive-compulsive disorder and attention deficit hyperactivity disorder,” he said.

The researchers followed 715 children with CTD (mean age 10.7 years, 76.8% male) who were drawn from 16 specialist clinics in nine countries. Almost all (90.8%) had a diagnosis of Tourette syndrome (TS); 31.7% had OCD, and 36.1% had ADHD.

Participants received a throat swab at baseline, and of these, 8.4% tested positive for GAS.

Participants were evaluated over a 16- to 18-month period, consisting of:

• Face-to-face interviews and collection of throat swabs and serum at 4-month intervals.
• Telephone interviews at 4-month intervals, which took place at 2 months between study visit.
• Weekly diaries: Parents were asked to indicate any worsening of tics and focus on detecting the earliest possible tic exacerbation.

Beyond the regularly scheduled visits, parents were instructed to report, by phone or email, any noticeable increase in tic severity and then attend an in-person visit.

Tic exacerbations were defined as an increase of greater than or equal to 6 points on the Yale Global Tic Severity Scale-Total Tic Severity Score (YGTSS-TTS), compared with the previous assessment.

OCD and ADHD symptoms were assessed according to the Yale-Brown Obsessive-Compulsive Scale and the parent-reported Swanson, Nolan, and Pelham-IV (SNAP-IV) questionnaire.

The researchers divided GAS exposures into four categories: new definite exposure; new possible exposure; ongoing definite exposure; and ongoing possible exposure.
 

Unlikely trigger

During the follow-up period, 43.1% (n = 308) of participants experienced tic exacerbations. Of these, 218 participants experienced one exacerbation, while 90 participants experienced two, three, or four exacerbations.

The researchers did not find a significant association between GAS exposure status and tic exacerbation.

Participants who did develop a GAS-associated exacerbation (n = 49) were younger at study exit (9.63 vs. 11.4 years, P < .0001) and were more likely to be male (46/49 vs. 210/259, Fisher’s = .035), compared with participants who developed a non-GAS-associated tic exacerbation (n = 259).

Additional analyses were adjusted for sex, age at onset, exposure to psychotropic medications, exposures to antibiotics, geographical regions, and number of visits in the time interval of interest. These analyses continued to yield no significant association between new or ongoing concurrent GAS exposure episodes and tic exacerbation events.

Of the children in the study, 103 had a positive throat swab, indicating a new definite GAS exposure, whereas 46 had a positive throat swab indicating an ongoing definite exposure (n = 149 visits). Of these visits, only 20 corresponded to tic exacerbations.

There was also no association between GAS exposure and OCD symptom severity. However, it was associated with longitudinal changes (between 17% and 21%, depending on GAS exposure definition) in the severity of hyperactivity-impulsivity symptoms in children with ADHD.

“It is known that immune activation may concur with tic severity in youth with CTDs and that psychosocial stress levels may predict short-term future tic severity in these patients,” the authors write.

“Our findings suggest that GAS is unlikely to be the main trigger for immune activation in these patients,” they add.
 

Brick or cornerstone?

Commenting on the study for this news organization, Margo Thienemann, MD, clinical professor of psychiatry, Stanford (Calif.) University, said that in the clinic population they treat, GAS, other pathogens, and other stresses can “each be associated with PANS symptom exacerbations.”

However, these “would not be likely to cause PANS symptoms exacerbations in the vast majority of individuals, only individuals with genetic backgrounds and immunologic dysfunctions creating susceptibility,” said Dr. Thienemann, who also directs the Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) Clinic at Stanford Children’s Health. She was not involved with the study.

In an accompanying editorial, Andrea Cavanna, MD, PhD, honorary reader in neuropsychiatry, Birmingham (England) Medical School and Keith Coffman, MD, director, Tourette Syndrome Center of Excellence, Children’s Mercy Hospital, Kansas City, Mo., suggest that perhaps the “interaction of psychosocial stress and GAS infections contributes more to tic exacerbation than psychosocial stress alone.”

“Time will tell whether this study stands as another brick – a cornerstone? – in the wall that separates streptococcus from tics,” they write.

The study was supported by the European Union’s Seventh Framework Program. Dr. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; research funding support from Dystonia Medical Research Foundation Canada, the University of Calgary (Alta.), the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. The other authors’ disclosures are listed in the original article. Dr. Cavanna, Dr. Coffman, and Dr. Thienemann have disclosed no relevant financial relationships.

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