Multiple Sclerosis

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.

dbrunk@mdedge.com

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.

dbrunk@mdedge.com

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.

dbrunk@mdedge.com

In patients with multiple sclerosis (MS), the risk of acute myocardial infarction (AMI) is elevated but may not be accounted for by traditional vascular risk factors, a new study found. Researchers conducted a retrospective matched cohort study using population-based administrative data in 2 Canadian provinces. Incident MS cases were identified and for each case, up to 5 controls without MS were matched on age, sex, and region. The incidence of AMI between cohorts was compared using incidence rate ratios (IRRs). Among the findings:

• 14,565 persons with MS and 72,825 matched controls were identified.
• The crude incidence of AMI per 100,000 population was 146.2 in the MS population vs 128.8 in the matched population.
• After age standardization, the incidence of AMI was higher in the MS population vs the matched population (IRR 1.18).
• After adjustment, the hazard of AMI was 60% higher in the MS population vs the matched population (hazard ratio 1.63).

Marrie RA, Garland A, Schaffer SA. Traditional risk factors may not explain increased incidence of myocardial infarction in MS. [Published online ahead of print March 6, 2019]. Neurology. doi:10.1212/WNL.0000000000007251.

In patients with multiple sclerosis (MS), the risk of acute myocardial infarction (AMI) is elevated but may not be accounted for by traditional vascular risk factors, a new study found. Researchers conducted a retrospective matched cohort study using population-based administrative data in 2 Canadian provinces. Incident MS cases were identified and for each case, up to 5 controls without MS were matched on age, sex, and region. The incidence of AMI between cohorts was compared using incidence rate ratios (IRRs). Among the findings:

• 14,565 persons with MS and 72,825 matched controls were identified.
• The crude incidence of AMI per 100,000 population was 146.2 in the MS population vs 128.8 in the matched population.
• After age standardization, the incidence of AMI was higher in the MS population vs the matched population (IRR 1.18).
• After adjustment, the hazard of AMI was 60% higher in the MS population vs the matched population (hazard ratio 1.63).

Marrie RA, Garland A, Schaffer SA. Traditional risk factors may not explain increased incidence of myocardial infarction in MS. [Published online ahead of print March 6, 2019]. Neurology. doi:10.1212/WNL.0000000000007251.

In patients with multiple sclerosis (MS), the risk of acute myocardial infarction (AMI) is elevated but may not be accounted for by traditional vascular risk factors, a new study found. Researchers conducted a retrospective matched cohort study using population-based administrative data in 2 Canadian provinces. Incident MS cases were identified and for each case, up to 5 controls without MS were matched on age, sex, and region. The incidence of AMI between cohorts was compared using incidence rate ratios (IRRs). Among the findings:

• 14,565 persons with MS and 72,825 matched controls were identified.
• The crude incidence of AMI per 100,000 population was 146.2 in the MS population vs 128.8 in the matched population.
• After age standardization, the incidence of AMI was higher in the MS population vs the matched population (IRR 1.18).
• After adjustment, the hazard of AMI was 60% higher in the MS population vs the matched population (hazard ratio 1.63).

Marrie RA, Garland A, Schaffer SA. Traditional risk factors may not explain increased incidence of myocardial infarction in MS. [Published online ahead of print March 6, 2019]. Neurology. doi:10.1212/WNL.0000000000007251.

In a recent survey, patients with multiple sclerosis (MS) displayed a wide range of risk tolerance (RT) to MS therapies. People with MS from the North American Research Committee on Multiple Sclerosis Registry’s online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risk levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). Researchers found:

• Both PML and kidney injury had the lowest RT; thyroid and infection risk had the highest tolerance.
• Men, younger individuals, and those with greater disability reported a higher tolerance to all risk scenarios.
• Participants currently taking an MS therapy reported higher tolerance vs those not taking any therapy.

Fox RJ, Cosenza C, Cripps L, et al. A survey of risk tolerance to multiple sclerosis therapies. [Published online ahead of print March 13, 2019]. Neurology. doi:10.1212/WNL.0000000000007245.

In a recent survey, patients with multiple sclerosis (MS) displayed a wide range of risk tolerance (RT) to MS therapies. People with MS from the North American Research Committee on Multiple Sclerosis Registry’s online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risk levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). Researchers found:

• Both PML and kidney injury had the lowest RT; thyroid and infection risk had the highest tolerance.
• Men, younger individuals, and those with greater disability reported a higher tolerance to all risk scenarios.
• Participants currently taking an MS therapy reported higher tolerance vs those not taking any therapy.

Fox RJ, Cosenza C, Cripps L, et al. A survey of risk tolerance to multiple sclerosis therapies. [Published online ahead of print March 13, 2019]. Neurology. doi:10.1212/WNL.0000000000007245.

In a recent survey, patients with multiple sclerosis (MS) displayed a wide range of risk tolerance (RT) to MS therapies. People with MS from the North American Research Committee on Multiple Sclerosis Registry’s online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risk levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). Researchers found:

• Both PML and kidney injury had the lowest RT; thyroid and infection risk had the highest tolerance.
• Men, younger individuals, and those with greater disability reported a higher tolerance to all risk scenarios.
• Participants currently taking an MS therapy reported higher tolerance vs those not taking any therapy.

Fox RJ, Cosenza C, Cripps L, et al. A survey of risk tolerance to multiple sclerosis therapies. [Published online ahead of print March 13, 2019]. Neurology. doi:10.1212/WNL.0000000000007245.

In an age and gender-based US national retrospective analysis, overall 30-day readmission in multiple sclerosis (MS) was ∼10%, with higher readmission rates observed in older patients. The retrospective observational cohort study included patients hospitalized with primary discharge diagnosis of MS using 2013 Nationwide Readmission Database (NRD). Age (<40 vs >40 years) and gender-based analyses were performed using multivariable logistic regression adjusting co-variables to identify the patient/system-specific factors associated with 30-day readmission. Researchers found:

• 30-day readmission rate in MS was 10.2% in the cohort.
• Higher 30-day readmission was observed in patients aged >40 years due to burden of comorbidities.
• Readmission causes were MS exacerbations, sepsis, and respiratory complications.
• Readmission was associated with higher cost of care and longer length of stay compared to index admissions.

Patel S, SirDeshpande P, Desai R, et al. Thirty-day readmissions in multiple sclerosis: An age and gender-based US national retrospective analysis. [Published online ahead of print March 20, 2019]. Mult Scler Relat Disord. doi:10.1016/j.msard.2019.03.012.

In an age and gender-based US national retrospective analysis, overall 30-day readmission in multiple sclerosis (MS) was ∼10%, with higher readmission rates observed in older patients. The retrospective observational cohort study included patients hospitalized with primary discharge diagnosis of MS using 2013 Nationwide Readmission Database (NRD). Age (<40 vs >40 years) and gender-based analyses were performed using multivariable logistic regression adjusting co-variables to identify the patient/system-specific factors associated with 30-day readmission. Researchers found:

• 30-day readmission rate in MS was 10.2% in the cohort.
• Higher 30-day readmission was observed in patients aged >40 years due to burden of comorbidities.
• Readmission causes were MS exacerbations, sepsis, and respiratory complications.
• Readmission was associated with higher cost of care and longer length of stay compared to index admissions.

Patel S, SirDeshpande P, Desai R, et al. Thirty-day readmissions in multiple sclerosis: An age and gender-based US national retrospective analysis. [Published online ahead of print March 20, 2019]. Mult Scler Relat Disord. doi:10.1016/j.msard.2019.03.012.

In an age and gender-based US national retrospective analysis, overall 30-day readmission in multiple sclerosis (MS) was ∼10%, with higher readmission rates observed in older patients. The retrospective observational cohort study included patients hospitalized with primary discharge diagnosis of MS using 2013 Nationwide Readmission Database (NRD). Age (<40 vs >40 years) and gender-based analyses were performed using multivariable logistic regression adjusting co-variables to identify the patient/system-specific factors associated with 30-day readmission. Researchers found:

• 30-day readmission rate in MS was 10.2% in the cohort.
• Higher 30-day readmission was observed in patients aged >40 years due to burden of comorbidities.
• Readmission causes were MS exacerbations, sepsis, and respiratory complications.
• Readmission was associated with higher cost of care and longer length of stay compared to index admissions.

Patel S, SirDeshpande P, Desai R, et al. Thirty-day readmissions in multiple sclerosis: An age and gender-based US national retrospective analysis. [Published online ahead of print March 20, 2019]. Mult Scler Relat Disord. doi:10.1016/j.msard.2019.03.012.

DALLAS – At least four new imaging approaches beyond the central vein sign are emerging to help clinicians to differentiate multiple sclerosis from other disorders.

“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 – At least four new imaging approaches beyond the central vein sign are emerging to help clinicians to differentiate multiple sclerosis from other disorders.

“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 – At least four new imaging approaches beyond the central vein sign are emerging to help clinicians to differentiate multiple sclerosis from other disorders.

“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

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

egreb@mdedge.com

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

egreb@mdedge.com

The Food and Drug Administration has approved siponimod (Mayzent) tablets for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS.

Wikimedia Commons/FitzColinGerald/Creative Commons License

Siponimod is a selective sphingosine 1-phosphate (S1P) receptor modulator that binds to S1P1 and S1P5 receptors. Its binding to the S1P1 receptor prevents lymphocytes from leaving the lymph nodes, which contributes to the treatment’s anti-inflammatory effects. Its binding to the S1P5 and S1P1 subreceptors on oligodendrocytes and astrocytes is intended to promote remyelination and prevent inflammation.

The treatment’s approval is based on the results of the phase 3 EXPAND study, according to the agency’s March 26 announcement. This randomized, double-blind study compared siponimod with placebo among 1,651 patients with secondary progressive MS. At baseline, the population’s mean age was 48 years, and mean disease duration was approximately 16 years. More than half the study population had a median Expanded Disability Status Scale score of 6.0 and relied on a walking aid.

Siponimod reduced the risk of 3-month confirmed disability progression (CDP) by 21%, compared with placebo (P = .013). Among participants with relapse activity in the 2 years prior to screening, siponimod reduced the risk of this outcome by 33%, compared with placebo (P = .0100). Siponimod delayed the risk of 6-month CDP by 26%, compared with placebo (P = .0058) and reduced the annualized relapse rate by 55%. In addition, the data suggested beneficial effects of siponimod on cognition, MRI disease activity, and brain volume loss. Siponimod did not provide significant improvements in patients with nonactive secondary progressive MS.

Common adverse events included headache, hypertension, and transaminase increase. The FDA requires siponimod to be dispensed with a medication guide that describes the treatment’s associated risks of infection, macular edema, decreased heart rate, and impaired lung function.

Novartis manufactures the drug. The company expects the drug to be available within 1 week, according to its press release.

egreb@mdedge.com

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

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.

dbrunk@mdedge.com

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

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.

dbrunk@mdedge.com

DALLAS – A multicenter, prospective study is underway to determine if the central vein sign can be incorporated into existing multiple sclerosis diagnostic criteria.

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.

dbrunk@mdedge.com

Discontinuing

How would you characterize the prevalence of MS in the elderly?

DR. CORBOY:  A recent large demographic study put together by the National MS Society found that there’s almost a million individuals diagnosed with MS over the course of the last 40 to 50 years. The largest population segment was those aged 55 to 64 years. People with MS aged 55 or older constituted 46% of all those with MS.

What disease-modifying therapies (DMTs) are approved by the FDA for the elderly?

DR. CORBOY: Of the drugs that have received FDA approval, most are for individuals over the age of 18 and there’s no specific age cutoff. However, there’s no data supporting DMT use in people over the age of 55 because they were excluded from the studies.

There’s one DMT, fingolimod, that was approved for use in patients under the age of 18; all others are approved for 18 and above. However, none of them are explicitly approved for people over the age of 55, because there is no data to support it.

What is the goal of your study, the DISCO MS trial?

DR. CORBOY: The DISCO MS trial will be the first randomized, controlled, blinded discontinuation trial in the MS space. The objective is to assess the benefit of DMTs in patients over the age of 55.

Part of the rationale for the trial is that prior subgroup analyses have shown that the vast majority of the benefit that we’ve been able to measure with all of these DMTs is seen in those who are under age 45.

A number of studies have examined existing databases and individuals who were either randomly or deliberately taken off of their medication as they age, including people who were felt to be stable with no recent relapses and no recent changes on their MRI brain. These studies reinforced that when discontinuing medications, the individuals who were much more likely to have recurrence of disease activity were younger patients.

Pathological studies clearly show the number of acutely inflamed plaques in the white matter is dramatically lower in autopsies of older vs younger patients. There are different changes in older patients, with lymphocytic nodules in the meninges, gray matter plaques related to these meningeal nodules, microglial activation, and smaller numbers of active, or mostly, inactive, white matter plaques. It’s been difficult to show any substantial benefit in slowing disability progression, much of which is felt to not be associated with acute inflammatory disease in the aging patient. All of these medicines, which can be thought of as anti-inflammatory medicines, are very beneficial when patients are young but less so as they age.

Would you describe the DISCO MS study design?

DR. CORBOY: Our study looks at individuals who are 55 and older who have not had a relapse for at least 5 years, and who’ve not had a change on their brain scan for at least 3 years.

Individuals will be randomized to either stay on the medication that they’re currently taking or discontinue that medicine. They will be followed then for 2 years. The primary outcome will be either a new relapse or a new scan change. The examining investigators are blinded to whether the patient is currently taking a MS disease modifying therapy.

Secondary outcomes include progression of disability as measured by confirmed change on the Extended Disability Status Scale (EDSS).

The enrollment goal is about 300 patients. There are presently 15 sites. The goal is to have the study completed in about 3 years. We’re presently over halfway through enrollment.

We also have a number of patient-reported outcomes because we’re particularly interested in the patient’s view of what’s going on in terms of how they feel. Understanding that dynamic will be extremely important.

We are including both patients with relapsing MS and progressive forms of MS, noting that they should have no relapse and no scan change at study entry.

What are the challenges with this study?

DR. CORBOY: One challenge is interpreting the information with the assumption that the hypothesis is validated. The hypothesis is that in a stable population of older patients that we can safely discontinue DMTs.

If that is found to be true, the question is how many people will be affected? We know that about 46% of people with MS are 55 and older, but there are not really good estimates of the number of individuals 55 and older who remain on a DMT and who are stable by the definition I just described.

It can be safely said, I think, that a substantial number of the individuals 55 and older are still on DMTs. If there’s almost a million people with MS and 46% are 55 and older, that means around 400,000 people with MS in the United States are aged 55 and older. If only half of those are on a DMT, that leaves 200,000. If only half of those are stable and could go off therapy, that would mean perhaps 100,000 people could discontinue DMTs in the United States. If all those assumptions are true, that would be a substantial savings in the health care burden of the United States from a relatively small population of individuals.

Beyond the cost, there are adverse events associated with using these medications. Older patients are more likely to be at risk of complications of MS DMTs. There also are doctor visits, blood monitoring, and other things that are done over time, and the inconvenience of taking a medicine on a routine basis if, indeed, it’s really not necessary because there is no benefit. Moreover, older individuals have other conditions (eg diabetes, hypertension, arrhythmias, cancer, etc) that may limit their ability to use medications due to risk. We’re very interested to see the outcome.

Discontinuing

How would you characterize the prevalence of MS in the elderly?

DR. CORBOY:  A recent large demographic study put together by the National MS Society found that there’s almost a million individuals diagnosed with MS over the course of the last 40 to 50 years. The largest population segment was those aged 55 to 64 years. People with MS aged 55 or older constituted 46% of all those with MS.

What disease-modifying therapies (DMTs) are approved by the FDA for the elderly?

DR. CORBOY: Of the drugs that have received FDA approval, most are for individuals over the age of 18 and there’s no specific age cutoff. However, there’s no data supporting DMT use in people over the age of 55 because they were excluded from the studies.

There’s one DMT, fingolimod, that was approved for use in patients under the age of 18; all others are approved for 18 and above. However, none of them are explicitly approved for people over the age of 55, because there is no data to support it.

What is the goal of your study, the DISCO MS trial?

DR. CORBOY: The DISCO MS trial will be the first randomized, controlled, blinded discontinuation trial in the MS space. The objective is to assess the benefit of DMTs in patients over the age of 55.

Part of the rationale for the trial is that prior subgroup analyses have shown that the vast majority of the benefit that we’ve been able to measure with all of these DMTs is seen in those who are under age 45.

A number of studies have examined existing databases and individuals who were either randomly or deliberately taken off of their medication as they age, including people who were felt to be stable with no recent relapses and no recent changes on their MRI brain. These studies reinforced that when discontinuing medications, the individuals who were much more likely to have recurrence of disease activity were younger patients.

Pathological studies clearly show the number of acutely inflamed plaques in the white matter is dramatically lower in autopsies of older vs younger patients. There are different changes in older patients, with lymphocytic nodules in the meninges, gray matter plaques related to these meningeal nodules, microglial activation, and smaller numbers of active, or mostly, inactive, white matter plaques. It’s been difficult to show any substantial benefit in slowing disability progression, much of which is felt to not be associated with acute inflammatory disease in the aging patient. All of these medicines, which can be thought of as anti-inflammatory medicines, are very beneficial when patients are young but less so as they age.

Would you describe the DISCO MS study design?

DR. CORBOY: Our study looks at individuals who are 55 and older who have not had a relapse for at least 5 years, and who’ve not had a change on their brain scan for at least 3 years.

Individuals will be randomized to either stay on the medication that they’re currently taking or discontinue that medicine. They will be followed then for 2 years. The primary outcome will be either a new relapse or a new scan change. The examining investigators are blinded to whether the patient is currently taking a MS disease modifying therapy.

Secondary outcomes include progression of disability as measured by confirmed change on the Extended Disability Status Scale (EDSS).

The enrollment goal is about 300 patients. There are presently 15 sites. The goal is to have the study completed in about 3 years. We’re presently over halfway through enrollment.

We also have a number of patient-reported outcomes because we’re particularly interested in the patient’s view of what’s going on in terms of how they feel. Understanding that dynamic will be extremely important.

We are including both patients with relapsing MS and progressive forms of MS, noting that they should have no relapse and no scan change at study entry.

What are the challenges with this study?

DR. CORBOY: One challenge is interpreting the information with the assumption that the hypothesis is validated. The hypothesis is that in a stable population of older patients that we can safely discontinue DMTs.

If that is found to be true, the question is how many people will be affected? We know that about 46% of people with MS are 55 and older, but there are not really good estimates of the number of individuals 55 and older who remain on a DMT and who are stable by the definition I just described.

It can be safely said, I think, that a substantial number of the individuals 55 and older are still on DMTs. If there’s almost a million people with MS and 46% are 55 and older, that means around 400,000 people with MS in the United States are aged 55 and older. If only half of those are on a DMT, that leaves 200,000. If only half of those are stable and could go off therapy, that would mean perhaps 100,000 people could discontinue DMTs in the United States. If all those assumptions are true, that would be a substantial savings in the health care burden of the United States from a relatively small population of individuals.

Beyond the cost, there are adverse events associated with using these medications. Older patients are more likely to be at risk of complications of MS DMTs. There also are doctor visits, blood monitoring, and other things that are done over time, and the inconvenience of taking a medicine on a routine basis if, indeed, it’s really not necessary because there is no benefit. Moreover, older individuals have other conditions (eg diabetes, hypertension, arrhythmias, cancer, etc) that may limit their ability to use medications due to risk. We’re very interested to see the outcome.

Discontinuing

How would you characterize the prevalence of MS in the elderly?

DR. CORBOY:  A recent large demographic study put together by the National MS Society found that there’s almost a million individuals diagnosed with MS over the course of the last 40 to 50 years. The largest population segment was those aged 55 to 64 years. People with MS aged 55 or older constituted 46% of all those with MS.

What disease-modifying therapies (DMTs) are approved by the FDA for the elderly?

DR. CORBOY: Of the drugs that have received FDA approval, most are for individuals over the age of 18 and there’s no specific age cutoff. However, there’s no data supporting DMT use in people over the age of 55 because they were excluded from the studies.

There’s one DMT, fingolimod, that was approved for use in patients under the age of 18; all others are approved for 18 and above. However, none of them are explicitly approved for people over the age of 55, because there is no data to support it.

What is the goal of your study, the DISCO MS trial?

DR. CORBOY: The DISCO MS trial will be the first randomized, controlled, blinded discontinuation trial in the MS space. The objective is to assess the benefit of DMTs in patients over the age of 55.

Part of the rationale for the trial is that prior subgroup analyses have shown that the vast majority of the benefit that we’ve been able to measure with all of these DMTs is seen in those who are under age 45.

A number of studies have examined existing databases and individuals who were either randomly or deliberately taken off of their medication as they age, including people who were felt to be stable with no recent relapses and no recent changes on their MRI brain. These studies reinforced that when discontinuing medications, the individuals who were much more likely to have recurrence of disease activity were younger patients.

Pathological studies clearly show the number of acutely inflamed plaques in the white matter is dramatically lower in autopsies of older vs younger patients. There are different changes in older patients, with lymphocytic nodules in the meninges, gray matter plaques related to these meningeal nodules, microglial activation, and smaller numbers of active, or mostly, inactive, white matter plaques. It’s been difficult to show any substantial benefit in slowing disability progression, much of which is felt to not be associated with acute inflammatory disease in the aging patient. All of these medicines, which can be thought of as anti-inflammatory medicines, are very beneficial when patients are young but less so as they age.

Would you describe the DISCO MS study design?

DR. CORBOY: Our study looks at individuals who are 55 and older who have not had a relapse for at least 5 years, and who’ve not had a change on their brain scan for at least 3 years.

Individuals will be randomized to either stay on the medication that they’re currently taking or discontinue that medicine. They will be followed then for 2 years. The primary outcome will be either a new relapse or a new scan change. The examining investigators are blinded to whether the patient is currently taking a MS disease modifying therapy.

Secondary outcomes include progression of disability as measured by confirmed change on the Extended Disability Status Scale (EDSS).

The enrollment goal is about 300 patients. There are presently 15 sites. The goal is to have the study completed in about 3 years. We’re presently over halfway through enrollment.

We also have a number of patient-reported outcomes because we’re particularly interested in the patient’s view of what’s going on in terms of how they feel. Understanding that dynamic will be extremely important.

We are including both patients with relapsing MS and progressive forms of MS, noting that they should have no relapse and no scan change at study entry.

What are the challenges with this study?

DR. CORBOY: One challenge is interpreting the information with the assumption that the hypothesis is validated. The hypothesis is that in a stable population of older patients that we can safely discontinue DMTs.

If that is found to be true, the question is how many people will be affected? We know that about 46% of people with MS are 55 and older, but there are not really good estimates of the number of individuals 55 and older who remain on a DMT and who are stable by the definition I just described.

It can be safely said, I think, that a substantial number of the individuals 55 and older are still on DMTs. If there’s almost a million people with MS and 46% are 55 and older, that means around 400,000 people with MS in the United States are aged 55 and older. If only half of those are on a DMT, that leaves 200,000. If only half of those are stable and could go off therapy, that would mean perhaps 100,000 people could discontinue DMTs in the United States. If all those assumptions are true, that would be a substantial savings in the health care burden of the United States from a relatively small population of individuals.

Beyond the cost, there are adverse events associated with using these medications. Older patients are more likely to be at risk of complications of MS DMTs. There also are doctor visits, blood monitoring, and other things that are done over time, and the inconvenience of taking a medicine on a routine basis if, indeed, it’s really not necessary because there is no benefit. Moreover, older individuals have other conditions (eg diabetes, hypertension, arrhythmias, cancer, etc) that may limit their ability to use medications due to risk. We’re very interested to see the outcome.

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.

Doug Brunk/MDedge News

“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.

dbrunk@mdedge.com

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.

Doug Brunk/MDedge News

“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.

dbrunk@mdedge.com

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.

Doug Brunk/MDedge News

“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.

dbrunk@mdedge.com

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.”

Doug Brunk/MDedge News

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.

dbrunk@mdedge.com

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.”

Doug Brunk/MDedge News

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.

dbrunk@mdedge.com

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.”

Doug Brunk/MDedge News

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.

dbrunk@mdedge.com