Neuromuscular Disorders

Physicians in China are reporting what they believe is the first case of COVID-19 initially presenting as acute Guillain-Barré syndrome (GBS). The patient was a 61-year-old woman returning home from Wuhan during the pandemic.

“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.

The case study was published online April 1 in Lancet Neurology.
 

GBS presentation

The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.

At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.

A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.

Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.

She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.

The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.

At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
 

Different pattern from Zika

Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.

Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.

“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.

“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.

“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.

This article was first published on Medscape.com.

Physicians in China are reporting what they believe is the first case of COVID-19 initially presenting as acute Guillain-Barré syndrome (GBS). The patient was a 61-year-old woman returning home from Wuhan during the pandemic.

“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.

The case study was published online April 1 in Lancet Neurology.
 

GBS presentation

The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.

At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.

A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.

Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.

She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.

The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.

At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
 

Different pattern from Zika

Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.

Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.

“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.

“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.

“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.

This article was first published on Medscape.com.

Physicians in China are reporting what they believe is the first case of COVID-19 initially presenting as acute Guillain-Barré syndrome (GBS). The patient was a 61-year-old woman returning home from Wuhan during the pandemic.

“GBS is an autoimmune neuropathy, which could be triggered by various infections,” said corresponding author Sheng Chen, MD, PhD, of Shanghai Jiao Tong University School of Medicine in China. However, “Our single case report only suggests a possible association between GBS and SARS-CoV-2 infection. It may or may not have a causal relationship,” Dr. Chen noted.

The case study was published online April 1 in Lancet Neurology.
 

GBS presentation

The female patient returned from Wuhan on January 19 but denied having any fever, cough, chest pain, or diarrhea. She presented on January 23 with acute weakness in both legs and severe fatigue that progressed.

At presentation, temperature was normal, oxygen saturation was 99% on room air, and the patient’s respiratory rate was 16 breaths per minute. She was not tested for SARS-CoV-2 at that point.

A neurologic examination revealed symmetric weakness (Medical Research Council grade 4/5) and areflexia in both legs and feet. The patient’s symptoms had progressed 3 days after admission, and testing revealed decreased sensation to light touch and pinprick.

Admission laboratory test results indicated a low lymphocyte count and thrombocytopenia. Results of nerve conduction studies performed on day 5 of hospitalization were consistent with demyelinating neuropathy.

She was diagnosed with GBS and given intravenous immunoglobulin. On day 8, she developed a dry cough and fever, and a chest CT showed ground-glass opacities in both lungs. At this point, she was tested for SARS-CoV-2, and the results were positive.

The patient was immediately transferred to an isolation room and received supportive care and antiviral drugs. Her condition improved gradually, and her lymphocyte and thrombocyte counts were normal on day 20.

At discharge on day 30, she had normal muscle strength in both arms and legs, and tendon reflexes in both legs and feet had returned. Her respiratory symptoms had resolved as well. A second SARS-CoV-2 test was negative.
 

Different pattern from Zika

Two relatives of the patient who had been with her during her hospital stay also tested positive for SARS-CoV-2 and were isolated and treated. All of the hospital staff that cared for the patient, including two neurologists and six nurses, tested negative for SARS-CoV-2.

Given the temporal association, a SARS-CoV-2 infection could be responsible for the development of GBS in this patient, the investigators noted. They added that the onset of GBS symptoms overlapped with the period of SARS-CoV-2 infection.

“Hence Guillain-Barré syndrome associated with SARS-CoV-2 might follow the pattern of a parainfectious profile, instead of the classic postinfectious profile, as reported in Guillain-Barré syndrome associated with Zika virus,” the researchers wrote.

“More cases with epidemiological data are necessary to support a causal relationship” between SARS-CoV-2 infection and GBS, said Dr. Chen.

“However, we still suggest physicians who encounter an acute GBS patient from a pandemic area protect themselves carefully and test [for the] virus on admission. If the result is positive, the patient needs to be isolated,” Dr. Chen said.

This article was first published on Medscape.com.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

A growing body of research links the gut with the brain and behavior, but compartmentalization within the medical community may be slowing investigation of the gut-brain axis, according to a leading expert.

Studies have shown that the microbiome may influence a diverse range of behavioral and neurological processes, from acute and chronic stress responses to development of Parkinson’s and Alzheimer’s disease, reported John F. Cryan, PhD, of University College Cork, Ireland.

Dr. Cryan began his presentation at the annual Gut Microbiota for Health World Summit by citing Hippocrates, who is thought to have stated that all diseases begin in the gut.

“That can be quite strange when I talk to my neurology or psychiatry colleagues,” Dr. Cryan said. “They sometimes look at me like I have two heads. Because in medicine we compartmentalize, and if you are studying neurology or psychiatry or [you are] in clinical practice, you are focusing on everything from the neck upwards.”

For more than a decade, Dr. Cryan and colleagues have been investigating the gut-brain axis, predominantly in mouse models, but also across animal species and in humans.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Cryan reviewed a variety of representative studies.

For instance, in both mice and humans, research has shown that C-section, which is associated with poorer microbiome diversity than vaginal delivery, has also been linked with social deficits and elevated stress responses. And in the case of mice, coprophagia, in which cesarean-delivered mice eat the feces of vaginally born mice, has been shown to ameliorate these psychiatric effects.

Dr. Cryan likened this process to an “artificial fecal transplant.”

“You know, co-housing and eating each other’s poo is not the translational approach that we were advocating by any means,” Dr. Cryan said. “But at least it tells us – in a proof-of-concept way – that if we change the microbiome, then we can reverse what’s going on.”

While the mechanisms behind the gut-brain axis remain incompletely understood, Dr. Cryan noted that the vagus nerve, which travels from the gut to the brain, plays a central role, and that transecting this nerve in mice stops the microbiome from affecting the brain.

“What happens in vagus doesn’t just stay in vagus, but will actually affect our emotions in different ways,” Dr. Cryan said.

He emphasized that communication travels both ways along the gut-brain axis, and went on to describe how this phenomenon has been demonstrated across a wide array of animals.

“From insects all the way through to primates, if you start to interfere with social behavior, you change the microbiome,” Dr. Cryan said. “But the opposite is also true; if you start to change the microbiome you can start to have widespread effects on social behavior.”

In humans, manipulating the microbiome could open up new psychiatric frontiers, Dr. Cryan said.

“[In the past 30 years], there really have been no real advances in how we manage mental health,” he said. “That’s very sobering when we are having such a mental health problem across all ages right now. And so perhaps it’s time for what we’ve coined the ‘psychobiotic revolution’ – time for a new way of thinking about mental health.”

According to Dr. Cryan, psychobiotics are interventions that target the microbiome for mental health purposes, including fermented foods, probiotics, prebiotics, synbiotics, parabiotics, and postbiotics.

Among these, probiotics have been a focal point of interventional research. Although results have been mixed, Dr. Cryan suggested that negative probiotic studies are more likely due to bacterial strain than a failure of the concept as a whole.

“Most strains of bacteria will do absolutely nothing,” Dr. Cryan said. “Strain is really important.”

In demonstration of this concept, he recounted a 2017 study conducted at University College Cork in which 22 healthy volunteers were given Bifidobacterium longum 1714, and then subjected to a social stress test. The results, published in Translational Psychiatry, showed that the probiotic, compared with placebo, was associated with attenuated stress responses, reduced daily stress, and enhanced visuospatial memory.

In contrast, a similar study by Dr. Cryan and colleagues, which tested Lactobacillus rhamnosus (JB-1), fell short.

“You [could not have gotten] more negative data into one paper if you tried,” Dr. Cryan said, referring to the study. “It did absolutely nothing.”

To find out which psychobiotics may have an impact, and how, Dr. Cryan called for more research.

“It’s still early days,” he said. “We probably have more meta-analyses and systematic reviews of the field than we have primary research papers.

Dr. Cryan concluded his presentation on an optimistic note.

“Neurology is waking up ... to understand that the microbiome could be playing a key role in many, many other disorders. ... Overall, what we’re beginning to see is that our state of gut markedly affects our state of mind.”

Dr. Cryan disclosed relationships with Abbott Nutrition, Roche Pharma, Nutricia, and others.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

Higher out-of-pocket costs for prescription drugs are associated with poorer adherence across common neurologic conditions, a new study has found, suggesting that physicians should take patient costs into consideration when choosing which drugs to prescribe.

For their study, published online Feb. 19 in Neurology, Brian C. Callaghan, MD, of the University of Michigan, Ann Arbor, and colleagues looked at claims records from a large national private insurer to identify new cases of dementia, Parkinson’s disease, and neuropathy between 2001 and 2016, along with pharmacy records following diagnoses.

The researchers identified more than 52,000 patients with neuropathy on gabapentinoids and another 5,000 treated with serotonin-norepinephrine reuptake inhibitors for the same. They also identified some 20,000 patients with dementia taking cholinesterase inhibitors, and 3,000 with Parkinson’s disease taking dopamine agonists. Dr. Callaghan and colleagues compared patient adherence over 6 months for pairs of drugs in the same class with similar or equal efficacy, but with different costs to the patient.

Such cost differences can be stark: The researchers noted that the average 2016 out-of-pocket cost for 30 days of pregabalin, a drug used in the treatment of peripheral neuropathy, was $65.70, compared with $8.40 for gabapentin. With two common dementia drugs the difference was even more pronounced: $79.30 for rivastigmine compared with $3.10 for donepezil, both cholinesterase inhibitors with similar efficacy and tolerability.

Dr. Callaghan and colleagues found that such cost differences bore significantly on patient adherence. An increase of $50 in patient costs was seen decreasing adherence by 9% for neuropathy patients on gabapentinoids (adjusted incidence rate ratio [IRR] 0.91, 0.89-0.93) and by 12% for dementia patients on cholinesterase inhibitors (adjusted IRR 0.88, 0.86-0.91, P less than .05 for both). Similar price-linked decreases were seen for neuropathy patients on SNRIs and Parkinson’s patients on dopamine agonists, but the differences did not reach statistical significance.

Black, Asian, and Hispanic patients saw greater drops in adherence than did white patients associated with the same out-of-pocket cost differences, leading the researchers to note that special care should be taken in prescribing decisions for these populations.

“When choosing among medications with differential [out-of-pocket] costs, prescribing the medication with lower [out-of-pocket] expense will likely improve medication adherence while reducing overall costs,” Dr. Callaghan and colleagues wrote in their analysis. “For example, prescribing gabapentin or venlafaxine to patients with newly diagnosed neuropathy is likely to lead to higher adherence compared with pregabalin or duloxetine, and therefore, there is a higher likelihood of relief from neuropathic pain.” The researchers noted that while combination pills and extended-release formulations may be marketed as a way to increase adherence, the higher out-of-pocket costs of such medicines could offset any adherence benefit.

Dr. Callaghan and his colleagues described as strengths of their study its large sample and statistical approach that “allowed us to best estimate the causal relationship between [out-of-pocket] costs and medication adherence by limiting selection bias, residual confounding, and the confounding inherent to medication choice.” Nonadherence – patients who never filled a prescription after diagnosis – was not captured in the study.

The American Academy of Neurology funded the study. Two of its authors reported financial conflicts of interest in the form of compensation from pharmaceutical or device companies. Its lead author, Dr. Callaghan, reported funding for a device maker and performing medical legal consultations.

SOURCE: Reynolds EL et al. Neurology. 2020 Feb 19. doi/10.1212/WNL.0000000000009039.

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

jremaly@mdedge.com

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

Focused ultrasound thalamotomy provides continued benefits for tremor, disability, and quality of life at 3 years in patients with medically refractory essential tremor, according to data published Nov. 20 in Neurology. Improvement from baseline remains significant at that time point, although the magnitude of effect may decrease. In addition, the treatment is not associated with progressive or delayed complications.

“For people who have disabling essential tremor that is not responding to medication, this treatment should be considered as a safe and effective option,” Casey H. Halpern, MD, assistant professor of neurosurgery at Stanford (Calif.) University, said in a press release.
 

Long-term follow-up of a prospective trial

Focused ultrasound thalamotomy is an emerging treatment for essential tremor. The procedure, which does not require an incision, is conducted with the guidance of magnetic resonance thermometry and patient feedback. A randomized controlled trial conducted by Elias and colleagues indicated that focused ultrasound ventral intermediate nucleus thalamotomy significantly suppressed tremor, reduced disability, and improved quality of life at 3 months, compared with sham treatment. This improvement was sustained at 12 months, and a follow-up study showed that improvements in tremor and functional disability were sustained at 24 months.

Dr. Halpern and colleagues sought to evaluate the continued safety and efficacy of focused ultrasound thalamotomy at 3 years’ follow-up in patients who participated in the original trial. Movement disorder specialists evaluated participants’ tremor severity and functional impairment using the Clinical Rating Scale for Tremor (CRST) at baseline and at 12, 24, and 36 months after treatment. Patients responded to the Quality of Life in Essential Tremor (QUEST) questionnaire, which assesses quality of life at baseline and at each follow-up visit. Neurologists evaluated and recorded all adverse events that occurred during the trial.
 

Postural tremor was eliminated

The original population included 75 patients who underwent focused ultrasound thalamotomy during the randomized, blinded phase or in an unblinded fashion during the crossover phase. The mean age of all treated patients was 71 years, and disease duration at treatment was 16.8 years. Fifty-two participants were observed at 36 months, and the 3-year attrition rate thus was 31%.

Dr. Halpern and colleagues found that the hand combined tremor–motor score, which was the trial’s primary endpoint, was significantly improved from baseline at 3 years. The median improvement from baseline was 56%. The median disability score decreased by 63% from baseline. Postural tremor was eliminated at 36 months, and QUEST score improved by 50%.

For patients who were missing at 3-year follow-up, data obtained at 3 months was used for comparison. These patients had less improvement in hand tremor–motor score, less reduction in disability, and less reduction in postural tremor, compared with patients who presented for 3-year follow-up. When the investigators reanalyzed their results to account for missing data, they found that the improvement from baseline remained significant.

Dr. Halpern and colleagues compared scores at 36 months and at 6 months to evaluate the durability of the treatment effect. Data were available for 49 patients at both time points, and their combined tremor–motor score had increased by a median of one point at 36 months. Disability score increased by a median of 2 points at 36 months. Posture and QUEST scores did not change significantly. About 58% of patients had at least 50% improvement in hand combined tremor–motor score at 36 months, compared with 64% at 24 months and 61% at 12 months.

The investigators described all adverse events as mild or moderate. No new procedure-related adverse events occurred between 24 and 36 months of follow-up, and none worsened during this period. Two adverse events, however, resolved between 24 and 36 months: one case of dysarthria and one of imbalance.
 

Reduction in improvement may have many causes

“A reduction in improvement is not unexpected, as essential tremor is a progressive disease,” wrote Dr. Halpern and colleagues. “In addition, diminishing performance of motor–functional tasks over time, particularly in this elderly population, may be multifactorial.” Decrease in tremor control has been reported after all surgical treatments for essential tremor (e.g., deep brain stimulation [DBS] and radiofrequency thalamotomy). Retreatment with invasive therapies or ionizing irradiation would be more problematic than retreatment with focused ultrasound thalamotomy, they added.

The researchers acknowledged that the main limitations of their study were the 31% dropout rate at 3 years and the fact that the cohort at 3-year follow-up differed from those at 2-year follow-up and in the original trial. The results nevertheless “demonstrate persistent, significant tremor reduction, as well as functional and quality of life improvement, with a positive safety profile,” they wrote.

Study funding was provided by the Focused Ultrasound Foundation, the Binational Industrial Research and Development Foundation of Israel, and InSightec, the maker of the focused ultrasound equipment that the researchers used. Dr. Halpern and other investigators received research funding from InSightec. One of the researchers is on the company’s medical advisory board, and another served as a consultant to the company.
 

Effect on axial tremor is unclear

The 50% improvement in hand tremor, disability, and quality of life that Halpern et al. report is similar to the improvement observed following DBS therapy, said Aparna Wagle Shukla, MD, director of the neurophysiology laboratory at the University of Florida in Gainesville, in an interview. Although the results are promising, neurologists should bear several points in mind, she added.

“DBS-induced side effects often are amenable to programming adjustments. However, similar to radiofrequency thalamotomy, focused ultrasound thalamotomy causes lesion effects. While the study discusses the nature of thalamotomy-induced adverse effects, the clinical practitioners also will benefit from learning about the severity of side effects and how they were individually addressed,” said Dr. Wagle Shukla. “The study acknowledges that there was a 30% dropout rate at 3 years’ follow-up. As the original plan included a 5-year follow-up, it would be beneficial to know why a large fraction of participants discontinued participation earlier than expected.”

Furthermore, the study by Halpern et al. leaves several questions unanswered. It does not indicate, for example, whether focused ultrasound thalamotomy can affect the control of axial tremor, including head and voice tremor, said Dr. Wagle Shukla. “Also, the potential of focused ultrasound thalamotomy to treat complex tremors with possible targeting of multiple brain regions such as ventralis oralis anterior and posterior and zona incerta stimulation is currently not known.

“There is no doubt that focused ultrasound thalamotomy is useful for the control of hand tremors in patients diagnosed with essential tremor, with long-term improvements in quality of life,” Dr. Wagle Shukla continued. “However, it is presently limited in its scope as a unilateral, single-target brain procedure.”

egreb@mdedge.com

SOURCE: Halpern CH et al. Neurology. 2019 Nov 20 (Epub ahead of print).

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

egreb@mdedge.com

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

egreb@mdedge.com

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.

SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.

AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.

At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.

Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.

Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
 

egreb@mdedge.com

SOURCE: Dabbous O et al. CNS 2019. Abstract 199.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Postural orthostatic tachycardia syndrome (POTS) is not a single disorder, but rather includes multiple overlapping subtypes, according to Steven Vernino, MD, PhD, a professor of neurology at the University of Texas, Dallas.

“It’s pretty well established that there’s a heterogeneous spectrum of disorders that can present this way,” Dr. Vernino told attendees at the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine. “Investigation is somewhat difficult because we have limited tools.”

In his overview of POTS, Dr. Vernino defined it as a chronic condition with an “inappropriate orthostatic increase in heart rate” and symptoms that persist for at least 6 months. The heart rate increase should be at least 30 beats per minute – or 40 bpm in those aged 12-19 years – within 5-10 minutes of quiet standing or an upright tilt, but the patient lacks orthostatic hypotension. Often, however, other symptoms continue even if the tachycardia is not always present.

These symptoms range widely, including fainting, shortness of breath, headaches, fatigue, fibromyalgia, dizziness, brain fog, chest tightens, sensitivity to light or sound, tingling, heat intolerance, and gastrointestinal problems. Pain is particularly common.

Though peak incidence occurs around age 14 years, the average age of patients with POTS is 30 years. Women comprise 86% of those with POTS and 93% of patients are white, though this last figure may result from multiple reporting biases. A quarter of patients are disabled to a degree similar to heart failure or chronic obstructive pulmonary disease, he said.

Prevalence estimates are all over the map, ranging in academic literature from “up to 1% of teens” to “millions of Americans,” Dr. Vernino said. A commonly accepted range puts the estimate at 500,000 to 3 million Americans, the number used by Dysautonomia International.

Key to treatment of POTS is assessing possible underlying causes and individualizing treatment based on likely contributing etiologies, such as hypovolemia, deconditioning, and autoimmunity, Dr. Vernino said.

Classifications and etiologies of POTS

With its various possible etiologies, “it’s our job as physicians to try to understand, if you can, what the underlying the etiology is and try to address that,” Dr. Vernino said. About 11% of patients have a family history of POTS, and some research has suggested genes that may be involved, including the one that encodes the norepinephrine transporter and alpha tryptase.

Patients with neuropathic POTS have a mild or partial peripheral autonomic neuropathy “that causes a problem with the vasomotor function so that when patients stand, they don’t have an adequate increase in vascular tone, blood pools in the feet and they develop relative hypovolemia, and the autonomic nervous system compensates with tachycardia,” he said. The Quantitative Sudomotor Axon Reflex Test may show distal sweating, and a skin biopsy can be done to assess intraepidermal nerve fiber density.

Hyperadrenergic POTS involves “the presence of a dramatic, excessive rise of norepinephrine” and can involve tremor, nausea, sweating, and headache when patients are upright, Dr. Vernino said.

“These are patients who appear, clinically and in laboratory testing, to have inappropriate sympathetic response to standing up,” he said, and they may have orthostatic hypertension along with an increased heart rate.

Other subtypes of POTS can overlap neuropathic and hyperadrenergic types, which can also overlap one another. About 30% of patients appear hypovolemic, with a 13%-17% volume deficit, even with copious intake of water and sodium, he said. Despite this deficit, renin levels are typically normal in these patients, and aldosterone levels may be paradoxically low. Reduced red blood cell mass may be present, too (Circulation. 2005 Apr 5;111[13]:1574-82).

“What causes that and how that’s related to the other features is a bit unclear, and then, either as a primary or as a secondary component of POTS, there can be cardiac deconditioning,” Dr. Vernino said, requiring quantitative ECG. “It’s unclear whether that deconditioning happens as a consequence of disability from POTS or as a primary part of it.”

Questions still exist regarding whether autoimmunity is one of the underpinnings of POTS, Dr. Vernino said. It’s associated with elevated inflammatory biomarker levels and systemic autoimmune disorders such as Sjögren’s syndrome, as well as with antiphospholipid antibodies.

“More recently there’s been evidence on specific autoantibodies that have been found in POTS patients, and we’re still working through what all that means,” he said. “The real question is whether these antibodies are the cause of POTS” versus an effect or an epiphenomenon.

These antibodies include some G protein–coupled receptor antibodies, such as adrenergic receptor autoantibodies, angiotensin II type 1 receptor antibodies, and muscarinic acetylcholine receptor M3 antibodies. Others include thyroid autoantibodies, ganglionic acetylcholine receptor antibodies, and IgG antibodies, as well as several dozen cardiac membrane proteins.

Comorbidities and risk factors

Although 41% of patients with POTS report some health event preceding onset of symptoms, it’s unclear which, if any, of these events may be related to the condition. The most common antecedent event is infection, reported by 41% of patients in the “Big POTS Survey” conducted by Dysautonomia International, Dr. Vernino said. Other antecedent events reported included surgery (12%), pregnancy (9%), an accident (6%), vaccination (6%), puberty (5%), concussion (4%), and emotional trauma (3%). Research has found associations with migraine, concussion, and infection.

Comorbidities are also common, reported by 84% of patients in the same survey. Migraine, vitamin D deficiency, and joint hypermobility (Ehlers-Danlos syndrome type 3) top the list of comorbidities, and various autoimmune conditions, particularly Sjögren’s syndrome, may co-occur with POTS. Other comorbidities include small fiber neuropathy, mast-cell activation syndrome, chronic fatigue, gastrointestinal problems, vasovagal syncope, and sleeping difficulties.

Joint hypermobility appears to be a “pretty strong risk factor for development” of POTS, Dr. Vernino said, and patients may even be involved in activities where that’s helpful, such as gymnastics. “You can make this diagnosis clinically – there isn’t a genetic test for joint hypermobility syndrome – and you usually don’t have the other features of Marfan syndrome,” he told attendees.

Other risk factors include low body mass, mitral valve prolapse, migraine, anxiety, irritable bowel syndrome, prolonged bed rest after an illness, and mast-cell activation syndrome.

Prognosis and treatment

POTS is very common but often still unrecognized, Dr. Vernino said, “because the symptoms are somewhat diverse and broad and vague.” Even providers who recognize POTS can become preoccupied with “the heart rate increase being the whole picture, but there are many other symptoms, and that leads to a significant impact on the quality of life of these patients.”

The course of POTS varies across patients. In about half of patients, symptoms persist but the severity improves, and one in five patients fully resolve. Severity only tends to worsen over time in about 3.5% of patients, and severity remains constant in 8.7% (J Pediatr. 2016 Jun;173:149-53. doi: 10.1016/j.jpeds.2016.02.035).

“It would probably be simpler if POTS was a single entity that had a single etiology that we could target,” Dr. Vernino said. But its heterogeneity means “we have to investigate patients individually and understand their particular situation, individualize their treatment, whether it be nonpharmacological or pharmacological, to their particular potential etiologies.”

Dr. Vernino has received research support from Genentech, Grifols, Athena/Quest, Biohaven Pharmaceutical, Dysautonomia International, and the Rex Griswold Foundation.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.

AUSTIN, TEX. – Neuromuscular complications from immunotherapy for cancer are rare, but they occur often enough that it is helpful to know which ones can result from different immunotherapies and how to distinguish them from non–adverse event conditions, according to Christopher Trevino, MD, a neuro-oncologist at Tulane University in New Orleans.

At the annual meeting of the American Association for Neuromuscular and Electrodiagnostic Medicine, Dr. Trevino reviewed immunotherapy types, particularly immune checkpoint inhibitors, and the most common neuromuscular complications – primarily neuropathy, myasthenia gravis (MG), myositis, and encephalitis or meningitis.

“Timing of onset is a critical component to assist in identifying immune checkpoint inhibitor–associated versus non–immune checkpoint inhibitor–associated neuromuscular disease,” Dr. Trevino told attendees. Prompt recognition can be particularly urgent for MG because crisis and death rates are higher when induced by immunotherapy and require quick treatment. “Understanding the mechanisms of action sets a foundation for treatment approach,” he added.

Any part of the nervous system can be affected by immunotherapy toxicity, he said, and syndromes often overlap, with the peripheral nervous system typically more often affected than the central nervous system. Neurologic immune-related adverse events typically occur within four cycles of therapy – about 12 weeks after therapy initiation – but should always involve a work-up to exclude effects from the cancer itself, other neuromuscular diagnoses unrelated to therapy, and other toxicities from chemotherapy.

Recommended first-line treatment is halting immunotherapy with or without corticosteroids, after which most patients improve, often with “rapid, complete resolution of symptoms,” Dr. Trevino said. Restarting immunotherapy treatment is possible in some patients, though.
 

CAR T-cell and dendritic cell vaccine therapies

Four main types of immunotherapy exist: viral therapy, vaccine therapy, immune checkpoint inhibitors, and adoptive cell transfer, such as chimeric antigen receptor (CAR) T-cell therapy. Dr. Trevino focused on checkpoint inhibitors and adoptive cell transfer.

CAR T-cell therapy is a multistep treatment process that involves first removing blood from the patient to obtain their T cells. These are used to create and grow CAR T cells in the lab so that they can be infused back into the patient. The cells then bind to cancer cells and destroy them. Examples of approved CAR T-cell therapy include Yescarta (axicabtagene ciloleucel) for some types of non-Hodgkin lymphoma and Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL).

Dendritic cell vaccines are similar to CAR T-cell therapy in that they also use the patient’s own immune cells to create cancer-killing cells that the patient then receives back. The only currently approved dendritic cell vaccine is Provenge (sipuleucel-T) for advanced prostate cancer.

The main toxicity to watch for from CAR T-cell therapy and dendritic cell vaccines is cytokine release syndrome (CRS). It can begin anywhere from 1-14 days after the infusion and involves T-cell expansion in the body that leads to a cytokine storm. Symptoms are wide ranging, including fatigue, fever, loss of appetite, tachycardia, hypotension, pain, rash, diarrhea, headache, confusion, seizures, muscle and joint pain, tachypnea, hypoxia and hallucinations, among others.

Specific central neurotoxicities that can result from CAR T-cell therapy include encephalopathy, cerebral edema, seizures and status epilepticus, cerebral vasospasm, and aphasia.
 

Immune checkpoint inhibitor toxicities

Immune checkpoint inhibitors are drugs that interrupt a cancer’s ability to hijack the immune system; they block the proteins that hold back T-cells from attacking the cancer, thereby releasing the immune system to go after the malignant cells.

The two most common types of immune checkpoint inhibitors are those targeting the programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathways. The three currently approved PD-1 inhibitors are pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo), which can treat nearly a dozen malignancies affecting different organs. Atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) are the three currently approved PD-L1 inhibitors, indicated for urothelial carcinoma and a handful of other cancers, such as small-cell and non–small cell lung cancer and triple negative breast cancer.

The only other type of approved checkpoint inhibitor is ipilimumab (Yervoy), which targets the CTLA-4 protein. A number of other checkpoint inhibitors are in trials, however, such as ones targeting pathways involving OX40, ICOS, TIM3, and LAG-3 (J Hematol Oncol. 2018. doi: 10.1186/s13045-018-0582-8).

Immune-related adverse events are less common with PD-1 or PD-L1 inhibitors – a rate of 5%-10% – compared with adverse events from CTLA-4 inhibitors, which occur in about 15% of patients. Neurologic complications occur even more rarely – about 1%-4% of all immune checkpoint inhibitor therapies – and primarily include MG, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and inflammatory myositis (Muscle Nerve. 2018;58[1]:10-22).

Treatment with multiple checkpoint inhibitors increases the likelihood of severe adverse events, with rates of up to 30%-50% of patients with dual treatment.
 

Distinguishing features of neuromuscular immunotherapy-related adverse events

MG is the most common neuromuscular immune-related adverse event from immune checkpoint inhibitors and tends to occur 3-12 weeks after beginning treatment, frequently comorbid with inflammatory myopathy or cardiomyopathy, Dr. Trevino said. About two-thirds of cases are de novo, while the remaining one-third involve preexisting MG; no reports of Lambert-Eaton myasthenic syndrome have been linked to checkpoint inhibitors.

Several characteristics distinguish checkpoint inhibitor–associated MG from standard MG. Standard MG can be ocular with or without bulbar or appendicular weakness, whereas immunotherapy-related MG is rarely only ocular (about 18% of cases). Immunotherapy-related MG involves an MG crisis at diagnosis in up to 50% of cases and has high mortality, both of which are rarer with standard MG.

While standard MG can be seronegative or involve AChR, MuSK, or LRP4 antibodies, about two-thirds of immunotherapy-related MG cases are positive for AChR antibodies. LRP4 antibodies are rare with MG from checkpoint inhibitors, and no MuSK antibodies have been reported in these cases. Creatine kinase (CK) or troponin I (TnI) elevation occurs in about 87% of patients with checkpoint inhibitor-induced MG, but standard MG doesn’t typically involve increased CK levels.

Inflammatory myositis (IM), the second most common neuromuscular adverse event from immunotherapy, tends to occur 2-15 weeks after immune checkpoint inhibitor therapy and can involve polymyositis, necrotizing autoimmune myopathy, dermatomyositis, granulomatous myositis, or other nonspecific myositis and myopathies.

Though proximal weakness occurs with IM both associated with immunotherapy and not, ocular symptoms are unique to cases associated with therapy and occur in about half of them. Myalgia, dyspnea, and dysphagia can all occur with checkpoint inhibitor–associated IM but don’t generally occur with standard IM. Immunotherapy-related IM is usually seronegative for myositis antibodies and doesn’t generally cause abnormalities in electromyography, compared with increased exertional activity and early recruitment of myopathic motor units in electromyography with standard IM.

GBS and CIDP are the third most common cause of neuromuscular complications from checkpoint inhibitors. The main distinguishing feature of these conditions from those not related to immunotherapy is that they occur anywhere from 4 to 68 weeks after therapy begins. Presentation is otherwise similar whether related to checkpoint inhibitors or not.

Aside from GBS and CIDP, other neuropathies that can result from immunotherapy complications include acute cranial neuropathies, axonal or demyelinating neuropathies, motor polyradiculopathy, vasculitic neuropathy, and plexopathy.

Neuromuscular complications other than those described above can also occur from checkpoint inhibitor therapy, such as enteric neuropathy, polyradiculitis, and meningo-radiculo-neuritis, but these are much rarer.

Four organizations have developed consensus guidelines for immune checkpoint inhibitor toxicities: the European Society for Medical Oncology (ESMO, 2017), Society for Immunotherapy of Cancer (SITC, 2017), American Society of Clinical Oncology (ASCO, 2018), and National Comprehensive Cancer Network (NCCN, 2019).

Dr Trevino had no disclosures.