Multiple Sclerosis Hub

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Dyschromatopsia in the non-optic neuritis eyes (NON-eyes) of MS patients is due to damage of retinal ganglion cells (RGC), according to a study of 106 patients with MS. Researchers found:

• There were moderate, significant correlations between color vision and macular retinal nerve fiber layer, ganglion cell complex (GCC), thalamus, and lesion volume within the optic radiations.

• Only GCC remained significant in a logistic regression model.

• In the final model including lesion load, and normalized brain parenchymal volume (NBPV) as markers of diffuse neuroaxonal damage, GCC remained associated with dyschromatopsia, an association that remained significant when sex, age, and disease duration were added as covariates.

Citation: Lampert EJ, Andorra M, Torres-Torres R, et al. Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. [Published online ahead of print August 11, 2015]. J Neurol. doi: 10.1007/s00415-015-7876-3.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Mixed amphetamine salts, extended release (MAS-XR) may be a potential treatment for MS patients with demonstrated processing speed (PS) impairment, according to a study of 52 patients randomized to MAS-XR 5 mg, MAS-XR 10 mg, or placebo. Researchers found:

• At baseline, mean score on the symbol digit modalities test (SDMT) was 43.3 and mean score on the paced auditory serial addition test (PASAT) was 34.8.

• 48.1% of patients were classified as impaired at baseline.

• After treatment, the MAS-XR 10 mg group showed significant improvement on SDMT score, improving 5.2 points vs 0.6 point improvement in the placebo group.

• Change on the PASAT was not significantly different in either treatment group.

Citation: Morrow SA, Rosehart H. Effects of single dose mixed amphetamine salts - extended release on processing speed in multiple sclerosis: a double blind placebo controlled study. [Published online ahead of print August 21, 2015]. Psychopharmacology. doi: 10.1007/s00213-015-4051-6.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Patients with MS have a lower increase in serum 25-hyroxyvitamin D (25(OH)D) levels with supplementation, even after accounting for putative confounders, according to a study of 27 female relapsing-remitting MS patients aged 18 to 60 years and 30 healthy controls. Researchers found:

• At baseline, there were no significant differences in 25(OH)D levels or demographics, except a higher body mass index (BMI) in the MS group.

• In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l lower increase in 25(OH)D levels compared with controls.

Citation: Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. [Published online ahead of print August 18, 2015]. Mult Scler. doi:10.1177/1352458515600248.

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Rates of mortality and several comorbidities are higher in an MS versus non-MS cohort, according to a study of 15, 864 patients with MS and 78,420 people without MS. Researchers found that in the MS cohort compared with the non-MS cohort:

• All-causes mortality was 2.9 times higher.

• Relative risks of mortality were: infectious disease (6.2), diseases of the nervous system (5.8), respiratory system (5.0), circulatory system (2.1), and suicide (2.6).

• Relative risks of comorbidities were: sepsis (5.7), ischemic stroke (3.8), attempted suicide (2.4), and ulcerative colitis (2.0).

• The rate of cancers was higher: lymphoproliferative disorders (2.2) and melanoma (1.7). 

Citation: Capkur G, Dahlke F, Lahoz R, et al. Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US department of defense administrative claims database. [Published online ahead of print August 18, 2015]. Mul Scler Rel Dis. doi: http://dx.doi.org/10.1016/j.msard.2015.08.005.

Comment: Multiple sclerosis (MS) is not a benign disease; people with MS die at a rate higher than those without MS. This study reinforces the importance of early effective treatment to reduce disease burden and treat symptomatic problems in people who have MS. It is also just as important to identify and treat other significant comorbidities in those we treat for MS.—Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

For the first time, progressive multifocal leukoencephalopathy (PML) has been reported in patients with multiple sclerosis (MS) treated with fingolimod who had not previously been treated with an immunosuppressant, according to an FDA warning issued on August 4.

The FDA described two cases of PML—one is considered definite and the second is considered probable—in patients who had not received prior treatment with an immunosupressant drug for MS or any other medical condition. Prior cases of PML in patients taking fingolimod, including a case in a European patient in 2013, were confounded by immunosuppressant use before or concurrent with the drug.

In addition, Novartis, the manufacturer of the drug, reported on August 17 that it had been informed of another case of PML in a patient who did not have prior exposure to natalizumab. This patient has a history of colorectal cancer that was treated with chemotherapy and radiation treatment, and Crohn’s disease.

Clinicians who suspect that a patient on fingolimod may have PML should stop treatment and evaluate the patient for a diagnosis of PML, according to the FDA. People on fingolimod should contact their health care professionals immediately “if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance,” said the agency.

Symptoms in the patient with definite PML, a 54-year-old who had had MS for about 14 years and had been treated with fingolimod for about 2.5 years, included instability while walking, clumsiness, inattention, somnolence, and mental sluggishness. John Cunningham virus (JCV) DNA was present in the patient’s CSF, and MRI findings were characteristic of PML. The probable case was in a 49-year-old who had been treated with fingolimod for about four years and had no symptoms, but had new MRI lesions consistent with PML and a CSF test that was positive for JCV DNA.

Fingolimod, taken once per day by mouth, is a sphingosine 1-phosphate receptor modulator marketed by Novartis as Gilenya. It was approved in 2010 and is indicated for treating relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. The fingolimod prescribing information and Medication Guide are being updated to include information about cases of PML. Possible cases of PML associated with fingolimod should be reported to the FDA’s MedWatch program website or by calling 1-800-332-1088.

—Elizabeth Mechcatie

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb

INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.

Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.

When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.

Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.

Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.

Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.

Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.

Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.

Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.

In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.

Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.

He and his colleagues published a proof-of-concept study of autologous MSCs for the treatment of MS in Lancet Neurology in 2012. They examined 10 patients with secondary progressive MS and previous optic neuritis before and after the latter received MSCs. The treatment significantly improved visual acuity, and the researchers found evidence that it might promote remyelination.

Organizations including the Consortium of MS Centers have supported the International MSC Transplantation Study Group, which will guide future research into MSCs. The study group published a consensus paper on MSCs in Multiple Sclerosis in 2010. The consensus paper drew on the current literature to set guidelines for phase I and phase II clinical trials of MSCs in patients with MS. “Useful collaborative work going on in this area [provides] a lot of cause for optimism,” said Dr. Thompson.

—Erik Greb

INDIANAPOLIS—Investigators are conducting clinical trials of various drugs that may slow clinical worsening in patients with progressive multiple sclerosis (MS), according to an overview provided at the 2015 CMSC Annual Meeting. Two such agents, anti-LINGO-1 antibody and rHIgM22 monoclonal antibody, are under active development in early clinical trials.

“Treatments that promote remyelination are going to prove to be the most effective way to prevent or treat progressive MS,” said Dennis Bourdette, MD, Roy and Eulalia Swank Family Research Professor and Chairman of the Department of Neurology at Oregon Health & Science University (OHSU) School of Medicine in Portland. Investigators are developing cell-based, large-molecule (ie, biologic), and small-molecule (ie, chemically manufactured) therapies that could promote remyelination.

Cell-Based Therapies
One potential treatment is to inject oligodendrocyte precursor cells (OPCs) into the brain and spinal cord. These OPCs then could become oligodendrocytes and produce myelin. Researchers in New York state under the leadership of Drs. Steven Goldman and Burk Jubelt are preparing for a phase I trial of this technique. They plan to use embryonic OPCs and are working with the FDA to establish the appropriate controls for the study.

Current surgical technology should allow the team to inject human OPCs into the brain safely, said Dr. Bourdette. “Researchers have shown that human embryonic-derived OPCs injected into the brains of rodents that have hypomyelination caused by a genetic defect will migrate long distances and myelinate axons.” The goal is for the OPCs to migrate into areas of demyelination in the brain of people with MS and remyelinate axons.

But how far the OPCs will migrate and whether this technique will succeed are open questions, added Dr. Bourdette. The brain of a patient with MS already has OPCs, and adding more OPCs may not promote remyelination, he said. “It might be an approach that is particularly useful, though, in people who are disabled from large plaques in the cervical cord.”

Large-Molecule Approaches
Another approach to promoting remyelination is to block the protein LINGO, which inhibits the differentiation of OPCs into oligodendrocytes. Biogen has developed an anti-LINGO-1 monoclonal antibody that appeared to promote remyelination in patients with optic neuritis during a small phase II trial. Investigators currently are studying this monoclonal antibody in patients with relapsing MS.

A group of investigators at the Mayo Clinic have developed recombinant human IgM22 antibody that promotes OPC differentiation and remyelination in animal models. The drug’s safety has been assessed in a phase I trial. Because the anti-LINGO antibody and the human IgM22 are large molecules, they will not penetrate the brain easily, said Dr. Bourdette. Large doses of these medicines thus will be required to achieve a therapeutic effect.

Small Molecules in Development
Small molecules also could stimulate OPC differentiation. These drugs can be modified to enhance their ability to penetrate the CNS, in contrast with large molecules.

One class of drugs that researchers are studying is thyromimetic medicines, which seek to simulate the effects of thyroid hormone. Thyroid hormone is necessary for OPCs to differentiate into oligodendrocytes and to promote myelination. Patients with hypothyroidism do not produce the normal amount of myelin. Investigators use thyroid hormone to promote OPC differentiation in vitro, and the drug is a potential treatment for patients with MS.

Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins University in Baltimore, and colleagues are preparing to begin a trial of thyroid hormone for promoting remyelination in patients with MS. Although the approach seems promising, “the problem is that you may have to make patients thyrotoxic in order to get enough of thyroid to be beneficial,” said Dr. Bourdette. Thyroid hormone also can be cardiotoxic.

Thyromimetic drugs may represent a better approach, said Dr. Bourdette. These drugs are modifications of the thyroid hormone that have preferential activity for the thyroid hormone receptors on oligodendrocytes, which differ from those on the heart. Investigators thus can make thyromimetic drugs with differential affinities for the brain and OPC. Thomas Scanlan, PhD, Director of the Program in Chemical Biology at OHSU, and colleagues created a thyromimetic drug as a means of lowering cholesterol with minimal effects on the heart. This drug can stimulate OPCs. Researchers at OHSU now are studying the agent in a mouse model of demyelination. “The drug does accelerate remyelination in the mouse model, but not as well as the thyroid hormone,” said Dr. Bourdette. The investigators hypothesize that the thyromimetic drug does not penetrate the brain effectively, and they are modifying the drug to improve its ability to enter the brain.

Other investigators are working on developing small-molecule drugs that can stimulate remyelination. There is thus reason to be optimistic that the small-molecule approach to promoting remyelination will prove to be beneficial, said Dr. Bourdette. Providing a strong stimulus to the OPCs may allow them to overcome the toxic environment that they inhabit, he concluded.

—Erik Greb

INDIANAPOLIS—Investigators are conducting clinical trials of various drugs that may slow clinical worsening in patients with progressive multiple sclerosis (MS), according to an overview provided at the 2015 CMSC Annual Meeting. Two such agents, anti-LINGO-1 antibody and rHIgM22 monoclonal antibody, are under active development in early clinical trials.

“Treatments that promote remyelination are going to prove to be the most effective way to prevent or treat progressive MS,” said Dennis Bourdette, MD, Roy and Eulalia Swank Family Research Professor and Chairman of the Department of Neurology at Oregon Health & Science University (OHSU) School of Medicine in Portland. Investigators are developing cell-based, large-molecule (ie, biologic), and small-molecule (ie, chemically manufactured) therapies that could promote remyelination.

Cell-Based Therapies
One potential treatment is to inject oligodendrocyte precursor cells (OPCs) into the brain and spinal cord. These OPCs then could become oligodendrocytes and produce myelin. Researchers in New York state under the leadership of Drs. Steven Goldman and Burk Jubelt are preparing for a phase I trial of this technique. They plan to use embryonic OPCs and are working with the FDA to establish the appropriate controls for the study.

Current surgical technology should allow the team to inject human OPCs into the brain safely, said Dr. Bourdette. “Researchers have shown that human embryonic-derived OPCs injected into the brains of rodents that have hypomyelination caused by a genetic defect will migrate long distances and myelinate axons.” The goal is for the OPCs to migrate into areas of demyelination in the brain of people with MS and remyelinate axons.

But how far the OPCs will migrate and whether this technique will succeed are open questions, added Dr. Bourdette. The brain of a patient with MS already has OPCs, and adding more OPCs may not promote remyelination, he said. “It might be an approach that is particularly useful, though, in people who are disabled from large plaques in the cervical cord.”

Large-Molecule Approaches
Another approach to promoting remyelination is to block the protein LINGO, which inhibits the differentiation of OPCs into oligodendrocytes. Biogen has developed an anti-LINGO-1 monoclonal antibody that appeared to promote remyelination in patients with optic neuritis during a small phase II trial. Investigators currently are studying this monoclonal antibody in patients with relapsing MS.

A group of investigators at the Mayo Clinic have developed recombinant human IgM22 antibody that promotes OPC differentiation and remyelination in animal models. The drug’s safety has been assessed in a phase I trial. Because the anti-LINGO antibody and the human IgM22 are large molecules, they will not penetrate the brain easily, said Dr. Bourdette. Large doses of these medicines thus will be required to achieve a therapeutic effect.

Small Molecules in Development
Small molecules also could stimulate OPC differentiation. These drugs can be modified to enhance their ability to penetrate the CNS, in contrast with large molecules.

One class of drugs that researchers are studying is thyromimetic medicines, which seek to simulate the effects of thyroid hormone. Thyroid hormone is necessary for OPCs to differentiate into oligodendrocytes and to promote myelination. Patients with hypothyroidism do not produce the normal amount of myelin. Investigators use thyroid hormone to promote OPC differentiation in vitro, and the drug is a potential treatment for patients with MS.

Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins University in Baltimore, and colleagues are preparing to begin a trial of thyroid hormone for promoting remyelination in patients with MS. Although the approach seems promising, “the problem is that you may have to make patients thyrotoxic in order to get enough of thyroid to be beneficial,” said Dr. Bourdette. Thyroid hormone also can be cardiotoxic.

Thyromimetic drugs may represent a better approach, said Dr. Bourdette. These drugs are modifications of the thyroid hormone that have preferential activity for the thyroid hormone receptors on oligodendrocytes, which differ from those on the heart. Investigators thus can make thyromimetic drugs with differential affinities for the brain and OPC. Thomas Scanlan, PhD, Director of the Program in Chemical Biology at OHSU, and colleagues created a thyromimetic drug as a means of lowering cholesterol with minimal effects on the heart. This drug can stimulate OPCs. Researchers at OHSU now are studying the agent in a mouse model of demyelination. “The drug does accelerate remyelination in the mouse model, but not as well as the thyroid hormone,” said Dr. Bourdette. The investigators hypothesize that the thyromimetic drug does not penetrate the brain effectively, and they are modifying the drug to improve its ability to enter the brain.

Other investigators are working on developing small-molecule drugs that can stimulate remyelination. There is thus reason to be optimistic that the small-molecule approach to promoting remyelination will prove to be beneficial, said Dr. Bourdette. Providing a strong stimulus to the OPCs may allow them to overcome the toxic environment that they inhabit, he concluded.

—Erik Greb

INDIANAPOLIS—Investigators are conducting clinical trials of various drugs that may slow clinical worsening in patients with progressive multiple sclerosis (MS), according to an overview provided at the 2015 CMSC Annual Meeting. Two such agents, anti-LINGO-1 antibody and rHIgM22 monoclonal antibody, are under active development in early clinical trials.

“Treatments that promote remyelination are going to prove to be the most effective way to prevent or treat progressive MS,” said Dennis Bourdette, MD, Roy and Eulalia Swank Family Research Professor and Chairman of the Department of Neurology at Oregon Health & Science University (OHSU) School of Medicine in Portland. Investigators are developing cell-based, large-molecule (ie, biologic), and small-molecule (ie, chemically manufactured) therapies that could promote remyelination.

Cell-Based Therapies
One potential treatment is to inject oligodendrocyte precursor cells (OPCs) into the brain and spinal cord. These OPCs then could become oligodendrocytes and produce myelin. Researchers in New York state under the leadership of Drs. Steven Goldman and Burk Jubelt are preparing for a phase I trial of this technique. They plan to use embryonic OPCs and are working with the FDA to establish the appropriate controls for the study.

Current surgical technology should allow the team to inject human OPCs into the brain safely, said Dr. Bourdette. “Researchers have shown that human embryonic-derived OPCs injected into the brains of rodents that have hypomyelination caused by a genetic defect will migrate long distances and myelinate axons.” The goal is for the OPCs to migrate into areas of demyelination in the brain of people with MS and remyelinate axons.

But how far the OPCs will migrate and whether this technique will succeed are open questions, added Dr. Bourdette. The brain of a patient with MS already has OPCs, and adding more OPCs may not promote remyelination, he said. “It might be an approach that is particularly useful, though, in people who are disabled from large plaques in the cervical cord.”

Large-Molecule Approaches
Another approach to promoting remyelination is to block the protein LINGO, which inhibits the differentiation of OPCs into oligodendrocytes. Biogen has developed an anti-LINGO-1 monoclonal antibody that appeared to promote remyelination in patients with optic neuritis during a small phase II trial. Investigators currently are studying this monoclonal antibody in patients with relapsing MS.

A group of investigators at the Mayo Clinic have developed recombinant human IgM22 antibody that promotes OPC differentiation and remyelination in animal models. The drug’s safety has been assessed in a phase I trial. Because the anti-LINGO antibody and the human IgM22 are large molecules, they will not penetrate the brain easily, said Dr. Bourdette. Large doses of these medicines thus will be required to achieve a therapeutic effect.

Small Molecules in Development
Small molecules also could stimulate OPC differentiation. These drugs can be modified to enhance their ability to penetrate the CNS, in contrast with large molecules.

One class of drugs that researchers are studying is thyromimetic medicines, which seek to simulate the effects of thyroid hormone. Thyroid hormone is necessary for OPCs to differentiate into oligodendrocytes and to promote myelination. Patients with hypothyroidism do not produce the normal amount of myelin. Investigators use thyroid hormone to promote OPC differentiation in vitro, and the drug is a potential treatment for patients with MS.

Peter Calabresi, MD, Director of the Division of Neuroimmunology at Johns Hopkins University in Baltimore, and colleagues are preparing to begin a trial of thyroid hormone for promoting remyelination in patients with MS. Although the approach seems promising, “the problem is that you may have to make patients thyrotoxic in order to get enough of thyroid to be beneficial,” said Dr. Bourdette. Thyroid hormone also can be cardiotoxic.

Thyromimetic drugs may represent a better approach, said Dr. Bourdette. These drugs are modifications of the thyroid hormone that have preferential activity for the thyroid hormone receptors on oligodendrocytes, which differ from those on the heart. Investigators thus can make thyromimetic drugs with differential affinities for the brain and OPC. Thomas Scanlan, PhD, Director of the Program in Chemical Biology at OHSU, and colleagues created a thyromimetic drug as a means of lowering cholesterol with minimal effects on the heart. This drug can stimulate OPCs. Researchers at OHSU now are studying the agent in a mouse model of demyelination. “The drug does accelerate remyelination in the mouse model, but not as well as the thyroid hormone,” said Dr. Bourdette. The investigators hypothesize that the thyromimetic drug does not penetrate the brain effectively, and they are modifying the drug to improve its ability to enter the brain.

Other investigators are working on developing small-molecule drugs that can stimulate remyelination. There is thus reason to be optimistic that the small-molecule approach to promoting remyelination will prove to be beneficial, said Dr. Bourdette. Providing a strong stimulus to the OPCs may allow them to overcome the toxic environment that they inhabit, he concluded.

—Erik Greb

Gray matter fraction (GMF) change is more meaningful than white matter fraction (WMF) as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials, according to a study of 140 patients with relapsing-remitting MS who were randomized to intramuscular interferon (IFN) beta-1a or placebo. Researchers found:

• Significantly less GM atrophy (during year 2), but not WM atrophy (at any point), was seen with IFN beta-1a compared with placebo.

• Pseudoatrophy effects were more apparent in WM than in GM; in year 1, greater WM volume loss was seen with IFN beta-1a than with placebo, but GM volume loss was similar between groups. 

• Risk of sustained disability progression was significantly associated with GM atrophy, but not WM atrophy.
 
Citation: Fisher E, Nakamura K, Lee JC, You X, Sperling B, Rudick RA. Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing−remitting multiple sclerosis: a retrospective analysis. [Published online ahead of print August 3, 2015]. Mult Scler. doi: 10.1177/1352458515599072.

Commentary: Understanding a disease requires thorough analysis of its impact. Multiple sclerosis is classically known as a white matter disease. It is also known that MS white matter plaques are in typical subcortical locations. This has been the tenet of MS care and diagnosis by MRI.  However, it is also a tenet that MRI changes do not always correlate with clinical exam or disease impact. Many people involved in MS care and research have explored the reason for this discrepancy.  This important article is another step along the path of understanding.  MS plaques have now been identified within the white matter of the gray matter.  This article provides more evidence that the disease impacts gray matter as well as white matter. The atrophy in gray matter correlates more with disease impact and burden than the atrophy in white matter.  MS should no longer be considered a disease of white matter or white matter atrophy. Perhaps it’s time to update our diagnostic approach, monitoring of disease impact and progression, and therapeutic intervention efficacy measures as well as the metrics of how we measure disease impact. —Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Gray matter fraction (GMF) change is more meaningful than white matter fraction (WMF) as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials, according to a study of 140 patients with relapsing-remitting MS who were randomized to intramuscular interferon (IFN) beta-1a or placebo. Researchers found:

• Significantly less GM atrophy (during year 2), but not WM atrophy (at any point), was seen with IFN beta-1a compared with placebo.

• Pseudoatrophy effects were more apparent in WM than in GM; in year 1, greater WM volume loss was seen with IFN beta-1a than with placebo, but GM volume loss was similar between groups. 

• Risk of sustained disability progression was significantly associated with GM atrophy, but not WM atrophy.
 
Citation: Fisher E, Nakamura K, Lee JC, You X, Sperling B, Rudick RA. Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing−remitting multiple sclerosis: a retrospective analysis. [Published online ahead of print August 3, 2015]. Mult Scler. doi: 10.1177/1352458515599072.

Commentary: Understanding a disease requires thorough analysis of its impact. Multiple sclerosis is classically known as a white matter disease. It is also known that MS white matter plaques are in typical subcortical locations. This has been the tenet of MS care and diagnosis by MRI.  However, it is also a tenet that MRI changes do not always correlate with clinical exam or disease impact. Many people involved in MS care and research have explored the reason for this discrepancy.  This important article is another step along the path of understanding.  MS plaques have now been identified within the white matter of the gray matter.  This article provides more evidence that the disease impacts gray matter as well as white matter. The atrophy in gray matter correlates more with disease impact and burden than the atrophy in white matter.  MS should no longer be considered a disease of white matter or white matter atrophy. Perhaps it’s time to update our diagnostic approach, monitoring of disease impact and progression, and therapeutic intervention efficacy measures as well as the metrics of how we measure disease impact. —Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Gray matter fraction (GMF) change is more meaningful than white matter fraction (WMF) as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials, according to a study of 140 patients with relapsing-remitting MS who were randomized to intramuscular interferon (IFN) beta-1a or placebo. Researchers found:

• Significantly less GM atrophy (during year 2), but not WM atrophy (at any point), was seen with IFN beta-1a compared with placebo.

• Pseudoatrophy effects were more apparent in WM than in GM; in year 1, greater WM volume loss was seen with IFN beta-1a than with placebo, but GM volume loss was similar between groups. 

• Risk of sustained disability progression was significantly associated with GM atrophy, but not WM atrophy.
 
Citation: Fisher E, Nakamura K, Lee JC, You X, Sperling B, Rudick RA. Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing−remitting multiple sclerosis: a retrospective analysis. [Published online ahead of print August 3, 2015]. Mult Scler. doi: 10.1177/1352458515599072.

Commentary: Understanding a disease requires thorough analysis of its impact. Multiple sclerosis is classically known as a white matter disease. It is also known that MS white matter plaques are in typical subcortical locations. This has been the tenet of MS care and diagnosis by MRI.  However, it is also a tenet that MRI changes do not always correlate with clinical exam or disease impact. Many people involved in MS care and research have explored the reason for this discrepancy.  This important article is another step along the path of understanding.  MS plaques have now been identified within the white matter of the gray matter.  This article provides more evidence that the disease impacts gray matter as well as white matter. The atrophy in gray matter correlates more with disease impact and burden than the atrophy in white matter.  MS should no longer be considered a disease of white matter or white matter atrophy. Perhaps it’s time to update our diagnostic approach, monitoring of disease impact and progression, and therapeutic intervention efficacy measures as well as the metrics of how we measure disease impact. —Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, NY

Patient characteristics that may help predict disease outcomes include number of relapses in the past 2 years, new MRI lesions in year 1, higher number of relapses in year 1, MRI activity, and the presence of neutralizing antibodies, according to a study of 857 patients with relapsing-remitting MS who were treated with interferon beta-1b. All 857 patients were included in the analysis of clinical outcomes and 765 of those were included in the MRI outcomes analysis. Researchers found:

• Future occurrence of relapses was predicted by a higher number of relapses in the past 2 years, ≥ 3 new MRI lesions in year 1, and, especially, a higher number of relapses in year 1.

• Future MRI activity was principally predicted by age, MRI activity, and the presence of neutralizing antibodies in year 1.

Citation: Hartung HP, Kappos L, Goodin DS, et al. Predictors of disease activity in 857 patients with MS treated with interferon beta-1b. [Published online ahead of print August 5, 2015]. J Neurol. doi: 10.1007/s00415-015-7862-9.

Patient characteristics that may help predict disease outcomes include number of relapses in the past 2 years, new MRI lesions in year 1, higher number of relapses in year 1, MRI activity, and the presence of neutralizing antibodies, according to a study of 857 patients with relapsing-remitting MS who were treated with interferon beta-1b. All 857 patients were included in the analysis of clinical outcomes and 765 of those were included in the MRI outcomes analysis. Researchers found:

• Future occurrence of relapses was predicted by a higher number of relapses in the past 2 years, ≥ 3 new MRI lesions in year 1, and, especially, a higher number of relapses in year 1.

• Future MRI activity was principally predicted by age, MRI activity, and the presence of neutralizing antibodies in year 1.

Citation: Hartung HP, Kappos L, Goodin DS, et al. Predictors of disease activity in 857 patients with MS treated with interferon beta-1b. [Published online ahead of print August 5, 2015]. J Neurol. doi: 10.1007/s00415-015-7862-9.

Patient characteristics that may help predict disease outcomes include number of relapses in the past 2 years, new MRI lesions in year 1, higher number of relapses in year 1, MRI activity, and the presence of neutralizing antibodies, according to a study of 857 patients with relapsing-remitting MS who were treated with interferon beta-1b. All 857 patients were included in the analysis of clinical outcomes and 765 of those were included in the MRI outcomes analysis. Researchers found:

• Future occurrence of relapses was predicted by a higher number of relapses in the past 2 years, ≥ 3 new MRI lesions in year 1, and, especially, a higher number of relapses in year 1.

• Future MRI activity was principally predicted by age, MRI activity, and the presence of neutralizing antibodies in year 1.

Citation: Hartung HP, Kappos L, Goodin DS, et al. Predictors of disease activity in 857 patients with MS treated with interferon beta-1b. [Published online ahead of print August 5, 2015]. J Neurol. doi: 10.1007/s00415-015-7862-9.

Higher serum high-density lipoprotein (HDL) is associated with lower levels of blood brain barrier (BBB) injury and decreased CD80+ and CD80+CD19+ cell extravasation into the cerebrospinal fluid (CSF), according to a study of 154 patients with MS who were receiving interferon beta-1a therapy following their first clinical demyelinating event. Researchers found:

• Higher levels of serum HDL cholesterol (HDL-C) and apolipoprotein A-1 were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgC level.

• HDL-C was also associated with CSF CD80+ amd with CSF CD80+CD19+ cell frequencies.

Citation: Fellows K, Uher T, Browne RW, et al. Protective associations of HDL with blood brain barrier injury in multiple sclerosis patients. [Published online ahead of print August 4, 2015]. J Lipid Res. doi: 10.1194/jlr.M060970.

Higher serum high-density lipoprotein (HDL) is associated with lower levels of blood brain barrier (BBB) injury and decreased CD80+ and CD80+CD19+ cell extravasation into the cerebrospinal fluid (CSF), according to a study of 154 patients with MS who were receiving interferon beta-1a therapy following their first clinical demyelinating event. Researchers found:

• Higher levels of serum HDL cholesterol (HDL-C) and apolipoprotein A-1 were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgC level.

• HDL-C was also associated with CSF CD80+ amd with CSF CD80+CD19+ cell frequencies.

Citation: Fellows K, Uher T, Browne RW, et al. Protective associations of HDL with blood brain barrier injury in multiple sclerosis patients. [Published online ahead of print August 4, 2015]. J Lipid Res. doi: 10.1194/jlr.M060970.

Higher serum high-density lipoprotein (HDL) is associated with lower levels of blood brain barrier (BBB) injury and decreased CD80+ and CD80+CD19+ cell extravasation into the cerebrospinal fluid (CSF), according to a study of 154 patients with MS who were receiving interferon beta-1a therapy following their first clinical demyelinating event. Researchers found:

• Higher levels of serum HDL cholesterol (HDL-C) and apolipoprotein A-1 were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgC level.

• HDL-C was also associated with CSF CD80+ amd with CSF CD80+CD19+ cell frequencies.

Citation: Fellows K, Uher T, Browne RW, et al. Protective associations of HDL with blood brain barrier injury in multiple sclerosis patients. [Published online ahead of print August 4, 2015]. J Lipid Res. doi: 10.1194/jlr.M060970.