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Gene-replacement therapy shows promise in X-linked myotubular myopathy
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.
The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.
X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
The ASPIRO trial
Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.
Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 1014 vg/kg of AAT132, 3 × 1014 vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.
The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
Treatment improved respiratory function
As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.
Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.
Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 1014 vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 1014 vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.
In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH2O for the low-dose group, 46.1 cmH2O for the high-dose group, and −8.0 cmH2O for controls.
Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.
Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
Deaths under investigation
In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.
“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.
Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.
SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.
FROM CNS-ICNA 2020
Ataluren delays disease milestones in patients with nonsense mutation DMD
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
(nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.
DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
Comparing treatment and standard of care
Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.
Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.
Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
Treatment delayed disease milestones
Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.
The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.
SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.
FROM CNS-ICNA 2020
Acute flaccid myelitis: More likely missed than diagnosed
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
and that can result in loss of valuable time to admit patients and begin treatment to get ahead of the virus that may cause the disease.
At the 2020 CNS-ICNA Conjoint Meeting, held virtually this year, Leslie H. Hayes, MD, of Boston Children’s Hospital presented findings of a retrospective case series from 13 institutions in the United States and Canada that determined 78% of patients eventually found to have AFM were initially misdiagnosed. About 62% were given an alternate diagnosis or multiple diagnoses, and 60% did not get a referral for further care or evaluation. The study included 175 children aged 18 years and younger when symptoms first appeared from 2014 to 2018 and who met the Centers for Disease Control and Prevention case definition of AFM.
“As it becomes more evident that AFM outbreaks are driven by enterovirus infections, treatments targeting the viral infection are likely to be most effective very early in the course of disease, necessitating a precise and early diagnosis,” Dr. Hayes said. “Thus awareness is needed to help recognize the signs of symptoms of AFM, particularly among frontline clinicians.”
One reason for misdiagnosis is that AFM has features that overlap with other neuroinflammatory disorders, she said. “In many cases the patients are misdiagnosed as having benign or self-limiting processes that would not prompt the same monitoring and level of care.”
Numbness and prodromal illnesses were associated with misdiagnosis, she said, but otherwise most presenting symptoms were similar between the misdiagnosed and correctly diagnosed patients.
Neurologic disorders with similar features to AFM that the study identified were Guillain-Barré syndrome, spinal cord pathologies such as transverse myelitis, brain pathologies including acute disseminating encephalomyelitis, acute inclusion body encephalitis and stroke, and other neuroinflammatory conditions.
“There were also many patients diagnosed as having processes that in many cases would not prompt inpatient admission, would not involve neurology consultation, and would not be treated in a similar fashion to AFM,” Dr. Hayes said.
Those diagnoses included plexopathy, neuritis, Bell’s palsy, meningoencephalitis, nonspecific infectious illness or parainfectious autoimmune disease, or musculoskeletal problems including toxic or transient synovitis, myositis, fracture or sprain, or torticollis.
“We identified preceding illness and numbness as two features associated with misdiagnosis,” Dr. Hayes said.
“We evaluated illness severity by evaluating the need for invasive and noninvasive ventilation and found that, while not statistically significant, misdiagnosed patients had a trend toward higher need for such respiratory support,” she noted. Specifically, 31.6% of misdiagnosed patients required noninvasive ventilation versus 15.8% of promptly diagnosed patients (P = .06).
Dr. Hayes characterized the rates of ICU admissions between the two groups as not statistically significant: 52.5% and 36.8% for the misdiagnosed and promptly diagnosed groups, respectively (P = .1).
Both groups of patients received intravenous immunoglobulin in similar rates (77.9% and 81.6%, respectively, P = .63), but the misdiagnosed patients were much more likely to receive steroids, 68.2% versus 44.7% (P = .008). That’s likely because steroids are the standard treatment for the neuroinflammatory disorders that they were misdiagnosed with, Dr. Hayes said.
Timely diagnosis and treatment was more of an issue for the misdiagnosed patients; their diagnosis was made on average 5 days after the onset of symptoms versus 3 days (P < .001). “We found that time to treatment, particularly time to IVIg, was significantly longer in the misdiagnosed group,” Dr. Hayes said, at 5 versus 2 days (P < .001).
Dr. Hayes has no relevant financial relationships to disclose.
FROM CNS-ICNA 2020
Nusinersen provides continued benefits to presymptomatic children with SMA
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.
“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”
Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
An ongoing open-label study
Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.
The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
Treatment improved motor development
Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.
Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.
Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.
Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.
SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.
FROM CNS-ICNA 2020
Drug combo slows functional decline in ALS
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
, according to results of the phase 2/3 CENTAUR study.
Patients with a fast-progressing form of ALS who were treated with AMX0035 “retained higher levels of physical function over 6 months compared with those who received placebo,” reported principal investigator Sabrina Paganoni, MD, PhD, of the Sean M. Healey and AMG Center for ALS at Massachusetts General Hospital, Boston.
“This is very hopeful news for people affected by ALS, especially because we were able to see a treatment effect in a relatively short period of time,” Dr. Paganoni said.
The study was published online Sept. 3 in the New England Journal of Medicine.
In this study, AMX0035 demonstrated a “clinically meaningful benefit and a favorable safety profile for people living with ALS,” Josh Cohen, co-CEO, chairman, and cofounder at Amylyx, said in a news release. The company is “working collaboratively and expeditiously with agencies worldwide to bring this potential new treatment option forward.”
“The data ... makes a clear and compelling case that AMX0035 should be made available to people with ALS as soon as possible,” Calaneet Balas, president and CEO of The ALS Association, said in the release.
The CENTAUR trial
Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. AMX0035 combines 3 g sodium phenylbutyrate and 1 g of taurursodiol.
The CENTAUR trial tested AMX0035 against placebo in 137 ALS patients with symptom onset within the prior 18 months, with 89 patients in the AMX0035 group and 48 in the placebo group. AMX0035 or matching placebo were administered once daily for 3 weeks and then twice daily for a planned duration of 24 weeks.
In a modified intention-to-treat analysis, the mean rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) score was −1.24 points per month with AMX0035 and −1.66 points per month with placebo (difference, 0.42 points per month; 95% CI, 0.03 - 0.81; P = .03). After 24 weeks, patients treated with AMX0035 scored on average 2.32 points higher on the ALSFRS-R than their peers on placebo group (P = .03).
“The score, consisting of four subdomains, showed a change that was most prominent for the fine-motor subscale and less apparent for the other subscales,” the investigators said.
Treatment with AMX0035 led to slowing of disease progression in a population in which many participants were receiving riluzole (Tiglutik), edaravone (Radicava) or both, they pointed out.
The secondary outcomes were rate of decline in isometric muscle strength and breathing function; change in plasma phosphorylated axonal neurofilament H subunit (pNF-H) levels; and the time to composite events of death, tracheostomy, permanent ventilation, and hospitalization. These outcomes did not differ significantly between the two groups.
Open-label extension ongoing
AMX0035 was generally well tolerated. Nearly all patients in both groups had one or more adverse events. Events occurring at 2% or greater frequency in the AMX0035 group were primarily gastrointestinal (diarrhea, nausea, salivary hypersecretion, and abdominal discomfort). Serious adverse events were more common in the placebo group (19% vs. 12%). The incidence of respiratory serious adverse events was 8% in the placebo group and 3% in the AMX0035 group.
More patients on active treatment than placebo (19% vs. 8%) stopped the trial regimen early owing to adverse events. The most common adverse events leading to discontinuation of the trial regimen were diarrhea and respiratory failure.
The trial was “too short for us to detect an effect on survival,” Dr. Paganoni said in an interview. Most of the participants who completed the trial elected to enroll in an open-label extension study and receive AMX0035 long-term. “This is important because it will teach us about the impact of AMX0035 on survival,” said Dr. Paganoni.
Interim data from the ongoing open-label extension study are being submitted to a peer-reviewed journal shortly and will be published in the coming months.
A cause for hope
“There has been understandable frustration with the slow pace of development of therapy for ALS,” Michael Benatar, MD, PhD, University of Miami, and Michael McDermott, PhD, University of Rochester (N.Y.), said in an accompanying editorial.
“Despite dozens of trials, few pharmacologic agents have emerged that affect functional decline or survival – and all only modestly so. Although the effects of sodium phenylbutyrate–taurursodiol are similarly modest, the incremental gains that they provide in the battle against ALS are a cause for hope,” they wrote.
They caution, however, that this study was enriched for patients with more rapidly progressive disease, which “raises questions about generalizability to the broader population of patients with ALS.
“Although the patients who were enrolled in the trial may not be biologically different from the broader population of patients with ALS, the magnitude of therapeutic effect may be smaller in the latter,” Dr. Benatar and Dr. McDermott noted.
They said that in light of “residual questions about efficacy and the ability of patients to continue taking the drug,” they agree with the authors’ conclusion that “longer and larger trials are needed to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS.”
Given these “tantalizing preliminary data,” Dr. Benatar and Dr. McDermott said they look forward to “a confirmatory phase 3 trial.”
The study was supported by Amylyx Pharmaceuticals, the ALS Finding a Cure Foundation, and the ALS Association. Dr. Paganoni has received grants from Revalesio, Ra Pharma, Biohaven, Clene, and Prilenia. A complete list of disclosures for authors and editorialists is available with the original article.
A version of this article originally appeared on Medscape.com.
From New England Journal of Medicine
FDA approves viltolarsen (Viltepso) for Duchenne muscular dystrophy
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
The FDA approved golodirsen (Vyondys 53, Sarepta Therapeutics) for this indication last year.
“The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” Billy Dunn, MD, director, Office of Neuroscience of the FDA’s Center for Drug Evaluation and Research, said in a statement.
The approval of viltolarsen provides “an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation,” Dr. Dunn said.
Viltolarsen is an antisense oligonucleotide that promotes production of functional dystrophin by masking exon 53 in the dystrophin gene. It was evaluated in two studies involving 32 male patients.
In one study of 16 patients, the increase in dystrophin production was established in eight patients receiving viltolarsen at the recommended dose. In this study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.
The increase in dystrophin production is “reasonably likely to predict clinical benefit,” but a “clinical benefit of the drug has not been established,” the FDA said.
In making the decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.
Viltolarsen was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments.
As part of the accelerated approval, the FDA requires the company to do a clinical trial to confirm the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may start proceedings to withdraw approval of the drug, the agency said.
The most common side effects with viltolarsen are upper respiratory tract infection, injection-site reaction, cough, and fever.
Kidney toxicity was not observed in the clinical studies, but the clinical experience with the drug is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed with some antisense oligonucleotides.
“Kidney function should be monitored in patients taking Viltepso,” the FDA advises.
A version of this article originally appeared on Medscape.com.
FDA expands Dysport use for cerebral palsy–related spasticity
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
– for patients as young as 2 years and older, according to manufacturer Ipsen Biopharmaceuticals.
When Dysport (abobotulinumtoxinA) initially was approved for treating pediatric lower limb spasticity by the FDA in 2016, Ipsen was granted Orphan Drug exclusivity for children whose lower-limb spasticity was caused by cerebral palsy. In 2019, Dysport was approved by the FDA for treating of upper-limb spasticity in children 2 years older. But if that spasticity was caused by cerebral palsy, Dysport could be used to treat it only through Orphan Drug exclusivity granted to another manufacturer, according to an Ipsen press release.
“The proactive step to resolve the uncertainty created by the previous CP [cerebral palsy] carve out enables us as physicians to prescribe consistent therapy for pediatric patients experiencing both upper- and lower-limb spasticity,” Sarah Helen Evans, MD, division chief of rehabilitation medicine in the department of pediatrics at the Children’s Hospital of Philadelphia, said in the press release.
The most common adverse effects among children with lower-limb spasticity treated with Dysport were nasopharyngitis, cough, and pyrexia. Among children with upper-limb spasticity, the most common effects associated with Dysport treatment were upper respiratory tract infection and pharyngitis.
The press release also included a warning of the distant spread of the botulinum toxin from the area of injection hours to weeks afterward, causing symptoms including blurred vision, generalized muscle weakness, and swallowing and breathing difficulties that can be life threatening; there have been reports of death.
Suspected adverse effects can be reported to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
First reported U.S. case of COVID-19 linked to Guillain-Barré syndrome
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
further supporting a link between the virus and neurologic complications, including GBS.
Physicians in China reported the first case of COVID-19 that initially presented as acute GBS. The patient was a 61-year-old woman returning home from Wuhan during the pandemic.
Subsequently, physicians in Italy reported five cases of GBS in association with COVID-19.
The first U.S. case is described in the June issue of the Journal of Clinical Neuromuscular Disease.
Like cases from China and Italy, the U.S. patient’s symptoms of GBS reportedly occurred within days of being infected with SARS-CoV-2. “This onset is similar to a case report of acute Zika virus infection with concurrent GBS suggesting a parainfectious complication,” first author Sandeep Rana, MD, and colleagues noted.
The 54-year-old man was transferred to Allegheny General Hospital after developing ascending limb weakness and numbness that followed symptoms of a respiratory infection. Two weeks earlier, he initially developed rhinorrhea, odynophagia, fevers, chills, and night sweats. The man reported that his wife had tested positive for COVID-19 and that his symptoms started soon after her illness. The man also tested positive for COVID-19.
His deficits were characterized by quadriparesis and areflexia, burning dysesthesias, mild ophthalmoparesis, and dysautonomia. He did not have the loss of smell and taste documented in other COVID-19 patients. He briefly required mechanical ventilation and was successfully weaned after receiving a course of intravenous immunoglobulin.
Compared with other cases reported in the literature, the unique clinical features in the U.S. case are urinary retention secondary to dysautonomia and ocular symptoms of diplopia. These highlight the variability in the clinical presentation of GBS associated with COVID-19, the researchers noted.
They added that, with the Pittsburgh patient, electrophysiological findings were typical of demyelinating polyneuropathy seen in patients with GBS. The case series from Italy suggests that axonal variants could be as common in COVID-19–associated GBS.
“Although the number of documented cases internationally is notably small to date, it’s not completely surprising that a COVID-19 diagnosis may lead to a patient developing GBS. The increase of inflammation and inflammatory cells caused by the infection may trigger an irregular immune response that leads to the hallmark symptoms of this neurological disorder,” Dr. Rana said in a news release.
“Since GBS can significantly affect the respiratory system and other vital organs being pushed into overdrive during a COVID-19 immune response, it will be critically important to further investigate and understand this potential connection,” he added.
A version of this article originally appeared on Medscape.com.
Huntington’s disease biomarkers appear 24 years before clinical symptoms
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
, according to a study published in the June Lancet Neurology. The data come from the Huntington’s disease Young Adult Study (HD-YAS) conducted in the United Kingdom.
The genetic cause of Huntington’s disease provides a potential target for biomarker treatment, wrote joint first authors Rachael I. Scahill, PhD, and Paul Zeun, BMBS, of University College London and colleagues.
“A detailed characterization of the premanifest period in Huntington’s disease is crucial for disease staging, informing the optimum time to initiate treatments, and identifying biomarkers for future trials in people with premanifest Huntington’s disease (preHD),” they said.
Identifying biomarkers of pre-Huntington’s disease
For their study, the researchers recruited 64 young adults with presymptomatic Huntington’s disease (preHD) and 67 controls, with an average age of 29 years. Brain imaging was conducted between Aug. 2, 2017, and April 25, 2019. Individuals with preexisting measurable cognitive and psychiatric disorders were excluded.
The researchers found no significant evidence of cognitive or psychiatric impairment in the preHD group at 23.6 years from the predicted onset of symptoms. The preHD group showed smaller putamen volumes, compared with controls, but this difference had no apparent relation to the timing of symptom onset, the researchers said.
Brain imaging revealed elevations in the CSF mutant huntingtin, neurofilament light protein (NfL), YKL-40, and plasma NfL among individuals with preHD, compared with controls. Of these, CSF NfL showed the highest effect size of measures in the study and showed a significant increasing association with estimated years to the onset of clinical symptoms of HD carriers. Overall, 53% of individuals with preHD had CSF NfL values in the normal range, and 47% had elevated values, compared with controls.
“NfL is therefore a potential candidate to provide a measure of disease progression in early preHD and might eventually be used as a marker of response to treatment in future preventive trials,” the researchers said.
The study findings were limited by several factors including potential underpowering to detect associations with age and CAG gene segment repeats, the researchers noted.
However, “By identifying a cohort of individuals with preHD and no detectable functional impairment but who begin to exhibit subtle elevations in select biological measures of neurodegeneration, we have highlighted a crucial point early in the disease process,” they concluded.
“Intervening at this stage might offer the prospect of delaying or preventing further neurodegeneration while function is intact, giving gene carriers many more years of life without impairment,” they added.
What is the best window for treatment?
The study is “particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington’s disease has no substantial effect on adults’ clinical pattern,” wrote Anne-Catherine Bachoud-Lévi, MD, of Université Paris Est, Créteil, France, in an accompanying comment.
“The most robust findings of [the study] are the sensitiveness of NfL, compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant,” she said. However, potential limitations to the study include the exclusion absence of language and calculation as part of the cognitive assessments, she noted. “Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants.”
In addition, the risks versus benefits of any long-term treatment must be considered, Dr. Bachoud-Lévi noted.
“The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years,” she said. “Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD,” she added.
The study was supported by the Wellcome Trust, CHDI Foundation. The researchers had no financial conflicts to disclose. Dr. Bachoud-Lévi disclosed grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique.
SOURCES: Scahill RI et al. Lancet Neurol. 2020 June;19:502-12; Bachoud-Lévi A-C. Lancet Neurol. 2020 June;19:473-5.
FROM LANCET NEUROLOGY
Dermatomyositis without dermatitis correlates with autoantibodies
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
The prevalence of dermatomyositis without dermatitis among patients with biopsy-confirmed dermatomyositis was approximately 8% in a Japanese cohort study. “Dermatomyositis sine dermatitis does exist and is significantly associated with anti–nuclear matrix protein 2 [anti-NXP-2] autoantibodies,” the researchers reported in JAMA Neurology.
Few case reports of dermatomyositis sine dermatitis have been documented. To confirm the existence of the condition, study its prevalence, and characterize its serologic features, Michio Inoue, MD, PhD, of the National Center of Neurology and Psychiatry in Tokyo, and colleagues conducted a cohort study of patients seen at the center between January 2009 and August 2019.
Of more than 8,800 patients whose muscle biopsies were examined for diagnostic purposes, 199 were tested for dermatomyositis-specific autoantibodies. The investigators excluded patients who did not have myxovirus resistance protein A expression in myofibers on muscle biopsy. In all, 182 patients with dermatomyositis were enrolled in the study (51% women; median age at biopsy, 56 years). Fourteen patients without a skin rash at the time of muscle biopsy received a diagnosis of dermatomyositis sine dermatitis. Before the muscle biopsy, most patients without a rash had a diagnosis of polymyositis.
Association with anti-NXP-2 autoantibodies
Anti-NXP-2 autoantibodies were detected in 86% of the patients without a rash at the time of biopsy, compared with 28% of the patients with rashes. “No other clinical or pathological characteristics were associated with [dermatomyositis sine dermatitis] except increased probability of developing perifascicular atrophy (71% vs. 43%),” Dr. Inoue and colleagues said.
During a median follow-up of 34 months, patients with dermatomyositis sine dermatitis received oral prednisolone with or without additional immunotherapy, and two patients had subcutaneous edema. Calcification was not seen during follow-up. “One patient with ... anti-NXP-2 autoantibodies had severe interstitial lung disease and needed noninvasive positive-pressure ventilation support,” the researchers said.
Four of the 14 patients with dermatomyositis sine dermatitis “developed skin rashes after muscle biopsy,” the researchers noted. “Similarly, a patient with [dermatomyositis sine dermatitis] was reported to have developed a skin rash 2 years after muscle biopsy.”
Potential therapies for refractory dermatomyositis, such as Janus kinase inhibitors, may not be effective for other types of myositis, so identifying patients with dermatomyositis may be “more essential than ever,” the authors said.
Effects on organ systems vary
The study is the first to systematically examine dermatomyositis sine dermatitis, said David Fiorentino, MD, PhD, professor of dermatology and director of the multidisciplinary rheumatic skin disease clinic at the Stanford (Calif.) University.
On the one hand, the results are not surprising because dermatomyositis is a systemic autoimmune disease. “There are no rules about which organs it will or won’t affect in a given individual,” Dr. Fiorentino said in an interview.
At the same time, dermatomyositis’s historical association with rash persists even though there is “no biological reason why that would have to be the case.”
Some patients with dermatomyositis have skin-predominant disease without clinically significant muscle involvement. Lung-predominant disease also may exist, although it has not been carefully studied, he said.
The findings remind clinicians that they need to consider the diagnosis of dermatomyositis “even if they do not have the skin findings,” he said. Dr. Fiorentino cautioned against interpreting the results to mean that certain patients never have signs of cutaneous inflammation. In the study, about a one-third of patients without dermatitis at the time of biopsy developed a rash. In addition, clinicians often miss subtle disease under the fingernails or on the scalp, or mild rash on the elbows.
The cohort of patients who underwent muscle biopsy may not be representative of the spectrum of patients with dermatomyositis, and the findings need to be verified in other populations, Dr. Fiorentino said.
The study was supported by an intramural research grant of the National Center of Neurology and Psychiatry and a grant from the Japan Society for the Promotion of Science. Authors disclosed personal fees from pharmaceutical companies and government and corporate grants outside the submitted work. Dr. Fiorentino had no relevant disclosures.
SOURCE: Inoue M et al. JAMA Neurol. 2020 Apr 20. doi: 10.1001/jamaneurol.2020.0673.
FROM JAMA NEUROLOGY