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The art of selecting an MS therapy
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
DALLAS – , said Mark Freedman, MD, MSc, in a presentation at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “Right now, we are probably dealing with more of an imprecise medicine,” said Dr. Freedman.
Information such as a patient’s ability to recover from relapses may indicate MS severity or the likelihood of disease progression, but selecting a therapy remains “an art of medicine,” said Dr. Freedman, professor of neurology at the University of Ottawa, director of the multiple sclerosis research unit at Ottawa Hospital, and senior scientist at the Ottawa Hospital Research Institute.
When prescribing a DMT, neurologists tend to consider three key elements: the disease, the treatment, and patient expectations. “Focus on these three aspects,” Dr. Freedman said.
It is no longer sufficient for neurologists to diagnose MS, hand the patient a drug, and “expect that things are going to go the way you want them to go,” he said.
Immunomodulating, anti–cell trafficking, or cell-depleting therapy?
Genetics, sex, types of relapses, recovery from relapses, response to therapy, MRI burden, and other biomarkers such as oligoclonal bands and neurofilaments may indicate which patients have severe disease and should receive aggressive treatment.
Determining the phase of the disease is a crucial first step “that is going to drive your choice of therapy,” he said.
Dr. Freedman likened the development of progressive MS to approaching the edge of a cliff. If patients appear to be nearing the progressive phase, “then your choice of therapy has to be an aggressive one – one that will hopefully hold them back from falling,” he said. In the earlier phases of MS, on the other hand, “you are looking at a long-term treatment that should probably be safe and still able to contain the disease,” such as an immunomodulator. If a patient is “about to fall off, you may want to go for temporary use of an antitrafficker to control things, and then eventually deplete the cells that are going to be causing the patient to fall off the cliff.”
Prognostic factors
Disease activity over time, and whether the disease is progressing faster or slower than would be expected, may be important prognostic factors. A patient’s sex also may be a factor because women tend to have more attacks and to have their attacks at a younger age, Dr. Freedman said.
The types of relapses and a patient’s ability to recover from them may provide important information. “Some attacks are quite mild. Others tend to build up disease,” Dr. Freedman said. “Some people are better healers than others. We have all seen people who have been quadriplegic in an ICU on a ventilator walk out of the hospital without even a numb toe. And other people who have a little bit of weakness in one leg seem to never be able to recover from that. Exactly what drives repair is still not clear.” Most patients do recover, however, “and the inability to recover early on is a bad omen,” Dr. Freedman said.
When researchers examined the relationship between functional components of the Expanded Disability Status Scale (EDSS) and disability progression, “not surprisingly ... pyramidal and spinal cord and cerebellar [functioning] are more associated with earlier progression” (Neuroepidemiology. 2015;44[1]:16-23).
A study by Lublin et al. found that patients with MS whose attacks left them with residual deficits had more EDSS accumulation over time (Neurology. 2003 Dec 9;61[11]:1528-32.).
Response to immunomodulators
“The inability to control the disease with an immunomodulator is a bad sign,” Dr. Freedman said. He pointed to data from a trial of teriflunomide that included patients who had had suboptimal responses to first-line therapy as well as patients who were treatment naive (Mult Scler. 2018 Apr;24[4]:535-9.). Some of the patients who had received prior MS therapy were randomized to placebo, which “is not something that would happen today,” he said.
“If you just focus on the [patients who received placebo] and look at the rate of attack in patients who had no prior DMT, at least one prior DMT, or two or more prior DMTs, the attack rates are much higher in those individuals who tried and failed first-line therapies,” Dr. Freedman said. These patients also had more EDSS progression. “The majority of people do respond [to first-line treatment], but those who do not you need to worry about a little bit more than those who do respond.”
MRI lesions and brain reserve
MRI activity over time tends to predict disease progression, and lesion location is important. One cohort study found that the likelihood of developing secondary progressive MS was lower among patients who did not develop new spinal cord or brainstem lesions in the first three years of the disease, compared with those who did.
In addition, patients who presented with more lesions were more likely to reach an EDSS score 3 or 6 over 10 years (Brain. 2008 Mar;131[Pt 3]:808-17.).
Brain reserve also may be important. Among 52 treatment-naive Serbian adults with MS, Sumowski et al. found that maximal lifetime brain growth as estimated with intracranial volume was associated with risk of disability progression over 5 years (Neurology. 2016 May 24;86[21]:2006-9.). “Those who had a greater reserve had a much lower risk of disease progression,” Dr. Freedman said. The results suggest that patients with more brain reserve may be better able to sustain damage as the disease progresses and they age, he said.
Comorbidities
In the past, neurologists may have left it up to general practitioners “to sort out the rest of the patient’s health,” Dr. Freedman said. “But we now recognize that having certain comorbidities already puts a higher burden onto the disease. And those patients who have more comorbidities ... are going to do worse. But not only are they going to do worse ... it turns out that patients who have more comorbidities are going to have less of a response to your various therapies.” Vascular comorbidities, in particular, may affect treatment response (Neurology. 2017 Nov 28;89[22]:2222-9.).
If hypertension or diabetes clinics can help control those conditions in patients with MS, “it will help us a lot in getting what we are expecting from the [MS] medications,” Dr. Freedman said.
Adherence, expectations, and symptomatic treatment
Ultimately, selecting an MS therapy is a decision that doctors share with their patients. “You’re going to have a discussion with them,” he said. “You can see what fits their lifestyle.” For example, a world traveler might not be a good candidate for a drug that requires regular monitoring. A patient’s risk averseness also may influence treatment choice.
If you involve patients in the selection process, it may improve medication adherence. In addition, patients need to understand what you aim to accomplish with a DMT, said Dr. Freedman. “That may sound like a trivial thing. But how many times has the patient come in and said, ‘The drug is not working. ... My eye is not better’” when that was not the goal of treatment to begin with. Let patients know that symptomatic treatments may address problems apart from MS DMT. This personalized but imprecise approach to treatment is “probably the best we can do for now,” Dr. Freedman said.
Dr. Freedman has received a research grant from Genzyme and is on the company’s speakers bureau. He has received honoraria and consulting fees from various pharmaceutical companies and serves on companies’ advisory boards.
SOURCE: Freedman MS. ACTRIMS Forum 2019, Session 2.
EXPERT ANALYSIS FROM ACTRIMS
A blood biomarker for MS: Coming to clinics soon?
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
DALLAS – Neurologists soon may use a blood biomarker of axonal damage to monitor patients with multiple sclerosis (MS) and guide treatment decisions, according to a lecture delivered at ACTRIMS Forum 2019.
said David Leppert, MD, senior research associate in the department of neurology at University Hopsital Basel (Switzerland).
Among patients with MS, blood NfL levels predict disability, brain volume loss, and spinal cord atrophy. In addition, studies have found that blood NfL decreases in response to disease-modifying therapy (DMT) and that second-line DMTs may decrease blood NfL more than first-line DMTs do.
The establishment of normative databases and reference biomarkers may allow neurologists to use NfL in their care of individual patients, Dr. Leppert predicted at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “I am very positive that we will make a breakthrough in the next 2 or 3 years for an individual use of neurofilaments,” he said.
Response to DMT
An analysis of blood NfL levels from patients with MS and from healthy controls in two phase 3 trials of fingolimod, FREEDOMS and TRANSFORMS, provides insights into NfL’s response to DMT (Neurology. 2019 Mar 5;92[10]:e1007-15). In FREEDOMS, which compared fingolimod with placebo, “fingolimod leads to a rapid decrease of neurofilament levels, close to normality, while placebo patients continue to have high levels,” said Dr. Leppert, a coauthor of the study.
TRANSFORMS compared interferon-beta and fingolimod. “The clinical experience that fingolimod is a more potent compound than interferon is actually reflected here by the NfL results,” Dr. Leppert said. “Both compounds lead to a decrease of neurofilaments – so, a decrease of neuronal damage – but one drug is more potent than the other one.”
Similarly, data from the observational EPIC study indicate that patients who do not receive DMT have a consistent increase in NfL levels, whereas those who receive platform therapies have a slight decrease in NfL and those who receive second-line therapies have a greater decrease, Dr. Leppert said.
Decades of research
For about 20 years, researchers have studied neurofilaments in cerebrospinal fluid (CSF) as a potential biomarker for MS and other diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and head trauma.
“What prevented the emergence of NfL to clinical practice was the inability to measure it in blood because levels are 50-100 times lower [in blood] than in CSF,” Dr. Leppert said.
The development of single molecule array (SIMOA) technology enabled researchers to show a proper correlation between levels of NfL in CSF and those in blood, Dr. Leppert said. “That is now allowing repetitive testing in an accessible fluid compartment, meaning serum or plasma,” he said.
Compared with brain MRI, NfL may provide novel insights into MS disease activity. “MRI is measuring a structural deficit of the past,” Dr. Leppert said. “NfL is measuring online, real time what axonal damage is occurring.”
Correlation with outcomes
At the group level, patients with MS have higher levels of NfL, compared with controls, and levels are higher in patients with progressive forms of MS versus relapsing forms. “Levels increase dramatically in the wake of relapse,” he said.
Barro et al. found that patients with higher serum levels of NfL are more likely to experience Expanded Disability Status Scale (EDSS) worsening (Brain. 2018 Aug 1;141[8]:2382-91). Furthermore, MRI lesions are independently associated with serum NfL, and patients with higher levels of serum NfL have significantly greater average loss in brain volume and spinal cord volume over 5 years.
A treatment algorithm
NfL someday could be incorporated into MS treatment algorithms, Dr. Leppert suggested. For instance, if a patient has high levels of disease activity based on MRI or clinical grounds, then prescribe a high-efficacy therapy. If not, measure NfL. “If the levels are low, then you can be assured to use platform therapies or continue what the patient has. But if NfL levels are high, then you should choose high efficacious therapies or switch to high-efficacious therapies in the long run,” he said.
Limitations and next steps
Although NfL is a specific marker of neuronal damage, it is not specific for the cause of the damage. Further studies are needed to better understand NfL metabolism and confounding factors such as age. Reference biomarkers likely will be needed “to conceptualize whether the signal of NfL is due to acute disease or chronic disease,” Dr. Leppert said.
“We need to optimize the assay and come to a worldwide agreement on the platform. We need to have prospective studies, mainly to achieve regulatory acceptance. And we need to have a normative database” to determine which NfL values are pathologic at a particular age, he said.
Despite the biomarker’s potential, blood NfL levels will not replace clinical expertise. “Biomarkers cannot be of value without a clinical backing and a clinical evaluation,” Dr. Leppert said. “The idea that this will replace us or any other person who makes a clinical judgment is a big error. NfL will prevail as a biomarker. ... But interpretation of the clinical background is germane.”
Dr. Leppert has been an employee of pharmaceutical companies, most recently Novartis.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
Cerebellar volume may predict disability in patients with relapsing-remitting MS
DALLAS – Among patients with relapsing-remitting multiple sclerosis (MS), cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test, according to a retrospective analysis of data from a phase 3 trial. Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months, researchers reported at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Investigators have found that demyelination in MS tends to occur in the cerebellum, and cerebellar atrophy contributes to clinical impairment in patients with the disease. In addition, cerebellar volume loss over one year may predict disease worsening in patients with progressive MS, said Maria Petracca, MD, PhD, a postdoctoral fellow at Icahn School of Medicine at Mount Sinai, New York, and her research colleagues. Prior studies, however, had not tested in a large group of patients whether baseline cerebellar volume predicts disability in relapsing-remitting MS.
To examine this question, Dr. Petracca and her colleagues analyzed MRI data from 838 of 1,008 patients in the phase 3 CombiRx trial. Patients in the multicenter, randomized trial had relapsing-remitting MS and received immunomodulatory treatment with glatiramer acetate, interferon beta-1a, or both. The researchers used an MRI analysis package to measure whole brain and cerebellar T2 and gadolinium-enhancing lesions, and they used statistical parametric mapping to measure gray matter fraction and cerebellar volume. Expanded Disability Status Scale (EDSS) scores and scores on the Multiple Sclerosis Functional Composite (MSFC) and its subcomponents were assessed at baseline and 36 months. The investigators assessed changes in clinical scores using repeated measure analysis of variance. They examined the relationship between MRI metrics and clinical disability at baseline and follow-up using ordinal and hierarchical multiple linear regression analysis.
At baseline, patients had a mean age of 37.7, and 72% were female. Median EDSS score was 2, and average cerebellar gray matter volume was 109.78 mL.
A regression model that included T2 and gadolinium-enhancing lesion volume, supratentorial gray matter volume, and cerebellar gray matter volume explained about 15% of the variance in EDSS and MSFC scores at baseline. Cerebellar volume was a significant predictor of MSFC (beta = 0.188).
The 25-foot walk test was the only clinical score that significantly worsened during follow-up – from an average of 4.94 seconds at baseline to 5.09 seconds at follow-up. “Baseline cerebellar gray matter volume was the only MRI metric to significantly predict 25-foot walk test scores at follow-up (beta = –0.172),” the researchers reported. “These results suggest that cerebellar volume is an independent predictor of clinical disability in MS patients as measured by 25-foot walk test.”
The researchers had no disclosures.
jremaly@mdedge.com
SOURCE: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
DALLAS – Among patients with relapsing-remitting multiple sclerosis (MS), cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test, according to a retrospective analysis of data from a phase 3 trial. Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months, researchers reported at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Investigators have found that demyelination in MS tends to occur in the cerebellum, and cerebellar atrophy contributes to clinical impairment in patients with the disease. In addition, cerebellar volume loss over one year may predict disease worsening in patients with progressive MS, said Maria Petracca, MD, PhD, a postdoctoral fellow at Icahn School of Medicine at Mount Sinai, New York, and her research colleagues. Prior studies, however, had not tested in a large group of patients whether baseline cerebellar volume predicts disability in relapsing-remitting MS.
To examine this question, Dr. Petracca and her colleagues analyzed MRI data from 838 of 1,008 patients in the phase 3 CombiRx trial. Patients in the multicenter, randomized trial had relapsing-remitting MS and received immunomodulatory treatment with glatiramer acetate, interferon beta-1a, or both. The researchers used an MRI analysis package to measure whole brain and cerebellar T2 and gadolinium-enhancing lesions, and they used statistical parametric mapping to measure gray matter fraction and cerebellar volume. Expanded Disability Status Scale (EDSS) scores and scores on the Multiple Sclerosis Functional Composite (MSFC) and its subcomponents were assessed at baseline and 36 months. The investigators assessed changes in clinical scores using repeated measure analysis of variance. They examined the relationship between MRI metrics and clinical disability at baseline and follow-up using ordinal and hierarchical multiple linear regression analysis.
At baseline, patients had a mean age of 37.7, and 72% were female. Median EDSS score was 2, and average cerebellar gray matter volume was 109.78 mL.
A regression model that included T2 and gadolinium-enhancing lesion volume, supratentorial gray matter volume, and cerebellar gray matter volume explained about 15% of the variance in EDSS and MSFC scores at baseline. Cerebellar volume was a significant predictor of MSFC (beta = 0.188).
The 25-foot walk test was the only clinical score that significantly worsened during follow-up – from an average of 4.94 seconds at baseline to 5.09 seconds at follow-up. “Baseline cerebellar gray matter volume was the only MRI metric to significantly predict 25-foot walk test scores at follow-up (beta = –0.172),” the researchers reported. “These results suggest that cerebellar volume is an independent predictor of clinical disability in MS patients as measured by 25-foot walk test.”
The researchers had no disclosures.
jremaly@mdedge.com
SOURCE: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
DALLAS – Among patients with relapsing-remitting multiple sclerosis (MS), cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test, according to a retrospective analysis of data from a phase 3 trial. Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months, researchers reported at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Investigators have found that demyelination in MS tends to occur in the cerebellum, and cerebellar atrophy contributes to clinical impairment in patients with the disease. In addition, cerebellar volume loss over one year may predict disease worsening in patients with progressive MS, said Maria Petracca, MD, PhD, a postdoctoral fellow at Icahn School of Medicine at Mount Sinai, New York, and her research colleagues. Prior studies, however, had not tested in a large group of patients whether baseline cerebellar volume predicts disability in relapsing-remitting MS.
To examine this question, Dr. Petracca and her colleagues analyzed MRI data from 838 of 1,008 patients in the phase 3 CombiRx trial. Patients in the multicenter, randomized trial had relapsing-remitting MS and received immunomodulatory treatment with glatiramer acetate, interferon beta-1a, or both. The researchers used an MRI analysis package to measure whole brain and cerebellar T2 and gadolinium-enhancing lesions, and they used statistical parametric mapping to measure gray matter fraction and cerebellar volume. Expanded Disability Status Scale (EDSS) scores and scores on the Multiple Sclerosis Functional Composite (MSFC) and its subcomponents were assessed at baseline and 36 months. The investigators assessed changes in clinical scores using repeated measure analysis of variance. They examined the relationship between MRI metrics and clinical disability at baseline and follow-up using ordinal and hierarchical multiple linear regression analysis.
At baseline, patients had a mean age of 37.7, and 72% were female. Median EDSS score was 2, and average cerebellar gray matter volume was 109.78 mL.
A regression model that included T2 and gadolinium-enhancing lesion volume, supratentorial gray matter volume, and cerebellar gray matter volume explained about 15% of the variance in EDSS and MSFC scores at baseline. Cerebellar volume was a significant predictor of MSFC (beta = 0.188).
The 25-foot walk test was the only clinical score that significantly worsened during follow-up – from an average of 4.94 seconds at baseline to 5.09 seconds at follow-up. “Baseline cerebellar gray matter volume was the only MRI metric to significantly predict 25-foot walk test scores at follow-up (beta = –0.172),” the researchers reported. “These results suggest that cerebellar volume is an independent predictor of clinical disability in MS patients as measured by 25-foot walk test.”
The researchers had no disclosures.
jremaly@mdedge.com
SOURCE: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
REPORTING FROM ACTRIMS FORUM 2019
Key clinical point: In patients with relapsing-remitting MS, cerebellar volume may independently predict clinical disability as measured by the 25-foot walk test.
Major finding: Baseline cerebellar gray matter volume was the only MRI metric that significantly predicted 25-foot walk test results at 36 months (Beta = –0.172).
Study details: A retrospective analysis of MRI data from 838 patients in the phase 3 CombiRx trial.
Disclosures: The researchers had no disclosures.
Source: Petracca M et al. ACTRIMS Forum 2019, Abstract 160.
Imaging mass cytometry sheds light on inflammation, demyelination in MS
DALLAS – Imaging mass cytometry is helping researchers to better understand how meningeal inflammation relates to cortical pathology in a subset of multiple sclerosis patients.
This technique for examining multiple proteins within intact tissue and distinguishing cell types based on complex combinations of markers has helped to spot evidence of meningeal inflammation in areas of patient brain samples with cortical gray matter lesions, confirming demyelination and meningeal inflammation observed in experimental allergic encephalomyelitis mouse models.
Imaging mass cytometry “allows us to potentially discriminate microglia from macrophages within brain lesions,” Jennifer Gommerman, PhD, said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We can look at lymphocytes as well. There’s a lot of potential with this technique, and we’re excited to apply it to the meningeal inflammatory sections of the brain.”
Dr. Gommerman, professor of immunology at the University of Toronto, noted that multiple sclerosis (MS) begins often with a relapsing form of the disease, which tracks with deep white matter lesions that clinicians can image with MRI. “But as the disease progresses, we know that pathology can change, and we can see more pathology in the cortex, including varied bands of demyelination that are adjacent to the meninges,” she said. “This phase of the disease is not effectively treated by therapeutics.”
In this later phase of the disease, she continued, “it’s thought perhaps that the immune system isn’t playing such a big role, but there has been a fair bit of evidence in the literature in recent years that there are in fact immune cells in the brains of people with progressive MS. You can find them in the meninges. They can form clusters of cells within the meninges and they tend to be adjacent to areas of cortical demyelination, suggesting they might be involved in this pathology.”
Dr. Gommerman and her colleagues developed an animal model to evaluate meningeal inflammation in an effort to determine if they can model cortical injury and disease progression. They used an adoptive transfer form of experimental allergic encephalomyelitis in which they prime T cells in SJL mice, remove them, polarize them toward a Th17 phenotype, and transfer them into naive recipients. “When we do this we can see clusters of immune cells forming in the meninges,” Dr. Gommerman said. “They start with T cells but then become overwhelmingly populated by B cells.” Adjacent to these clusters they noted disruption of the glia limitans and demyelination in the cortex. “There’s clearly something going on in the cortex of these animals.”
Mindful that age is one of the most significant predictors of disease progression, the researchers transferred young T cells into mice that were 6-8 months old in addition to animals that were 6-8 weeks old. “Upon sacrifice, the younger mice that got the young T cells had largely resolved their cortical pathology, while the old mice that got the young T cells still showed evidence of demyelination, very angry microglia, and a continual disruption of the glial limitans,” Dr. Gommerman said. “We were able to see axonal stress in comparison to the young mice. We also saw some evidence of synapse loss. It seems that these animals not only have demyelination in the cortex, but there are problems with the axons and the synapses.”
To apply this model in humans, she and her colleagues collaborated with Netherlands Brain Bank in order to obtain brain samples for analysis with imaging mass cytometry, which provides a time-of-flight mass spectrometry readout of the staining pattern of heavy metal ion–tagged antibodies on a single slide-mounted tissue section.
“We really have to be careful which [brain] samples we choose, because not all samples from progressive MS patients have evidence of meningeal inflammation,” she noted. So far, they have observed that meningeal inflammation is associated with gray matter lesions, rather than with normal-appearing gray matter.
“We also need to look at appropriate controls, so our plan is to look at patients who have meningeal inflammation but do not have MS,” she said.
Dr. Gommerman reported having received grants from Novartis, Roche, and Merck, as well as a consulting agreement with Roche.
DALLAS – Imaging mass cytometry is helping researchers to better understand how meningeal inflammation relates to cortical pathology in a subset of multiple sclerosis patients.
This technique for examining multiple proteins within intact tissue and distinguishing cell types based on complex combinations of markers has helped to spot evidence of meningeal inflammation in areas of patient brain samples with cortical gray matter lesions, confirming demyelination and meningeal inflammation observed in experimental allergic encephalomyelitis mouse models.
Imaging mass cytometry “allows us to potentially discriminate microglia from macrophages within brain lesions,” Jennifer Gommerman, PhD, said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We can look at lymphocytes as well. There’s a lot of potential with this technique, and we’re excited to apply it to the meningeal inflammatory sections of the brain.”
Dr. Gommerman, professor of immunology at the University of Toronto, noted that multiple sclerosis (MS) begins often with a relapsing form of the disease, which tracks with deep white matter lesions that clinicians can image with MRI. “But as the disease progresses, we know that pathology can change, and we can see more pathology in the cortex, including varied bands of demyelination that are adjacent to the meninges,” she said. “This phase of the disease is not effectively treated by therapeutics.”
In this later phase of the disease, she continued, “it’s thought perhaps that the immune system isn’t playing such a big role, but there has been a fair bit of evidence in the literature in recent years that there are in fact immune cells in the brains of people with progressive MS. You can find them in the meninges. They can form clusters of cells within the meninges and they tend to be adjacent to areas of cortical demyelination, suggesting they might be involved in this pathology.”
Dr. Gommerman and her colleagues developed an animal model to evaluate meningeal inflammation in an effort to determine if they can model cortical injury and disease progression. They used an adoptive transfer form of experimental allergic encephalomyelitis in which they prime T cells in SJL mice, remove them, polarize them toward a Th17 phenotype, and transfer them into naive recipients. “When we do this we can see clusters of immune cells forming in the meninges,” Dr. Gommerman said. “They start with T cells but then become overwhelmingly populated by B cells.” Adjacent to these clusters they noted disruption of the glia limitans and demyelination in the cortex. “There’s clearly something going on in the cortex of these animals.”
Mindful that age is one of the most significant predictors of disease progression, the researchers transferred young T cells into mice that were 6-8 months old in addition to animals that were 6-8 weeks old. “Upon sacrifice, the younger mice that got the young T cells had largely resolved their cortical pathology, while the old mice that got the young T cells still showed evidence of demyelination, very angry microglia, and a continual disruption of the glial limitans,” Dr. Gommerman said. “We were able to see axonal stress in comparison to the young mice. We also saw some evidence of synapse loss. It seems that these animals not only have demyelination in the cortex, but there are problems with the axons and the synapses.”
To apply this model in humans, she and her colleagues collaborated with Netherlands Brain Bank in order to obtain brain samples for analysis with imaging mass cytometry, which provides a time-of-flight mass spectrometry readout of the staining pattern of heavy metal ion–tagged antibodies on a single slide-mounted tissue section.
“We really have to be careful which [brain] samples we choose, because not all samples from progressive MS patients have evidence of meningeal inflammation,” she noted. So far, they have observed that meningeal inflammation is associated with gray matter lesions, rather than with normal-appearing gray matter.
“We also need to look at appropriate controls, so our plan is to look at patients who have meningeal inflammation but do not have MS,” she said.
Dr. Gommerman reported having received grants from Novartis, Roche, and Merck, as well as a consulting agreement with Roche.
DALLAS – Imaging mass cytometry is helping researchers to better understand how meningeal inflammation relates to cortical pathology in a subset of multiple sclerosis patients.
This technique for examining multiple proteins within intact tissue and distinguishing cell types based on complex combinations of markers has helped to spot evidence of meningeal inflammation in areas of patient brain samples with cortical gray matter lesions, confirming demyelination and meningeal inflammation observed in experimental allergic encephalomyelitis mouse models.
Imaging mass cytometry “allows us to potentially discriminate microglia from macrophages within brain lesions,” Jennifer Gommerman, PhD, said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “We can look at lymphocytes as well. There’s a lot of potential with this technique, and we’re excited to apply it to the meningeal inflammatory sections of the brain.”
Dr. Gommerman, professor of immunology at the University of Toronto, noted that multiple sclerosis (MS) begins often with a relapsing form of the disease, which tracks with deep white matter lesions that clinicians can image with MRI. “But as the disease progresses, we know that pathology can change, and we can see more pathology in the cortex, including varied bands of demyelination that are adjacent to the meninges,” she said. “This phase of the disease is not effectively treated by therapeutics.”
In this later phase of the disease, she continued, “it’s thought perhaps that the immune system isn’t playing such a big role, but there has been a fair bit of evidence in the literature in recent years that there are in fact immune cells in the brains of people with progressive MS. You can find them in the meninges. They can form clusters of cells within the meninges and they tend to be adjacent to areas of cortical demyelination, suggesting they might be involved in this pathology.”
Dr. Gommerman and her colleagues developed an animal model to evaluate meningeal inflammation in an effort to determine if they can model cortical injury and disease progression. They used an adoptive transfer form of experimental allergic encephalomyelitis in which they prime T cells in SJL mice, remove them, polarize them toward a Th17 phenotype, and transfer them into naive recipients. “When we do this we can see clusters of immune cells forming in the meninges,” Dr. Gommerman said. “They start with T cells but then become overwhelmingly populated by B cells.” Adjacent to these clusters they noted disruption of the glia limitans and demyelination in the cortex. “There’s clearly something going on in the cortex of these animals.”
Mindful that age is one of the most significant predictors of disease progression, the researchers transferred young T cells into mice that were 6-8 months old in addition to animals that were 6-8 weeks old. “Upon sacrifice, the younger mice that got the young T cells had largely resolved their cortical pathology, while the old mice that got the young T cells still showed evidence of demyelination, very angry microglia, and a continual disruption of the glial limitans,” Dr. Gommerman said. “We were able to see axonal stress in comparison to the young mice. We also saw some evidence of synapse loss. It seems that these animals not only have demyelination in the cortex, but there are problems with the axons and the synapses.”
To apply this model in humans, she and her colleagues collaborated with Netherlands Brain Bank in order to obtain brain samples for analysis with imaging mass cytometry, which provides a time-of-flight mass spectrometry readout of the staining pattern of heavy metal ion–tagged antibodies on a single slide-mounted tissue section.
“We really have to be careful which [brain] samples we choose, because not all samples from progressive MS patients have evidence of meningeal inflammation,” she noted. So far, they have observed that meningeal inflammation is associated with gray matter lesions, rather than with normal-appearing gray matter.
“We also need to look at appropriate controls, so our plan is to look at patients who have meningeal inflammation but do not have MS,” she said.
Dr. Gommerman reported having received grants from Novartis, Roche, and Merck, as well as a consulting agreement with Roche.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
MS researchers aim to build MRI diagnostic portfolio beyond the central vein sign
DALLAS –
“The goal is to have something to guide us, even before we think about applying the McDonald criteria, to give us some probability of whether or not the patient has MS,” Andrew J. Solomon, MD, said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.
Thalamic atrophy
Measuring thalamic volume is one approach of interest (see Neurol Neuroimmunol Neuroinflamm. 2017 Sep;4[5]:e387). “Thalamic atrophy occurs early in MS,” said Dr. Solomon, division chief of multiple sclerosis in the department of neurological sciences at the University of Vermont, Burlington. “It certainly reflects pathology that seems to be specific to MS, compared to other diseases that mimic MS.”
In a recent analysis, investigators prospectively studied 520 patients with relapse-onset MS and 81 healthy controls who received annual MRI brain scans. MS patients received 2,485 scans during a mean follow-up of 4.1 years, while controls received 147 scans during a mean follow-up of 1.3 years (Ann Neurol. 2018;83[2]:223-34). They found that the annual thalamic volume loss from baseline was significantly greater in MS patients than in controls (–0.71% vs. –0.28%). In addition, lower thalamic volume at baseline correlated modestly with worse baseline disability and functional measures of cognition, ambulation, and upper extremity function.
“Thalamic atrophy can be assessed from clinically acquired 3-D scans,” said Dr. Solomon, who was not involved with the study. “Maybe it can serve as an adjunct for patients who have a low number of lesions for central vein sign evaluation. We can look at their thalamic volume in combination with that and develop a threshold that’s helpful. We need larger cohorts and standardized, automated segmentation.”
Cortical myelin content
Using imaging techniques to detect cortical myelin content also may be beneficial. “We’ve known for a long time that cortical gray matter is involved in MS,” Dr. Solomon said. “It’s really hard to image these lesions on 3T [Tesla] MRI scanners. Some data suggest that patients with migraine don’t have cortical lesions. Patients with neuromyelitis optica don’t seem to have cortical lesions. There is some interesting data using T1 and T2 scans from routine MRI [see Ann Neurol. 2017;82[4]:519-29]. The research suggests that you can develop this ratio and look at myelin content of the cortex.”
Dr. Solomon and his colleagues validated this approach by evaluating data from 20 patients with MS and 10 with migraine. They used the Human Connectome Project pipelines version 3.16.1 to create cortical myelin maps. Specifically, signal intensities from the T1-weighted and FLAIR volumes were used to create maps of ratio and signal intensities as a proxy for cortical myelin content and cortical thickness. Z-score maps were created for each subject, and they used vertices with a Z score of less than 3 as a threshold. They found that the number of vertices in MS vs. non-MS had an area under the curve (AUC) of 0.837. “Maybe looking at cortical myelin content can help us differentiate MS from other disorders,” he said. “It reflects pathology that may be specific to MS. We can use routine clinically acquired sequences. We certainly need much larger cohorts, and we’re working on this.”
Dark rim on gray matter–double inversion recovery
Another promising imaging technique, developed by researchers at the Mayo Clinic, was found to enhance diagnostic specificity in MS (AJNR Am J Neuroradiol. 2018;39[6]:1052-8). Using a novel double inversion recovery sequence that suppresses cerebrospinal fluid and gray matter signal (GM–double inversion recovery), they compared white matter lesions in a group of 107 MS patients and in a second group of 36 positive controls with white matter lesions who did not have a diagnosis of MS. In patients with MS lesions, 35% had a dark rim visible on GM–double inversion recovery, compared with only 1% of the positive control group. Dark rims were associated with a decrease in the lesion T1 ratio. “We need a larger prospective study to see how this pans out,” Dr. Solomon said.
Lesion morphology
Evaluation of lesion morphology also holds promise. In one recent study, researchers performed standardized 3T 3-D brain MRI studies on 19 MS patients and 11 patients with nonspecific white matter (NSWM) disease (J Neuroimaging. 2017;27[6]:613-9). They identified focal supratentorial lesions, used maximum intensity projection to reconstruct them, and created 3-D printed models. The models were randomly evaluated by three blinded raters who scored lesions based on symmetry (symmetrical or asymmetrical), surface morphology (simple or complex), and a long list of secondary characteristics. In all, the researchers evaluated 1,001 supratentorial lesions, including 710 in MS patients and 291 in patients with NSWM disease.
MS vs. NSWM disease lesions had a higher percentage of asymmetry (75.9% vs. 43%; odds ratio, 4.39; P less than .001); complex surface morphologies (65.9% vs. 27.8%; OR, 2.3; P less than .001); multilobular lesions (11% vs. 3%; P less than .001), and elongated lesion (12.8% vs. 2.4%; P less than .001). “This is interesting, but it was a small study,” Dr. Solomon said. “We need to look at this in other diagnoses, and we need prospective data.”
Dr. Solomon disclosed that he has received consulting fees from EMD Serono and research funding from Biogen. He has also performed contracted research for Biogen, Novartis, Actelion, and Genentech/Roche.
dbrunk@mdedge.com
DALLAS –
“The goal is to have something to guide us, even before we think about applying the McDonald criteria, to give us some probability of whether or not the patient has MS,” Andrew J. Solomon, MD, said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.
Thalamic atrophy
Measuring thalamic volume is one approach of interest (see Neurol Neuroimmunol Neuroinflamm. 2017 Sep;4[5]:e387). “Thalamic atrophy occurs early in MS,” said Dr. Solomon, division chief of multiple sclerosis in the department of neurological sciences at the University of Vermont, Burlington. “It certainly reflects pathology that seems to be specific to MS, compared to other diseases that mimic MS.”
In a recent analysis, investigators prospectively studied 520 patients with relapse-onset MS and 81 healthy controls who received annual MRI brain scans. MS patients received 2,485 scans during a mean follow-up of 4.1 years, while controls received 147 scans during a mean follow-up of 1.3 years (Ann Neurol. 2018;83[2]:223-34). They found that the annual thalamic volume loss from baseline was significantly greater in MS patients than in controls (–0.71% vs. –0.28%). In addition, lower thalamic volume at baseline correlated modestly with worse baseline disability and functional measures of cognition, ambulation, and upper extremity function.
“Thalamic atrophy can be assessed from clinically acquired 3-D scans,” said Dr. Solomon, who was not involved with the study. “Maybe it can serve as an adjunct for patients who have a low number of lesions for central vein sign evaluation. We can look at their thalamic volume in combination with that and develop a threshold that’s helpful. We need larger cohorts and standardized, automated segmentation.”
Cortical myelin content
Using imaging techniques to detect cortical myelin content also may be beneficial. “We’ve known for a long time that cortical gray matter is involved in MS,” Dr. Solomon said. “It’s really hard to image these lesions on 3T [Tesla] MRI scanners. Some data suggest that patients with migraine don’t have cortical lesions. Patients with neuromyelitis optica don’t seem to have cortical lesions. There is some interesting data using T1 and T2 scans from routine MRI [see Ann Neurol. 2017;82[4]:519-29]. The research suggests that you can develop this ratio and look at myelin content of the cortex.”
Dr. Solomon and his colleagues validated this approach by evaluating data from 20 patients with MS and 10 with migraine. They used the Human Connectome Project pipelines version 3.16.1 to create cortical myelin maps. Specifically, signal intensities from the T1-weighted and FLAIR volumes were used to create maps of ratio and signal intensities as a proxy for cortical myelin content and cortical thickness. Z-score maps were created for each subject, and they used vertices with a Z score of less than 3 as a threshold. They found that the number of vertices in MS vs. non-MS had an area under the curve (AUC) of 0.837. “Maybe looking at cortical myelin content can help us differentiate MS from other disorders,” he said. “It reflects pathology that may be specific to MS. We can use routine clinically acquired sequences. We certainly need much larger cohorts, and we’re working on this.”
Dark rim on gray matter–double inversion recovery
Another promising imaging technique, developed by researchers at the Mayo Clinic, was found to enhance diagnostic specificity in MS (AJNR Am J Neuroradiol. 2018;39[6]:1052-8). Using a novel double inversion recovery sequence that suppresses cerebrospinal fluid and gray matter signal (GM–double inversion recovery), they compared white matter lesions in a group of 107 MS patients and in a second group of 36 positive controls with white matter lesions who did not have a diagnosis of MS. In patients with MS lesions, 35% had a dark rim visible on GM–double inversion recovery, compared with only 1% of the positive control group. Dark rims were associated with a decrease in the lesion T1 ratio. “We need a larger prospective study to see how this pans out,” Dr. Solomon said.
Lesion morphology
Evaluation of lesion morphology also holds promise. In one recent study, researchers performed standardized 3T 3-D brain MRI studies on 19 MS patients and 11 patients with nonspecific white matter (NSWM) disease (J Neuroimaging. 2017;27[6]:613-9). They identified focal supratentorial lesions, used maximum intensity projection to reconstruct them, and created 3-D printed models. The models were randomly evaluated by three blinded raters who scored lesions based on symmetry (symmetrical or asymmetrical), surface morphology (simple or complex), and a long list of secondary characteristics. In all, the researchers evaluated 1,001 supratentorial lesions, including 710 in MS patients and 291 in patients with NSWM disease.
MS vs. NSWM disease lesions had a higher percentage of asymmetry (75.9% vs. 43%; odds ratio, 4.39; P less than .001); complex surface morphologies (65.9% vs. 27.8%; OR, 2.3; P less than .001); multilobular lesions (11% vs. 3%; P less than .001), and elongated lesion (12.8% vs. 2.4%; P less than .001). “This is interesting, but it was a small study,” Dr. Solomon said. “We need to look at this in other diagnoses, and we need prospective data.”
Dr. Solomon disclosed that he has received consulting fees from EMD Serono and research funding from Biogen. He has also performed contracted research for Biogen, Novartis, Actelion, and Genentech/Roche.
dbrunk@mdedge.com
DALLAS –
“The goal is to have something to guide us, even before we think about applying the McDonald criteria, to give us some probability of whether or not the patient has MS,” Andrew J. Solomon, MD, said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis.
Thalamic atrophy
Measuring thalamic volume is one approach of interest (see Neurol Neuroimmunol Neuroinflamm. 2017 Sep;4[5]:e387). “Thalamic atrophy occurs early in MS,” said Dr. Solomon, division chief of multiple sclerosis in the department of neurological sciences at the University of Vermont, Burlington. “It certainly reflects pathology that seems to be specific to MS, compared to other diseases that mimic MS.”
In a recent analysis, investigators prospectively studied 520 patients with relapse-onset MS and 81 healthy controls who received annual MRI brain scans. MS patients received 2,485 scans during a mean follow-up of 4.1 years, while controls received 147 scans during a mean follow-up of 1.3 years (Ann Neurol. 2018;83[2]:223-34). They found that the annual thalamic volume loss from baseline was significantly greater in MS patients than in controls (–0.71% vs. –0.28%). In addition, lower thalamic volume at baseline correlated modestly with worse baseline disability and functional measures of cognition, ambulation, and upper extremity function.
“Thalamic atrophy can be assessed from clinically acquired 3-D scans,” said Dr. Solomon, who was not involved with the study. “Maybe it can serve as an adjunct for patients who have a low number of lesions for central vein sign evaluation. We can look at their thalamic volume in combination with that and develop a threshold that’s helpful. We need larger cohorts and standardized, automated segmentation.”
Cortical myelin content
Using imaging techniques to detect cortical myelin content also may be beneficial. “We’ve known for a long time that cortical gray matter is involved in MS,” Dr. Solomon said. “It’s really hard to image these lesions on 3T [Tesla] MRI scanners. Some data suggest that patients with migraine don’t have cortical lesions. Patients with neuromyelitis optica don’t seem to have cortical lesions. There is some interesting data using T1 and T2 scans from routine MRI [see Ann Neurol. 2017;82[4]:519-29]. The research suggests that you can develop this ratio and look at myelin content of the cortex.”
Dr. Solomon and his colleagues validated this approach by evaluating data from 20 patients with MS and 10 with migraine. They used the Human Connectome Project pipelines version 3.16.1 to create cortical myelin maps. Specifically, signal intensities from the T1-weighted and FLAIR volumes were used to create maps of ratio and signal intensities as a proxy for cortical myelin content and cortical thickness. Z-score maps were created for each subject, and they used vertices with a Z score of less than 3 as a threshold. They found that the number of vertices in MS vs. non-MS had an area under the curve (AUC) of 0.837. “Maybe looking at cortical myelin content can help us differentiate MS from other disorders,” he said. “It reflects pathology that may be specific to MS. We can use routine clinically acquired sequences. We certainly need much larger cohorts, and we’re working on this.”
Dark rim on gray matter–double inversion recovery
Another promising imaging technique, developed by researchers at the Mayo Clinic, was found to enhance diagnostic specificity in MS (AJNR Am J Neuroradiol. 2018;39[6]:1052-8). Using a novel double inversion recovery sequence that suppresses cerebrospinal fluid and gray matter signal (GM–double inversion recovery), they compared white matter lesions in a group of 107 MS patients and in a second group of 36 positive controls with white matter lesions who did not have a diagnosis of MS. In patients with MS lesions, 35% had a dark rim visible on GM–double inversion recovery, compared with only 1% of the positive control group. Dark rims were associated with a decrease in the lesion T1 ratio. “We need a larger prospective study to see how this pans out,” Dr. Solomon said.
Lesion morphology
Evaluation of lesion morphology also holds promise. In one recent study, researchers performed standardized 3T 3-D brain MRI studies on 19 MS patients and 11 patients with nonspecific white matter (NSWM) disease (J Neuroimaging. 2017;27[6]:613-9). They identified focal supratentorial lesions, used maximum intensity projection to reconstruct them, and created 3-D printed models. The models were randomly evaluated by three blinded raters who scored lesions based on symmetry (symmetrical or asymmetrical), surface morphology (simple or complex), and a long list of secondary characteristics. In all, the researchers evaluated 1,001 supratentorial lesions, including 710 in MS patients and 291 in patients with NSWM disease.
MS vs. NSWM disease lesions had a higher percentage of asymmetry (75.9% vs. 43%; odds ratio, 4.39; P less than .001); complex surface morphologies (65.9% vs. 27.8%; OR, 2.3; P less than .001); multilobular lesions (11% vs. 3%; P less than .001), and elongated lesion (12.8% vs. 2.4%; P less than .001). “This is interesting, but it was a small study,” Dr. Solomon said. “We need to look at this in other diagnoses, and we need prospective data.”
Dr. Solomon disclosed that he has received consulting fees from EMD Serono and research funding from Biogen. He has also performed contracted research for Biogen, Novartis, Actelion, and Genentech/Roche.
dbrunk@mdedge.com
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
Study launched to further evaluate the central vein sign in MS
DALLAS –
At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”
While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.
“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”
With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.
The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.
CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.
The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”
He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”
Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.
DALLAS –
At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”
While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.
“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”
With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.
The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.
CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.
The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”
He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”
Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.
DALLAS –
At the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis, Daniel Ontaneda, MD, said that up to 20% of individuals referred for a diagnosis of multiple sclerosis (MS) are incorrectly diagnosed with the disease, and about two-thirds of misdiagnosed patients are exposed to unnecessary and sometimes life-threatening risks associated with disease-modifying therapies. “MRI is a sensitive tool for diagnosis of MS and is an integral component of the diagnostic criteria for MS,” said Dr. Ontaneda, a neurologist at the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research. “However, there are problems with its implementation. Approximately half of individuals referred to an MS clinic present with atypical symptoms [fatigue, cognitive disturbance, pain] and not typical syndromes [unilateral optic neuritis, brain stem syndromes, partial myelitis]. Increasing diagnostic sensitivity may have come at the price of decreased specificity. MRI criteria have a specificity of 32% for dissemination in space and 42% for dissemination in time.”
While misdiagnosis appears to be mainly caused by overinterpretation of abnormal MRI findings, the central vein sign (CVS) is an effective method to overcome such challenges. Recent studies have demonstrated that CVS may help to identify MS, as 85% of white matter lesions in MS have a central vein, compared with only 8% of small vessel ischemic disease, 34% of migraine, and 14% of other inflammatory or autoimmune diseases.
“We think there is a significant and unmet need for more specific and accurate diagnostic tests to facilitate early confirmation of a diagnosis of MS,” Dr. Ontaneda said. “We propose a prospective evaluation of the central vein sign, which we hypothesize will reduce misdiagnosis, hasten early diagnosis, and simplify clinical decision making.”
With funding from the Race to Erase MS Foundation, he and his associates have designed CAVS-MS (Central Vein Sign in MS), a multicenter, prospective, observational trial being conducted at 10 sites. The first phase of the study is a cross-sectional pilot at the 10 sites. The primary objective is to establish the contrast-to-noise ratio of lesion to normal-appearing white matter and central vein to lesion across the 10 sites using 3-tesla FLAIR imaging in subjects with a clinical or radiologic suspicion of MS. The secondary objectives are to investigate the difference in contrast-to-noise ratio identified in the primary objective between pre- and postcontrast FLAIR imaging to identify whether gadolinium injection improves central vein detection, to determine the reproducibility of different methods for detection of positive CVS across sites, and to determine the sensitivity and specificity of the different methods for the diagnosis of MS, compared with the McDonald 2010 MS criteria.
The study population will consist of 100 individuals referred to an MS center based on clinical or radiologic suspicion of MS; 30 participants are currently enrolled. The 10 sites include the Cleveland Clinic; Johns Hopkins University, Baltimore; the University of California, San Francisco; the University of Texas, Houston; the University of Toronto; the University of Vermont, Burlington; the University of Southern California, Los Angeles; Cedars-Sinai Medical Center, Los Angeles; Yale University, New Haven, Conn.; and the University of Pennsylvania, Philadelphia.
CAVS-MS includes development of a software platform for rating of central veins through an imaging software partner, QMENTA. “We are going to have the individual clinicians at each site rate the lesions, so we will have information from 10 different raters,” Dr. Ontaneda said. The study will be coordinated at the Cleveland Clinic, central image analysis will be conducted at the National Institutes of Health, and statistical analysis will be performed at the University of Pennsylvania.
The researchers also hope to perform a prospective study with three objectives. The first is to determine if incorporation of CVS for the diagnosis of MS improves diagnostic accuracy and hastens diagnosis in individuals presenting with typical first clinical events. The second objective “is to determine if incorporation of CVS for the diagnosis of MS improves specificity among individuals presenting with atypical syndromes,” Dr. Ontaneda said. “The third aim is to look at central vein volume as a predictor of clinical/MRI disease activity associated with disability in MS.”
He concluded his remarks by describing the CVS as “a tool that offers promise both for increasing specificity and perhaps enabling earlier diagnosis of MS. Studies will determine if the central vein sign can be incorporated into the diagnostic criteria. The NIH is working with MRI manufacturers to make sequences available for disseminated clinical use.”
Dr. Ontaneda reported that he has received grant support from the National Institutes of Health, the Race to Erase MS Foundation, the Patient-Centered Outcomes Research Institute, the National Multiple Sclerosis Society, Genentech, Genzyme, and Novartis. He has also received consulting fees from Biogen, Genentech, and Novartis.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
Expert calls for more ‘ethnocentric’ research in MS
DALLAS – The way Lilyana Amezcua, MD, sees it, researchers should look beyond using race and ethnicity only as demographic variables when reporting results from multiple sclerosis studies.
“As a demographic variable we see it all the time: white versus non-white, and the methods to arrive at a category are seldom discussed,” Dr. Amezcua said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis. “We need to think about ethnocentric research, where the method for determination for race and ethnicity becomes important. This includes examining self-identity (ethnicity), along with physical characteristics and medical records, and confirming that beyond the individual.”
The goal, she continued, is to identify who is at risk for inferior health, such as trying to sort out biological and genetic explanations from non-biological explanations. Ethnocentric research also helps to address health care disparities. “But there’s a broad intersection between race and ethnicity, and depending on the question, genetic ancestry could help,” said Dr. Amezcua, a neurologist at the Keck School of Medicine at the University of Southern California, Los Angeles. “Race tries to infer biological differences, ethnicity infers societal differences, and ancestry infers genetic variations.”
While genetic and biologic features are often used to evaluate how race and ethnicity affects those with MS, Dr. Amezcua noted that several additional factors could influence outcomes. These include access to care as well as individual and community factors that relate to social determinants of health, such as poverty, exposures, and environmental stress. “These could be contributing to worse outcomes,” she said. “So could modifiable factors such as illness beliefs, health literacy, illness management, and acculturation.”
In terms of health literacy, there are reports suggesting that there is a general lack of adequate education and understanding about MS treatment and realistic expectations in African Americans and Hispanics, she said.
In addition, research has shown there is a lower probability of being under the care of a neurologist if you lack health insurance (odds ratio = 0.38) or are African American (OR = 0.52) or Hispanic (OR = 0.61), based on nationally representative data from the 2006-2013 Medical Expenditure Panel Survey (Neurology. 2017;88[24]:2268-75). “Just being African American or Hispanic lowered the probability of seeing a neurologist,” she said.
Published evidence also exists to suggest that illness beliefs drive some people away from MS treatment. “These are beliefs embedded in social and cultural factors known as cultural idioms,” Dr. Amezcua explained. “In a study that was able to capture qualitative and quantitative data, researchers found that social and cultural factors were more frequently reported in immigrant groups, alluding to the fact that we need to look beyond whether they are African American or Hispanic, and look at acculturation” (Int J MS Care. 2017;19[3]:131-9).
Then there’s the issue of Food and Drug Administration-approved disease-modifying therapies in MS and minorities. In an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study, researchers found that African-American subjects experienced more exacerbations and were less likely to remain exacerbation free, compared with whites (Arch Neurol. 2005;62[11]:1681-3). The African-American subjects also developed more new MS lesions on T2-weighted brain MRI at 48 weeks (P = .04).
“There are a lot of unanswered questions, but understanding the effect of race/ethnicity is crucial to understanding MS disparities,” Dr. Amezcua said. “To better understand genetic variation in the context of health disparities, using ‘genetic ancestry’ could help with precision medicine. We must remember that minorities with MS face barriers related to access and education in MS care much more so than whites.”
She concluded her remarks by underscoring the importance of increasing minority participation in research and clinical trials. “But today, clinical trial participation by minorities is less than 10%. As we progress, and as we get closer to precision medicine, the health disparities will widen.”
She reported having no financial disclosures.
DALLAS – The way Lilyana Amezcua, MD, sees it, researchers should look beyond using race and ethnicity only as demographic variables when reporting results from multiple sclerosis studies.
“As a demographic variable we see it all the time: white versus non-white, and the methods to arrive at a category are seldom discussed,” Dr. Amezcua said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis. “We need to think about ethnocentric research, where the method for determination for race and ethnicity becomes important. This includes examining self-identity (ethnicity), along with physical characteristics and medical records, and confirming that beyond the individual.”
The goal, she continued, is to identify who is at risk for inferior health, such as trying to sort out biological and genetic explanations from non-biological explanations. Ethnocentric research also helps to address health care disparities. “But there’s a broad intersection between race and ethnicity, and depending on the question, genetic ancestry could help,” said Dr. Amezcua, a neurologist at the Keck School of Medicine at the University of Southern California, Los Angeles. “Race tries to infer biological differences, ethnicity infers societal differences, and ancestry infers genetic variations.”
While genetic and biologic features are often used to evaluate how race and ethnicity affects those with MS, Dr. Amezcua noted that several additional factors could influence outcomes. These include access to care as well as individual and community factors that relate to social determinants of health, such as poverty, exposures, and environmental stress. “These could be contributing to worse outcomes,” she said. “So could modifiable factors such as illness beliefs, health literacy, illness management, and acculturation.”
In terms of health literacy, there are reports suggesting that there is a general lack of adequate education and understanding about MS treatment and realistic expectations in African Americans and Hispanics, she said.
In addition, research has shown there is a lower probability of being under the care of a neurologist if you lack health insurance (odds ratio = 0.38) or are African American (OR = 0.52) or Hispanic (OR = 0.61), based on nationally representative data from the 2006-2013 Medical Expenditure Panel Survey (Neurology. 2017;88[24]:2268-75). “Just being African American or Hispanic lowered the probability of seeing a neurologist,” she said.
Published evidence also exists to suggest that illness beliefs drive some people away from MS treatment. “These are beliefs embedded in social and cultural factors known as cultural idioms,” Dr. Amezcua explained. “In a study that was able to capture qualitative and quantitative data, researchers found that social and cultural factors were more frequently reported in immigrant groups, alluding to the fact that we need to look beyond whether they are African American or Hispanic, and look at acculturation” (Int J MS Care. 2017;19[3]:131-9).
Then there’s the issue of Food and Drug Administration-approved disease-modifying therapies in MS and minorities. In an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study, researchers found that African-American subjects experienced more exacerbations and were less likely to remain exacerbation free, compared with whites (Arch Neurol. 2005;62[11]:1681-3). The African-American subjects also developed more new MS lesions on T2-weighted brain MRI at 48 weeks (P = .04).
“There are a lot of unanswered questions, but understanding the effect of race/ethnicity is crucial to understanding MS disparities,” Dr. Amezcua said. “To better understand genetic variation in the context of health disparities, using ‘genetic ancestry’ could help with precision medicine. We must remember that minorities with MS face barriers related to access and education in MS care much more so than whites.”
She concluded her remarks by underscoring the importance of increasing minority participation in research and clinical trials. “But today, clinical trial participation by minorities is less than 10%. As we progress, and as we get closer to precision medicine, the health disparities will widen.”
She reported having no financial disclosures.
DALLAS – The way Lilyana Amezcua, MD, sees it, researchers should look beyond using race and ethnicity only as demographic variables when reporting results from multiple sclerosis studies.
“As a demographic variable we see it all the time: white versus non-white, and the methods to arrive at a category are seldom discussed,” Dr. Amezcua said at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis. “We need to think about ethnocentric research, where the method for determination for race and ethnicity becomes important. This includes examining self-identity (ethnicity), along with physical characteristics and medical records, and confirming that beyond the individual.”
The goal, she continued, is to identify who is at risk for inferior health, such as trying to sort out biological and genetic explanations from non-biological explanations. Ethnocentric research also helps to address health care disparities. “But there’s a broad intersection between race and ethnicity, and depending on the question, genetic ancestry could help,” said Dr. Amezcua, a neurologist at the Keck School of Medicine at the University of Southern California, Los Angeles. “Race tries to infer biological differences, ethnicity infers societal differences, and ancestry infers genetic variations.”
While genetic and biologic features are often used to evaluate how race and ethnicity affects those with MS, Dr. Amezcua noted that several additional factors could influence outcomes. These include access to care as well as individual and community factors that relate to social determinants of health, such as poverty, exposures, and environmental stress. “These could be contributing to worse outcomes,” she said. “So could modifiable factors such as illness beliefs, health literacy, illness management, and acculturation.”
In terms of health literacy, there are reports suggesting that there is a general lack of adequate education and understanding about MS treatment and realistic expectations in African Americans and Hispanics, she said.
In addition, research has shown there is a lower probability of being under the care of a neurologist if you lack health insurance (odds ratio = 0.38) or are African American (OR = 0.52) or Hispanic (OR = 0.61), based on nationally representative data from the 2006-2013 Medical Expenditure Panel Survey (Neurology. 2017;88[24]:2268-75). “Just being African American or Hispanic lowered the probability of seeing a neurologist,” she said.
Published evidence also exists to suggest that illness beliefs drive some people away from MS treatment. “These are beliefs embedded in social and cultural factors known as cultural idioms,” Dr. Amezcua explained. “In a study that was able to capture qualitative and quantitative data, researchers found that social and cultural factors were more frequently reported in immigrant groups, alluding to the fact that we need to look beyond whether they are African American or Hispanic, and look at acculturation” (Int J MS Care. 2017;19[3]:131-9).
Then there’s the issue of Food and Drug Administration-approved disease-modifying therapies in MS and minorities. In an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study, researchers found that African-American subjects experienced more exacerbations and were less likely to remain exacerbation free, compared with whites (Arch Neurol. 2005;62[11]:1681-3). The African-American subjects also developed more new MS lesions on T2-weighted brain MRI at 48 weeks (P = .04).
“There are a lot of unanswered questions, but understanding the effect of race/ethnicity is crucial to understanding MS disparities,” Dr. Amezcua said. “To better understand genetic variation in the context of health disparities, using ‘genetic ancestry’ could help with precision medicine. We must remember that minorities with MS face barriers related to access and education in MS care much more so than whites.”
She concluded her remarks by underscoring the importance of increasing minority participation in research and clinical trials. “But today, clinical trial participation by minorities is less than 10%. As we progress, and as we get closer to precision medicine, the health disparities will widen.”
She reported having no financial disclosures.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
Smartphone technology helps to detect, track eye changes in MS
DALLAS – A battery of smartphone tests have been developed to help clinicians detect and monitor eye changes in MS patients.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, Randy H. Kardon, MD, PhD, said that there are two main high priority gaps to fill when it comes to better understanding the effects of MS on vision. “One, I think we need a way for early detection of visual pathway disturbances after either an acute clinical event or a subclinical event,” said Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City. “Two, we need to monitor changes in the visual pathway over time in MS patients and capture variations due to changes in nerve conduction. The idea is, can we have a suite of smartphone tests that you can use in the clinic, but the patient can also use at home unsupervised, to get a time domain, so if there are fluctuations of core body temperature due to myelination, or subclinical changes going on, could we detect it earlier and monitor these patients? That’s the motivation.”
Although use of smartphone technology and mobile devices are emerging in health care settings, most of this technology is used sparingly in vision testing, mostly due to a lack of rigorous calibration of instruments and validation, said Dr. Kardon, who also directs the Iowa City VA Center for Prevention and Treatment of Visual Loss. To make a visual smartphone test viable, he continued, the visual output of the device must match the intended input in terms of multiple parameters (technical validation). Important parameters for vision tests include brightness, luminance, spatial resolution, and temporal resolution. Confounding variables include ambient lighting and viewing distance.
In his work with researchers from Aalborg University in Denmark, Dr. Kardon has developed four smartphone visual tests intended to be intuitive for patients. “We didn’t want something that was going to take more than 15 seconds,” he said. The visual tests include:
1. Critical flicker fusion, a test of optic nerve conduction. “This tests how well you can see a light flickering at a given temporal frequency at different levels of contrast, or how fast it can flicker before you don’t see a flicker anymore,” Dr. Kardon said. “The user sees spots that are flickering and just touches the ones they perceive to be flickering; they eliminate them by touching them.” When the test ends, the software “brackets what they did to a finer scale, and it finds the contrast at which that flicker wasn’t perceived anymore.”
2. The Landolt C visual acuity test. For this, the user must indicate the direction of the gap in the ring in a forced-choice task. “The user touches which arrow on the screen is pointing to where the location of the break in the Landolt C is perceived,” Dr. Kardon said. The Landolt C becomes progressively smaller until the location of the break can no longer be seen. “It’s pretty simple, and it finds the smallest size of the ‘C’ at which you’re making mistakes about 50% of the time, which is the threshold value for visual acuity,” he said.
3. Contrast sensitivity test at a fixed spatial frequency. “In this test, we fix the size of the letter to a large size, so spatial frequency is not at play, and we vary the contrast,” he said. “Users push the arrow wherever they see the break.” The contrast between the “C” and the background is sequentially reduced until a threshold is determined for the lowest contrast at which the location of the break in the “C” can still be observed.
4. Contrast sensitivity test at different spatial frequencies. This measure, also known as a vanishing optotype, is a line drawing of an object on a smooth, diffuse grayscale background. By altering the line properties used to define the shape of the vanishing optotype, one can vary its spatial frequency and contrast independent of target size. “This makes it an easy test because what the patient is asked to do is to touch wherever they see an object on the screen to eliminate it from the series of optotypes on the screen,” Dr. Kardon said. “The test is very fast, very intuitive.”
The researchers piloted use of these tests in a study of 104 age-matched control subjects and 117 MS patients. Of the 117 MS patients, 74 had a history of optic neuritis and 43 did not. The four tests were used in conjunction with standardized assessments, including the near-contrast acuity card test at 2.5%, the distant Early Treatment Diabetic Retinopathy Study (ETDRS) acuity test, as well as optical coherence tomography (OCT) of the retinal nerve fiber layer and ganglion cell layer thickness. Dr. Kardon and his colleagues found that when clinicians used a large target and varied the contrast, the test “did very well at differentiating normal from eyes with either previous optic neuritis or no previous optic neuritis,” he said. “It also differentiated eyes with previous optic neuritis and those with no optic neuritis. The visual acuity test didn’t perform as well because this is a near test. What we discovered afterward is that even at a fixed distance, many people who are presbyopic, or don’t have their optimal near correction, don’t do so well, because you’re testing spatial acuity. That’s a warning sign for future tests. You have to be careful as to how these are interpreted if they don’t have their best correction at near.”
Results from the critical flicker fusions tests were significant, except that they didn’t differentiate eyes affected by optic neuritis from those that weren’t. “The reason is that conduction was down in all of those eyes, so the combination of using contrast sensitivity and flicker fusion may not only help you diagnose MS, but whether that eye had been involved with optic neuritis before,” Dr. Kardon said. To date, he and his colleagues have completed technical validation of temporal frequency and contrast parameters. They’ve also completed preliminary investigations for determining test-retest variability, blurring effects, binocular summation effects, and quantification of normative ranges and abnormal subject data.
“A benefit of smartphone testing in MS is that visual dysfunction can be detected, leading to earlier interventions,” Dr. Kardon concluded. “We can study this on a time scale that wasn’t previously available. Wouldn’t you like to know on a daily or even a weekly basis what the fluctuations are in a home environment for MS patients? It’s low-cost, large-scale, and enables you to study genotype-phenotype comparisons.”
Going forward, Dr. Kardon and his colleagues have developed video cameras that go around the periphery of the iPad that can assess pupil and ocular motility, as well as eyelid and facial features in real time. He disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.
DALLAS – A battery of smartphone tests have been developed to help clinicians detect and monitor eye changes in MS patients.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, Randy H. Kardon, MD, PhD, said that there are two main high priority gaps to fill when it comes to better understanding the effects of MS on vision. “One, I think we need a way for early detection of visual pathway disturbances after either an acute clinical event or a subclinical event,” said Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City. “Two, we need to monitor changes in the visual pathway over time in MS patients and capture variations due to changes in nerve conduction. The idea is, can we have a suite of smartphone tests that you can use in the clinic, but the patient can also use at home unsupervised, to get a time domain, so if there are fluctuations of core body temperature due to myelination, or subclinical changes going on, could we detect it earlier and monitor these patients? That’s the motivation.”
Although use of smartphone technology and mobile devices are emerging in health care settings, most of this technology is used sparingly in vision testing, mostly due to a lack of rigorous calibration of instruments and validation, said Dr. Kardon, who also directs the Iowa City VA Center for Prevention and Treatment of Visual Loss. To make a visual smartphone test viable, he continued, the visual output of the device must match the intended input in terms of multiple parameters (technical validation). Important parameters for vision tests include brightness, luminance, spatial resolution, and temporal resolution. Confounding variables include ambient lighting and viewing distance.
In his work with researchers from Aalborg University in Denmark, Dr. Kardon has developed four smartphone visual tests intended to be intuitive for patients. “We didn’t want something that was going to take more than 15 seconds,” he said. The visual tests include:
1. Critical flicker fusion, a test of optic nerve conduction. “This tests how well you can see a light flickering at a given temporal frequency at different levels of contrast, or how fast it can flicker before you don’t see a flicker anymore,” Dr. Kardon said. “The user sees spots that are flickering and just touches the ones they perceive to be flickering; they eliminate them by touching them.” When the test ends, the software “brackets what they did to a finer scale, and it finds the contrast at which that flicker wasn’t perceived anymore.”
2. The Landolt C visual acuity test. For this, the user must indicate the direction of the gap in the ring in a forced-choice task. “The user touches which arrow on the screen is pointing to where the location of the break in the Landolt C is perceived,” Dr. Kardon said. The Landolt C becomes progressively smaller until the location of the break can no longer be seen. “It’s pretty simple, and it finds the smallest size of the ‘C’ at which you’re making mistakes about 50% of the time, which is the threshold value for visual acuity,” he said.
3. Contrast sensitivity test at a fixed spatial frequency. “In this test, we fix the size of the letter to a large size, so spatial frequency is not at play, and we vary the contrast,” he said. “Users push the arrow wherever they see the break.” The contrast between the “C” and the background is sequentially reduced until a threshold is determined for the lowest contrast at which the location of the break in the “C” can still be observed.
4. Contrast sensitivity test at different spatial frequencies. This measure, also known as a vanishing optotype, is a line drawing of an object on a smooth, diffuse grayscale background. By altering the line properties used to define the shape of the vanishing optotype, one can vary its spatial frequency and contrast independent of target size. “This makes it an easy test because what the patient is asked to do is to touch wherever they see an object on the screen to eliminate it from the series of optotypes on the screen,” Dr. Kardon said. “The test is very fast, very intuitive.”
The researchers piloted use of these tests in a study of 104 age-matched control subjects and 117 MS patients. Of the 117 MS patients, 74 had a history of optic neuritis and 43 did not. The four tests were used in conjunction with standardized assessments, including the near-contrast acuity card test at 2.5%, the distant Early Treatment Diabetic Retinopathy Study (ETDRS) acuity test, as well as optical coherence tomography (OCT) of the retinal nerve fiber layer and ganglion cell layer thickness. Dr. Kardon and his colleagues found that when clinicians used a large target and varied the contrast, the test “did very well at differentiating normal from eyes with either previous optic neuritis or no previous optic neuritis,” he said. “It also differentiated eyes with previous optic neuritis and those with no optic neuritis. The visual acuity test didn’t perform as well because this is a near test. What we discovered afterward is that even at a fixed distance, many people who are presbyopic, or don’t have their optimal near correction, don’t do so well, because you’re testing spatial acuity. That’s a warning sign for future tests. You have to be careful as to how these are interpreted if they don’t have their best correction at near.”
Results from the critical flicker fusions tests were significant, except that they didn’t differentiate eyes affected by optic neuritis from those that weren’t. “The reason is that conduction was down in all of those eyes, so the combination of using contrast sensitivity and flicker fusion may not only help you diagnose MS, but whether that eye had been involved with optic neuritis before,” Dr. Kardon said. To date, he and his colleagues have completed technical validation of temporal frequency and contrast parameters. They’ve also completed preliminary investigations for determining test-retest variability, blurring effects, binocular summation effects, and quantification of normative ranges and abnormal subject data.
“A benefit of smartphone testing in MS is that visual dysfunction can be detected, leading to earlier interventions,” Dr. Kardon concluded. “We can study this on a time scale that wasn’t previously available. Wouldn’t you like to know on a daily or even a weekly basis what the fluctuations are in a home environment for MS patients? It’s low-cost, large-scale, and enables you to study genotype-phenotype comparisons.”
Going forward, Dr. Kardon and his colleagues have developed video cameras that go around the periphery of the iPad that can assess pupil and ocular motility, as well as eyelid and facial features in real time. He disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.
DALLAS – A battery of smartphone tests have been developed to help clinicians detect and monitor eye changes in MS patients.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, Randy H. Kardon, MD, PhD, said that there are two main high priority gaps to fill when it comes to better understanding the effects of MS on vision. “One, I think we need a way for early detection of visual pathway disturbances after either an acute clinical event or a subclinical event,” said Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City. “Two, we need to monitor changes in the visual pathway over time in MS patients and capture variations due to changes in nerve conduction. The idea is, can we have a suite of smartphone tests that you can use in the clinic, but the patient can also use at home unsupervised, to get a time domain, so if there are fluctuations of core body temperature due to myelination, or subclinical changes going on, could we detect it earlier and monitor these patients? That’s the motivation.”
Although use of smartphone technology and mobile devices are emerging in health care settings, most of this technology is used sparingly in vision testing, mostly due to a lack of rigorous calibration of instruments and validation, said Dr. Kardon, who also directs the Iowa City VA Center for Prevention and Treatment of Visual Loss. To make a visual smartphone test viable, he continued, the visual output of the device must match the intended input in terms of multiple parameters (technical validation). Important parameters for vision tests include brightness, luminance, spatial resolution, and temporal resolution. Confounding variables include ambient lighting and viewing distance.
In his work with researchers from Aalborg University in Denmark, Dr. Kardon has developed four smartphone visual tests intended to be intuitive for patients. “We didn’t want something that was going to take more than 15 seconds,” he said. The visual tests include:
1. Critical flicker fusion, a test of optic nerve conduction. “This tests how well you can see a light flickering at a given temporal frequency at different levels of contrast, or how fast it can flicker before you don’t see a flicker anymore,” Dr. Kardon said. “The user sees spots that are flickering and just touches the ones they perceive to be flickering; they eliminate them by touching them.” When the test ends, the software “brackets what they did to a finer scale, and it finds the contrast at which that flicker wasn’t perceived anymore.”
2. The Landolt C visual acuity test. For this, the user must indicate the direction of the gap in the ring in a forced-choice task. “The user touches which arrow on the screen is pointing to where the location of the break in the Landolt C is perceived,” Dr. Kardon said. The Landolt C becomes progressively smaller until the location of the break can no longer be seen. “It’s pretty simple, and it finds the smallest size of the ‘C’ at which you’re making mistakes about 50% of the time, which is the threshold value for visual acuity,” he said.
3. Contrast sensitivity test at a fixed spatial frequency. “In this test, we fix the size of the letter to a large size, so spatial frequency is not at play, and we vary the contrast,” he said. “Users push the arrow wherever they see the break.” The contrast between the “C” and the background is sequentially reduced until a threshold is determined for the lowest contrast at which the location of the break in the “C” can still be observed.
4. Contrast sensitivity test at different spatial frequencies. This measure, also known as a vanishing optotype, is a line drawing of an object on a smooth, diffuse grayscale background. By altering the line properties used to define the shape of the vanishing optotype, one can vary its spatial frequency and contrast independent of target size. “This makes it an easy test because what the patient is asked to do is to touch wherever they see an object on the screen to eliminate it from the series of optotypes on the screen,” Dr. Kardon said. “The test is very fast, very intuitive.”
The researchers piloted use of these tests in a study of 104 age-matched control subjects and 117 MS patients. Of the 117 MS patients, 74 had a history of optic neuritis and 43 did not. The four tests were used in conjunction with standardized assessments, including the near-contrast acuity card test at 2.5%, the distant Early Treatment Diabetic Retinopathy Study (ETDRS) acuity test, as well as optical coherence tomography (OCT) of the retinal nerve fiber layer and ganglion cell layer thickness. Dr. Kardon and his colleagues found that when clinicians used a large target and varied the contrast, the test “did very well at differentiating normal from eyes with either previous optic neuritis or no previous optic neuritis,” he said. “It also differentiated eyes with previous optic neuritis and those with no optic neuritis. The visual acuity test didn’t perform as well because this is a near test. What we discovered afterward is that even at a fixed distance, many people who are presbyopic, or don’t have their optimal near correction, don’t do so well, because you’re testing spatial acuity. That’s a warning sign for future tests. You have to be careful as to how these are interpreted if they don’t have their best correction at near.”
Results from the critical flicker fusions tests were significant, except that they didn’t differentiate eyes affected by optic neuritis from those that weren’t. “The reason is that conduction was down in all of those eyes, so the combination of using contrast sensitivity and flicker fusion may not only help you diagnose MS, but whether that eye had been involved with optic neuritis before,” Dr. Kardon said. To date, he and his colleagues have completed technical validation of temporal frequency and contrast parameters. They’ve also completed preliminary investigations for determining test-retest variability, blurring effects, binocular summation effects, and quantification of normative ranges and abnormal subject data.
“A benefit of smartphone testing in MS is that visual dysfunction can be detected, leading to earlier interventions,” Dr. Kardon concluded. “We can study this on a time scale that wasn’t previously available. Wouldn’t you like to know on a daily or even a weekly basis what the fluctuations are in a home environment for MS patients? It’s low-cost, large-scale, and enables you to study genotype-phenotype comparisons.”
Going forward, Dr. Kardon and his colleagues have developed video cameras that go around the periphery of the iPad that can assess pupil and ocular motility, as well as eyelid and facial features in real time. He disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019
Study eyes serious adverse events from long-term rituximab use in MS
DALLAS – An analysis of two large cohorts treated with rituximab (Rituxan) showed that the rate of serious infections was 8.1%, yet no life-threatening infusion reactions occurred.
The finding comes from a retrospective chart review of 500 patients treated at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado at Denver, Aurora, and 269 treated at the New York University Multiple Sclerosis Comprehensive Care Center.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, one of the study authors, Brandi L. Vollmer, MPH, noted that while rituximab is used off-label to treat multiple sclerosis (MS) and related disorders, limited long-term data for MS patients exist. Ms. Vollmer, a professional research assistant in the department of neurology in the division of neuroimmunology at the University of Colorado at Denver, and her associates identified all patients at the two MS centers who received at least one dose of rituximab. They reviewed patient charts from rituximab start date until 12 months after the last rituximab end date, or last ocrelizumab (Ocrevus) infusion in cases where patients switched to ocrelizumab without interruption with any other disease-modifying therapy. Data were abstracted from each chart using a case report form that systematically queried for demographic and clinical characteristics, serious adverse events, and significant laboratory abnormalities. The researchers used descriptive statistics to describe the sample group.
Key outcomes of interest were infusion reactions that were life-threatening or resulted in a hospitalization; infections that resulted in hospitalization, the need for IV antibiotics, or extended antibiotics; abnormal lab values; new diagnosis of malignant cancer; new diagnosis of autoimmune disease; diagnosis of serious thromboembolism; and mortality within 12 months of last infusion. At baseline, the mean age of the 769 patients was 43 years, 69% were female, 64% were white, and 16% were black. More than half (58%) had a diagnosis of relapsing-remitting MS, followed by secondary progressive MS (20%), primary progressive MS (11%), neuromyelitis optica spectrum disorder (9%), or other, and their mean disease duration was 8 years.
The researchers reported that the mean cumulative rituximab dose was 4,124 mg (median of 3,000 mg), the mean dose of ocrelizumab for ocrelizumab-switchers was 1,087 mg, and the mean time of follow-up was 33 months. Infections while on rituximab/ocrelizumab resulting in a hospitalization were observed in 50 patients (6.5%), which were primarily urinary tract infections (UTIs; 19 cases), pneumonia (12 cases), and sepsis (12 cases), while 7 patients (0.9%) experienced an infection that resulted in extended dosing antibiotics, including 5 recurrent UTIs, 1 case of bacteremia, and 1 case of osteomyelitis.
Ms. Vollmer and her colleagues also found that five patients (0.7%) experienced an infection that resulted in IV antibiotics without hospitalization, including one case each of pneumonia, cellulitis, UTI, infected wound, and aspiration pneumonia with respiratory syncytial virus. Serious de novo diagnoses while on rituximab were reported for 18 patients (2%), including autoimmune disease in 4, non-skin neoplasm in 7, and serious thromboembolic events in 7.
No patient experienced an infusion reaction requiring hospitalization. However, one patient received epinephrine after seeking care at an emergency department post infusion. Twelve patients (2%) died within 12 months of their last rituximab dose, although none were deemed by the treating clinician to be related to rituximab. Significant neutropenia was observed in 12 (2%), lymphopenia in 46 (6%), and IgG values below 500 mg/dL in 28 (4%).
“So far, this is just a descriptive analysis,” Ms. Vollmer said. “We want to look further into how abnormal lab values correlate with serious infections in particular.”
She acknowledged certain limitations of the study, including its retrospective design. Ms. Vollmer reported having no financial disclosures. Many of her coauthors reporting having numerous financial ties to the pharmaceutical industry.
SOURCE: Vollmer B et al. ACTRIMS Forum 2019, Poster 113
DALLAS – An analysis of two large cohorts treated with rituximab (Rituxan) showed that the rate of serious infections was 8.1%, yet no life-threatening infusion reactions occurred.
The finding comes from a retrospective chart review of 500 patients treated at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado at Denver, Aurora, and 269 treated at the New York University Multiple Sclerosis Comprehensive Care Center.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, one of the study authors, Brandi L. Vollmer, MPH, noted that while rituximab is used off-label to treat multiple sclerosis (MS) and related disorders, limited long-term data for MS patients exist. Ms. Vollmer, a professional research assistant in the department of neurology in the division of neuroimmunology at the University of Colorado at Denver, and her associates identified all patients at the two MS centers who received at least one dose of rituximab. They reviewed patient charts from rituximab start date until 12 months after the last rituximab end date, or last ocrelizumab (Ocrevus) infusion in cases where patients switched to ocrelizumab without interruption with any other disease-modifying therapy. Data were abstracted from each chart using a case report form that systematically queried for demographic and clinical characteristics, serious adverse events, and significant laboratory abnormalities. The researchers used descriptive statistics to describe the sample group.
Key outcomes of interest were infusion reactions that were life-threatening or resulted in a hospitalization; infections that resulted in hospitalization, the need for IV antibiotics, or extended antibiotics; abnormal lab values; new diagnosis of malignant cancer; new diagnosis of autoimmune disease; diagnosis of serious thromboembolism; and mortality within 12 months of last infusion. At baseline, the mean age of the 769 patients was 43 years, 69% were female, 64% were white, and 16% were black. More than half (58%) had a diagnosis of relapsing-remitting MS, followed by secondary progressive MS (20%), primary progressive MS (11%), neuromyelitis optica spectrum disorder (9%), or other, and their mean disease duration was 8 years.
The researchers reported that the mean cumulative rituximab dose was 4,124 mg (median of 3,000 mg), the mean dose of ocrelizumab for ocrelizumab-switchers was 1,087 mg, and the mean time of follow-up was 33 months. Infections while on rituximab/ocrelizumab resulting in a hospitalization were observed in 50 patients (6.5%), which were primarily urinary tract infections (UTIs; 19 cases), pneumonia (12 cases), and sepsis (12 cases), while 7 patients (0.9%) experienced an infection that resulted in extended dosing antibiotics, including 5 recurrent UTIs, 1 case of bacteremia, and 1 case of osteomyelitis.
Ms. Vollmer and her colleagues also found that five patients (0.7%) experienced an infection that resulted in IV antibiotics without hospitalization, including one case each of pneumonia, cellulitis, UTI, infected wound, and aspiration pneumonia with respiratory syncytial virus. Serious de novo diagnoses while on rituximab were reported for 18 patients (2%), including autoimmune disease in 4, non-skin neoplasm in 7, and serious thromboembolic events in 7.
No patient experienced an infusion reaction requiring hospitalization. However, one patient received epinephrine after seeking care at an emergency department post infusion. Twelve patients (2%) died within 12 months of their last rituximab dose, although none were deemed by the treating clinician to be related to rituximab. Significant neutropenia was observed in 12 (2%), lymphopenia in 46 (6%), and IgG values below 500 mg/dL in 28 (4%).
“So far, this is just a descriptive analysis,” Ms. Vollmer said. “We want to look further into how abnormal lab values correlate with serious infections in particular.”
She acknowledged certain limitations of the study, including its retrospective design. Ms. Vollmer reported having no financial disclosures. Many of her coauthors reporting having numerous financial ties to the pharmaceutical industry.
SOURCE: Vollmer B et al. ACTRIMS Forum 2019, Poster 113
DALLAS – An analysis of two large cohorts treated with rituximab (Rituxan) showed that the rate of serious infections was 8.1%, yet no life-threatening infusion reactions occurred.
The finding comes from a retrospective chart review of 500 patients treated at the Rocky Mountain Multiple Sclerosis Center at the University of Colorado at Denver, Aurora, and 269 treated at the New York University Multiple Sclerosis Comprehensive Care Center.
At a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis, one of the study authors, Brandi L. Vollmer, MPH, noted that while rituximab is used off-label to treat multiple sclerosis (MS) and related disorders, limited long-term data for MS patients exist. Ms. Vollmer, a professional research assistant in the department of neurology in the division of neuroimmunology at the University of Colorado at Denver, and her associates identified all patients at the two MS centers who received at least one dose of rituximab. They reviewed patient charts from rituximab start date until 12 months after the last rituximab end date, or last ocrelizumab (Ocrevus) infusion in cases where patients switched to ocrelizumab without interruption with any other disease-modifying therapy. Data were abstracted from each chart using a case report form that systematically queried for demographic and clinical characteristics, serious adverse events, and significant laboratory abnormalities. The researchers used descriptive statistics to describe the sample group.
Key outcomes of interest were infusion reactions that were life-threatening or resulted in a hospitalization; infections that resulted in hospitalization, the need for IV antibiotics, or extended antibiotics; abnormal lab values; new diagnosis of malignant cancer; new diagnosis of autoimmune disease; diagnosis of serious thromboembolism; and mortality within 12 months of last infusion. At baseline, the mean age of the 769 patients was 43 years, 69% were female, 64% were white, and 16% were black. More than half (58%) had a diagnosis of relapsing-remitting MS, followed by secondary progressive MS (20%), primary progressive MS (11%), neuromyelitis optica spectrum disorder (9%), or other, and their mean disease duration was 8 years.
The researchers reported that the mean cumulative rituximab dose was 4,124 mg (median of 3,000 mg), the mean dose of ocrelizumab for ocrelizumab-switchers was 1,087 mg, and the mean time of follow-up was 33 months. Infections while on rituximab/ocrelizumab resulting in a hospitalization were observed in 50 patients (6.5%), which were primarily urinary tract infections (UTIs; 19 cases), pneumonia (12 cases), and sepsis (12 cases), while 7 patients (0.9%) experienced an infection that resulted in extended dosing antibiotics, including 5 recurrent UTIs, 1 case of bacteremia, and 1 case of osteomyelitis.
Ms. Vollmer and her colleagues also found that five patients (0.7%) experienced an infection that resulted in IV antibiotics without hospitalization, including one case each of pneumonia, cellulitis, UTI, infected wound, and aspiration pneumonia with respiratory syncytial virus. Serious de novo diagnoses while on rituximab were reported for 18 patients (2%), including autoimmune disease in 4, non-skin neoplasm in 7, and serious thromboembolic events in 7.
No patient experienced an infusion reaction requiring hospitalization. However, one patient received epinephrine after seeking care at an emergency department post infusion. Twelve patients (2%) died within 12 months of their last rituximab dose, although none were deemed by the treating clinician to be related to rituximab. Significant neutropenia was observed in 12 (2%), lymphopenia in 46 (6%), and IgG values below 500 mg/dL in 28 (4%).
“So far, this is just a descriptive analysis,” Ms. Vollmer said. “We want to look further into how abnormal lab values correlate with serious infections in particular.”
She acknowledged certain limitations of the study, including its retrospective design. Ms. Vollmer reported having no financial disclosures. Many of her coauthors reporting having numerous financial ties to the pharmaceutical industry.
SOURCE: Vollmer B et al. ACTRIMS Forum 2019, Poster 113
REPORTING FROM ACTRIMS 2019
Optical coherence tomography emerging as a promising biomarker for MS
DALLAS – Optical coherence tomography (OCT) has emerged as a promising biomarker in multiple sclerosis.
Thanks to OCT, clinicians are gaining an improved understanding of how MS affects certain eye structures. An optical analogue of ultrasound B mode imaging, OCT achieves a resolution of about 3-6 microns with commercially available devices. “That allows us to quantify the layers of the retina with quite a degree of accuracy,” Shiv Saidha, MD, said at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
At postmortem, up to 99% of MS patients have demyelinated plaques in their optic nerves. “This implies that optic neuropathy is an ubiquitous phenomenon as part of the MS disease process,” said Dr. Saidha, a neurologist at Johns Hopkins University, Baltimore. “The prevailing hypothesis is that there is demyelination or axonal transection related to acute inflammation that occurs within the optic nerve. There’s a retrograde degeneration of its constituent axons, and that results in thinning of the inner retinal nerve fiber layer as well as the neuronal derivative of this layer called the ganglion cell layer. In addition to neurodegenerative mechanisms in the retina, there is also perivascular inflammation, called retinal periphlebitis, which we know occurs in about 20% of MS patients. At postmortem, there are also activate microglia present within the retina of MS patients.”
One of the principal findings of OCT in MS to date is that the retinal nerve fiber layer (RNFL) and ganglion cell plus inner plexiform layer (GCIP) thinning reflects MS-related optic nerve neurodegeneration. In addition, RNFL and GCIP thinning occur after optic neuritis and also as part of the MS disease course in eyes without a history of optic neuritis. “RNFL and GCIP thinning in MS are clinically relevant and correlate with visual function, global disability, and brain atrophy,” Dr. Saidha said. Researchers have also found that rates of GCIP thinning are accelerated in MS patients exhibiting clinical and/or radiological disease activity and are altered by disease-modifying therapies, and that increased inner nuclear layer (INL) thickness correlates with T2 lesion volume and predicts clinical and radiological disease activity. “In numerous trials of putatively neuroprotective and restorative treatments, we see OCT incorporated more and more, either as a secondary or a primary outcome,” he said.
Predicting disability and brain atrophy
In a study expected to be appear in a forthcoming issue of the Annals of Translational and Clinical Neurology, colleagues of Dr. Saidha found that OCT derived retinal layer measurements and visual function predict disability at 10 years in patients with MS. The researchers used an earlier generation, lower quality OCT device to examine tertiles of total macular volume, “an old, nonspecific composite measure of all of the retinal components,” he explained. “Even with inferior technology, a single measurement at a point in time not only could predict the change in EDSS [Expanded Disability Status Scale] scores from baseline to 10 years, but the accumulation of meaningful disability.”
In an earlier study, Dr. Saidha and his colleagues conducted a 4-year study of OCT and MRI in MS (Ann Neurol 2015; 78[5]:801-13). It consisted of six monthly spectral domain OCT scans (including automated intra-retinal segmentation) and baseline and annual 3 T brain MRI (including substructure volumetrics). Patients with ocular relapses (optic neuritis) during the study were excluded. The researchers correlated individual-specific rates of change in retinal and brain measurements, adjusting for age, sex, disease duration, and optic neuritis history. They found that cerebral volume fraction (analogous to whole brain volume) “had a decent correlation between rates of GCIP atrophy and rates of whole brain volume loss,” he said. “That was predominately driven by cortical gray matter atrophy.”
Measuring effects of disease-modifying therapies
What about the effects of disease-modifying therapies? According to Dr. Saidha, there has been a paucity of studies assessing the effects of DMTs on retinal layer thickness, and they are limited by small patient numbers, cross-sectional design, and/or short periods of observation. In a retrospective analysis, he and his associates examined the effects of treatments in relapsing-remitting MS patients at his center who underwent OCT (Neurology. 2017;88[6]:525-32). Over a mean 3 years of follow-up, they examined the effects of glatiramer acetate (Copaxone), natalizumab (Tysabri), and interferon beta-1a subcutaneously (Rebif) and intramuscularly (Avonex). They adjusted for gap time, which is the interval between when a patient started a treatment and when they started to undergo retinal observation with OCT. “This is to try to account for some of the biological changes that might have occurred during that period of time,” he explained. The researchers observed that rates of GCIP atrophy as well as other retinal measures were significantly lower in people treated with natalizumab, relative to all other DMTs. “What I found fascinating was the rate of GCIP atrophy of those on natalizumab was basically the same as healthy controls,” Dr. Saidha said. “It didn’t differ.”
Retinal inflammation and treatment’s impact
Significant inflammation in the unmyelinated retina may inform clinicians about other aspects of MS, he continued. For example, retinal periphlebitis occurs in about 20% of MS patients and may be a marker of CNS inflammation. In addition, intermediate uveitis occurs in about 16% of MS patients, and postmortem studies reveal retinal inflammation with microglia. Specifically, macular microcystoid changes occur in the eyes of about 5% of MS patients and may represent a breakdown of the blood-retinal barrier and inflammation. “Since it’s a dynamic process, increased thickness of the INL in the absence of visible microcystoid changes might occur,” Dr. Saidha said. “We found that baseline INL thickness is predictive of clinico-radiologic disease activity.”
In a separate analysis of 108 MS patients and 40 healthy controls, German researchers evaluated the impact of DMTs on INL volume (Brain. 2016;11[1]:2855-63). They found that higher baseline INL volume correlated with new T2 and GAD lesions over 1 year. The reduction in INL volume was significantly associated with reduced activity, and overall, DMTs reduced INL volume over 6 months. Patients who were not treated, or who were treated and did not achieve NEDA-3 (no evidence of disease activity) did not show reductions in INL volume. They concluded that INL volume might be a novel outcome of DMT treatment.
Finding prognostic and diagnostic biomarkers
In an ongoing multisite study, Dr. Saidha and his colleagues are assessing the use of OCT in patients with progressive MS (including 186 patients from Johns Hopkins), and also determining if OCT changes differ over time between relapsing-remitting MS and different subtypes of progressive MS. So far, they have found that progressive MS is associated with accelerated inner and in particular outer layer retinal atrophy. “Although this is a decent-sized cohort, at this stage I’m not sure I would definitively say that these novel retinal biomarkers have utility specific to progressive MS, but I’m very excited about it,” he said. “The goal is to take a much deeper look at this.”
Findings from a large collaborative IMSVISUAL inter-eye asymmetry study showed that peripapillary RNFL and ganglion cell–inner plexiform layer inter-eye differences of 5 microns, respectively, were optimal for identifying patients with prior unilateral optic neuritis in the MS cohort. “In the future, the possibility of using OCT to identify subclinical optic neuropathy so we can define when a lesion is present in the optic nerve has huge diagnostic implications for MS, because the optic nerve is not currently recognized as a lesion site in current MS diagnostic criteria,” Dr. Saidha said.
Dr. Saidha disclosed that he has served on scientific advisory boards for Biogen, Genzyme, Genentech, EMD Serono, and Novartis. He has also received consulting fees from JuneBrain LLC and is the site investigator of a trial sponsored by MedDay Pharmaceuticals.
DALLAS – Optical coherence tomography (OCT) has emerged as a promising biomarker in multiple sclerosis.
Thanks to OCT, clinicians are gaining an improved understanding of how MS affects certain eye structures. An optical analogue of ultrasound B mode imaging, OCT achieves a resolution of about 3-6 microns with commercially available devices. “That allows us to quantify the layers of the retina with quite a degree of accuracy,” Shiv Saidha, MD, said at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
At postmortem, up to 99% of MS patients have demyelinated plaques in their optic nerves. “This implies that optic neuropathy is an ubiquitous phenomenon as part of the MS disease process,” said Dr. Saidha, a neurologist at Johns Hopkins University, Baltimore. “The prevailing hypothesis is that there is demyelination or axonal transection related to acute inflammation that occurs within the optic nerve. There’s a retrograde degeneration of its constituent axons, and that results in thinning of the inner retinal nerve fiber layer as well as the neuronal derivative of this layer called the ganglion cell layer. In addition to neurodegenerative mechanisms in the retina, there is also perivascular inflammation, called retinal periphlebitis, which we know occurs in about 20% of MS patients. At postmortem, there are also activate microglia present within the retina of MS patients.”
One of the principal findings of OCT in MS to date is that the retinal nerve fiber layer (RNFL) and ganglion cell plus inner plexiform layer (GCIP) thinning reflects MS-related optic nerve neurodegeneration. In addition, RNFL and GCIP thinning occur after optic neuritis and also as part of the MS disease course in eyes without a history of optic neuritis. “RNFL and GCIP thinning in MS are clinically relevant and correlate with visual function, global disability, and brain atrophy,” Dr. Saidha said. Researchers have also found that rates of GCIP thinning are accelerated in MS patients exhibiting clinical and/or radiological disease activity and are altered by disease-modifying therapies, and that increased inner nuclear layer (INL) thickness correlates with T2 lesion volume and predicts clinical and radiological disease activity. “In numerous trials of putatively neuroprotective and restorative treatments, we see OCT incorporated more and more, either as a secondary or a primary outcome,” he said.
Predicting disability and brain atrophy
In a study expected to be appear in a forthcoming issue of the Annals of Translational and Clinical Neurology, colleagues of Dr. Saidha found that OCT derived retinal layer measurements and visual function predict disability at 10 years in patients with MS. The researchers used an earlier generation, lower quality OCT device to examine tertiles of total macular volume, “an old, nonspecific composite measure of all of the retinal components,” he explained. “Even with inferior technology, a single measurement at a point in time not only could predict the change in EDSS [Expanded Disability Status Scale] scores from baseline to 10 years, but the accumulation of meaningful disability.”
In an earlier study, Dr. Saidha and his colleagues conducted a 4-year study of OCT and MRI in MS (Ann Neurol 2015; 78[5]:801-13). It consisted of six monthly spectral domain OCT scans (including automated intra-retinal segmentation) and baseline and annual 3 T brain MRI (including substructure volumetrics). Patients with ocular relapses (optic neuritis) during the study were excluded. The researchers correlated individual-specific rates of change in retinal and brain measurements, adjusting for age, sex, disease duration, and optic neuritis history. They found that cerebral volume fraction (analogous to whole brain volume) “had a decent correlation between rates of GCIP atrophy and rates of whole brain volume loss,” he said. “That was predominately driven by cortical gray matter atrophy.”
Measuring effects of disease-modifying therapies
What about the effects of disease-modifying therapies? According to Dr. Saidha, there has been a paucity of studies assessing the effects of DMTs on retinal layer thickness, and they are limited by small patient numbers, cross-sectional design, and/or short periods of observation. In a retrospective analysis, he and his associates examined the effects of treatments in relapsing-remitting MS patients at his center who underwent OCT (Neurology. 2017;88[6]:525-32). Over a mean 3 years of follow-up, they examined the effects of glatiramer acetate (Copaxone), natalizumab (Tysabri), and interferon beta-1a subcutaneously (Rebif) and intramuscularly (Avonex). They adjusted for gap time, which is the interval between when a patient started a treatment and when they started to undergo retinal observation with OCT. “This is to try to account for some of the biological changes that might have occurred during that period of time,” he explained. The researchers observed that rates of GCIP atrophy as well as other retinal measures were significantly lower in people treated with natalizumab, relative to all other DMTs. “What I found fascinating was the rate of GCIP atrophy of those on natalizumab was basically the same as healthy controls,” Dr. Saidha said. “It didn’t differ.”
Retinal inflammation and treatment’s impact
Significant inflammation in the unmyelinated retina may inform clinicians about other aspects of MS, he continued. For example, retinal periphlebitis occurs in about 20% of MS patients and may be a marker of CNS inflammation. In addition, intermediate uveitis occurs in about 16% of MS patients, and postmortem studies reveal retinal inflammation with microglia. Specifically, macular microcystoid changes occur in the eyes of about 5% of MS patients and may represent a breakdown of the blood-retinal barrier and inflammation. “Since it’s a dynamic process, increased thickness of the INL in the absence of visible microcystoid changes might occur,” Dr. Saidha said. “We found that baseline INL thickness is predictive of clinico-radiologic disease activity.”
In a separate analysis of 108 MS patients and 40 healthy controls, German researchers evaluated the impact of DMTs on INL volume (Brain. 2016;11[1]:2855-63). They found that higher baseline INL volume correlated with new T2 and GAD lesions over 1 year. The reduction in INL volume was significantly associated with reduced activity, and overall, DMTs reduced INL volume over 6 months. Patients who were not treated, or who were treated and did not achieve NEDA-3 (no evidence of disease activity) did not show reductions in INL volume. They concluded that INL volume might be a novel outcome of DMT treatment.
Finding prognostic and diagnostic biomarkers
In an ongoing multisite study, Dr. Saidha and his colleagues are assessing the use of OCT in patients with progressive MS (including 186 patients from Johns Hopkins), and also determining if OCT changes differ over time between relapsing-remitting MS and different subtypes of progressive MS. So far, they have found that progressive MS is associated with accelerated inner and in particular outer layer retinal atrophy. “Although this is a decent-sized cohort, at this stage I’m not sure I would definitively say that these novel retinal biomarkers have utility specific to progressive MS, but I’m very excited about it,” he said. “The goal is to take a much deeper look at this.”
Findings from a large collaborative IMSVISUAL inter-eye asymmetry study showed that peripapillary RNFL and ganglion cell–inner plexiform layer inter-eye differences of 5 microns, respectively, were optimal for identifying patients with prior unilateral optic neuritis in the MS cohort. “In the future, the possibility of using OCT to identify subclinical optic neuropathy so we can define when a lesion is present in the optic nerve has huge diagnostic implications for MS, because the optic nerve is not currently recognized as a lesion site in current MS diagnostic criteria,” Dr. Saidha said.
Dr. Saidha disclosed that he has served on scientific advisory boards for Biogen, Genzyme, Genentech, EMD Serono, and Novartis. He has also received consulting fees from JuneBrain LLC and is the site investigator of a trial sponsored by MedDay Pharmaceuticals.
DALLAS – Optical coherence tomography (OCT) has emerged as a promising biomarker in multiple sclerosis.
Thanks to OCT, clinicians are gaining an improved understanding of how MS affects certain eye structures. An optical analogue of ultrasound B mode imaging, OCT achieves a resolution of about 3-6 microns with commercially available devices. “That allows us to quantify the layers of the retina with quite a degree of accuracy,” Shiv Saidha, MD, said at ACTRIMS Forum 2019, the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
At postmortem, up to 99% of MS patients have demyelinated plaques in their optic nerves. “This implies that optic neuropathy is an ubiquitous phenomenon as part of the MS disease process,” said Dr. Saidha, a neurologist at Johns Hopkins University, Baltimore. “The prevailing hypothesis is that there is demyelination or axonal transection related to acute inflammation that occurs within the optic nerve. There’s a retrograde degeneration of its constituent axons, and that results in thinning of the inner retinal nerve fiber layer as well as the neuronal derivative of this layer called the ganglion cell layer. In addition to neurodegenerative mechanisms in the retina, there is also perivascular inflammation, called retinal periphlebitis, which we know occurs in about 20% of MS patients. At postmortem, there are also activate microglia present within the retina of MS patients.”
One of the principal findings of OCT in MS to date is that the retinal nerve fiber layer (RNFL) and ganglion cell plus inner plexiform layer (GCIP) thinning reflects MS-related optic nerve neurodegeneration. In addition, RNFL and GCIP thinning occur after optic neuritis and also as part of the MS disease course in eyes without a history of optic neuritis. “RNFL and GCIP thinning in MS are clinically relevant and correlate with visual function, global disability, and brain atrophy,” Dr. Saidha said. Researchers have also found that rates of GCIP thinning are accelerated in MS patients exhibiting clinical and/or radiological disease activity and are altered by disease-modifying therapies, and that increased inner nuclear layer (INL) thickness correlates with T2 lesion volume and predicts clinical and radiological disease activity. “In numerous trials of putatively neuroprotective and restorative treatments, we see OCT incorporated more and more, either as a secondary or a primary outcome,” he said.
Predicting disability and brain atrophy
In a study expected to be appear in a forthcoming issue of the Annals of Translational and Clinical Neurology, colleagues of Dr. Saidha found that OCT derived retinal layer measurements and visual function predict disability at 10 years in patients with MS. The researchers used an earlier generation, lower quality OCT device to examine tertiles of total macular volume, “an old, nonspecific composite measure of all of the retinal components,” he explained. “Even with inferior technology, a single measurement at a point in time not only could predict the change in EDSS [Expanded Disability Status Scale] scores from baseline to 10 years, but the accumulation of meaningful disability.”
In an earlier study, Dr. Saidha and his colleagues conducted a 4-year study of OCT and MRI in MS (Ann Neurol 2015; 78[5]:801-13). It consisted of six monthly spectral domain OCT scans (including automated intra-retinal segmentation) and baseline and annual 3 T brain MRI (including substructure volumetrics). Patients with ocular relapses (optic neuritis) during the study were excluded. The researchers correlated individual-specific rates of change in retinal and brain measurements, adjusting for age, sex, disease duration, and optic neuritis history. They found that cerebral volume fraction (analogous to whole brain volume) “had a decent correlation between rates of GCIP atrophy and rates of whole brain volume loss,” he said. “That was predominately driven by cortical gray matter atrophy.”
Measuring effects of disease-modifying therapies
What about the effects of disease-modifying therapies? According to Dr. Saidha, there has been a paucity of studies assessing the effects of DMTs on retinal layer thickness, and they are limited by small patient numbers, cross-sectional design, and/or short periods of observation. In a retrospective analysis, he and his associates examined the effects of treatments in relapsing-remitting MS patients at his center who underwent OCT (Neurology. 2017;88[6]:525-32). Over a mean 3 years of follow-up, they examined the effects of glatiramer acetate (Copaxone), natalizumab (Tysabri), and interferon beta-1a subcutaneously (Rebif) and intramuscularly (Avonex). They adjusted for gap time, which is the interval between when a patient started a treatment and when they started to undergo retinal observation with OCT. “This is to try to account for some of the biological changes that might have occurred during that period of time,” he explained. The researchers observed that rates of GCIP atrophy as well as other retinal measures were significantly lower in people treated with natalizumab, relative to all other DMTs. “What I found fascinating was the rate of GCIP atrophy of those on natalizumab was basically the same as healthy controls,” Dr. Saidha said. “It didn’t differ.”
Retinal inflammation and treatment’s impact
Significant inflammation in the unmyelinated retina may inform clinicians about other aspects of MS, he continued. For example, retinal periphlebitis occurs in about 20% of MS patients and may be a marker of CNS inflammation. In addition, intermediate uveitis occurs in about 16% of MS patients, and postmortem studies reveal retinal inflammation with microglia. Specifically, macular microcystoid changes occur in the eyes of about 5% of MS patients and may represent a breakdown of the blood-retinal barrier and inflammation. “Since it’s a dynamic process, increased thickness of the INL in the absence of visible microcystoid changes might occur,” Dr. Saidha said. “We found that baseline INL thickness is predictive of clinico-radiologic disease activity.”
In a separate analysis of 108 MS patients and 40 healthy controls, German researchers evaluated the impact of DMTs on INL volume (Brain. 2016;11[1]:2855-63). They found that higher baseline INL volume correlated with new T2 and GAD lesions over 1 year. The reduction in INL volume was significantly associated with reduced activity, and overall, DMTs reduced INL volume over 6 months. Patients who were not treated, or who were treated and did not achieve NEDA-3 (no evidence of disease activity) did not show reductions in INL volume. They concluded that INL volume might be a novel outcome of DMT treatment.
Finding prognostic and diagnostic biomarkers
In an ongoing multisite study, Dr. Saidha and his colleagues are assessing the use of OCT in patients with progressive MS (including 186 patients from Johns Hopkins), and also determining if OCT changes differ over time between relapsing-remitting MS and different subtypes of progressive MS. So far, they have found that progressive MS is associated with accelerated inner and in particular outer layer retinal atrophy. “Although this is a decent-sized cohort, at this stage I’m not sure I would definitively say that these novel retinal biomarkers have utility specific to progressive MS, but I’m very excited about it,” he said. “The goal is to take a much deeper look at this.”
Findings from a large collaborative IMSVISUAL inter-eye asymmetry study showed that peripapillary RNFL and ganglion cell–inner plexiform layer inter-eye differences of 5 microns, respectively, were optimal for identifying patients with prior unilateral optic neuritis in the MS cohort. “In the future, the possibility of using OCT to identify subclinical optic neuropathy so we can define when a lesion is present in the optic nerve has huge diagnostic implications for MS, because the optic nerve is not currently recognized as a lesion site in current MS diagnostic criteria,” Dr. Saidha said.
Dr. Saidha disclosed that he has served on scientific advisory boards for Biogen, Genzyme, Genentech, EMD Serono, and Novartis. He has also received consulting fees from JuneBrain LLC and is the site investigator of a trial sponsored by MedDay Pharmaceuticals.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2019