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Neurologists Lack Awareness of Steroid Toxicity
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a US survey showed.
For both MG and CIDP specialists, uncertainty around corticosteroid dosing, duration, and toxicity underscores the need for more guidance, the investigators noted. Over 85% of respondents indicated that a tool for systematically monitoring corticosteroid toxicity would be valuable.
The results indicate “a lack of knowledge by this pool of neurologists about the guidelines and what they contain,” said study investigator Gil Wolfe, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York.
Clearer guidance on how to administer corticosteroids and manage toxicities in patients with gMG and CIDP “would be welcomed by neurologists and have potential for benefit to patient care,” the team noted.
The findings were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Lack of Knowledge
Although guidelines for both CIDP and gMG recommend corticosteroids as first-line treatment and emphasize using the lowest effective dose to control symptoms, they do not include specific recommendations on dosing, duration, or toxicity monitoring, the researchers noted.
Despite this, a large proportion of survey respondents reported using guidelines to make clinical decisions on monitoring toxicity, with up to a third actually endorsing a guideline that doesn’t exist.
The cross-sectional, online survey was deployed in November and December 2023 and included 200 US neurologists. Of these, 99 answered questions on CIDP, and 101 answered similar questions on gMG.
To participate in the survey, respondents had to be board-certified neurologists, practicing for at least 2 years post-residency, and have treated or consulted on at least three patients with CIDP or 10 patients with gMG in the past year who were on a corticosteroid dose of at least 10 mg daily for 1 month or more.
CIDP respondents had been practicing a mean of 18.1 years since residency and were board certified in neuromuscular (20%), electrodiagnostic medicine/clinical neurophysiology (21%), and pediatric neurology (8%). Two thirds of them accepted referrals from other neurologists.
The gMG respondents had been practicing a mean of 20.5 years since residency and were board certified in neuromuscular (45%), electrodiagnostic medicine/clinical neurophysiology (35%), and pediatric neurology (17%). A total of 72% accepted referrals from other neurologists.
Respondents estimated that about 60% of their patients with gMG and 58% of patients with CIDP were being treated with corticosteroids, with gMG and CIDP respondents reporting a mean of 26.4 and 15.6 patients, respectively, meeting the study’s dosing criteria.
Appropriate Dosing
When asked what chronic, long-term (≥ 6 months) corticosteroid dose they considered safe in terms of minimizing adverse events, 43% of CIDP respondents and 51% of gMG respondents considered corticosteroid doses of 10 mg/d or less (prednisone equivalent) well tolerated; additionally, 32% and 31%, respectively, considered 20-40 mg/d well tolerated. Moreover, they said only about half of their patients would be able to taper to less than 10 mg/d in less than 6 months.
“Studies suggest safety is not seen until patients are on doses at 5 mg/d or less,” Wolfe said. “There is not enough appreciation that doses at levels we once considered safe really do pose significant risk,” he added.
“With the increasing number of treatment options in MG and to a lesser extent in CIDP, we need to do all we can to use corticosteroids as judiciously as possible and be aware of side effects our patients may not even report unless we make a pointed effort to ask about them.”
Familiarity with corticosteroid toxicities was more common among gMG respondents, of whom 77% reported being very/extremely familiar, than among 55% of CIDP respondents. Appetite/weight gain was reported among the most common adverse effects (AEs) associated with long-term CS use (reported by 68% of CIDP and 58% of gMG respondents). Other common AEs reported were insulin resistance (53% of CIDP and 50% of gMG respondents), decreased bone density (47% and 48%, respectively), immunosuppression (37% and 45%, respectively). Mood and behavioral change were noted by 56% of CIDP and 37% of gMG respondents, particularly mood swings, irritability, mania, and sleep disorders.
When asked how they balanced the risk for and benefit of corticosteroids, more than 80% of CIDP specialists reported personally monitoring for corticosteroid-related toxicity, and 42% reported they collaborated with the patient’s primary care provider. However, fewer than 10% reported ordering lab tests. Among neurologists treating gMG, 84% said they typically monitor corticosteroid toxicity independently, while 41% reported doing so in collaboration with primary care providers.
Two thirds of CIDP respondents and 53% of gMG respondents reported using guidelines to make clinical decisions on monitoring toxicity, and 34% of gMG respondents actually endorsed using the Guideline for Systematic Surveillance of Steroid Safety, which does not exist.
‘A Big Issue’ in Neurology
Commenting on the results, Said R. Beydoun, MD, professor and division chief, Neuromuscular Medicine, Department of Neurology at Keck Medicine of University of Southern California, Los Angeles, said steroid toxicity is “a big issue” in neurology.
These patients can be on chronic therapy, and they aren’t really monitored for osteoporosis or other complications, he said, adding that neurologists aren’t always taking the necessary precautions to prevent steroid toxicity.
Beydoun estimated that about half of neurologists are not adequately familiar with balancing the efficacy of corticosteroids versus in toxicity.
“Objective improvement, either on the functional scale or the muscle impairment scale — that’s really response treatment. Whereas adverse effects of a treatment are something separate. The patient may be improving but also maybe developing other complications from the treatment,” he said.
Also commenting, Ghazala Hayat, MD, professor of neurology and director of neuromuscular and clinical neurophysiology services at Saint Louis University in St. Louis, said there is a clear need for more education.
“I always say prednisone is our best friend initially, and then it becomes the worst enemy. If you don’t see lots of neuromuscular patients, you might not know even how to recognize toxicity or how to taper. Or the opposite to that, if you taper too quickly, patients relapse.”
The study was funded by argenx. Wolfe reported serving on advisory boards for Alexion, argenx, UCB, and Johnson & Johnson. Neelam Goyal, MD, is a consultant/advisor for Alexion, argenx, Amgen, Janssen, Lycia Therapeutics, and UCB and has received grant support from argenx. Beydoun reported receiving research support and consulting and speaking fees from Healey Center, Amylyx, AB Science, Sanofi, Janssen, Genentech, Regeneron, UCB, Abcuro argenx, Alnylam, AstraZeneca, Amylyx, CSL Behring, Grifols, Takeda, Octapharma, UCB, and Janssen. Hayat reported speaker and advisory roles with argenx, Alexion, and MTPA.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Veterans Affairs Hailed as a ‘Bright Spot’ in ALS Care
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , said one expert.
In a plenary address at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024, Ileana Howard, MD, medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, said the recently released National Academies report “Living with ALS” cited the Veterans Administration as “a bright spot in the landscape of ALS care due to its interdisciplinary, holistic, and proactive approach to care.”
Since the early 2000s and the publication of several studies linking active military service with ALS, the US Department of Veterans Affairs (VA) has opened an ALS registry, a tissue and brain biobank, and in 2008, granted 100% presumptive service connection to any individual who served more than 90 days of active duty and was later diagnosed with ALS, she said.
“We now serve approximately 4000 veterans with ALS across the system, and we count 47 full interdisciplinary clinics within VA across the nation, with ALS coordinators designated for all 170 VA facilities, regardless of whether they had an ALS clinic or not, to serve as a navigator for patients and their families, to identify the closest ALS clinic that could meet their needs.”
Multidisciplinary vs Interdisciplinary
Howard emphasized that transdisciplinary collaboration is essential for maintaining an effective system. She pointed out that the term “multidisciplinary” is outdated, referring to teams that work independently but in parallel on the same issue.
In contrast, interdisciplinary teams integrate their assessments into a cohesive plan of care, whereas transdisciplinary teams take it further by combining both their assessments and care plans, allowing for greater intentional overlap.
The VA’s ALS handbook lists approximately 20 essential clinicians for a VA ALS clinic, including recreation therapists, assistive technology specialists, and veteran benefit service officers to assist with disability benefits application, among others, she said.
Essential to this collaboration is “role release,” which deliberately blurs the boundaries between disciplines. “The future of our specialty hinges on effective and selfless collaboration,” she said.
Howard encouraged ALS healthcare providers to move away from outdated terminology rooted in hierarchical team models and to break down silos that no longer benefit either the patients or the care teams.
She noted that while teamwork can enhance patient outcomes and overall health, it has also been associated with better health among healthcare providers. It’s well-known, she said, that neurologists and physiatrists are among the specialties with the highest burnout rates, and ALS teams, in particular, experience significant stress and burnout.
Better Together
A recent Canadian study on resiliency and burnout in ALS clinics surveyed a wide range of practitioners within ALS centers and found respondents drew resiliency through relationships with patients and colleagues, and that there was a strongly expressed desire for increased resources, team building/debriefing, and formal training in emotional exhaustion and burnout.
“A consistent theme was the lack of adequate allied health support (nursing, social work, occupational therapy) to address the complex needs of patients,” said the report’s senior author Kerri Lynn Schellenberg, MD, medical director of the ALS/Motor Neuron Diseases clinic and associate professor at the University of Saskatchewan College of Medicine in Saskatoon, Saskatchewan, Canada.
“The majority of participants felt they would benefit from more consistent team building exercises and debriefing,” noted the authors.
Schellenberg agreed, emphasizing that care teams perform best when there is mutual appreciation and support among members. By learning from one another and reaching consensus together, the care plan benefits from the collective expertise of the team. “We are stronger together,” she said.
Howard and Schellenberg reported no disclosures.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Digital Tool May Help Neurologists Assess Steroid Toxicity
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The Glucocorticoid Toxicity Index-Metabolic Domains (GTI-MD), an abbreviated version of the GTI (Steritas), used weighted, standardized clinical outcome assessments to calculate steroid toxicity using a de-identified electronic health record (EHR) dataset.
“The results of our study indicate that patients with MG who initiated steroids demonstrated evidence of steroid toxicity in as little as 90 days after initial exposure, which was significant for patients with 20+ mg at index with repeated use,” noted study investigators, led by Neelam Goyal, MD, clinical professor of neurology and neurological sciences at Stanford University School of Medicine in Palo Alto, California.
The findings were presented at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Rapid Evidence of Toxicity
The GTI uses nine health domains to calculate steroid toxicity scores, and the GTI-MD, which has been shown to be closely correlated, uses four domains collected routinely in clinical practice: Body mass index (BMI), blood pressure, glucose tolerance, and lipid metabolism.
The study used the Optum EHR dataset to identify 682 adult patients with MG, mean age of 70 years, 38% women, with at least two confirmed diagnoses of MG between 30 and 730 days apart and information on steroid utilization.
Patients were divided into two groups: Steroid initiators (SI; n = 377) were those whose steroid use was already in progress at the index date, whereas steroid-naive (SN) patients (n = 305) began their steroid use at the index date. Among the SI group, 30% were on doses greater than 20 mg/d and 22% were on lower doses. Among the SN group, 22% were on doses greater than 20 mg/d and 26% were on lower doses.
As expected, mean GTI-MD scores measured 90 days after the index date were higher in the SI group than in the SN group, indicating a higher level of steroid toxicity in the SI group. This was measured with two subscores of the GTI-MD: The Cumulative Worsening Score (22.6 vs 18.7; P = .007) and the Aggregate Improvement Score (4.9 vs 1.9; P = .27), the latter incorporating resolved toxicities resulting from the introduction of steroid-sparing agents.
The authors commented that scores were higher in the SN group than expected, “which could be explained by age, previous steroid exposure, comorbidities, and side effects from other medications.” However, they concluded that the findings suggest utility of the tool retrospectively, with EHR data.
Clinical Application
The GTI and related measurements are proprietary tools and therefore not readily available to all clinicians, noted Marie Beaudin, MD, another neurologist at Stanford University School of Medicine, who was not involved in the research.
In a separate, observational, ongoing study, Beaudin and Goyal’s team are examining the use of the tool prospectively for following the steroid toxicity burden in 50 patients with MG and correlating it with MG outcomes measured using the MG-Activities of Daily Living, MG Composite, and MG-Quality of Life 15R validated scales, as well as the adverse event unit.
“The objective of this study is to quantify the burden of toxicity that our patients are having from glucocorticoids, see how sensitive to change the scale is as their dosage of prednisone changes, and explore the correlations between the score and their disease outcome measures,” Beaudin said.
Unlike the abbreviated GTI-MD, the GTI measures nine domains: Bone mineral density, BMI, lipid metabolism, blood pressure, glucose tolerance, myopathy, skin toxicity, neuropsychiatric symptoms, and infections.
The score involves actively prompting and examining the patient, making it quite comprehensive. Beaudin said the study has revealed interesting insights into how patients report their side effects. When asked broadly about steroid-related side effects, many patients mention issues like weight or skin issues.
However, she noted, when prompted specifically about symptoms like insomnia, irritability, depression, or cognitive changes, there was an unexpected increase in positive responses, as patients are often unaware these could be side effects. This suggests the study may capture a greater burden than originally anticipated, said Beaudin.
She added that the long-term utility of the GTI score might be to help clinicians predict steroid toxicity and guide management.
“Then we would get more aggressive in trying to wean or taper patients. But these are often complicated cases because as soon as we taper, the disease flares. It’s a difficult decision whether to reduce the dosage of prednisone because toxicity burden is high, when disease burden is high too, and that’s where other medications can come into play.”
For example, she said, for insurance coverage, a high steroid toxicity score could justify the need to initiate more expensive steroid-sparing agents.
Both studies were funded by argenx. Goyal reported that she has consulted and received grant support from argenx, UCB, Alexion, and Janssen argenx. Beaudin is supported by a McLaughlin Scholarship from Laval University, Quebec, Canada.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Remote Assessments: A Win-Win for ALS Patients and Clinics?
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , results of a retrospective study showed.
The findings, along with those of another study by the same group, suggest that remote monitoring of patients with ALS is a feasible option for both maximizing quality of life and minimizing cost and disruption.
Both studies were presented at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
“What we’re trying to do is look for screening tools that we can use when these patients are in the community to see if a specific score transition is associated with a high probability of needing an intervention that would require bringing them in to do gold standard tests,” said study investigator Tefani Perera, MD, a neurology resident at the University of Calgary, in Alberta, Canada.
Optimizing Quality of Life
Tailoring in-person care is particularly important for patients with ALS who often face significant challenges with mobility, Perera said. However, most multidisciplinary ALS clinics schedule in-person follow-ups at regular intervals rather than “as needed.
“These are very long clinic days where they are assessed for one thing after another, even if they don’t need it. So maybe we can actually select for what they need to be assessed for at each specific visit? Life expectancy is not that long for these patients, so we want to make sure their quality of life is optimized.”
For the BiPAP study, the investigators used the Pooled Resource Open-Access ALS Clinical Trials database to identify patients with ALS with two or more respiratory assessments on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
The ALSFRS-R is a 12-item questionnaire, which includes three respiratory sub-scores for respiratory insufficiency (RiS), dyspnea (DyS) and orthopnea (OS).
Patients with a baseline RiS sub-score of 4 — meaning no need for BiPAP — were included in the study (n = 3838), with the primary outcome being a drop in RiS sub-score indicating the need for BiPAP.
The median time from baseline to transition to BiPAP was 563 days, with 3.4% of patients reaching this outcome by 3 months.
Results showed the probability of needing BiPAP was significantly associated with baseline DyS and OS scores (P < .0001). Among patients with baseline DyS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 5.5%, 8.7%, and 20.1%, respectively. In addition, in patients with baseline OS scores of 3, 2, and 1, the percentages of patients needing BiPAP within 3 months were 9.1%, 12.7%, and 24.2%, respectively.
Regardless of the baseline score, any drop in either of these sub-scores over the study period was also associated with an increased likelihood of requiring BiPAP within 3 months, with a DyS transition from 3 to 2 and an OS transition from 4 to 3 being most notable.
These scores could be used to trigger gold standard assessments for BiPAP, such as nocturnal oximetry, overnight polysomnography, daytime hypercapnia, and forced and slow vital capacities, Perera said. On the other hand, the scores could also help patients and clinicians avoid unnecessary visits.
“When the dyspnea and orthopnea scores are high, they might not need this intervention until 2 years later, so do we even need to bring them in to do these tests or see a respirologist when they don’t actually need it?”
The group’s second study was a systematic review of 26 papers on ALS remote assessment devices and methods, including accelerometers (15.4%), telenursing protocols (3.8%), speech collection apps (26.9%), questionnaires (15.4%), multifactorial sensors (15.4%), and respiratory function monitors (19.2%). Domains of symptoms monitored included speech (12 studies), motor (11 studies), respiratory (11 studies), cardiac (three studies), and bulbar, psychiatric, and autonomic (one study each).
The researchers characterized various remote tools as having potential and concluded that a multidomain approach to symptom monitoring is achievable. They also noted that the majority of studies assessing adherence and patient feedback indicated a favorable response to patient monitoring.
“I work in a resource-rich center, where we have these huge multidisciplinary clinics, and we have the capacity to bring patients back every 3 months, but outside these big centers, in resource-limited settings, to have an ability to track remotely and bring patients in when they really need it is very important,” said Perera.
Best of Both Worlds
Ileana Howard, MD, physiatrist and professor of rehabilitation medicine at the University of Washington and medical co-director of the ALS Center of Excellence at VA Puget Sound in Seattle, agreed.
“One of the biggest challenges in ALS care today is ensuring equitable access to high quality care and supports, and telehealth was adopted by the VA early on as a means of doing that,” she said. “Remote monitoring technology is a really key development to help improve that type of care.”
However, she added that it should not be a question of one type of care versus the other. “The ideal care is when we have access to providing both face-to-face and virtual care for our patients so that we can meet their needs and preferences for care,” she said.
“Sometimes, in my experience, patients don’t understand why it’s important to go to an ALS specialty center. In those cases, I’ve been able to make initial contact with those individuals through telehealth and be able to provide education, which, in turn, often results in them making the decision to come to the specialty center once they understand what resources we have to offer.”
Also commenting on the research, Ghazala Hayat, MD, also endorsed a mixed approach.
“Telehealth is a very good tool that we should use interspersed with in-person visits,” said Hayat, director of the multidisciplinary ALS clinic at St. Louis University School of Medicine, St. Louis, Missouri, and professor of neurology and director of neuromuscular and clinical neurophysiology.
“I think the first few visits should always be in person — you need to connect with the patient,” she said. “But then, once they feel comfortable, remote monitoring is a very good idea, especially later in the disease process, when it becomes really difficult for the family to bring the patient in.”
The authors reported no relevant disclosures. Howard reported no disclosures. Hayat reported serving as a speaker and in advisory roles for argenx, Alexion, and MTPA. The study was funded by Amylyx Pharmaceuticals.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Pediatric Myasthenia Gravis: Don’t Treat Children Like Adults
SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.
For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
Case In Point: A 13-Year-Old With MG
Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”
Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.
“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”
The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.
“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
Consider Prescription Eye Drops for Ptosis
Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”
However, it can be difficult to get insurers to cover these medications, he said.
The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
The Young Patient Worsens. Now What?
The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.
Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.
However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.
Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”
Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
Don’t Neglect Supportive Care
Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.
He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”
How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”
Ginsberg had no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.
For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
Case In Point: A 13-Year-Old With MG
Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”
Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.
“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”
The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.
“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
Consider Prescription Eye Drops for Ptosis
Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”
However, it can be difficult to get insurers to cover these medications, he said.
The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
The Young Patient Worsens. Now What?
The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.
Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.
However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.
Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”
Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
Don’t Neglect Supportive Care
Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.
He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”
How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”
Ginsberg had no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — At a pathophysiological level, juvenile myasthenia gravis (MG) seems to be identical to the adult form, neuromuscular specialists learned. But there are still important differences between children and their elders that affect pediatric care.
For example, “we have to think a little bit differently about the side effect profiles of the medications and their toxicity because children may react to medications differently,” said Matthew Ginsberg, MD, a pediatric neurologist based in Akron, Ohio, in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
And then there’s the matter of adherence. “It’s hard to get adults to take medication, but a teenager is sometimes an exceptional challenge,” Ginsberg said.
Case In Point: A 13-Year-Old With MG
Pediatric MG is rare. Cases in children are estimated to account for 10% of MG cases diagnosed each year. According to a 2020 report, “the majority will present with ptosis and a variable degree of ophthalmoplegia [paralysis of eye muscles].”
Ginsberg highlighted a case of a 13-year-old girl who’d been healthy but developed fatigable ptosis and mild restriction of extraocular movements. The patient’s acetylcholine receptor antibodies were very elevated, but she didn’t have MuSK antibodies.
“This isn’t a diagnostic conundrum. She has autoimmune myasthenia gravis with ocular manifestations,” Ginsberg said. “For someone like this, whether it’s an adult or a child, many people would start symptomatic treatment with an acetylcholinesterase inhibitor like pyridostigmine.”
The use of the drug in children is similar to that in adults, he said, although weight-based dosing is used. “Usually it’s around 3-7 mg/kg/d, but it’s still very individualized based on patient response.” The timing of symptoms can affect the distribution of doses throughout the day, he said.
“There are extended-release formulations of the medication, and I think some people use them more than I do,” he said. “The side effects are basically similar to adults. Most of the patients I have on it tolerate it really well and don’t have a lot of the muscarinic side effects that you would expect.”
Consider Prescription Eye Drops for Ptosis
Alpha-1A agonists oxymetazoline and apraclonidine in the form of topical eye drops can help with ptosis. “They potentially avoid some of the systemic toxicity of the other medications,” Ginsberg said. “So they might be an option if you’re really just trying to target ptosis as a symptom.”
However, it can be difficult to get insurers to cover these medications, he said.
The 13-year-old patient initially improved but developed difficulty walking. “Her hands began to feel heavy, and she had difficulty chewing and nasal regurgitation. On her exam, she still had fatigable ptosis plus hypernasal speech and generalized weakness. At this point, we’re starting to see that she has generalized myasthenia gravis that may be an impending crisis.”
The Young Patient Worsens. Now What?
The patient was admitted and given intravenous immunoglobulin at 2 g/kg over a couple days. But her symptoms worsened following initial improvement.
Glucocorticoids can play a larger role in treatment at this stage, and the patient was initially on prednisone. But there are reasons for caution, including effects on bone growth and interference with live vaccines.
However, live vaccines aren’t common in children, with the exception of the MMRV vaccine, he said. “It’s worth noting that you can give that second dose as early as 3 months after the initial one, so most patients really should be able to complete a course before they start on immunosuppression,” he said.
Another option is immunotherapy. “There’s a really large menu of options for immunotherapy in myasthenia gravis right now,” Ginsberg said. “It’s great that we have all these options, but it adds to the complexity.”
Rituximab may be considered based on early data, he said. And thymectomy — removal of the thymus gland — should be considered early.
Don’t Neglect Supportive Care
Ginsberg urged colleagues to consider supportive care measures. Advocacy groups such as the Myasthenia Gravis Foundation of America can help with weight management and diet/exercise counseling, especially in patients taking glucocorticoids.
He added that “school accommodations are very important in this age group. They might need a plan, for example, to have modified gym class or an excuse not to carry a book bag between classes.”
How did the 13-year-old do? She underwent thymectomy, and her disease remained stable after 6 months. “Her rituximab was discontinued,” Ginsberg said. “She considered participating in a clinical trial but then started seeing improvements. About a year after the thymectomy, she just stopped her steroids on her own, and she was fine.”
Ginsberg had no disclosures.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
New Clinician Tool Aims to Stop ALS Diagnosis Delays
SAVANNAH, GEORGIA —
The one-page “thinkALS” tool, designed for clinicians who don’t specialize in neuromuscular disorders, offers a guide to recognize ALS symptoms and determine when it’s time to refer patients to ALS clinics.
“Time is of the essence. It’s really important because the paradigm of looking at ALS is shifting from this being a fatal disease that nobody can do anything about,” said Suma Babu, MBBS, MPH, assistant professor of neurology at Massachusetts General Hospital/Harvard Medical School in Boston, in a presentation at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “As a community, we need to think about how can get to the diagnosis point early and get patients started on therapies.”
On Average, ALS Diagnosis Takes 12-15 Months
As Babu noted, the percentage of patients initially diagnosed with something else may be as high as 52%. The time to diagnosis in ALS remained steady at a mean 12-15 months from 1996-1998 to 2000-2018.
“If you keep in mind that an average ALS patient lives only 3-5 years from symptom onset, they’re spending one third of their survival time in just trying to figure out what the diagnosis is,” Babu said. “Often, they may even undergo unnecessary testing and unnecessary surgeries — carpal tunnel releases, spinal surgeries, and so on.”
Babu’s own research, which is under review for publication, examined 2011-2021 Medicare claims to determine the typical time from first neurologist consult to confirmed ALS diagnosis. The mean for ALS/neuromuscular specialists is 9.6 months, while it’s 16.7 months for nonspecialist neurologists.
“It’s a hard pill to swallow,” Babu said, referring to the fact that neurologists are contributing to some of this situation. “But it is a challenge because ALS does not have a definitive diagnostic test, and you’re ruling out other possibilities.”
A ‘Sense of Nihilism’ About Prognoses
She added that “unless you’re seeing a lot of ALS patients, this is not going to be on a neurologist’s or a nurse practitioner’s radar to think about ALS early and then refer them to the right place.”
There’s also an unwarranted “sense of nihilism” about prognoses for patients, she said. “Sometimes people do not understand what’s going on within the ALS field in terms of ‘What are we going to do about it if it’s diagnosed?’ ”
The new one-page tool will be helpful in making diagnoses, she said. “If you have a patient who has asymmetric, progressive weakness, there is an instrument you can turn to that will walk you through the most common symptoms. It’ll also walk you through what to do next.”
The tool lists features of ALS and factors that support — or don’t support — an ALS diagnosis. Users are told to “think ALS” if features in two categories are present and no features in a third category are present.
Referral Wording Is Crucial
Babu added that the “important key feature of this instrument” is guidance for non-neurologists regarding what to write on a referral to neurology so the patient is channeled directly to an ALS clinic. The recommended wording: “CLINICAL SUSPICION FOR ALS.”
Neurologist Ximena Arcila-Londono, MD, of Henry Ford Health in Detroit, spoke after Babu’s presentation and agreed that wording is crucial in referrals. “Please include in your words ‘Rule out motor neuron disorder’ or ‘Rule out ALS,’ ” she said. “Some people in the community are very reluctant to use those words in their referral. If you don’t use the referral and you send them [regarding] weakness, that person is going to get stuck in the general neurology pile. The moment you use the word ‘motor neuron disorder’ or ALS, most of us will get to those patients within a month.”
The tool’s wording adds that “most ALS centers can accommodate urgent ALS referrals within 2 weeks.”
Babu disclosed receiving research funding from the AANEM Foundation, American Academy of Neurology, Muscular Dystrophy Association, OrphAI, Biogen, Ionis, Novartis, Denali, uniQure, and MarvelBiome. Arcila-Londono had no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The one-page “thinkALS” tool, designed for clinicians who don’t specialize in neuromuscular disorders, offers a guide to recognize ALS symptoms and determine when it’s time to refer patients to ALS clinics.
“Time is of the essence. It’s really important because the paradigm of looking at ALS is shifting from this being a fatal disease that nobody can do anything about,” said Suma Babu, MBBS, MPH, assistant professor of neurology at Massachusetts General Hospital/Harvard Medical School in Boston, in a presentation at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “As a community, we need to think about how can get to the diagnosis point early and get patients started on therapies.”
On Average, ALS Diagnosis Takes 12-15 Months
As Babu noted, the percentage of patients initially diagnosed with something else may be as high as 52%. The time to diagnosis in ALS remained steady at a mean 12-15 months from 1996-1998 to 2000-2018.
“If you keep in mind that an average ALS patient lives only 3-5 years from symptom onset, they’re spending one third of their survival time in just trying to figure out what the diagnosis is,” Babu said. “Often, they may even undergo unnecessary testing and unnecessary surgeries — carpal tunnel releases, spinal surgeries, and so on.”
Babu’s own research, which is under review for publication, examined 2011-2021 Medicare claims to determine the typical time from first neurologist consult to confirmed ALS diagnosis. The mean for ALS/neuromuscular specialists is 9.6 months, while it’s 16.7 months for nonspecialist neurologists.
“It’s a hard pill to swallow,” Babu said, referring to the fact that neurologists are contributing to some of this situation. “But it is a challenge because ALS does not have a definitive diagnostic test, and you’re ruling out other possibilities.”
A ‘Sense of Nihilism’ About Prognoses
She added that “unless you’re seeing a lot of ALS patients, this is not going to be on a neurologist’s or a nurse practitioner’s radar to think about ALS early and then refer them to the right place.”
There’s also an unwarranted “sense of nihilism” about prognoses for patients, she said. “Sometimes people do not understand what’s going on within the ALS field in terms of ‘What are we going to do about it if it’s diagnosed?’ ”
The new one-page tool will be helpful in making diagnoses, she said. “If you have a patient who has asymmetric, progressive weakness, there is an instrument you can turn to that will walk you through the most common symptoms. It’ll also walk you through what to do next.”
The tool lists features of ALS and factors that support — or don’t support — an ALS diagnosis. Users are told to “think ALS” if features in two categories are present and no features in a third category are present.
Referral Wording Is Crucial
Babu added that the “important key feature of this instrument” is guidance for non-neurologists regarding what to write on a referral to neurology so the patient is channeled directly to an ALS clinic. The recommended wording: “CLINICAL SUSPICION FOR ALS.”
Neurologist Ximena Arcila-Londono, MD, of Henry Ford Health in Detroit, spoke after Babu’s presentation and agreed that wording is crucial in referrals. “Please include in your words ‘Rule out motor neuron disorder’ or ‘Rule out ALS,’ ” she said. “Some people in the community are very reluctant to use those words in their referral. If you don’t use the referral and you send them [regarding] weakness, that person is going to get stuck in the general neurology pile. The moment you use the word ‘motor neuron disorder’ or ALS, most of us will get to those patients within a month.”
The tool’s wording adds that “most ALS centers can accommodate urgent ALS referrals within 2 weeks.”
Babu disclosed receiving research funding from the AANEM Foundation, American Academy of Neurology, Muscular Dystrophy Association, OrphAI, Biogen, Ionis, Novartis, Denali, uniQure, and MarvelBiome. Arcila-Londono had no disclosures.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA —
The one-page “thinkALS” tool, designed for clinicians who don’t specialize in neuromuscular disorders, offers a guide to recognize ALS symptoms and determine when it’s time to refer patients to ALS clinics.
“Time is of the essence. It’s really important because the paradigm of looking at ALS is shifting from this being a fatal disease that nobody can do anything about,” said Suma Babu, MBBS, MPH, assistant professor of neurology at Massachusetts General Hospital/Harvard Medical School in Boston, in a presentation at American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “As a community, we need to think about how can get to the diagnosis point early and get patients started on therapies.”
On Average, ALS Diagnosis Takes 12-15 Months
As Babu noted, the percentage of patients initially diagnosed with something else may be as high as 52%. The time to diagnosis in ALS remained steady at a mean 12-15 months from 1996-1998 to 2000-2018.
“If you keep in mind that an average ALS patient lives only 3-5 years from symptom onset, they’re spending one third of their survival time in just trying to figure out what the diagnosis is,” Babu said. “Often, they may even undergo unnecessary testing and unnecessary surgeries — carpal tunnel releases, spinal surgeries, and so on.”
Babu’s own research, which is under review for publication, examined 2011-2021 Medicare claims to determine the typical time from first neurologist consult to confirmed ALS diagnosis. The mean for ALS/neuromuscular specialists is 9.6 months, while it’s 16.7 months for nonspecialist neurologists.
“It’s a hard pill to swallow,” Babu said, referring to the fact that neurologists are contributing to some of this situation. “But it is a challenge because ALS does not have a definitive diagnostic test, and you’re ruling out other possibilities.”
A ‘Sense of Nihilism’ About Prognoses
She added that “unless you’re seeing a lot of ALS patients, this is not going to be on a neurologist’s or a nurse practitioner’s radar to think about ALS early and then refer them to the right place.”
There’s also an unwarranted “sense of nihilism” about prognoses for patients, she said. “Sometimes people do not understand what’s going on within the ALS field in terms of ‘What are we going to do about it if it’s diagnosed?’ ”
The new one-page tool will be helpful in making diagnoses, she said. “If you have a patient who has asymmetric, progressive weakness, there is an instrument you can turn to that will walk you through the most common symptoms. It’ll also walk you through what to do next.”
The tool lists features of ALS and factors that support — or don’t support — an ALS diagnosis. Users are told to “think ALS” if features in two categories are present and no features in a third category are present.
Referral Wording Is Crucial
Babu added that the “important key feature of this instrument” is guidance for non-neurologists regarding what to write on a referral to neurology so the patient is channeled directly to an ALS clinic. The recommended wording: “CLINICAL SUSPICION FOR ALS.”
Neurologist Ximena Arcila-Londono, MD, of Henry Ford Health in Detroit, spoke after Babu’s presentation and agreed that wording is crucial in referrals. “Please include in your words ‘Rule out motor neuron disorder’ or ‘Rule out ALS,’ ” she said. “Some people in the community are very reluctant to use those words in their referral. If you don’t use the referral and you send them [regarding] weakness, that person is going to get stuck in the general neurology pile. The moment you use the word ‘motor neuron disorder’ or ALS, most of us will get to those patients within a month.”
The tool’s wording adds that “most ALS centers can accommodate urgent ALS referrals within 2 weeks.”
Babu disclosed receiving research funding from the AANEM Foundation, American Academy of Neurology, Muscular Dystrophy Association, OrphAI, Biogen, Ionis, Novartis, Denali, uniQure, and MarvelBiome. Arcila-Londono had no disclosures.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Cardiac Monitoring Is Crucial in Neuromuscular Disorder Care
SAVANNAH, GEORGIA — , a neurologist told an audience of nerve/muscle specialists.
The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
Protein Alterations May Disrupt Heart Muscles
In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.
In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.
Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”
Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
ECGs and Echos Are Recommended
Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”
The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”
Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
Worse Outcomes in Becker Muscular Dystrophy (BMD)
Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.
Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.
Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.
“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
Pacemakers May Be Considered in Type 1 Myotonic Dystrophy
In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.
Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.
“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”
Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , a neurologist told an audience of nerve/muscle specialists.
The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
Protein Alterations May Disrupt Heart Muscles
In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.
In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.
Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”
Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
ECGs and Echos Are Recommended
Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”
The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”
Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
Worse Outcomes in Becker Muscular Dystrophy (BMD)
Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.
Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.
Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.
“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
Pacemakers May Be Considered in Type 1 Myotonic Dystrophy
In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.
Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.
“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”
Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , a neurologist told an audience of nerve/muscle specialists.
The cardiac conditions can range from asymptomatic to potentially lethal, Nicholas J. Silvestri, MD, professor of neurology at the Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, in New York, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. “It’s really important to know when to do tests and refer to cardiology, and it’s really important to find a cardiologist who can work in concert in taking care of these patients.”
Protein Alterations May Disrupt Heart Muscles
In muscular dystrophies, a prevailing theory suggests that alterations to proteins such as dystrophin disrupt structural integrity in both muscle and cardiac cells, he said.
In Duchenne muscular dystrophy (DMD), cardiomyopathy, cardiac conduction abnormalities, or both usually appear in patients by age 10. “It’s important to know that it’s probably present to some degree before that, and it’s not going to get better over time,” he said.
Cardiac problems are universal in DMD by age 18, he said. “Men and boys are living longer, so they have the opportunity to develop the cardiac abnormalities that accrue with time.” Conduction abnormalities typically appear first. “In a lot of these boys, you’ll typically see persistent sinus tachycardia. But they can also develop atrial arrhythmias and bundle branch blocks.”
Sudden cardiac death is responsible for mortality in an estimated 15% patients with DMD. “Very sadly, I lost a patient this way just a few months ago,” Silvestri said.
ECGs and Echos Are Recommended
Screening is crucial. “Make sure that patients get that referral and get these tests done,” he said. “You need an ECG and echo by diagnosis or age 6. This is usually repeated annually or biannually, typically by the cardiologist you’re working with.”
The good news is that there’s evidence of survival benefits from treatment with angiotensin-converting enzyme inhibitors for dilated cardiomyopathy. “Some cardiac experts feel treatment with angiotensin receptor blockers (ARBs) is equivalent.”
Most boys will get echocardiograms, he said, “but there’s a lot of evidence showing that cardiac MRI is probably preferable for a number of reasons,” including better visualization. But the need for sedation limits access, he said, and cardiac MRI may not be available at some facilities.
Worse Outcomes in Becker Muscular Dystrophy (BMD)
Cardiac involvement is more common and more severe in BMD than in DMD. About 50% of deaths in BMD are attributed to malignant arrhythmias or congestive heart failure, he said.
Screening requirements and treatment options in BMD are similar to those in DMD, with the added option of heart transplantation.
Silvestri cautioned that up to 40% of female carriers of dystrophin mutations can develop cardiac dysfunction similar to that seen in DMD and BMD. Cardiac assessments are recommended every 5 years. “It’s important to genotype Mom,” he said, especially in light of the fact that two thirds of DMD cases may be inherited.
“When I send genetic testing on the mother and find her to be a carrier, I send her to a cardiologist so she has the appropriate screening done,” he said.
Pacemakers May Be Considered in Type 1 Myotonic Dystrophy
In type 1 myotonic dystrophy, cardiac conduction abnormalities are seen in two thirds of patients, and sudden cardiac death in up to 30% of patients. “When it is diagnosed, patients do need an ECG at that time, as well as annually,” he said.
Holter monitoring or implantable loop recorders may be recommended, and permanent pacing via an implantable cardioverter-defibrillator might be appropriate.
“Based on the literature to date, the exact timing is not is not clear,” Silvestri said. “The electrophysiologists in my area tend to be very aggressive, thankfully, and treat them fairly soon with pacemakers when we see the first sign of trouble.”
Silvestri disclosed consultant/advisory relationships with argenx, Alexion, Amgen, UCB, Immunovant, and Janssen.
A version of this article appeared on Medscape.com.
FROM AANEM 2024
ALS Update: Drug Therapy Continues to Offer Little Benefit
SAVANNAH, GEORGIA — , nerve specialists learned.
The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
Earlier Treatment Could Pay Dividends
A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.
Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).
There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.”
He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
Edaravone Could Lack Relevant Benefit
No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.
The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.
That’s a “substantial delay,” Weiss said.
The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*
Other Options
As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.
In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”
Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.
Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.
*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , nerve specialists learned.
The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
Earlier Treatment Could Pay Dividends
A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.
Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).
There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.”
He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
Edaravone Could Lack Relevant Benefit
No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.
The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.
That’s a “substantial delay,” Weiss said.
The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*
Other Options
As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.
In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”
Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.
Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.
*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”
A version of this article appeared on Medscape.com.
SAVANNAH, GEORGIA — , nerve specialists learned.
The glutamate blocker riluzole (Rilutek), which became the first ALS drug to receive US Food and Drug Administration (FDA) approval in 1995, continues to be used, Michael D. Weiss, MD, professor of neurology at University of Washington School of Medicine, Seattle, said in a presentation at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
Weiss highlighted a 2012 Cochrane Library review that examined research and found the drug is “reasonably safe” and prolongs median survival by about 2-3 months. “About 12% develop liver disease. It’s pretty rare that we stop the medicine due to liver toxicity.”
Earlier Treatment Could Pay Dividends
A recent study “suggests we might be able to get more bang for our buck from riluzole” by initiating treatment earlier, Weiss said.
Researchers tracked 4778 patients with ALS, including 3446 (72.1%) who took riluzole. Those who took the drug survived a median 2 extra months (22.6 vs 20.2 months; P < .001). The data suggested that delaying riluzole initiation by 1 year (from 6 months to 18 months after diagnosis) reduced the median survival by 1.9 months (from 40.1 to 38.2 months).
There’s “a relatively significant additional benefit” to earlier treatment, Weiss said, although patients will vary on whether they think it’s meaningful. As for limitations, “there’s no clear impact on disease progression, and there’s a need for periodic monitoring of liver function profile.”
He added that there’s an out-of-pocket co-pay. “Even as a generic, it’s not that cheap. Depending on the source, it could cost anywhere from $1800 to $8400 a year.”
Edaravone Could Lack Relevant Benefit
No other ALS treatment appeared until 2017, when the FDA approved the novel antioxidant edaravone (Radicava). In 2022, the agency approved an oral suspension version, but a study published that year suggested there may not be a clinically relevant benefit.
The University of Washington, where Weiss works, offered the drug to 144 patients, according to an analysis. Eighty percent of the patients wanted it, but insurers refused to cover it for more than 20%. The average time to treatment with the drug was 28 days after patients said they wanted it.
That’s a “substantial delay,” Weiss said.
The cost is about $171,000 a year, he said, and assistance is limited for underinsured patients.*
Other Options
As Weiss noted, another drug, AMX0035 (Relyvrio), received FDA approval in 2022, but its manufacturer pulled it from the US/Canada market in April 2024 following poor phase 3 trial findings.
In 2023, the FDA approved another drug, the antisense oligonucleotide tofersen (Qalsody), in patients with ALS associated with a mutation in the superoxide dismutase 1 gene. According to the FDA, reductions in plasma neurofilament light concentration were “reasonably likely to predict a clinical benefit in patients.”
Only 1%-2% of patients with ALS fit the criteria to get the drug, Weiss said. He noted other limitations such as the cost ($180,000 a year), the need for lifelong monthly intrathecal injections, and serious neurological side effects in 7% of patients per a 2022 trial.
Weiss disclosed advisory board (Alexion, Ra [now UCB], argenx, Biogen, Mitsubishi Tanabe Pharma, Amylyx), data safety monitoring board (Sanofi, AI), consulting (Cytokinetics, CSL Behring), and speaker (Soleo) relationships.
*Correction, 10/23/2024: This story originally quoted Weiss as saying the maker of edaravone provides no assistance to underinsured patients. Weiss has clarified that he should have said this coverage is “limited.”
A version of this article appeared on Medscape.com.
FROM AANEM 2024
Myasthenia Gravis: Similar Symptoms in Relatives Raise Question of Genes
SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?
“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.
“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.
“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
Two Cases
In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.
A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.
The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.
In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.
This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.
“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
Genetics and Environment May Each Play a Role
Shanina called for research exploring mutations and inheritance patterns in families with MG.
“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”
Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.”
Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.”
While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”
While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.
Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”
Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.
There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.
A version of this article first appeared on Medscape.com.
SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?
“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.
“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.
“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
Two Cases
In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.
A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.
The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.
In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.
This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.
“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
Genetics and Environment May Each Play a Role
Shanina called for research exploring mutations and inheritance patterns in families with MG.
“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”
Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.”
Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.”
While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”
While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.
Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”
Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.
There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.
A version of this article first appeared on Medscape.com.
SAVANNAH, GEORGIA — One patient with autoimmune myasthenia gravis (MG) has a niece with the same diagnosis, and at least one of his other close relatives may have it too. Another patient with MG lost his father and brother to complications from the disease, while a surviving brother also has it. These two cases, reported at a meeting of nerve/muscle specialists, spotlight one of the mysteries of MG: What role does heredity play in this disorder?
“Clinical familial associations — when transmission appears to be vertical, from parent to offspring — suggest that there is much yet to learn about genetic bases for autoimmunity and how certain mutations could favor selection for specific immune disorders,” said Elena Shanina, MD, PhD, a neurology professor at the University of Texas Medical Branch, Galveston, in an interview. She and colleagues presented the two case reports at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024.
As Shanina noted, MG is usually sporadic without a link to heredity. However, she said, research suggests that up to 7% of patients have MG in their family history.
“There are well-described genetic causes for congenital myasthenic syndromes, in which mutations occur in genes for neuromuscular junction (NMJ) proteins affecting NMJ function. However, much less is known about genetic associations to autoimmune MG,” she said.
“More than a decade ago, differences in HLA DQ haplotype-associated presentation of AChR alpha-chain peptides were suggested to suffice in producing MG, and specific HLA DQ susceptibility links were found predisposing to MG. More recent studies have tried to identify specific genes such as CTLA4 mutations that enhance autoimmunity and neuroinflammation.”
Two Cases
In one of the case reports, a 75-year-old White man with hereditary coagulopathy presented with myasthenic crisis in the setting of acute pulmonary embolism. Chronic symptoms included diplopia, ptosis, and proximal muscle weakness.
A niece of the patient has been diagnosed with MG and suffers from ocular symptoms. Meanwhile, an uncle has ptosis but no diagnosis yet, and a daughter has dermatomyositis. Like MG, dermatomyositis is an autoimmune disease that causes muscle weakness.
The patient, who’s CTLA4 negative, is faring well on eculizumab after failing standard therapies, Shanina said.
In the other case, a 67-year-old Hispanic man presented with diplopia, generalized fatigue, and weakness. Like the other patient, he was seropositive for acetylcholine receptor antibodies.
This patient lost his father and brother to complications from MG. Another brother, who’s still living, also has MG.
“The patient has minimal manifestation status with disease and is currently controlled using oral immunomodulatory therapies,” Shanina said. “He is also CTLA4 negative.”
Genetics and Environment May Each Play a Role
Shanina called for research exploring mutations and inheritance patterns in families with MG.
“If there are genetic causes that increase autoimmunity with specific propensity for certain immune diseases, correcting those mutations could fundamentally change how we treat — and prevent — at least some autoimmune diseases,” she said. “For example, if HLA linkage is directly involved in determining susceptibility to MG, and if the presence of a specific HLA locus allele is sufficient to produce disease, HLA gene editing could be a future therapy to prevent such diseases. Likewise, monoclonal antibodies that target products of genes that increase risk for autoimmunity might be able to reduce such risks without modifying the patient’s genome.”
Henry J. Kaminski, MD, professor of neurology at George Washington University, Washington, DC, is familiar with the report’s findings. In an interview, he noted that while genetic profiles can make MG more likely, “the situation is not like Huntington’s or Alzheimer’s where there is a strong genetic risk.”
Instead, he said, there’s “a genetic risk coupled to some environmental stimulus that leads to the development of MG, which is true for many complex autoimmune conditions.”
While he doesn’t think the two new case reports are especially noteworthy, Kaminski said “the ability to assess genetic risk factors across patients will elucidate understanding of MG. Personalized medicine choices will likely require understanding of genetic risks.”
While understanding MG in families is “always good to know from a research perspective,” there’s no reason to launch surveillance of relatives to see if they also have the disease, he said.
Also, Kaminski cautioned that it’s important to differentiate autoimmune MG from congenital myasthenia, an even more rare genetic disorder of neuromuscular transmission. “Congenital myasthenias will not improve with immune therapy, and patients will suffer complications for no reason,” he said. “A patient who is seronegative should be assessed for congenital myasthenia with the right clinical presentation. The condition would be more likely in patients with a family history of symptoms similar to MG. It may be symptomatic at birth, but patients may present in adulthood.”
Kaminski noted that his team is collecting saliva samples from patients with MuSK-MG, a rare MG subtype linked to more severe cases, for genetic testing and genome-wide association studies.
There was no study funding, and the authors have no disclosures. Kaminski is principal investigator of a rare disease network dedicated to MG.
A version of this article first appeared on Medscape.com.
FROM AANEM 2024
At Last, Treatment Is in Sight for Charcot-Marie-Tooth Disease
SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.
neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
A Common Genetic Neuromuscular Disorder
As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”
Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”
As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
Genetic Therapy
In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.
“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”
A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.
Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.
Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.
“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
Preclinical Treatment Approaches
However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”
Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.
One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.
The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.
Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”
Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.
Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.
A version of this article first appeared on Medscape.com.
SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.
neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
A Common Genetic Neuromuscular Disorder
As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”
Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”
As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
Genetic Therapy
In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.
“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”
A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.
Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.
Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.
“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
Preclinical Treatment Approaches
However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”
Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.
One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.
The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.
Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”
Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.
Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.
A version of this article first appeared on Medscape.com.
SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.
neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
A Common Genetic Neuromuscular Disorder
As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”
Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”
As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
Genetic Therapy
In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.
“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”
A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.
Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.
Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.
“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”
Preclinical Treatment Approaches
However, there are challenges. Drug delivery to Schwann cells, which insulate axons, is difficult, she said. “The other problem is that we want to avoid overly silencing PMP22 because that runs the theoretical risk of causing a different condition, HNPP [hereditary neuropathy with liability to pressure palsies]. HNPP is caused by deletions of PMP22, so we want to avoid that situation.”
Mukherjee-Clavin highlighted two RNA therapeutic products that she expects to move from preclinical to clinical research soon.
One is TVR110 by Armatus Bio, a microRNA intrathecal injection product, which aims to reduce PMP22 overexpression. “It targets basically reduces PMP22 mRNA expression and then normalizes the amount of PMP22 protein that is ultimately generated,” she said.
The other therapy, a small interfering RNA intravenous product delivered to Schwann cells, is being developed by DTx Pharma/Novartis.
Outside of the RNA arena, “there are a number of other programs that are in the preclinical phases that I think will be moving through this pipeline,” Mukherjee-Clavin said. “We’ll see if some of these enter first-in-human clinical trials.”
Meanwhile, Saporta highlighted small-molecule strategies that target a subtype of CMT called sorbitol dehydrogenase (SORD) deficiency that’s caused by mutations in the SORD gene. He noted that Applied Therapeutics is testing an investigational drug called govorestat (AT-007) in 56 patients in a double-blind, randomized, placebo-controlled phase 3 registrational study. The company recently reported that interim 12-month results are promising.
Saporta disclosed consulting for DTx Pharma/Novartis, Applied Therapeutics, and Pharnext. Mukherjee-Clavin had no disclosures.
A version of this article first appeared on Medscape.com.
FROM AANEM 2024