ICYMI Multiple Sclerosis

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

NEW ORLEANS—“Ocrelizumab is the first investigational treatment to reach primary and key secondary efficacy end points in a phase III primary progressive MS [PPMS] study,” reported Jerry S. Wolinsky, MD, Bartels Family Professor and Opal C. Rankin Professor in Neurology at the University of Texas Health Science Center at Houston. On behalf of his study collaborators, Dr. Wolinsky presented the results from a subgroup analysis of the ORATORIO study at the ACTRIMS 2016 Forum.

Consistent with other PPMS study populations, ORATORIO study patients included several individuals with T1 gadolinium-enhancing lesions at baseline. “The efficacy of ocrelizumab versus placebo in patients with and without gadolinium–positive lesions at baseline was consistent with what was seen in the overall study population,” Dr. Wolinsky concluded.

Ocrelizumab is a humanized monoclonal antibody that selectively targets and depletes CD20+ B cells. In ORATORIO, a randomized, double-blind, placebo-controlled phase III trial, ocrelizumab significantly reduced disease activity in patients with PPMS. Further, ORATORIO was the first major clinical trial in PPMS to achieve positive results. The main study results were reported in 2015 at the ECTRIMS meeting in Barcelona.

For the study reported at ACTRIMS, Dr. Wolinsky and his reseach colleagues sought to evaluate the efficacy of ocrelizumab in the ORATORIO patient subgroups with and without T1 gadolinium-enhancing lesions at baseline.

A total of 732 patients were randomized 2 to 1 to receive ocrelizumab (600 mg) or placebo as two 300-mg IV infusions 14 days apart every 24 weeks for at least 120 weeks and until a prespecified number of 12-week confirmed disability progression events occurred. Key eligibility criteria included age between 18 and 55, diagnosis of PPMS according to the 2005 revised McDonald criteria, Expanded Disability Status Scale (EDSS) score of 3 to 6.5, and documented history of elevated immunoglobulin index and/or presence of two or more oligoclonal bands in the CSF.

Although not powered for comparisons, prespecified subgroups included age (45 or younger vs older than 45), sex, BMI (less than 25 versus 25 or greater), weight (less than 75 kg vs 75 kg or more), region (US vs the rest of the world), treatment history, symptom duration, and disease activity (EDSS score of 5.5 or less vs more than 5 and presence or absence of T1 gadolinium-enhancing lesions) at baseline.

Efficacy of ocrelizumab on confirmed disability progression at 12 weeks or more and at 24 weeks or more, change in total T2 lesion volume at 120 weeks, and other secondary outcomes were evaluated in the subgroups with presence or absence of T1 gadolinium-enhancing lesions at baseline.

Compared with placebo, ocrelizumab significantly reduced the relative risk of 12-week confirmed disability progression by 24% (hazard ratio, 0.76) and 24-week confirmed disability progression by 25% (hazard ratio, 0.75). T1 gadolinium-enhancing lesions were present at baseline in 27.5% of ocrelizumab-treated patients versus 24.7% of placebo-treated patients. In patients with and without T1 gadolinium-enhancing lesions at baseline, respectively, ocrelizumab reduced the risk of 12-week confirmed disability progression by 35% (hazard ratio, 0.65) and 16% (hazard ratio, 0.84), the risk of 24-week confirmed disability progression by 33% (hazard ratio, 0.67) and 19% (hazard ratio, 0.81), and total T2 lesion volume by –3.8% versus +12.0% with placebo and by –3.1% versus +6.1% with placebo. Because of confidence intervals, not all of these end points analyses reached statistical significance.

“The study was in no way powered to approach this type of subgroup analysis. Rather, the analysis was an attempt to understand the data better,” said Dr. Wolinsky.

—Glenn S. Williams

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

High coffee consumption decreases the odds of developing multiple sclerosis (MS), according to two case–control studies published online ahead of print March 3 in the Journal of Neurology, Neurosurgery & Psychiatry. Anna K. Hedström, MD, PhD, a postdoctoral researcher at the Karolinska Institute, Stockholm, and her associates conducted the studies.

The investigators analyzed coffee consumption among 1,620 adults with MS and 2,788 healthy controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS). They also examined coffee consumption in 1,159 adults with MS and 1,172 healthy controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

In EIMS, the adjusted odds ratio (OR) for developing MS was 0.70 among participants who drank more than six cups of coffee (ie, greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding ORs for those who reported high coffee consumption at five or 10 years before the study were 0.72 and 0.71, respectively, but these results were not statistically significant.

In KPNC, those who consumed four or more cups of coffee (ie, more than 948 mL) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69). In addition, people who drank four or more cups of coffee daily at least five years prior to the index year had significantly reduced odds of MS (OR, 0.64).

A meta-analysis of the combined results of the two studies indicated a significant 29% reduction in the likelihood of developing MS among the people with the greatest coffee consumption (ie, greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and BMI at age 20.

No evidence indicated any associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

—Lori Laubach

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS—The lack of a therapy that slows or stops disease progression represents the greatest unmet need among patients with progressive multiple sclerosis (MS), according to a lecture presented at the ACTRIMS 2016 Forum. Future therapeutics for progressive MS will need to address mechanisms such as microglial and macrophage-driven neurodegeneration, mitochondrial dysfunction, and oxidative stress, said Claudia F. Lucchinetti, MD, Professor of Neurology at Mayo Clinic in Rochester, Minnesota.

Research efforts should aim to develop drugs that treat smoldering plaques and meningeal inflammation, she added. Furthermore, patients need a therapy that protects axons and promotes remyelination. “Finally, our therapies are going to need to consider targeting both inflammation and neurodegeneration early and concurrently,” said Dr. Lucchinetti.

White Matter Plaques Indicate Disease Duration

MS progression generally affects the white matter, the axons, the cortex, the meninges, and the deep gray matter. As white matter undergoes demyelination, it may develop any of four types of plaques, including active, inactive, smoldering, and remyelinated shadow plaques. In 2015, Dr. Lucchinetti and colleagues studied autopsy results for 120 patients with MS who had 2,476 white-matter plaques. They found that most plaques in early MS were active, while inactive plaques predominated in chronic MS. Smoldering plaques were rare in early MS, but reached peak levels at 18 to 20 years’ disease duration, which is when many patients convert to secondary progressive MS. The frequency of shadow plaques was similar throughout the disease duration.

In addition, the investigators found that active plaques predominated among patients with ongoing relapses, indicating that the plaques may be “the substrate of the relapse itself,” said Dr. Lucchinetti. Active plaques were less frequent in secondary progressive MS without attacks and in primary progressive MS. Shadow plaques occurred in all clinical forms of the disease, but smoldering plaques occurred only in progressive MS.

Axonal Injury May Promote Progression

Axonal injury in MS mostly occurs in small axons. The main causes of axonal loss are repeated demyelination, lack of trophic support for myelin in oligodendrocytes, Wallerian degeneration, and acute and chronic mitochondrial dysfunction, which may result from enhanced production of reactive oxygen species in macrophages and active microglia.

Mitochondria are especially susceptible to oxidative damage, and microarray gene studies have found mitochondrial dysfunction in MS. Oxidized lipids are common within active plaques and promote calcium accumulation in the axon and, hence, axonal degeneration. In cells such as oligodendrocytes, injury to the mitochondria activates apoptosis-inducible factor, which can be transferred into the nucleus. MS also causes chronic energy failure in axons, which leak current when they have been demyelinated. In a compensatory response, sodium channels increase within the axon, and mitochondria are recruited, but this response eventually fails. Demyelinated axons subsequently undergo neurodegeneration and irreversible injury, potentially leading to disease progression.

Cortical Lesions Predict Disability

“Cortical lesion load is the strongest predictor of MS disability,” said Dr. Lucchinetti. Cortical lesion load correlates with cognitive dysfunction and is present early in the disease. Approximately 40% of patients with clinically isolated syndrome have cortical lesions, which include leukocortical, intracortical, and subpial plaques.

Dr. Lucchinetti and colleagues demonstrated in one investigation that early MS lesions in the cortex are inflammatory, unlike lesions found in chronic MS. Furthermore, they found myelinated macrophages in early cortical plaques. A finding of large numbers of CD68 and CD8 cells near neurons suggests that early neurodegeneration occurs against a background of inflammation, said Dr. Lucchinetti.

Demyelination in the cortex is extensive in chronic MS. It occurs in multiple gyri and mainly affects areas involved in cognition. Research indicates that areas of cortical demyelination often are topographically related to areas in which one finds follicular light structures. “This topographical association of meningeal inflammation and cortical demyelination is striking, and it also seems to be associated with microglial activation in the underlying cortex and neuritic damage, again pointing to the fact that there is a potential soluble myelinotoxic factor mediating this aspect of MS pathology,” said Dr. Lucchinetti.

Meningeal Inflammation and Aggressive Disease

Although meningeal infiltrates may not be true follicles, meningeal inflammation is associated with greater inflammation and a shorter, more aggressive disease course. Data suggest that patients have more aggressive disease and die sooner when they have more meningeal inflammation.

In 2015, Absinta et al found that 3-T postcontrast T2-weighted FLAIR MRI may identify areas of fixed leptomeningeal inflammation. Histopathology indicated that the inflammation included perivascular lymphocytic and mononuclear infiltration in association with nearby subpial cortical demyelination. “When they looked further within these areas, they found prominent, meningeal diffuse inflammation positive for CD45 and CD68 cells,” said Dr. Lucchinetti.

The results indicate that neurologists may now have a marker to track this aspect of MS pathology, she continued. Diffuse and focal meningeal inflammation is present within days to weeks of initial presentation. This inflammation increases the likelihood of cortical demyelination and may contribute to disease progression. In a cohort of patients with early MS, meningeal inflammation was associated with subpial demyelination, similar to the association in chronic MS.

Mainero et al found that sparse areas of abnormality within the upper 25% of the brain tissue correspond with focal myelin loss or iron loss. Deeper areas of the cortex have more extensive involvement (ie, prolonged T2), and these changes are strongly associated with Expanded Disability Status Scale score. This process begins early and is not associated with white matter lesion burden, thus “highlighting the importance of this pathology to some elements of disease progression,” said Dr. Lucchinetti.

Deep Gray Matter Damage

Damage to deep gray matter in MS is focused in the caudate and the hypothalamus. As the disease progresses, it may involve the deep gray matter more extensively. Atrophy of the third ventricle is one potential way to measure the degree to which MS affects the thalamus. This atrophy seems to be associated with cognitive decline, motor deficits, and fatigue. It correlates with cortical demyelination, but not white matter demyelination.

Current approved therapies “are really targeting what we can see, [such as] inflammation and white matter plaques, but there’s much more going on,” concluded Dr. Lucchinetti.

—Erik Greb

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Repeated intrathecal administration of autologous mesenchymal bone marrow-derived stromal stem cells for the treatment of multiple sclerosis was safe and induced accelerated beneficial effects in some patients in an uncontrolled, prospective study.

Of 28 patients with either secondary progressive or relapsing-progressive MS who were experiencing severe clinical deterioration and failure to respond to first- and second-line immunomodulatory treatments, 25 experienced either stable or improved Expanded Disability Status Scale (EDSS) scores following autologous mesenchymal stem cell (MSC) injections. The mean score decreased from 6.76 at study entry to 6.57 at a mean follow-up of 3.6 years, Dr. Panayiota Petrou of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, and her colleagues reported in a poster at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Zerbor/thinkstockphotos.com

In addition, 17 patients experienced improvements in at least one functional system of the EDSS, including 14 who experienced improved motor function, 5 who experienced improved speech/bulbar functions, 4 who experienced improved urinary functions, and 6 who experienced improved cerebellar function. Eight patients remained stable during the entire follow-up period.

In a prior pilot trial, intrathecal administration of MSCs was shown to be safe and provided “some indications of potentially clinically meaningful beneficial effects on the progression of the disease,” the investigators said.

The current study provides further support for those findings. It included patients who experienced severe clinical deterioration (at least 0.5-1 points in the EDSS) during the year prior to study enrollment, or who had at least one major relapse without sufficient recovery following steroid treatment. Study subjects had a mean age of 56 years and mean disease duration of 15.4 years. They received at least 2 courses and up to 10 injections with 1 million cells/kg; most received 2 (8 patients) or 3 (9 patients) injections, and they were followed for up to 6 years.

No serious side effects were observed during long-term follow-up after repeated intrathecal injections. Eight patients experienced headaches and/or fever in the hours and days after injection, and two experienced symptoms of encephalopathy, which resolved within a few hours. Also, one patient experienced back pain and one had neck rigidity, but no long-term side effects were reported, the investigators said.

Immunological follow-up showed a transient up-regulation of regulatory T cells and down-regulation of the proliferative ability of lymphocytes and of several immune activation surface markers for up to 3 months, they noted.

The investigators reported having no disclosures.

sworcester@frontlinemedcom.com

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com

High coffee consumption decreased the odds of developing multiple sclerosis (MS) in two separate case-control studies conducted by Dr. Anna K. Hedström of the Karolinska Institute, Stockholm, and her associates.

The investigators analyzed coffee consumption across certain ages among 1,620 cases and 2,788 controls in the Swedish Epidemiological Investigation of Multiple Sclerosis (EIMS) and 1,159 cases and 1,172 controls in the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC).

s-photo/iStockphoto.com

In EIMS, the adjusted odds ratio (OR) was 0.70 (95% confidence interval, 0.49-0.99; P = .04) among participants who drank six or more cups of coffee (greater than 900 mL) daily at the index year, which was defined as the year of the initial appearance of symptoms indicative of MS. The corresponding OR for those who reported high coffee consumption at 5 and 10 years before the study was 0.72 and 0.71, respectively, but neither comparison reached statistical significance.

In KPNC, those who consumed four or more cups of coffee (more than 948 mL in this study) daily were significantly less likely to develop MS than were those who never drank coffee (OR, 0.69; 95% CI, 0.50-0.96; P = .05). And the cohorts who drank four or more cups of coffee daily at least 5 years prior to the study were associated with significantly reduced odds of MS (OR, 0.64).

The combined results of the two studies in a meta-analysis found a significant, 29% reduction in the likelihood of developing MS among the highest drinkers of coffee (greater than 900 mL daily in EIMS and greater than 948 mL in KPNC). The investigators adjusted all the analyses for many demographic and environmental risk factors for MS, including age, gender, residential area, ancestry, smoking habits, exposure to passive smoking, sun exposure habits, and body mass index at age 20 years.

No evidence was found for associations between increased amounts of tea or soda intake and MS.

“Further studies are required to establish if it is in fact caffeine, or if there is another molecule in coffee underlying the findings, to longitudinally assess the association between consumption of coffee and disease activity in MS, and to evaluate the mechanisms by which coffee may be acting, which could thus lead to new therapeutic targets,” the researchers concluded.

Find the full study in the Journal of Neurology, Neurosurgery & Psychiatry (doi: 10.1136/jnnp-2015-312176).

llaubach@frontlinemedcom.com

NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.

Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Eraxion/thinkstockphotos.com

In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.

The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).

Neoplasms occurred in 3.7% and 3.6%; most were benign.

“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.

The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.

This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.

sworcester@frontlinemedcom.com

NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.

Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Eraxion/thinkstockphotos.com

In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.

The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).

Neoplasms occurred in 3.7% and 3.6%; most were benign.

“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.

The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.

This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.

sworcester@frontlinemedcom.com

NEW ORLEANS – The long-term safety of interferon beta-1b for the treatment of multiple sclerosis is well established, and 11-year outcomes from the randomized, placebo-controlled BENEFIT trial (BENEFIT 11) provide further support for the existing data.

Eleven years after patients with clinically isolated syndrome were randomized to receive 250 mcg every other day or placebo (with an option at 2 years to switch to active treatment), no new safety signals were found, and the safety profile remained favorable, Dr. Mark S. Freedman of the University of Ottawa and his colleagues reported in a poster at the meeting sponsored by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©Eraxion/thinkstockphotos.com

In the 278 of the 468 patients originally enrolled in BENEFIT who were evaluated at 11 years, 107 (38.5%) reported one or more safety events (total, 278). Interferon beta-1b was used continuously during the 2 years prior to the 11-year evaluation in 82 patients (29.5%), and 28 (34.1%) of those reported an adverse event or medical history event (total, 72 events). Of 196 patients not treated continuously with interferon beta-1b in the 2 years prior to BENEFIT 11, 79 (40.3%) reported an adverse event or medical history event (total, 206 events), the investigators said.

The events reported in BENEFIT 11 were consistent with those seen previously in interferon beta-1b–treated patients; back pain was the most commonly reported musculoskeletal/connective tissue adverse event (reported by 2.4% of patients in the continuous treatment group and 2.6% in the remaining patients, and headache was the most common neurologic adverse event (reported by 1.2% and 2.0% of patients in the groups, respectively).

Neoplasms occurred in 3.7% and 3.6%; most were benign.

“Overall, the safety results from BENEFIT 11 supported the already well-established long-term safety profile of interferon beta-1b,” the investigators wrote.

The higher rates of some events in patients without continuous interferon beta-1b treatment may be due to escalation to second-line therapy in some patients who required agents that may be associated with greater frequency of safety events, they explained.

This study was supported by Bayer. Dr. Freedman has received compensation from Actelion, Bayer, Biogen Idec, Chugai, EMD Canada, Genzyme, Merck Serono, Novartis, Roche Canada, Sanofi-Aventis, and Teva Canada Innovation for consulting services. He also participates in a Genzyme-sponsored speakers bureau.

sworcester@frontlinemedcom.com

NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.

In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©RusN/Thinkstock.com

Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.

The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.

Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.

To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.

“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.

Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”

Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.

This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.

In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©RusN/Thinkstock.com

Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.

The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.

Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.

To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.

“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.

Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”

Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.

This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

NEW ORLEANS – Fatigue: Take Control (FTC), a 6-week group education and behavioral program widely used to address fatigue in patients with multiple sclerosis, was comparable to a general MS education program for decreasing fatigue and improving self-efficacy in a randomized, controlled study.

In 218 subjects randomized to participate in either FTC or a general MS education program (MS: Take Control, or MSTC), Modified Fatigue Impact Scale scores improved significantly, compared with baseline and regardless of group assignment; there was no difference between the groups at visit 6 (mean change, –4.5 and –3.6 in the FTC and MSTC groups, respectively), Cinda L. Hugos of the VA Portland (Ore.) Health Care System and her colleagues reported at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

©RusN/Thinkstock.com

Multiple Sclerosis Self-Efficacy scale scores did, however, improve significantly in the FTC group vs. the MSTC group (mean increase of 45.5 vs. a decrease of 15.8), but the improvement was not maintained at 6 months, the investigators reported in a poster at the meeting.

The two groups had comparable baseline characteristics, with a mean age of nearly 54 years, as well as similar mean time since diagnosis (12.5 years), self-administered Expanded Disability Status Scale scores (5.2), and demographics.

Fatigue is common in MS patients, occurring in up to 95% of patients, and many report that it is the most disabling symptom. FTC, which addresses medical management of fatigue, exercise, environment, and changes and choices with respect to energy and fatigue control, is often used by chapters of the National MS Society, but its effectiveness for decreasing fatigue or improving self-efficacy has not been proven, the investigators noted.

To determine if FTC decreases fatigue and increases self-efficacy, compared with a general MS education program that addresses issues such as nutrition, emotional health, cognitive problems, and fitness, the investigators randomized subjects at four sites in groups of between 3 and 10 participants to either an FTC or MSTC group. All subjects had moderate to severe fatigue. Those with pregnancy, severe depression, uncontrolled problems that would limit participation, relapse in the prior month, or initiation of a new disease-modifying treatment within the prior 3 months were excluded.

“Both FTC and MSTC structured small group programs were associated with improved self-reported fatigue at program completion and at 3- and 6-month follow-up, but there were no significant differences in fatigue scores between FTC and MSTC participants at any time point,” the investigators wrote.

Self-efficacy was significantly better among FTC participants at program completion, but was not sustained, they noted, concluding that the findings suggest that “participating in structured small group programs is associated with prolonged reductions in fatigue in people with MS and that supporting goal setting provides short-term improvements in self-efficacy.”

Further research is needed to determine whether booster sessions would be beneficial for sustaining improvements in self-efficacy, they added.

This study was supported by the Rehabilitation, Research, & Development Service of the Veterans Affairs Office of Research & Development. The authors reported having no disclosures.

sworcester@frontlinemedcom.com

The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.

These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”

Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.

In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.

In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.

Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

—Jeff Evans

The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.

These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”

Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.

In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.

In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.

Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

—Jeff Evans

The expression of L-selectin (CD62L) on specific T cells in peripheral blood in patients with relapsing forms of multiple sclerosis (MS) does not predict the risk of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment reliably, according to findings published January 26 in Neurology.

These findings contradict those of a previous preliminary study that used a different analytical technique. Investigators in the earlier study found a decrease in the percentage of CD4- and CD3-positive T cells expressing CD62L at least four months and often two years before PML diagnosis. They concluded that measuring the percentage of CD4- and CD3-positive T cells expressing CD62L “may improve stratification of patients taking natalizumab who are at risk for developing PML.”

Linda A. Lieberman, PhD, a research scientist at Biogen in Cambridge, Massachusetts, and colleagues sought to confirm the findings, enhance the reproducibility of the CD62L assay, “and potentially enable the deployment of CD62L as a biomarker for PML in a global setting.” The investigators, however, did not find a significant difference in the percentage of CD62L in cryopreserved peripheral blood mononuclear cells between 104 patients with relapsing forms of MS who received natalizumab and did not develop PML, and 21 patients who developed PML.

In the current study, the investigators detected a large range of CD62L (ie, 0.31% to 68.4%) in a subset of natalizumab-treated MS patients without PML at two time points at least six months apart. Because CD62L and the chemokine receptor CCR7 are coexpressed on CD4- and CD3-positive T cells, the researchers also examined the level of variation in simultaneous measurements of CD62L and CCR7 on the same cells at two separate time points in the same patients. They found that CD62L expression varied substantially, whereas CCR7 varied little, and the difference between the two was significant, “signifying that CD62L is not a stable outcome measure,” they wrote.

Dr. Lieberman and her colleagues also confirmed a positive correlation between lymphocyte viability and CD62L expression, which highlights the “technique-driven variability of the assay” used in the preliminary study.

In patient samples collected at least six months before PML diagnosis, the percentage of CD62L did not discriminate significantly between non-PML and active PML (defined as 0 to 6 months prior to diagnosis). The median percentage of CD62L varied according to the viability of cryopreserved CD4- and CD3-positive T cells. Median percentage of CD62L was no different between non-PML and pre-PML samples with lymphocyte viability greater than 75% (25.9% vs 26.3%, respectively), but was significantly lower than with non-PML and pre-PML samples with lymphocyte viability less than 75% (10.55% and 5.41%). There was no difference in lymphocyte viability between non-PML and pre-PML samples.

In a case–control comparison of patients receiving natalizumab who had multiple pre-PML samples, nine patients who developed PML had CD62L levels that in most samples were similar to those of nine matched control patients without PML.

Examination of samples from healthy controls demonstrated that CD62L also varied significantly in various disease states, such as after influenza vaccination and during hospitalization for total knee replacement surgery or methicillin-resistant Staphylococcus aureus infection, the researchers found.

—Jeff Evans

A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.

The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.

In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”

According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.

The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.

The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.

Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.

—Bianca Nogrady

A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.

The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.

In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”

According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.

The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.

The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.

Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.

—Bianca Nogrady

A European expert group has proposed several revisions to the 2010 McDonald criteria for the use of MRI in diagnosing multiple sclerosis (MS). In the January 25 online issue of Lancet Neurology, the MAGNIMS collaborative research network asserted that new data on the application of MRI, as well as improvements in MRI technology, demanded changes to the MS diagnostic criteria.

The first proposed recommendation is that three or more focal lesions, rather than a single lesion, should be present for a physician to diagnose the involvement of the periventricular region and to show disease dissemination in space. “A single lesion was deemed not sufficiently specific to determine whether involvement of the periventricular region is due to a demyelinating inflammatory event, and the use of one periventricular lesion for assessing dissemination in space has never been formally validated,” said Massimo Filippi, MD, Professor of Neurology at Vita-Salute San Raffaele University in Milan, and his coauthors. The authors also pointed out that incidental periventricular lesions are observed in as much as 30% of patients with migraine, and in individuals with other neurologic disorders.

In addition, the group recommended that optic nerve lesions be added to the criteria for dissemination in space. “Clinical documentation of optic nerve atrophy or pallor, neurophysiological confirmation of optic nerve dysfunction (slowed conduction), or imaging features of clinically silent optic nerve inflammation (MRI lesions or retinal nerve fiber layer thinning) support dissemination in space and, in patients without concurrent visual symptoms, dissemination in time.”

According to the new recommendations, disease dissemination in space can be shown by the involvement of at least two areas from a list of the following five possibilities: three or more periventricular lesions, one or more infratentorial lesions, one or more spinal cord lesions, one or more optic nerve lesions, or one or more cortical or juxtacortical lesions.

The group did not propose any significant changes to the criteria for dissemination in time. They did note, however, that the presence of nonenhancing black holes should not be considered as a potential alternative criterion to show dissemination in time in adult patients.

The committee also supported the existing recommendations that children age 11 or older with nonacute disseminated encephalomyelitis-like presentation should be diagnosed with the same criteria for dissemination in time and space as are applied to adults. “Several studies have confirmed that the 2010 McDonald criteria perform better than or similarly to previously proposed pediatric MS criteria for diagnosis of children with nonacute disseminated encephalomyelitis presentations and pediatric patients older than 11 years, and the consensus group therefore recommend caution when using these criteria in children younger than 11 years,” they said.

Other recommendations include that there be no distinction required between symptomatic and asymptomatic MRI lesions for diagnosing dissemination in time or space; that the whole spinal cord be imaged to define dissemination in space, particularly in patients who do not fulfill the brain MRI criteria; and that the same criteria for dissemination in space be used for primary progressive MS and relapse-onset MS, with CSF results considered for clinically uncertain cases of primary progressive MS.

—Bianca Nogrady

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady

Patients with acute demyelinating optic neuritis who received phenytoin lost 30% less of their retinal nerve fiber layer (RNFL) than did placebo-treated patients in a randomized phase II study published online ahead of print January 25 in Lancet Neurology. “The results of this clinical trial support the concept of neuroprotection using phenytoin to inhibit voltage-gated sodium channels in patients with acute optic neuritis,” said Rhian Raftopoulos, MD, of the National Hospital for Neurology and Neurosurgery in London, and coauthors.

In the study of 86 people with acute optic neuritis, investigators randomized 29 participants to receive 4 mg/kg/day of oral phenytoin, 13 participants to receive 6 mg/kg/day of oral phenytoin, and 44 participants to receive placebo for three months. All participants were randomized within 14 days of vision loss. One-third of the patients had previously been diagnosed with multiple sclerosis or was diagnosed at presentation, and 74% had at least one brain lesion on MRI.

Treatment with phenytoin was associated with a decline of mean RNFL thickness in the affected eye from 130.62 μm at baseline to 81.46 μm at six months, compared with a decline from 125.20 μm to 74.29 μm in the placebo group, representing a statistically significant adjusted mean difference of 7.15 μm.

The researchers also noted a significant 34% reduction in macular volume loss in the treatment arm, compared with placebo, representing an adjusted mean difference of 0.20 mm³. However, the treatment had no significant effect on low-contrast visual acuity and visual evoked potentials.

The most common adverse event in the treatment arm was maculopapular rash, which was judged as severe in one patient treated with phenytoin.

“The absence of regular, early outcome assessments around one to two months after initiation of treatment makes it hard to interpret the results because they would have helped to rule out a primarily anti-inflammatory effect of the treatment by tracking RNFL swelling and possible optic nerve inflammation, especially given that there was higher baseline RNFL thickness and worse low-contrast visual acuity in the patients who received phenytoin,” said Shiv Saidha, MBBCh, Assistant Professor of Neurology, and Peter A. Calabresi, MD, Director of the Division of Neuroimmunology, both at Johns Hopkins University in Baltimore, in an accompanying editorial. “If the true RNFL thickness at baseline in the affected eye of patients in the pheny­toin group was higher than those in the placebo group, it could have accounted for the findings, even though the investigators made a prespecified adjustment for it.

“Although the results of this study are a major advancement and undeniably encouraging, future studies need to include more frequent optical coherence tomography (OCT) sampling, as well as more detailed OCT-segmentation-derived retinal measures such as ganglion cell plus inner plexiform layer thickness, which do not swell during acute optic neuritis, mitigating the need for statistical corrections involving the unaffected eye,” they concluded.

—Bianca Nogrady