Neuromuscular Disorders

The anticipated biennial peak in acute flaccid myelitis cases did not occur in 2020, possibly because of “nonpharmaceutical interventions implemented during the COVID-19 pandemic,” suggested researchers at the Centers for Disease Control and Prevention.

Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.

Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.

Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.

The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.

Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.

The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
 

[email protected]

The anticipated biennial peak in acute flaccid myelitis cases did not occur in 2020, possibly because of “nonpharmaceutical interventions implemented during the COVID-19 pandemic,” suggested researchers at the Centers for Disease Control and Prevention.

Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.

Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.

Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.

The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.

Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.

The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
 

[email protected]

The anticipated biennial peak in acute flaccid myelitis cases did not occur in 2020, possibly because of “nonpharmaceutical interventions implemented during the COVID-19 pandemic,” suggested researchers at the Centers for Disease Control and Prevention.

Acute flaccid myelitis (AFM) is an uncommon but serious complication of some viral infections, including West Nile virus and nonpolio enteroviruses. It is “characterized by sudden onset of limb weakness and lesions in the gray matter of the spinal cord,” they said, and more than 90% of cases occur in young children.

Cases of AFM, which can lead to respiratory insufficiency and permanent paralysis, spiked during the late summer and early fall in 2014, 2016, and 2018 and were expected to do so again in 2020, Sarah Kidd, MD, and associates at the division of viral diseases at the CDC’s National Center for Immunization and Respiratory Diseases, Atlanta, said in the Morbidity and Mortality Weekly Report.

Monthly peaks in those previous years – each occurring in September – reached 51 cases in 2014, 43 cases in 2016, and 88 cases in 2018, but in 2020 there was only 1 case reported in September, with a high of 4 coming in May, CDC data show. The total number of cases for 2020 (32) was, in fact, lower than in 2019, when 47 were reported.

The investigators’ main objective was to see if there were any differences between the 2018 and 2019-2020 cases. Reports from state health departments to the CDC showed that, in 2019-2020, “patients were older; more likely to have lower limb involvement; and less likely to have upper limb involvement, prodromal illness, [cerebrospinal fluid] pleocytosis, or specimens that tested positive for EV [enterovirus]-D68” than patients from 2018, Dr. Kidd and associates said.

Mask wearing and reduced in-school attendance may have decreased circulation of EV-D68 – the enterovirus type most often detected in the stool and respiratory specimens of AFM patients – as was seen with other respiratory viruses, such as influenza and respiratory syncytial virus, in 2020. Previous studies have suggested that EV-D68 drives the increases in cases during peak years, the researchers noted.

The absence of such an increase “in 2020 reflects a deviation from the previously observed biennial pattern, and it is unclear when the next increase in AFM should be expected. Clinicians should continue to maintain vigilance and suspect AFM in any child with acute flaccid limb weakness, particularly in the setting of recent febrile or respiratory illness,” they wrote.
 

[email protected]

When treating oromandibular dystonia with botulinum toxin injection to the lateral pterygoid muscle, an intraoral approach is the safest way to avoid injury to the maxillary artery, new research suggests.

Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.

In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.

“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.

Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
 

Significant gender differences

The maxillary artery is the largest branch of the external carotid artery.

In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.

Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.

“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.

Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).

In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”

“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
 

Useful education

Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.

Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.

“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.

When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.

If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.

Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.

There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.

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

When treating oromandibular dystonia with botulinum toxin injection to the lateral pterygoid muscle, an intraoral approach is the safest way to avoid injury to the maxillary artery, new research suggests.

Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.

In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.

“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.

Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
 

Significant gender differences

The maxillary artery is the largest branch of the external carotid artery.

In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.

Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.

“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.

Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).

In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”

“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
 

Useful education

Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.

Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.

“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.

When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.

If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.

Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.

There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.

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

When treating oromandibular dystonia with botulinum toxin injection to the lateral pterygoid muscle, an intraoral approach is the safest way to avoid injury to the maxillary artery, new research suggests.

Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.

In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.

“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.

Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
 

Significant gender differences

The maxillary artery is the largest branch of the external carotid artery.

In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.

Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.

“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.

Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).

In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”

“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
 

Useful education

Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.

Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.

“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.

When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.

If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.

Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.

There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.

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

An investigative formulation of a botulinum neurotoxin (BoNT) for cervical dystonia may significantly reduce the risk of dysphagia after injection compared with existing injections, and may have a longer duration of beneficial effect, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.

The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.

“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said. 

“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.

Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.

“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.

The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.

The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.

Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.

Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.

The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”

The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”

The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.

An investigative formulation of a botulinum neurotoxin (BoNT) for cervical dystonia may significantly reduce the risk of dysphagia after injection compared with existing injections, and may have a longer duration of beneficial effect, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.

The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.

“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said. 

“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.

Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.

“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.

The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.

The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.

Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.

Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.

The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”

The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”

The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.

An investigative formulation of a botulinum neurotoxin (BoNT) for cervical dystonia may significantly reduce the risk of dysphagia after injection compared with existing injections, and may have a longer duration of beneficial effect, according to results of a phase 3 clinical trial presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders.

The ASPEN-1 trial evaluated 301 patients with moderate to severe cervical dystonia for up to 36 weeks and found that those receiving two doses of DaxibotulinumtoxinA, known as DAXI, versus placebo improved their scores on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), said Joseph Jankovic, MD, professor of neurology and director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston.

“Botulinum neurotoxin is clearly the treatment of choice for cervical dystonia,” Dr. Jankovic said in an interview. “While the majority of patients obtain satisfactory benefit from BoNT injections, some experience adverse effects such as neck weakness and difficulty swallowing.” Another limitation of BoNT is that its effects wear off after about 3 months or less and patients have to be re-injected, he said. 

“This is why I am quite encouraged by the results of the DAXI study that suggest that this formulation of BoNT (type A) may have a longer response and relatively few side effects,” he said.

Patients in the study were randomized 1:3:3 to placebo, DAXI 125U or DAXI 250U. The average TWSTRS score upon enrollment was 43.3. The placebo group had a mean ± standard error TWSTRS improvement of 4.3 ± 1.8 at 4 or 6 weeks, while the treatment groups had mean ± SE improvements of 12.7 ± 1.3 for 125U and 10.9 ± 1.2 for 250U (P = .0006 vs. placebo). They translate into improvements of 12%, 31%, and 27% for the placebo and low- and high-dose treatment groups, respectively.

“Even though paradoxically it seems the high-dose group did slightly less well than the low-dose group, there was no difference between the two groups,” Dr. Jankovic said in the presentation.

The median duration of benefit was 24 weeks in the low-dose group and 20.3 weeks in the high-dose group.

The treatment groups demonstrated similar benefit compared with placebo in TWSTRS subscales for disease severity, disability, and pain, Dr. Jankovic said. “The majority of the patients had little better, moderately better, or very much better from the botulinum toxin injection with respect to clinical global impression of change and patient global impression of change,” he said.

Likewise, both the Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) demonstrated improvement versus placebo: 77.6% and 76.9% in the 125U and 250U doses versus 45.7% for the former; and 71.2% and 73.1% versus 41.3% for the latter.

Side effects “were remarkably minimal,” Dr. Jankovic said, “but I want to call attention to the low frequency of neck weakness or dysphagia in comparison with other studies of botulinum toxin in cervical dystonia.” The rates of dysphagia were 1.6% and 3.9% in the 125U and 250U treatment groups, respectively. Sixteen of the 255 patients in the treatment groups reported muscular weakness or musculoskeletal pain, and seven had dysphagia.

The rate of dysphagia after injection is noteworthy, said David Charles, MD, professor and vice chair of neurology at Vanderbilt University in Nashville, Tenn., who was not involved in the research. “The one thing we worry about most in people with cervical dystonia are swallowing and choking – dysphagia – and the numbers are very modest: 2 out of 127 in the 125U dose and 5 of 130 in the 250U dose,” he said. “That’s a very low rate of that adverse event.”

The duration of action for both doses is “rather remarkable,” Dr. Charles said. “With the other formulations, my patients are coming back every 12 weeks for treatment; the BoNT helps so much that [these] patients make their appointments every 3 months for as far out as they can,” he said. “This could potentially mean two or three trips a year as opposed to four trips a year.”

The trial was funded by Revance Therapeutics. Dr. Jankovic is an investigator for Revance, and three coauthors are employees of Revance. Dr. Charles is a consultant to the company.

The synthetic medium-chain triglyceride triheptanoin has shown potential to restore brain energy and decrease caudate atrophy in Huntington’s disease, and improved motor function for up to a year, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.

Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.

“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”

TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.

TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).

Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).

Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
 

‘The first good news’

Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.

“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”

She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.

As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.

However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given  triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.

Dr. Mochel said that the findings are prompting the investigators to consider just that.

Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.

The synthetic medium-chain triglyceride triheptanoin has shown potential to restore brain energy and decrease caudate atrophy in Huntington’s disease, and improved motor function for up to a year, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.

Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.

“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”

TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.

TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).

Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).

Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
 

‘The first good news’

Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.

“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”

She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.

As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.

However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given  triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.

Dr. Mochel said that the findings are prompting the investigators to consider just that.

Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.

The synthetic medium-chain triglyceride triheptanoin has shown potential to restore brain energy and decrease caudate atrophy in Huntington’s disease, and improved motor function for up to a year, according to data presented at the International Congress of Parkinson’s Disease and Movement Disorders.

Reporting results of TRIHEP3 and an extension study, Fanny Mochel, MD, PhD, of Sorbonne University in Paris and the Paris Brain Institute, said in an interview that her group is the only one investigating triheptanoin to target caudate atrophy in Huntington’s disease. The Food and Drug Administration last year approved triheptanoin for the treatment of long-chain fatty acid oxidation disorders.

“The main findings are two observations: that patients were clinically stable based on their gradation of total motor score (TMS) on UHDRS (Unified Huntington’s Disease Rating Scale) after 1 year,” Dr. Mochel said in an interview. “The other is that we observed a reduction of the caudate atrophy progression that we usually see over 1 year by about 50%.”

TRIHEP3 randomized 100 patients with early-stage Huntington’s disease to triheptanoin 1g/kg daily and placebo. It followed on previous research in which the group used 31-phosphorus brain MR spectroscopy to demonstrate triheptanoin restored a normal brain energetic profile in patients with Huntington’s disease. TRIHEP3 was a 6-month randomized controlled trial at two centers, followed by a 6-month open-label phase. After that, 42 patients opted to participate in the 1-year extension study.

TRIHEP3 found no difference in caudate boundary shift integral (cBSI) at 6 months – the primary endpoint. But in the extension study, TMS tended to stabilize in patients treated for 1 year (0.6 ± 5.1), compared with those treated for 6 months (2.5 ± 4.5, P = .072).

Using a placebo control group from an external study of patients with Huntington’s disease with what Dr. Mochel described as “identical clinical characteristics,” she said the research confirmed TMS clinical stability in treated patients at 1 year (2.6 ± 4.6 vs. 0.6 ± 5.1, P = .057) and found significantly lower caudate atrophy (–3% vs. –6.7%, compared with baseline, P < .001).

Dr. Mochel also noted that Diffusion Tensor Imaging and Fixed-based analyses (FBA) showed fewer alterations in fiber metrics at 24 months in patients treated from baseline. FBA also showed improved fiber trophicity at 24 months in both groups.
 

‘The first good news’

Dr. Mochel noted that the Huntington’s disease community had been shaken in the spring by the failure of three trials of gene-targeting therapies for Huntington’s disease. Roche halted a phase 3 study of its antisense oligonucleotide (ASO) tominersen, and Wave Life Sciences scuttled two ASO programs in phase 1/2 trials.

“Triheptanoin is not going to cure Huntington’s disease; it’s a disease with many components, but it does work on the energy aspects and that seems to stabilize patients over the time of observation,” Dr. Mochel said. “That’s the first good news.”

She also noted that side effects were mainly gastrointestinal in nature, and they typically resolved with dietary management.

As a target in Huntington disease, the caudate nucleus is highly desirable, and caudate atrophy has been shown to occur even before the onset of motor symptoms, said N. Ahmad Aziz, MD, PhD, a neurologist and epidemiologist at the German Center for Neurodegenerative Diseases at the University of Bonn (Germany). “In this light, the findings of the trial conducted by Dr. Mochel and colleagues, which suggest that triheptanoin intake may slow down the rate of caudate atrophy in patients with early-stage Huntington’s disease, are highly promising,” Dr. Aziz said in an interview.

However, he noted that the improvement in caudate atrophy was only a secondary endpoint in the extension study. “Nevertheless, given  triheptanoin’s biologically plausible mechanism of action – i.e., provision of substrates to the Krebs cycle and at least partial restoration of the well-documented defective mitochondrial function in Huntington’s disease – combined with its apparently relatively mild side-effect profile and good tolerability, I think that the preliminary findings of this trial are very promising and justify a larger phase 3 trial,” Dr. Aziz said.

Dr. Mochel said that the findings are prompting the investigators to consider just that.

Dr. Mochel has received consulting fees from and conducted investigator‐sponsored studies supported by Ultragenyx Pharmaceuticals. Dr. Aziz has no relevant financial relationships to disclose.

Efgartigimod (argenx) is an effective and well-tolerated therapy for patients with generalized myasthenia gravis (gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.

The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.

The findings were published online June 17 in Lancet Neurology.
 

Targeted molecular therapy

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
 

Primary endpoint met

The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).

Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).

Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients. 
 

Safety profile

“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.

The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection. 

Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.

The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
 

Expanding therapeutic landscape

In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.

“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.

He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.

“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.

The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.

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

Efgartigimod (argenx) is an effective and well-tolerated therapy for patients with generalized myasthenia gravis (gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.

The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.

The findings were published online June 17 in Lancet Neurology.
 

Targeted molecular therapy

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
 

Primary endpoint met

The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).

Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).

Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients. 
 

Safety profile

“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.

The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection. 

Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.

The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
 

Expanding therapeutic landscape

In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.

“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.

He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.

“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.

The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.

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

Efgartigimod (argenx) is an effective and well-tolerated therapy for patients with generalized myasthenia gravis (gMG), new research suggests. Results from the phase 3, randomized, placebo-controlled ADAPT trial showed that reduction in disease burden and improvement in strength and quality of life in patients with gMG were consistent across four MG-specific scales for those receiving the novel treatment. In addition, these benefits were observed early and were reproducible and durable, the researchers noted.

Efgartigimod is a “very rapidly acting drug relative to other treatments that may take 4, 6, sometimes 10 months before they start to work, and the side effect profile is much like placebo,” said principal investigator James Howard, Jr., MD, Distinguished Professor of Neuromuscular Disease, department of neurology, University of North Carolina at Chapel Hill.

The ADAPT results are “important for the MG community, and I am hopeful efgartigimod will provide a first-in-class targeted therapy that can be dosed in an individual way for people living with this chronic autoimmune disease,” Dr. Howard added in a news release.

The findings were published online June 17 in Lancet Neurology.
 

Targeted molecular therapy

The rare and chronic autoimmune neuromuscular disorder of gMG causes debilitating and potentially life-threatening muscle weakness and significantly impaired independence and quality of life. Most patients with gMG have immunoglobulin G (IgG) antibodies, which are most often directed against skeletal muscle nicotinic acetylcholine receptors.

Efgartigimod is an investigational antibody fragment designed to reduce pathogenic IgG antibodies and block the IgG recycling process in patients with gMG.

The novel agent binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation. Blocking FcRn reduces IgG antibody levels.

The ADAPT trial was conducted at 56 neuromuscular academic and community centers in 15 countries in North America, Europe, and Japan. The study included 167 adults with gMG, regardless of acetylcholine receptor antibody status. All had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (greater than 50% non-ocular) on a background of a stable dose of at least one MG drug.

For 26 weeks, 84 patients were randomly assigned to receive efgartigimod 10 mg/kg and 83 to receive matching placebo. Both treatments were administered as four infusions per cycle at one infusion per week. The process was repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle.

ADAPT was designed to allow an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles, the investigators noted.
 

Primary endpoint met

The primary efficacy endpoint was number of acetylcholine receptor antibody-positive (AChR-Ab+) patients who achieved a clinically meaningful response on the MG-ADL score. This was defined as at least a 2-point improvement from baseline for 4 or more consecutive weeks. Forty-four (68%) of 65 AChR-Ab+ patients treated with efgartigimod met this endpoint versus 19 (30%) of 64 patients treated with placebo (odds ratio, 4.95; 95% confidence interval, 2.21-11.53; P < .0001).

Many of the patients treated with efgartigimod showed improvement “beyond the clinically meaningful threshold, achieving up to 9-point reductions in MG-ADL,” the investigators reported. In addition, 40% of the efgartigimod group attained an MG-ADL score of 0 or 1 (minimal symptom expression) in cycle 1 versus 11% of the placebo group (P < .0001).

Nearly two-thirds (63%) of AChR-Ab+ patients responded to the first cycle of efgartigimod, and most of these patients (83%) responded to treatment within the first 2 weeks. Among the AChR-Ab+ participants who responded to efgartigimod in cycle 1, the duration of responder status was 6 to 7 weeks in 32% of patients, 8 to 11 weeks in 23% of patients, and 12 weeks or more in 34% of patients. 
 

Safety profile

“Some patients never required retreatment over the 26-week period that they were under observation,” Dr. Howard said. “Patients want to be individuals. They don’t want to be assigned to a regimented therapy, and I think these results show that this therapy can be tailored to the individual patient, rather than simply giving it to them in a cookbook fashion,” he added.

The safety profile of efgartigimod was comparable to placebo. Most adverse events were mild or moderate in severity. The most commonly reported adverse events were headache, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, and urinary tract infection. 

Four (5%) efgartigimod-treated patients had a serious adverse event, which included thrombocytosis, rectal adenocarcinoma, worsening MG, and depression.

The novel agent is currently under review with the U.S. Food and Drug Administration for the treatment of gMG, with a Prescription Drug User Fee Act target action date of Dec. 17. If approved, it would become the first FDA-approved FcRn antagonist.
 

Expanding therapeutic landscape

In a linked commentary, Shigeaki Suzuki, MD, PhD, department of neurology, Keio University School of Medicine, Tokyo, noted that the therapeutic landscape for patients with MG is “expanding year by year,” with several additional complement inhibitors and FcRn antagonists now in phase 3 testing.

“Biological drugs should be preferentially used as the treatment for patients with refractory myasthenia gravis, although the definition of refractory myasthenia gravis is different depending on the criteria used,” Dr. Suzuki wrote.

He noted that when “cost-effectiveness is not taken into account, targeted molecular therapy might be used widely” in patients with MG.

“Risks of myasthenic exacerbation and crises should be substantially decreased, particularly in patients with refractory myasthenia gravis,” Dr. Suzuki added.

The ADAPT study was supported by argenx. Dr. Howard has reported receiving research support from argenx, Alexion Pharmaceuticals, the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Ra Pharmaceuticals; honoraria from argenx, Alexion, Immunovant, Ra, Regeneron Pharmaceuticals, and Viela Bio; and nonfinancial support from argenx, Alexion, Ra, and Toleranzia. Disclosures for the other investigators are listed in the original article. Dr. Suzuki has reported relationships with Alexion Pharmaceuticals, Japan Blood Products Organization, and Asahi Kasei Medical.

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

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

Stroke, dementias, and migraine cause the most disability among neurological disorders in the United States, according to new findings derived from the 2017 Global Burden of Disease study. 

The authors of the analysis, led by Valery Feigin, MD, PhD, of New Zealand’s National Institute for Stroke and Applied Neurosciences, and published in the February 2021 issue of JAMA Neurology, looked at prevalence, incidence, mortality, and disability-adjusted life years for 14 neurological disorders across 50 states between 1990 and 2017. The diseases included in the analysis were stroke, Alzheimer’s disease and other dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, headaches, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus.
 

Tracking the burden of neurologic diseases

Dr. Feigin and colleagues estimated that a full 60% of the U.S. population lives with one or more of these disorders, a figure much greater than previous estimates for neurological disease burden nationwide. Tension-type headache and migraine were the most prevalent in the analysis by Dr. Feigin and colleagues. During the study period, they found, prevalence, incidence, and disability burden of nearly all the included disorders increased, with the exception of brain and spinal cord injuries, meningitis, and encephalitis.

The researchers attributed most of the rise in noncommunicable neurological diseases to population aging. An age-standardized analysis found trends for stroke and Alzheimer’s disease and other dementias to be declining or flat. Age-standardized stroke incidence dropped by 16% from 1990 to 2017, while stroke mortality declined by nearly a third, and stroke disability by a quarter. Age-standardized incidence of Alzheimer’s disease and other dementias dropped by 12%, and their prevalence by 13%, during the study period, though dementia mortality and disability were seen increasing.

The authors surmised that the age-standardized declines in stroke and dementias could reflect that “primary prevention of these disorders are beginning to show an influence.” With dementia, which is linked to cognitive reserve and education, “improving educational levels of cohort reaching the age groups at greatest risk of disease may also be contributing to a modest decline over time,” Dr. Feigin and his colleagues wrote.

Parkinson’s disease and multiple sclerosis, meanwhile, were both seen rising in incidence, prevalence, and disability adjusted life years (DALYs) even with age-standardized figures. The United States saw comparatively more disability in 2017 from dementias, Parkinson’s disease, epilepsy, multiple sclerosis, motor neuron disease, and headache disorders, which together comprised 6.7% of DALYs, compared with 4.4% globally; these also accounted for a higher share of mortality in the U.S. than worldwide. The authors attributed at least some of the difference to better case ascertainment in the U.S.
 

Regional variations

The researchers also reported variations in disease burden by state and region. While previous studies have identified a “stroke belt” concentrated in North Carolina, South Carolina, and Georgia, the new findings point to stroke disability highest in Alabama, Arkansas, and Mississippi, and mortality highest in Alabama, Mississippi, and South Carolina. The researchers noted increases in dementia mortality in these states, “likely attributable to the reciprocal association between stroke and dementia.”

Northern states saw higher burdens of multiple sclerosis compared with the rest of the country, while eastern states had higher rates of Parkinson’s disease.

Such regional and state-by state variations, Dr. Feigin and colleagues wrote in their analysis, “may be associated with differences in the case ascertainment, as well as access to health care; racial/ethnic, genetic, and socioeconomic diversity; quality and comprehensiveness of preventive strategies; and risk factor distribution.”

The researchers noted as a limitation of their study that the 14 diseases captured were not an exhaustive list of neurological conditions; chronic lower back pain, a condition included in a previous major study of the burden of neurological disease in the United States, was omitted, as were restless legs syndrome and peripheral neuropathy. The researchers cited changes to coding practice in the U.S. and accuracy of medical claims data as potential limitations of their analysis. The Global Burden of Disease study is funded by the Bill and Melinda Gates Foundation, and several of Dr. Feigin’s coauthors reported financial relationships with industry.
 

Time to adjust the stroke belt?

Amelia Boehme, PhD, a stroke epidemiologist at Columbia University Mailman School of Public Health in New York, said in an interview that the current study added to recent findings showing surprising local variability in stroke prevalence, incidence, and mortality. “What we had always conceptually thought of as the ‘stroke belt’ isn’t necessarily the case,” Dr. Boehme said, but is rather subject to local, county-by-county variations. “Looking at the data here in conjunction with what previous authors have found, it raises some questions as to whether or not state-level data is giving a completely accurate picture, and whether we need to start looking at the county level and adjust for populations and age.” Importantly, Dr. Boehme said, data collected in the Global Burden of Disease study tends to be exceptionally rigorous and systematic, adding weight to Dr. Feigin and colleagues’ suggestions that prevention efforts may be making a dent in stroke and dementia. 

“More data is always needed before we start to say we’re seeing things change,” Dr. Boehme noted. “But any glimmer of optimism is welcome, especially with regard to interventions that have been put in place, to allow us to build on those interventions.”

Dr. Boehme disclosed no financial conflicts of interest.

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

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

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

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

Approved – with cautions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Approved – with cautions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Approved – with cautions

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

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

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

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

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

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

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

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

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

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

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

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

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

The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

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

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

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

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

The findings of a new randomized trial support the rapid tapering of prednisone in patients with generalized myasthenia gravis requiring combined corticosteroid and azathioprine therapy. The trial showed that the conventional slow tapering regimen enabled discontinuation of prednisone earlier than previously reported but the new rapid-tapering regimen enabled an even faster discontinuation.

Noting that although both regimens led to a comparable myasthenia gravis status and prednisone dose at 15 months, the authors stated: “We think that the reduction of the cumulative dose over a year (equivalent to 5 mg/day) is a clinically relevant reduction, since the risk of complications is proportional to the daily or cumulative doses of prednisone.

“Our results warrant testing of a more rapid-tapering regimen in a future trial. In the meantime, our trial provides useful information on how prednisone tapering could be managed in patients with generalized myasthenia gravis treated with azathioprine,” they concluded.

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

Myasthenia gravis is a disorder of neuromuscular transmission, resulting from autoantibodies to components of the neuromuscular junction, most commonly the acetylcholine receptor. The incidence ranges from 0.3 to 2.8 per 100,000, and it is estimated to affect more than 700,000 people worldwide.

The authors of the current paper, led by Tarek Sharshar, MD, PhD, Groupe Hospitalier Universitaire, Paris, explained that many patients whose symptoms are not controlled by cholinesterase inhibitors are treated with corticosteroids and an immunosuppressant, usually azathioprine. No specific dosing protocol for prednisone has been validated, but it is commonly gradually increased to 0.75 mg/kg on alternate days and reduced progressively when minimal manifestation status (MMS; no symptoms or functional limitations) is reached.  

They noted that this regimen leads to high and prolonged corticosteroid treatment – often for several years – with the mean daily prednisone dose exceeding 30 mg/day at 15 months and 20 mg/day at 36 months. As long-term use of corticosteroids is often associated with significant complications, reducing or even discontinuing prednisone treatment without destabilizing myasthenia gravis is therefore a therapeutic goal.


 

Evaluating dosage regimens

To investigate whether different dosage regimens could help wean patients with generalized myasthenia gravis from corticosteroid therapy without compromising efficacy, the researchers conducted this study in which the current recommended regimen was compared with an approach using higher initial corticosteroid doses followed by rapid tapering.

In the conventional slow-tapering group (control group), prednisone was given on alternate days, starting at a dose of 10 mg then increased by increments of 10 mg every 2 days up to 1.5 mg/kg on alternate days without exceeding 100 mg. This dose was maintained until MMS was reached and then reduced by 10 mg every 2 weeks until a dosage of 40 mg was reached, with subsequent slowing of the taper to 5 mg monthly. If MMS was not maintained, the alternate-day prednisone dose was increased by 10 mg every 2 weeks until MMS was restored, and the tapering resumed 4 weeks later.

In the new rapid-tapering group, oral prednisone was immediately started at 0.75 mg/kg per day, and this was followed by an earlier and rapid decrease once improved myasthenia gravis status was attained. Three different tapering schedules were applied dependent on the improvement status of the patient.

First, If the patient reached MMS at 1 month, the dose of prednisone was reduced by 0.1 mg/kg every 10 days up to 0.45 mg/kg per day, then 0.05 mg/kg every 10 days up to 0.25 mg/kg per day, then in decrements of 1 mg by adjusting the duration of the decrements according to the participant’s weight with the aim of achieving complete cessation of corticosteroid therapy within 18-20 weeks for this third stage of tapering.

Second, if the state of MMS was not reached at 1 month but the participant had improved, a slower tapering was conducted, with the dosage reduced in a similar way to the first instance but with each reduction introduced every 20 days. If the participant reached MMS during this tapering process, the tapering of prednisone was similar to the sequence described in the first group.

Third, if MMS was not reached and the participant had not improved, the initial dose was maintained for the first 3 months; beyond that time, a decrease in the prednisone dose was undertaken as in the second group to a minimum dose of 0.25 mg/kg per day, after which the prednisone dose was not reduced further. If the patient improved, the tapering of prednisone followed the sequence described in the second category.

Reductions in prednisone dose could be accelerated in the case of severe prednisone adverse effects, according to the prescriber’s decision.

In the event of a myasthenia gravis exacerbation, the patient was hospitalized and the dose of prednisone was routinely doubled, or for a more moderate aggravation, the dose was increased to the previous dose recommended in the tapering regimen.

Azathioprine, up to a maximum dose of 3 mg/kg per day, was prescribed for all participants. In all, 117 patients were randomly assigned, and 113 completed the study.

The primary outcome was the proportion of participants having reached MMS without prednisone at 12 months and having not relapsed or taken prednisone between months 12 and 15. This was achieved by significantly more patients in the rapid-tapering group (39% vs. 9%; risk ratio, 3.61; P < .001).

Rapid tapering allowed sparing of a mean of 1,898 mg of prednisone over 1 year (5.3 mg/day) per patient.

The rate of myasthenia gravis exacerbation or worsening did not differ significantly between the two groups, nor did the use of plasmapheresis or IVIG or the doses of azathioprine.

The overall number of serious adverse events did not differ significantly between the two groups (slow tapering, 22% vs. rapid-tapering, 36%; P = .15).

The researchers said it is possible that prednisone tapering would differ with another immunosuppressive agent but as azathioprine is the first-line immunosuppressant usually recommended, these results are relevant for a large proportion of patients.

They said the better outcome of the intervention group could have been related to one or more of four differences in prednisone administration: An immediate high dose versus a slow increase of the prednisone dose; daily versus alternate-day dosing; earlier tapering initiation; and faster tapering. However, the structure of the study did not allow identification of which of these factors was responsible.

“Researching the best prednisone-tapering scheme is not only a major issue for patients with myasthenia gravis but also for other autoimmune or inflammatory diseases, because validated prednisone-tapering regimens are scarce,” the authors said.

The rapid tapering of prednisone therapy appears to be feasible, beneficial, and safe in patients with generalized myasthenia gravis and “warrants testing in other autoimmune diseases,” they added.
 

Particularly relevant to late-onset disease

Commenting on the study, Raffi Topakian, MD, Klinikum Wels-Grieskirchen, Wels, Austria, said the results showed that in patients with moderate to severe generalized myasthenia gravis requiring high-dose prednisone, azathioprine, a widely used immunosuppressant, may have a quicker steroid-sparing effect than previously thought, and that rapid steroid tapering can be achieved safely, resulting in a reduction of the cumulative steroid dose over a year despite higher initial doses.

Dr. Topakian, who was not involved with the research, pointed out that the median age was advanced (around 56 years), and the benefit of a regimen that leads to a reduction of the cumulative steroid dose over a year may be disproportionately larger for older, sicker patients with many comorbidities who are at considerably higher risk for a prednisone-induced increase in cardiovascular complications, osteoporotic fractures, and gastrointestinal bleeding. 

“The study findings are particularly relevant for the management of late-onset myasthenia gravis (when first symptoms start after age 45-50 years), which is being encountered more frequently over the past years,” he said.

“But the holy grail of myasthenia gravis treatment has not been found yet,” Dr. Topakian noted. “Disappointingly, rapid tapering of steroids (compared to slow tapering) resulted in a reduction of the cumulative steroid dose only, but was not associated with better myasthenia gravis functional status or lower doses of steroids at 15 months. To my view, this finding points to the limited immunosuppressive efficacy of azathioprine.”

He added that the study findings should not be extrapolated to patients with mild presentations or to those with muscle-specific kinase myasthenia gravis.

Dr. Sharshar disclosed no relevant financial relationships. Disclosures for the study coauthors appear in the original article.
 

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

New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.

This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.

“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
 

When to use and not to use PCR

Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.

Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.

To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.

“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”

Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.

Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”

If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.

Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.

They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.

The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.

Timelines for antibiotics

Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.

Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.

“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.

Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.

“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.

For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.

“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.

Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.

Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.

Advice on antibodies testing ‘particularly cogent’

For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.

“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.

The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.

The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.

SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.

New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.

This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.

“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
 

When to use and not to use PCR

Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.

Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.

To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.

“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”

Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.

Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”

If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.

Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.

They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.

The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.

Timelines for antibiotics

Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.

Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.

“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.

Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.

“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.

For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.

“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.

Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.

Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.

Advice on antibodies testing ‘particularly cogent’

For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.

“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.

The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.

The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.

SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.

New clinical practice guidelines on Lyme disease place a strong emphasis on antibody testing to assess for rheumatologic and neurologic syndromes. “Diagnostically, we recommend testing via antibodies, and an index of antibodies in cerebrospinal fluid [CSF] versus serum. Importantly, we recommend against using polymerase chain reaction [PCR] in CSF,” Jeffrey A. Rumbaugh, MD, PhD, a coauthor of the guidelines and a member of the American Academy of Neurology, said in an interview.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

The Infectious Diseases Society of America, AAN, and the American College of Rheumatology convened a multidisciplinary panel to develop the 43 recommendations, seeking input from 12 additional medical specialties, and patients. The panel conducted a systematic review of available evidence on preventing, diagnosing, and treating Lyme disease, using the Grading of Recommendations Assessment, Development and Evaluation model to evaluate clinical evidence and strength of recommendations. The guidelines were simultaneous published in Clinical Infectious Diseases, Neurology, Arthritis & Rheumatology, and Arthritis Care & Research.

This is the first time these organizations have collaborated on joint Lyme disease guidelines, which focus mainly on neurologic, cardiac, and rheumatologic manifestations.

“We are very excited to provide these updated guidelines to assist clinicians working in numerous medical specialties around the country, and even the world, as they care for patients suffering from Lyme disease,” Dr. Rumbaugh said.
 

When to use and not to use PCR

Guideline authors called for specific testing regimens depending on presentation of symptoms. Generally, they advised that individuals with a skin rash suggestive of early disease seek a clinical diagnosis instead of laboratory testing.

Recommendations on Lyme arthritis support previous IDSA guidelines published in 2006, Linda K. Bockenstedt, MD, professor of medicine at Yale University, New Haven, Conn., and a coauthor of the guidelines, said in an interview.

To evaluate for potential Lyme arthritis, clinicians should choose serum antibody testing over PCR or culture of blood or synovial fluid/tissue. However, if a doctor is assessing a seropositive patient for Lyme arthritis diagnosis but needs more information for treatment decisions, the authors recommended PCR applied to synovial fluid or tissue over Borrelia culture.

“Synovial fluid can be analyzed by PCR, but sensitivity is generally lower than serology,” Dr. Bockenstedt explained. Additionally, culture of joint fluid or synovial tissue for Lyme spirochetes has 0% sensitivity in multiple studies. “For these reasons, we recommend serum antibody testing over PCR of joint fluid or other methods for an initial diagnosis.”

Serum antibody testing over PCR or culture is also recommended for identifying Lyme neuroborreliosis in the peripheral nervous system (PNS) or CNS.

Despite the recent popularity of Lyme PCR testing in hospitals and labs, “with Lyme at least, antibodies are better in the CSF,” Dr. Rumbaugh said. Studies have shown that “most patients with even early neurologic Lyme disease are seropositive by conventional antibody testing at time of initial clinical presentation, and that intrathecal antibody production, as demonstrated by an elevated CSF:serum index, is highly specific for CNS involvement.”

If done correctly, antibody testing is both sensitive and specific for neurologic Lyme disease. “On the other hand, sensitivity of Lyme PCR performed on CSF has been only in the 5%-17% range in studies. Incidentally, Lyme PCR on blood is also not sensitive and therefore not recommended,” Dr. Rumbaugh said.

Guideline authors recommended testing in patients with the following conditions: acute neurologic disorders such as meningitis, painful radiculoneuritis, mononeuropathy multiplex; evidence of spinal cord or brain inflammation; and acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting.

They did not recommend testing in patients with typical amyotrophic lateral sclerosis; relapsing remitting multiple sclerosis; Parkinson’s disease, dementia, or cognitive decline; new-onset seizures; other neurologic syndromes or those lacking clinical or epidemiologic history that would support a diagnosis of Lyme disease; and patients with chronic cardiomyopathy of unknown cause.

The authors also called for judicious use of electrocardiogram to screen for Lyme carditis, recommending it only in patients signs or symptoms of this condition. However, patients at risk for or showing signs of severe cardiac complications of Lyme disease should be hospitalized and monitored via ECG.

Timelines for antibiotics

Most patients with Lyme disease should receive oral antibiotics, although duration times vary depending on the disease state. “We recommend that prophylactic antibiotic therapy be given to adults and children only within 72 hours of removal of an identified high-risk tick bite, but not for bites that are equivocal risk or low risk,” according to the guideline authors.

Specific antibiotic treatment regimens by condition are as follows: 10-14 days for early-stage disease, 14 days for Lyme carditis, 14-21 days for neurologic Lyme disease, and 28 days for late Lyme arthritis.

“Despite arthritis occurring late in the course of infection, treatment with a 28-day course of oral antibiotic is effective, although the rates of complete resolution of joint swelling can vary,” Dr. Bockenstedt said. Clinicians may consider a second 28-day course of oral antibiotics or a 2- to 4-week course of ceftriaxone in patients with persistent swelling, after an initial course of oral antibiotics.

Citing knowledge gaps, the authors made no recommendation on secondary antibiotic treatment for unresolved Lyme arthritis. Rheumatologists can play an important role in the care of this small subset of patients, Dr. Bockenstedt noted. “Studies of patients with ‘postantibiotic Lyme arthritis’ show that they can be treated successfully with intra-articular steroids, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologic response modifiers, and even synovectomy with successful outcomes.” Some of these therapies also work in cases where first courses of oral and intravenous antibiotics are unsuccessful.

“Antibiotic therapy for longer than 8 weeks is not expected to provide additional benefit to patients with persistent arthritis if that treatment has included one course of IV therapy,” the authors clarified.

For patients with Lyme disease–associated meningitis, cranial neuropathy, radiculoneuropathy, or other PNS manifestations, the authors recommended intravenous ceftriaxone, cefotaxime, penicillin G, or oral doxycycline over other antimicrobials.

“For most neurologic presentations, oral doxycycline is just as effective as appropriate IV antibiotics,” Dr. Rumbaugh said. “The exception is the relatively rare situation where the patient is felt to have parenchymal involvement of brain or spinal cord, in which case the guidelines recommend IV antibiotics over oral antibiotics.” In the studies, there was no statistically significant difference between oral or intravenous regimens in response rate or risk of adverse effects.

Patients with nonspecific symptoms such as fatigue, pain, or cognitive impairment following treatment should not receive additional antibiotic therapy if there’s no evidence of treatment failure or infection. These two markers “would include objective signs of disease activity, such as arthritis, meningitis, or neuropathy,” the guideline authors wrote in comments accompanying the recommendation.

Clinicians caring for patients with symptomatic bradycardia caused by Lyme carditis should consider temporary pacing measures instead of a permanent pacemaker. For patients hospitalized with Lyme carditis, “we suggest initially using IV ceftriaxone over oral antibiotics until there is evidence of clinical improvement, then switching to oral antibiotics to complete treatment,” they advised. Outpatients with this condition should receive oral antibiotics instead of intravenous antibiotics.

Advice on antibodies testing ‘particularly cogent’

For individuals without expertise in these areas, the recommendations are clear and useful, Daniel E. Furst, MD, professor of medicine (emeritus) at the University of California, Los Angeles, adjunct professor at the University of Washington, Seattle, and research professor at the University of Florence (Italy), said in an interview.

“As a rheumatologist, I would have appreciated literature references for some of the recommendations but, nevertheless, find these useful. I applaud the care with which the evidence was gathered and the general formatting, which tried to review multiple possible scenarios surrounding Lyme arthritis,” said Dr. Furst, offering a third-party perspective.

The advice on using antibodies tests to make a diagnosis of Lyme arthritis “is particularly cogent and more useful than trying to culture these fastidious organisms,” he added.

The IDSA, AAN, and ACR provided support for the guideline. Dr. Bockenstedt reported receiving research funding from the National Institutes of Health and the Gordon and the Llura Gund Foundation and remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research. Dr. Rumbaugh had no conflicts of interest to disclose. Dr. Furst reported no conflicts of interest in commenting on these guidelines.

SOURCE: Rumbaugh JA et al. Clin Infect Dis. 2020 Nov 30. doi: 10.1093/cid/ciaa1215.