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How Do Cognitively Normal Adults Understand Elevated Brain Amyloid Results?
Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”
“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.
Trials in Asymptomatic Populations
Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”
To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).
The researchers conducted two semistructured telephone interviews with 80 participants from nine study sites. Fifty of the participants had elevated amyloid PET scan results and 30 had not-elevated amyloid PET scan results. Researchers conducted the interviews about four to 12 weeks after result disclosure and one year later. The present study examined the first interviews of 50 participants with elevated amyloid results.
Of the 50 participants, 49 (98%) were white, 40 (80%) had a family history of Alzheimer’s disease, and 30 (60%) had a postgraduate educational level. Patients were between ages 65 and 85, and half were men. Data were collected between November 5, 2014, and December 10, 2015.
The A4 Study and SOKRATES
SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.
Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.
A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.
The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”
Understanding Risk
When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).
More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.
When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.
Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.
Implications
The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”
A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.
Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.
Potential Interventions and Ethical Concerns
The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”
Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”
“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment
Suggested Reading
Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.
Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.
Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”
“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.
Trials in Asymptomatic Populations
Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”
To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).
The researchers conducted two semistructured telephone interviews with 80 participants from nine study sites. Fifty of the participants had elevated amyloid PET scan results and 30 had not-elevated amyloid PET scan results. Researchers conducted the interviews about four to 12 weeks after result disclosure and one year later. The present study examined the first interviews of 50 participants with elevated amyloid results.
Of the 50 participants, 49 (98%) were white, 40 (80%) had a family history of Alzheimer’s disease, and 30 (60%) had a postgraduate educational level. Patients were between ages 65 and 85, and half were men. Data were collected between November 5, 2014, and December 10, 2015.
The A4 Study and SOKRATES
SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.
Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.
A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.
The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”
Understanding Risk
When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).
More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.
When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.
Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.
Implications
The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”
A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.
Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.
Potential Interventions and Ethical Concerns
The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”
Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”
“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment
Suggested Reading
Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.
Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.
Most cognitively normal adults with elevated brain amyloid in an Alzheimer’s disease prevention trial “understood that elevated amyloid conferred an increased but uncertain risk of developing Alzheimer’s disease,” according to research published in the January issue of JAMA Neurology. Some participants, however, “desired clarification of the term ‘elevated’ beyond its being a categorical result enabling trial entry eligibility.”
“Clinicians should be prepared to explain how and why a dimensional biomarker, in this case amyloid-β as measured using PET, is converted to a categorical state … and what the result means in terms of a person’s risk for developing Alzheimer disease dementia,” the researchers said.
Trials in Asymptomatic Populations
Advances in understanding the pathophysiology of Alzheimer’s disease have led to clinical trials in cognitively normal adults with evidence of Alzheimer’s disease biomarkers, but data are limited regarding how cognitively normal adults, comprehend biomarker results. A person’s knowledge of his or her amyloid status “may generate clinical and ethical problems, including the potential for misunderstanding, discrimination, stigma, depression, anxiety, and, in the most extreme cases, suicide in the face of a debilitating disease with no treatment,” the researchers said. “There is no consensus … about whether and how to return Alzheimer’s disease biomarker results to cognitively normal adults, given the prognostic uncertainty and absence of available treatments.”
To determine participants’ comprehension of an elevated amyloid PET biomarker result, Jessica Mozersky, PhD, of the Department of Medical Ethics and Health Policy at Perelman School of Medicine, University of Pennsylvania in Philadelphia, and colleagues conducted the Study of Knowledge and Reactions to Amyloid Testing (SOKRATES).
The researchers conducted two semistructured telephone interviews with 80 participants from nine study sites. Fifty of the participants had elevated amyloid PET scan results and 30 had not-elevated amyloid PET scan results. Researchers conducted the interviews about four to 12 weeks after result disclosure and one year later. The present study examined the first interviews of 50 participants with elevated amyloid results.
Of the 50 participants, 49 (98%) were white, 40 (80%) had a family history of Alzheimer’s disease, and 30 (60%) had a postgraduate educational level. Patients were between ages 65 and 85, and half were men. Data were collected between November 5, 2014, and December 10, 2015.
The A4 Study and SOKRATES
SOKRATES is a substudy of the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, which is testing whether solanezumab, compared with placebo, affects the rate of cognitive decline in cognitively normal adults with elevated amyloid.
Clinicians informed all A4 study participants of their amyloid PET scan result through a disclosure process that was designed to maximize safety and effectiveness. The process included a depression and anxiety prescreen, an educational session, a teach-back exercise to check comprehension, an in-person disclosure by a trained clinician, and a telephone follow-up to assess mood. In addition, a study guide provided information about the amyloid PET scan, its purpose, possible results, and limitations. “The study guide describes ‘preclinical’ or ‘asymptomatic’ Alzheimer’s disease as a new concept in development and explains that elevated amyloid ‘does not necessarily mean you will develop Alzheimer’s disease-related memory loss’ but can be associated with an increased risk, and individual risk estimates are not possible. It further explains that ‘not elevated’ does not mean you will never develop Alzheimer’s disease or ‘elevated amyloid’ in the future,” the researchers said.
A4 trial sites provided participants with materials describing the SOKRATES substudy, and interested participants contacted the SOKRATES researchers at the University of Pennsylvania.
The researchers examined comprehension of an elevated amyloid PET scan result by analyzing participants’ responses to the following questions: “What was the result of your amyloid PET scan?” (followed by “Can you tell me in your own words what that means?” or “How would you explain it to a friend?”), “Was it the result you expected?” and “Did the result teach you anything or clarify anything for you?”
Understanding Risk
When asked, “What was your result,” 64% used the word “amyloid” or “amyloids,” and the remaining participants primarily referred to the presence of “plaques” or to the result being “positive.” Two answers suggested misunderstanding. Six participants used the word “elevated” to describe their amyloid result, while most participants used other words (eg, “increased,” “higher levels,” or “excessive”). Nineteen participants described the result in terms of qualifying for the A4 study (eg, “enough amyloid buildup to qualify for the study”).
More than half of the participants (54%) expected their elevated result due to a family history of Alzheimer’s disease or subjective memory problems. Fifteen participants (30%) were unsure what result they had expected or were prepared for either result. Eight participants (16%) expected not to have elevated amyloid because they had led a healthy lifestyle, had no family history of Alzheimer’s disease, and had no subjective memory concerns.
When asked about the meaning of the result, 94% responded with their understanding of the risk of developing Alzheimer’s disease conferred by elevated amyloid. Thirty-one participants (62%) interpreted the result as signaling an increased risk of developing Alzheimer’s disease, while 10 participants (20%) perceived the risk conferred by elevated amyloid to be equivocal. Six participants (12%) perceived elevated amyloid to mean that Alzheimer’s disease was imminent or that it was diagnostic of Alzheimer’s disease.
Twenty participants (40%) were dissatisfied “with the lack of specificity regarding the meaning of ‘elevated,’” the researchers said. Some wanted “a granular result describing the degree of amyloid elevation … and how close they were to the threshold for study entry,” and some participants expressed frustration at the lack of detail.
Implications
The results suggest that some people who are cognitively normal but have subjective memory concerns “will use an Alzheimer’s disease biomarker test to explain their memory concerns, potentially pathologizing normal and nondisease-related cognitive aging,” the researchers said. In addition, people without a family history of Alzheimer’s disease or subjective memory concerns “may be unprepared to receive their biomarker results.”
A desire for more specific and detailed information about the results may be especially relevant to cognitively normal adults. “Such specific information is likely less relevant for symptomatic individuals who receive a binary result that either confirms or rules out a diagnosis that explains their history of cognitive decline,” the researchers said.
Because most participants were highly educated and had a family history of Alzheimer’s disease, the applicability of the results to other populations is limited. In future studies, the researchers plan to assess how elevated versus not-elevated brain amyloid results influenced SOKRATES participants’ sense of self, social relationships, and behaviors.
Potential Interventions and Ethical Concerns
The long prodromal period of Alzheimer’s disease “represents our greatest hope for effective therapeutic intervention as well as a domain of serious ethical concern,” said Winston Chiong, MD, PhD, of the Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, in an accompanying editorial. “Prevailing appropriate use criteria advise against clinical use of amyloid imaging in asymptomatic individuals, citing ‘a significant potential for patients and families to make inaccurate assumptions about risk and future outcomes on the basis of amyloid PET results.’” The A4 trial, however, “not only requires that amyloid imaging be performed but also effectively requires that the results of such imaging be disclosed to participants.”
Qualitative research may elicit unanticipated beliefs or concerns, and in SOKRATES, “a sizable proportion of participants … expressed dissatisfaction with the categorical characterization of results.”
“Overall, the findings of Mozersky and colleagues are broadly reassuring regarding research participants’ ability to understand the prognostic uncertainty of amyloid imaging. But as the authors note, caution is needed in generalizing their results,” Dr. Chiong said. “These participants represent a selected subpopulation of an already rarified group: prospective participants in the A4 study were provided with study materials for this substudy, and interested participants themselves contacted the study investigators. These participants were thus likely to be particularly supportive of the Alzheimer’s disease research enterprise, and given their family histories and high educational attainment
Suggested Reading
Chiong W. Challenges in communicating and understanding predictive biomarker imaging for Alzheimer disease. JAMA Neurol. 2018;75(1):18-19.
Mozersky J, Sankar P, Harkins K, et al. Comprehension of an elevated amyloid positron emission tomography biomarker result by cognitively normal older adults. JAMA Neurol. 2018;75(1):44-50.
MAGNIMS and McDonald Criteria Have Similar Accuracy
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”
An Effort to Draft Revisions
In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.
Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.
MRI Abnormalities May Not Indicate MS
As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”
Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.
—Doug Brunk
Suggested Reading
Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”
An Effort to Draft Revisions
In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.
Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.
MRI Abnormalities May Not Indicate MS
As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”
Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.
—Doug Brunk
Suggested Reading
Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
The 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria have accuracy similar to that of the 2010 McDonald criteria in predicting the development of clinically definite multiple sclerosis (MS), according to a retrospective study.
“Among the different modifications proposed, our results support removal of the distinction between symptomatic and asymptomatic lesions, which simplifies the clinical use of MRI criteria, and suggest that further consideration be given to increasing the number of lesions needed to define periventricular involvement from one to three, because this might slightly increase specificity,” said Massimo Filippi, MD, of the neuroimaging research unit in the division of neuroscience at San Raffaele Scientific Institute at Vita-Salute San Raffaele University in Milan, and colleagues. The report was published online ahead of print December 21, 2017, in Lancet Neurology. “Further effort is still needed to improve cortical lesion assessment, and more studies should be done to evaluate the effect of including optic nerve assessment as an additional dissemination in space [DIS] criterion.”
An Effort to Draft Revisions
In an effort to guide revisions of MS diagnostic criteria, Dr. Filippi and other members of the MAGNIMS network compared the performance of the 2010 McDonald and 2016 MAGNIMS criteria for MS in a cohort of 368 patients with clinically isolated syndrome (CIS) who were screened between June 16, 1995, and January 27, 2017. They used a time-dependent receiver operating characteristic curve analysis to evaluate MRI criteria performance for DIS, dissemination in time (DIT), and DIS plus DIT. Changes to the DIS definition contained in the 2016 MAGNIMS criteria included removal of the distinction between symptomatic and asymptomatic lesions, increasing the number of lesions needed to define periventricular involvement to three, combining cortical and juxtacortical lesions, and inclusion of optic nerve evaluation. For DIT, removal of the distinction between symptomatic and asymptomatic lesions was suggested.
Dr. Filippi and his coauthors at eight centers reported that 189 (51%) of the 368 patients had developed clinically definite MS by the last evaluation, which occurred at a median of 50 months from baseline. At 36 months, DIS alone showed high sensitivity in the 2010 McDonald and 2016 MAGNIMS criteria (91% vs 93%, respectively), similar specificity (33% vs 32%), and similar area under the curve values (AUC, 0.62 vs 0.63). Inclusion of symptomatic lesions did not alter performance. The researchers also found that requiring three periventricular lesions reduced sensitivity to 85% and increased specificity to 40%, but did not affect AUC values (AUC, 0.63). When optic nerve evaluation was included, sensitivity was similar (92%), while specificity decreased to 26%, and AUC declined to 0.59.
The 2016 MAGNIMS and 2010 McDonald criteria achieved similar sensitivity, specificity, and AUC values when compared on the performance of DIT criteria and DIS plus DIT criteria.
“For both sets of criteria, specificity was lower than that of previous studies that evaluated the diagnostic performance of the 2010 McDonald criteria,” the authors wrote. “Several factors could help explain our findings, including the different follow-up durations, the statistical methods (eg, using a time-to-event analysis in our study), and the effect of treatment, which might have delayed or prevented the occurrence of the second attack during the study period.” They acknowledged certain limitations of the study, including its retrospective design and the fact that patients were recruited in highly specialized centers, which may have resulted in the selection of patients at higher risk of conversion to clinically definite MS.
MRI Abnormalities May Not Indicate MS
As MS diagnosis evolves, revisions to existing diagnostic criteria have increased sensitivity, thus helping clinicians establish earlier diagnoses. Although the study by Dr. Filippi et al showed that for both sets of MRI criteria, sensitivity was greater than specificity for predicting clinically definite MS, the modest specificity is cause for concern, said Anne H. Cross, MD, Head of the Neuroimmunology (MS) Section, and Robert N. Naismith, MD, Associate Professor of Neurology, both at Washington University in St. Louis, in an accompanying editorial. They cited one study that emphasized the importance of not misdiagnosing other CNS diseases as MS. “In that study at four academic medical centers, 110 people seen over a period of less than 1.5 years were found to have been misdiagnosed,” said Drs. Cross and Naismith. “[Seventy percent] of the 110 individuals had received disease-modifying therapy, and 31% had unnecessary morbidity. Leading factors contributing to erroneous diagnosis in the study included overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms.”
Vascular and other diseases can cause MRI abnormalities that could meet the 2016 MAGNIMS recommendations or the 2010 and 2017 McDonald MRI criteria, the authors continued. For example, patients with monophasic inflammatory and infectious diseases might have gadolinium-enhancing lesions that meet the 2017 McDonald criteria for DIT, which require only the simultaneous presence of gadolinium-enhancing and gadolinium-negative lesions in the proper locations. For patients with an atypical presentation who meet the 2010 and 2017 McDonald or 2016 MAGNIMS recommendations, clinicians should weigh all of the observed imaging features (including the number of periventricular lesions, along with lesion size, shape, and location) to improve diagnostic specificity and help to limit misdiagnoses, they concluded.
—Doug Brunk
Suggested Reading
Cross AH, Naismith RT. Refining the use of MRI to predict multiple sclerosis. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
Filippi M, Preziosa P, Meani A, et al. Prediction of a multiple sclerosis diagnosis in patients with clinically isolated syndrome using the 2016 MAGNIMS and 2010 McDonald criteria: a retrospective study. Lancet Neurol. 2017 Dec 21 [Epub ahead of print].
Epilepsy Drug May Reduce Risk of Recurrent Stroke
The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.
The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.
An Analysis of Three Large Cohort Studies
Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.
Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.
Valproate Halved Risk of Recurrent Stroke
In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.
Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.
For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.
Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).
“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”
—Erik Greb
Suggested Reading
Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.
The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.
The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.
An Analysis of Three Large Cohort Studies
Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.
Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.
Valproate Halved Risk of Recurrent Stroke
In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.
Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.
For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.
Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).
“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”
—Erik Greb
Suggested Reading
Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.
The antiepileptic drug (AED) sodium valproate may reduce the risk of recurrent ischemic stroke, according to data published in the January issue of Stroke. The treatment deserves further evaluation, according to investigators. A randomized controlled trial could confirm its effect on the risk of recurrent stroke, they said.
The Wellcome Trust Case Control Consortium 2 genome-wide association study found an association between a mutation in HDAC9 and an increased risk of ischemic stroke resulting from large artery disease. Valproate is a nonspecific inhibitor of HDAC9 activity and attenuates atherosclerosis in mice deficient in apolipoprotein E. Two large studies found an association between valproate and a decreased risk of incident stroke.
An Analysis of Three Large Cohort Studies
Hugh S. Markus, DM, lead author of the article and a neurologist in the Stroke Research Group at the University of Cambridge in the United Kingdom, and colleagues hypothesized that inhibiting HDAC9 activity could prevent large artery atherosclerotic ischemic stroke. To test this hypothesis, they examined data from three large cohort studies—the South London Stroke Register, the Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. These prospective studies enrolled patients with stroke or transient ischemic attack and had long follow-up periods.
Dr. Markus and colleagues chose recurrent stroke as their primary end point. They examined prescription data for AEDs, as well as other variables such as study, age, sex, and diagnosis of epilepsy. The researchers examined the data using survival analysis and Cox regression.
Valproate Halved Risk of Recurrent Stroke
In all, 11,949 patients were included in the pooled analysis. A total of 168 participants received valproate, and 530 received other AEDs. Recurrent stroke occurred in 17 patients receiving valproate, 1,470 of 11,781 participants who never were prescribed valproate, 105 patients receiving other AEDs, and 1,426 of 11,312 patients not prescribed AEDs.
Throughout follow-up, stroke-free survival was greater among participants receiving valproate than among other participants. At year 15, stroke-free survival was 86% among patients receiving valproate, compared with 74% among patients without valproate exposure.
For nonselective control populations, the difference in survival between valproate exposure and nonexposure was not significant, but the difference between valproate exposure and exposure to other AEDs was significant. For selective control populations, the difference in survival between valproate exposure and no AED exposure was not significant, nor was the difference between valproate exposure and other AED exposure.
Cox hazard models adjusted for all covariates indicated that valproate was associated with a reduced risk of stroke, compared with all patients without valproate exposure (hazard ratio [HR], 0.50). In addition, valproate exposure was associated with reduced risk of stroke, compared with the group prescribed other AEDs (HR, 0.41).
“Although the design of our study is prone to systematic and random error and cannot infer causality, the results provide some evidence for the prestudy hypothesis and suggest that sodium valproate ... may be associated with a reduced stroke recurrence rate,” said Dr. Markus and colleagues. “Sodium valproate is a nonspecific HDAC inhibitor (inhibiting a wide range of HDACs) and has other actions independent of HDAC9 inhibition. Hence, a more specific inhibitor of HDAC9 might have a stronger effect in reducing the risk of recurrent stroke.”
—Erik Greb
Suggested Reading
Brookes RL, Crichton S, Wolfe CDA, et al. Sodium valproate, a histone deacetylase inhibitor, is associated with reduced stroke risk after previous ischemic stroke or transient ischemic attack. Stroke. 2018;49(1):54-61.
Rituximab May Provide Greater Benefits Than Other First-Line MS Therapies
Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.
The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.
The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
—Andrew D. Bowser
Suggested Reading
Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].
Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.
The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.
The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
—Andrew D. Bowser
Suggested Reading
Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].
Rituximab is associated with a lower drug discontinuation rate than all other commonly prescribed disease-modifying treatments (DMTs) used as initial therapy for relapsing-remitting multiple sclerosis (MS), according to a retrospective study of patient data from a Swedish MS registry.
In addition, relapse rates were lower with rituximab (Rituxan) than they were with injectable DMTs and dimethyl fumarate (Tecfidera), according to the study, which was published online ahead of print January 8 in JAMA Neurology.
The results suggest that rituximab “can be considered an option” for treatment-naive patients with relapsing-remitting MS, according to Mathias Granqvist, MD, a graduate student in the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, and his coauthors.
Anti-CD20 agents such as rituximab are “likely to become an additional treatment option” for relapsing-remitting MS, and off-label use of rituximab for this indication has “increased considerably” in Sweden in recent years, the investigators said. Relapsing-remitting MS is not an approved indication for rituximab in the United States, but in Sweden “there is no difference in reimbursement policy ... because all DMTs are covered by the national health insurance, including off-label medications.”
The emergence of new DMTs for relapsing-remitting MS has changed the treatment landscape recently, although in real-world practice, there is a lack of “detailed knowledge about how to tailor therapy,” the authors said. They noted that the majority of patients discontinue traditional first-line treatment with injectable DMTs (ie, interferon beta and glatiramer acetate) within two years, suggesting a need for better treatment options.
To evaluate the real-world effectiveness of rituximab in this setting, Dr. Granqvist and his colleagues selected patient registry data for two Swedish counties that included 494 participants who received a diagnosis of relapsing-remitting MS between January 1, 2012, and October 31, 2015.
The largest subset of patients (215) received injectable DMTs, while 120 received rituximab, 86 received dimethyl fumarate, 50 received natalizumab (Tysabri), 17 received fingolimod (Gilenya), and six received other treatments, according to the authors.
The proportion of patients who stayed on treatment was significantly higher for rituximab versus all other DMTs. Compared with rituximab, the hazard ratios for drug discontinuation, after adjusting for covariates and propensity score, were 11.4 for injectable DMTs, 15.1 for dimethyl fumarate, 5.9 for fingolimod, and 11.3 for natalizumab.
Rituximab-treated patients also had lower rates of clinical relapse, neuroradiologic disease activity, and adverse events, compared with patients who received injectable DMTs or dimethyl fumarate, according to the investigators.
In comparison with fingolimod and natalizumab, rituximab was associated with lower relapse rates and fewer gadolinium-enhancing lesions, but those differences did not reach statistical significance in all analyses.
The study was funded by the Swedish Medical Research Council, among other sources. Study authors reported conflicts of interest related to Biogen, Novartis, and Genzyme.
—Andrew D. Bowser
Suggested Reading
Granqvist M, Boremalm M, Poorghobad A, et al. Comparative effectiveness of rituximab and other initial treatment choices for multiple sclerosis. JAMA Neurol. 2018 Jan 8 [Epub ahead of print].
Life Expectancy Varies by Epilepsy Type
Compared with the general population, patients with newly diagnosed symptomatic epilepsy have reduced life expectancy, according to an investigation published in the November 2017 issue of Epilepsia. Patients with newly diagnosed idiopathic or cryptogenic epilepsy, however, have a normal or prolonged life expectancy. The year of diagnosis and the type of epilepsy appear to influence life expectancy.
Previous Estimates Had Weaknesses
Many studies have suggested increased mortality among patients with epilepsy. Two previous investigations have reported the more specific measure of life expectancy in epilepsy, but both had methodologic weaknesses and were prone to substantial bias, said Claudia A. Granbichler, MD, PhD, a neurology resident in Tel-Aviv.
Dr. Granbichler and colleagues examined data for all patients visiting the epilepsy outpatient clinic of Innsbruck Medical University in Austria to calculate their life expectancy. They included 1,112 adults who presented between January 1, 1970, and December 31, 2010, in their analysis. Patient data were recorded and updated continuously over time. Dr. Granbichler and colleagues compared patients’ life expectancies at the year of diagnosis and at five, 10, 15, and 20 years following diagnosis to those of the general population.
The authors classified patients’ epilepsies as symptomatic, idiopathic, or cryptogenic. They defined symptomatic epilepsy as the result of a known or suspected CNS disorder. Epilepsies not preceded by another disorder were considered idiopathic. The authors defined epilepsies of unknown cause as cryptogenic.
Life Expectancy Improved With Time
The difference in life expectancy between patients with epilepsy and the general population depended on the type of epilepsy and the time of diagnosis. Between 1970 and 1980, patients diagnosed with symptomatic epilepsy had a substantially greater reduction in life expectancy (–7.4 years in women and –7.2 years in men) than people diagnosed with idiopathic epilepsy (–5.5 years in women and –5.2 years in men) and people diagnosed with cryptogenic epilepsy (–1.8 years in women and –1.4 years in men).
Regardless of the type of epilepsy, patients diagnosed in subsequent decades had progressively smaller reductions in life expectancy, relative to the general population, or prolonged life expectancy. For all three groups, life expectancy increased with increasing duration of epilepsy.
Participants diagnosed with cryptogenic epilepsy between 2001 and 2010 had increased life expectancy, compared with the general population (2.5 years in women and 3.4 years in men). This increased life expectancy could be explained by lower mortality resulting from decreased engagement in risky activities such as driving motorcycles, skiing, and mountain climbing, said Dr. Granbichler. People with epilepsy also may benefit from more frequent medical follow-ups and laboratory testing.
A potential limitation of the study is that patients had different follow-up durations because of their varying dates of entry and the investigation’s fixed end date. The comparatively short follow-up duration may have introduced positive bias into the estimates of life expectancy for patients diagnosed after 2000, said Dr. Granbichler.
—Erik Greb
Suggested Reading
Granbichler CA, Zimmermann G, Oberaigner W, et al. Potential years lost and life expectancy in adults with newly diagnosed epilepsy. Epilepsia. 2017;58(11):1939-1945.
Compared with the general population, patients with newly diagnosed symptomatic epilepsy have reduced life expectancy, according to an investigation published in the November 2017 issue of Epilepsia. Patients with newly diagnosed idiopathic or cryptogenic epilepsy, however, have a normal or prolonged life expectancy. The year of diagnosis and the type of epilepsy appear to influence life expectancy.
Previous Estimates Had Weaknesses
Many studies have suggested increased mortality among patients with epilepsy. Two previous investigations have reported the more specific measure of life expectancy in epilepsy, but both had methodologic weaknesses and were prone to substantial bias, said Claudia A. Granbichler, MD, PhD, a neurology resident in Tel-Aviv.
Dr. Granbichler and colleagues examined data for all patients visiting the epilepsy outpatient clinic of Innsbruck Medical University in Austria to calculate their life expectancy. They included 1,112 adults who presented between January 1, 1970, and December 31, 2010, in their analysis. Patient data were recorded and updated continuously over time. Dr. Granbichler and colleagues compared patients’ life expectancies at the year of diagnosis and at five, 10, 15, and 20 years following diagnosis to those of the general population.
The authors classified patients’ epilepsies as symptomatic, idiopathic, or cryptogenic. They defined symptomatic epilepsy as the result of a known or suspected CNS disorder. Epilepsies not preceded by another disorder were considered idiopathic. The authors defined epilepsies of unknown cause as cryptogenic.
Life Expectancy Improved With Time
The difference in life expectancy between patients with epilepsy and the general population depended on the type of epilepsy and the time of diagnosis. Between 1970 and 1980, patients diagnosed with symptomatic epilepsy had a substantially greater reduction in life expectancy (–7.4 years in women and –7.2 years in men) than people diagnosed with idiopathic epilepsy (–5.5 years in women and –5.2 years in men) and people diagnosed with cryptogenic epilepsy (–1.8 years in women and –1.4 years in men).
Regardless of the type of epilepsy, patients diagnosed in subsequent decades had progressively smaller reductions in life expectancy, relative to the general population, or prolonged life expectancy. For all three groups, life expectancy increased with increasing duration of epilepsy.
Participants diagnosed with cryptogenic epilepsy between 2001 and 2010 had increased life expectancy, compared with the general population (2.5 years in women and 3.4 years in men). This increased life expectancy could be explained by lower mortality resulting from decreased engagement in risky activities such as driving motorcycles, skiing, and mountain climbing, said Dr. Granbichler. People with epilepsy also may benefit from more frequent medical follow-ups and laboratory testing.
A potential limitation of the study is that patients had different follow-up durations because of their varying dates of entry and the investigation’s fixed end date. The comparatively short follow-up duration may have introduced positive bias into the estimates of life expectancy for patients diagnosed after 2000, said Dr. Granbichler.
—Erik Greb
Suggested Reading
Granbichler CA, Zimmermann G, Oberaigner W, et al. Potential years lost and life expectancy in adults with newly diagnosed epilepsy. Epilepsia. 2017;58(11):1939-1945.
Compared with the general population, patients with newly diagnosed symptomatic epilepsy have reduced life expectancy, according to an investigation published in the November 2017 issue of Epilepsia. Patients with newly diagnosed idiopathic or cryptogenic epilepsy, however, have a normal or prolonged life expectancy. The year of diagnosis and the type of epilepsy appear to influence life expectancy.
Previous Estimates Had Weaknesses
Many studies have suggested increased mortality among patients with epilepsy. Two previous investigations have reported the more specific measure of life expectancy in epilepsy, but both had methodologic weaknesses and were prone to substantial bias, said Claudia A. Granbichler, MD, PhD, a neurology resident in Tel-Aviv.
Dr. Granbichler and colleagues examined data for all patients visiting the epilepsy outpatient clinic of Innsbruck Medical University in Austria to calculate their life expectancy. They included 1,112 adults who presented between January 1, 1970, and December 31, 2010, in their analysis. Patient data were recorded and updated continuously over time. Dr. Granbichler and colleagues compared patients’ life expectancies at the year of diagnosis and at five, 10, 15, and 20 years following diagnosis to those of the general population.
The authors classified patients’ epilepsies as symptomatic, idiopathic, or cryptogenic. They defined symptomatic epilepsy as the result of a known or suspected CNS disorder. Epilepsies not preceded by another disorder were considered idiopathic. The authors defined epilepsies of unknown cause as cryptogenic.
Life Expectancy Improved With Time
The difference in life expectancy between patients with epilepsy and the general population depended on the type of epilepsy and the time of diagnosis. Between 1970 and 1980, patients diagnosed with symptomatic epilepsy had a substantially greater reduction in life expectancy (–7.4 years in women and –7.2 years in men) than people diagnosed with idiopathic epilepsy (–5.5 years in women and –5.2 years in men) and people diagnosed with cryptogenic epilepsy (–1.8 years in women and –1.4 years in men).
Regardless of the type of epilepsy, patients diagnosed in subsequent decades had progressively smaller reductions in life expectancy, relative to the general population, or prolonged life expectancy. For all three groups, life expectancy increased with increasing duration of epilepsy.
Participants diagnosed with cryptogenic epilepsy between 2001 and 2010 had increased life expectancy, compared with the general population (2.5 years in women and 3.4 years in men). This increased life expectancy could be explained by lower mortality resulting from decreased engagement in risky activities such as driving motorcycles, skiing, and mountain climbing, said Dr. Granbichler. People with epilepsy also may benefit from more frequent medical follow-ups and laboratory testing.
A potential limitation of the study is that patients had different follow-up durations because of their varying dates of entry and the investigation’s fixed end date. The comparatively short follow-up duration may have introduced positive bias into the estimates of life expectancy for patients diagnosed after 2000, said Dr. Granbichler.
—Erik Greb
Suggested Reading
Granbichler CA, Zimmermann G, Oberaigner W, et al. Potential years lost and life expectancy in adults with newly diagnosed epilepsy. Epilepsia. 2017;58(11):1939-1945.
Surgery or Medical Management for Refractory Pediatric Epilepsy?
Children and adolescents with drug-resistant epilepsy who undergo surgery appear to have significantly higher rates of seizure freedom and better quality of life and behavior scores at 12 months than those who receive medical therapy alone, according to a study published in the October 26, 2017, issue of the New England Journal of Medicine. Serious anticipated adverse events may occur after surgery, however.
“The improvements that were observed in other cognitive, behavioral, and quality of life scores in the surgery group may have been due to a reduction in the frequency of seizures; conversely, the deterioration in these measures in the medical-therapy group may be attributed to a continuation of seizures,” said Rekha Dwivedi, PhD, a postdoctoral fellow at the All India Institute of Medical Sciences in New Delhi, and colleagues.
Comparing Methods Intended to Improve Outcomes
Children and adolescents with drug-resistant epilepsy have an increased risk of poor long-term intellectual and psychosocial outcomes, along with a poor health-related quality of life. Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but evidence of benefit from randomized trials in this age group is limited.
A meta-analysis of uncontrolled studies comparing seizure outcomes of surgeries in children indicated that 74% of patients with brain lesions and 45% without lesions had become seizure-free at one year of follow-up. In a retrospective analysis involving 142 children and adolescents with drug-resistant epilepsy who had undergone surgery, 79.3% of patients were free from disabling seizures after a mean follow-up of approximately four years.
To investigate the effects of surgery further, Dr. Dwivedi and colleagues performed a single-center trial. They sought to compare epilepsy surgery with continued medical therapy alone in patients on a waiting list for surgery.
Researchers randomized 116 patients age 18 or younger with drug-resistant epilepsy to brain surgery appropriate to the underlying cause of epilepsy, along with appropriate medical therapy, or to medical therapy alone. Patients for whom there was no consensus regarding the location of an epileptic focus, patients who had any other systemic illness, and patients with a history of status epilepticus were excluded.
Participants assigned to the surgery group underwent the procedure within a month after randomization. Those assigned to the medical-therapy group remained on a waiting list. Surgery for these patients was scheduled for one year or longer after randomization. The primary outcome was seizure freedom at 12 months. Secondary outcomes included the Hague Seizure Severity scale score, the Binet–Kamat intelligence quotient or the social quotient on the Vineland Social Maturity Scale, the T score on the Child Behavior Checklist, and the Pediatric Quality of Life Inventory score.
Most of the Surgery Group Became Seizure-Free at 12 Months
Median age was 9 in the surgery group and 10 in the medical-therapy group. In all, 14 patients had temporal lobe resections, 12 patients had resection of a lesion in a lobe other than the temporal lobe, 15 patients had hemispherotomy, 10 patients had a corpus callosotomy, and six patients had a disconnection or resection of hypothalamic hamartoma.
At 12 months, 44 of 57 patients (77%) in the surgery group became seizure-free, compared with four of 59 patients (7%) in the medical-therapy group. Furthermore, 21 patients (37%) in the surgery group were completely seizure-free during the entire 12-month period.
All patients who had undergone temporal lobectomy or hypothalamic hamartoma surgeries were seizure-free at the last follow-up. Of the patients who had undergone extratemporal resection or hemispherotomy, 11 of 12 patients (92%) and 13 of 15 (87%), had complete freedom from seizures, respectively.
Two of 15 patients (13%) in the medical-therapy group who were on the waiting list for a temporal lobectomy were seizure-free at 12 months, along with one of 19 patients (5%) who were on a waiting list for extratemporal resection and one of 16 patients (6%) who were waiting for a corpus callostomy. Patients with a planned hemispherotomy or intervention for hypothalamic hamartoma were not seizure-free at 12 months.
In addition, between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the Hague Seizure Severity scale score, the Child Behavior Checklist, the Pediatric Quality of Life Inventory, and the Vineland Social Maturity Scale, but not the Binet–Kamat intelligence quotient, said the researchers.
Adverse Events and Study Limitations
Serious adverse events occurred in 19 patients (33%) in the surgery group and no patients in the medical-therapy group. Monoparesis occurred in two patients who had undergone temporal lobectomy or resection of parietal focal cortical dysplasia. Hemiparesis occurred in 15 patients who had undergone hemispherotomy. Finally, generalized hypotonia and language deficits occurred in one patient who had undergone frontal lobectomy.
Ten patients in the medical-therapy group had physical injuries associated with seizures (eg, cuts, burns, and fractures). One patient had an adverse event associated with an antiepileptic drug, and autistic features developed in another patient. No deaths occurred in either group.
One study limitation was that patients included in this trial underwent many types of epilepsy surgeries to treat various underlying pathologic causes of seizures. Another limitation was that there was an overrepresentation of hypothalamic hamartomas, compared with some other series, said the researchers.
—Erica Tricarico
Suggested Reading
Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. N Engl J Med. 2017;377(17):1639-1647.
Children and adolescents with drug-resistant epilepsy who undergo surgery appear to have significantly higher rates of seizure freedom and better quality of life and behavior scores at 12 months than those who receive medical therapy alone, according to a study published in the October 26, 2017, issue of the New England Journal of Medicine. Serious anticipated adverse events may occur after surgery, however.
“The improvements that were observed in other cognitive, behavioral, and quality of life scores in the surgery group may have been due to a reduction in the frequency of seizures; conversely, the deterioration in these measures in the medical-therapy group may be attributed to a continuation of seizures,” said Rekha Dwivedi, PhD, a postdoctoral fellow at the All India Institute of Medical Sciences in New Delhi, and colleagues.
Comparing Methods Intended to Improve Outcomes
Children and adolescents with drug-resistant epilepsy have an increased risk of poor long-term intellectual and psychosocial outcomes, along with a poor health-related quality of life. Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but evidence of benefit from randomized trials in this age group is limited.
A meta-analysis of uncontrolled studies comparing seizure outcomes of surgeries in children indicated that 74% of patients with brain lesions and 45% without lesions had become seizure-free at one year of follow-up. In a retrospective analysis involving 142 children and adolescents with drug-resistant epilepsy who had undergone surgery, 79.3% of patients were free from disabling seizures after a mean follow-up of approximately four years.
To investigate the effects of surgery further, Dr. Dwivedi and colleagues performed a single-center trial. They sought to compare epilepsy surgery with continued medical therapy alone in patients on a waiting list for surgery.
Researchers randomized 116 patients age 18 or younger with drug-resistant epilepsy to brain surgery appropriate to the underlying cause of epilepsy, along with appropriate medical therapy, or to medical therapy alone. Patients for whom there was no consensus regarding the location of an epileptic focus, patients who had any other systemic illness, and patients with a history of status epilepticus were excluded.
Participants assigned to the surgery group underwent the procedure within a month after randomization. Those assigned to the medical-therapy group remained on a waiting list. Surgery for these patients was scheduled for one year or longer after randomization. The primary outcome was seizure freedom at 12 months. Secondary outcomes included the Hague Seizure Severity scale score, the Binet–Kamat intelligence quotient or the social quotient on the Vineland Social Maturity Scale, the T score on the Child Behavior Checklist, and the Pediatric Quality of Life Inventory score.
Most of the Surgery Group Became Seizure-Free at 12 Months
Median age was 9 in the surgery group and 10 in the medical-therapy group. In all, 14 patients had temporal lobe resections, 12 patients had resection of a lesion in a lobe other than the temporal lobe, 15 patients had hemispherotomy, 10 patients had a corpus callosotomy, and six patients had a disconnection or resection of hypothalamic hamartoma.
At 12 months, 44 of 57 patients (77%) in the surgery group became seizure-free, compared with four of 59 patients (7%) in the medical-therapy group. Furthermore, 21 patients (37%) in the surgery group were completely seizure-free during the entire 12-month period.
All patients who had undergone temporal lobectomy or hypothalamic hamartoma surgeries were seizure-free at the last follow-up. Of the patients who had undergone extratemporal resection or hemispherotomy, 11 of 12 patients (92%) and 13 of 15 (87%), had complete freedom from seizures, respectively.
Two of 15 patients (13%) in the medical-therapy group who were on the waiting list for a temporal lobectomy were seizure-free at 12 months, along with one of 19 patients (5%) who were on a waiting list for extratemporal resection and one of 16 patients (6%) who were waiting for a corpus callostomy. Patients with a planned hemispherotomy or intervention for hypothalamic hamartoma were not seizure-free at 12 months.
In addition, between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the Hague Seizure Severity scale score, the Child Behavior Checklist, the Pediatric Quality of Life Inventory, and the Vineland Social Maturity Scale, but not the Binet–Kamat intelligence quotient, said the researchers.
Adverse Events and Study Limitations
Serious adverse events occurred in 19 patients (33%) in the surgery group and no patients in the medical-therapy group. Monoparesis occurred in two patients who had undergone temporal lobectomy or resection of parietal focal cortical dysplasia. Hemiparesis occurred in 15 patients who had undergone hemispherotomy. Finally, generalized hypotonia and language deficits occurred in one patient who had undergone frontal lobectomy.
Ten patients in the medical-therapy group had physical injuries associated with seizures (eg, cuts, burns, and fractures). One patient had an adverse event associated with an antiepileptic drug, and autistic features developed in another patient. No deaths occurred in either group.
One study limitation was that patients included in this trial underwent many types of epilepsy surgeries to treat various underlying pathologic causes of seizures. Another limitation was that there was an overrepresentation of hypothalamic hamartomas, compared with some other series, said the researchers.
—Erica Tricarico
Suggested Reading
Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. N Engl J Med. 2017;377(17):1639-1647.
Children and adolescents with drug-resistant epilepsy who undergo surgery appear to have significantly higher rates of seizure freedom and better quality of life and behavior scores at 12 months than those who receive medical therapy alone, according to a study published in the October 26, 2017, issue of the New England Journal of Medicine. Serious anticipated adverse events may occur after surgery, however.
“The improvements that were observed in other cognitive, behavioral, and quality of life scores in the surgery group may have been due to a reduction in the frequency of seizures; conversely, the deterioration in these measures in the medical-therapy group may be attributed to a continuation of seizures,” said Rekha Dwivedi, PhD, a postdoctoral fellow at the All India Institute of Medical Sciences in New Delhi, and colleagues.
Comparing Methods Intended to Improve Outcomes
Children and adolescents with drug-resistant epilepsy have an increased risk of poor long-term intellectual and psychosocial outcomes, along with a poor health-related quality of life. Neurosurgical treatment may improve seizures in children and adolescents with drug-resistant epilepsy, but evidence of benefit from randomized trials in this age group is limited.
A meta-analysis of uncontrolled studies comparing seizure outcomes of surgeries in children indicated that 74% of patients with brain lesions and 45% without lesions had become seizure-free at one year of follow-up. In a retrospective analysis involving 142 children and adolescents with drug-resistant epilepsy who had undergone surgery, 79.3% of patients were free from disabling seizures after a mean follow-up of approximately four years.
To investigate the effects of surgery further, Dr. Dwivedi and colleagues performed a single-center trial. They sought to compare epilepsy surgery with continued medical therapy alone in patients on a waiting list for surgery.
Researchers randomized 116 patients age 18 or younger with drug-resistant epilepsy to brain surgery appropriate to the underlying cause of epilepsy, along with appropriate medical therapy, or to medical therapy alone. Patients for whom there was no consensus regarding the location of an epileptic focus, patients who had any other systemic illness, and patients with a history of status epilepticus were excluded.
Participants assigned to the surgery group underwent the procedure within a month after randomization. Those assigned to the medical-therapy group remained on a waiting list. Surgery for these patients was scheduled for one year or longer after randomization. The primary outcome was seizure freedom at 12 months. Secondary outcomes included the Hague Seizure Severity scale score, the Binet–Kamat intelligence quotient or the social quotient on the Vineland Social Maturity Scale, the T score on the Child Behavior Checklist, and the Pediatric Quality of Life Inventory score.
Most of the Surgery Group Became Seizure-Free at 12 Months
Median age was 9 in the surgery group and 10 in the medical-therapy group. In all, 14 patients had temporal lobe resections, 12 patients had resection of a lesion in a lobe other than the temporal lobe, 15 patients had hemispherotomy, 10 patients had a corpus callosotomy, and six patients had a disconnection or resection of hypothalamic hamartoma.
At 12 months, 44 of 57 patients (77%) in the surgery group became seizure-free, compared with four of 59 patients (7%) in the medical-therapy group. Furthermore, 21 patients (37%) in the surgery group were completely seizure-free during the entire 12-month period.
All patients who had undergone temporal lobectomy or hypothalamic hamartoma surgeries were seizure-free at the last follow-up. Of the patients who had undergone extratemporal resection or hemispherotomy, 11 of 12 patients (92%) and 13 of 15 (87%), had complete freedom from seizures, respectively.
Two of 15 patients (13%) in the medical-therapy group who were on the waiting list for a temporal lobectomy were seizure-free at 12 months, along with one of 19 patients (5%) who were on a waiting list for extratemporal resection and one of 16 patients (6%) who were waiting for a corpus callostomy. Patients with a planned hemispherotomy or intervention for hypothalamic hamartoma were not seizure-free at 12 months.
In addition, between-group differences in the change from baseline to 12 months significantly favored surgery with respect to the Hague Seizure Severity scale score, the Child Behavior Checklist, the Pediatric Quality of Life Inventory, and the Vineland Social Maturity Scale, but not the Binet–Kamat intelligence quotient, said the researchers.
Adverse Events and Study Limitations
Serious adverse events occurred in 19 patients (33%) in the surgery group and no patients in the medical-therapy group. Monoparesis occurred in two patients who had undergone temporal lobectomy or resection of parietal focal cortical dysplasia. Hemiparesis occurred in 15 patients who had undergone hemispherotomy. Finally, generalized hypotonia and language deficits occurred in one patient who had undergone frontal lobectomy.
Ten patients in the medical-therapy group had physical injuries associated with seizures (eg, cuts, burns, and fractures). One patient had an adverse event associated with an antiepileptic drug, and autistic features developed in another patient. No deaths occurred in either group.
One study limitation was that patients included in this trial underwent many types of epilepsy surgeries to treat various underlying pathologic causes of seizures. Another limitation was that there was an overrepresentation of hypothalamic hamartomas, compared with some other series, said the researchers.
—Erica Tricarico
Suggested Reading
Dwivedi R, Ramanujam B, Chandra PS, et al. Surgery for drug-resistant epilepsy in children. N Engl J Med. 2017;377(17):1639-1647.
Generic Glatiramer Acetate Remains Safe and Effective for Two Years
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
Generic glatiramer acetate remains effective and safe over two years of treatment for patients with relapsing-remitting multiple sclerosis (MS), according to data published in the December 2017 issue of Multiple Sclerosis Journal. The data also indicate that switching from branded glatiramer acetate to a generic formulation is safe and well tolerated.
The European Medicines Agency required clinical trial data to support the authorization of generic glatiramer acetate. Krzysztof Selmaj, MD, a neurologist at the Neurology Center Lodz in Poland, and colleagues conducted a nine-month study to assess the equivalence of generic glatiramer acetate with that of Copaxone, a branded formulation of the drug. The double-blind, phase III GATE trial suggested that the drugs had equivalent efficacy, safety, and tolerability.
An Open-Label Extension
Patients who completed the nine-month trial were eligible to continue into a 15-month open-label extension on generic glatiramer acetate. The goals of the extension were to evaluate the effects of long-term exposure to the drug and to assess whether switching from branded to generic glatiramer acetate influenced drug safety and efficacy.
The researchers enrolled 796 patients from 17 countries into the double-blind study. Eligible patients were between ages 18 and 55, had relapsing-remitting MS, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. Patients were randomized to receive 20 mg/mL/day of generic glatiramer acetate, 20 mg/mL/day of branded glatiramer acetate, or matching placebo.
The investigators performed safety evaluations at months 12, 15, 18, 21, and 24. They conducted EDSS scoring and brain MRI scans at months 12, 18, and 24. To assess glatiramer acetate antidrug antibodies, the researchers collected serum samples at baseline and months 1, 3, 6, 9, 12, 18, and 24.
Branded and Generic Formulations Produced Similar Outcomes
In all, 735 participants completed the double-blind study. In addition, 728 patients entered the open-label extension, and 670 completed it.
The proportion of patients completing the trial was 93.8% among patients who received generic treatment throughout, 92.9% among patients who switched from branded to generic, and 81.5% among patients who switched from placebo to generic glatiramer acetate.
The mean number of gadolinium-enhancing lesions was similar at months 12, 18, and 24 for patients who had started the blinded study on generic glatiramer acetate and those who had started on branded glatiramer acetate. The changes in the other MRI outcomes were similar for these two groups.
The estimated annualized relapse rates in the extension study were 0.21 for patients who took generic glatiramer acetate throughout, 0.24 for patients who switched from branded to generic glatiramer acetate, and 0.23 for patients who switched from placebo to generic glatiramer acetate.
The rate of adverse events was similar for patients who took generic glatiramer acetate throughout (33.3%) and those who switched from branded to generic treatment (36.5%). The rate of adverse events was 43.2% among patients who switched from placebo to generic glatiramer acetate. Severe and serious adverse events were uncommon and occurred at similar rates among patients who started on generic treatment and those who started on branded treatment.
During the blinded phase, antidrug antibodies formed with comparable frequency among patients who received generic and branded glatiramer treatment. During the open-label extension, the antidrug antibody titers in the group switching from branded to generic glatiramer treatment remained similar to that of the group continuing on generic treatment.
“These data should help patients and prescribers to positively consider generic glatiramer acetate as an alternative to branded glatiramer acetate,” said Dr. Selmaj.
—Erik Greb
Suggested Reading
Selmaj K, Barkhof F, Belova AN, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler. 2017;23(14):1909-1917.
Surface Electromyography May Detect Generalized Tonic-Clonic Seizures
A wearable surface electromyographic (sEMG) monitoring device may help to detect generalized tonic-clonic seizures (GTCS), according to research published in the November 2017 issue of Epilepsia. The monitoring system provides timely detection of GTCS within an average of 7.7 seconds of the onset of bilateral appendicular tonic motor manifestations.
“Since GTCS can cause patient injury and are associated with SUDEP, the [wearable] device should be useful to provide a method for caretakers to check on patient safety shortly after a GTCS,” said Jonathan J. Halford, MD, Associate Professor of Neurology at the Medical University of South Carolina in Charleston.
The prevalence of active epilepsy is between 0.4% and 1% worldwide. The prevalence of patients with frequent GTCS is unknown, but is estimated at between 10% and 20% of patients with active epilepsy. These patients have the highest risk for injuries, sudden unexpected death in epilepsy (SUDEP), and mortality from any cause. Early detection of GTCS and intervention may help to decrease morbidity and mortality, cases of status epilepticus, and SUDEP.
Evaluating Device Performance and Tolerability
A previous single-site study of an sEMG detection algorithm in an epilepsy monitoring unit detected 95% of 20 GTCS recorded in 11 epilepsy patients with one false positive. To evaluate the performance and tolerability in the epilepsy monitoring unit of an investigational wearable sEMG monitoring system for the detection of GTCS, Dr. Halford and colleagues conducted a prospective, multicenter phase III trial.
One hundred ninety-nine participants ranging in age from 3 to 72 with a history of GTCS (either primary GTCS or partial onset seizures with secondary generalization) and an upper-arm circumference adequate for proper fit of the device were included in the study. Participants had been admitted to an epilepsy monitoring unit for standard clinical care.
Researchers used a custom-designed device to record sEMG data. Recording electrodes were placed transversely over the belly of the biceps brachii muscle. The reference electrode was positioned proximally. The device was taken off and replaced every 12 hours during battery changes. In addition, patients were questioned once daily about adverse events, and skin in contact with the device was examined. Recorded sEMG data were processed at a central site using a previously developed detection algorithm. Finally, detected GTCS were compared with events confirmed by three expert reviewers.
Device Detected Most GTCS
For all participants, the detection algorithm detected 35 of 46 GTCS (ie, 76%), with a positive predictive value of 0.03 and a mean false alarm rate of 2.52 per 24 hours. When the device was placed over the midline of the biceps, the system detected 29 of 29 GTCS with a detection delay average of 7.70 seconds, a positive predictive value of 6.2%, and a mean false alarm rate of 1.44 per 24 hours.
When the device was placed between the biceps and triceps, it caused in-phase cancellation, significantly weakening the sEMG signal. After this discovery, all staff at all study sites were retrained to place the device over the midline biceps. Sixty-four percent of false alarms occurred during activity, and 62% of false alarms contained signal artifact commonly associated with loose electrodes, said the
Adverse Events and Study Limitations
Mild to moderate adverse events were reported in 28% of participants and led to withdrawal in 9%. Most adverse events consisted of skin irritation from the electrode patch (eg, skin tears, general discomfort, blisters, and bruising). No serious adverse events were reported.
In all, 23% of respondents said that the device was uncomfortable to sleep with. Forty-two percent of these participants reported that they would ask their physician to prescribe the system, and 26% reported that they would not. Thirteen percent of respondents had no opinion, and 18% did not comment.
One study limitation was the initially improper placement of the device. Furthermore, although this study shows that this system works in the epilepsy monitoring unit, it is unclear whether this device will work in the home environment.
In future research, Dr. Halford intends to study the sEMG signal from the scalp, recorded as part of standard EEG, to determine whether it could be used to detect GTCS during ambulatory or inpatient monitoring. He also plans to investigate ways to improve the tolerability of the sEMG monitoring device.
—Erica Tricarico
Suggested Reading
Halford JJ, Sperling MR, Nair DR, et al. Detection of generalized tonic-clonic seizures using surface electromyographic monitoring. Epilepsia. 2017;58(11):1861-1869.
A wearable surface electromyographic (sEMG) monitoring device may help to detect generalized tonic-clonic seizures (GTCS), according to research published in the November 2017 issue of Epilepsia. The monitoring system provides timely detection of GTCS within an average of 7.7 seconds of the onset of bilateral appendicular tonic motor manifestations.
“Since GTCS can cause patient injury and are associated with SUDEP, the [wearable] device should be useful to provide a method for caretakers to check on patient safety shortly after a GTCS,” said Jonathan J. Halford, MD, Associate Professor of Neurology at the Medical University of South Carolina in Charleston.
The prevalence of active epilepsy is between 0.4% and 1% worldwide. The prevalence of patients with frequent GTCS is unknown, but is estimated at between 10% and 20% of patients with active epilepsy. These patients have the highest risk for injuries, sudden unexpected death in epilepsy (SUDEP), and mortality from any cause. Early detection of GTCS and intervention may help to decrease morbidity and mortality, cases of status epilepticus, and SUDEP.
Evaluating Device Performance and Tolerability
A previous single-site study of an sEMG detection algorithm in an epilepsy monitoring unit detected 95% of 20 GTCS recorded in 11 epilepsy patients with one false positive. To evaluate the performance and tolerability in the epilepsy monitoring unit of an investigational wearable sEMG monitoring system for the detection of GTCS, Dr. Halford and colleagues conducted a prospective, multicenter phase III trial.
One hundred ninety-nine participants ranging in age from 3 to 72 with a history of GTCS (either primary GTCS or partial onset seizures with secondary generalization) and an upper-arm circumference adequate for proper fit of the device were included in the study. Participants had been admitted to an epilepsy monitoring unit for standard clinical care.
Researchers used a custom-designed device to record sEMG data. Recording electrodes were placed transversely over the belly of the biceps brachii muscle. The reference electrode was positioned proximally. The device was taken off and replaced every 12 hours during battery changes. In addition, patients were questioned once daily about adverse events, and skin in contact with the device was examined. Recorded sEMG data were processed at a central site using a previously developed detection algorithm. Finally, detected GTCS were compared with events confirmed by three expert reviewers.
Device Detected Most GTCS
For all participants, the detection algorithm detected 35 of 46 GTCS (ie, 76%), with a positive predictive value of 0.03 and a mean false alarm rate of 2.52 per 24 hours. When the device was placed over the midline of the biceps, the system detected 29 of 29 GTCS with a detection delay average of 7.70 seconds, a positive predictive value of 6.2%, and a mean false alarm rate of 1.44 per 24 hours.
When the device was placed between the biceps and triceps, it caused in-phase cancellation, significantly weakening the sEMG signal. After this discovery, all staff at all study sites were retrained to place the device over the midline biceps. Sixty-four percent of false alarms occurred during activity, and 62% of false alarms contained signal artifact commonly associated with loose electrodes, said the
Adverse Events and Study Limitations
Mild to moderate adverse events were reported in 28% of participants and led to withdrawal in 9%. Most adverse events consisted of skin irritation from the electrode patch (eg, skin tears, general discomfort, blisters, and bruising). No serious adverse events were reported.
In all, 23% of respondents said that the device was uncomfortable to sleep with. Forty-two percent of these participants reported that they would ask their physician to prescribe the system, and 26% reported that they would not. Thirteen percent of respondents had no opinion, and 18% did not comment.
One study limitation was the initially improper placement of the device. Furthermore, although this study shows that this system works in the epilepsy monitoring unit, it is unclear whether this device will work in the home environment.
In future research, Dr. Halford intends to study the sEMG signal from the scalp, recorded as part of standard EEG, to determine whether it could be used to detect GTCS during ambulatory or inpatient monitoring. He also plans to investigate ways to improve the tolerability of the sEMG monitoring device.
—Erica Tricarico
Suggested Reading
Halford JJ, Sperling MR, Nair DR, et al. Detection of generalized tonic-clonic seizures using surface electromyographic monitoring. Epilepsia. 2017;58(11):1861-1869.
A wearable surface electromyographic (sEMG) monitoring device may help to detect generalized tonic-clonic seizures (GTCS), according to research published in the November 2017 issue of Epilepsia. The monitoring system provides timely detection of GTCS within an average of 7.7 seconds of the onset of bilateral appendicular tonic motor manifestations.
“Since GTCS can cause patient injury and are associated with SUDEP, the [wearable] device should be useful to provide a method for caretakers to check on patient safety shortly after a GTCS,” said Jonathan J. Halford, MD, Associate Professor of Neurology at the Medical University of South Carolina in Charleston.
The prevalence of active epilepsy is between 0.4% and 1% worldwide. The prevalence of patients with frequent GTCS is unknown, but is estimated at between 10% and 20% of patients with active epilepsy. These patients have the highest risk for injuries, sudden unexpected death in epilepsy (SUDEP), and mortality from any cause. Early detection of GTCS and intervention may help to decrease morbidity and mortality, cases of status epilepticus, and SUDEP.
Evaluating Device Performance and Tolerability
A previous single-site study of an sEMG detection algorithm in an epilepsy monitoring unit detected 95% of 20 GTCS recorded in 11 epilepsy patients with one false positive. To evaluate the performance and tolerability in the epilepsy monitoring unit of an investigational wearable sEMG monitoring system for the detection of GTCS, Dr. Halford and colleagues conducted a prospective, multicenter phase III trial.
One hundred ninety-nine participants ranging in age from 3 to 72 with a history of GTCS (either primary GTCS or partial onset seizures with secondary generalization) and an upper-arm circumference adequate for proper fit of the device were included in the study. Participants had been admitted to an epilepsy monitoring unit for standard clinical care.
Researchers used a custom-designed device to record sEMG data. Recording electrodes were placed transversely over the belly of the biceps brachii muscle. The reference electrode was positioned proximally. The device was taken off and replaced every 12 hours during battery changes. In addition, patients were questioned once daily about adverse events, and skin in contact with the device was examined. Recorded sEMG data were processed at a central site using a previously developed detection algorithm. Finally, detected GTCS were compared with events confirmed by three expert reviewers.
Device Detected Most GTCS
For all participants, the detection algorithm detected 35 of 46 GTCS (ie, 76%), with a positive predictive value of 0.03 and a mean false alarm rate of 2.52 per 24 hours. When the device was placed over the midline of the biceps, the system detected 29 of 29 GTCS with a detection delay average of 7.70 seconds, a positive predictive value of 6.2%, and a mean false alarm rate of 1.44 per 24 hours.
When the device was placed between the biceps and triceps, it caused in-phase cancellation, significantly weakening the sEMG signal. After this discovery, all staff at all study sites were retrained to place the device over the midline biceps. Sixty-four percent of false alarms occurred during activity, and 62% of false alarms contained signal artifact commonly associated with loose electrodes, said the
Adverse Events and Study Limitations
Mild to moderate adverse events were reported in 28% of participants and led to withdrawal in 9%. Most adverse events consisted of skin irritation from the electrode patch (eg, skin tears, general discomfort, blisters, and bruising). No serious adverse events were reported.
In all, 23% of respondents said that the device was uncomfortable to sleep with. Forty-two percent of these participants reported that they would ask their physician to prescribe the system, and 26% reported that they would not. Thirteen percent of respondents had no opinion, and 18% did not comment.
One study limitation was the initially improper placement of the device. Furthermore, although this study shows that this system works in the epilepsy monitoring unit, it is unclear whether this device will work in the home environment.
In future research, Dr. Halford intends to study the sEMG signal from the scalp, recorded as part of standard EEG, to determine whether it could be used to detect GTCS during ambulatory or inpatient monitoring. He also plans to investigate ways to improve the tolerability of the sEMG monitoring device.
—Erica Tricarico
Suggested Reading
Halford JJ, Sperling MR, Nair DR, et al. Detection of generalized tonic-clonic seizures using surface electromyographic monitoring. Epilepsia. 2017;58(11):1861-1869.
As Many as 47 Million Americans May Have Preclinical Alzheimer’s Disease
A treatment that would reduce the risk of developing amyloid plaques in the brain by 50% could save more than four million Americans from mild cognitive impairment (MCI) and 2.5 million Americans from Alzheimer’s disease by 2060, according to a study published online ahead of print November 29 in Alzheimer’s & Dementia.
The conclusion that modestly effective preventive therapy could greatly improve the Alzheimer’s disease outlook is especially important, given another finding in a new mathematical modeling study by Ron Brookmeyer, PhD, a biostatistician at the University of California, Los Angeles, and colleagues. They assert that 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease.
This study is the first to quantify the number of cognitively healthy US residents who could eventually experience cognitive changes that put them at risk of developing Alzheimer’s dementia, according to a statement from the Alzheimer’s Association.
Model Predicted Increase in Preclinical Alzheimer’s Disease
“This is the first major attempt to forecast these proposed preclinical Alzheimer’s disease and [MCI] due to Alzheimer’s disease numbers. If confirmed, these data [will] provide essential information for public health planning and for informing and guiding the public and private investment in Alzheimer’s and dementia research,” said Dr. Brookmeyer. “We need more research to confirm the findings from this model, and more Alzheimer’s disease and dementia research that includes diverse populations.”
“I want to emphasize that of the 47 million [people] with these Alzheimer’s brain changes, but without clinical symptoms, most will not progress to clinical disease during their lifetimes. In fact, perhaps only one in seven will progress to full-blown dementia.” Nevertheless, the numbers represent a reality that must be confronted and managed proactively, said Dr. Brookmeyer.
The results may sound alarming, he said, “but I have every confidence in them. And they are important because they allow us to understand how many people could potentially benefit from treatment, at what point on the disease continuum it would be useful to implement treatment, and how those treatments could impact public health.”
Studies Provided Rates of Transition Between Disease States
To create predictive models, Dr. Brookmeyer used data from two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging and a study conducted by Stephanie J. Vos, PhD, a postdoctoral researcher at Maastricht University in the Netherlands.
The Mayo Clinic study followed 1,541 cognitively normal older adults and provided data on the rate of transition from normal cognition to MCI. The study by Dr. Vos and her associates followed 353 patients with MCI and brain amyloid and 222 patients with late MCI as they progressed. It is the largest prospective study of progression from MCI to Alzheimer’s disease that also contains data on baseline neurodegeneration and amyloid burden.
“These studies gave us the rates of transition from one state to another,” said Dr. Brookmeyer. “For example, the Mayo Clinic study gave us rates of transition from normal [health] to amyloidosis: 3% of normal 60-year-olds will convert to this state every year.”
Dr. Vos’s study determined rates of progression from MCI to Alzheimer’s dementia, given two preclinical states: asymptomatic amyloid brain plaques alone, or plaques with evidence of neurodegeneration and cognitive signs, said Dr. Brookmeyer. Both of these transitional states were first defined in 2011 in a joint paper by the Alzheimer’s Association and the National Institute on Aging. While acknowledging that the root causes of Alzheimer’s disease are unknown, the paper hypothesized a pathophysiologic time line beginning with a three-stage preclinical phase.
Asymptomatic cerebral amyloidosis is the first stage. It entails amyloid-positive PET brain imaging with an amyloid-binding ligand, a CSF assay with a low level of amyloid-beta 42 in the presence of normal cognition, or both. Stage 2 is one of amyloid positivity and evidence of synaptic dysfunction or early neurodegeneration in the presence of normal cognition. Finally, stage 3 entails amyloid positivity with evidence of neurodegeneration in the presence of subtle cognitive decline.
“Using those definitions, and piecing together the numbers from these studies, we constructed a computer model based on US census population projections to [estimate] how many people might be in these different states of disease,” said Dr. Brookmeyer.
In 2017, six million Americans were in one of the clinical disease states (ie, MCI due to Alzheimer’s disease, early clinical Alzheimer’s disease, or late clinical Alzheimer’s disease). Dr. Brookmeyer and his colleagues predicted that that number would grow to 15 million by 2060. Similarly, in 2017, about 47 million Americans were in one of the preclinical Alzheimer’s disease states, including 22 million with amyloidosis, 8.3 million with neurodegeneration alone, and 16.2 million with both. He projects that this number will increase to 75.7 million by 2060.
Prevention Strategies
The team remodeled those numbers in three hypothetical intervention scenarios. Researchers say that a treatment that slows decline by at least 30% would have a meaningful clinical, financial, and societal impact. However, Dr. Brookmeyer modeled treatment scenarios with a greater effect.
A primary prevention method that reduced the annual risk of new amyloidosis by 50% could decrease the prevalence of MCI by about 700,000 in 2060. A secondary prevention strategy that reduced the annual risk progression to MCI by 50% would decrease the prevalence of MCI by more than two million and the prevalence of Alzheimer’s disease by about 3.8 million.
The results were more complicated with a secondary prevention strategy that would reduce annual risk of conversion from MCI to Alzheimer’s disease by 50%. In this scenario, the prevalence of MCI in 2060 would increase by 2.8 million, but the prevalence of Alzheimer’s disease would decrease by 2.5 million. These scenarios developed over different time courses, said the researchers.
“We find that the highly effective primary prevention strategy resulted in the lowest Alzheimer’s disease prevalence by the year 2060. However, [it] was associated with the largest Alzheimer’s disease prevalence in the 15 years immediately after its introduction ... The explanation for this finding is that the full benefits of delaying amyloidosis, in terms of reduced Alzheimer’s disease prevalence, are not realized for many years because of the long lag time between amyloidosis and clinical Alzheimer’s disease. A take-home message is that the full impact on disease burden of primary prevention that targets the early stages of the pathogenesis of Alzheimer’s disease may not be realized for decades.”
Decreasing preclinical conversion to MCI with a secondary prevention strategy would result in the highest Alzheimer’s disease prevalence reduction for most of the period. But the reduction resulting from the primary prevention strategy would surpass it by 2054.
The intervention targeting conversion from MCI to Alzheimer’s disease would reduce Alzheimer’s disease prevalence the quickest, with a slight decrease in the first three years after introduction. “The explanation for this finding is that MCI is proximate to clinical Alzheimer’s disease diagnosis, and thus the impact of delaying progression of MCI will be seen relatively quickly on Alzheimer’s disease prevalence, compared to interventions that delay onset of amyloidosis or MCI.
“By focusing attention on a concerning reality—that tens of millions of American adults may face the possibility of dementia due to Alzheimer’s disease—the results reported in this new article, if confirmed, illustrate and greatly amplify the need for more research to develop effective treatments and proven prevention strategies for Alzheimer’s disease,” said Dr. Brookmeyer. “This is especially true as we get better at early detection and are able to more accurately identify people who have the early brain changes associated with Alzheimer’s disease and other dementias.”
Dr. Brookmeyer reported receiving fees from Takeda for serving as a member of a data safety monitoring board.
—Michele G. Sullivan
Suggested Reading
Brookmeyer R, Abdalla N, Kawas CH, Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2017 Nov 29 [Epub ahead of print].
Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74(11):1345-1351.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
Vos SJ, Verhey F, Frölich L, et al. Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain. 2015;138(Pt 5):1327-1338.
A treatment that would reduce the risk of developing amyloid plaques in the brain by 50% could save more than four million Americans from mild cognitive impairment (MCI) and 2.5 million Americans from Alzheimer’s disease by 2060, according to a study published online ahead of print November 29 in Alzheimer’s & Dementia.
The conclusion that modestly effective preventive therapy could greatly improve the Alzheimer’s disease outlook is especially important, given another finding in a new mathematical modeling study by Ron Brookmeyer, PhD, a biostatistician at the University of California, Los Angeles, and colleagues. They assert that 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease.
This study is the first to quantify the number of cognitively healthy US residents who could eventually experience cognitive changes that put them at risk of developing Alzheimer’s dementia, according to a statement from the Alzheimer’s Association.
Model Predicted Increase in Preclinical Alzheimer’s Disease
“This is the first major attempt to forecast these proposed preclinical Alzheimer’s disease and [MCI] due to Alzheimer’s disease numbers. If confirmed, these data [will] provide essential information for public health planning and for informing and guiding the public and private investment in Alzheimer’s and dementia research,” said Dr. Brookmeyer. “We need more research to confirm the findings from this model, and more Alzheimer’s disease and dementia research that includes diverse populations.”
“I want to emphasize that of the 47 million [people] with these Alzheimer’s brain changes, but without clinical symptoms, most will not progress to clinical disease during their lifetimes. In fact, perhaps only one in seven will progress to full-blown dementia.” Nevertheless, the numbers represent a reality that must be confronted and managed proactively, said Dr. Brookmeyer.
The results may sound alarming, he said, “but I have every confidence in them. And they are important because they allow us to understand how many people could potentially benefit from treatment, at what point on the disease continuum it would be useful to implement treatment, and how those treatments could impact public health.”
Studies Provided Rates of Transition Between Disease States
To create predictive models, Dr. Brookmeyer used data from two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging and a study conducted by Stephanie J. Vos, PhD, a postdoctoral researcher at Maastricht University in the Netherlands.
The Mayo Clinic study followed 1,541 cognitively normal older adults and provided data on the rate of transition from normal cognition to MCI. The study by Dr. Vos and her associates followed 353 patients with MCI and brain amyloid and 222 patients with late MCI as they progressed. It is the largest prospective study of progression from MCI to Alzheimer’s disease that also contains data on baseline neurodegeneration and amyloid burden.
“These studies gave us the rates of transition from one state to another,” said Dr. Brookmeyer. “For example, the Mayo Clinic study gave us rates of transition from normal [health] to amyloidosis: 3% of normal 60-year-olds will convert to this state every year.”
Dr. Vos’s study determined rates of progression from MCI to Alzheimer’s dementia, given two preclinical states: asymptomatic amyloid brain plaques alone, or plaques with evidence of neurodegeneration and cognitive signs, said Dr. Brookmeyer. Both of these transitional states were first defined in 2011 in a joint paper by the Alzheimer’s Association and the National Institute on Aging. While acknowledging that the root causes of Alzheimer’s disease are unknown, the paper hypothesized a pathophysiologic time line beginning with a three-stage preclinical phase.
Asymptomatic cerebral amyloidosis is the first stage. It entails amyloid-positive PET brain imaging with an amyloid-binding ligand, a CSF assay with a low level of amyloid-beta 42 in the presence of normal cognition, or both. Stage 2 is one of amyloid positivity and evidence of synaptic dysfunction or early neurodegeneration in the presence of normal cognition. Finally, stage 3 entails amyloid positivity with evidence of neurodegeneration in the presence of subtle cognitive decline.
“Using those definitions, and piecing together the numbers from these studies, we constructed a computer model based on US census population projections to [estimate] how many people might be in these different states of disease,” said Dr. Brookmeyer.
In 2017, six million Americans were in one of the clinical disease states (ie, MCI due to Alzheimer’s disease, early clinical Alzheimer’s disease, or late clinical Alzheimer’s disease). Dr. Brookmeyer and his colleagues predicted that that number would grow to 15 million by 2060. Similarly, in 2017, about 47 million Americans were in one of the preclinical Alzheimer’s disease states, including 22 million with amyloidosis, 8.3 million with neurodegeneration alone, and 16.2 million with both. He projects that this number will increase to 75.7 million by 2060.
Prevention Strategies
The team remodeled those numbers in three hypothetical intervention scenarios. Researchers say that a treatment that slows decline by at least 30% would have a meaningful clinical, financial, and societal impact. However, Dr. Brookmeyer modeled treatment scenarios with a greater effect.
A primary prevention method that reduced the annual risk of new amyloidosis by 50% could decrease the prevalence of MCI by about 700,000 in 2060. A secondary prevention strategy that reduced the annual risk progression to MCI by 50% would decrease the prevalence of MCI by more than two million and the prevalence of Alzheimer’s disease by about 3.8 million.
The results were more complicated with a secondary prevention strategy that would reduce annual risk of conversion from MCI to Alzheimer’s disease by 50%. In this scenario, the prevalence of MCI in 2060 would increase by 2.8 million, but the prevalence of Alzheimer’s disease would decrease by 2.5 million. These scenarios developed over different time courses, said the researchers.
“We find that the highly effective primary prevention strategy resulted in the lowest Alzheimer’s disease prevalence by the year 2060. However, [it] was associated with the largest Alzheimer’s disease prevalence in the 15 years immediately after its introduction ... The explanation for this finding is that the full benefits of delaying amyloidosis, in terms of reduced Alzheimer’s disease prevalence, are not realized for many years because of the long lag time between amyloidosis and clinical Alzheimer’s disease. A take-home message is that the full impact on disease burden of primary prevention that targets the early stages of the pathogenesis of Alzheimer’s disease may not be realized for decades.”
Decreasing preclinical conversion to MCI with a secondary prevention strategy would result in the highest Alzheimer’s disease prevalence reduction for most of the period. But the reduction resulting from the primary prevention strategy would surpass it by 2054.
The intervention targeting conversion from MCI to Alzheimer’s disease would reduce Alzheimer’s disease prevalence the quickest, with a slight decrease in the first three years after introduction. “The explanation for this finding is that MCI is proximate to clinical Alzheimer’s disease diagnosis, and thus the impact of delaying progression of MCI will be seen relatively quickly on Alzheimer’s disease prevalence, compared to interventions that delay onset of amyloidosis or MCI.
“By focusing attention on a concerning reality—that tens of millions of American adults may face the possibility of dementia due to Alzheimer’s disease—the results reported in this new article, if confirmed, illustrate and greatly amplify the need for more research to develop effective treatments and proven prevention strategies for Alzheimer’s disease,” said Dr. Brookmeyer. “This is especially true as we get better at early detection and are able to more accurately identify people who have the early brain changes associated with Alzheimer’s disease and other dementias.”
Dr. Brookmeyer reported receiving fees from Takeda for serving as a member of a data safety monitoring board.
—Michele G. Sullivan
Suggested Reading
Brookmeyer R, Abdalla N, Kawas CH, Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2017 Nov 29 [Epub ahead of print].
Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74(11):1345-1351.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
Vos SJ, Verhey F, Frölich L, et al. Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain. 2015;138(Pt 5):1327-1338.
A treatment that would reduce the risk of developing amyloid plaques in the brain by 50% could save more than four million Americans from mild cognitive impairment (MCI) and 2.5 million Americans from Alzheimer’s disease by 2060, according to a study published online ahead of print November 29 in Alzheimer’s & Dementia.
The conclusion that modestly effective preventive therapy could greatly improve the Alzheimer’s disease outlook is especially important, given another finding in a new mathematical modeling study by Ron Brookmeyer, PhD, a biostatistician at the University of California, Los Angeles, and colleagues. They assert that 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease.
This study is the first to quantify the number of cognitively healthy US residents who could eventually experience cognitive changes that put them at risk of developing Alzheimer’s dementia, according to a statement from the Alzheimer’s Association.
Model Predicted Increase in Preclinical Alzheimer’s Disease
“This is the first major attempt to forecast these proposed preclinical Alzheimer’s disease and [MCI] due to Alzheimer’s disease numbers. If confirmed, these data [will] provide essential information for public health planning and for informing and guiding the public and private investment in Alzheimer’s and dementia research,” said Dr. Brookmeyer. “We need more research to confirm the findings from this model, and more Alzheimer’s disease and dementia research that includes diverse populations.”
“I want to emphasize that of the 47 million [people] with these Alzheimer’s brain changes, but without clinical symptoms, most will not progress to clinical disease during their lifetimes. In fact, perhaps only one in seven will progress to full-blown dementia.” Nevertheless, the numbers represent a reality that must be confronted and managed proactively, said Dr. Brookmeyer.
The results may sound alarming, he said, “but I have every confidence in them. And they are important because they allow us to understand how many people could potentially benefit from treatment, at what point on the disease continuum it would be useful to implement treatment, and how those treatments could impact public health.”
Studies Provided Rates of Transition Between Disease States
To create predictive models, Dr. Brookmeyer used data from two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging and a study conducted by Stephanie J. Vos, PhD, a postdoctoral researcher at Maastricht University in the Netherlands.
The Mayo Clinic study followed 1,541 cognitively normal older adults and provided data on the rate of transition from normal cognition to MCI. The study by Dr. Vos and her associates followed 353 patients with MCI and brain amyloid and 222 patients with late MCI as they progressed. It is the largest prospective study of progression from MCI to Alzheimer’s disease that also contains data on baseline neurodegeneration and amyloid burden.
“These studies gave us the rates of transition from one state to another,” said Dr. Brookmeyer. “For example, the Mayo Clinic study gave us rates of transition from normal [health] to amyloidosis: 3% of normal 60-year-olds will convert to this state every year.”
Dr. Vos’s study determined rates of progression from MCI to Alzheimer’s dementia, given two preclinical states: asymptomatic amyloid brain plaques alone, or plaques with evidence of neurodegeneration and cognitive signs, said Dr. Brookmeyer. Both of these transitional states were first defined in 2011 in a joint paper by the Alzheimer’s Association and the National Institute on Aging. While acknowledging that the root causes of Alzheimer’s disease are unknown, the paper hypothesized a pathophysiologic time line beginning with a three-stage preclinical phase.
Asymptomatic cerebral amyloidosis is the first stage. It entails amyloid-positive PET brain imaging with an amyloid-binding ligand, a CSF assay with a low level of amyloid-beta 42 in the presence of normal cognition, or both. Stage 2 is one of amyloid positivity and evidence of synaptic dysfunction or early neurodegeneration in the presence of normal cognition. Finally, stage 3 entails amyloid positivity with evidence of neurodegeneration in the presence of subtle cognitive decline.
“Using those definitions, and piecing together the numbers from these studies, we constructed a computer model based on US census population projections to [estimate] how many people might be in these different states of disease,” said Dr. Brookmeyer.
In 2017, six million Americans were in one of the clinical disease states (ie, MCI due to Alzheimer’s disease, early clinical Alzheimer’s disease, or late clinical Alzheimer’s disease). Dr. Brookmeyer and his colleagues predicted that that number would grow to 15 million by 2060. Similarly, in 2017, about 47 million Americans were in one of the preclinical Alzheimer’s disease states, including 22 million with amyloidosis, 8.3 million with neurodegeneration alone, and 16.2 million with both. He projects that this number will increase to 75.7 million by 2060.
Prevention Strategies
The team remodeled those numbers in three hypothetical intervention scenarios. Researchers say that a treatment that slows decline by at least 30% would have a meaningful clinical, financial, and societal impact. However, Dr. Brookmeyer modeled treatment scenarios with a greater effect.
A primary prevention method that reduced the annual risk of new amyloidosis by 50% could decrease the prevalence of MCI by about 700,000 in 2060. A secondary prevention strategy that reduced the annual risk progression to MCI by 50% would decrease the prevalence of MCI by more than two million and the prevalence of Alzheimer’s disease by about 3.8 million.
The results were more complicated with a secondary prevention strategy that would reduce annual risk of conversion from MCI to Alzheimer’s disease by 50%. In this scenario, the prevalence of MCI in 2060 would increase by 2.8 million, but the prevalence of Alzheimer’s disease would decrease by 2.5 million. These scenarios developed over different time courses, said the researchers.
“We find that the highly effective primary prevention strategy resulted in the lowest Alzheimer’s disease prevalence by the year 2060. However, [it] was associated with the largest Alzheimer’s disease prevalence in the 15 years immediately after its introduction ... The explanation for this finding is that the full benefits of delaying amyloidosis, in terms of reduced Alzheimer’s disease prevalence, are not realized for many years because of the long lag time between amyloidosis and clinical Alzheimer’s disease. A take-home message is that the full impact on disease burden of primary prevention that targets the early stages of the pathogenesis of Alzheimer’s disease may not be realized for decades.”
Decreasing preclinical conversion to MCI with a secondary prevention strategy would result in the highest Alzheimer’s disease prevalence reduction for most of the period. But the reduction resulting from the primary prevention strategy would surpass it by 2054.
The intervention targeting conversion from MCI to Alzheimer’s disease would reduce Alzheimer’s disease prevalence the quickest, with a slight decrease in the first three years after introduction. “The explanation for this finding is that MCI is proximate to clinical Alzheimer’s disease diagnosis, and thus the impact of delaying progression of MCI will be seen relatively quickly on Alzheimer’s disease prevalence, compared to interventions that delay onset of amyloidosis or MCI.
“By focusing attention on a concerning reality—that tens of millions of American adults may face the possibility of dementia due to Alzheimer’s disease—the results reported in this new article, if confirmed, illustrate and greatly amplify the need for more research to develop effective treatments and proven prevention strategies for Alzheimer’s disease,” said Dr. Brookmeyer. “This is especially true as we get better at early detection and are able to more accurately identify people who have the early brain changes associated with Alzheimer’s disease and other dementias.”
Dr. Brookmeyer reported receiving fees from Takeda for serving as a member of a data safety monitoring board.
—Michele G. Sullivan
Suggested Reading
Brookmeyer R, Abdalla N, Kawas CH, Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2017 Nov 29 [Epub ahead of print].
Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74(11):1345-1351.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
Vos SJ, Verhey F, Frölich L, et al. Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain. 2015;138(Pt 5):1327-1338.